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 Chapter 1 

The structure of the normal lungs

CHAPTER CONTENTS Lymphoid tissue of the lungs 26

Intrapulmonary lymph nodes 26
Anatomy of the lungs and airways 1 Bronchus-associated lymphoid tissue 27
Microscopy of the airways 6 Lymphoreticular aggregates 27
Ciliated cells 10 Lymphocytes 27
Basal cells 10 Dendritic cells 28
Mucous cells 10 Langerhans cells 28
Submucosal glands 12 Mast cells 28
Neuroendocrine cells 13 Innervation of the lungs 28
Clara cells 14 References 30
Brush cells 14
Microscopy of the alveolar tissue 15
Type I alveolar epithelial cells 17
Type II alveolar epithelial cells 17 ANATOMY OF THE LUNGS AND AIRWAYS
Pulmonary surfactant 18
Alveolar interstitium 18 The trachea starts in the neck and extends downwards from the larynx
Alveolar macrophages 19 to enter the thorax at about its midpoint. It terminates by bifurcating
into the main bronchi at about the level of the manubriosternal joint
Blood supply of the lungs 21
and the upper border of the fifth vertebral body. From its origin in
Pulmonary arteries 22 the midline it inclines slightly to the right and is angled backwards
Ventilation–perfusion matching 22 by up to 30°. Posteriorly the trachea is related to the oesophagus
Alveolar capillaries 22 and azygos vein while arrayed around it anteriorly and laterally are
Pulmonary veins 23 the innominate artery, the left common carotid artery, the arch of
the aorta, the brachiocephalic veins and the superior vena cava.
Pulmonary arteriovenous shunts 23
The right main bronchus follows more closely the direction of the
Non-chromaffin paraganglia 23 trachea and, because it branches earlier, is only half the length of the
Metabolic functions of the pulmonary left. The right main bronchus is wider than the left and carries 55%
endothelium 23 of each breath. It enters the lung behind the right pulmonary artery
Megakaryocytes in the pulmonary circulation: and is said to be ‘eparterial’ whereas the left main bronchus crosses
the lung as a source of platelets 23 behind the left pulmonary artery to enter the lung below it and is
Bronchial vasculature 24 therefore said to be ‘hyparterial’ (Fig. 1.1).
The two lungs, enclosed within the visceral pleura, fill their respec-
Bronchopulmonary anastomoses 26 tive pleural cavities. Tissue is reduced to a minimum in the interests
Lymphatic drainage of the lungs 26 of gas exchange. At mid-inspiration over 80% of lung volume is air,
Regional differences in ventilation and perfusion 10% is blood, 3% comprises conductive airways and blood vessels
relevant to the location of lung disease 26 and only 3% is alveolar tissue. The normal combined weight of the

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00001-X 1
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 Pathology of the Lungs

Right Left Figure 1.1  Medial aspects of the

lungs. (A) The arrangement and
nomenclature of the lobes and
Apical Upper their segments. (B) The positions of
Apical the main bronchi, arteries and
Upper posterior
veins at the hila.
Anterior
Lower Anterior
apical
Upper

Superior
Medial lingular
Middle and
Inferior
lateral
lingular
Lower
posterior
basal
Anterior Medial Lateral Lateral Anterior
basal basal basal basal basal
A Lower Lower

Eparterial bronchus Pulmonary artery

Pulmonary artery
Hyparterial bronchus
Pulmonary veins Pulmonary veins

Pulmonary
ligament

lungs averages 850 g in men and 750 g in women. Lung weights in and the pathological findings correlated with those of radiologists and
children are given in Table 1.1.1 surgeons. Figure 1.2 illustrates the trachea, main, lobar and segmental
The lungs abut the mediastinum medially, rest on the diaphragm bronchi diagrammatically, using an internationally recommended
below and elsewhere are enclosed by the ribcage. On their medial nomenclature.2 A plastic cast of the proximal airways coloured accord-
surface the main bronchovascular structures connect the hilum of the ing to the lung segments is shown in Figure 1.3. It will be noted that
lung with the mediastinum and here the visceral pleura is reflected off the following anatomical features are common to the two lungs:
the lung to become the parietal pleura. The pleural reflection also • Each upper lobe has apical, anterior and posterior segments.
extends from the inferior aspect of the hilum to the medial border of • Each lower lobe has an apical segment and anterior, lateral and
the base of the lung at what is termed the pulmonary ligament (see posterior basal segments.
Fig. 1.1B) The pleura is described in more detail in Chapter 13.
Oblique fissures divide the lungs into upper and lower lobes and The two lungs differ in the following respects:
on the right a transverse fissure separates off a middle lobe. The main • After giving off the upper lobe bronchus, the right main
bronchi divide in a corresponding manner to give five lobar bronchi. bronchus continues through a lower (intermediate) part to
The next division supplies the lung segments, of which there are 19, supply the middle and lower lobes, whereas the left main
a segment being the smallest bronchopulmonary unit that can be bronchus continues as the left lower lobe bronchus.
distinguished and excised separately by a surgeon. The airways branch • The right lung has a middle lobe served by a branch of the
repeatedly and there may be as many as 23 divisions before alveoli lower (intermediate) part of the main bronchus, whereas the
furthest from the trachea are reached, as opposed to alveoli nearer the lingula of the left lung, which is the homologue of the right
hilum of the lung which are reached after as few as eight divisions. middle lobe, is served by a lingular division of the upper-lobe
The pattern of branching is one of asymmetrical dichotomy, meaning bronchus, the other branch of which is known as the upper or
that each airway has two branches that often differ in diameter or superior division.
length. • The two segments of the right middle lobe are medial and lateral
The airways of the first four generations are individually named and whereas the two segments of the lingula are superior and inferior.
the pathologist must be familiar with the terminology of the 19 lung • The right lower lobe has an extra segment, known as the medial
segments and their bronchi so that lesions can be localised accurately or cardiac segment.

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 The structure of the normal lungs Chapter |1|

Table 1.1  Lung weights in children1 Table 1.2  The Weibel model of the bronchial tree3

Age Body length Right lung Left lung Number of Generation Diameter Length Structure
(cm) (g) (g) branches (mm) (mm)

Birth–3 days 49 21 18 1 0 18.0 120.0 Trachea

3–7 days 49 24 22 2 1 12.2 47.6 B
1–3 weeks 52 29 26 4 2 8.3 19.0 B
3–5 weeks 52 31 27 8 3 5.6 7.6 B
5–7 weeks 53 32 28 16 4 4.5 12.7 B
7–9 weeks 55 32 29 32 5 3.5 10.7 B
3 months 56 35 30 64 6 2.8 9.0 B
4 months 59 37 33 128 7 2.3 7.6 B
5 months 61 38 35 256 8 1.86 6.4 B
6 months 62 42 39 512 9 1.54 5.4 MB
7 months 65 49 41 1024 10 1.30 4.6 MB
8 months 65 52 45 2048 11 1.09 3.9 MB
9 months 67 53 47 4096 12 0.95 3.3 MB
10 months 69 54 51 8192 13 0.82 2.7 MB
11 months 70 59 53 16 384 14 0.74 2.3 MB
12 months 73 64 57 32 768 15 0.66 2.0 MB
14 months 74 66 60 65 536 16 0.60 1.65 TB
16 months 77 72 64 131 072 17 0.54 1.41 RB
18 months 78 72 65 262 144 18 0.50 1.17 RB
20 months 79 80 74 524 288 19 0.47 0.99 RB
22 months 82 83 75 1 048 576 20 0.45 0.83 AD
24 months 84 88 76 2 097 152 21 0.43 0.70 AD
3 years 88 89 77 4 194 304 22 0.41 0.59 AD
4 years 99 90 85 8 388 608 23 0.41 0.50 AD
5 years 106 107 104 B, bronchi; MB, membranous bronchioles; TB, terminal bronchioles;  
RB, respiratory bronchioles; AD, alveolar ducts. The data are based on  
6 years 109 121 122
a combination of morphometry and assumption.
7 years 113 130 123
8 years 119 150 140
9 years 125 174 152
bronchioles; they both conduct gas and participate in gas exchange.
10 years 130 177 166 Such airways form what is termed a transitional zone between the
11 years 135 201 190 purely conductive airways and the alveoli. It comprises about three
generations of respiratory bronchioles and two to nine generations of
alveolar ducts, the last of which terminate in alveolar sacs; all these
structures have increasing numbers of alveoli opening off their walls.
The subdivisions and structure of the intrapulmonary airways are
Beyond the segmental bronchi, individual airways are unnamed but represented diagrammatically in Figure 1.4 and numerical data apper-
a distinction is drawn between bronchi, which have glands and carti- taining to individual orders (generations) of airways are shown in
lage in their wall, and bronchioles, which do not. Transition from Table 1.2.3
bronchus to bronchiole takes place in airways approximately 1 mm The lung substance is divided into primary and secondary lobules.
in diameter. The first orders of bronchioles, which are known as The primary lobule is that portion of the lung supplied by one respira-
membranous bronchioles, are purely conductive. The last order of tory bronchiole but it is seldom referred to today and the unqualified
these bronchioles is known as terminal bronchioles, despite them term ‘lobule’ generally equates to the secondary lung lobule. The
leading into further orders of bronchioles. These further bronchioles secondary lobule is a portion of lung surrounded by fibrous septa that
have alveoli opening directly off them and are known as respiratory are visible on the cut surface of the lung (Figs 1.5 and 1.6) and

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 Pathology of the Lungs

Trachea Figure 1.2  Nomenclature of the main, lobar

and segmental bronchi. Beyond the segmental
bronchi individual airways are unnamed.

Right main bronchus Left main bronchus

Apical
Posterior Apical
Upper
Anterior Posterior
lobe
(Apicoposterior)
(Intermediate) Anterior Upper
(Superior division) lobe
Middle (Lingular division)
Lateral
lobe Apical Superior lingular
Medial
Inferior lingular
Medial basal Anterior basal
Lower Anterior basal
lobe Lateral basal Lateral basal Lower
Poaterior basal lobe
Posterior basal

of an acinus approximately 0.2 ml. An acinus is 0.5–1 cm long,4

so that the bronchi and purely conductive bronchioles make up all
but this length of the total gas pathway. Each acinus contains about
2000 alveoli and it is estimated that the two lungs together contain
about 300 million alveoli.5 The edges of adjacent acini interdigitate
without any intervening septa and it is impossible to detect where one
acinus ends and the next begins, either with the naked eye or the
microscope. However, in adult lungs, the centres of the acini are gen-
erally ‘tattooed’ with carbon for it is here that lymphatics commence
and dust-laden cells accumulate in what Macklin termed ‘dust sumps’
(see Figs 1.7 and 7.1.12, p. 339).6
The term ‘terminal respiratory unit’ has been applied to an impre-
cise number of bronchioles and the alveoli they supply, mainly
by embryologists and more recently by pathologists and molecular
biologists interested in the histogenesis of adenocarcinomas com-
posed of bronchiolar Clara cells and type II alveolar cells (see
below and p. 553).7,8 This is because these cells ubiquitously express
the regulatory thyroid transcription factor-1 (TTF-1), which
is potentially a lineage-specific survival oncogene of some lung
adenocarcinomas.9,10
Each generation of airways is shorter than its predecessor and,
whereas individual members of each generation are narrower than
their parents, beyond the segmental bronchi the summed cross-sec-
tional area for each generation progressively increases logarithmically
(Fig. 1.8),3,11 and at the periphery resistance to airflow is negligible.
Figure 1.3  Posterior view of a plastic cast of the proximal airways with Because of this, gas flow velocity falls rapidly in the respiratory bron-
individual segments distinguished by colour. chioles and gas mixing in the last few airways is largely by diffusion.
Diffusion across tissue is less efficient than in the gas phase but at the
surface of the alveolar walls gas transfer is maximised as the inspired
gas is spread over an area of about 70 m2.12 There is therefore consid-
through the visceral pleura, particularly when their contained lym- erable reserve in the conductive capacity of the peripheral airways,
phatics are outlined by dust or tumour (Fig. 1.7). However, the fibrous large numbers of which may be obliterated before there is any appreci-
septa that demarcate the secondary lobules are unevenly developed. able shortness of breath; for this reason the finer airways have been
They are quite well represented laterally in the lower lobes (where termed the ‘silent area of the lung’.
they appear as Kerley B lines when thickened by interstitial oedema) Lambert’s canals are tubular communications approximately 30 µm
but are poorly represented medially and deep in the lungs. The lobules in diameter that connect terminal and respiratory bronchioles with
they demarcate are polyhedral. In the adult lung, each lobule meas- adjacent peribronchiolar alveoli, thus bypassing the main pathway.13
ures 1–2 cm across and is in turn made up of about 3–10 acini, an They represent accessory air inlets to, or outlets from, the more distant
acinus being that portion of the lung supplied by one terminal alveoli. In coal miners, these canals and their associated alveoli are
bronchiole. The volume of a lobule is approximately 2 ml and that early sites of dust cell accumulation, whilst in fibrotic lung disease,

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 The structure of the normal lungs Chapter |1|

Section of bronchiole
Cilated cuboidal epithelium
with few goblet cells, smooth
muscle ring, blood vessels,
and nerve fiber stroma
contains many elastic fibers.
Cartilaginous plates, glands,
and lymph vessels absent

Smooth muscle
Terminal Elastic fibers
bronchiole
Alveolus

Cartilage
Respiratory
1st order bronchioles
2nd order (Aveoli appear
3rd order at this level.)
Bronchi

Cartilage
becomes Alveolar ducts
sparser
Alveolar sac
Alveoli

Acinus
(part of lung
supplied by
No terminal
further bronchiole)
cartilage
Bronchioles

Lobule

Acinus

Opening of alveolar duct Pores of Kohn

Subdivisions of
intrapulmonary airways Structure of intrapulmonary airways
Figure 1.4  Subdivisions and structure of the intrapulmonary airways from a segmental bronchus to the alveoli. (Netter medical illustration used with
permission of Elsevier. All rights reserved.)

cuboidal bronchiolar epithelial cells often extend through them to cal pathway than the 2–13-µm diameter pores of Kohn, described
line the peribronchiolar alveoli, a metaplastic process that is termed below, but may be less effective than certain interconnecting respira-
alveolar bronchiolisation, peribronchiolar metaplasia or lambertosis tory bronchioles that measure 120 µm in diameter,15 and the 200-µm
(Figs 1.9 and 3.37A, p. 121).14 diameter interacinar and 80–150-µm diameter intersegmental con-
To what extent the 30-µm diameter Lambert’s canals provide col- nections that have been demonstrated using injection techniques16
lateral circulation is uncertain. They appear to offer a better anatomi- and corrosion casts17 respectively.

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 Pathology of the Lungs

Figure 1.5  Poorly demarcated fibrous septa incompletely separate

the lung lobules. The pulmonary arteries accompany the airways in the
centres of the lung acini whereas the pulmonary veins are situated at  
the periphery of the lung lobules in the interlobular septa.

The two main pulmonary arteries arise from the bifurcation of the
pulmonary trunk shortly after its origin from the right ventricle and
divide to follow the lobar bronchi. Segmental and subsegmental pul-
monary arteries continue alongside their corresponding airways and
in the periphery of the lungs most small pulmonary arteries enter an
Figure 1.6  A lung lobule demarcated by the pleura and interlobular
acinus with the terminal bronchiole and are thus found at the centre septa, which are stained red in this elastin van Gieson preparation, as are
of the acinus (Figs 1.10 and 1.11). As well as these axial vessels there the periarterial cuffs of connective tissue. The arteries (and poorly stained
are also small supernumerary branches which do not accompany accompanying airways) mark the centres of the lung acini while the veins
airways.18 The pulmonary arteries divide to supply the pulmonary are situated in the interlobular septa.
capillaries, which form a meshwork situated in the alveolar walls,
regrouping at the periphery of the acinus to form pulmonary veins
(Fig. 1.12). In the periphery of the lung the pulmonary veins run in
the interlobular septa and are thus separate from the artery and airway
in the centre of the acinus (see Figs 1.6 and 1.10), but they take up a In the extrapulmonary bronchi and trachea the cartilage forms
position alongside the artery and bronchus proximal to the entry of irregular, sometimes branching, rings that are incomplete dorsally, the
these structures into the lung lobule. gaps being bridged by smooth muscle. In intrapulmonary bronchi
the intercartilaginous gaps are more numerous and haphazardly
distributed but in large bronchi at least the cartilage plates are numer-
ous enough to be found in any cross-section. In small bronchi,
the cartilage is less abundant and may be missed in some sections.
MICROSCOPY OF THE AIRWAYS Airways that completely lack cartilage and glands are termed
bronchioles.
The bronchial wall consists of a thin mucosa and a more substantial Smooth muscle, present only in the dorsal intercartilaginous
submucosal coat, outside which there is the peribronchial sheath of gaps of the trachea, completely encircles the intrapulmonary bronchi,
loose connective tissue that also surrounds the accompanying pulmo- internal to the cartilage. It comprises two sets of fibres that wind
nary artery. The mucosa consists of respiratory epithelium resting on around the bronchial tree as opposing spirals, thereby appearing
a basement membrane and beneath that a supportive connective incomplete in individual cross-sections. The arrangement is such that,
tissue layer rich in elastin fibres. There is no clear boundary between as the muscle contracts, the airway both shortens and constricts. The
the mucosa and the submucosa but muscle, glands and cartilage muscle forms a more complete ring in the membranous bronchioles
are conventionally regarded as belonging to the submucosal coat than in bronchi or respiratory bronchioles. When respiratory bronchi-
(Fig. 1.13). oles are encountered in longitudinal section, the muscle is seen only

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 The structure of the normal lungs Chapter |1|

Figure 1.7  A Gough–Wentworth paper-mounted whole-lung section of

a city-dweller’s lung in which the interlobular septa and centriacinar
structures are particularly well seen because of dust in the lymphatics.

10000 Figure 1.9  Canal of Lambert in organising pneumonia. (A) The canal
10000 (arrow) provides a direct connection between bronchiole and alveolus.  
(B) Fibronopurulent debris tracks directly between airway and alveolus.

1000 8000

6000
100 as small knobs between the mouths of the numerous alveoli that open
off these airways.
4000 If the trachea and main bronchi are opened from the front, longi-
tudinal mucosal corrugations or ridges are evident on the posterior
10
wall.19 Most of those in the trachea pass into the right main bronchus
2000
but there is an equal number in the left main bronchus where they
commence anew beyond the carina. In the trachea and main bronchi
1 the ridges are limited to the membranous parts but distal to the lobar
1 5 10 15 20 23 bronchi the ridges are distributed all around the walls of the airways.
2 They represent longitudinal bundles of elastin fibres situated in
Figure 1.8  Summed cross-sectional area (cm ) plotted against airway
generation. Logarithmic scale on the left (open circles), linear scale on the subepithelial mucosal lamina propria (Fig. 1.14). Although the
the right (solid circles). Note the striking increase in total cross-sectional bundles become progressively thinner they persist throughout the
area of the peripheral airways. The arithmetic plot is often duplicated in bronchial tree and link up with spiral elastin fibres described in
mirror-image fashion to illustrate a classic trumpet-shaped concept of the the alveolar ducts20 and with the elastic tissue of the alveolar walls.
increasing airway cross-sectional area in the paired lungs. Weibel’s data3 They are thought to contribute to elastic recoil during expiration and
redrawn from Horsfield (1974).11 are more prominent in men, older subjects, smokers and asthmatics.21

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 Pathology of the Lungs

the airway lumen (Figs 1.15 and 1.16). Most epithelial cells are
columnar and ciliated but these are interspersed with mucous
cells, finely granulated neuroendocrine cells, basal cells, brush cells,
nerve terminals and migratory lymphocytes and mast cells.22–24 The
airway epithelium decreases in height distally, becoming cuboidal in
the bronchioles. The mucous cells decrease in number as the bronchi-
oles are approached and in these small airways Clara25 and serous26
cells are found amongst the ciliated cells.27 Major histocompatibility
antigens of both class I (HLA-A, B and C) and II (HLA-DR) are
expressed by bronchial, bronchiolar and alveolar epithelium.28
All airway epithelial cells express cytokeratin 19 while the basal cells
also express cyto­keratin 17.29 In contrast to pleural mesothelium,
cytokeratins 5 and 6 are not expressed by airway epithelium and rarely
by its malignant derivatives, providing a useful point of distinction
between pulmonary adenocarcinoma and epithelioid mesotheliomas
(see p. 724).30
In the main airways there is a surface layer of mucus supported by
Figure 1.10  A plastic cast showing that the pulmonary arteries (red) an aqueous hypophase (Fig. 1.17). More distally, the bronchial
accompany the airways (white) and that pulmonary veins (blue) are mucous layer is discontinuous.31 In the smaller bronchioles there
separate. is a continuous surface layer similar to that lining the alveoli (see
below).32
The thickness of the surface layer is of considerable importance. In
its proximal movement, the surface layer is constantly being added to
by airway secretions yet this material has all to be accommodated on
a progressively reducing surface area (see Fig. 1.8). Despite losses
through evaporation, and clearance being faster proximally (Fig.
1.18),33 the larger airways would be occluded by the bronchial secre-
tions if these were not concentrated by an epithelial ion exchange
mechanism. This vital function is under the control of an epithelial
transmembrane regulator, faults in which underlie the development
of cystic fibrosis (see p. 65). The same control mechanism operates in
reverse in panting dogs to facilitate heat loss. The thickness of the
aqueous hypophase is also of crucial importance to ciliary function
(see below).
The various epithelial cells are held together by desmosomes,
gap junctions and near the lumen by terminal bars that prevent
excessive fluid movement across the epithelium.34 However, irritants
such as tobacco smoke, sulphur dioxide and mast cell mediators render
the terminal bar permeable to particulate markers placed in the
lumen.35–37
The epithelial cells rest on a basement membrane that consists
of three layers: a lamina lucida, which makes contact with overlying
epithelial cells, a lamina densa and a lamina reticularis. The last of
these consists of fine fibrillary collagen and is only present in adults.
Figure 1.11  Bronchioles and pulmonary arteries lie alongside each other It is not considered to be part of the ‘true’ basement membrane but
in the centres of the lung acini, sharing a connective tissue sheath. it is this layer that is thickened in asthma and, to a lesser extent, a
variety of other airway diseases. The laminae lucida and densa com-
prise the ‘true’ basement membrane. They each measure 50 nm in
thickness, well below the resolution of the light microscope. They are
Transverse ridges are also evident in the bronchial mucosa; these lack made up of type IV collagen, laminin and fibronectin. They have a
elastin fibres and probably represent folds produced by muscular negative charge, due to sulphate and carboxyl moieties, which partly
shortening of the airways. contributes to their permeability. This is relatively high; the basement
Around the pulmonary arteries and to a lesser extent the airways membrane is a relatively poor barrier to the movement of macromol-
there is a sheath of loose connective tissue (see Fig. 1.11). This con- ecules and even cells.
nects with the visceral pleura at the hilum and distally with the deli- Surface epithelial cells are replaced only slowly, less than 1% being
cate connective tissue of the respiratory bronchioles and the alveolar in division at any one time, although the mitotic index increases in
interstitium, and through the latter with the interlobular septa and response to various forms of injury.38 The role of the basal cell as the
the visceral pleura. The periarterial sheath carries nerves and lym- sole progenitor has been questioned following recognition that other
phatic vessels and is expanded considerably in oedema, acting as an non-ciliated cells, notably the mucous, Clara and neuroendocrine
interstitial sump for extravascular fluid and thus protecting against cells, have an important stem cell function.38–45
this spilling over into the alveoli. Approximately 10 000 litres of air are inhaled each day and consid-
The epithelium of the main airways is pseudostratified, meaning erable amounts of potentially harmful environmental agents escape
that all its cells rest on the basement membrane but not all reach the filtering action of the nose to reach the lower respiratory tract. The

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 The structure of the normal lungs Chapter |1|

Terminal bronchiole
Bronchial artery (from left heart
via thoracic aorta)
Pulmonary vein
(to left heart)

Pulmonary
artery (from
right heart) Respiratory
bronchioles

Capillary plexuses
within alveolar
wall
Pulmonary
vein (to
left heart)

Septum

Septum

Visceral pleura and subpleural capillaries Capillary bed within alveolar wall
(cut away in places)
Pulmonary arteries and their branches distribute segmentally with the bronchi.
Pulmonary veins and their tributaries drain intersegmentally.
Figure 1.12  Intra-acinar pulmonary blood circulation. (Netter medical illustration used with permission of Elsevier. All rights reserved.)

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 Pathology of the Lungs

Ciliated cells
Ciliated cells49 possess numerous mitochondria and two types of
surface projection: stubby microvilli about 0.4 µm in length and long
slender cilia up to 6 µm in length. There are 200–300 cilia per cell,
each beating at about 20 times a second. The rate at which the cilia
beat falls with temperature50 and the upper respiratory tract plays an
important role in warming and moistening the inspired air. The ciliary
beat consists of a straight-armed effective stroke followed by a curling
return stroke.51 Ciliated cells are arranged in groups within which the
cilia beat in a co-ordinated fashion, probably governed by contact
with the overlying mucus. The beating appears to be spontaneous.
It is independent of nervous control and persists for several hours
after death.
The cilia beat in a low viscosity layer beneath the surface mucus
and move the overlying mucus only by their tips, which possess
minute terminal hooklets (see Fig. 1.17).52 The depth of the aqueous
hypophase is crucial to ciliary action: too much and the mucus is lifted
off the tips of the cilia, too little and the cilia become clogged
by mucus. The periciliary fluid is thought to derive from the airway
epithelial cells under the control of the transmembrane regulator
referred to above. The cell surface available for fluid transport is
greatly increased by its microvilli, which are akin to the brush border
of the intestinal epithelium.
The fine structure of cilia has become of medical importance with
the recognition of the ciliary dyskinesia syndromes (see p. 63). Cilia
have an axial central pair of microtubules with an outer ring of nine
double microtubules (9 + 2 structure) (see Fig. 2.44, p. 64). Small
dynein side arms extend from one doublet towards the next and
spokes connect each doublet with the central microtubules. All the
microtubules fuse together near the tip while near the cell the central
pair disappears and the doublets become triploid and fuse together
as a cylinder which extends into the cytoplasm as the ciliary basal
body. Cilia beat when the microtubules, powered by adenosine
tripho­sphate elaborated in the dynein arms, slide past each other.

Basal cells
Figure 1.13  Normal bronchus, showing surface epithelium resting on
elastin-rich connective tissue (these elements constitute the mucosa:   Basal cells are found particularly in the large airways but, although
see Fig. 1.14), beneath which are the submucosal glands and cartilage. they diminish in number peripherally, they reach down as far as the
The glands are of mixed seromucous type. The apparent absence of bronchioles. They have only sparse cytoplasm, which often contains
submucosal muscle at this point is attributable to its double spiral bundles of cytokeratin tonofilaments that lead into prominent
arrangement. hemidesmosomes.53 The basal cell was formerly thought to be
the main stem cell of the airways but with the recognition that
Clara, mucous and neuroendocrine cells are important in this
respect,38–40,42,45 this view has had to be modified. Although they con-
tinue to be recognised as progenitor cells,54 adhesion of the columnar
cells to the basement membrane is now thought to be an additional
respiratory epithelium provides the first line of defence against these.46
major function of basal cells.55,56
It does this in three ways:
1. by providing an intact surface barrier comparable to the skin
and the epithelium of the alimentary tract Mucous cells
2. by secreting an array of substances that act against physical and Mucous cells24,49 vary in appearance with a cycle of secretory activity
biological agents that culminates in the discharge of mucus into the airways. Devoid of
3. by co-ordinating secretory and ciliary function so that there is mucus, they are slender and possess abundant endoplasmic reticulum
effective mucociliary clearance. and well-developed Golgi apparatus. As they synthesise mucus, elec-
Nevertheless, immune reactions are constantly at play in the lungs tronlucent mucous granules accumulate, enlarge and fuse together to
and if these were allowed to proceed unchecked, inflammation would produce a large secretion vacuole that distends the apical cell cyto-
be a permanent feature of the airways. That this is not the case is due plasm, giving the mature cell its characteristic wine glass or goblet
at least in part to an inhibitory action that airway epithelial cells exert shape. Discharge takes place by further fusion involving the secretion
on dendritic cells within the epithelial milieu.47,48 vacuole and apical cell membranes.
The morphology and function of the individual epithelial cells will Mucins are high-molecular-weight glycoproteins in which oligosac-
now be considered in turn. charide side chains are attached to an elongated protein core.57 The

10
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 The structure of the normal lungs Chapter |1|

A B

Figure 1.14  (A) If the trachea is opened from the front, longitudinal ridges are evident in the posterior membranous portion. The ridges continue into
the right main bronchus whilst others commence in the left main bronchus. (B) Microscopy shows that the ridges consist of longitudinal bands of
elastic tissue staining black (top). Together with the surface epithelium, not evident in this preparation, this elastin-rich connective tissue constitutes the
bronchial mucosa. The bronchial cartilage is also darkly stained but the intervening submucosal glands and muscle are poorly stained. Elastin van
Gieson stain.

mucous granules of the surface mucous cells contain an acidic mucin,

with sialic acid or sulphate groups at the end of the oligosaccharide
side chains of the peptide core. The amount and viscoelasticity of the
mucus are important to airway clearance and the chemical structure
of the mucus probably influences its physical properties and hence
the ease with which it is cleared by ciliary activity or coughing. Out
of the nine different mucin genes identified in human tissues, seven
are expressed in the respiratory tract: MUC1–MUC4, MUC5AC,
MUC5B and MUC7.58,59 While MUC5B and MUC7 expression is pre-
dominantly restricted to cells of the submucosal glands,60 MUC2 and
MUC5AC mucins are located more in the surface epithelium.61 The
predominant components of respiratory mucus are MUC5AC and
MUC5B,62 and these are upregulated by various stimuli such as air
pollutants or bacteria and also in asthma and cystic fibrosis.63,64 The
number of mucous cells increases in response to irritation. This also
induces inflammation and, although the viscosity of mucus is prima-
Figure 1.15  Bronchial epithelium composed of pseudostratified columnar rily dependent on its glycoprotein content, it is markedly augmented
ciliated cells interspersed with occasional mucus-secreting (goblet) cells. by DNA released from effete inflammatory cells. It is impossible to
state at exactly what point goblet cell hyperplasia begins as numbers

11
tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

Figure 1.16  Bronchial epithelium. Transmission electron micrograph

showing basal, ciliated and mucous cells. The electron-lucent mucus
granules fuse together before discharge. Most of the surface is formed
of ciliated cells. (Courtesy of Mrs D Bowes, Midhurst, UK.)

vary dependent on the site of the biopsy, but a crude figure is more
than 3 per 10 cells at any point in the respiratory tract.
Apart from the mucus secreted by mucous cells in the surface epi-
thelium and submucosal glands (see below), non-secretory cells such
as the ciliated cells have a thin mucoid glycocalyx forming the outer
part of their cell membrane.57 This differs chemically from the main
mucous lining and is probably formed by the cell of which it forms
the outermost part. The glycocalyx of the cilia differs chemically from
that of the microvilli on the same cell, whilst in the alveolus, different
lining cells have chemically different forms of glycocalyx.65 B

Figure 1.17  (A) Scanning electron micrograph of the bronchial surface

Submucosal glands showing mucus (top) resting on the tips of the cilia. The cilia beat in an
aqueous hypophase. (B) High-power transmission electron microscopy
The submucosal glands far exceed the secretory elements of the surface shows that the tips of the cilia are equipped with hooklets. (Courtesy of
epithelium in cell mass and are the major source of bronchial secre- Professor PK Jeffery, Brompton, UK.)
tion. They are situated between the muscle coat and the cartilage (see
Fig. 1.13), and between individual cartilage plates, their ducts piercing
the muscle coat and mucosa to reach the lumen. They are mixed
seromucous glands, and the secretory acini are arranged so that the implying a variety of secretory products. The mucous cells contain
serous secretion has to pass through the mucous tubules.66 The two large amounts of both acid and neutral glycoprotein whilst the serous
secretions are therefore well mixed before they reach the bronchial cell granules contain smaller amounts of these glycoproteins65,68
lumen. Serous and mucous cells both have abundant rough endoplas- together with lysozyme,67 lactoferrin68 and a small-molecular-weight
mic reticulum and Golgi apparatus but the secretory granules of the antiprotease specific to the airways.69 The demonstration of carbonic
serous cells are electron-dense, small and discrete, whereas mucous anhydrase in serous cells implicates them in the production of a
granules are electron-lucent, large and confluent (Fig. 1.19).67 The watery non-viscous secretion that could facilitate transport of the
serous granules often show zonal variations in their fine structure, more viscous mucus secreted downstream.66 The serous cells are also

12
tahir99-VRG & vip.persianss.ir
 The structure of the normal lungs Chapter |1|

0.4 0.4
0.6
1.7 3.4
1.7 9.1

3.26 5.4 11.54

6.8 9.1

1 mm

Figure 1.18  Velocity of mucus transport in the airways of a rat.

The figures indicate the velocity of transport in millimetres per minute  
at a particular site at 37°C. From left to right the velocity increases
sevenfold. (Reproduced from Iravani & van As (1972)33 by permission of the editor
of the Journal of Pathology.)

Figure 1.20  A seromucinous gland showing oncocytic metaplasia.

the major site of the secretory component of IgA70–72 and of epithelial

peroxidase.73
Collecting-duct cells are devoid of secretory granules but often have
the characteristics of oncocytes, their cytoplasm being packed with
numerous mitochondria. The oncocytes increase in number with age
and may form metaplastic nodules (Fig. 1.20).74 A fluid-regulating
role has been suggested for them but similar cells present in several
other organs are considered to be degenerative. Glandular secretion
is assisted by myoepithelial cells which are situated between the secre-
tory and duct lining cells and the basement membrane. Neuroendocrine
cells similar to those in the surface epithelium are also found in this
situation, whilst unmyelinated nerve axons are observed in close asso-
ciation with serous, mucous, collecting-duct and myoepithelial cells.75

Neuroendocrine cells
Neuroendocrine cells, which are also known as Kultschitsky-type
cells, Feyrter cells and APUD cells, are found in the basal layer of the
surface epithelium and in the bronchial glands.75,76 In the surface epi­
thelium they occur singly and in groups, the latter known as neuro­
epithelial bodies.77,78 Single neuroendocrine cells are basally situated
but send a thin cytoplasmic process to the surface. They are found
throughout the airways from the main bronchi to the bronchioles but
are only rarely found in the terminal bronchioles and alveoli.79,80
Neuroepithelial bodies extend from the basement membrane to the
surface. They are found particularly at airway bifurcations and have
sensory neuronal connections but are less numerous in humans than
in many laboratory animals.78,81–85 Adjacent capillaries have a fenes-
trated endothelium, as found in many endocrine organs.
Neuroendocrine cells are characterised by numerous small gran­
ules, 70–150 nm in diameter, consisting of a round electron-dense
Figure 1.19  Bronchial gland composed of serous cells (top) which have central core separated from an outer membrane by a clear halo (Fig.
discrete electron-dense granules, and mucous cells (bottom) in which   1.21). In the fetus, two other morphological varieties of granule have
the secretory granules are electron-lucent and fuse together before
been described.77 The granules are scattered throughout the cyto-
discharge. In close proximity to the serous cells is a group of plasma cells
(centre right). Immunoglobulin A is produced by plasma cells that lie
plasm, but are often concentrated near the basal cell membrane.
close to the bronchial glands: it passes through the serous cells to reach The neuroendocrine cells only occasionally display argyrophilia or
the lumen and in so doing acquires its secretory component which is formaldehyde-induced fluorescence but these reactions, indicative of
synthesised by the serous cells. Transmission electron micrograph. biogenic amines, may be enhanced by prior incubation with precursor
(Reproduced from Bowes & Corrin (1977)67 with permission of the editor of substances such as 5-hydroxytryptophan and dihydroxyphenyl­
Thorax.) alanine.86 Immunohistochemistry shows that both single neuroend­

13
tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

Figure 1.22  Terminal bronchiole showing non-ciliated Clara cells

Figure 1.21  Bronchial neuroendocrine cell granules consist of a dense protruding above the adjacent cilia. Scanning electron micrograph.
central core separated from an investing membrane by a thin electron- (Courtesy of Professor PK Jeffery, Brompton, UK.)
lucent zone. Transmission electron micrograph. (Courtesy of Miss A Dewar,
Brompton, UK.)

ocrine cells and the neuroepithelial bodies may contain l-amino acid numerous in the terminal bronchioles where they protrude above the
decarboxylase87 and 5-hydroxytryptamine,88 general neuroendocrine ciliated cells (Fig. 1.22). The region immediately above the nucleus
markers such as neuron-specific enolase,89 chromogranin A,80,90 contains many large mitochondria with unusually sparse cristae. The
synaptophysin91 and neural cell adhesion molecule (CD56)92 and apical portion is notable for a rich smooth endoplasmic reticulum
peptides such as human bombesin (gastrin-releasing peptide),80,93–96 network and, immediately beneath the luminal cell membrane, small
calcitonin,80,94,97,98 leu-encephalin,94 substance P,99 guanine nucleotide- electron-dense secretory granules of about 500 nm diameter. The
binding protein100 and adrenocorticotrophic hormone.95 Chro­ granules are angulated in humans but round in many species. There
mogranin, a constituent of the granules, and CD56 are probably the is considerable species variation in the internal structure of Clara cells.
most sensitive and specific immunocytochemical markers.80,92,101,102 The nature of the secretory product of the Clara cell and its precise
The main function of the pulmonary neuroendocrine system in mode of secretion are uncertain, but the major constituent of the
humans is thought to concern the control of growth and development granules is a 10-kDa protein (CC10) that inhibits several inflamma-
of the lungs in utero and thereafter the regulation of pulmonary tory cytokines and is therefore thought to be important in modulating
regeneration and repair. Neuroendocrine cells are more numerous in bronchiolar inflammation and protecting the lung against emphy-
the fetal than the adult lung and one of their products, human bombe- sema69; mice that are deficient in this protein are more susceptible to
sin, has trophic properties in regard to the other cells. Hyperplasia of the damaging effects of hyperoxia.114 Cytochrome P-450-dependent
neuroendocrine cells has been described during epithelial repair,42,103,104 mixed-function oxidase activity115 has also been identified in Clara
following asbestos exposure105 and in pulmonary fibrosis,106 infantile cells. Mixed-function oxidases are involved in metabolising many
bronchopulmonary dysplasia,107 pulmonary arterial disease,108 bron- environmental chemicals, including carcinogens that require catalytic
chiectasis associated with tumourlets95 and bronchi bearing carcino- activation. Intracellular levels of glutathione are important in protect-
mas of all cell types.109 Neuroendocrine hyperplasia plays a role in the ing the Clara cells from injury by reactive intermediates produced by
development of carcinoids and is thus regarded as a preneoplastic the metabolism of xenobiotics such as 3-methylindole, trichloro­
condition. ethylene and naphthylamine.41,116,117 Clara cell secretion of endothe-
A subsidiary function of the neuroendocrine cells, which appears lin, a powerful bronchoconstrictor and vasoconstrictor, has also been
to be better developed in lower species, concerns the pulmonary demonstrated.118 The Clara cell also has stem-cell potentiality and in
response to hypoxia. Animal experiments have demonstrated that response to irritation gives rise to both ciliated and mucous cells.39,41,44
neuroendocrine cells increase in number and degranulate in hypoxic
conditions, suggesting a chemoreceptor function.110–113 In the case of
the neuroepithelial bodies this function is modulated by intrapulmo-
Brush cells
nary axon reflexes.82 However, the relevance of these observations to Brush cells occur infrequently at all levels of the airways from the
humans is uncertain. trachea to the alveoli, where they have been called type III pneumo-
cytes.119,120 They have a brush border of closely packed stubby micro-
villi up to 2 µm in length, the axial filaments of which continue into
Clara cells
the cell without ending in a terminal web. A resemblance to intestinal
These cells are named after the Austrian histologist Max Clara who cells has led to a belief that they are concerned in fluid absorption but
provided a detailed description of them in 1937.25 They are most their function remains obscure.121

14
 The structure of the normal lungs Chapter |1|

Figure 1.24  The cut surface of part of a lung lobule, showing some
Figure 1.23  A terminal bronchiole dividing into alveolated respiratory
of the branches of an acinus. TB, terminal bronchiole; RB 1, 2 and 3,
bronchioles, representing the termination of the purely conductive
successive orders of respiratory bronchioles; AD, alveolar duct. The
membranous bronchioles, the commencement of the transitional zone of
fibrous septa that border the lobule are also seen. (Reproduced from
the lung and the apex of a pulmonary acinus. A pulmonary artery is seen
Heard and Izukawa (1964)122 with permission of the late Professor B E Heard
alongside the bronchiole. Artery and bronchiole are of roughly the same
calibre. Between them is a lymphoreticular aggregate, marking the point and the editor of the Journal of Pathology.)
at which lymphatics commence.

The human adult lungs contain about 300–500 million alveoli,5,124

each measuring about 250 µm in diameter when expanded, although
MICROSCOPY OF THE ALVEOLAR TISSUE gravitational forces result in them being bigger in the upper than the
lower parts of the lung.125 The size of the alveoli and the surface
Beyond the terminal bronchioles, which constitute the last of the tension of their lining layer are the major determinants of distensibil-
purely conductive airways, alveoli are found in progressively increas- ity and hence elastic recoil of the lungs; tissue components such as
ing numbers through three orders of respiratory bronchioles and two elastin and collagen contribute to a lesser degree.126 The Laplace equa-
to nine orders of alveolar ducts (Figs 1.23 and 1.24).122 The walls of tion indicates that the collapsing force acting on the lungs is propor-
the alveolar ducts consist only of a thin spiral band of collagen and tional to alveolar surface tension and inversely proportional to
elastin, between which are the mouths of the alveoli, also arranged in alveolar size. Surface tension is reduced, and expansion of the lung
a spiral fashion.20 The arrangement is like the coils of a spring, length- thereby facilitated, by certain lipids, collectively known as pulmonary
ening in inspiration and closing up in expiration. The alveolar open- surfactant, that are secreted by alveolar lining cells (see below).
ings usually have four straight sides whilst the alveolar walls consist Small holes, the pores of Kohn, are found in the alveolar walls of
of flat pentagonal or hexagonal plates arranged as a polyhedron. The many species, including humans (Fig. 1.25). Their diameter ranges
alveoli are thus like boxes with one open side123: if the alveoli were from 2 to 13 µm and there are from one to seven in each alveolus.
spherical, their walls would stretch on inspiration and the alveolar The pores are absent at birth and only develop after the first year of
capillaries would close. The alveolar duct system and the polyhedral life. For this reason some argue that they are abnormal and represent
shape of the alveoli act together like a concertina and thereby permit the beginnings of emphysema. Others believe that they are normal
changes in volume without alterations in surface area. and provide collateral ventilation, although perfusion fixation, which

15
 Pathology of the Lungs

Figure 1.25  Scanning electron micrograph of normal mouse lung.

The small holes in the alveolar walls are the pores of Kohn. (Courtesy of
the late Professor B E Heard, Brompton, UK.)

Figure 1.27  Parts of two alveolar walls, the lower and upper respectively
showing the thin and thick portions of the air–blood barrier respectively.
The upper alveolar wall is lined by the nucleated portion of a type I cell
(solid arrow) and a type II (open arrow) cell, the former partly covered by
an alveolar macrophage (M). Abundant connective tissue is seen beneath
these epithelial cells, in contrast to the thin part of the air–blood barrier
where the interstitum consists of no more than the fused epithelial and
endothelial basement membranes. A, air space; C, capillary lumen.
Transmission electron micrograph. (Courtesy of Mrs D Bowes, Midhurst, UK.)

Figure 1.26  An immunocytochemical preparation of normal alveolar

tissue shows that epithelial cells are plentiful but by light microscopy it is
not apparent that the epithelial lining is complete. Immunoperoxidase for age-old dispute concerning the nature of the alveolar lining layer,
cytokeratin. showing that a complete simple epithelium extends throughout all
alveoli (Figs 1.27 and 1.28).128 It is continuous with that of the
airways. The lining epithelium is separated from the underlying con-
preserves the alveolar lining layer, demonstrates that the pores are nective tissue by a supportive basement membrane.
normally plugged by this layer.127 In pneumonia, however, threads of On one side of the alveolar wall the capillary is closely applied to
fibrin can sometimes be seen passing through the pores from one the alveolar epithelium. Here the endothelial and epithelial basement
alveolus to another. Transmission electron microscopy shows the edge membrane fuse and the air–blood barrier is at its thinnest, about
of the pores to be lined by an intact epithelium. 0.15 µm. On the opposite side of the alveolar wall, interstitial tissue
Under the light microscope the alveolar wall is evidently rich in separates endothelium from epithelium; this is known as the thick
blood capillaries but it is not generally clear whether cells bordering side of the air–blood barrier (see Figs 1.27 and 1.28). The alveolar
the capillaries are endothelial, epithelial or interstitial. Cytokeratin epithelium, interstitium and capillary endothelium constitute about
immunocytochemistry shows that epithelial cells are plentiful but by 30%, 40% and 30% respectively of the air–blood barrier.129
light microscopy the alveolar epithelium appears to be incomplete The alveolar epithelium consists of two principal cell types, vari-
(Fig. 1.26). It was not until 1953 that electron microscopy clarified an ously known as I and II, A and B, small and large, non-vacuolated

16
 The structure of the normal lungs Chapter |1|

Figure 1.29  Two type II alveolar epithelial cells with surface microvilli and
two surface pits through which surfactant has been secreted from
vacuoles within the cytoplasm. Scanning electron micrograph. (Courtesy of
Dr J H L Watson, Detroit, USA.)

Figure 1.28  Alveolar wall with the nuclear portion of a type I cell and but as a clearance pathway the alveolar epithelium is of trifling impor-
the thin part of the air–blood barrier on the right-hand side. The tance compared with the alveolar macrophages.
interstitium contains bundles of collagen surrounding very electron-dense The long thin cytoplasmic processes of the type I epithelial cells are
elastin. Transmission electron micrograph. (Courtesy of Miss A Dewar, extremely sensitive to damage by various injurious agents. Together
Brompton, UK.) with the capillary endothelium these cells represent the component
of the lung most vulnerable to damage (see Chapter 4).

and vacuolated, squamous and granular respectively, which will now

Type II alveolar epithelial cells
be considered.
These cells are taller and twice as numerous as the type I cells but they
cover only 7% of the alveolar surface.131 They usually occupy the
Type I alveolar epithelial cells corners of alveoli and often all but the apex of the cell is covered by
These cells have few cytoplasmic organelles but are remarkable for neighbouring type I cells. The free surface has blunt microvilli and the
their attenuated cytoplasm, which extends long distances from the cytoplasm includes mitochondria, endoplasmic reticulum, Golgi
nuclear zone of the cell (see Figs 1.27 and 1.28) and may even apparatus and characteristic osmiophilic lamellar structures which
penetrate the alveolar wall so that one cell contributes to the lining represent the secretory vacuoles of pulmonary surfactant (Figs 1.29
of more than one alveolus.130 They each cover up to 5000 µm2 of the and 1.30). These appear in fetal life at the time when surfactant can
alveolar surface yet generally measure no more than 0.2 µm in thick- first be identified and an extrauterine existence first becomes possible.
ness.131 Their function is to provide a complete but thin covering, Their role in surfactant secretion has been established by experimental
preventing fluid loss but facilitating rapid gas exchange. Type I cells ultrastructural autoradiography, tracing the incorporation of sur-
are connected to each other and to type II cells by tight junctions, and factant precursors in a sequential fashion through secretory organelles
the alveolar epithelium provides the major barrier to fluid movement and into the lamellar structures.137–140 Cell separation techniques
into and out of the alveolus. Nevertheless, a variety of proteins known en­abling pure type II cell suspensions to be studied in vitro support
as aquaporins that facilitate water transport across epithelia have been the role of these cells as secretors of surfactant.141 Lysosomal enzymes
identified in the cell membrane of type I alveolar cells.132 Following identified in the lamellar structures are derived from multivesicular
large-volume alveolar lavage for lipoproteinosis (see p. 318) it has bodies which fuse with them.142,143 One of these hydrolases, phospha-
been found that about 53% of the residual fluid is absorbed within 1 tidic acid phosphatase, controls an essential step in surfactant synthe-
hour.133 Numerous small pinocytotic vesicles are seen within the type sis.144 Further vesicles and multivesicular bodies located immediately
I cells and macromolecules are absorbed from the alveolus by this beneath the cell membrane are concerned in the secretion of certain
route.134 Very fine particles reach the interstitium from the alveolar surfactant-specific proteins, which are described below.145
lumen by the same vesicular transport mechanism.135,136 Such absorp- After injury there are found occasional alveolar epithelial cells that
tion is probably important in sensitising the host to inhaled antigens possess features of both type I and type II cells (see Fig. 4.10, p. 139).

17
 Pathology of the Lungs

These are flattened squamoid cells but they have the surface microvilli Pulmonary surfactant
and osmiophilic lamellar inclusions of the type found in type II alveo-
lar epithelial cells. Such intermediate cell forms are explained by The tendency of the lung to contract is due partly to its elastic frame-
labelling experiments which indicate that the type II cells are the stem work but largely to the surface tension at the alveolar air–liquid
cells from which type I cells differentiate.146,147 The type II cell is there- interface. Pattle reasoned from Laplace’s law that if the alveolar lining
fore not only the source of surfactant but the progenitor cell from film had the surface tension of serum, the small radius of the alveolus
which the alveolar wall is relined after injury to the more delicate type would mean that the power required to expand the newborn’s lungs
I cell. With chronic damage, type II cells multiply, but do not differ- would far exceed the force of even an adult’s respiratory muscles, and
entiate and the alveolar wall becomes lined by a cuboidal epithelium concluded that the surface tension in the alveoli must be considerably
recognisable with the light microscope (see Fig. 4.8, p. 139). Animal less than that of an aqueous film. He went on to squeeze the fluid
studies have shown that in the normal lung the turnover time of type from mature and immature animal lungs and noted that, whereas the
II cells is 25 days and transformation of type II to type I cells takes 2 bubbles in the foam derived from mature animals were stable, those
days.147 In the developing lung a similar mechanism operates: from fetal lungs lacked stability. This led to a series of experiments,
undifferentiated cells rich in glycogen first differentiate into type II from which it is now known that an extracellular layer that has the
cells and these then transform into type I cells.148 surface tension-reducing properties necessary to permit expansion of
the lung covers the alveolar epithelium and lines the alveolus.149–152
In immersion fixed tissue, surfactant is represented by irregular frag-
ments of osmiophilic material apparently floating free in the alveolar
lumen but perfusion fixation shows that it is smooth and continu-
ous.153 The lining is relatively thick in the corners of the alveoli and
thin over the lateral extensions of the type I cells. It is biphasic and
consists of an aqueous hypophase and a thin surface layer of osmi-
ophilic lattice-work material derived from the lamellar inclusions of
type II cells via intermediate tubular myelin (Fig. 1.31).
The biophysical properties of the lining layer are largely due to
a series of phospholipids that are notable for their high content
of saturated fatty acids, in particular palmitic acid (Table 1.3).
Dipalmitoyl-phosphatidylcholine is the surfactant component which
is predominantly responsible for the reduction of alveolar surface
tension. It includes a small fraction of surfactant-specific proteins,
upon which the surface activity is also dependent154; some of them
also promote phagocytosis and are thus important in lung defence
(Table 1.4).155,156 These proteins (surfactant apoproteins A–D)64 also
play a role in some congenital disorders through gene mutations and
subsequent deficiencies. The lining layer also contains antioxidants
that are probably important in protecting the lung against inhaled
pollutants.157
Some spent surfactant is removed by alveolar macrophages158 but
most is taken up again by type II cells to be first degraded and then
reused in surfactant synthesis.159–162

Alveolar interstitium
Figure 1.30  The surface of a type II cell showing microvilli and a
surfactant-secreting vacuole discharging its lamellar body. Transmission The interstitium of the lung is its connective tissue framework. It is
electron micrograph. abundant around the airways and arteries in the centres of the lobules

Figure 1.31  Alveolar epithelium covered by

a biphasic lining layer. The osmiophilic
latticework material represents surfactant
resting on an aqueous hypophase.
Transmission electron micrograph. (Courtesy of
Mrs D Bowes, Midhurst, UK.)

18
 The structure of the normal lungs Chapter |1|

Lymphatics are not found in alveolar walls. From the alveoli, inter-
Table 1.3  Surfactant composition
stitial fluid drains to the more abundant connective tissue in the two
Saturated phosphatidylcholine 50% main connective tissue locations mentioned above the centres of the
lung acini and the intralobular septa, which is where the lymphatics
Unsaturated phosphatidylcholine 17% commence (see below).
Phosphatidylglycerol 7%
Alveolar macrophages
Phosphatidylethanolamine 4%
These cells are the lung’s principal means of ridding the alveoli of
Phosphatidylinositol 2%
inhaled exogenous particles and endogenous detritus. Increased
Sphingomyelin 2% numbers are found in smokers171 and those exposed to dust, and as
a non-specific reaction accompanying many lung diseases.
Other phospholipids 3%
The ultimate source of alveolar macrophages is the bone marrow
Other lipids 5% but their immediate origin is the population of pulmonary interstitial
cells referred to above.167,172,173 In disease states marked by an increase
Serum proteins 8%
in alveolar macrophages, poorly differentiated interstitial cells are
Surfactant-specific proteins 2% increased in number, and are occasionally seen breaking through the
alveolar epithelium, or interposed between the alveolar epithelium
and its basement membrane.174 Kinetic studies show that most mono-
cytes destined to become alveolar macrophages pass quickly into the
alveoli but that a minority first divide in the interstitium.167,172,175
Table 1.4  Surfactant-specific proteins Maturation of monocytes into macrophages involves cytoplasmic
enlargement, loss of myeloperoxidase and the development of lyso-
Molecular Surface Main functions somes more characteristic of mature macrophages. When demand is
weight (kDa) activity brisk many immature macrophages with scanty lysosomes are found
in the alveolar lumen.176 Mitoses are occasionally observed amongst
A 26–38 None Promotes phagocytosis
macrophages free in the alveolar space177 and there is evidence that
Regulates surfactant secretion
proliferation in this site is the main mechanism by which alveolar
B 9 High Optimises surface activity macrophage numbers are maintained.178 The number of alveolar mac-
rophages may therefore increase by both enhanced migration from
C 4 Very high Optimises surface activity
the interstitium and division of cells which have already gained the
D 43 None Promotes phagocytosis alveolar lumen. Phagocytes lining the hepatic sinusoids may enter the
Regulates surfactant secretion circulation and utilise this transpulmonary route as an excretory
mechanism.179 Phenotypically distinct subsets of alveolar macro-
Surfactant apoproteins A and D are hydrophilic and act as opsonins. They also
phages reflecting the functional maturity of the cells can be recognised
promote the unwinding of the lamellar bodies and are thereby involved
indirectly in lowering alveolar surface activity, which, in conjunction with with appropriate antibodies and separated by density-gradient
surfactant phospholipids, is the prime function of the hydrophobic apoproteins centrifugation.180–182
B and C. The normal sojourn of macrophages in the alveolus is 7 days,175 the
vast majority being drawn to the terminal bronchiole along with the
alveolar lining film and hence to the pharynx to be swallowed or
expectorated. Up to five million macrophages leave the lungs by this
and around the veins at their periphery where it forms the interlobular route every hour.183 Respiratory movements appear to promote the
septa. At the alveolar level these two main connective tissue locations movement of alveolar macrophages, for these cells tend to accumulate
are connected by fine ramifications that make up the alveolar inter- in alveoli bordering the relatively fixed bronchovascular structures at
stitium. On the thin side of the air–blood barrier this consists of only the centres of the lung acini.6 Re-entry of macrophages into the inter-
the fused epithelial and endothelial basement membranes whereas on stitium takes place principally at this site.184,185 It is estimated that
the thick side it also comprises all the intervening elements – collagen 8700 alveolar macrophages reach the hilar lymph nodes daily in the
and elastin fibres, fibroblasts, myofibroblasts, pericytes, histiocytes, normal guinea pig.186 This interstitial translocation of macrophages is
mast cells and scanty nerves and nerve terminals (see Fig. 1.28). thought to be critical to antigen presentation and the induction of
The myofibroblasts are notable in that their myofibrils are oriented lung immunity.185 It is also important in the development of dust-
perpendicular to the plane of the alveolar wall and are attached to induced lung disease.
dense insertion points on the epithelial or endothelial cell mem- Although of similar origin to macrophages in other sites, the alveo-
brane.163 The myofibroblasts therefore span the interstitium and lar macrophage differs from the peritoneal macrophage in having an
appear to restrict its compliance. It is also suggested that they control aerobic rather than anaerobic metabolism.187 Non-specific esterase is
perfusion of the alveoli and counteract capillary distending pres- an ectoenzyme prominent on the surface of alveolar macrophages and
sure.164,165 Pericytes are sparse but also appear to control perfusion for in this position may be important in controlling the behaviour of
they too contain myofilaments and are closely applied to capillaries. these cells in relation to others or in the response of the macrophage
They also show many pinocytotic vesicles and have long processes to factors released by other cells, such as lymphokines.188 Lymphokines
that are intimately related to the basement membranes.166 to which the alveolar macrophage responds include a macrophage
Further interstitial cells include mast cells, which are considered fusion factor which induces the formation of multinucleate giant
later (see p. 28), and a form of histiocyte intermediate between blood cells189 and macrophage aggregation, migration and inhibition
monocytes and alveolar macrophages.167–170 The lymphoid elements factors.190 Alveolar macrophages or their immediate precursors in the
of the lung, including Langerhans and dendritic reticular cells, are interstitial tissues interact with pulmonary lymphocytes in a reciprocal
dealt with separately (see p. 26). manner. As well as responding to lymphokines released by antigen-

19
 Pathology of the Lungs

Figure 1.32  An alveolar macrophage with prominent lysosomal dense

bodies and pseudopodia is seen close to the alveolar wall. Transmission
electron micrograph. (Courtesy of Professor P K Jeffery, Brompton, UK.)

stimulated T lymphocytes, they are important in presenting antigen Figure 1.33  Two alveolar macrophages near a pore of Kohn. Unstained
to lymphocytes, and are aided in this by the presence of immu- electron micrograph to show the electron-dense reaction product of
noglobulin and complement receptors on their surface.188 Furthermore, lysosomal acid phosphatase, thus confirming the lysosomal nature of  
alveolar macrophages appear to modulate the expression of immune the cytoplasmic dense bodies. (Reproduced from Corrin et  al. (1969)143 by
reactions in the lung for in differing circumstances they appear either permission of the editor of the Journal of Anatomy.)
to enhance or to suppress the proliferation, differentiation and func-
tion of antigen-stimulated lymphocytes.191
The alveolar macrophages are normally situated within the alveolar alcohol, cigarette smoke, metabolic acidosis and viral infections202–207
lining film, but are floated off into the alveolar lumen during immer- and is defective in chronic granulomatous disease (see p. 484 [sys-
sion fixation. They are irregular in outline and have prominent pseu- temic diseases]). Bacteria killed within macrophages are digested by
dopodial cytoplasmic extensions (Fig. 1.32). The cytoplasm contains the action of lysosomal acid hydrolases.
many dense bodies rich in lysosomal enzymes (Fig. 1.33).142,143 Although primarily concerned with intracellular digestion, lyso-
Phagosomal vacuoles and multiloculated phagolysosomes are also somal enzymes are known to be released during phagocytosis. This
numerous. was initially thought to represent inadvertent leakage due to prema-
The alveolar macrophage is avidly phagocytic135,136,192 (Fig. 1.34) ture membrane fusion, but it is now appreciated that macrophages
and represents an important defence mechanism against inhaled bac- actively secrete certain substances and the release of acid hydrolases
teria. It also provides the major means of clearing the alveolus of during phagocytosis may not be fortuitous.208,209 Indeed, the bulk of
inhaled dust. In smokers, the phagolysosomal inclusions are more the lysozyme within macrophages appears to be destined for secretion
plentiful and pleomorphic and contain characteristic ‘tar bodies’ or outside the cell rather than intracellular digestion; its secretion is
minute kaolinite crystals (see Fig. 7.2.3, p. 374).193 Lung lining mate- independent of phagocytic activity. Other antimicrobial factors
rial is a chemotactant for alveolar macrophages194 and the phagocytic secreted by macrophages include interferon. The excessive release of
action of alveolar macrophages is potentiated by the surfactant-asso- reactive oxygen metabolites, nitric oxide and lysosomal enzymes from
ciated proteins SP-A and SP-D.155,195 Conversely, alveolar macrophages macrophages may have deleterious results, possibly contributing to
provide one means of removing spent surfactant.158 lung injury in processes such as septic shock (see p. 143). Macrophages
Phagocytosis involves a process of membrane fusion concerning can also be an abundant source of matrix metalloproteinases such as
first the cell membrane and then those of the phagosome and lyso- collagenase, gelatinase and elastase, the release of which is implicated
somes. In addition to acid hydrolases, alveolar macrophages contain in the development of emphysema.210,211
catalase and a peroxidase distinct from myeloperoxidase, but which Other macrophage factors of interest are those influencing the activ-
in the presence of iodide and peroxide has similar antibacterial prop- ity of other host cells and the identification of a fibroblast-stimulating
erties.196,197 Superoxide production by alveolar macrophages is char­ substance is clearly relevant to fibrotic lung disease.212–215 Trans­
acterised by a burst in oxygen consumption and glycogenolysis that formation of macrophages into epithelioid and multinucleated giant
is stimulated by the phagocytosis of a variety of inhaled pollutants.198 cells is particularly associated with the development of organelles
Another powerful antibacterial agent formed in macrophages, and more associated with secretory than phagocytic cells, e.g. Golgi appa-
other phagocytic cells, is nitric oxide.199–201 The antibacterial activity ratus and vesicles (see Fig. 6.1.32, p. 286). This is associated with the
of alveolar macrophages is depressed by hypoxia, hyperoxia, cold, secretion of an array of cytokines.

20
 The structure of the normal lungs Chapter |1|

Figure 1.34  Unstained electron micrograph of rat lung injected with

finely divided electron-dense tracer particles via the trachea. Numerous
large phagosomes are evident in an alveolar macrophage (M) but are
scanty and minute in the alveolar epithelium (arrows). II, type II
pneumocyte. (Reproduced from Corrin (1970) by permission of the editor of
Thorax.135)

BLOOD SUPPLY OF THE LUNGS

The pulmonary vasculature is unique in that it receives the whole Figure 1.35  A pulmonary arteriogram produced by injecting the arteries
of an excised lung with a molten barium–gelatine mixture.
of the cardiac output, but it perfuses rather than nourishes the lungs,
this latter function being undertaken by the bronchial vasculature.
The pulmonary circulation is a low-pressure system. At rest a mean
pressure of only 10 mmHg is sufficient to distribute the cardiac output There is a sharp transition from elastic to muscular pulmonary
through the lungs. This barely counteracts gravity and in the upright arteries at a level of the bronchovascular tree where bronchi give way
position blood flow through the apices of the lungs is minimal at rest. to bronchioles (such airways having a diameter close to 1 mm and
Cardiac output may double without any increase in pulmonary artery the accompanying arteries being of similar or slightly smaller size).
pressure because closed capillaries in the underperfused upper zones Muscular pulmonary arteries have well-defined internal and external
of the lungs are first recruited. Thus there is considerable reserve in elastic laminae enclosing their muscular media. The whole wall is very
the pulmonary vascular bed and many vessels may be lost in disease thin compared with systemic arteries of comparable diameter, reflect-
or surgically without incurring a significant rise in pulmonary vascular ing the different pressures in the two circulations. In normal un­injected
resistance. The full extent of the pulmonary arterial system is shown lungs, the medial thickness of muscular pulmonary arteries is about
in Figure 1.35. 5% of the external diameter compared with 15–20% in systemic arter-
ies.216 Injection of the pulmonary arteries with fixative or contrast
medium yields lower values. Despite blood flow being greater in the
Pulmonary arteries
base of the lung than the apex, there is normally no quantitative dif-
The anatomy of the main pulmonary arteries and the relationship of ference in pulmonary artery structure between these zones (although
their branches to the airways have been described above (see p. 6). such differences develop when venous pressure is raised).
The major pulmonary arteries are elastic vessels and at birth the The muscle of the media thins progressively as the arteries narrow
pattern of their elastic laminae closely resembles that of the aorta. with repeated branching, and in vessels between 100 and 30 µm in
Within the first few months of life there is fragmentation of the elastic diameter the muscle coat is represented only by a spiral, so that in
fibres and an irreversible ‘adult pattern’ is reached by about the age cross-section, arteries of this size are only muscularised for part of
of 6 months (see Fig. 8.2.8, p. 423). their circumference. Below 30 µm diameter, precapillary vessels have

21
 Pathology of the Lungs

no muscle in their walls, which consist only of fibroelastic tissue. The

existence of partially muscularised blood vessels obscures the distinc-
tion between arteries and arterioles. For this reason many workers
A
prefer to call all precapillary vessels arteries.
The pulmonary artery endothelium has many fine cytoplasmic pro-
jections which increase the surface area considerably.217 Myofilaments
are found in the endothelium of pulmonary arteries and precapil­
laries, but not capillaries.218 Distinctive inclusions first found in the
endothelium of pulmonary arteries have subsequently been identified
in systemic arteries and are occasionally also observed in alveolar
capillaries. They consist of parallel microtubules forming rod-shaped
membrane-bound granules up to 3 µm in length and are frequently
termed Weibel–Palade bodies after those who first described them.219
Their function is uncertain but it has been shown that they contain
von Willebrand protein.220

Ventilation–perfusion matching
The muscular pulmonary arteries are unique in contracting in response
to hypoxia and an important consequence of defective ventilation of
the lung is that it induces a corresponding fall in pulmonary per-
fusion. This mechanism operates at the local level. There is a remark-
ably fine local matching of pulmonary perfusion to ventilation,
PA PV
brought about by vasoconstriction in poorly ventilated areas.221,222 It
is important that such a mechanism should operate, for blood leaving
the lungs is normally fully saturated with oxygen and, if poorly ven-
tilated lung tissue was perfused, hypoxaemia would inevitably result
(Fig. 1.36). Local perfusion/ventilation matching minimises the
Figure 1.36  The blood leaving the lungs is normally fully oxygenated
danger of hypoxaemia. This is an important adaptive mechanism and
and perfusion of any poorly ventilated areas (as on the left) would
beneficial when there is focal ventilatory impairment, as with an inevitably result in hypoxaemia. This is prevented by matching perfusion
inhaled foreign body, but if airflow limitation is generalised, as in to ventilation through arteriolar constriction at the local level, which is
chronic bronchitis and emphysema, there is widespread pulmonary probably mediated by reduced nitric oxide release from the endothelium
vasoconstriction, which causes right-heart strain and eventual failure. in response to low oxygen tension. A, airway; PA, pulmonary artery;  
The immediate cause of the pulmonary vasoconstriction is low oxygen PV, pulmonary vein.
tension in the inspired air but how this operates has been the subject
of much debate. The rise in pulmonary vascular resistance is virtually
unaffected by vagotomy, indicating that it is a local response.
Mechanisms that have been suggested include a local axon reflex,
paracrine activity by neuroendocrine cells in the airway mucosa (see
p. 13) and a direct vascular response to the low oxygen tension.223 The 1.38). Where the caveolar membrane, diaphragm and cell membrane
last of these mechanisms has most support; arterial endothelia syn- fuse, dense knobs are found, possibly representing a ring structure that
thesise and secrete various vasoactive substances, notably the vaso­ may maintain the patency of the stoma and the integrity of the dia-
constrictor, endothelin224 and the relaxing factor, nitric oxide. In the phragm. Nucleotide-splitting enzymes thought to minimise the risk
lungs hypoxia has the effect of increasing the release of endothelin of thrombosis have been localised within these caveolae.230
and inhibiting the release of nitric oxide.225 The resultant vasoconstric- The capillary diameter is about 5 µm, less than that of the blood
tion is most profound in small muscular pulmonary arteries of about cells, but erythrocytes at least are fairly deformable. White blood cells
30–50 µm diameter.221,222 Generalised pulmonary vasoconstriction are less deformable and transit of these cells through the alveolar
imposes a considerable burden on the right side of the heart, which capillaries is slower than that of erythrocytes.231 This delay is increased
counters by releasing atrial natriuretic factor. This decreases pulmo- in pulmonary inflammation. The alveolar capillaries are the vessels
nary vasoconstriction, as well as opposing the action of renin and involved in neutrophil sequestration and migration,232 in contrast to
aldosterone on the kidney and promoting diuresis.226 the systemic circulation where these processes take place in venules.
The endothelial cell is similar to the type I epithelial cell in thick-
ness (see Fig. 1.27) but covers only one-third the area and the alveolar
Alveolar capillaries wall contains many more endothelial than type I epithelial cells.131 In
The alveolar capillaries form a tightly matted network of short inter- contrast to the alveolar epithelium the endothelial cell junctions
secting tubules (Fig. 1.37).227 There are about 1000 such capillary readily permit the passage of small-molecular-weight proteins and the
segments per alveolus228 and a blood cell passing through the lungs basement membrane similarly offers no barrier to fluid transport.233
would have to traverse about 60.229 The capillary wall consists merely Larger molecules such as albumin are retained by the intercellular
of endothelium of the usual continuous type and a basement mem- junctions but small amounts of albumin cross the endothelium to
brane (see Figs 1.27 and 1.28). reach the interstitium by pinocytotic transport.234 Alveolar capillaries
Pinocytotic vesicles are numerous in the endothelial cells. They are attended by pericytes, elongated contractile cells rich in cytoplas-
open as caveolae on to both the luminal and interstitial aspects, but mic filaments and which are ensheathed by the endothelial basement
are more noticeable on the former where many of them have a special membrane.166 The role of pericytes and myofibroblasts in controlling
structure, being ‘sealed’ by a thin single membrane or diaphragm (Fig. perfusion is discussed above (see alveolar interstitium, p. 18).

22
 The structure of the normal lungs Chapter |1|

Pulmonary veins
The walls of the intrapulmonary veins consist largely of multiple
irregular elastic laminae and collagen with little intervening muscle.
However, with increased venous pressure, they may acquire a muscu-
lar media and become ‘arterialised’ (see Fig. 8.2.16, p. 428). In disease
states therefore the structure of the vessel wall is not a wholly reliable
criterion in distinguishing veins from arteries. More valuable is an
assessment of the location of the vessel, remembering that pulmonary
veins are found at the periphery of the lung lobule and in the inter-
lobular septa. Intralobular veins less than 30 µm in diameter are
identical in structure to arteries of comparable size and are distin-
guishable from them only by their connections to larger veins.
Pulmonary veins are not valved but sphincters have been described in
the pulmonary veins of rats.235
Sometimes small cellular collections are observed adjacent to the
pulmonary veins. They have been likened to chemoreceptor tissue but
ultrastructural studies show that they have a remarkable resemblance
to meningeal arachnoid cells. Some authors refer to them as arach-
noid nodules and suggest that, like those in the meninges that transfer
interstitial fluid to the dural veins, those in the lungs may transfer
interstitial lung fluid to the pulmonary veins and so minimise the
danger of pulmonary oedema.236 These structures are described more
fully in the section dealing with lung tumours (see multiple minute
meningothelioid nodules, p. 700).
The intrapulmonary veins join to form extrapulmonary vessels con-
necting the lungs to the left atrium. There are generally four of these
vessels, the right and left superior and inferior pulmonary veins, but
they may number three or five.237 Immediately before the pulmonary
veins enter the left atrium they acquire a sheath of myocardium,
which varies from 0.2 to 1.7 cm in length.237 Ectopic foci within these
myocardial sleeves communicate with the cardiac conducting system
and are now believed to be the commonest cause of atrial fibrillation
(see p. 76).238–240

Pulmonary arteriovenous shunts

Shunts that bypass the capillary bed have been demonstrated in exper-
imental animals by perfusing glass spheres 20–40 times the diameter
of the capillaries.241 In humans, these shunts have been shown to be
Figure 1.37  The alveolar capillaries (which are unduly prominent in this
at the entry to the bronchopulmonary segments, the entry to the acini
congested lung) form many short, interconnecting segments. Scanning
electron micrograph. (Courtesy of Professor PK Jeffery, Brompton, UK.)
and within the visceral pleura.242 They normally conduct little of the
pulmonary blood flow but widen when small pulmonary vessels are
narrowed.

Non-chromaffin paraganglia
Non-chromaffin paraganglia (‘glomera’) were identified widely dis-
tributed throughout an infant’s lung in a search of 5250 serial
sections, being found particularly at the branching point of pulmo-
nary arteries in close relation to nerves.243 In fine structure they
resembled chemoreceptors and a regulatory role in respiration and
pulmonary blood flow was proposed. The possibility that non-
chromaffin paragangliomas arise from these structures is discussed
on page 638.

Metabolic functions of
the pulmonary endothelium
Figure 1.38  The air–blood barrier showing three caveolae (arrows) in It is now recognised that many serum factors, including certain drugs
the surface of the capillary endothelium, each sealed by a thin single and hormones, are modified as they pass through the lung, and that
membrane. Transmission electron micrograph. (Courtesy of Mrs D Bowes, the pulmonary endothelium is not just a smooth inert vascular lining.
Midhurst, UK.) Some substances are merely bound to the endothelium and may be

23
 Pathology of the Lungs

dislodged by others. For example, imipramine is a drug for which the pulmonary hypertension, where there is evidence of excess endothelin
lung has a high affinity but no metabolic capability and further infu- activity,252 and in septic shock, where excess nitric oxide is released
sions of imipramine or chlorpromazine will displace imipramine pre- from activated neutrophils and macrophages.201
viously accumulated in the lung.244 Other substances are taken up by The alveolar capillary endothelium also shares antigens with a
the endothelium and actively metabolised, either on the surface or macrophage subset capable of presenting antigens to lymphocytes,
within the cytoplasm of the endothelial cell, resulting in the serum suggesting that it may play a role in the immunological response
factor being either activated or inactivated. For example, angiotensin of the lung.253
is activated and bradykinin inactivated by a peptidase* that is distrib-
uted uniformly along the endothelial cell surface.230 Substances
taken up and metabolised within the endothelial cells include Megakaryocytes in the pulmonary
5-hydroxytryptamine (by monoamine oxidase), noradrenaline (nor­ circulation: the lung as a source of platelets
epinephrine: by catechol-o-methyl transferase) and prostaglandins
of the E and F series (by 14-hydroxyprostaglandin dehydrogenase). Megakaryocytes are produced in the bone marrow and some at least
5-Hydroxytryptamine is taken up by endothelial cells throughout the are evidently released intact for they are also found in mixed venous
pulmonary circulation, whereas noradrenaline is preferentially taken blood. The dimensions of megakaryocytes and pulmonary capillaries
up by small pre- and postcapillary vessels and by veins.245,246 Some are such that any megakaryocytes arriving in the lungs would be held
substances that the endothelium is capable of metabolising pass there. Occasional megakaryocytes are indeed seen in normal lung,
through the pulmonary circulation unchanged because there is no trapped in alveolar capillaries.254–256 They generally appear as irregular
uptake mechanism. For example, despite the presence within the pul- haematoxyphil clumps representing only the condensed nuclei of
monary endothelial cells of peptidases capable of splitting oxytocin, these platelet precursor cells.256,257 They are devoid of cytoplasm and
vasopressin and substance P, these substances are unchanged on have evidently discharged their platelets. The fact that platelets are
passage through the pulmonary circulation because there is no uptake. more numerous in arterial than mixed venous blood whereas the
Similarly histamine and prostaglandin A pass through the lung converse applies for megakaryocytes suggests that many platelets are
unchanged despite the presence of intracellular imidazole-N-methyl first released from megakaryocytes trapped in the lungs,258–264 but this
transferase and 14-hydroxyprostaglandin dehydrogenase, again does not mean that the lungs are the principal site of platelet produc-
because of the low affinity the lung has for these substances.247 tion.256 Megakaryocytes are particularly easy to find in pulmonary
Prostacyclin synthetase is found particularly in relation to the arte- capillaries when there is an increased demand for platelets, as in
rial intima.248 Prostacyclin is spontaneously released from the lungs conditions such as shock and carcinomatosis which lead to increased
and it has been proposed that this represents active secretion by the platelet consumption (see Fig. 4.22B, p. 145).256,265,266
endothelium.249 Prostacyclin is vasodilatory and, in regard to platelets,
antiaggregatory: in particular, prostacyclin is antagonistic to throm-
boxane, the platelet-aggregating factor released from platelets them-
Bronchial vasculature
selves. Prostacyclin therefore plays an important role in minimising Whereas the pulmonary circulation receives the whole venous return
pulmonary thrombosis. Nucleotidases found in the endothelial of the body, the bronchial circulation is part of the systemic circula-
caveolae described above are also thought to minimise the risk of tion and receives only 1–2% of the output of the left ventricle. The
thrombosis. However, thrombogenic factors are also found in the pulmonary circulation is a high-capacity, low-resistance system
endothelium: for example, von Willebrand protein has been localised whereas the bronchial circulation is a low-capacity, high-resistance
to Weibel–Palade bodies, which are widely distributed in vascular system.267,268 In response to hypoxaemia the pulmonary arteries con-
endothelium,220 and factor VIII-related antigen is strongly represented strict but the bronchial arteries dilate. Bronchial blood flow also
in pulmonary endothelium. increases in response to the inhalation of cold air.
The endothelium lining pulmonary arteries, and to a lesser extent
pulmonary veins, also secretes potent vasoactive substances outwards,
that is, away from the lumen towards the smooth muscle in the Bronchial arteries
medial coat of the vessel. Two substances are of note here, endothe- The bronchial arteries supply oxygenated blood to the walls of the
lin,224,250 which is a particularly powerful vasoconstrictor, and nitric airways, the interlobular septa and the visceral pleura. There is usually
oxide,199,200,251 which was known as endothelium-derived relaxing one bronchial artery on the right, which arises from the third posterior
factor before its simple chemical structure was appreciated. Enhanced intercostal artery or from the upper left bronchial artery. The left
nitric oxide activity is thought to contribute to the normal decline in bronchial arteries usually number two and arise from the descending
pulmonary vascular resistance at birth. Neither of these vasoactive thoracic aorta inferior to the origin of the third posterior intercostal
factors is unique to the pulmonary circulation, being formed in artery. However, bronchial arteries may arise from the thyrocervical
endothelia throughout the body. Indeed, neither is confined to blood trunk, an internal mammary artery, the costocervical trunk, a subcla-
vessels and both function quite differently in other tissues. In the lung, vian artery, a lower intercostal artery, an inferior phrenic artery or even
endothelin is also formed in airway epithelium118,224 and when the abdominal aorta. They anastomose with tracheal arteries derived
administered via the airways has a strong bronchoconstrictor effect. from the inferior thyroid artery. Bronchopulmonary anastomoses are
Nitric oxide, which is cytotoxic and has only a very short tissue half- considered below.
life, is an important neurotransmitter and, in phagocytes, an effective Within the lung, bronchial arteries are best seen at the level of the
bactericidal agent. In blood vessels, endothelin and nitric oxide have larger bronchi where the pulmonary arteries are still of the elastic type,
opposing actions and normal vascular tone depends upon them bal- which contrasts sharply with the muscular structure of the bronchial
ancing one another. This equilibrium is disturbed in diseases such as arteries. Bronchial arteries have a thicker medial coat than pulmonary
arteries, commensurate with the higher pressure they have to with-
stand. They also lack an outer elastic membrane, having only a single
*Since this enzyme cleaves the carboxyl terminal dipeptide from both bradykinin internal elastic lamina (Fig. 1.39). Bronchial arteries also lie within
and angiotensin I, it is preferable to use its biochemical name dipeptidyl
carboxypeptidase rather than either of its trivial names, kininase or angiotensin the wall of the bronchi whereas pulmonary blood vessels lie
converting enzyme. alongside.

24
 The structure of the normal lungs Chapter |1|

Figure 1.40  A bronchial arteriogram showing a greatly hypertrophied

artery (right) supplying congeries of new vessels (left) in the wall of a
bronchiectactic cavity.

Figure 1.39  A bronchial artery, which lacks an external elastic lamina

and, in comparison to pulmonary arteries, has a thick medial coat. Elastin
van Gieson stain.

Normally the bronchial arteries are inconspicuous but the bron-

chial circulation is greatly expanded in many pathological conditions:
lesions as diverse as bronchiectasis and carcinoma are largely supplied
by bronchial arteries (Fig. 1.40).269–272 The bronchial circulation can
also make an important contribution to gas exchange in conditions
where the pulmonary blood supply is reduced, as in certain forms of
congenital heart disease and thromboembolic lung disease.
Small peripheral bronchial arteries sometimes exhibit longitudinal
bundles of smooth muscle. These develop both within and outwith
the elastic lamina and on occasion are so well developed that they
seriously compromise or even completely obliterate the lumen (Fig.
1.41) Such Sperrarterien (from the German word Sperr meaning dam A
or valve) are generally thought to represent sphincters controlling the
flow through arteriovenous or bronchopulmonary anastomoses (see
below).273 It is postulated that the longitudinal muscle hypertrophy
is a response to intermittent stretching,273 but this is disputed.274

Bronchial capillaries
Bronchial capillaries form a profuse subepithelial network, the extent
of which reflects the high metabolic rate of an epithelium involved in
warming the inspired air, ion exchange and ciliary activity. The sub-
epithelial capillaries are connected to a deeper system of muscularised
sinusoidal vessels which are distensible and so influence bronchial
wall thickness, thus narrowing the lumen,275–277 albeit at the expense
of ventilation. Bronchial capillaries generally have the usual continu-
ous type of endothelium but a fenestrated type is found in the vicinity
of neuroepithelial bodies and submucosal glands, raising the possibil-
ity that circulating or endothelial factors may regulate the function of B
these structures.278–280 A fenestrated capillary endothelium is also
found in many fibrotic disorders of the lung.278,281 Figure 1.41  A Sperrarterie (arrows). These vascular structures, believed
to represent valvular arteriovenous or bronchopulmonary anastomoses,
Bronchial veins are often markedly narrowed by bundles of hyperplastic longitudinal
muscle. This one lies next to a pulmonary artery (to its right) but they
The bronchial veins, usually two on each side, open into the may be found as far out as the pleura. (A) Haematoxylin and eosin;  
azygos vein on the right and the superior intercostal vein, the superior (B) elastin van Gieson stain.

25
 Pathology of the Lungs

hemiazygos vein or the innominate vein on the left. They drain only free lymphatic communication between the two lungs. Nevertheless,
blood supplied to the proximal bronchi, the blood supplied to the lymph from the left lung largely drains via ipsilateral nodes to the
distal airways being drained into pulmonary veins via bronchopulmo- thoracic duct and on to the left subclavian vein while that from the
nary anastomoses described below. Thus, part of this systemic blood right lung drains via right-sided nodes to the right bronchomediasti-
is destined for the right side of the heart and part for the left. nal trunk and the right subclavian vein. The evidence for this is based
upon studies of the nodal distribution of pulmonary tumour metas-
tases289 and gainsays an older, widely held view that lymph from the
Bronchopulmonary anastomoses
lower lobe of the left lung drains to the right.
The bronchial and pulmonary circulations mix through precapillary, The thoracic duct drains lymph from most of the body. It enters the
capillary and venous bronchopulmonary anastomoses; flow is nor- mediastinum through the diaphragmatic aortic hiatus in front of the
mally from systemic to pulmonary vessels. At the arterial level mixing 12th thoracic vertebral body, between the aorta to its left and the
is normally very limited but up to two-thirds of the bronchial venous azygos vein to its right, and ascends in front of the vertebral column
flow escapes the right side of the heart by entering anastomotic chan- to reach the neck where it empties into the left subclavian vein.
nels which connect with the pulmonary veins. By this means up to
4% of the output of the left ventricle consists of blood from the bron-
chial circulation.282 When the bronchial circulation expands, as in a Regional differences in ventilation
variety of lung diseases (see above), new bronchopulmonary anasto- and perfusion relevant to the location
moses are established. Large bronchopulmonary anastomoses bypass of lung disease
stenosed pulmonary valves or arteries in congenital heart disease.
Similarly, bronchopulmonary anastomoses develop in diseases char- Gravity affects both ventilation and perfusion and in so doing results
acterised by thrombotic occlusion of pulmonary arteries.283 The exper- in several diseases of the lung having a characteristic upper- or lower-
imental ligation of a pulmonary artery results in an enormous lobe predominance. In our customary upright position pulmonary
expansion of thick-walled bronchopulmonary collaterals that is well blood pressure barely matches the hydrostatic pressure difference
advanced by 12 weeks.284 Bronchopulmonary anastomoses minimise between the right ventricle and the apices of the lungs so that at rest
the likelihood of full ischaemic necrosis, as does reversed anastomotic the apices are hardly perfused at all. They are also less well ventilated
flow when there is acute occlusion of a bronchial artery. because gravity drags on the upper lobes and compresses the bases so
At the venous level, pulmonobronchial anastomoses direct oxygen- that alveoli in the upper lobes are larger than those in the lower,
ated blood back to the right ventricle in conditions such as mitral allowing more room for expansion in the lower lobes.290,291 Inhaled
stenosis and pulmonary veno-occlusive disease, whilst there may be dust particles are therefore preferentially directed to the lower lobes.
increased flow in the reverse direction when precapillary causes of However, because these regions are also better perfused, lymph flow
pulmonary hypertension lead to right-sided heart failure and vena is greater there and clearance is superior. Thus, although the bases
caval hypertension: blood from the azygos veins may then flow receive more dust, less accumulates there and most pneumoconioses
through the bronchial veins into the pulmonary veins and cause therefore show an upper-lobe predominance.
cyanosis.285 As with dust, inhaled bacteria are directed preferentially to the
lower lobes and many infections consequently commence there. Thus
the Ghon focus of primary tuberculosis is found more often in the
Lymphatic drainage of the lungs lower lobes than in the upper. The classic upper-lobe location of
Lymphatics are not found in the alveolar walls but commence in the postprimary tuberculosis has a more complex basis but this is also
centriacinar region and in the interlobular septa. They are wide in entirely dependent upon the regional differences in ventilation and
relation to their wall thickness, and are attached to adjacent connec- perfusion, as explained on page 207 (see Fig. 5.3.14). A similar mecha-
tive tissue fibres by special anchoring filaments which hold the lym- nism may underlie the upper-lobe predominance of diseases such as
phatics open when interstitial fluid accumulates, interstitial pressure sarcoidosis, Langerhans cell histiocytosis and extrinsic allergic
rises and compression might otherwise be expected.286 There is con- alveolitis.
siderable reserve in the clearance capability of the pulmonary lym-
phatics which may increase their load 10-fold when pulmonary
oedema threatens.287 Pulmonary lymphatics are valved structures and, LYMPHOID TISSUE OF THE LUNGS
in addition to the above features, their capillaries differ from blood
capillaries in that their endothelium has poorly developed junctions. This section first describes three principal locations within the lung in
Adjacent endothelial cells often merely overlap and the endothelial which lymphoid cells are found and then outlines the important
basal lamina is discontinuous. Although lymphatics are not found at features of the lymphoid cells themselves.
the alveolar level their commencement near the smallest bronchioles
means that no part of the lung is removed from a lymphatic vessel by
much more than 2 mm. They accompany the blood vessels to the
Intrapulmonary lymph nodes
hilum of the lung, which they also reach by joining a pleural plexus Encapsulated lymph nodes of classic structure are found within the
on the outer surface of the lung. At the hila of the lungs they drain lungs, mainly related to the bifurcations of large bronchi. They are
into hilar and thence mediastinal lymph nodes. situated in the peribronchial tissues and do not come into direct
The lymph nodes of the mediastinum receive most clinical atten- contact with respiratory epithelium. Although mainly related to
tion in the staging of lung cancer, for which purpose they are grouped bronchi of the first three or four orders they may rarely be found in
as inferior, aortic and superior. The inferior group comprises sub­ the peripheral lung, generally close to the visceral pleura of the
carinal, paraoesophageal and pulmonary ligament nodes, the aortic middle lobe, lingula or lower lobes (see Fig. 12.4.1, p. 654). Although
group comprises subaortic and paraaortic nodes, and the superior they are not of direct clinical relevance, they are becoming more
group comprises lower paratracheal, pre- and retrotracheal, upper important in relation to the differential diagnosis of peripheral
paratracheal and highest mediastinal nodes (see Box 12.1.6, p. 572).288 nodules, especially in relation to computed tomography screening for
A network of lymphatics connects these lymph nodes so that there is carcinoma.292–294

26
 The structure of the normal lungs Chapter |1|

Figure 1.42  A focus of bronchial mucosa-associated lymphoid tissue

shows follicular hyperplasia in a case of follicular bronchiectasis. Note
how the lymphoid cells infiltrate the overlying epithelium, which at this
point is not ciliated.

Bronchus-associated lymphoid tissue

Certain lymphoid collections are closely related to the bronchial
epithelium and because of their resemblance to Peyer’s patches
(gut-associated lymphoid tissue or GALT) are termed bronchial
mucosa-associated lymphoid tissue (MALT).295,296 Bronchial MALT is
not thought to be a normal constituent of the human bronchial tree
but acquired in response to various antigenic stimuli.297–299 It is better Figure 1.43  The dome region of bronchus-associated lymphoid tissue
represented in children300 and in smokers,299,301 and is prominent in consisting of a collection of lymphocytes, one of which is located within
surface epithelium that at this point is non-ciliated. Transmission electron
certain inflammatory diseases, such as follicular bronchiectasis (Fig.
micrograph. (Courtesy of Miss A Dewar, Brompton, UK.)
1.42). It is also better developed in species such as the rabbit and rat
where again it may undergo hypertrophy when subjected to antigenic
stimulation.297,302–304 Bronchial MALT is found especially at the airway
bifurcations, which is where inhaled antigens are particularly likely to one part of this system tend to recur in the mucosae of other organs
impinge. (see p. 659).
In many species bronchial MALT is formed of follicular lymphoid
tissue which is closely applied to a distinctive overlying ‘lymphoepi-
thelium’ consisting of flattened non-ciliated epithelial cells known as Lymphoreticular aggregates
microfold or ‘M cells’, intimately involved with which are lymphocytes
that form part of the outer mantle or dome region of the underlying Lymphoreticular aggregates were described before bronchial MALT
lymphoid follicle (Figs 1.42 and 1.43). Antigen is taken up by the M and today many would probably be classified as such. However, they
cells304 and passed to follicular dendritic cells (see below) within the are more widely distributed, being found throughout the lungs, about
bronchial MALT.305 The germinal centres consist of a mesh of follicu- bronchi and in alveolar tissue, interlobular septa and the pleura. They
lar dendritic cells that sustain rapidly dividing B lymphocytes and are particularly noticeable at the centres of the acini, interposed
present them with antigenic information. More than half the lym- between the terminal or a respiratory bronchiole and its accompany-
phocytes of the bronchial MALT are B cells, with IgA being the pre- ing artery (see Fig. 1.23).308 This is the point at which lymphatics
dominant isotope.72,306 T cells comprise about 18% of lymphocytes in commence and the aggregates are well placed to monitor fluid and
bronchial MALT. cells draining from the alveolar tissue in the interstitial plane. They
In humans bronchial MALT is not so well organised or so closely consist of small collections of lymphocytes with a few plasma cells
applied to the surface epithelium, being better seen in the outer coat and eosinophils. Reticulin stains show a delicate connective tissue
of the bronchus301 and around the bronchial glands.299 IgA-secreting network but the sinusoidal and nodal architecture of a lymph node
plasma cells are concentrated about the serous acini of the bronchial is lacking. Dust-laden macrophages accumulate in the lymphoreticu-
glands299,306 where the secretory component of IgA is synthesised and lar aggregates, leading Macklin to refer to the aggregates as ‘dust
incorporated into the IgA dimer as this passes across the epithelium sumps’.6 On the cut surface of a city-dweller’s or smoker’s lung they
to reach the lumen (see Fig. 1.19).70–72 provide a useful marker of the centres of the lung acini (see Fig. 1.7).
After an immune response is induced in the bronchial MALT,
lymphocytes enter the blood and travel to mucosal effector sites
Lymphocytes
such as the lamina propria throughout the body where large amounts
of IgA are produced.307 This migratory pathway forms part of a Lymphocytes of all classes are present in the lung: B and T, T-helper
common mucosal immune system in which responses induced in one and T-suppressor, and T-helper-1 and -2. The functions of B and T
location can be replicated elsewhere. Similarly, lymphomas arising in cells in humoral and cellular immunity and hypersensitivity are well

27
 Pathology of the Lungs

known, as are the promoter and suppressor/cytotoxic functions of dendritic cells into Langerhans cells are influenced by factors affecting
T-helper (CD4+) and T-suppressor (CD8+) cells. T-helper cells are the epithelium, notably smoking and epithelial metaplasia.317,322,325–327
cytokine secretors whereas T-suppressor cells are mainly cytotoxic Like dendritic cells, Langerhans cells do not normally enter the
killer cells. Their respective roles are dealt with in some detail under air space but lavage fluid from smokers and patients with bronchial
various granulomatous diseases, notable tuberculosis (see p. 200) epithelial hyperplasia contains up to 5% Langerhans cells. They
and sarcoidosis (see p. 286). The subsets of T-helper cells (Th1 and are referred to again under the disease Langerhans cell histiocytosis
Th2) determine whether an immune response is directed towards (see p. 288).
phagocytosis and bacterial elimination or hypersensitivity reactions
characterised by eosinophilia. The former is effected by activated
Th1 lymphocytes through the elaboration of cytokines such as
Mast cells
interleukin-2 and interferon-γ and the latter by elective activation of There are at least two types of mast cell, mucosal and connective
the Th2 lymphocytes resulting in interleukin-4, -5, -6 and -10 secre- tissue, both of which originate in the bone marrow and are repre-
tion. Interleukin-4 is responsible for plasma cells forming IgE rather sented in the lung.328,329 It is not known whether they are interchange-
than IgG while interleukin-5 is responsible for tissue eosinophilia. able but this is likely as with an appropriate stimulus their relative
Both cell types produce granulocyte–macrophage colony-stimulating proportions may change rapidly.330 The two types differ in many
factor. Further T-cell subsets identified in the lungs include alpha beta respects but are usually distinguished by their content of tryptase and
and gamma delta cells, the former thought to be important for immu- chymase, of which only tryptase is found in mucosal mast cells
nological memory while the latter contribute to the early immune whereas connective tissue mast cells contain both these proteases.
response.309 Mucosal mast cells predominate in the lungs and are the prevailing
type in the airway mucosa and alveoli, whereas connective tissue mast
cells are the more numerous in airway muscle and blood vessels.
Dendritic cells In the airways mast cells are mainly situated in the subepithelial
tissues but some are found in the surface epithelium and may be
There are two types of dendritic cells, both of which are described in
recovered by bronchoalveolar lavage.331–337 Airway mast cells progres-
the lungs: follicular dendritic cells, mentioned above as a component
sively increase in number distally so that in the small bronchioles total
of the bronchial MALT, and interdigitating dendritic cells.310–316 They
mast cell numbers are 100–150-fold greater than in the trachea. Mast
are both derived from bone marrow stem cells and reach the lung by
cells make up about 2% of the cross-sectional area of the alveolar
the blood stream. Both function as antigen presenters to T lym-
walls, with higher values in disease states.338
phocytes. They do this by processing the antigen intracellularly into
In both normal and fibrotic lung, mast cells show remarkably close
short peptides before presenting it to T lymphocytes on their surface
apposition to fibroblasts,339 and there is evidence that they promote
in association with the HLA-DR histocompatibility complex. Dendritic
fibrosis.340–342 However, they are best known for their role in type I
cells are also activated by endogenous signals such as interferon-α
allergic reactions and are referred to again under asthma (see p. 114).
released from virus-infected cells and heat-shock proteins released by
Various mediators are released when the mast cell degranulates.
dying cells.
Preformed mediators include histamine, serine proteases (tryptase,
Interdigitating dendritic cells are found in T-cell-dependent areas of
chymase) and eosinophil and neutrophil chemotactic factors.
lymph nodes and are widely distributed in the lung, being found
Degranulation also stimulates the generation and release of newly
around and within the walls of bronchi and bronchioles, and
formed mediators, including prostaglandin D2, platelet-activating
in alveolar walls, interlobular septa and the pleura. They have long
factor and leukotrienes C4 and D4. Mast cells also produce a variety
cytoplasmic processes and irregular, convoluted nuclei.317 In the
of cytokines, notably interleukins-1–5, granulocyte–macrophage
airways interdigitating dendritic cells form a network at the base of
colony-stimulating factor, interferon-γ and tumour necrosis factor-α.343
the epithelium that is ideally positioned to sample inhaled antigens
Release is tailored to the stimulus. Lipopolysaccharide, for example,
(Fig. 1.44).317 They are not present at birth but develop in the respira-
induces cytokine secretion but not degranulation.344
tory mucosa after about 1 year of life, probably in response to infec-
tion.318 Interdigitating dendritic cells are also found deeper in the
airway wall, outside the muscle coat, and it is here that they interact
with T cells.319 INNERVATION OF THE LUNGS
In addition to the Langerhans cells described below, phenotypically
varying subsets of dendritic cells are described: myeloid type 1 express-
Several nerve bundles enter the lung from a plexus formed at the
ing CD1c, myeloid type 2 expressing CD141 and plasmacytoid
hilum by parasympathetic fibres derived from the vagus nerve and
expressing CD303, but whether these are distinct cell types or
sympathetic fibres from the upper thoracic ganglia of the sympathetic
variations of the same is uncertain.320–322 However, the experimental
chain. Peptidergic (non-cholinergic, non-adrenergic) fibres are also
evidence suggests that they are capable of a significant degree of
included.345–350
plasticity.323
On entering the lung, the nerves divide into peribronchial and
perivascular plexuses, the former further ramifying about the cartilage
plates and beneath the surface epithelium. Sensory endings include
Langerhans cells
rapidly adapting receptors within the surface epithelium responding
These cells constitute a subpopulation of dendritic cells, from which to irritants and promoting the cough reflex, those supplying the neu-
they are derived by a process of differentiation.311 They differ from roepithelial chemoreceptors, slowly adapting stretch receptors associ-
other dendritic cells by expressing CD1a and langerin (CD207) and ated with muscle and thought to be responsible for the Hering–Breuer
by the presence of certain pentalaminar structures known as Birbeck reflex, and juxtacapillary (J-type) receptors in the alveolar walls sensi-
granules324 (see Fig. 6.1.38, p. 289), which develop in the cytoplasm tive to rises in pulmonary venous pressure and possibly interstitial
during the internalisation of surface-bound antigens. They are essen- oedema.78,80–85,351–353
tially a cell of the epidermis but small numbers are found in the Terminals identified by vital staining in the walls of pulmonary
bronchial epithelium. Proliferation and differentiation of pulmonary veins and bronchial arteries, but not pulmonary arteries, are probably

28
 The structure of the normal lungs Chapter |1|

Figure 1.44  Bronchial dendritic cells (DC). (A) Transmission electron micrograph of a DC in the mucosa of a normal non-atopic adult with a
cytoplasmic extension (pseudopod) which straddles the basement membrane (arrows) with its nucleus within the epithelium. A mast cell (M) and
fibroblasts (F) are observed in the subepithelium. Scale bar = 10 µm. (B) Transmission electron micrograph showing a DC in the bronchial mucosa of a
stable asthmatic in the epithelium in close proximity to the reticular basement membrane (RBM) with cytoplasmic projections/pseudopodia (arrows)
which extend amongst the basal cells (BC). An associated lymphocyte (L) is indicated. The DC exhibits a characteristic electron-lucent cytoplasm and
nuclei with a distinctive narrow rim of heterochromatin. Scale bar = 5 µm. (C) Transmission electron micrograph montage of a DC in two consecutive
tissue sections from the epithelium of an asthmatic subject. The dotted line indicates the boundary between sections. The cell body extensions or
pseudopodia (see outline) observed in this plane of sectioning of the stellate DC extend between the BC. A lymphocyte (L) is present at the RBM.  
Scale bar = 5 µm. (Courtesy of Dr AV Rogers, Brompton, UK; reproduced from Rogers et  al. (2008).317)

further pressor receptors.354 Histochemical and ultrastructural studies lamines and peptides such as vasoactive intestinal peptide356 and
have shown that the whole pulmonary vasculature is innervated by substance P.357 Cholinergic innervation appears to be the most impor-
noradrenergic and cholinergic nerves, and that rapid changes take tant effector drive to bronchial contraction and secretion but may be
place in these nerves during the postnatal adaptation of the pulmo- augmented by the peptide substance P. Inhibition of contraction may
nary circulation.355 Non-chromaffin paraganglia that possibly act as be by catecholamines or by peptidergic nerves, particularly those
vascular chemoreceptors are described above (p. 23). releasing vasoactive intestinal peptide.358 Cholinergic stimulation also
Motor terminals are also found in bronchial glands, muscle and appears to extend to alveolar secretory cells, for bilateral vagotomy in
surface epithelium, whilst ganglia containing Kultschitsky-like cells the rat results in atelectasis359 whilst cholinergic drugs increase the
in addition to nerve cells and fibres have been identified in the bron- production of type II cell lamellar bodies360 and the secretion of
chial submucosa.75 Neurotransmitters include acetylcholine, catecho- surfactant.361

29
 Pathology of the Lungs

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330. Hsieh FH, Sharma P, Gibbons A, et al. electronmicroscopic study. J Clin Pathol 350. Belvisi MG. Overview of the innervation of
Human airway epithelial cell determinants 1981;34:1333–42. the lung. Curr Opin Pharmacol
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primary human mast cells. Proceedings of of fibroblasts to mast cells and 351. Fox B, Bull TB, Guz A. Innervation of
the National Academy of Sciences of the lymphocytes in normal human lung and alveolar walls in the human lung: an
United States of America in cryptogenic fibrosing alveolitis – electron microscopical study. J Anat
2005;102:14380–5. ultrastructure and cell perimeter 1980;131:683–92.
331. Guerzon GM, Pare PD, Michoud M-C, measurements. J Pathol 1992;166: 352. Laitinen A. Ultrastructural organisation of
et al. The number and distribution of mast 303–10. intraepithelial nerves in the human airway
cells in monkey lungs. Am Rev Respir Dis 340. Chanez P, Lacoste JY, Guillot B, et al. Mast tract. Thorax 1985;40:488–92.
1979;119:59–66. cells’ contribution to the fibrosing 353. Larson SD, Schelegle ES, Hyde DM, et al.
332. Lamb D, Lumsden A. Intra-epithelial mast alveolitis of the scleroderma lung. Am Rev The three-dimensional distribution of
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evidence for smoking-induced changes in 341. Qu ZH, Liebler JM, Powers MR, et al. Mast airway tree of the adult rat and the
their frequency. Thorax 1982;37: cells are a major source of basic fibroblast anatomical relationship between nerves
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Progress. Oxford: Blackwell; 1986. 1996;149:2037–54. Postnatal development of the innervation
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Mol Biol 1990;3:71–8. Innervation of the lungs Substance P-like immunoreactive nerves in
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347. Barnes PJ, Baraniuk JN, Belvisi MG. SC. Pulmonary alveolar lesions in
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neutrophils, and macrophages in bronchial
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biopsy specimens from atopic subjects
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Epithelial Barriers. London: Academic
human alveolar wall: an
Press; 1994. p. 85–118.

37
 Chapter 2 

Development of the lungs; perinatal and

developmental lung disease

CHAPTER CONTENTS Congenital ‘emphysema’ 72

Ectopia 73
Development of the lungs 39 Hamartomas 74
Airway development 39 Anomalies of the pulmonary blood vessels 74
Vascular and neural development 41 Anomalies of the pulmonary lymphatics 77
Factors controlling lung development 41 Anomalies of the thoracic cage 77
Perinatal disorders 43 References 80
Meconium aspiration 43
Massive pulmonary haemorrhage 43
Neonatal pneumonia 43
Infantile respiratory distress syndrome The traditional division of disease into congenital and acquired is less
(hyaline membrane disease) 43 useful in the case of the lungs than one that considers developmental
as opposed to non-developmental disorders. This is because lung
Bronchopulmonary dysplasia and chronic lung
development continues long after birth. Developmental disease may
disease of prematurity 45
therefore be acquired well into the postnatal period. Conversely some
Surfactant dysfunction disorders 46 congenital lung disease is non-developmental but acquired in utero,
Chronic pneumonitis of infancy 47 a good example of which is congenital pneumonia. Other abnormali-
Cellular interstitial pneumonitis and pulmonary ties may be acquired in utero because of adjacent developmental
interstitial glycogenosis 47 anomalies, one example of which is a defect in the diaphragm
Interstitial emphysema 48 admitting abdominal viscera into the thorax and thereby causing
pulmonary hypoplasia.
Persistent tachypnoea of infancy associated with
Knowledge of embryology is often helpful in understanding devel-
neuroendocrine cell hyperplasia 48
opmental diseases but, except for a few conditions such as tracheo-
Persistent fetal circulation (persistent pulmonary oesophageal fistula and anomalous pulmonary veins, this is hardly
hypertension of the newborn) 48 true of the lungs as the embryological basis of most developmental
Diffuse developmental lung disorders 49 lung disease is poorly understood. Nor is the pathogenesis of most
Tracheobronchomalacia acquired in infancy 51 pulmonary malformations at all clear.
Further disorders of development and growth 51
Anomalies of the larynx and trachea 51
Anomalies of the bronchi and bronchioles 53 DEVELOPMENT OF THE LUNGS
Congenital bronchiectasis 62
Anomalies promoting bronchiectasis in later life 63 Airway development
Pulmonary aplasia (agenesis) 69
Human lung development is first marked by a longitudinal groove
Pulmonary hypoplasia 70 that appears on the ventral side of the primitive foregut 26 days after
Pulmonary hyperplasia 72 fertilisation. This separates from the foregut, first at its caudal end,

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00002-1 39
 Pathology of the Lungs

1 2 3

Lung bud
R L R L

Oesophagus

4 5 6

Figure 2.1  Development of the human lungs from the 26th to the 33rd
day of gestation. l. At 26 days a bud appears at the lower end of the
laryngopharyngeal sulcus. 2–4. The bud elongates to form a primitive
trachea and lungs. 5. At 33 days there is early lobation of the lungs. 6.
The primitive lungs extend dorsally on either side of the oesophagus.

and then progressively forward until a connection is retained only at

the cranial end. This bud then bifurcates and grows on either side of
the foregut as the embryonic lungs, with successive branching giving
rise to the lobar (about 33 days), segmental and further divisions
of the airways (Fig. 2.1).1 The developing lungs protrude into the
coelomic cavity, the mesothelial lining of which forms from the
mesoderm about the 14th day of gestation. With the development of
Figure 2.2  Cross-section of a human embryo at 44 days’ gestation. At
the diaphragm and a pleuropericardial membrane the lungs become this stage the pleural, pericardial and peritoneal cavities have separated
confined to the pleural cavities (Fig. 2.2). from the primitive coelomic cavity and the main and lobar bronchi have
The phases of lung development and the major events therein are formed. A vertebral body is seen at the top and anterior to this lie the
summarised in Table 2.1. The embryonic stage of lung development dorsal aorta, the oesophagus, the lungs in their pleural cavities and the
lasts until 6 weeks’ gestation, by which time the lungs have acquired heart, of which the two thin-walled structures represent the atria and  
a pseudoglandular appearance (Fig. 2.3). At this time the primitive the more solid lower part the ventricles. Immunoperoxidase stain for  
potential air spaces are widely separated by abundant mesenchyme the cell junction marker vinculin. (Courtesy of Dr Alison Hislop, London, UK.)
and lined by a vacuolated columnar or cuboidal epithelium rich in
glycogen. The glycogen is particularly plentiful in the budding termi-
nal epithelium where mitoses are most frequent. The pseudoglandular
stage of development lasts until 16 weeks by which time division of increase in alveolar number with continued but slower increase there-
the conductive airways down to the terminal bronchiole is complete.2 after, up to about 8 years of age and perhaps well into adolescence.5
This is followed by a canalicular stage marked by the appearance of There is also remodelling of airways in the first year of life. This entails
further air spaces which have an attenuated lining epithelium (Fig. an increase in length of all airway generations, further branching of
2.4). During this period the epithelium loses its glycogen and differ- alveolar ducts to give more generations, transformation of distal
entiates into the type I and II cells seen in adult alveoli. Although no respiratory bronchioles into alveolar ducts by increasing alveolisation
proper alveoli are yet present, respiration is possible towards the end of their walls, and transformation of terminal into respiratory bron-
of the canalicular period around 28 weeks. Substantial amounts of chiole by centripetal alveolisation.6–8 An important facet of postnatal
connective tissue still separate the air spaces at this time but in the lung development is that events in infancy and childhood may pre-
saccular stage of intrauterine lung development the connective tissue dispose to pulmonary disease in adult life. Thus, an increased fre-
progressively diminishes by an apoptotic mechanism3 as new air quency of respiratory infections in childhood has been identified in
spaces called terminal sacs develop. These resemble adult alveoli but adults with chronic airflow obstruction.9–11
are shallower and their walls still have enough connective tissue to All the epithelial tissues of the lung, down to and including the
separate the capillaries abutting air spaces into two layers. The devel- alveoli, are of endodermal origin and all the interstitial elements are
opment of true alveoli, first apparent at 36 weeks’ gestation, is char- mesodermal in origin. This is contrary to older views on the develop-
acterised by infolding of one of the two capillary layers, further ment of the lung which envisaged the peripheral parts being purely
thinning of the connective tissue and the eventual fusion of the mesodermal, but is demonstrated quite conclusively by electron
double capillary layer into one.4 microscopic studies of the developing mammalian lung. These show
Alveoli develop mainly in the first year of extrauterine life and lung that the epithelial cells of the primitive endodermal bud extend con-
disease in infancy seriously impairs this. At birth, there are about 24 tinuously down to the smallest air spaces and that the epithelial
million terminal sacs and alveoli, compared to the adult figure of lining of these spaces is not contributed to by any mesodermal
about 300 million alveoli. In the first year of life there is a fivefold elements.12–14

40
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Table 2.1  Major events during lung development

Phase Gestation Major events

Embryonic Up to 6 Lung buds form

weeks Segmental airways appear  
(6 weeks)
Pseudoglandular 6–16 weeks Bronchial smooth muscle appears
(7 weeks)
Neuroendocrine cells and
submucosal glands appear  
(8 weeks)
Bronchial cartilages appear  
(10 weeks)
Airway branching complete  
(16 weeks)
Canalicular 17–28 weeks Basal cells appear (17 weeks) Figure 2.4  The canalicular stage of lung development at 20 weeks’
Clara cells appear (25 weeks) gestation. Further air spaces have developed and the lining epithelium is
Basic structure of the acinus more attenuated.
develops
Mesenchyme starts to regress
Blood vessels grow into acinar Vascular and neural development
mesenchyme The blood supply to the developing lung buds is derived from the
Type II alveolar cells appear   sixth pair of aortic arches. On the right, the ventral part of this arch
(22 weeks)
persists as the right pulmonary artery whilst the dorsal part disappears.
Saccular 29–35 weeks Subdivision of saccules On the left, the ventral part persists as the ductus arteriosus. Within
Further thinning of mesenchyme the lung buds blood vessels are formed by two processes. Angiogenesis
(the sprouting of new from pre-existing vessels) underlies the forma-
Alveolara 36 weeks to Terminal air spaces lined by flat
tion of proximal lung vessels whilst vasculogenesis within the mesen-
term epithelial cells
chyme (the formation of vascular lakes by precursor angioblasts)
Inconspicuous interstitium
Double layer of alveolar capillaries
contributes the peripheral vascular component, the two ultimately
fuses to give a single layer fusing by a lytic process.15,16 The pulmonary arteries develop alongside
newly formed airways, the latter seemingly acting as templates for the
Birth Lung liquid rapidly cleared arteries.17 A well-defined branching pattern is apparent by 14 weeks’
a
gestation and all preacinar arteries are present by 16 weeks. At 20
Alveolar multiplication continues from 36 weeks well into childhood.
weeks the branching pattern resembles that of adults. However, many
peripheral arteries develop after birth (Fig. 2.5).18
The processes of vasculogenesis and angiogenesis are also involved
in the development of the pulmonary veins.19 Veins and arteries both
first develop close to the primitive lung bud but the veins gradually
take up a more peripheral position and by the time that the lung has
a lobular structure the primitive veins are found in their adult position
between the lobules. They initially enter a plexus around the foregut
but later switch to a primary pulmonary vein that grows from the
developing left atrium towards the lung buds. Incorporation of
the primary pulmonary vein and its first two orders of branches into
the wall of the left atrium results in two pulmonary veins from each
lung entering the left atrium separately. Failure of the intrapulmonary
veins to switch from the enteric venous plexus to the primary pulmo-
nary vein underlies the congenital condition of anomalous pulmo-
nary venous drainage (see p. 76).
Lymphatic development is first seen in the lung from about the
eighth gestational week and by 14 weeks the pulmonary lymphatics
are well established.
Neural tissue derived from the vagus nerve extends into the growing
tips of the fetal airways and bronchial smooth muscle, which develops
from 7 weeks’ gestation, contracts in response to nervous stimulation
from early gestation.20

Figure 2.3  The pseudoglandular stage of lung development at 12 Factors controlling lung development
weeks’ gestation showing air spaces widely separated by abundant
mesenchyme and lined by columnar epithelium showing marked Molecular mechanisms play an important role throughout lung devel-
subnuclear vacuolation. opment from the early induction of tracheal separation from the

41
 Pathology of the Lungs

Figure 2.5  Pulmonary arteriograms showing the development of the pulmonary circulation after birth. (A) Life-size pulmonary arteriogram of
the left lung of a baby at term. The arterial branching pattern is complete but there is little background haze as there are as yet few peripheral
arteries. (B) Life-size pulmonary arteriogram of the left lung of an infant aged 18 months. The branching pattern is similar to that seen at birth but
there is now a dense background haze made up of numerous peripheral arteries that have grown in the alveolar region of the lung after birth and
that are too small to be identified individually. (Reproduced with permission from Jeffery and Hislop (2003).18)

embryonic oesophagus to the appearance of cells specific to the lung chyme expresses signalling molecules such as fibroblast growth factor
such as the bronchiolar Clara cell and the alveolar pneumocytes. that are important in pulmonary epithelial development. Contacts
Various members of the forkhead homologue hepatocyte nuclear between interstitial and type II epithelial cells have been identified in
factor-3 (HNF-3) family are essential for the formation of the foregut the newborn and shown to diminish during a postnatal proliferative
endoderm and derivative organs, including the lung, while the induc- phase.31 Experiments demonstrate that respiratory epithelium has an
tion of tracheal budding is dependent upon the simultaneous expres- inhibitory effect on the growth of the underlying mesenchyme,32,33
sion of the transcription marker Nkx2.1 (also known as thyroid whilst in fetal organ culture, intestinal mesoderm will induce bron-
transcription factor-1 or TTF-1).21–23 TTF-1 is expressed throughout the chial budding but not branching, bronchial mesoderm will induce the
embryonic lung in the early stages of its development but later tracheal endoderm to branch, and tracheal mesoderm will inhibit
becomes restricted to the more distal elements where growth is most bronchial branching.34 Furthermore, whilst the bronchial mesoderm
active. It is particularly involved in epithelial cell differentiation. of one species will induce the endoderm of another to branch, the
The endodermal and mesodermal elements of the lung are each pattern of endodermal branching is that of the species contributing
important to the proper development of the other with the basement the mesoderm. These experiments clearly demonstrate the inter­
membrane, cell adhesion factors such as fibronectin and integrin, and dependence of mesoderm and endoderm in pulmonary development.
a variety of growth factors all playing a role in this interaction.24–30 They are reinforced by the arrested development of endodermal lung
Growth factors include epithelial signalling molecules such as bone buds within ectopic neuroglia (see p. 73).
morphogenetic factor, transforming growth factor and sonic hedge- The fetal air spaces are filled by a chloride-rich fluid secreted by their
hog that influence the underlying mesenchyme while the mesen- lining epithelium, which makes a substantial contribution to the

42
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

production of amniotic fluid.35 Its presence in the airways appears to reversible. The natural clearance mechanisms can be augmented with
be important to fetal lung growth for this is retarded if the fluid is suction but such treatment may need to be prolonged, in which case
drained.36 Conversely, ligation of the trachea results in large lungs.37 oxygenation of the blood has to be maintained with an extracorporeal
Neuroendocrine cells are particularly numerous in the respiratory device; mechanical ventilation would only impair clearance. The mor-
epithelium of the developing airways38–42 and at least one of their tality remains high, although corticosteroid and surfactant treatment
products, gastrin-releasing peptide (human bombesin), is known are of some benefit.51–53
to stimulate lung growth and maturation during the later stages of
development.43 The expression of gastrin-releasing peptide receptor
gene peaks at a time and at sites of most rapid airway growth Massive pulmonary haemorrhage
and development.44 This is a fairly common finding in perinatal necropsies and has several
Respiratory movements take place in utero and these too are causes. In some cases of apparent pulmonary haemorrhage the find-
thought to be important for fetal lung growth and maturation.45 ings are due to heavy blood-staining of oedema fluid rather than true
Section of the cervical cord above, but not below, the phrenic nucleus haemorrhage and in these patients shock and left ventricular failure
leads to severe pulmonary hypoplasia.46 are important contributory factors. A coagulopathy, usually acquired,
Hormones are also important in lung development. The lungs bear may cause true haemorrhage but the commonest cause is asphyxia.
steroid receptors, and maturation, but not growth, is promoted by Cerebral oedema and haemorrhage are often also present and prob-
glucocorticosteroids and probably other hormones. Glucocorticoid ably represent further manifestations of asphyxial damage. The condi-
treatment of the fetus accelerates epithelial glycogen depletion, dif- tion is disproportionately frequent among preterm babies with very
ferentiation into type I and II cells, the appearance of lamellar bodies low birth weights54 and it is postulated that abnormal alveolar surface
in type II cells, and their release into the air spaces.47 This is utilised forces may contribute to the bleeding.55
in clinical practice to minimise the risk of respiratory distress in pre-
mature infants (see below): a decreased incidence of the respiratory
distress syndrome and increased survival are reported in premature Neonatal pneumonia
infants exposed to maternal steroid therapy.48 The steroids appear to
Pulmonary infection in the neonate may be due to transplacental
act, at least in part, by stimulating lung fibroblasts to produce an
transmission from the mother, aspiration of either infected amniotic
oligopeptide known as fibroblast pneumonocyte factor which in turn
fluid before birth or infected material during birth, or environmental
stimulates surfactant synthesis by the type II cells, an example of
contacts after birth.
paracrine activity.49
With transplacental transmission the pneumonia is only part of a
generalised infection. Causative agents include cytomegalovirus,
rubella virus, herpes simplex virus, varicella virus, mycoplasmas,
PERINATAL DISORDERS Listeria monocytogenes, Treponema pallidum, Mycobacterium tuberculosis
and Toxoplasma gondii. Many of these microbes elicit specific reactions
Meconium aspiration that are dealt with in later chapters. However, it may be mentioned
here that eosinophilic nuclear inclusions that represent parvovirus
The expulsion of meconium into the amniotic fluid occurs as a may be found in the lungs and other organs of premature stillbirths
response to fetal stress from a wide range of causes and its aspiration and neonates with non-immune hydrops.56
may cause a chemical or infective fetal pneumonia,50 described below Pneumonia acquired by aspiration of infected amniotic fluid is
under neonatal pneumonia. Fetal stress also increases the normal known as congenital or intrauterine pneumonia. It is particularly
respiratory excursions that take place before birth and may result in likely if there is prolonged rupture of the membranes. Chorioamnionitis
the airways being obstructed by numerous fetal squames and mucus suggests this mechanism and examination of the placenta and its
(Fig. 2.6). Pathologists are likely to encounter only fatal cases but membranes is therefore helpful. Vaginal group B haemolytic strepto-
the lungs are inherently normal and the obstruction is potentially cocci or Candida albicans may be responsible, as may bowel bacteria
such as Escherichia coli, klebsiellae and Pseudomonas aeruginosa. The air
spaces contain polymorphonuclear leukocytes and fibrin but neither
of these is as prominent as in an adult with pneumonia (Fig. 2.7).
The distribution of the process is that of a bronchopneumonia. In
some cases there is a combination of hyaline membrane disease and
pneumonia. Bacteria may then be seen in the hyaline membranes,
rendering them haematoxyphilic. It is possible that in such cases the
bacteria promote the formation of the membranes by damaging the
alveolar epithelium. Acute pneumonia and hyaline membranes may
also result from the chemical toxicity of the bilirubin in aspirated
meconium.50 The fact that atelectasis is minimal helps to distinguish
pneumonia with hyaline membranes from the infantile respiratory
distress syndrome, which is dealt with next.57 The combination of
pneumonia and hyaline membranes is also seen in immature babies
requiring ventilator support when there is secondary infection.58,59

Infantile respiratory distress syndrome

(hyaline membrane disease)
Figure 2.6  Meconium aspiration. Fetal hypoxia has led to excessive
respiratory movements in utero, resulting in the alveoli being filled with By 28 weeks’ gestation, the alveolar epithelium has differentiated into
amniotic squamous cells. type I and type II pneumocytes, surfactant can be detected and an

43
 Pathology of the Lungs

Figure 2.7  Fetal (intrauterine) pneumonia. Neutrophils are evident in the Figure 2.9  Infantile respiratory distress syndrome (hyaline membrane
alveoli but they are not as numerous as in fatal bacterial pneumonia in disease). The interlobular septa are broadened by oedema and lymphatics
an adult. within them are dilated. Alveoli have collapsed and air is confined to the
bronchioles.

Figure 2.8  The lungs of a premature infant dying of the infantile

respiratory distress syndrome (hyaline membrane disease) are dark and
airless.

extrauterine existence is possible. With modern intensive care, an

increasing number of babies born before 28 weeks are surviving, but
without it the chances of successful respiration at this age are slim. By
34–36 weeks, premature birth is generally followed by successful
respiration but the capacity of type II pneumocytes to replenish spent
stocks of surfactant is frequently inadequate, in which case respiratory
distress becomes evident within a few hours of birth.60 This is apparent
as grunting, indrawing of the intercostal tissues on inspiration and
hypoxia. Radiographically there is opacification of the whole lung
fields except for an ‘air bronchogram’. Without respiratory support the
death rate in the first few days is high.

Pathological findings Figure 2.10  Infantile respiratory distress syndrome (hyaline membrane
At necropsy the lungs are heavy, dark and airless (Fig. 2.8). Microscopy disease). Hyaline membranes separate collapsed alveoli from aerated
bronchioles.
confirms the atelectasis, with air limited to the bronchioles (Fig. 2.9).
There is also lymphatic distension and interstitial oedema, best seen
in the perivascular connective tissue sheaths (see Fig. 2.9). Alveolar strated in them by immunocytochemistry and epithelial necrosis by
collapse and interstitial oedema are the expected consequences of electron microscopy.61 The hyaline membranes are yellow if there has
high surface tensive forces acting on the alveolar walls. Hyaline mem- also been unconjugated hyperbilirubinaemia (Fig. 2.11).62,63
branes are found at the boundary of the air-filled bronchioles and the Hyaline membranes are not specific to premature babies and may
collapsed alveoli (Fig. 2.10). They are not found when death occurs be found in term infants who die of birth asphyxia some hours later.
in the first few hours of life and they are no longer thought to play a Virtually identical pathological changes are seen in the adult respira-
causal role in the alveolar collapse. The hyaline membranes represent tory distress syndrome (see p. 135). Hyaline membrane disease is
compacted plasma exudates and cellular debris. They do not stain for evidently a consequence of non-specific injury to the bronchiolar and
fibrin with conventional histological stains but fibrin can be demon- alveolar lining. In premature infants the injury is likely to be physical;

44
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.11  Yellow hyaline membranes in a premature infant with

hyperbilirubinaemia.

ventilatory efforts in the surfactant-deficient lung put undue shear

forces on the epithelium at the air–liquid interface, which at end-
expiration is at the bronchiolar level, the alveoli having collapsed
completely. Such mechanical stress operates during each ventilatory
cycle so that it is repeated several thousand times in the first few hours
of extrauterine life.61

Therapy and its complications

If premature birth is expected, or induction of premature labour
planned, the risks of respiratory distress can be reduced by administer-
ing corticosteroids to the mother.48 This promotes maturation of the
B
fetal lung, including surfactant secretion.47 It is a preventive measure
that is only feasible when premature birth can be anticipated.
After birth, mechanical respiratory support with oxygen enrichment Figure 2.12  Bronchopulmonary dysplasia. (A) A bronchiole is lined by
atypical regenerative epithelium. Hyaline membranes are seen in the
is the main means of maintaining oxygenation. This is being increas-
bronchiolar lumen. Adjacent alveolar tissue shows interstitial fibroblast
ingly supplemented by the insufflation of natural or synthetic proliferation. (B) A bronchiole shows mucosal thickening by cellular
surfactant into the infant’s airways.64 Such surfactant therapy is fibrosis and there is squamous metaplasia.
proving very successful but, if the infant does come to autopsy, the
exogenous surfactant is seen in the air spaces as a yellow birefringent
material. Another useful measure is the administration of nitric oxide Bronchopulmonary dysplasia and chronic
gas in low concentrations (less than 80 parts per million) to induce
lung disease of prematurity
pulmonary arterial dilatation and improve ventilation/perfusion
matching. Extracorporeal oxygenation of the infant’s blood may also Bronchopulmonary dysplasia is the condition found in premature
be undertaken but results are best in babies greater than 37 weeks’ infants who are enabled with the help of artificial ventilation to
gestation: preterm babies weighing less than 2 kg have blood vessels survive the respiratory distress syndrome but die in the first few
that are too fragile to withstand the damage from cannulae and are months of life.68,69 As infants who recover spontaneously do not
at risk of ventricular haemorrhage from the heparinised circuits. develop this condition it must be attributed to the respirator support
With these measures the survival rate of preterm infants who but it is controversial whether oxygen toxicity or barotrauma is mainly
develop respiratory distress has been greatly increased and hyaline responsible.70,71 Other factors that have been incriminated include
membrane disease is now seen far less frequently. However, there are prematurity, infection, tracheal intubation, patency of the ductus
cardiopulmonary complications of such treatment. Immediate com- arteriosus and fluid overload.
plications of positive-pressure ventilation include interstitial emphy- It represents disordered prolongation of the healing phase of
sema and pneumothorax (see below), while patency of the ductus hyaline membrane disease in which the original damage is augmented
arteriosus and cardiac failure (persistent fetal circulation, see below) by the supportive therapy. Interstitial oedema persists and granulation
may dominate the clinical picture after a few days. Some infants who tissue develops in the walls of the airways and alveoli, progressing to
survive the first weeks of life on ventilator support develop diffuse interstitial fibrosis. The air–blood barrier is thickened and the alveolar
lung disease and die in the succeeding months from extensive capillaries are reduced in number. There is also organisation of the
bronchopulmonary dysplasia (see below). Long-term survivors tend hyaline membranes, and intraluminal fibrosis leads to the oblitera-
to have impaired lung function for some months65,66 and a high tion of many bronchioles. Regenerative hyperplasia is evident in the
incidence of bronchiolitis and pneumonia in infancy.67 Babies epithelium of alveoli, bronchioles and bronchi, often with metaplas-
who recover spontaneously from the respiratory distress syndrome do tic changes (Fig. 2.12). Distal air spaces are lined by cuboidal type II
so completely and suffer none of these pulmonary complications. pneumocytes or atypical elongated cells which represent type II cells

45
 Pathology of the Lungs

Box 2.1  A comparison of the pathological features of

bronchopulmonary dysplasia and chronic lung disease of
prematurity (‘Old and New BPD’)

Bronchopulmonary dysplasia (‘Old BPD’)

Alternating areas of hyperinflation and atelectasis
Severe airway epithelial lesions (hyperplasia and squamous
metaplasia)
Decreased internal surface area and alveoli
Airway smooth muscle hyperplasia
Extensive fibroproliferation
Prominent vascular hypertensive lesions
Chronic lung disease of prematurity (‘New BPD’)
Deceased large, simplified alveoli (alveolar hypoplasia, decreased
alveolar complexity)
Negligible airway epithelial lesions
Variable airway smooth muscle hyperplasia
Variable interstitial fibroproliferation
Decreased, dysmorphic capillaries
Less severe vascular hypertensive lesions
Less but more diffuse septal fibrosis

Modified from Coalson76 with permission of Elsevier.

born at about 24–26 weeks’ gestation. The pathological findings in

these children differ sufficiently from the classic picture described
above to warrant the introduction of a new term, chronic lung disease
of prematurity. That the features differ from the classic ones described
above should occasion no surprise given the dramatic changes that
take place in the normal lung between 22 and 32 weeks’ gestation.
This period encompasses the change from the canalicular to the sac-
cular phase of lung development and the changes represent disrupted
alveolar and capillary development.
Chronic lung disease of prematurity is characterised by large simple
air spaces lined by undifferentiated cuboidal cells and separated by
cellular fibroelastic septa of even thickness. Mean linear intercept
counts are low, indicating reduced numbers of air spaces and arrested
alveolar development. The squamous metaplasia and alternating areas
of collapse and overinflation seen in bronchopulmonary dysplasia
are not well represented in chronic lung disease of prematurity
(Box 2.1).75,76

Figure 2.13  Bronchopulmonary dysplasia. Solid areas of collapse and Surfactant dysfunction disorders
fibrosis alternate with lighter distended areas. (Courtesy of Dr W Geddie,
formerly of Toronto, Canada.) The surfactant deficiency underlying the great majority of cases of the
infantile respiratory distress syndrome (hyaline membrane disease) is
attributable to immaturity of the lung but the syndrome is also seen
differentiating into type I. Severe squamous metaplasia is often in a few mature babies who have an inherited defect in surfactant
evident in the larger airways. The epithelial changes resolve with time production.77 To date, three such conditions have been identified in
and in babies who survive longer than 3 months the changes are more humans, respectively involving surfactant proteins B and C and an
marked in the lung parenchyma. The changes are often patchy and integral membrane protein known as ABCA3 (Table 2.2).78
consist of fibrotic airless areas of lung tissue alternating with distended The best known is that involving faults in surfactant protein B syn-
or even emphysematous areas (Fig. 2.13). Fibrosis predominates in thesis.79–82 Various mutations of the surfactant protein B gene have
babies who die in the first 2 months and emphysema in those who been identified, resulting in considerable molecular and phenotypic
survive a year or more.72 Long-term survivors generally have impaired variability.83–85 These babies may die with hyaline membrane disease
lung function.73 They also show hypertrophy of the right ventricle.74 or bronchopulmonary dysplasia or survive the neonatal period only
These may be considered the classic features of bronchopulmonary to develop changes that resemble pulmonary alveolar proteinosis,
dysplasia, as described in infants born at about 32 weeks’ gestation. desquamative interstitial pneumonia or cholesterol pneumonitis
However, with improved therapy most such babies now survive and together with type II cell hyperplasia, features that overlap with those
autopsy is today largely limited to extremely immature infants, those of chronic pneumonitis of infancy, described below.79,86 It seems likely

46
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Table 2.2  Surfactant dysfunction disorders78

Surfactant Surfactant ABCA3 Others?

apoprotein-B apoprotein-C

Genetic Autosomal recessive Autosomal dominant, Autosomal recessive Unrecognised

inheritance sporadic
Chromosome 2p12-11.2 8p21 16p13.3 Unrecognised
Clinical Neonatal respiratory Infants and older Neonatal and early infantile Unexplained neonatal or infantile
features failure and death children with respiratory failure. Some respiratory failure
respiratory failure cases reported of older
children with pattern similar
to adult desquamative
interstitial pneumonia
Lung Alveolar type II cell Variety of patterns Alveolar type II cell Endogenous lipid pneumonia, cholesterol
histology hyperplasia and including hyperplasia, accumulation pneumonitis, alveolar proteinosis,
alveolar proteinosis, desquamative, usual of macrophages and chronic pneumonitis of infancy,
interstitial inflammation or non-specific proteinaceous material in desquamative interstitial pneumonia or
and fibrosis interstitial pneumonia air spaces non-specific interstitial pneumonia

that in protein B deficiency the alveolar proteinosis is due to excessive by the Hermansky–Pudlak syndrome described on page 491, and the
amounts of surfactant being secreted in order to compensate for its pale ear mouse, which provides an animal model of the human
defective protein content. As in autoimmune alveolar proteinosis, syndrome, where it appears that faulty production of surfactant
there is an initial stage of endogenous lipid pneumonia, representing protein A leads to the development of giant lamellar bodies and pul-
macro­phage ingestion of the excess surfactant. Electron microscopy monary fibrosis.106,107
shows abnormal type II cell inclusions: these lack their normal
whorled lamellae and resemble those described in mice in which the
surfactant protein B gene has been disrupted.87,88 The diagnosis of Chronic pneumonitis of infancy
surfactant protein B deficiency may be established by immunostaining Chronic pneumonitis of infancy represents a pattern of disease first
bronchoalveolar lavage material or lung tissue for the various sur- described in full-term infants of either sex whose mothers experienced
factant proteins and thereby demonstrating an absence of surfactant uncomplicated pregnancies and deliveries.108 The infants are normal
protein B and increased amounts of surfactant protein A. at birth but cough, respiratory distress and a failure to thrive develop
Abnormalities involving surfactant protein C have also been at ages varying from 2 weeks to 11 months (average 3.6 months).
reported,89 again with considerable phenotypic variation.90 Most Radiographs show a predominantly interstitial pattern of opacifica-
patients have been neonates or infants but some have been older tion. The prognosis is variable: some of the children recover spontane-
children or adults. Young children generally show the changes of ously whereas others die of respiratory failure within 3 months of the
chronic pneumonitis of infancy described below,91 but some show onset of symptoms.
alveolar proteinosis whilst other cases have been adults displaying The aetiology is unknown and may be multifactorial. It has been
histological patterns of usual desquamative or non-specific interstitial suggested that the condition represents recurrent or poorly cleared
pneumonia.90 infection108 but there is no firm evidence of this. The changes within
An absence of surfactant lamellar bodies from type II alveolar cells the air spaces often resemble those of alveolar proteinosis, suggesting
in term infants who develop respiratory distress soon after birth rep- that causes of this disease in infancy such as surfactant protein
resents a further genetic error in surfactant production, one involving B or C deficiency, as described above, and lysinuric protein intoler-
an integral membrane protein known as ABCA3.92–95 This is an ATP- ance109–111 may be responsible. Gastro-oesphageal reflux with aspira-
binding cassette protein, one of several concerned in transmembrane tion is another possibility.
delivery of a variety of substances, including lipids. In the lung it has Biopsy shows alveolar wall thickening with a variety of air space
been localised to the limiting membrane of the surfactant lamellar abnormalities. There is little inflammation. The alveolar wall thicken-
bodies. ABCA3 deficiency is associated with a histological pattern of ing is due to interstitial spindle cell proliferation and type II epithelial
desquamative interstitial pneumonia, non-specific interstitial pneu- cell hyperplasia. Collagen is not a feature in the early stages but the
monia, endogenous lipid pneumonia, alveolar proteinosis or, rarely, disease may progress to interstitial fibrosis. Within the alveolar lumen,
usual interstitial pneumonia.92,93,96,97 A variant of ABCA3 deficiency is macrophages are increased and there is often an accumulation of
characterised by the presence of abnormal lamellar bodies that granular eosinophilic material in which acicular cholesterol crystal
have been likened to fried eggs.98 Genetic studies have subsequently clefts may be seen. The macrophages may have foamy cytoplasm
identified ABCA3 deficiency in older children and young adults with (Fig. 2.14).
a variety of obscure interstitial lung diseases.95,99
It is likely that children reported in the older literature as showing
a combination of endogenous lipid pneumonia, cholesterol granulo- Cellular interstitial pneumonitis and
mas and alveolar proteinosis of obscure etiology represented further
pulmonary interstitial glycogenosis
cases of abnormal surfactant production, possibly due to as-yet
unrecognised defects.100–105 Deficiency of surfactant protein A has Cellular interstitial pneumonitis shows less marked interstitial
not yet been firmly established in humans but may be represented thickening, type II cell hyperplasia and alveolar filling than chronic

47
 Pathology of the Lungs

Figure 2.15  Pulmonary interstitial glycogenosis. The alveolar interstitium

is expanded by cytologically bland round cells with clear cytoplasm. These
changes are seen in other paediatric disorders and pulmonary interstitial
Figure 2.14  Chronic pneumonitis of infancy. The alveolar walls are glycogenosis is only diagnosed if these interstitial changes predominate.
thickened by immature connective tissue cells; there is little interstitial
inflammation. Type II pneumocytes are hyperplastic and there is focal
proteinaceous debris in alveoli.
Microscopically the differential diagnosis is from congenital lym-
phangiectasia (see p. 77). This can be extremely difficult, not least
because the air tracks within lymphatics as well as the surrounding
pneumonitis of infancy and appears to have a better prognosis. connective tissue.125 It is therefore helpful if the nature of the content
However, whether this means that the two represent separate condi- of the cysts, gaseous or fluid, is ascertained at necropsy. If the emphy-
tions91 or are variations of one112,113 is debatable. sema has been present for a few days before death the diagnosis is
Some of those that distinguish cellular interstitial pneumonitis and simplified by the development of a foreign-body giant cell reaction to
chronic pneumonitis of infancy equate the former with what has been the air (Fig. 2.18). The presence of interstitial emphysema has been
described as pulmonary interstitial glycogenosis,91 a term that was used forensically as evidence of live birth.126
coined when vacuoles in the interstitial cells were shown to represent
glycogen (Fig. 2.15).114 Such glycogenosis appears to be self-limiting115
and may be merely an epiphenomenon, as interstitial cells with clear Persistent tachypnoea of infancy associated
cytoplasm are not infrequently seen in association with other disor- with neuroendocrine cell hyperplasia
ders such as antibody deficiency116 and alveolar capillary dysplasia.117
The term ‘glycogenosis’ is unfortunate as it usually refers to an inborn Neuroendocrine cell hyperplasia was identified by immunostaining
error of glycogen metabolism due to enzyme deficiency for which for bombesin when it was decided to review the archival tissue of a
there is no evidence in this condition: the term ‘pulmonary interstitial group of infants less than 2 years of age who had presented with
glycogen accumulation disorder’ is therefore preferred by some persistent tachypnoea, hypoxia, rib retraction or respiratory crackles,
authors.118 and had had a lung biopsy reported as showing seemingly insignifi-
cant non-specific changes (Fig. 2.19). These infants showed an
increased number of neuroendocrine cells compared to a group of
Interstitial emphysema controls.127 The mean onset of symptoms was 3.8 months (range,
0–11 months). Radiographs demonstrated hyperinflation, interstitial
This condition is a form of barotrauma and in infancy is often a markings and ground-glass densities. Oxygen was initially required
complication of mechanical ventilation. High ventilatory pressures for prolonged periods, and medication trials did not eliminate symp-
rupture the alveolar walls and permit air to enter the interstitial tissue. toms. After a mean of 5 years, no deaths had occurred, and the
The air is seen particularly in the abundant connective tissue that sur- patients’ condition had improved. It was suggested that these infants
rounds the pulmonary artery and bronchiole in the centre of the represented a distinct group of patients defined by the absence of
acinus and forms the interlobular septa. Lines of bubbles are seen known lung diseases, the clinical signs and symptoms of interstitial
through the pleura, outlining the lung lobules. Blebs may project from lung disease and idiopathic neuroendocrine cell hyperplasia of
the pleura, and cyst-like spaces up to 3 cm in diameter are found on infancy. More reports are awaited.
the cut surface of the lung (Figs 2.16 and 2.17).119–121 Pneumothorax
and surgical emphysema of the mediastinum and neck frequently
accompany interstitial emphysema. The air may track into the other Persistent fetal circulation (persistent
serosal cavities causing pneumopericardium or pneumoperitoneum.
pulmonary hypertension of the newborn)
Rarely, large subpleural cysts develop.122 In some cases the changes
resolve spontaneously whereas in others they persist and may require In this condition the high pulmonary blood pressure of the fetus fails
excision of affected tissue.123,124 to fall at birth and right-to-left shunting through the foramen ovale

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 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.17  Interstitial emphysema. Air-filled spaces are seen in the

interlobular septa.

Figure 2.18  Interstitial emphysema. Within a few days the cysts are lined
by a foreign-body giant cell reaction to the air.

not normally muscular.129 The condition may be idiopathic or second-

ary to a wide variety of neonatal cardiopulmonary disorders, including
hyaline membrane disease, asphyxia, meconium aspiration and dia-
phragmatic hernia. The idiopathic cases are poorly understood but
autopsy has shown that some are secondary to alveolar capillary dys-
plasia (see p. 50) that was undetected until autopsy,130,131 whilst others
show alveolar dysplasia with good capillary growth.117 All these under-
lying causes reduce the stimuli that normally initiate pulmonary vas-
cular dilatation at birth, namely pulmonary expansion, raised
pulmonary oxygen tension and lowered pulmonary carbon dioxide
B tension. Notable amongst the agents that mediate the vasodilatation
is nitric oxide (endothelium-derived relaxation factor – see p. 22), and
the inhalation of low levels of this gas appears to reverse the hypox-
Figure 2.16  Interstitial emphysema. (A) Lines of air bubbles are seen
through the pleura, outlining the lung lobules. (B) Cyst-like spaces are aemia of persistent pulmonary hypertension of the newborn.132,133
seen on the cut surface of the lung.

Diffuse developmental lung disorders

and ductus arteriosus continues in neonatal life.128 The incidence of
the condition is about one in 1000 live births and prior to the intro- Three conditions come under this heading: congenital acinar dyspla-
duction of nitric oxide therapy the mortality was about 50%. Autopsy sia, congenital alveolar dysplasia and alveolar capillary dysplasia with
studies show that the muscular pulmonary arteries have a thickened misalignment of pulmonary veins. The abnormality in each is one
media and that muscle extends into small peripheral arteries that are of arrested development, the first at the pseudoglandular phase of

49
 Pathology of the Lungs

A B

Figure 2.19  Neuroendocrine cell hyperplasia of infancy. (A) A small airway showing only minimal chronic inflammation on routine staining but
(B) staining for bombesin shows increased numbers of neuroendocrine cells within the surface epithelium.

development, the second at the canalicular or early saccular phase and Congenital alveolar dysplasia
the third involving the vascularisation of the acinus so that capillaries
Congenital alveolar dysplasia was first described in 1948, since when
remain close to their supplying artery in the centre of the acinus and
there have been few further reports.140 The condition is characterised
veins also develop in this position rather than in the interlobular
by poorly developed air spaces separated by varying degrees of undif-
septa.117,134
ferentiated mesenchyme that may histologically resemble pulmonary
These disorders of development have to be distinguished from
intersitital glycogenosis. Features of persisitent pulmonary hyperten-
several other conditions that affect the neonatal lungs in a diffuse
sion may also be present. It is generally incompatible with an extra­
manner. A useful classification of them has recently been promulgated
uterine existence but some children survive the neonatal period
by a North American consortium, dividing them into the diffuse
despite severe respiratory embarrassment.117
developmental disorders now to be considered, acquired growth
abnormalities, specific conditions of undefined etiology and sur-
factant dysfunction disorders (Table 2.3).134 Alveolar capillary dysplasia with misalignment of
pulmonary veins
Alveolar capillary dysplasia with misalignment of pulmonary veins
Congenital acinar dysplasia represents a failure of capillaries and veins to migrate away from
Congenital acinar dysplasia is the rarest and most severe condition of the centres of the primitive lung acini. It is an unusual cause of per­
the diffuse developmental lung disorders, being characterised by a sistent pulmonary hypertension and respiratory distress of the
complete absence of acinar development. The affected babies, who newborn.117,130,141–146 Cases reported to date have all been fatal, with
may be born at term or premature, are cyanosed from birth and survival generally not exceeding a few hours. Many cases show associ-
survive only a few hours.136–138 They usually have other abnormalities, ated gastrointestinal or genitourinary malformations. Occasionally,
such as cardiovascular anomalies, dermal hypoplasia and renal hypo- siblings are affected and an autosomal-recessive genetic abnormality
plasia. The lungs are small and firm throughout. Microscopically, has been demonstrated in some cases.145,147
bronchial-type airways that have cartilage, smooth muscle and glands The pulmonary lobules are small and radial alveolar counts are
are separated by abundant mesenchymal tissue. No alveoli are seen decreased. The alveolar septal connective tissue is increased and alveo-
(Fig. 2.20).139 An absence of TTF-1, which is implicated in respiratory lar capillaries are greatly reduced (Figs 2.21 and 2.22). Those present
epithelial differentiation, is reported and occasionally siblings are are in poor contact with the alveolar epithelium, which shows type II
affected, suggesting that the condition has a genetic basis. It is referred cell hyperplasia.117 The pulmonary veins accompany small pulmonary
to again on page 59. arteries in the centres of the acini rather than occupying their normal

50
tahir99-VRG & vip.persianss.ir
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Table 2.3  Diffuse parenchymal disorders of infancy134

Disorders

Primary disorders of lung development 5.8%

(aberration in primary molecular mechanism of lung  
and/or pulmonary vascular development)
Congenital acinar dysplasia
Congenital alveolar dysplasia
Alveolar capillary dysplasia with misalignment of
pulmonary veins
Growth abnormalities reflecting deficient alveolarisation 24.6%
(usually secondary)
Pulmonary hypoplasia
Chronic lung disease of prematurity
Specific conditions of undefined aetiology
Pulmonary interstitial glycogenosis 3.2%
Neuroendocrine cell hyperplasia of infancy 9.6%
Surfactant dysfunction disorders 9.6%
Surfactant protein B mutations
Surfactant protein C mutations
ABCA3 mutations
Histology consistent with surfactant dysfunction but as
yet without a recognised genetic etiology:
Alveolar proteinosis
Figure 2.21  Persistent pulmonary hypertension of the newborn in a case
Chronic pneumonitis of infancy of alveolar capillary dysplasia. A pulmonary artery showing marked
Desquamative interstitial pneumonia medial hypertrophy (arrow) is seen within underdeveloped alveoli. The
Non-specific interstitial pneumonia vessel next to the artery is a pulmonary vein: misalignment of pulmonary
Miscellaneous 35.5% vessels is a major feature of alveolar capillary dysplasia.
(e.g. systemic disease processes, immunocompromised
states) position in the interlobular septa (see Figs 2.21 and 2.22B). The pul-
Unclassified 11.7% monary arteries are decreased in number and show increased muscu-
larisation. These changes are more easily appreciated if immunostains
that localise vascular markers such as CD34 are employed.

Tracheobronchomalacia acquired in infancy

Tracheobronchomalacia (softening of the major airways) may be con-
genital or acquired but the two are often confused because the condi-
tion is most commonly acquired as a complication of congenital lung
disease or its treatment, notably intubation.148 This section is con-
cerned with acquired disease. Congenital tracheobronchomalacia is
dealt with below. The acquired disease is seen most commonly in
premature babies who are intubated because of respiratory distress.
Airway infection may also contribute to tracheobronchomalacia being
acquired in infancy. Other causes include pressure from congenital
abnormalities such as pectus excavatum, bronchogenic cyst or an aber-
rant artery. Whatever its cause, tracheobronchomalacia causes undue
collapsibility of the airways and, hence, respiratory obstruction.
Histopathological examination shows fibrous replacement of the tra-
cheobronchial cartilages.

FURTHER DISORDERS OF DEVELOPMENT

AND GROWTH

Anomalies of the larynx and trachea

Figure 2.20  Acinar dysplasia. The lung lobules are composed of irregular Laryngeal atresia
air spaces lined throughout by ciliated columnar epithelium and
separated by abundant loose stroma. (Reproduced from Current Diagnostic This condition is usually due to cartilaginous overgrowth just
Pathology by permission of Dr C Wright, Newcastle-upon-Tyne, UK.139) below the vocal cords leaving only a narrow channel between the

51
tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

Figure 2.23  Tracheal stenosis due to segmental absence of the posterior

membranous portion so that the cartilaginous plates form complete rings
(associated in this patient with an aberrant left pulmonary artery forming
a sling round the trachea, the two abnormalities making a ‘ring–sling’
complex). (Courtesy of Dr M Kearney, Tromso, Norway.)

Tracheal aplasia
With total or partial absence of the trachea, the main bronchi either
communicate only with each other, in which case the lungs are hyper-
plastic, or with the oesophagus.150 A minor degree of tracheal hypo-
plasia, with both the sagittal and coronal diameters being reduced,
may be seen in Down’s syndrome.151 The normal diameters of the
adult trachea are given on page 63 under Mounier-Kuhn’s syndrome
of tracheobronchomegaly, a genetic disorder which generally becomes
B evident in adult life.

Figure 2.22  Alveolar capillary dysplasia. (A) There is a low density of

alveoli. (B) High power shows alveolar septal thickening, scarcity of
alveolar capillaries and misalignment of pulmonary vessels, both artery Tracheal stenosis
(A) and vein (V) lying alongside an airway.
Tracheal stenosis may result from intrinsic or extrinsic lesions, which
may be congenital or acquired. Congenital intrinsic stenosis may take
the form of a gradual tapering, an isolated segmental narrowing or a
membranous web, or be due to a nodule of ectopic oesophageal
pharynx and trachea that is insufficient to permit respiration. tissue.154 Congenital extrinsic compression may be due to various
Viewed from above the larynx appears normal but attempts at intuba- anomalies of the great vessels forming (vascular) rings or a sling
tion are unsuccessful and the baby quickly asphyxiates. In utero around the trachea (see p. 481). The left pulmonary artery sling syn-
diagnosis may be possible because the airway obstruction often drome may form part of a (tracheal) ring–sling complex in which the
causes the lungs to be hyperplastic149 and therefore hyperechogenic, tracheal cartilages form complete rings, the left bronchus is short and
in which case an immediate tracheostomy undertaken before the the right is long (bronchial pseudoisomerism).152 The complete carti-
cord is clamped may prove life-saving. However, the condition is often lage rings represent an absence of the posterior membranous part of
associated with other congenital abnormalities, notably those com- the trachea (Fig. 2.23) and the abnormally long trachea is conse-
prising Fraser’s syndrome. The identification of pulmonary hyperpla- quently narrowed, the stenosis generally being funnel-shaped. This
sia should therefore lead to a search for additional malfor­mations. abnormality is difficult to correct surgically and the prognosis is poor.
Pulmonary hyperplasia is described in more detail on page 70. The trachea normally has 22 cartilages. More are generally seen in the
Laryngeal webs may also be congenital, the majority involving the ring–sling complex and fewer in infants with a congenitally short
anterior glottis. They show a strong association with the velocardiofa- neck. A congenitally short trachea may not be recognised until the
cial syndrome (chromosome 22q11.2 deletion). seventh decade.153

52
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 Development of the lungs; perinatal and developmental lung disease Chapter |2|

A B C

Figure 2.24  Tracheo-oesophageal fistula. The oesophagus has been

opened from the rear to show the orifice of a tracheo-oesophageal
fistula towards its lower end.

Tracheo-oesophageal fistula
The mesodermal separation of those parts of the primitive foregut
destined to become oesophagus and trachea may be incomplete,
resulting in a tracheo-oesophageal fistula (Fig. 2.24). Separation of
trachea and oesophagus normally proceeds in a cephalad direction
and if this is incomplete the two may communicate. Usually the
proximal part of the oesophagus ends in a blind sac and the distal D E
part takes origin from the lower part of the trachea, but the anatomy
Figure 2.25  Tracheo-oesophageal fistula. (A) The arrangement found in
varies (Fig. 2.25). Histological examination shows that abnormalities
87% of cases where the upper oesophagus ends blindly and the lower
in the wall of the trachea extend beyond the fistula; there is often oesophagus joins the trachea. (B–D) Rare variants of tracheo-oesophageal
widespread loss of cartilage and squamous metaplasia.154,155 Tracheal fistula. (E) Oesophageal atresia without fistula.
communication with remnants of the branchial clefts (branchial
cysts) is also recorded.156 Occasionally it is a bronchus that commu-
nicates with the oesophagus.157 Tracheo-oesophageal fistula some-
times forms part of a so-called VACTERL association, which represents
a non-random grouping of birth defects involving mesodermal struc-
tures for which no genetic basis has yet been identified, VACTERL Anomalies of the bronchi and bronchioles
being a mnemonic for vertebral, anal, cardiovascular, tracheo­ Abnormal bronchial branching and
esophageal, renal and limb abnormalities.
pulmonary lobation
The main bronchi may be displaced so that one or both whole lungs
Congenital tracheobronchomalacia arise from the alimentary tract rather than the trachea (Fig. 2.26).150
Tracheobronchomalacia (softening of the major airways) may be con- This often accompanies tracheal agenesis and probably represents a
genital or acquired but the two are often confused because the condi- variety of tracheo-oesophageal fistula, but a bronchobiliary fistula
tion is most commonly acquired as a complication of congenital (connecting the biliary and tracheobronchial trees, usually near the
disease (e.g., cardiovascular abnormalities compressing the airways) carina) may be part of a duplication of the upper alimentary tract from
or its treatment, notably intubation.148,158,159 Acquired tracheobron- the level of the fistula to the ampulla of Vater.161,162 Bile causes intense
chomalacia has been dealt with above (see p. 51) and this section is inflammation of the bronchial tree and in infancy the combination
confined to congenital tracheobronchomalacia, a condition in which of cough with bile-stained sputum forms a distinctive clinical picture
there is softening of the airway cartilages, often as part of a generalised indicative of this type of fistula. An unusual case of bronchial diver-
chondrodystrophy seen in several skeletal dysplasia syndromes, e.g. ticulosis possibly represents abnormal bronchial branching.163
Kneist dysplasia.160 The trachea and bronchi may be affected alone or Abnormalities of the lobar bronchi include a tracheal right upper-
in combination. Other causes of congenital tracheobronchomalacia lobe bronchus, either displaced or supernumerary (Fig. 2.27), a
include the presence of oesophageal remnants in the wall of the double upper-lobe bronchus and an accessory cardiac lobe bronchus
trachea, which is generally seen in association with oesophageal arising from the intermediate bronchus. There is a high incidence of
atresia and tracheo-oesophageal fistula.154 tracheal upper-lobe bronchus in association with the tetralogy of
Tracheobronchomalacia causes undue collapsibility of the airways Fallot.164 A ‘bridging bronchus’ crossing the mediastinum from left to
and, hence, respiratory obstruction. However, as a cause of respiratory right represents origin of the right lower-lobe bronchus from the left
obstruction congenital tracheobronchomalacia is less common than bronchial tree.165
focal absence of airway cartilages, the supposed basis of both congeni- Abnormalities of segmental bronchi include double bronchi to the
tal bronchiectasis (Williams–Campbell syndrome, see p. 62) and apical segment of either upper lobe, origin of the apical segmental
infantile lobar emphysema (see p. 72). bronchus of the right upper lobe from the trachea, either displaced or

53
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 Pathology of the Lungs

Table 2.4  Relative frequency of abnormalities of pulmonary

lobation172

Right Left

Deficient transverse fissure 25% Lingular fissure 25%

Superior accessory fissure 18% Superior accessory 2%
fissure
Medial basal fissure 10% Medial basal fissure 18%
Other 2%

The abnormalities may be complete or partial and in 20% of cases they are
multiple.

of the right or left upper lobes by the azygos and hemiazygos veins
respectively. Absence of a lobe (and its bronchus) is rare.
Bronchopulmonary isomerism represents symmetry of the lungs
and bronchi, with both sides having the pattern of either the normal
right lung or the normal left lung. As emphasised above, lobation is
an unreliable indicator of whether a lung is ‘right’ or ‘left’. This can
however be assessed by examining the extrapulmonary bronchi
and pulmonary arteries. It will be remembered that the right main
bronchus is shorter than the left and enters the lung behind the
pulmonary artery whereas the longer left main bronchus is ‘hyparte-
rial’, crossing behind the main left pulmonary artery to enter the lung
below the artery. Bronchopulmonary isomerism is often associated
with atrial isomerism, anomalous pulmonary veins and abnormalities
of the spleen and liver (Fig. 2.29).164,173 The Ivemark asplenia syn-
drome consists of bilateral right-sidedness with two morphologically
right lungs, absence of the spleen, a symmetrical liver, malrotation of
the gut and a variety of cardiac abnormalities including a common
ventricle, totally anomalous pulmonary veins and bilateral superior
venae cavae and right atria.174 Bilateral morphologically left lungs are
found in association with multiple minute spleens (polysplenia), a
symmetrical liver, malrotation of the gut, partially anomalous pulmo-
Figure 2.26  Origin of main bronchus from the oesophagus. The lungs, nary venous drainage and cardiac septal defects. Either right- or left-
oesophagus and stomach viewed from behind to show the right main sided bronchopulmonary isomerism may be associated with multiple
bronchus arising from the lower oesophagus. (Courtesy of the late Dr AH spleens of varying size (anisopolysplenia). Although non-familial,
Cameron, Birmingham, UK.) Ivemark’s syndrome is confined to males whereas the other isomerism
syndromes may affect either sex.

supernumerary, an absent right upper-lobe apical segmental bronchus

and separate origin of the apical segmental bronchus of the left lower Bronchogenic cyst
lobe from the main bronchus. A crossover lung segment is one with Bronchogenic cysts, recognisable by cartilage and glands in their wall
bronchial and arterial connections from the other side.166–168 Usually and a lining of respiratory epithelium (Fig. 2.30), are a variety of
the crossover is from right to left, the right lung is hypoplastic and the foregut duplication cyst, related to oesophageal and gastroenteric
venous drainage anomalous, a variant of the ‘scimitar’ syndrome (see cysts. They are usually situated in the mediastinum close to the carina
p. 76). These are features that crossover lung segment shares with the (51%) but may be found in the right paratracheal region (19%),
equally rare condition ‘horseshoe’ lung, where there is fusion of the alongside the oesophagus (14%), the hilum of the lung (9%) or a
lungs behind the heart and in front of the oesophagus.168–171 However, variety of other locations (7%), including the substance of the lungs,
unlike ‘horseshoe’ kidney, there is no fusion of the lungs; there are and even beneath the diaphragm.175–181 Occasionally air–fluid levels
separate pleural cavities and the crossover segment lies in a pleural are demonstrated radiographically suggesting a connection with the
recess behind the heart that communicates with the pleural cavity on airways. Cysts lined by respiratory epithelium but lacking cartilage
the side from which the segment derives.167,168 in their walls should be regarded as undifferentiated foregut cysts
Abnormal lobation of the lungs does not imply an abnormal (also termed simple congenital cysts). These differ from type I con-
pattern of bronchial branching: lack or incomplete development of genital cystic adenomatoid malformations as the latter show polypoid
one or more interlobar fissures is common despite the presence of five infoldings, mucous cell hyperplasia and disordered parenchymal
lobar bronchi. Extra fissures separating segments off as extra lobes are growth with smaller cysts resembling bronchioles (see p. 59).
also common, particularly the lingula and the medial basal and apical Con­genital lung cysts are often not discovered until adult life, either
segments of the lower lobes (Table 2.4 and Fig. 2.28).172 Fissures as an incidental radiographic finding or because of complications,
accommodating blood vessels may also be found, so that an azygos which include infection, haemorrhage and, in rare instances, neoplas-
lobe may be formed by the parasagittal separation of the medial part tic transformation.182

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 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.27  (A) Anomalous origin of the right upper-lobe bronchus from the trachea (which has been opened anteriorly), an arrangement that is
normal in the pig, sheep, goat and ox. (Courtesy of the late Dr AH Cameron, Birmingham, UK.) (B) Three-dimensional computed tomography scan of the
same condition TB, tracheal bronchus; C, carina. (Courtesy of Dr Sharon McGrath-Morrow, Baltimore, USA.)

3-lobed 3-lobed 2-lobed 2-lobed

lung lung lung lung

Central liver Central liver

Stomach Stomach

No splenic tissue

Multiple spleens
Figure 2.29  Right- and left-sided isomerism. Note the symmetrical
extrapulmonary bronchoarterial anatomy (compared with the normal
asymmetrical arrangement – see Figs 1.1B, p. 2 and 10.11, p. 482).

being 17 years.184–187 The radiological appearances are virtually diag-

Figure 2.28  Abnormal lobation of the left lung. Extra fissures partly nostic, consisting of an ovoid hilar opacity, most commonly in the
separate the apical segments of both lobes and the complete posterior left upper lobe, with branches radiating out into a distal area of
basal segment of the lower lobe. (Courtesy of the late Dr AH Cameron, hyperinflation.
Birmingham, UK.) The opacity represents a distended, mucus-filled bronchus that is
continuous with the distal airways but has no connection with the
more proximal airways, the corresponding one of which ends blindly.
Other varieties of lung cyst encountered in childhood are listed in
Infection may result in inflammation and fibrosis. The interruption
Box 2.2.183
to the airway may take the form of a membrane, a fibrous cord or a
gap. The distal hyperinflation is due to collateral ventilation and air-
Bronchial atresia trapping. Failure to identify the atresia may lead to the mucous plug-
This anomaly is generally detected radiographically in an asympto- ging being wrongfully identified as allergic bronchopulmonary
matic individual: the age range is therefore wide, with the average age aspergillosis or plastic bronchitis. Bronchial atresia differs from

55
tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

B
Figure 2.31  Aberrant systemic artery supplying an intralobar
Figure 2.30  An intrapulmonary bronchogenic cyst. (A) Gross sequestration. A systemic artery (lower right) enters the lateral aspect of
appearances. On the left the cyst is filled by mucus. On the right the the lung to supply a well-demarcated partly solid and partly cystic
mucus has been removed to show the cyst wall. (Courtesy of Dr M Jagusch, intralobar sequestration. A cystically dilated airway is seen centrally,
formerly of Auckland, New Zealand.) (B) Microscopy shows respiratory consistent with lack of communication with the bronchial tree.
epithelium, cartilage and seromucous glands.

Sequestration
The term ‘sequestration’ indicates that a portion of lung exists without
Box 2.2  Pulmonary ‘cysts’ in infancy and childhood183 appropriate bronchial and vascular connections. Classically, no airway
connects the lesion to the tracheobronchial tree and the blood supply
Developmental Non-developmental
is systemic (Figs 2.31 and 2.32), but the separation may be purely
Bronchogenic cysta Pneumatocoele vascular.189 Alternatively, an ‘airway’ may connect the sequestration to
Sequestration Bronchiectasis the oesophagus or stomach in a complex ‘bronchopulmonary–foregut
Congenital cystic adenomatoid Interstitial emphysema
malformation’,190 or ectopic pancreatic tissue may be present within
malformation Low-grade cystic
the sequestration.191,192 Sequestrations may be associated with a variety
Lobar ‘emphysema’ pleuropulmonary blastoma
of other malformations such as foregut duplications180,192,193 and
Bronchial atresia
venous anomalies such as the scimitar syndrome while the histologi-
Lymphangiectasia
Birt–Hogg–Dubé syndrome
cal features may be those of a congenital adenomatoid malformation
(Fig. 2.33).194–196 There is therefore a spectrum of abnormalities associ-
a
Generally mediastinal rather than pulmonary. Other mediastinal cysts include ated with pulmonary sequestration.197–199 Pathologists dealing with
thymic, pericardial, lymphatic (cystic hygroma), oesophageal, gastroenteric, these malformations should report on all their connections (bron-
neurenteric and teratomatous (‘dermoid’) cysts. chial, arterial and venous) and on the presence of any associated
abnormalities.
Two forms of sequestration are recognised: extralobar, which has
its own covering of visceral pleura, and intralobar, which is embedded
infantile lobar emphysema in that it is focal and does not affect a in otherwise normal lung (Fig. 2.34). The first was called an accessory
whole lobe. The continuity of the cyst with the distal airways and the lobe until Pryce200 described the intralobar variety, related it embryo-
hyperinflation of the distal lung distinguish bronchial atresia logically to accessory lobe and coined the term ‘sequestration’.
from bronchogenic cyst, but the two conditions are occasionally Intralobar sequestrations are much the commoner. The major differ-
associated.188 ences between the two types are summarised in Table 2.5.

56
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.33  Pulmonary sequestration. The sequestered lung tissue is

A poorly developed and resembles a type 2 cystic congenital adenomatoid
malformation.

Table 2.5  Pulmonary sequestration

Intralobar Extralobar
sequestration sequestration

Age at diagnosis 50% over 20 years 60% less than 6 months

(15% asymptomatic) (10% asymptomatic)
Sex ratio (M : F) 1.5 : 1 4 : 1
Typical site Posterior basal Between the left lower
segment of the lobe and the
left lower lobe diaphragm
Arterial supply Systemic Systemic
Venous drainage Pulmonary Systemic
Associated Uncommon (6–12%) Common (50–70%)
B anomalies
Aetiology Uncertain whether Developmental anomaly
Figure 2.32  Arterial supply to an intralobar sequestration. (A) A systemic developmental or
artery forms the predominant blood supply, and a pulmonary artery (left) acquired
shows fibrous obliteration. (B) The same stained for elastin (elastin van
Gieson stain).

and its rarity in perinatal autopsies.202,203 However, although the

Extralobar sequestration is generally detected in infancy because of incidence of associated anomalies is lower than with extralobar
associated malformations and affects males four times more fre- sequestrations (50–70%), it is still appreciable (6–12%),204 and the
quently than females. In contrast, intralobar sequestration is often an rarity of the condition in neonates may be because it is easily over-
isolated anomaly and therefore escapes recognition until adult life, looked until there is cystic degeneration or infection. Advocates of a
and has a male-to-female ratio of only 1.5 : 1.201 congenital aetiology generally propose that accessory lung buds are
Intralobar sequestrations are typically located in the posterior basal fundamental to both forms of pulmonary sequestration and liken
segment of the left lower lobe and extralobar sequestrations beneath them to intestinal duplications,199 but are undecided whether the
the left lower lobe. There is often a defect in the diaphragm and about aberrant systemic arteries play a causative role by pulling on the devel-
15% of extralobar sequestrations are abdominal. The veins leaving an oping lung200 or are merely compensatory to a primary failure of the
extralobar sequestration generally join the azygos or other systemic pulmonary arteries.205 The absence of a bronchial connection has led
veins whereas an intralobar sequestration usually has normal pulmo- some to link sequestration to bronchial atresia, bronchogenic and
nary venous connections. simple congenital lung cysts, infantile lobar emphysema and congeni-
The embryological basis of pulmonary sequestration is poorly tal cystic adenomatoid malformation,197–199 whilst on the basis of
understood. Indeed, some workers believe that the intralobar variety cases in which there is communication with the oesophagus or
is an acquired condition in which the aberrant artery is a dilated stomach it has been proposed that the lesions are congenital foregut
systemic collateral to a focus of infection, basing this on the relative malformations,190,206 attributable to a fault within embryonic organ-
sparcity of malformations associated with this type of sequestration iser centres.207

57
 Pathology of the Lungs

A B

Figure 2.34  Pulmonary sequestration. (A) Extralobar sequestration. The left lung has been reflected to the right to reveal a separate nodule of lung
tissue lying against the ribs. The sequestration is completely detached from the rest of the lung but has a thin pedicle containing systemic blood
vessels through which it is supplied from the aorta. (Courtesy of Dr GA Russell, Tunbridge Wells, UK.) (B) Intralobar sequestration in which the sequestered
lung tissue is cystically dilated. (Courtesy of the late Dr AH Cameron, Birmingham, UK.)

Although there is no bronchial connection, small bronchi may ered and the possibility of unusual blood vessels investigated
be found within the sequestration (see Fig. 2.33). The lung tissue angiographically. Inadvertent severance of anomalous systemic arter-
in the lesion is often poorly developed and cystically dilated (see ies has led to fatal haemorrhage, whilst ligation of anomalous veins
Fig. 2.34b). The cysts are lined by columnar or cuboidal epithelium, from adjacent non-sequestered lung has led to infarction of poten-
or the sequestered lung may be entirely composed of structures tially salvable tissue.
resembling bronchioles surrounded by alveolar ducts and alveoli,
histologically resembling a type 2 congenital adenomatoid malfor-
Congenital cystic adenomatoid malformation
mation in up to 60% of cases (see Fig. 2.33).204,208 Mucus distends
the multiple intercommunicating spaces and the lesion appears solid (congenital pulmonary airway malformation)
radiographically, unless air enters through a bronchial connection or, The term ‘congenital cystic adenomatoid malformation’ encom­
in the case of intralobar sequestration, by collateral ventilation, when passes a spectrum of conditions, the interrelationship of which is
fluid levels are often seen. Features of pulmonary hypertension are contentious. The aetiology of the condition is obscure but a matura-
also frequently present within sequestrations, but this appears to be tion defect is envisaged.209–211
of no clinical significance.208 In the absence of associated anomalies, Early reports date from 1897212 and only in 1949 was the term
detection is unlikely unless a radiograph is undertaken for some ‘congenital adenomatoid malformation’ introduced.213 It was applied
other reason or infection ensues, this being most likely when there is to a newborn infant’s greatly enlarged and apparently airless left lower
air entry. When operation is contemplated for any cystic or suppura- lobe, which microscopically consisted solely of bronchiole-like struc-
tive lesion of the lungs it is important that sequestration be consid- tures so that it had an adenomatoid appearance. Subsequently, cystic

58
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Table 2.6  Congenital cystic adenomatoid malformation (congenital pulmonary airway malformation)

Stocker Proportional Gross appearance Microscopy Other features

type217 incidence

0 1–3% Solid Pseudostratified ciliated Neonates

cells, cartilage, glands, Other malformations
mucous cells Poor prognosis
Also known as congenital acinar dysplasia
1 60–70% Large cysts (up to Pseudostratified ciliated Presentation may be late
10 cm) cells, often with rows of Resectable
mucous cells Good prognosis except for rare carcinomatous change
2 10–15% Small cysts (up to 2 cm) Simple columnar epithelium Neonates
Striated muscle in 5% Other malformations
Poor prognosis
Rare rhabdomyosarcomatous change
3 5% Solid Simple cuboidal epithelium Male neonates
Poor prognosis
4 15% Large cysts (up to Flattened epithelium Neonates, infants
10 cm) Good prognosis
Uncertain relation to pleuropulmonary blastoma

and intermediate (microcystic) varieties were described and the name The five types are compared in Table 2.6 and will now be considered
changed to congenital cystic adenomatoid malformation.209,214–216 individually. Despite the above contentions regarding their interrela-
These were initially numbered I–III but with the addition of two tionships and appropriate classification, their distinction is important
further lesions the numbering switched to 0–4, it being envisaged that because certain varieties carry an albeit low risk of malignant
the spectrum represented malformations of five successive groups of transformation.
airways, type 0 being tracheobronchial and type 4 alveolar.214,217 This
is not wholly convincing because, except for type 4, which tends to
Type 0 congenital pulmonary airway malformation
be peripheral, the lesions are not obviously distributed along the
bronchial pathway. Types 0 and 3 tend to affect a whole lobe or lung. (acinar dysplasia)
Furthermore, although cartilaginous airways are a prominent feature This rare form of the anomaly is incompatible with life, being seen in
of the type 0 (‘tracheobronchial’) lesion, the complete absence of term or premature babies who are cyanosed at birth and survive only
bronchioles and alveoli cannot be overlooked. Previous workers con- a few hours.136–138 It is described on page 50 under its older title of
centrated upon the undifferentiated stroma that separates the carti- congenital acinar dysplasia.
laginous airways and preferred the term ‘acinar dysplasia’, implying a
developmental error affecting the periphery of the lung rather than Type 1 congenital pulmonary airway malformation
the central airways, a view with which we concur.136,218,219
(cystic type of congenital cystic adenomatoid
A further development is the proposed introduction of the term
‘congenital pulmonary airway malformation’ in place of congenital malformation)
cystic adenomatoid malformation. This is advocated because only This is the commonest type and the one with the best prognosis as it
types 1, 2 and 3 are adenomatoid and only types 1, 2 and 4 are is a localised lesion that typically affects only part of a lobe and lends
cystic.217 itself to surgical resection. The boundary between the lesion and the
An alternative view is that types 0, 3 and 4 all represent adjacent normal lobe is sharply delineated but there is no capsule.
different pathogenetic processes: congenital acinar dysplasia (type 0), Presentation usually takes the form of neonatal respiratory distress
pulmonary hyperplasia (type 3) and regressed type 1 pleuropulmo- but the condition may be detected in utero by ultrasonography229 and
nary blastoma (type 4).220,221 This reduces the five types to two, the surgery undertaken soon after birth. Alternatively, recurrent infections
commoner types 1 and 2, for which the term ‘congenital cystic adeno- in older children or even young adults may prompt initial investiga-
matoid malformation’ remains appropriate. Many examples of these tion.230 Radiographically, air-filled cysts that are usually limited to one
have now been reported.209,214,215,222–226 lobe compress the rest of the lung, depress the diaphragm and cause
Some workers envisage an even wider ‘sequestration spectrum’ mediastinal shift.
encompassing both sequestration and congenital cystic adenomatoid The cysts range in size from 1 to 10 cm (Figs 2.35 and 2.36). The
malformation199 and others extend this by adding bronchial atresia, relevant bronchus is often atretic,198,222,223,227,231,232 yet the cysts are
bronchogenic cysts, simple foregut cysts and infantile lobar emphy- usually radiolucent, presumably due to collateral ventilation. They are
sema.198 Congenital cystic adenomatoid malformation is also associ- lined by pseudostratified ciliated columnar epithelium, sometimes
ated with abnormalities of the bronchial tree on occasion.227 Examples interspersed with rows of mucous cells (Fig. 2.37).217 The type 1 ade-
of extralobar sequestrations containing tissue with the distinctive fea- nomatoid malformation is occasionally complicated by malignant
tures of congenital cystic adenomatoid malformation strengthen the change, nearly always to a mucous adenocarcinoma of lepidic
proposed link between these two conditions (see Fig. 2.33).194,195,228 pattern.233–239 Mucous cell proliferation within the cyst is regarded as

59
 Pathology of the Lungs

Figure 2.37  Congenital cystic adenomatoid malformation – type 1 cystic

variety. In places the respiratory epithelium is replaced by a row of
mucous cells.

Figure 2.35  Congenital cystic adenomatoid malformation – type 1

cystic variety. The right lung is enlarged, causing mediastinal shift to  
the left and hypoplasia of the left lung. (Courtesy of Dr GA Russell, hyperplasia whereas extensions of this process into the adjacent
Tunbridge Wells, UK.) alveoli, where it assumes a lepidic growth pattern, is taken to represent
carcinoma (Fig. 2.38).226 However, this division is wholly arbitrary
and genetic studies have shown chromosomal aberrations in the
mucous cells both within and beyond the cyst similar to those seen
in adenocarcinomas encountered in non-smokers.238,240 As would be
expected of a localised adenocarcinoma of lepidic pattern, survival
following excision is good and metastasis is exceptional.241 Numbers
are too small to give a precise estimate of the risk of malignant trans-
formation but extension of the mucinous cells beyond the cyst wall
is probably seen in no more than 1–2% of cases.
The complex cystic nature of the malformation and sparsity of
bronchial cartilage in the walls of cystic spaces distinguish this lesion
from bronchogenic cyst. The distinction from intralobar sequestration
may be difficult but a systemic blood supply indicates sequestration.

Type 2 congenital pulmonary airway malformation

(intermediate type of congenital cystic
adenomatoid malformation)
This is the second most frequent type. It generally involves only one
lobe but nevertheless usually causes respiratory distress in the first
month of life. Associated anomalies such as renal agenesis, cardiovas-
cular defects, diaphragmatic hernia and syrenomelia often have a
further adverse effect on the prognosis but occasional cases present
later in childhood with infection.230 It is often identified within
extralobar sequestrations (Figs 2.33, 2.39).194,196,228 The lesion is
sponge-like, consisting of multiple small cysts measuring up to 2 cm
and solid pale tumour-like tissue (Fig. 2.39). Microscopically the cysts
are seen to comprise an excess of dilated structures resembling bron-
chioles separated by poorly developed alveoli or alveolar ducts (Fig.
2.40).217 Occasional examples contain striated muscle, which if exten-
sive has been termed rhabdomyomatous dysplasia.217,242,243

Type 3 congenital pulmonary airway malformation (solid

type of congenital cystic adenomatoid malformation)
This uncommon type occurs almost exclusively in male babies. Some
consider it to be the original congenital adenomatoid malformation
described in 1949213,217 whereas others view it as a form of pulmonary
hyperplasia similar to that seen in laryngeal atresia.220 It is a large,
Figure 2.36  Congenital cystic adenomatoid malformation – type 1 cystic bulky lesion that typically involves and expands a whole lobe, the
variety. (Courtesy of Professor LJ Holloway, formerly of Wellington, New Zealand.) others being compressed and the mediastinum displaced. The result-

60
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.39  An extralobar sequestration with the structure of a

congenital cystic adenomatoid malformation – type 2 microcystic variety.
The sequestered lobe has the spongy appearance of this pattern of
adenomatoid malformation. The cord-like structure entering from bottom
right is an aberrant systemic artery from the descending aorta.
(Reproduced from Current Diagnostic Pathology by permission of Dr C Wright,
Newcastle-upon-Tyne, UK.139)
B

Figure 2.38  Adenocarcinoma complicating congenital cystic

adenomatoid malformation – type 1 cystic variety. (A) A high-resolution
computed tomograph of a long-standing type 1 congenital adenomatoid Type 4 congenital pulmonary airway malformation
malformation shows foci of consolidation in the ipsilateral lung adjacent This relatively uncommon type typically presents as infantile respira-
to the cyst, with additional nodules of consolidation on the opposite
tory distress or repeated pneumonia in childhood, but may occasion-
(right) side. (B) Biopsy of the right side shows mucinous adenocarcinoma
ally present in adult life.226 Radiographically, large air-filled cysts are
of lepidic pattern.
seen with compression of the other thoracic structures and occasion-
ally pneumothorax. The cysts are peripheral and thin-walled. They are
lined by alveolar or bronchiolar epithelial cells resting upon loose
ant venous compression usually causes the mother to suffer from mesenchymal tissue (Fig. 2.42). Occasionally the stroma is focally
hydramnios and the baby from generalised anasarca.229 It also results hypercellular and one underwent malignant change to recur as a high-
in hypoplasia of the remaining pulmonary tissue. The prognosis is grade pleuropulmonary blastoma.244 At present the interrelationship
dependent upon the amount of unaffected lung and hence on the size of these two conditions is uncertain and some now advocate classify-
of the lesion. Microscopically, bronchiolar structures separated by air ing lesions of type 4 congenital cystic adenomatoid malformation
spaces that are small, have a cuboidal lining and resemble late fetal morphology with any degree of hypercellularity as type 1 pleuropul-
lung, are seen (Fig. 2.41). There are virtually no arteries within monary blastomas,226,245 with those lacking any blastematous compo-
the lesion.217 Unlike the preceding types there is little or no cystic nent being viewed as regression of the malignant elements of the
change. tumour.221

61
 Pathology of the Lungs

Figure 2.40  Congenital cystic adenomatoid malformation – type 2.

There is an excess of bronchioles, which are separated by poorly
developed alveolar tissue. This pattern is also sometimes seen in
sequestrations (see Figs 2.33 and 2.39). Figure 2.42  Congenital pulmonary airway malformation type 4.
The cysts are thin-walled and multiloculated. They are lined by alveolar  
or bronchiolar cells resting upon loose mesenchymal tissue.

bronchoarterial bundles to involve the pleura and interlobular septa.

It is suggested that it develops from the condensed mesenchyme that
surrounds the proximal bronchi at about the 12th week of intra­
uterine development. The condition is probably akin to other organ-
specific lesions that are collectively termed fibromatoses of early
infancy,249 rather than representing a neoplasm or hamartoma, as
implied by some of the other terms that have been applied – congeni-
tal leiomyosarcoma, bronchopulmonary fibrosarcoma, massive con-
genital mesenchymal malformation. The lesion has no metastatic
capability and outcome depends entirely upon resectability.
The histological appearances are characteristic. They show interlac-
ing bundles of spindle cells surrounding the bronchovascular bundles
and extending into the interlobular septa and occasionally the
pleura (Fig. 2.43). Foci of hypercellularity, necrosis, calcification and
cartilaginous differentiation may be seen but there is no atypia.
Immunohistochemistry is positive for vimentin and may be focally
Figure 2.41  Congenital cystic adenomatoid malformation – type 3 solid positive for smooth-muscle actin, muscle-specific actin and desmin.
variety. Densely packed irregular air spaces are lined by cuboidal
Electron microscopy supports a myofibroblastic derivation.
epithelium. (Reproduced from Current Diagnostic Pathology by permission of Dr C
Wright, Newcastle-upon-Tyne, UK.139)

Congenital bronchiectasis
Fetal surgery for congenital cystic Several congenital defects lead to the development of bronchiectasis
after birth. These are dealt with in the next section. Conditions
adenomatoid malformation
characterised by bronchiectasis at birth are less numerous but the
Uterine ultrasound is now routine in many obstetric practices and on Williams–Campbell syndrome possibly falls into this category.
occasion it detects a chest mass. Such lesions are prone to change
character with time and even regress246 but those that enlarge are often
referred for fetal surgery because they lead to mediastinal shift, cardiac Williams–Campbell syndrome
compression and hydrops. Many are cystic but pathologists dealing This syndrome is characterised by bilateral diffuse cylindrical bron-
with the excised lesions report difficulty in applying the above five- chiectasis associated with deficiency of bronchial cartilage.252–254 There
part classification.247,248 Subdivision of these fetal lesions does not is also panlobular alveolar distension. The deficiency is similar to that
appear warranted at present. found in infantile lobar emphysema (see p. 72) but more widespread.
Secondary infection leads to chronic inflammation and bronchiolitis
obliterans, and hence confusion with the Swyer–James or Macleod
Congenital peribronchial myofibroblastic tumour syndrome of hyperlucent lung which, as explained on page 73, is
This rare lesion is found in the newborn, sometimes causing heart probably postinfective. The occasional association of other congenital
failure or hydrops fetalis.249,250 It forms a localised mass that shows a abnormalities,255 its early onset and rare instances of the disease in
characteristic peribronchial infiltrate of spindle cells of mixed smooth siblings all favour a congenital deficiency.256,257 The most convincing
muscle and fibroblast phenotype. The proliferation spreads from the cases are those in which there is only minimal inflammation.

62
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

A B

Figure 2.43  Congenital peribronchial myofibroblastic tumour (A and B). Interlacing bundles of myofibroblasts surround the bronchovascular bundles
and extend into the interlobular septa. (Courtesy of Dr M Ashworth, London, UK.)

Anomalies promoting bronchiectasis absence of the embryonic nodal monocilia that normally control the
direction of flow of extraembryonic fluid.275,276 The term ‘immotile
in later life
cilia syndrome’ was introduced to encompass all patients with a devel-
Certain familial diseases predispose to recurrent respiratory infections opmental ciliary defect, regardless of their visceral anatomy, but later
and hence bronchiectasis. The bronchiectasis develops after birth but the term ‘primary ciliary dyskinesia’ was substituted because the cilia
the basic defect is congenital. These conditions are tracheobron- show some movement although they do not beat effectively.277–279 The
chomegaly (Mounier-Kuhn’s syndrome), Kartagener’s and other condition is inherited as an autosomal recessive with variable pene-
primary ciliary dyskinesia syndromes (including polycystic kidney trance and to date two gene mutations that result in dynein arm
disease), Young’s syndrome and cystic fibrosis. Apart from these con- defects have been identified, one affecting the DNA11 gene located
ditions, which will now be considered, bronchiectasis may be caused on bands 9p13 to 9p21 and the DNAH5 gene located on chromosome
by many of the primary immune deficiencies258 and is recorded in a 5p.280,281 A third gene defect, involving the DNAH11 gene on band
young adult with homozygous α1-antitrypsin deficiency,259 which is 7p21, has been identified in patients with primary ciliary dyskinesia
more often associated with emphysema. whose cilia show no ultrastructural abnormalities but are
inflexible.282,282a
As well as dynein arm defects, primary ciliary dyskinesia may
Mounier-Kuhn’s syndrome (tracheobronchomegaly
be caused by absence of ciliary spokes, transposition of one of the
or trachiectasis) outer microtubular doublets of the cilium to replace the central
In this rare disease the major airways are dilated by saccular bulges pair, random ciliary orientation or abnormally long cilia (Fig. 2.44B–
between the cartilages, and bronchial clearance is impaired, resulting D).283–288 The relative frequency of these abnormalities is shown in
in recurrent respiratory infection.260–265a It generally becomes manifest Table 2.7. These primary ciliary defects must not be confused with
between the ages of 30 and 50 years, and occurs predominantly in acquired ciliary abnormalities, such as compound or cystic cilia,
males.266 A congenital connective tissue defect with autosomal- which commonly result from infection or chemical injury (Fig.
recessive inheritance is suggested.267 This is supported by the occa- 2.44E).289 More recently described primary ciliary defects289–291 require
sional association of Mounier-Kuhn’s syndrome with Ehler–Danlos further evaluation.
syndrome,268 cutis laxa269 or Kenny–Caffey syndrome.270 When con- Sperm tails have a similar structure to cilia and dynein arm defects
sidering the diagnosis it is useful to know that in the normal adult often result in affected males being infertile due to immotility of their
the maximum transverse diameters of the trachea and main bronchi spermatozoa.292,293 Female fertility also appears to be impaired, but
are 20 and 14.5 mm respectively.271 the incidence of ectopic pregnancy does not appear to be increased.294
Some patients are more concerned with their infertility than their
respiratory problems, which may be relatively minor.
Kartagener’s syndrome and primary ciliary dyskinesia
The various primary abnormalities are not clearly evident in every
The triad of situs inversus, bronchiectasis and sinusitis was first ciliary profile and their recognition requires rather tedious electron
described in 1904272 but its usual eponym, Kartagener’s syndrome, microscopic quantitation.295–298 This is only justified if functional
derives from the Swiss paediatrician who described four cases with studies are abnormal. These include (i) the saccharine test, in which
these features in 1933.273 The syndrome was given a firm pathogenetic a saccharine particle is placed on the anterior end of the inferior tur-
basis when it was recognised that in many cases the respiratory infec- binate and the time taken for the patient to notice the taste is recorded,
tions were the consequence of a developmental anomaly consisting (ii) in vitro assessment of ciliary beat frequency, suitable cells for
of a reduced number of ciliary dynein arms (Fig. 2.44).274 Roughly which may be obtained by brushing the back of the nose; and (iii)
half the patients with dynein arm defects do not have situs inversus, the assessment of nitric oxide emanating from the nasal sinuses; low
indicating random lateralisation of the viscera, which is attributed to levels of this gas in the exhaled breath are characteristic of primary

63
 Pathology of the Lungs

A B C

Figure 2.44  Ciliary ultrastructure. (A) Normal: an axial pair of microtubules is connected by radiating spokes to nine outer double microtubules (9 + 2
arrangement). Small dynein arms extend from one outer microtubule to one in the adjacent pair. The dynein arms are involved in the outer double
microtubules sliding on each other and thereby causing the cilium to beat. (B–D) Ciliary dyskinesia syndromes: (B) absent dynein arms; (C) absent
spokes; (D) transposition of one of the nine outer doublets to replace the central pair of microtubules, which is absent, so that there are only eight
doublets in the outer ring. (E) Compound cilia, a secondary focal abnormality that is to be distinguished from the diffuse congenital abnormalities of
the ciliary dyskinesia syndromes. (Courtesy of Professor P Cole and Miss A Dewar, Brompton, UK.)

64
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Table 2.7  Abnormal ciliary ultrastructure identified in 275 Table 2.8  Frequency of cystic fibrosis and the carrier state in
patients with primary ciliary dyskinesia at the Brompton different populations
Hospital 1988–2008 (unpublished data provided by Dr Amelia
Shoemark, Brompton, UK) Race Homozygotes Heterozygotes

Ciliary defect n % UK white 1 : 2500 1 : 25

US white 1 : 3500 1 : 30
Outer dynein arm defect 105 38
Sweden 1 : 7700 1 : 45
Outer and inner dynein arm defect 57 21
US black 1 : 14 000 1 : 60
Inner dynein arm defect 30 11
US Asian 1 : 25 500 1 : 80
Transposition defect 28 10
Radial spoke defect 22 8
No ultrastructural abnormality 33 12
persistence of the condition is puzzling. It suggests that there is either
a high mutation rate or the heterozygotes carry some advantage, either
in reproductive fitness or resistance to other diseases. One possibility
is that the defect minimises dehydration when severe diarrhoeal dis-
ciliary dyskinesia.278,299–302 Where possible, ultrastructural studies eases are contracted.306
should be conducted on more than one occasion or on ciliated cells The gene responsible for cystic fibrosis is located on the long arm
from different organs,303 whilst in adult men, sperm tail ultrastructure of chromosome 7,307–309 and DNA probes now provide a test by which,
may demonstrate a primary abnormality.292,293 in families having an affected infant, it is possible to identify the
abnormality in further pregnancies as early as the first trimester.310
This test has also enabled the identification of carrier status in the
healthy siblings of an affected person or in couples contemplating
Autosomal-dominant polycystic kidney disease
parenthood.311–313 Although more than 800 cystic fibrosis mutations
Autosomal-dominant polycystic kidney disease (ADPKD) is a rela- have been identified, one (ΔF508) accounts for about 70% of alleles314
tively common disease with several extrarenal manifestations but and another (G551D) for a further 5%.315 The identification of specific
until recently no known pulmonary features. However, the renal cysts genetic defects has led to trials of gene therapy involving the insuffla-
have been attributed to dysfunction of primary cilia and the cilia- tion of the airways with preparations of the normal gene carried
associated proteins polycystin-1 and -2, and this prompted one group within liposomes or on a viral vector.316
to examine respiratory cilia in these patients. Immunostaining revealed
polycystin-1 in the airway epithelia of non-ADPKD patients while Pathogenesis317
autopsy material from one of five patients showed histological evi- Cystic fibrosis is thought to depend upon abnormal secretions, as
dence of bronchiectasis. This led to a review of computed tomography indicated by its alternative name ‘mucoviscidosis’, although this term
scans for evidence of bronchiectasis in 95 ADPKD patients and an has no direct relevance to the abnormally salty sweat that characterises
equal number of non-ADPKD chronic kidney disease patients, which the condition. Furthermore, the hyperviscous mucus is not the primary
revealed a threefold increased prevalence of radiographic bronchiecta- abnormality. Ciliary beat frequency and ultrastructure are normal,318,319
sis in ADPKD (37% versus 13%).304 and claims that there is a serum factor that inhibits ciliary function in
vivo offer no explanation for the intestinal and pancreatic lesions of
Cystic fibrosis the disease. It is now known that an abnormality of chloride ion
transport underlies both the sweat hypersalinity and the mucus hyper-
Incidence and inheritance viscosity.320,321 The genetic abnormalities referred to above affect a
Fifty years ago, four out of five patients with cystic fibrosis died in the protein named the cystic fibrosis transmembrane conductance regula-
first year of life, whereas today most can expect to survive until tor (CFTR) that acts as a cyclic adenosine monophosphate-regulated
the fourth decade. The predicted median survival for babies born in chloride channel and thereby controls ion and hence water movement
the UK in the twenty-first century now exceeds 50 years.305 This across the cell membrane.322,323 This protein is made up of 1480
improvement in survival is attributable to a combination of earlier amino acids, of which the 508th from the N-terminus (phenyla-
diagnosis, better management of meconium ileus, dietary control, lanine) is deleted when there is ΔF508 gene homozygosity. The abnor-
pancreatic enzyme supplementation, physiotherapy, the introduction mal protein is trapped in the endoplasmic reticulum leading to
of potent antibiotics, and the development of specialist centres. defective ion transport at the apical cell membrane.324,325 Another
Cystic fibrosis has been reported in all racial groups but is common- variant, G551D, is properly transported to the plasma membrane but
est in white people (Table 2.8). In Great Britain it is the commonest is unresponsive to cyclic adenosine monophosphate.325 Such defects
lethal genetic disorder, affecting 1 in 2500 live births with the gene result in excessive reabsorption of water and hence hyperviscosity of
responsible for the condition being carried by 1 in 25 of the Caucasian mucus and hypersalinity of sweat and mucosal secretions. About 96%
population. About 1 in 400 marriages involves two carriers and, of male patients are infertile due to congenital absence or focal atresia
because transmission is by an autosomal-recessive gene, the children of the vas deferens.326 The cause of this is uncertain but it has been
of such marriages have a 1 in 4 chance of having the disease. The attributed to obstruction in early fetal life rather than anomalous
carriers are entirely normal and, apart from the siblings of an affected development.326,327 Female fertility is slightly impaired, probably
child, a family history of cystic fibrosis is unusual. Because the because the cervical mucus is unduly viscid.
homozygotes have only recently survived to sexual maturity and the In the airways, hypersalinity impairs the antibacterial action of
males are generally infertile due to agenesis of the vasa deferentia, constituents such as lactoferrin and lysozyme,328,329 and this, coupled

65
 Pathology of the Lungs

Box 2.3  Effects of cystic fibrosis in chronological order Table 2.9  Extrapulmonary manifestations of cystic fibrosis

Primary effects Secondary effects Cardiac Cor pulmonale

Meconium ileus Peritonitis Fibrosis of left ventricle
Rectal prolapse Enlarged carotid bodies
Salty sweat Hyponatraemia Gastrointestinal Upper Barrett’s oesophagus
Pancreatic duct obstruction Failure to thrive Varices (due to cirrhosis)
Steatorrhoea Lower Meconium ileus (leading to
Diabetes mellitus obstruction, perforation,
Respiratory Bronchiectasis prolapse)
Recurrent infections Appendicitis
Hyperreactive airways Fibrosing colonopathy (due to
Atelectasis treatment)
Subpleural cysts and pneumothorax Liver Sclerosing cholangitis
Allergic bronchopulmonary Biliary cirrhosis
aspergillosis Gallbladder Cholecystitis and microgallbladder
Hepatic duct obstruction Biliary cirrhosis Pancreas Pancreatic insufficiency
Vas deferens atresia Male infertilitya (steatorrhoea)
a
Chronic pancreatitis
Atresia of the vasa deferentia is responsible for 6% of obstructive aspermia326 Diabetes mellitus
and 1–2% of male infertility.327
Kidney Nephrolithiasis
Diabetic glomerulopathy
Immune complex-mediated
glomerulonephritis
with the difficulty in clearing hyperviscous mucus, inevitably leads to
permanent infection and inflammation of the respiratory tract. A Genital tract Male Atresia of vas deferens
deficiency of surfactant apoproteins A and D is a further factor Female Multiple follicular cysts
promoting continued bacterial infection.330 Deoxyribonucleic acid Cervicitis, mucous gland
released in large amounts from effete neutrophils331 polymerises with hyperplasia, vaginitis
glycoprotein to exacerbate the hyperviscosity of the mucus. Further Reduced fertility
neutrophil and bacterial products damage the bronchial wall, result- Musculoskeletal Osteoporosis
ing in bronchiectasis. Muscle wasting
Cystic fibrosis patients benefit from lung transplantation332 and it Hypertrophic pulmonary
is relevant to the pathogenesis that the donor lungs maintain normal osteoarthropathy
membrane ion transport333 and do not develop the changes found in Clubbing
the explanted lungs. Skin Salty sweat, hyponatraemia
The phenotypic spectrum associated with mutations of the CFTR Acrodermatitis
gene is now known to extend beyond the classic features of cystic Dilation of eccrine and apocrine
fibrosis and includes several monosymptomatic diseases such as iso- glands
lated forms of pancreatitis, lung disease,334 nasal polyposis335 and
atresia of the vasa deferentia (which is responsible for 6% of obstruc- General Malnutrition
Vitamin deficincies (E, K,a B12)
tive aspermia and 1–2% of male infertility).326,327,336
Amyloidosis
Clinical features a
Vitamin K deficiency at birth may lead to bleeding.
Despite improvements in patient care, repeated pulmonary infection
remains the major clinical problem in cystic fibrosis. Bronchopulmonary
infection, respiratory failure and cor pulmonale are the usual causes
of death in adults,337 but there are also many extrapulmonary features
(Box 2.3 and Table 2.9).326,327 Advanced age is no bar to a new diag- testing. Once the diagnosis has been confirmed, other family members
nosis of cystic fibrosis338–340 but in most cases the diagnosis is made may be offered screening. All siblings need this while asymptomatic
in the first year of life, often through newborn screening. adult relatives may wish to be screened for carrier status.
The diagnosis may also be made before birth by chorionic villous
sampling or amniocentesis, which is performed in high-risk families Bacteriology
or following the identification of intestinal abnormalities by ultra- The episodic attacks of airway infection represent acute exacerbations
sound. After birth several countries screen all newborns using the of a permanent colonisation of the lower respiratory tract by
Guthrie blood spot test to detect raised concentrations of immuno­ Staphylococcus aureus, Haemophilus influenzae or Pseudomonas aerugi-
reactive trypsinogen.341 Bronchoalveolar lavage shows infection and nosa, which defies eradication with long-term antibiotics. This is asso-
inflammation to be already established in a substantial proportion of ciated with the emergence of mucoid alginate-producing mutants that
affected but asymptomatic neonates diagnosed by newborn screen- develop into bacterial microcolonies embedded in exopolysaccharide
ing.342 The diagnosis is generally confirmed by a skin test that detects biofilms on the bronchial mucosa, leading to an exaggerated tissue-
high sodium levels in the sweat, but some mutations are associated damaging immune response.344–346
with normal sweat salinity.334 Alternative diagnostic procedures More recently, Burkholderia (formerly Pseudomonas) cepacia infection
include recognition of an unduly negative potential difference across has also proved troublesome in cystic fibrosis.347 This plant pathogen
a mucosal surface, such as that lining the nose,343,343a and genetic was previously regarded as a harmless commensal in humans but is

66
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.45  Cystic fibrosis. The earliest changes in the lungs consist of Figure 2.46  Cystic fibrosis. In advanced cases the bronchi are dilated
plugs of viscid mucus distending bronchial gland ducts. and filled with pus.

now recognised to attack the lungs of patients with cystic fibrosis and tion of the bronchial cartilage and bronchiectasis.360 At necropsy, pus-
hasten their deterioration. B. cepacia is resistant to most antibiotics. filled bronchiectatic cavities, abscesses and areas of pneumonic
Acquisition is by person-to-person transmission and advice based on consolidation are found throughout the lungs (Figs 2.47 and 3.32A,
this that the infected should not mix with other cystic fibrosis patients p. 122). The upper lobes are generally more severely affected than the
is very distressing to individuals who derive much comfort from lower.361 Lymphoid follicles often develop in relation to the bron-
mutual support groups.348 Chlamydia pneumoniae and opportunistic chiectatic cavities.356 Air cysts are another frequent finding in older
mycobacteria have also been identified as troublesome pathogens in patients.362 Some of these are bronchiectatic cysts, some have multiple
cystic fibrosis. communications with bronchi showing that they are pneumatoceles
derived from former abscesses, some represent interstitial emphysema
Immunological abnormalities and others are emphysematous bullae. Their rupture largely accounts
Atopy and immunological abnormalities are common in cystic fibro- for the high incidence of pneumothorax that is seen in adults with
sis but it is uncertain whether these are primary or secondary. They cystic fibrosis.362,363 Attenuated and shortened interalveolar septa may
include circulating immune complexes, which are deposited in the be evident microscopically, resulting in appearances resembling
respiratory and intestinal tracts and could conceivably contribute to panacinar emphysema but probably representing retarded postnatal
the tissue damage there.349 These complexes presumably also underlie lung growth.358 In older patients pulmonary hypertension and cor
the cutaneous vasculitis and arthritis that are occasionally encoun- pulmonale may develop.364,365 Large haemoptyses may occur,337 prob-
tered in cystic fibrosis.350 Bronchial hyperactivity is common, possibly ably from the highly vascularised granulation tissue that lines the
due to easier penetrance of the damaged epithelium by common bronchiectatic cavities and which is supplied by systemic arteries.
environmental allergens. Serum immunoglobulins are generally Nasal polyps are common in cystic fibrosis, but they differ from those
raised and there is a high prevalence of positive skin reactions (type of atopic subjects in that they lack eosinophils.366
I and III) to common allergens such as Aspergillus fumigatus.337,351 The
incidence of allergic bronchopulmonary aspergillosis is markedly Extrapulmonary disease (Table 2.9)
increased in cystic fibrosis.352,353 Aspergillomas are rare but the increas- The many extrapulmonary effects of cystic fibrosis include serious
ing use of immunosuppressive and antipseudomonal drugs in cystic consequences before birth, notably meconium ileus obstructing the
fibrosis has led to an increase in invasive aspergillosis. fetal bowel to such a degree that the intestine ruptures in utero,
leading to a sterile chemical peritonitis and severe ascites, which may
Structural changes in the respiratory tract prolong labour. If the child dies during delivery, the deficiency in the
The earliest histological change in the respiratory tract in cystic fibrosis bowel wall may have healed but extensive peritoneal calcification is
is mucous plugging of the tracheobronchial glands (Fig. 2.45).354 This often present and this gives a clue to the nature of the peritonitis.
is found in infants who succumb to meconium ileus or its complica- More often meconium ileus causes constipation or intestinal obstruc-
tions and who show no bronchopulmonary inflammation,355 indicat- tion after birth. If bowel is resected or autopsy undertaken, the intes-
ing that it is a primary change. The plugging develops to obstruct tine is found to be obstructed by hard rubbery meconium and the
bronchi and infection invariably follows (Fig. 2.46), resulting in recur- appropriateness of the term ‘mucoviscidosis’ can be readily appreci-
rent attacks of bronchitis, bronchiolitis and ultimately pneumonia. ated. Older children and even adults may be similarly affected by a
The bronchitis is characterised by secondary hyperplasia of the bron- ‘meconium ileus-equivalent’. Microscopy shows the bowel to be filled
chial glands indistinguishable from that seen in the chronic bronchitis and the crypts of Lieberkuhn distended by mucus (Fig. 2.48). Mucus
of cigarette smokers.356,357 There may also be papillary hyperplasia of may also plug the ducts of salivary and labial glands.
the bronchial mucosa. The bronchiolitis is accompanied by peribron- Pancreatic disease is a further manifestation of cystic fibrosis.
chiolar fibrosis, which constricts these airways.358 An obstructive pneu- Indeed, the term ‘cystic fibrosis’ was coined specifically for the late
monitis consisting of interstitial inflammation and fibrosis develops.359 changes in the pancreas. The first change is mucous plugging of the
There may also be evidence of organising pneumonia, air-trapping pancreatic ducts, which leads to atrophy and fatty replacement of the
and collapse. The chronic sepsis leads to bronchial ulceration, destruc- exocrine portion of the gland. Low-grade inflammation is common

67
 Pathology of the Lungs

Figure 2.49  Cystic fibrosis. Pancreas. The exocrine portion is reduced to

dilated ducts in a fibrous stroma or shows fatty replacement. Islets of
Langerhans survive, but these too may eventually atrophy.

Figure 2.47  Cystic fibrosis. At necropsy the lungs are largely replaced by
pus-filled bronchiectatic cavities and abscesses, more marked in the
upper lobe.

Figure 2.50  Cystic fibrosis. Liver. Small bile ducts are plugged by
eosinophilic secretions.

and this leads to fibrosis (Fig. 2.49) while the obstructed ducts become
cystically dilated. The administration of pancreatic enzymes is possi-
bly responsible for an increasing incidence of colonic strictures. The
endocrine portion of the gland is initially spared but eventually even
the islets of Langerhans atrophy; diabetes mellitus is a common late
result, generally preceded by years of malabsorption.
Hepatic disease has a similar basis to that in the pancreas. Initially
small bile ducts are plugged by mucus (Fig. 2.50), leading to biliary
cirrhosis (Figs 2.51 and 2.52).
Renal disease includes diabetic glomerulopathy, amyloidosis and
immune complex-mediated glomerulonephritis. There is also an
increase in urinary oxalate excretion, which is linked to the malab-
sorption and results in microscopic nephrocalcinosis367 and urolith­
iasis.368,369 Cardiac disease includes cor pulmonale and focal myocardial
necrosis, suggested causes of which include malnourishment and
Figure 2.48  Cystic fibrosis. Meconium ileus-equivalent in an adult hypovitaminosis.370,371
patient. The crypts of Lieberkuhn are distended by mucus, which also The vasa deferentia are frequently atretic and the patient is conse-
forms a thick coat on the surface. quently sterile.326,327 At autopsy, the epididymes and testes show

68
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.51  Cystic fibrosis. Liver, showing well-established cirrhosis. Figure 2.53  Cystic fibrosis. Epididymis, showing glandular dilatation and
stromal fibrosis.

Figure 2.52  Cystic fibrosis. Liver, showing the gross appearances of

macronodular biliary cirrhosis.

obstructive features (Figs 2.53 and 2.54) and the vasa cannot be
identified or are represented by thin fibrous bands. The female genital
tract is anatomically normal and patients reach the menarche,
although this may be delayed by chronic pulmonary sepsis. However,
cervical mucus is abnormal and cervicitis, cervical erosions and cervi-
cal mucous gland hyperplasia are commonly found. Nevertheless, Figure 2.54  Cystic fibrosis. Testis, showing basement membrane
pregnancy is possible and with improved support is now becoming thickening but normal spermatogenesis.
more frequent.
Generalised changes include all those classically associated with the
secondary effects of cystic fibrosis, including malnutrition, systemic frequency in vitro are both normal,373,374 yet in vivo tracer studies
amyloidosis and the immunological abnormalities referred to above. show impaired mucociliary clearance.375 The basic defect in Young’s
Thus there may be generalised muscle wasting and osteoporosis. syndrome is obscure but it may be hyperviscosity of the respiratory
Other changes include hypertrophic pulmonary osteoarthropathy and and epididymal secretions.
clubbing, and the craniofacial alterations seen in children with nasal
obstruction.372 Pulmonary aplasia (agenesis)
Absence of one lung (Fig. 2.55) is not uncommon but absence of a
Young’s syndrome lobe (as distinct from left-sided isomerism – see above) or of both
Young’s syndrome consists of sinusitis, bronchiectasis and obstructive lungs is distinctly rare. The bronchi may also be absent or there may
oligospermia caused by mucociliary dysfunction in the respiratory be a rudimentary stump, an important point in unilateral aplasia as
tract and epididymes. Spermatozoa accumulate in the head of the secretions tend to pool in the stump, become infected and spill over
epididymis, which is markedly dilated. Ciliary ultrastructure and beat to infect the sole lung.376 Also in unilateral aplasia the single lung is

69
 Pathology of the Lungs

Figure 2.56  Bilateral pulmonary agenesis. The larynx is well formed but
the trachea is short and the bronchi are blind-ending. (Reproduced from
Current Diagnostic Pathology by permission of Dr C Wright, Newcastle-upon-Tyne,
UK.139)

of loss depending upon how early lung development was impaired.

Development of airways down to the terminal bronchioles is com-
plete by 16 weeks and the whole gas conductive system is complete
Figure 2.55  Left-sided pulmonary aplasia. The left chest cavity contains
only the heart which is partly overlapped by the anterior border of the by birth, unlike the alveoli and alveolar ducts, which continue to grow
right lung. (Courtesy of the late Dr AH Cameron, Birmingham, UK.) throughout infancy and into childhood. It follows that correction after
birth of such causes of hypoplasia as diaphragmatic hernia may
permit growth of alveoli but not airways.385
Hypoplasia of the lungs is seldom an isolated finding. It is usually
enlarged and contains twice the normal number of alveoli, but the associated with a variety of other abnormalities.386 These include dia-
bronchi are normal.377 Nevertheless there is a significant reduction in phragmatic defects, renal anomalies, extralobar pulmonary sequestra-
vital capacity and exercise tolerance.378 In bilateral pulmonary aplasia tion and severe musculoskeletal disorders. Most of these associations
the trachea or proximal bronchi end blindly (Fig. 2.56) and the pul- have a causal relationship (see below) but some, such as that with
monary artery joins the aorta. Aplasia is often associated with other Down’s syndrome387 and the low-set ears of Potter’s syndrome (see
malformations and, if the aplasia is unilateral, these are often on the below), are not readily explained. Lung growth before birth is depend-
same side of the body.378–380 They include anomalous pulmonary ent upon blood supply, availability of space, respiratory movements
venous drainage.381 taking place in utero and fluid filling the airways. The causes of pul-
monary hypoplasia therefore include the following:
1. Congenital abnormalities of blood vessels supplying the lungs,
Pulmonary hypoplasia as in pulmonary valve stenosis.
Hypoplastic lungs are small but normal in form and it is possible that 2. Compression of the lungs by intrathoracic masses, as with
some cases are misdiagnosed as atelectasis. Hypoplasia of the lungs herniation of abdominal viscera through a congenital dia­
signifies that the alveoli are reduced in number or size. This may be phragmatic defect (Figs 2.57 and 2.58) or cystic malformation
assessed by counting the intercepts made by alveolar walls on a line of the contralateral lung.
from the terminal bronchiole to the interlobular septum.382,383 3. Compression of the lungs due to deformities of the thorax such
Alternatively, the lungs may be weighed. Normal right and left lung as Jeune’s asphyxiating thoracic dystrophy (see p. 80). Because
weights at term are 21 and 18 g respectively (see Table 1.1, p. 3) but the lungs continue to grow after birth, infantile scoliosis may
hypoplasia is best considered to be present in term babies when the also cause postnatal hypoplasia.388,389
lung-to-body weight ratio is less than 0.012.384 The reduction in 4. Lack of respiratory movements due to the antenatal onset of
alveoli may be associated with fewer airway generations, the degree neuromuscular diseases such as myotonic dystrophy.

70
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.58  Pulmonary hypoplasia due to diaphragmatic hernia.

The left lung, seen as a small nodule (arrow) between the right lung  
and the heart, is hypoplastic.

Figure 2.57  Pulmonary hypoplasia due to diaphragmatic hernia.

Loops of bowel and the stomach fill much of the left side of the chest,
compressing the thoracic viscera. (Courtesy of Dr GA Russell, Tunbridge
Wells, UK.)

5. Oligohydramnios, caused by either chronic leakage or deficient

production of amniotic fluid. The mechanism whereby
oligohydramnios causes pulmonary hypoplasia could again be
compression of the lungs, but manometry shows that amniotic
pressure is reduced rather than raised in oligohydramnios.390
Loss of lung liquid is probably more important, being
implicated by the demonstration that experimental tracheal
ligation prevents the adverse pulmonary effects of
oligohydramnios,391 and by the observation that human fetuses
with renal agenesis do not develop pulmonary hypoplasia if
there is also laryngeal atresia.392 Indeed, laryngeal atresia is
recorded in association with pulmonary hyperplasia rather than
hypoplasia.149 Lung liquid therefore appears to act as a stent and
thereby provide internal support essential to proper lung
development. Fetal urine contributes greatly to amniotic fluid
and renal agenesis and urethral stricture are important causes of
oligohydramnios-associated pulmonary hypoplasia. The Potter Figure 2.59  Potter facies consisting of low-set ears and a small hooked
syndrome consists of abnormal facies (Fig. 2.59), pulmonary nose is seen in association with renal agenesis and pulmonary hypoplasia.
hypoplasia and renal agenesis: oligohydramnios due to the renal (Courtesy of the late Dr AH Cameron, Birmingham, UK.)

71
 Pathology of the Lungs

than the larynx is more easily overlooked and probably accounts for
seemingly inexplicable localised areas of pulmonary hyperplasia,
which may not be recognised as such and therefore thought to repre-
sent a form of congenital cystic adenomatoid malformation or new
forms of congenital ‘emphysema’, e.g. polyalveolar lobe.

Congenital ‘emphysema’
Emphysema is defined in a later chapter as enlargement of air spaces
distal to the terminal bronchiole due to breakdown of their walls. This
is not found at birth: so-called congenital emphysema is a miscellany
of other conditions in which the lungs are light and airy. A single
segment, a lobe, a whole lung or all the lung tissue may be so affected
in the neonatal period. Most of these conditions represent alveolar
distension rather than destruction. Familial α1-antitrypsin deficiency
causes true emphysema and is congenital but the onset of the emphy-
sema is not until adult life and this condition is therefore considered
later in Chapter 3.
Alveolar distension may be compensatory to collapse or hypoplasia
of the adjacent lung,394 or it may be obstructive.395 If the obstructed
airway supplies a segment of a lobe or less, inflation of the distal lung
may be by collateral ventilation, but if a lobar or main bronchus is
affected collateral ventilation is not possible and a check valve mecha-
nism is generally invoked to explain the distension. Bronchial atresia
typically affects a segmental bronchus, and any distension is focal
and due to collateral ventilation, in contrast to infantile lobar
emphysema.

Infantile lobar emphysema (congenital

lobar emphysema)
Infantile lobar emphysema is due to partial obstruction of the lobar
bronchus leading to air-trapping. The other lobes are thereby com-
pressed and mediastinal structures displaced causing severe respira-
tory distress, which generally necessitates early surgical resection. The
condition generally affects neonates but cases occasionally come to
light in adult life.396,397 Males are affected more than females but
Figure 2.60  Pulmonary hyperplasia due to laryngeal atresia. The heart is the condition is not familial. The condition affects the left upper
enveloped by the voluminous lungs. (Reproduced from Current Diagnostic lobe in about half the cases, with the right middle and right upper
Pathology by permission of Dr C Wright, Newcastle-upon-Tyne, UK.139) lobes being involved in most of the remainder and the lower lobes
in less than 10%.
The obstruction may be caused by intrinsic abnormalities of the
agenesis is generally thought to be the cause of the pulmonary
bronchus, such as mucosal flaps, mucous plugs or twisting of the lobe
abnormality,393 although a lack of renal metabolites has also
on its pedicle, or by external compression from causes such as a bron-
been proposed.37
chogenic cyst or abnormal blood vessels.395,398 In the absence of such
Hypoplasia is evident on antenatal scans and some of these causes causes, a deficiency of bronchial cartilage is generally postulated. This
are amenable to various surgical interventions before birth. Thus, may be demonstrated in the resected lobe by dissecting out the
diaphragmatic herniae have been repaired in utero, the fetal trachea bronchi, staining the cartilage with toluidine blue and clearing the
has been occluded by the insertion of a balloon catheter (to retain specimen with potassium hydroxide or an organic solvent such as
lung liquid) and lung cysts have been drained into the amniotic cavity cedarwood oil or xylol (Fig. 2.61).399–401
by the insertion of a catheter. In practice the cause is frequently not identified. Explanations based
on simple air-trapping are possibly too facile as the lobe is not only
Pulmonary hyperplasia distended to its normal maximum but hyperinflated. This implies a
connective tissue defect at the alveolar level,402 although none has
It is mentioned above that lung fluid is important to lung growth, that been convincingly demonstrated so far. About 20% of patients also
deficient liquid within the lungs leads to hypoplasia and that obstruc- have congenital cardiac anomalies and it is possible that the relation-
tion to fluid outflow, as in laryngeal atresia, leads to overgrowth.149 ship is causal.403 The bronchi supplying the lobes that are predomi-
The latter takes the form of pulmonary hyperplasia, which is the exact nantly affected (the left upper and right middle lobes) are in
opposite of pulmonary hypoplasia in that it is characterised by hyper- particularly close proximity to pulmonary arteries and, if these are
alveolisation. This is manifest in the linear intercepts described above distended, as in acyanotic congenital heart disease, they are liable to
as being greater than normal and in the lungs being heavy. Hyperplastic be compressed; the narrow, pliable bronchi of neonates are particu-
lungs are voluminous, envelop the heart and show a pleural pattern larly susceptible (see Fig. 10.9, p. 481).
of rib indentation (Fig. 2.60). They depress the diaphragm and com- The causes of external compression cannot be identified by examin-
press veins, causing ascites and hydrops. Airway atresia at a lower level ing the excised lobe and it is therefore essential that as well as paying

72
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.62  Swyer–James syndrome. A chest radiograph shows

hyperlucency of the right lung due to diminished vascularity. (Courtesy of
Professor DM Hansell, Brompton, UK.)

are diminished (Fig. 2.62). The syndrome was originally thought to be

due to unilateral hypoplasia of the pulmonary artery but vascular shut-
down in response to hypoventilation caused by postinfective oblitera-
Figure 2.61  Infantile lobar emphysema. A fatal case in which the tive bronchiolitis is now the favoured explanation.406,407 The airway
bronchi have been dissected out, their cartilages stained with toluidine obstruction may add an element of distension but, in contrast to the
blue and the tissues cleared. Bronchi to the right are devoid of cartilage. forms of overinflation discussed above, the affected lung is not enlarged.
(Courtesy of the late Professor BE Heard, Brompton, UK.) This is compatible with an infective aetiology as this could well impair
the normal postnatal growth of the lung at the alveolar level.

particular attention to the lobar bronchus the pathologist is aware of Ectopia

the clinical, radiological and surgical findings.
Two categories of ectopia need to be considered – ectopia of non-
pulmonary tissues in the thorax and ectopia of lung tissue outside the
Polyalveolar lobe thoracic cavity. Pleural endometriosis and splenosis, teratomas of the
A polyalveolar lobe has a normal number of conductive airways but lung and traumatic embolism of bone marrow, liver or brain tissue to
an increased number of alveoli in each acinus.404 The affected lobe is the lung are dealt with separately.
enlarged, light and airy but individual alveoli are not increased in size. Ectopia of adrenocortical tissue,408 thyroid (lacking C cells)409 and
The number of alveoli in an acinus is best assessed by counting the liver410 has been described in the lung and pancreatic tissue has been
intercepts made by alveolar walls on a line from the terminal bron- noted within intralobar sequestrations with gastrointestinal connec-
chiole to the interlobular septum.382 The number of alveoli depends tions.191,192 Ectopic striated muscle is recorded in sequestered and
on the age of the child, but in general, fetuses have a radial count of hypoplastic lungs242,411,412 and occasionally as an isolated pulmonary
2–5, infants have a count of 5–10 and children a few years old have abnormality,413 sometimes tumour-like.414 Rarely, a whole kidney may
a count of 10–12. These figures are increased by as much as three to be found above the diaphragm but outside the lung.415
five times in a polyalveolar lobe. Ectopia of glial tissue within the lung is well recognised.416–422
Clinically, polyalveolar lobe resembles infantile lobar emphysema Nodules of glial tissue may be implanted in the embryonic lung by
and often the true diagnosis only becomes apparent on examination aspiration of amniotic fluid in some cases of anencephaly416,418,419 and
of the excised specimen.405 Affected babies are dyspnoeic and chest in the absence of anencephaly by embolisation due to intrauterine
radiographs show lobar enlargement with displacement of the other trauma421 or, with small macerated fetuses, merely normal uterine
thoracic viscera. The prognosis following surgery is good, and it may contractions.422 The ectopic glial tissue lacks neurones but may
be preferable to operate early rather than late to maximise compensa- contain cysts lined by ciliated epithelium: devoid of their normal
tory lung growth. mesenchyme these primitive lung buds fail to develop bronchial car-
tilage and muscle or differentiate into alveoli. Two patients with
unexplained glial ectopia survived surgery for neonatal respiratory
Hyperlucent lung (hypertransradiant lung;
distress to reach adult life, one with mental retardation417 and one
Swyer–James or Macleod syndrome) without.420
This is a condition in which the normal radiographic markings of the Ectopia of lung tissue in the neck, the abdomen or the chest wall
lungs, which predominantly represent the pulmonary blood vessels, is often termed herniation but is probably due neither to raised

73
 Pathology of the Lungs

dentally in the lung. They are generally stellate in outline and almost
always the muscle is intermingled with fibrous tissue. Such lesions
more likely represent old scars in which there is prominent reactive
smooth-muscle hyperplasia. Diffuse changes of this nature are often
seen in end-stage diffuse pulmonary fibrosis and the term ‘muscular
cirrhosis of the lung’ has been used for this. Genuine examples of
smooth-muscle hamartomas are reported in the lung, sometimes
associated with similar lesions in the bowel and liver,435 but they are
much rarer than focal scars.

Anomalies of the pulmonary blood vessels

The condition known as alveolar capillary dysplasia with misalign-
ment of lung vessels represents arrested development in the canalicu-
lar stage of lung development and is accordingly described with
other diffuse developmental disorders of infancy on page 50. The left
pulmonary artery sling syndrome is also described elsewhere – on
page 481, together with the various ring anomalies of systemic vessels
that may similarly result in compression of the major airways in
infancy.

Unilateral absence of a pulmonary artery

Absence of one of the main pulmonary arteries leads to the lung on
Figure 2.63  Ectopia of the lungs. The diaphragm and abdominal that side receiving only systemic blood, through either anomalous
contents are viewed from above. The left hemidiaphragm is largely arteries or enlarged bronchial arteries.436,437 Either lung may be affected
absent and through this deficiency dark unaerated lung tissue and and the defect may be isolated or associated with other cardiovascular
abdominal viscera can be seen. (Courtesy of the late Dr AH Cameron, anomalies, typically the tetrad of Fallot with an absent left pulmonary
Birmingham, UK.) artery and a patent ductus arteriosus with an absent right pulmonary
artery.436 Patients with an isolated anomaly of this type may lead a
normal life or symptoms may not arise until adult life, when they are
generally attributable to pulmonary infection or to bleeding from
intrathoracic pressure nor deficiencies in the thoracic boundaries, as bronchopulmonary anastomoses.438–442 Clinically, the condition may
often proposed, for the one causes pulmonary hypoplasia and the be difficult to distinguish from embolic occlusion but an association
other leads to herniation of structures into, rather than from, the with other congenital vascular defects would support the diagnosis.438
thorax. Although it is often associated with skeletal or diaphragmatic Only a short segment of the artery may be lacking and surgical cor-
abnormalities (Fig. 2.63), it appears to represent genuine ectopia. rection may be possible.443 In other cases, pulmonary arteries may be
Some examples of abdominal pulmonary ectopia represent extralobar difficult to identify in lung sections, where they tend to be over­
sequestration as well as ectopia.423 shadowed by hypertrophied bronchial arteries, sometimes showing
plexiform lesions.441 Pulmonary hypertension develops in 18% of
patients with an isolated defect and more often when there are other
Hamartomas
vascular anomalies. Relevant to this is the observation that ligation of
Hamartomas represent abnormal mixtures of tissue elements, or an one main pulmonary artery, for example during pneumonectomy, has
abnormal proportion of a single element normally present in an little effect on the contralateral vasculature in adults but when the
organ resulting in changes that are tumour-like but not neoplastic. ligation is conducted in the perinatal period the high fetal pulmonary
Pleuropulmonary examples include vascular malformations, and mes- pressure is maintained.436
enchymal malformation of the chest wall. However, the so-called
(chondroid) hamartoma shows an increasing incidence with age and
Pulmonary artery stenosis and Fallot’s tetrad
is probably a true neoplasm. It is therefore dealt with in the tumour
section. It is also debatable whether the so-called mesenchymal cystic Stenosis may affect the main pulmonary artery or any of its branches.
hamartoma is a valid entity. It was first described in 1986,424 since There may be multiple constrictions and, as with absence of a pulmo-
when only a few more cases have been reported.425–429 Some appear nary artery, the condition may be isolated or associated with other
to have represented metastases of either endometrial stromal sarcoma vascular anomalies. Stenosis of the main pulmonary artery is the
or cellular fibrous histiocytoma,430,432 while others have resembled the dominant factor in the tetrad of Fallot, in which it is combined with
type 4 congenital cystic adenomatoid malformation or a type 1 pleu- a ventricular septal defect, an overriding aorta and right ventricular
ropulmonary blastoma. hypertrophy. It leads to a right-to-left ventricular shunt, the clinical
The condition of so-called benign metastasising leiomyoma is gen- features of which – cyanosis, polycythaemia and clubbing – develop
erally considered to represent metastasis from an occult extrapulmo- in infancy, in contrast to Eisenmenger’s syndrome in which cyanosis
nary tumour and is dealt with in Chapter 12.6, but some suggest that develops later. In all patients with cyanotic congenital heart disease,
the condition represents hamartomatous growth, showing that some but particularly those with Fallot’s tetrad, a sudden reduction in sys-
of the lesions are polyclonal.433 However, other molecular studies temic resistance or increase in pulmonary resistance leads to episodes
support the concept of metastatic growth.434 of more profound cyanosis and hypoxaemia, which can be fatal. With
The term ‘muscular hamartoma’ is often applied to small focal pulmonary stenosis, the attenuation of the pulmonary artery walls
proliferations of smooth muscle that are occasionally observed inci- that normally takes place after birth proceeds apace so that the normal

74
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

medial thinning is greatly exaggerated, in contrast to Eisenmenger’s

syndrome in which the pulmonary arteries are hypertrophied.
Following the experimental ligation of a pulmonary artery there
occurs an enormous expansion of thick-walled bronchial collaterals
that is well advanced by 12 weeks.444

Congenital anomalies characterised by direct

communication between the two circulations
Some of the more severe pulmonary effects of cardiovascular disease
are caused by congenital abnormalities that establish a direct com-
munication between the systemic and pulmonary circulations –
anomalies such as septal defects, patent ductus arteriosus, transposition
of the great arteries and variants of the tetrad of Fallot in which there
is little obstruction to right ventricular outflow. These all lead to
shunting of oxygenated blood back into the lesser circulation.
With atrial septal defects the principal effect is that the output of
the right ventricle is greater than that of the left. In many cases the
increased flow is accommodated by underperfused vessels being
A
recruited. This lowers pulmonary artery resistance so that there is no
rise in pressure. However, with large defects hyperkinetic pulmonary
hypertension eventually develops, a complication that occurs much
earlier with communications at the ventricular or aortic level than
with atrial septal defects. Hyperkinetic pulmonary hypertension is
characterised by plexogenic arteriopathy (see p. 420). The major pul-
monary arteries are distended and, where they are in close proximity
to bronchi, the latter may be compressed, particularly in young infants
in whom the bronchial cartilages are still soft and pliable, as explained
above (see Fig. 10.9, p. 481).403 The result is pulmonary collapse, or if
the obstruction is partial, infantile lobar emphysema. Eventually
the right ventricle becomes dominant and the left-to-right shunt is
reversed, causing cyanosis, a process known as Eisenmenger’s reaction
or syndrome. Eisenmenger’s own case combined a ventricular septal
defect with an overriding aorta, an arrangement that is termed
Eisenmenger’s complex. Eisenmenger attributed the cyanosis to the
biventricular origin of the aorta but cardiac catheter studies have
subsequently shown that acquired pulmonary hypertension is the
responsible factor.

Dieulafoy’s disease B

This vascular malformation is best known in the gastrointestinal tract Figure 2.64  Dieulafoy’s disease. (A) Rupture of an aneurysmally dilated
but a few cases affecting bronchial arteries have been described.445–447 mucosal artery proved to be the cause of intractable haemoptysis that
The patients generally present with massive haemoptysis and are necessitated lobectomy. (B) An elastin stain highlights the eroded
found to have an isolated aneurysmally dilated bronchial artery that bronchial artery. (Courtesy of Dr MM Burke, Harefield, UK.)
has bled into a bronchus (Fig. 2.64).

Anomalous systemic arteries primary pulmonary vein which grows from the developing left atrium
Anomalous systemic arteries to the lung are an essential feature of toward the lung buds. The anomalous veins may join the inferior vena
pulmonary sequestration. They are also found with pulmonary artery cava or hepatic, portal or splenic veins below the diaphragm, or above
aplasia and arteriovenous malformations, or they may be an isolated the diaphragm they may drain into the superior vena cava or its tribu-
abnormality. They are usually small but sometimes the right pulmo- taries, the coronary sinus or the right atrium (Table 2.10). The anomaly
nary artery arises from the aorta.448 As well as these congenital anoma- may be total or partial, unilateral or bilateral, and isolated or associ-
lies, conditions such as bronchiectasis often acquire a systemic blood ated with other cardiopulmonary developmental defects. These
supply, usually via enlarged bronchial arteries but also from inter­ include bronchopulmonary isomerism, dextrocardia, asplenia, pul-
costal or mediastinal arteries if there are pleural adhesions.449 monary stenosis, patent ductus arteriosus and a small interatrial com-
munication.450 The type of isomerism gives a good indication as to
whether the anomaly is total or partial; right-sided isomerism suggests
Anomalous pulmonary veins totally anomalous veins and left-sided isomerism suggests a partial
Anomalous pulmonary veins result in blood from the lungs returning anomaly.164 Occasionally the anomalous vein runs much of its course
to the right side of the heart rather than entering the left atrium. The buried within the lung substance.451 Anomalous pulmonary venous
embryological basis is a failure of the veins within the primitive lungs connections are often narrow and this may cause pulmonary hyper-
to switch from draining into channels around the foregut to a new tension of the relatively mild, reversible venous variety.452 Occasional

75
 Pathology of the Lungs

Table 2.10  Anomalous pulmonary veins. Venous drainage in 27

cases of totally anomalous pulmonary venous drainage 1
documented by the late Dr AH Cameron at the Birmingham
Children’s Hospital over a 15-year period (excluding cases of
asplenia and situs inversus)
2 PA
Tributaries of the superior vena cava 9

Right atrium 8
Coronary sinus 4
Portal vein 3 RA LA
3
Hepatic vein 1
Splenic vein 1
Inferior vena cava 1

reports of plexogenic pulmonary hypertension probably reflect the

association with a patent ductus arteriosus.450 Ao
Atresia of the pulmonary veins453,454 or narrowing of their ostia
entering the left atrium (collectively termed pulmonary vein steno- IVC
sis453) does not in itself constitute anomalous drainage but similarly
results in pulmonary venous obstruction and may be associated with
partial anomalous pulmonary venous drainage. The atresia may be Figure 2.65  Scimitar syndrome. 1. The right upper lobe is often supplied
unilateral or bilateral but in either case severe hypertensive changes by a hypoplastic pulmonary artery (PA). 2. The blood from the upper  
develop in both lungs. Small capillary-sized vessels may be found part of the lung drains into the left atrium (LA). 3. The remainder of the
within all coats of the thickened arteries, or congeries of them may right lung is supplied by vessels arising from the aorta (Ao). 4. The blood
from a variable part of the right lung drains by a prominent vein (evident
be seen alongside the larger blood vessels. They represent abortive
radiologically as a curved, scimitar-shaped linear opacity) which joins  
anastomotic attempts at bypassing the obstruction, which are doomed the inferior vena cava (IVC) below the diaphragm. Less frequently, the
to failure because the obstruction is extrapulmonary. They bear some drainage of the lower part of the right lung is by veins which pass
resemblance to plexiform lesions but the necrotising arteritis that directly to the right atrium (RA). (Redrawn from Brewis RAL, Corrin B,
leads to plexogenic arteriopathy is not a feature. There is a closer Geddes DM et  al. Respiratory Medicine, 2nd edn. London: Saunders, 1995.)
resemblance to pulmonary capillary haemangiomatosis, supporting
the view that this supposedly neoplastic condition merely represents
a reaction to pulmonary venous occlusion (see p. 429). Congenital
pulmonary vein atresia carries a very poor prognosis; few children
with the condition survive longer than a year. surround the pulmonary veins immediately prior to their entry into
Partial anomalous pulmonary venous drainage is an essential the left atrium, prompting attempts to ameliorate the dysrrhythmia
feature of the scimitar syndrome, in which an anomalous right pul- by catheter ablation.457,458 The commonest technique aims to isolate
monary vein descending to join the inferior vena cava just below the the source of these ectopic beats by delivering radiofrequency energy
diaphragm gives a characteristic, supposedly scimitar-like, vertical at the junctions of the four veins and the atrium. Whilst it can succeed
radiographic opacity parallel to the right side of the heart (Fig. 2.65). in curing the dysrrhythmia several patients have developed pulmonary
The right pulmonary artery is hypoplastic and the arterial supply of venous stenosis.458a,459
the right lung is often largely from the aorta, so that there is some
overlap with pulmonary sequestration. Due to the deficient pulmo-
Arteriovenous fistula
nary artery supply the right lung is hypoplastic with consequent medi-
astinal shift to the right. The vascular connections of the left lung are Arteriovenous fistulas may be developmental or acquired. The latter
normal. Cardiovascular, diaphragmatic, gastrointestinal and other result from injuries such as penetrating chest wounds or they may
pulmonary anomalies are often found. The syndrome can be familial complicate liver disease. This account will be confined to the devel-
with an autosomal-dominant pattern of inheritance. Some patients opmental variety, which was first reported in 1897,460 since when
are asymptomatic and the lesion is detected only on routine radio- many further cases have been reported.461–466 The lesion is a vascular
graphs. Others suffer from recurrent pneumonia, breathlessness or hamartoma resulting from persistence of anastomotic fetal capillaries.
haemoptysis.455,456 The anomaly represents a left-to-right shunt and This results in abnormal communication between pulmonary arteries
surgical correction may be required if this is large. and veins, bypassing the normal pulmonary capillary bed. More rarely
the lesion connects systemic and pulmonary vessels.467–470 The lesions
may be single or multiple and often increase in size with age.471
Pulmonary vein stenosis and atrial fibrillation About 70% of patients have hereditary haemorrhagic telangiectasia
Atrial fibrillation is the commonest form of cardiac dysrhythmia and (Rendu–Osler–Weber disease), which is an autosomal-dominant con-
one that is associated with significant morbidity and mortality. The dition (see p. 481).463,472,473 Conversely, about 15% of patients with
condition is multifactorial but it appears that in most patients the hereditary haemorrhagic telangiectasia have pulmonary arteriovenous
fibrillation is triggered by ectopic foci in the muscular sleeves that fistulae.474 This association portends an increased risk of multiple

76
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

fistulae and progressive symptoms, which is important as surgical interstitial emphysema because of some underlying disease which
correction is only possible with limited disease. Patients with multiple necessitated artificial respiration. In both conditions the interlobular
fistulae are more suitable for treatment by balloon occlusion or septa are widened and on the visceral pleural surface there is a pro-
embolisation. However, migration of a coil embolus into a bronchus nounced reticular pattern of small cysts which accentuates the lobular
is recorded.475 The role of lung transplantation is controversial.476,477 architecture of the lungs. Pricking the cysts gives invaluable evidence
of their content; clear serous fluid will run out in lymphangiectasia.
Clinical features On slicing the lungs, further fluid runs from the cut surfaces, which
Although the lesion is a developmental anomaly, it may remain show a microcystic pattern (Fig. 2.67A). The cysts measure up to
asymptomatic until late in life. The average age at presentation is 5 mm in diameter and are situated in the interlobular septa and about
about 40 years but the condition has been first identified in both the the bronchovascular bundles. Near the hila of the lungs the cysts are
newborn and the very old.462,463,468 Fistulae with an appreciable arte- elongated.487
riovenous shunt cause cyanosis, clubbing of the fingers, breathless- Microscopy confirms that the cysts are located in connective tissue
ness, polycythaemia and an extracardiac murmur. Haemorrhage from under the pleura, in the interlobular septa and about the bronchioles
the lungs, as opposed to nasal telangiectasia, is an uncommon but and arteries (Fig. 2.67B). Serial sections show that they are part of an
potentially fatal complication.478 The proximity of most malforma- intricate network of intercommunicating channels which vary greatly
tions to the pleura explains the occasional complication of haemotho- in width and are devoid of valves.487 The cysts are lined by an attenu-
rax. Systemic complications may be caused by hypoxaemia, thrombosis ated simple endothelium, an appearance which may be mimicked by
secondary to the polycythaemia, haemorrhage due to associated compressed connective tissue cells in interstitial emphysema. Never
hereditary telangiectasia, and paradoxical embolism or metastatic seen in lymphangiectasia is the foreign-body giant cell reaction to air
abscesses due to loss of the filtering effect of the pulmonary capillaries which develops after a few days in interstitial emphysema (see Fig.
or, rarely, infective endarteritis within the fistula. Cerebral abscess is 2.18). Apart from this the two conditions can be virtually indistin-
reported in 20% of patients, stroke in 18% and transient ischaemic guishable microscopically, which is understandable as in interstitial
attacks in 37%.472 Sarcomatous change has been reported479 but emphysema the air is contained within lymphatics as well as dissect-
is very rare. ing the interstitial tissues.125 Interstitial emphysema rather than lym-
phangiectasia may also be suspected if there is some other underlying
Pathology disease that necessitated ventilator support.
It is important not to confuse lymphangiectasia with artefactual
The lower lobes are most commonly affected but any lobe may be
expansion of the interlobular septa by overzealous injection of
involved. The lesions are multiple in one-third of cases and in one-
formalin.
sixth the condition is bilateral. Resected lesions will almost certainly
have been demonstrated angiographically before operation (Fig.
Klippel–Trenaunay syndrome
2.66A, B). If not, the pathologist may do this with a barium gelatin
mixture before fixing the specimen but the results are rarely better This congenital condition is characterised by varicosities of systemic
than the images produced in vivo. The lesion is usually peripheral and veins, cutaneous haemangiomas, soft-tissue hypertrophy and pleuro-
visible as a bluish swelling beneath the visceral pleura. It consists of pulmonary abnormalities that include pulmonary lymphatic
vascular channels of various size and wall thickness, with little hyperplasia, pleural effusions, pulmonary thromboembolism and
supportive tissue, separated by normal lung tissue (Fig. 2.66C, D). pulmonary vein varicosities.488,489
Individual vessels may be narrowed by intimal fibrosis or there may
be dilatation associated with medial atrophy. Without prior angio­ Yellow-nail syndrome
graphy, arteriovenous communication can only be demonstrated by Lymphatic hypoplasia of varied distribution underlies this syndrome,
semi-serial sections. which is characterised by lymphoedema accompanied by discolora-
tion of the nails and pleural effusions. Although widely regarded as
Anomalies of the pulmonary lymphatics representing a hereditary disorder, the family history is generally nega-
tive and the condition is not usually manifest until adult life (see also
Congenital pulmonary lymphangiectasia p. 709).
Congenital pulmonary lymphangiectasia may be caused by obstruc-
tion to pulmonary lymphatic or venous drainage or be ‘primary’, the
latter either limited to the lung or part of generalised lymph­ Anomalies of the thoracic cage
angiectasia.480 There is a high association of primary pulmonary
lymphangiectasia with other congenital abnormalities, particularly Diaphragmatic anomalies
asplenia481 and cardiac anomalies. When the other abnormalities The diaphragm forms from the fetal septum transversum, which grows
entail impaired pulmonary venous drainage there is obviously a across the common coelomic cavity to divide the peritoneal from the
causal relationship, but this is not always the case.481,482 pleural and pericardial cavities. The posterolateral portions containing
Primary pulmonary lymphangiectasia is presumed to result from the foramina of Bochdalek are the last to form and arrested develop-
developmental failure of the pulmonary lymphatics to link with the ment here results in widened foramina through which herniation of
main drainage channels. It causes severe respiratory distress and is abdominal viscera is prone to occur, particularly on the left, resulting
generally fatal in the neonatal period, but some children survive, in mediastinal shift to the right.490 Hernias of this type are among the
albeit with respiratory impairment,483 and presentation may be commonest congenital defects. They occur in about 1 in 2000 fetuses
delayed until adult life.484–486 but many of these have other major anomalies, in particular cardiac
The macroscopic findings can be very instructive diagnostically. The abnormalities, and are stillborn. Chromosomal abnormalities are
microscopic distinction of lymphangiectasia from interstitial emphy- only common when there are other anomalies. Most isolated congeni-
sema can be extremely difficult and it is regrettable that sure macro- tal diaphragmatic hernias appear to be sporadic. Several teratogens,
scopic distinctions are often omitted from the autopsy report. In including phenmetrazine, thalomide, quinine, nitrofen and vitamin
lymphangiectasia the lungs are heavy but this is often also the case in A deficiency, have been identified. If the infant is suitable for surgical

77
 Pathology of the Lungs

A B

Figure 2.66  Arteriovenous aneurysm of the right lung demonstrated angiographically (A, B: (B) shows delayed emptying) and after lobectomy when
unusually large thin-walled blood vessels were evident on the cut surface of the lung (C). (A–C courtesy of Dr M Jagusch, formerly of Auckland, New Zealand.)
The lobectomy specimen from another patient is shown in (D). (d courtesy of Dr T Jelihovsky, Sydney, Australia.)

78
 Development of the lungs; perinatal and developmental lung disease Chapter |2|

Figure 2.68  Asphyxiating thoracic dystrophy (Jeune’s syndrome).

Deformity of the chest wall reduces the thoracic cavity to a narrow
funnel and thereby causes pulmonary hypoplasia. (Courtesy of the late Dr
AH Cameron, Birmingham, UK.)

tration. The whole diaphragm may be affected but more often the
defect is unilateral.
B Posterolateral herniation and eventration are both commoner on
the left and affect boys twice as often as girls. Anterior and para­
Figure 2.67  Congenital pulmonary lymphangiectasia. (A) Cystically oeso­phageal hernias each account for only 5% of the total, while
dilated lymphatics are evident on the cut surface of the lung. (Courtesy of total absence of half or the whole diaphragm is very unusual.491 All
Dr M Jagusch, formerly of Auckland, New Zealand.) (B) Lymphatics in the these diaphragmatic defects result in abdominal viscera moving
interlobular septa are markedly dilated. into a pleural space and compromising lung development (see pul-
monary hypoplasia, p. 70). Hepatopulmonary fusion is a much rarer
association.491a
Duplication of the diaphragm results in a fibromuscular septum
correction, respiratory insufficiency and persistent fetal circulation are dividing one pleural cavity in two, usually between the right upper
frequent postoperative problems. The foramina are normally sealed and middle lobes. Associated anomalies of the heart and lungs are
at about 8 weeks’ gestation by the pleural and peritoneal mem­ frequent.
branes so that hernias forming after this time tend to be enclosed in
a serosal sac. Pectus excavatum (funnel chest)
The diaphragmatic muscle is formed between the pleural and peri- This condition is relatively common, being found in approximately 1
toneal membranes and if it is deficient the diaphragm is reduced to a child in 400. Males are affected more commonly than females. The
thin membrane, which rises into the thorax, a process known as even- condition appears soon after birth and is occasionally associated with

79
 Pathology of the Lungs

kyphosis, scoliosis or mitral valve prolapse. It may be familial or Asphyxiating thoracic dystrophy (Jeune’s syndrome)
associated with Marfan’s syndrome, the Ehlers–Danlos syndrome and
This is a rare disorder of the ribs, which are shortened and the ribcage
hyperflexibility of the joints. It may also be acquired in infancy by
narrowed so that lung development is retarded and there is pulmo-
upper-airway obstruction from enlargement of the tonsils and ade-
nary hypoplasia (Fig. 2.68).493,494 Less severe degrees are compatible
noids necessitating an increase in the force of the respiratory move-
with life but respiratory movements are entirely abdominal and
ments. Initially the condition is reversible but it may become
respiratory failure often develops in infancy or childhood. Although
permanent. The respiratory effects are minor but the heart may be
rare, Jeune’s syndrome is the commonest of several generalised
compressed between the depressed sternum and the spine so that
skeletal disorders that result in a small chest. In many of them the
cardiac filling is impaired.492 Surgical correction is sometimes under-
thoracic deformity is associated with short limbs, syndactyly or
taken, largely for cosmetic or psychological reasons as it confers only
polydactyly.495
marginal functional benefit. It is best deferred until the growth spurt
of puberty is over as the basic fault of both pectus excavatum and
pectus carinatum is an overgrowth of the costal cartilages, causing the
sternum to buckle inwards in the former condition and outwards in
Scoliosis
the latter. Scoliosis (lateral curvature of the spine) is generally accompanied by
rotation of the spine. If the condition is present at birth there is often
a recognisable congenital abnormality of the spine, such as hemiver-
Pectus carinatum (pigeon breast)
tebra, and other congenital skeletal abnormalities such as absent or
In this condition the sternum protrudes anteriorly and may lie fused ribs may also be present. However, most cases are idiopathic.
obliquely if the excessive growth of the ribs is asymmetrical. It may Some idiopathic cases present in infancy. These tend to progress to
be present at birth but usually becomes prominent during adoles- respiratory failure in later life.388,389 However, it is commoner for idi-
cence. About 1 in 1500 children are so affected. Respiratory function opathic scoliosis to appear during adolescence and not progress in
is normal as there is no loss of lung volume and little interference this way. Scoliosis may also be secondary to neuromuscular disorders,
with rib movement. both hereditary and acquired.

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463. Dines DE, Arms RA, Bernatz PE, et al.
Cardiovasc Intervent Radiol study. Chest 1992;102:1274–7.
Pulmonary arteriovenous fistulas. Mayo
1990;13:345–6. 489. Gianlupi A, Harper RW, Dwyre DM, et al.
Clin Proc 1974;49:460–5.
476. Reynaud-Gaubert M, Thomas P, Gaubert Recurrent pulmonary embolism associated
464. Przybojewski JZ, Maritz F. Pulmonary
JY, et al. Pulmonary arteriovenous with Klippel–Trenaunay–Weber syndrome.
arteriovenous fistulas. A case presentation
malformations: lung transplantation as a Chest 1999;115:1199–201.
and review of the literature. S Afr Med J
therapeutic option. Eur Resp J 490. Clugston RD, Klattig J, Englert C, et al.
1980;57:366–73.
1999;14:1425–8. Teratogen-induced, dietary and genetic
465. Prager RL, Laws KH, Bender Jr HW.
477. Faughnan ME, Lui YW, Wirth JA, et al. models of congenital diaphragmatic hernia
Arteriovenous fistula of the lung. Ann
Diffuse pulmonary arteriovenous share a common mechanism of
Thorac Surg 1983;36:231–9.
malformations – Characteristics and pathogenesis. Am J Pathol
466. Gossage JR, Kanj G. Pulmonary prognosis. Chest 2000;117:31–8. 2006;169:1541–9.
arteriovenous malformations – A state of
478. Ference BA, Shannon TM, White RI, et al. 491. Sheehan JJ, Kearns SR, McNamara DA,
the art review. Am J Respir Crit Care Med
Life-threatening pulmonary hemorrhage et al. Adult presentation of agenesis of the
1998;158:643–61.
with pulmonary arteriovenous hemidiaphragm. Chest 2000;117:901–2.
467. Grishman A, Poppel MH, Simpson RS, malformations and hereditary hemorrhagic
et al. The roentgenographic and 491a.  Gander JW, Kadenhe-Chiweshe A, Fisher
telangiectasia. Chest 1994;106:1387–90. JC, et al. Hepatic pulmonary fusion in an
angiocardiographic aspects of (1) aberrant
479. Wang N-S, Seemayer TA, Ahmed MN, et al. infant with a right-sided congenital
insertion of pulmonary veins associated
Pulmonary leiomyosarcoma associated diaphragmatic hernia and contralateral
with interatrial septal defect and (2)
with an arteriovenous fistula. Arch Pathol mediastinal shift. J Pediatr Surg 2010;45:
congenital arteriovenous aneurysm of the
1974;98:100–5. 265–8.
lung. Am J Roentgenol 1949;62:500–8.
480. Faul JL, Berry GJ, Colby TV, et al. Thoracic 492. Theerthakarat R, El Halees W, Javadpoor S,
468. Gomes MR, Bernatz PE, Dines DE.
lymphangiomas, lymphangiectasis, et al. Severe pectus excavatum associated
Pulmonary arteriovenous fistulas. Ann
lymphangiomatosis, and lymphatic with cor pulmonale and chronic
Thorac Surg 1969;7:582–93.
dysplasia syndrome. Am J Respir Crit Care respiratory acidosis in a young woman.
469. Pouwels HMM, Janevski BK, Penn OCKM, Med 2000;161:1037–46. Chest 2001;119:1957–61.
et al. Systemic to pulmonary vascular
481. Esterly JR, Oppenheimer EH. 493. Jeune M, Carron R, Beraud C, et al.
malformation. Eur Respir J
Lymphangiectasis and other pulmonary Polychondrodystrophie avec blocage
1992;5:1288–91.
lesions in the asplenia syndrome. Arch thoracique d’évolution fatale. Pediatrie,
470. Akahane T, Yaegashi H, Kurokawa Y, et al. Pathol 1970;90:553–60. Lyon 1954;9:390–2.
Systemic-to-pulmonary vascular
482. Reference deleted in text. 494. Jeune M, Beraud C, Carron R. Dystrophie
malformation of lung visualized by
computer-assisted 3-D reconstruction. 483. Barker PM, Esther CR, Jr., Fordham LA, thoracique asphyxiante de charactère
Histopathology 1997;31:252–7. et al. Primary pulmonary lymphangiectasia familial. Arch Fr Pediatrie 1955;12:886–91.
in infancy and childhood. Eur Respir J 495. Greenough A. Abnormalities of the
471. Hoffman R, Rabens R. Evolving pulmonary
2004;24:413–9. skeleton. In: Greenough A, Milner AD,
nodules: multiple pulmonary
arteriovenous fistulas. AJR Am J 484. Wagenaar SS, Swierenga J, Wagenvoort CA. editors. Neonatal Respiratory Disorders.
Roentgenol 1974;120:861–4. Late presentation of primary pulmonary 2nd ed. London: Arnold; 2003. p. 505–18.
lymphangiectasis. Thorax 1978;33:791–5.
472. Hughes JMB. Intrapulmonary shunts: coils
to transplantation. J R Coll Physicians 485. White JES, Veale D, Fishwick D, et al.
Lond 1994;28:247–53. Generalised lymphangiectasia: pulmonary

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 Chapter 3 

Diseases of the conductive airways

The function of the airways is to conduct gas in and out of the lungs
CHAPTER CONTENTS
and all airway diseases are liable to impede this, resulting in ‘obstruc­
Atelectasis and pulmonary collapse 91 tive lung disease’, as opposed to the ‘restrictive lung disease’ that is
Collateral ventilation 92 caused by many diseases of the lung parenchyma. Airway obstruction
has important effects on the lung parenchyma and this chapter first
Middle-lobe syndrome 92
considers one of these, pulmonary collapse. Another important con­
Obstruction of the upper airways 93 sequence of airway obstruction is obstructive pneumonia, which is
Obstructive sleep apnoea 93 dealt with on page 315, while if airway obstruction is not relieved,
Tracheobronchopathia osteochondroplastica 94 distal infection is almost inevitable.
Relapsing polychondritis 95
Idiopathic tracheal stenosis 96
Acute tracheobronchitis and bronchiolitis 96 ATELECTASIS AND PULMONARY COLLAPSE
Diphtheria 96
The term ‘atelectasis’ means imperfect expansion, and is applied
Whooping cough (pertussis) 96
specifically to failure of the lungs to expand fully at birth. This may
Necrotising sialometaplasia 97 be due to congenital airway obstruction or pulmonary compression,
Chronic obstructive pulmonary disease 97 and is of course found in stillbirths. Once the lungs have expanded,
Chronic bronchitis 98 return to the airless state is sometimes referred to as secondary atel­
‘Wheezy’ bronchitis 100 ectasis, but is more widely known as pulmonary collapse. Two types
of pulmonary collapse are recognised, one due to pressure changes
Small-airway disease (chronic obstructive
and the other to absorbed alveolar gas not being replenished.
bronchiolitis) 100
Pressure collapse may result from external forces exerted by air or
Emphysema 102 fluid in the pleural cavity, enlargement of the heart or mediastinum,
Plastic bronchitis 109 or a thoracic tumour. Alternatively, pressure collapse may be due to
Chronic idiopathic cough 109 a rise in alveolar surface tension from depletion of pulmonary surfac­
Bronchial asthma 109 tant, as in the infantile and adult respiratory distress syndromes.
Absorption collapse is likely when bronchial obstruction prevents
Non-eosinophilic asthma 116 free entry of air into the lungs. The causes are listed in Box 3.1. Mucus
Eosinophilic bronchitis 117 frequently collects during anaesthesia, when respiratory movements
Bronchiectasis 117 are reduced and the cough reflex suppressed, whilst mucus plugging
Broncholithiasis 120 is a cardinal feature of asthma, allergic bronchopulmonary aspergil­
losis and plastic bronchitis. The inhalation of a foreign body is
Chronic bronchiolitis 120
especially common in children while the narrow, pliable bronchi of
Diffuse panbronchiolitis 124 infants are particularly liable to be compressed by distended pulmo­
References 125 nary arteries at points where they are in close anatomical proximity

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00003-3 91
 Pathology of the Lungs

Box 3.1  Causes of absorption collapse

Intraluminal lesions
Mucus
Foreign body
Endobronchial tumoura
Mural lesions
Bronchogenic carcinoma
Sarcoid
Extrinsic lesions
Enlarged lymph nodes
Distended or aneurysmally dilated arteries
a
Tumours particularly prone to grow into the lumen of an airway include
carcinosarcoma, carcinoid, bronchial gland neoplasms, metastases, lymphoma,
chondroid hamartoma, papillary neoplasms, granular cell tumour, amyloid
tumour and broncholith.

(see Fig. 10.9, p. 481) or by abnormally located systemic arteries. In

time, the alveolar air – first the oxygen and later the nitrogen – is
removed by the blood that passes through the affected area and the
alveoli then progressively collapse.
Pulmonary collapse has been seen quite commonly in the crew of
high-performance aircraft. An important cause is breathing pure
oxygen, which washes nitrogen from the alveoli and is more rapidly
absorbed into the blood. Parts of the lung filled with oxygen but
temporarily closed off by increased gravitational forces distorting
airways are liable to absorption collapse. These forces operate when­
ever the pilot makes a tight turn at high speed or pulls out of a steep
dive. Clothing designed to protect the aviator from burst lung (see p.
369) increases the adverse effect on the basal parts of the lungs by
raising the diaphragm and reducing lung volume.
Figure 3.1  Chronic pulmonary collapse due to long-standing pleural
effusion. On the right pleuropulmonary fibrosis has developed,
Pathological findings preventing the lung from ever expanding.
Whatever the cause, collapsed lungs are small and firm, and have a
deeply wrinkled pleural surface. Portions of collapsed lungs tend to
tilation, a process by which one portion of lung is ventilated through
sink when dropped into water but this is not an infallible test of
another via the pores of Kohn and other peripheral communications
airlessness. Where part of a lung has recently collapsed, the immedi­
(see p. 15). Collateral ventilation is best developed at the acinar level,
ately adjacent, pale pink, aerated lobules are sharply separated from
being hindered by the interlobular septa and prevented by interlobar
the dark red depressed areas of collapse by zigzag lines that cor­
fissures, but because interlobular septa are incomplete, it may prevent
respond to the interlobular septa (see Fig. 4.3, p. 137). The collapse
whole segments undergoing absorption collapse. However, air flow
involves alveoli and bronchioles but bronchial cartilage maintains the
through the tortuous bypass channels afforded by many pores of
patency of these larger airways. Subsequent changes differ according
Kohn is poor and collateral ventilation plays little part in gas exchange.2
to whether the collapse is due to absorption or compression. With
Its function is to maintain inflation of alveoli when their supplying
absorption collapse the affected lung resembles splenic tissue, both
airways are obstructed by secretions or a foreign body. This is essential
grossly and microscopically.1 Alveolar walls are in apposition and
to the cough mechanism, dependent upon which is the expulsion of
their capillaries are greatly dilated so that the bulk of the collapsed
the obstructive material and the restoration of bronchial patency.
lung no longer consists of air space but of sinusoidal vessels engorged
with blood, although the circulation may be reduced. The interlobular
septa are thickened but there is little fibrosis of the alveolar tissue. The Middle-lobe syndrome
changes are irreversible, suggesting that there is fusion of the apposed
alveolar walls. With pressure collapse congestion is less marked and The term ‘middle-lobe syndrome’ was coined to describe a condition
fibrosis of both the alveolar tissue and overlying pleura is more of chronic or recurrent absorption collapse of the right middle lobe
marked (Fig. 3.1). In either case, reinflation is prevented. that was originally described in 1937.3 The collapse was most fre­
quently caused by tuberculous involvement of lymph nodes com­
pressing the right middle-lobe bronchus. Tuberculosis is less common
Collateral ventilation
today but any disease enlarging these lymph nodes may have the same
When obstruction to an airway is only partial, permitting inspiration effect. Predilection for involvement of the middle lobe was considered
but hindering expiration, air is retained in the affected area and there to be the result of a combination of factors: the prominent collar of
is full inflation rather than collapse (see infantile lobar emphysema, nodes about its bronchus, the lymphatic drainage of these nodes
p. 72). Absorption collapse may also be prevented by collateral ven­ being from much of the right lung and parts of the left, and the

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 Diseases of the conductive airways Chapter |3|

Bronchiectasis involving the middle lobe or lingula of middle-aged

women has also been termed the Lady Windermere syndrome, based
upon the belief that such a fastidious person as the eponymous person
in Oscar Wilde’s play Lady Windermere’s Fan would refrain from expec­
torating and thereby retain any infected bronchial secretions.6
However, the bronchi to these portions of the lungs extend forwards
so that unless the person spent a considerable time in the prone posi­
tion the middle lobe and lingula are the least likely parts of the lungs
to be affected by aspiration (see Fig. 5.2.14, p. 189).7 Infection (or
colonisation) by Mycobacterium avium-intracellulare is frequently iden­
tified in this ‘syndrome’.

OBSTRUCTION OF THE UPPER AIRWAYS

Obstruction of the upper airways may be complete, and cause rapid

asphyxial death, or incomplete, when there is stridor or wheezing,
or distal complications such as obstructive pneumonia may ensue.
Foreign bodies are an important cause, especially in children and
edentulous adults. Tumours are another important cause. Rare causes
include amyloid tumours, Wegener’s granulomatosis8 and tracheo­
bronchomalacia. In infancy the airways are unduly pliable and may
be compressed by distended arteries, particularly where the two are in
close contact (see Fig. 10.9, p. 481). Anomalous arteries may also
compress airways in infancy, as in the vascular sling and ring syn­
dromes (see Figs 10.10 and 10.11, pp. 481, 482).

A Obstructive sleep apnoea

Obstructive sleep apnoea is characterised by repeated periods during
which the patient stops breathing for 10 or more seconds whilst
asleep. The patient may not waken but is repeatedly aroused so that
the quality of the sleep is poor and daytime sleepiness is consequently
excessive.9 Snoring is a common accompaniment. The patient is gen­
erally obese and it is postulated that cervical fat pads obstruct the
upper airway.10 Other family members are often similarly affected,
possibly because of similarities in cervicofacial structure. Charles
Dickens was evidently familiar with such individuals, portraying one
in his novel The Pickwick Papers. Such patients have therefore been
termed ‘pickwickian’, although the Dickens character was the ‘fat boy’
rather than Mr Pickwick himself. Defects in the secretion of testoster­
one and growth hormone may also be identified.11 These are
reversible and are probably due to the central effects of sleep fragment­
B ation and hypoxaemia.
The principal problem in obstructive sleep apnoea is the daytime
Figure 3.2  Middle-lobe syndrome. (A) The middle lobe is collapsed and tiredness, which leads to poor performance at work and a tendency
its bronchi are dilated. (B) In this patient the syndrome was caused by a to fall asleep at inappropriate moments. The consequences of this can
bronchiolith (arrow) blocking the lobar bronchus. be very serious if, for example, the patient drives. The periods of
apnoea result in hypoxaemia, which in turn causes pulmonary hyper­
relatively narrow calibre and possibly undue compressibility of the tension. The apnoeic episodes are also accompanied by systemic
middle-lobe bronchus. A further possible factor is the limited capacity hypertension and death may be caused by biventricular cardiac
for collateral ventilation (see above) within the middle lobe: this failure.12 The pulmonary blood vessels show the usual changes found
stems from the fact that its two segments have relatively large propor­ with hypoxia, principally hypertrophy of the arterial media (see p.
tions of their surfaces covered by pleura and, together with the inferior 424). Pulmonary haemorrhage and haemosiderosis are further fea­
segment of the lingula, are the only ones that abut no more than one tures, possibly attributable to the left ventricular failure. Pronounced
other segment.4 capillary proliferation resembling capillary haemangiomatosis (see
Patients with the middle-lobe syndrome complain of chronic p. 429) is also described.13 Continuous positive airway pressure pro­
cough, haemoptysis, chest pain and dyspnoea, and the diseased lobe vides effective treatment.14
may be removed to relieve this. Pathological changes in the resected Obstructive sleep apnoea is to be distinguished from a central
lobe include bronchiectasis, chronic bronchitis and bronchiolitis, variety of apnoea known as Ondine’s curse. In German legend, the
lymphoid hyperplasia, organising pneumonia and abscess formation, water nymph Ondine, having been jilted by her mortal lover, took
in addition to collapse (Fig. 3.2).5 A similar syndrome may affect the from him all automatic functions, requiring him to remember to
lingula. breathe. When he finally fell asleep, he died. Central apnoea has been

93
 Pathology of the Lungs

Figure 3.3  Tracheobronchopathia osteochondroplastica. (A) Bronchoscopic view. The nodules affect all but the posterior membranous portion of the
trachea, compatible with them arising from the tracheal cartilages. (B) Extensive roughening of the tracheal mucosa is seen at necropsy. (Courtesy of Dr
Sj Sc Wagenaar, Utrecht, Netherlands.)

encountered with bulbar poliomyelitis and it is likely that the syn­ Aschoff).16,23 A superficial resemblance to tracheobronchial amyloid­
drome results from damage to the medullary CO2 receptor. Airway osis (which is prone to ossify) has led to erroneous suggestions that
patency is maintained but respiratory drive is weak, especially during these two conditions are related.24–26 Growth factors that induce new
sleep. bone formation have been demonstrated about the ossifying nodules
but not about those composed of mature lamellar bone.27
Tracheobronchopathia osteochondroplastica
The first descriptions of this condition date back to the middle of the
Pathology
nineteenth century,15,16 since when it has continued to arouse interest At necropsy the tracheobronchial mucosa is roughened by numerous
because of its apparent rarity and disputed aetiology.17,18 It is confined nodular excresences (see Fig. 3.3B). Microscopy shows that the
to the trachea and bronchi and does not infiltrate surrounding tissues nodules consist of cartilage, which, like the normal cartilage of the
or metastasise but it endangers life through airway obstruction.19 It airways may calcify and ossify.19,22,28–30 These osseocartilaginous
affects men more often than women, and is seldom recognised before nodules are situated between the normal cartilage and the surface
the age of 50. Symptomatic cases are rare but it is possible that mild epithelium of the airway, causing the mucosa to protrude into and
cases are overlooked20: four cases were reported in one series of 500 compromise the lumen. The new cartilage differs from that normally
bronchoscopies.21 found in the airways only in its abnormal position. Cytologically it is
Tracheobronchoscopy reveals multiple mucosal nodules and rele­ quite normal and in a small fibreoptic biopsy is likely to be mistaken
vant to both the diagnosis and aetiology of the condition is the for the normal cartilage of the large airways. It generally appears to
observation that the membranous portion of the trachea is spared have no connection with the normal cartilage but step sections show
(Fig. 3.3).22 This suggests that the condition is related to the airway that there is indeed continuity through narrow pedicles,22,30 support­
cartilage and that the lesions represent exostoses (as suggested by ing the view that the condition represents multiple ecchondroses of
Virchow) rather than submucosal metaplasia (as suggested by the tracheobronchial cartilages,28 as originally proposed by Virchow.16

94
 Diseases of the conductive airways Chapter |3|

A C

Figure 3.4  Relapsing polychondritis. The bronchial cartilage is cuffed (A) and its edge eroded (B) by a heavy lymphoid infiltrate. (C) The burnt-out
stage. The inflammation has resolved but the bronchial cartilage is disrupted by fibrosis.

Treatment consists of nibbling the nodules away endoscopically as joints and may further contribute to respiratory difficulties. Blood
often as proves necessary. vessel involvement is characterised by vasculitis involving vessels of
all sizes and leading to aneurysms of major arteries. Occasionally,
medium-sized arteries develop aneurysms and the changes are then
Relapsing polychondritis those of polyarteritis nodosa.44 Glomerulonephritis may also
This condition is characterised by recurrent inflammation of cartilagi­ develop.45
nous structures and other tissues rich in glycosaminogycans.31–35
Immunoglobulins and complement have been identified at the chon­
Pathology
drofibrous junction,36 and the presence of circulating anticartilage
immunoglobulin and the ability of cartilage antigens to transform The affected bronchi may feel soft. Microscopically, the appearances
lymphocytes from these patients provide evidence that the disease has vary according to the degree of inflammatory activity. In the active
a tissue-specific autoimmune basis.37 stage of the disease, the tracheobronchial cartilage is less basophilic
than normal, reflecting loss of acidic proteoglycans, which may appear
in the urine.33 The tracheal and bronchial cartilages are cuffed by a
Clinical features chronic inflammatory infiltrate of lymphocytes, plasma cells and occa­
The disease affects patients of both sexes and any age but the maximum sional multinucleate histiocytes that is limited to the edge of the
frequency is in the fourth decade. It typically causes distortion of the cartilage, which is ragged and evidently under attack (Fig. 3.4A, B).32
pinnae and collapse of the nose. Other tissues involved include the In the late stages of the disease the inflammation may have resolved,
larynx, trachea, bronchi, joints, eyes, inner ears and blood vessels. leaving collagen surrounding and intersecting the cartilage matrix,
The trachea and bronchi are involved in 21% of patients but very which at this stage is fibrillary rather than amorphous and shows
rarely are they affected in isolation.38–42 Tracheobronchial involvement increased basophilia (Fig. 3.4C).33,38,40 Other components of the
is characterised by airflow obstruction due to airway collapse, manifest airway appear normal and there is generally no evidence of vasculitis
as breathlessness, cough, hoarseness and stridor.38–40 Less commonly in the airways. These features are characteristic but not specific, being
there is bronchorrhoea.43 The arthritis has a predilection for thoracic seen for example in a postintubation tracheal stricture.

95
 Pathology of the Lungs

Idiopathic tracheal stenosis The damage inflicted by soluble noxious gases and fumes is liable
to be concentrated on the main airways whereas less soluble gases are
Idiopathic tracheal stenosis is reputedly rare but one group was able prone to damage more distal air spaces, including alveoli as well as
to review 63 such patients who had required surgery at one hospital the finer conductive airways (see Fig. 7.2.2 and Table 7.2.2, p. 372).47
over a 19-year period.46 The patients were all middle-aged women Examples of the former include chlorine and ozone, whilst the latter
(mean age 49 years), one-third of whom gave a history of gastro- include beryllium, mercury and cadmium fumes, oxides of nitrogen
oesophageal reflux. None had evidence of rheumatoid disease, sys­ and high concentrations of oxygen.
temic lupus erythematosus or polychondritis and ANCA testing was
uniformly negative. The stenosis affected the subglottis or upper one-
third of the trachea and showed extensive keloid formation with dila­ Microbial causes
tation of the tracheal glands. A form of fibromatosis was postulated. In recent decades, great changes have taken place in the relative
importance of bacteria and viruses in the aetiology of acute tracheo­
bronchitis.48 Prophylactic immunisation against measles, diphtheria
and pertussis, and the availability of antibiotics effective against the
ACUTE TRACHEOBRONCHITIS
bacterial causes of secondary pneumonia, particularly pneumococci,
AND BRONCHIOLITIS have together greatly lessened the frequency of both the primary dis­
eases and the respiratory complications. Most of these microbial dis­
Acute inflammation of the conductive airways is common, especially eases are dealt with in the chapters devoted to viral and bacterial
among young children and the elderly, and a number of factors, infections (Chapters 5.1–5.3) but diphtheria and whooping cough
environmental and microbial, may contribute to its causation. There will now be described.
is a marked seasonal incidence. In the summer months the mortality
is low, but from early winter the death rate rises steadily to reach a
peak in the late winter or early spring. The time of greatest mortality Diphtheria
varies considerably from year to year, and depends partly on the sever­
Diphtheria is caused by infection with the bacterium Corynebacterium
ity of the weather and partly on the prevalence of epidemic respiratory
diphtheriae. It formerly cost many lives each year but immunisation
diseases such as influenza.
programmes have been highly successful and the disease is now very
In the normal person, the defensive mechanisms of the respiratory
rare. It is characteristic of diphtheria that the bacteria responsible
tract usually destroy or remove any inhaled microbes that may be
inhabit a surface membrane of fibrin and necrotic epithelium and that
caught on its mucus-covered surface. But if the combined defences of
much of the ill effects are due to powerful exotoxins that are dis­
mucus, ciliated epithelium and the cough reflex are weakened from
tributed throughout the body by the blood stream, typically causing
any cause, such as exposure to cold, irritant dust or vapours, or certain
myocardial degeneration and peripheral neuropathy. Infection is
specific infections, the potentially pathogenic bacteria that are ordi­
generally limited to the pharynx and only occasionally does it
narily resident in the nose and pharynx may succeed in temporarily
spread down to cause acute laryngitis, tracheitis and bronchitis. The
colonising the mucosa of the trachea and bronchi. In the pathogenesis
typical membrane may obstruct the larynx and cause death from
of acute tracheobronchitis, therefore, these potentiating factors are of
asphyxia. More often the primary injury to the respiratory mucosa by
particular significance, for without them the responsible organisms
the locally released toxin lays the lungs open to invasion by various
might be unable to establish themselves in these portions of the
other organisms, among them Haemophilus influenzae and the pyo­
respiratory tract, which are normally sterile.
genic cocci.

Environmental causes
Whooping cough (pertussis)
Atmospheric pollution by hydrocarbon combustion products is
common in many cities, and from time to time, often in particular Whooping cough is a highly infectious bacterial disease of childhood
meteorological conditions, the level of pollution may rise to values caused by the bacterium Bordetella pertussis. It is spread by droplet
that cause an attack of acute tracheobronchitis. Los Angeles, Liège and infection. The incubation period is 7–10 days and a case is infectious
London have been notorious for their smogs but in recent years they from 7 days after exposure to 3 weeks after the onset of typical par­
have been overtaken in this respect by such rapidly growing oxysms. An initial catarrhal stage is the most infectious period. An
conurbations as Athens and São Paulo. In some cities, smoke control irritating cough then develops and gradually becomes paroxysmal,
has reduced the levels of visible particulates and sulphur dioxide but which is responsible for the typical ‘whoop’. Whooping cough
not pollution by ozone and oxides of nitrogen, which are chiefly may be complicated by bronchopneumonia, post-tussive vomiting
derived from internal combustion engines. and cerebral hypoxia, most commonly in infants under 6 months
In men engaged in industries in which irritant gases or dusts may of age.
be inhaled, the mucous membrane of the trachea and bronchi may At one time, whooping cough was one of the commonest causes of
become acutely inflamed, and occasionally noxious gases such as death in children, and its decline in the developed countries of the
ammonia, oxides of nitrogen and sulphur dioxide may be breathed world since the Second World War represents one of the notable
in such concentrations that widespread injury to the respiratory contributions of prophylaxis to public health. In the UK, for example,
mucosa may follow. Silo-filler’s disease, described on page 356 widespread immunisation resulted in a 30-fold reduction in the
[ch 7.1], is one such example. The use of thermal lances on steel is number of notifications, and deaths became rare. Understandably,
ordinarily safe but if special alloys of steel are attacked with these complacency followed, and when publicity was given to cerebral com­
tools the inhalation of beryllium, cadmium and other hot metal plications of the vaccine in 1974, its acceptance rate dropped dramati­
fumes may cause acute bronchiolitis and diffuse alveolar damage. In cally, followed in 1977 by the biggest epidemic for 20 years (Fig. 3.5).
the First World War, the military use of chlorine and phosgene as Subsequent studies showed that the risk of permanent brain damage
poisonous gases was often followed by destructive lesions throughout was very small – 1 in 310 000 injections. Increased vaccine uptake
the respiratory tracts of the exposed troops. resulting from a return of public confidence cut short an expected

96
 Diseases of the conductive airways Chapter |3|

lobular distribution. There is often mucous extravasation and a mixed

acute and chronic inflammatory infiltrate. Regenerative hyperplasia,
200,000 100
often with squamous metaplasia, is usually first evident in the gland

Vaccine coverage percentage

80 ducts. The changes are benign and self-limiting but in small biopsies
150,000 may be mistaken for those of squamous cell carcinoma or muco­
60
Notifications

epidermoid carcinoma. Identification of the investing myoepithelial

Immunisation
40 cells by staining for smooth-muscle actin favours sialometaplasia as
100,000 initiated
20 these cells are soon destroyed by invasive growths.56 Low immuno­
reactivity for p53 also favours this benign process.53
50,000 0

0 CHRONIC OBSTRUCTIVE
1940 1940 1960 1970 1980 1990 2000 PULMONARY DISEASE57
Year
Figure 3.5  Whooping cough notifications and vaccine coverage, England The term ‘chronic obstructive pulmonary disease’ (COPD) encom­
and Wales 1940–2003. passes three quite distinct conditions that have much in common:
chronic bronchitis, emphysema and one that was formerly thought to
be a subtype of chronic bronchitis but is now increasingly recognised
as a separate disease. No specific name exists for this condition but it
epidemic in 1986 and in 1991, when uptake had risen to 88%, an is generally known as small-airway disease or chronic obstructive
anticipated epidemic failed to materialise. bronchiolitis. It is important to understand how these three diseases
B. pertussis has a marked tendency to attach itself to respiratory differ and what features they share. One obvious difference is that
epithelium.49 In fatal cases, B. pertussis can be recovered from the chronic bronchitis and small-airway disease involve conducting
lungs, and the organisms can be seen microscopically in large numbers airways of differing size whereas emphysema involves the alveoli.
in the thick mucopurulent film that covers the mucosa of the trachea Another is that, whilst chronic bronchitis is hypersecretory in nature,
and the bronchi. The mucus may be so viscous that it obstructs the small-airway disease is essentially obstructive, and emphysema is a
passage of air and so leads to segmental lung collapse. Spread of the purely destructive process. However, they are related in their causa­
infection via the airways results in bronchopneumonia. In recent years tion. The most important aetiological factors in all are cigarette
intractable pulmonary hypertension has been recognised in some fatal smoking and atmospheric pollution, and for this reason they fre­
cases, with large collections of leukocytes being found within the quently coexist. They all show airflow limitation to some degree and
pulmonary vessels in such cases.50 can therefore be difficult to distinguish clinically, although the ventila­
Although B. pertussis itself seems to be capable of establishing an tory defect is based on very different structural abnormalities. In
acute inflammatory reaction in the lower respiratory passages, it chronic bronchitis the airflow limitation is due to inflammatory
would appear from bacteriological studies at necropsy that the termi­ thickening of the wall and intermittent luminal plugging; in small-
nal, fatal bronchopneumonia is more often caused by Haemophilus airway disease, to inflammatory thickening of the wall and peribron­
influenzae or by one of the pyogenic cocci; these are enabled to enter chiolar fibrosis; and in emphysema to premature closure of inherently
the lungs by the damage caused by the Bordetella, which impairs the normal or atrophic airways because of diminished pulmonary elastic
tracheobronchial defence mechanisms. In infants this complication is recoil.
the chief cause of death in whooping cough, which in many countries
is still one of the most fatal infectious diseases in the first 2 years of
Morbidity and mortality
life. Bronchiectasis is a notable complication amongst survivors.
COPD is the fourth leading cause of death in Europe and North
America and with the increase in smoking in developing countries it
Necrotising sialometaplasia is expected to become the third leading cause of death worldwide by
Throughout the lower respiratory tract regenerative processes may be 2020.58 Death comes many years after the onset of the disease and
so atypical that carcinomatous transformation has to be considered COPD is therefore also a major cause of sickness and incapacity for
in the differential diagnosis. This impression is often augmented by work. The social gradient of the disease is steep; the death rate in
excessive mitotic activity and metaplasia. Thus, at the alveolar level the poorest section of the population is some five times that in the
necrotising lesions such as infarcts and the granulomatoses may be most prosperous. Death is due to respiratory insufficiency, often
bordered by foci of atypical squamous hyperplasia that are easily complicated by bronchopneumonia, cardiac failure or pulmonary
mistaken for squamous cell carcinoma. Similarly, damage to the thromboembolism.59 There is also a four- to fivefold increased risk of
bronchial epithelium is often followed by atypical regeneration that lung cancer in patients with COPD, as compared with controls
is easily mistaken for carcinoma,51 particularly when exfoliated cells matched for cigarette smoking.60,61
are being examined. Bronchoscopy inevitably involves bronchial
injury and cytopathologists have to be aware of the atypicalities that
follow this procedure. Necrotising lesions of the larynx are sometimes Clinical features
accompanied by atypical regeneration that involves both the surface Patients with COPD are generally current or former smokers over 35
epithelium and the submucosal glands: the term ‘necrotising sialom­ years of age. The sex ratio reflects recent smoking patterns so that in
etaplasia’52,53 has been applied to this and to a similar process involv­ the UK, for example, the disease formerly showed a marked male
ing the trachea in patients with herpetic tracheitis undergoing repeated predominance but is now becoming less common in men and more
intubation.54,55 Microscopically there is coagulative necrosis of the common in women. Whether or not there is a sex difference in sus­
tracheal glands with the ghost outlines of the acinar cells retaining a ceptibility is uncertain.61a

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 Pathology of the Lungs

Patients complain of breathlessness, impaired exercise tolerance while simple mucoid bronchitis progresses to the mucopurulent
and cough. Wheeze is more suggestive of asthma but the conditions variety, this does not progress in turn to the obstructive form. In line
may coexist. The cough is particularly likely to be productive in with this, neither bronchial gland size nor sputum production is
chronic bronchitis. The sputum is typically mucoid and white but the significantly related to airflow limitation.76 The view that the develop­
disease is marked by episodes of acute bronchitis when the sputum ment of obstructive bronchitis is independent of the repeated respira­
becomes purulent and yellow. Later the sputum may become purulent tory infections that characterise mucopurulent bronchitis has been
continuously; it accumulates in the bronchi during sleep and causes challenged77 but the obstructive form of the disease is now
severe obstruction of the airways until it is coughed up in the morning. nevertheless widely recognised as a separate condition – small-airway
Whilst a change from white to yellow sputum usually signifies infec­ disease.
tion it should be noted that large numbers of eosinophils also render
the sputum yellow, a potential pitfall in the clinical distinction of
bronchitis and asthma.
Aetiology
Microbiological examination of the sputum in chronic bronchitis Chronic bronchitis affects mainly the middle-aged and elderly and is
has shown that the most frequent and important pathogens commoner in men; cigarette smoking is by far the most important
are Haemophilus influenzae, Streptococcus pneumoniae, Branhamella cause.58,78,79 The influence of cigarette smoke often begins in infancy
(Moraxella) catarrhalis and Chlamydia pneumoniae.62–67 Purulent sputum when the child is exposed passively to parental cigarette smoke. This
usually contains one or more of these organisms in abundance: they is generally augmented by active cigarette smoking when the child
tend to disappear after antimicrobial therapy when the sputum emulates parents or schoolmates and acquires the habit, often becom­
becomes mucoid again. ing addicted for life. However, as with lung cancer, many indulge
The productive cough appears at first only in the winter months; in smoking with impunity, indicating that susceptibility to disease
later it is present all through the year, characteristically with acute varies considerably,57 probably reflecting genetic differences in the
exacerbations in winter that are usually precipitated by a viral control of factors such as the balance of helper and cytotoxic T lym­
infection.68,69 phocytes.80 Marijuana smoke is likely to be recognised as a further
The majority of patients with COPD suffer from both obstructive aetiological agent as it has similar morphological effects on the
airway disease and emphysema but a minority of patients have only airways as tobacco smoke.81
one of these conditions. Two clinical syndromes, types A (‘pink Other factors contributing to chronic bronchitis include general air
puffer’) and B (‘blue bloater’), have been described with the former pollution, which accounts for the higher prevalence of the disease in
thought to indicate emphysema and the latter chronic bronchitis.70,71 urban communities, domestic air pollution, which is important in
The association of the type A syndrome with emphysema is fairly well many poor communities due to the combustion of biomass,82–84a
established but the association of type B with chronic bronchitis is occupational dust exposure,85,86 fog, and a damp, cold climate. The
not well substantiated morphologically. Type A patients show rapid morbidity from the disease rises every winter, and remains high
shallow breathing and this maintains near normal blood gases at the throughout the colder, damper months. The occurrence of fog, espe­
cost of subjective breathlessness. They are usually thin and because cially that form known as smog in which the water vapour becomes
their blood gases are not severely deranged they tend not to develop heavily contaminated with smoke and sulphurous gases, causes a
polycythaemia or cor pulmonale. Type B patients on the other hand prompt increase in both morbidity and mortality among older people.
are hypoxic and therefore suffer from polycythaemia and repeated The heavy 4-day smog in London in 1952 is believed to have precipi­
bouts of congestive cardiac failure. They are usually obese and oede­ tated 4000 deaths.
matous and have a productive cough but they are seldom severely Infections by respiratory viruses and bacteria are also of importance
breathless. It is important to realize that most patients with chronic in both initiating and promoting chronic bronchitis.87 Some patients
airflow limitation do not fit neatly into one or other of these types. may recall a liability in their earlier years for head colds to go to their
Nor do these two types reflect pure bronchitis or pure emphysema.72 chest.88 Relatives are often similarly affected. An increased frequency
The fundamental difference between type A and type B patients may of respiratory infection in childhood has been identified in adults
be in the brain rather than the lungs: type B patients seem to have a with chronic bronchitis.89
respiratory centre that is relatively unresponsive to the usual stimuli, These various irritants initiate mucus secretion by a combination of
an abnormality that may be genetically determined. direct action on the mucous cells and nervous reflexes involving
sensory nerve endings in the airway epithelium and both local pepti­
dergic and spinal cholinergic pathways. Upregulation of the mucin
Chronic bronchitis (MUC) genes is involved and epidermal growth factor is a key media­
tor in the mucous cell hyperplasia.
Definition
Chronic bronchitis is defined in clinical terms as a persistent or recur­
rent excess of secretion in the bronchial tree on most days for at least Morbid anatomy
3 months in the year, over at least 2 years.73 The secretions of the When the lungs of a patient with chronic bronchitis are dissected
normal human respiratory tract are believed to total less than 100 ml at necropsy, the exposed bronchi, especially those in the lower lobes,
in 24 hours, all of which is swallowed without the conscious need to are typically filled with a mixture of mucus and pus. When the puru­
clear the throat or cough so that the normal person produces no lent material is washed away from bronchi that have been opened
sputum. The diagnosis of chronic bronchitis may be made only when longitudinally, the underlying mucous membrane is seen to be a
other conditions that cause expectoration, such as tuberculosis and dusky red. The calibre of the main bronchi may remain unchanged
bronchiectasis, have been excluded. but distal bronchi characteristically are slightly dilated: when they
Chronic bronchitis was formerly subdivided into simple mucoid are opened with fine scissors, the dilation is found to reach almost
bronchitis, mucopurulent bronchitis and obstructive bronchitis.74 It to the pleura (Fig. 3.6).90 Some consider the dilation to be due to
was widely thought that these subdivisions represented successive atrophy of the bronchial wall and describe it in association with
phases of the disease but a strong counterargument to this was emphysema rather than as a feature of chronic bronchitis.91,92 Others
advanced by British epidemiologists.75 These workers showed that, have described degenerative changes in the bronchial cartilage

98
 Diseases of the conductive airways Chapter |3|

Figure 3.6  Chronic bronchitis. The bronchi do not show the normal
peripheral narrowing; their calibre is maintained until they approach the
pleura. (Courtesy of the late Professor BE Heard, Brompton, UK.)

Figure 3.8  (A) Normal bronchus. (B) Chronic bronchitis. As well as

enlargement of the submucosal glands, chronic bronchitis is characterised
by a shift in the nature of the glands from the normal mixed seromucous
pattern to one that is almost entirely mucous, while within the mucous
acini there is a shift from mixed neutral and acidic (red/blue) mucus to
purely acidic (blue) mucus. A further shift within the acidic mucus, one
from sialomucin to sulphomucin, is not apparent with this Alcian
blue-periodic acid–Schiff stain.

acidic and within the acidic mucins sulphomucin increases at the

expense of sialomucin, alterations that possibly increase sputum
viscosity. The mucous acini and their ducts become distended with
Figure 3.7  Chronic bronchitis. The bronchial glands are greatly enlarged;
retained mucus.94,96
the Reid index measures 0.6, double the normal. The bronchial glands
are also almost entirely mucous in type.
It is possible to correlate the clinical history of chronic bronchitis
with the size of the bronchial glands. This may be done by measuring
the ratio of the thickness of the gland layer to the thickness of the wall
in chronic bronchitis and emphysema and have correlated this between the base of the surface epithelium and the internal limit of
with the degree of inflammation.93 The lung substance is often emphy­ the cartilage plates. The fraction occupied by the glands is known as
sematous in patients with chronic bronchitis and there may be the Reid index.94 In chronic bronchitis this may double from the
bronchopneumonia. normal value of 0.3 (see Figs 3.7 and 3.8). The Reid index takes no
account of the glands situated between the cartilaginous plates and a
more accurate method of assessing the size of the glands is to estimate
Histological appearances their cross-sectional area as a percentage of that of all the bronchial
The main features of chronic bronchitis become apparent only when wall components.97,98 This is now greatly facilitated by the use of a
the lungs are examined histologically. The submucosal glands are computerised digitising tablet rather than relying on the accurate but
much enlarged, and there is a shift in gland type from mixed seromu­ tedious method of point counting.
cous to pure mucous (Figs 3.7 and 3.8).94 The enlargement is primarily As well as the glands, the epithelium that lines the bronchi shows
a hyperplastic change.95 Furthermore the usual mixture of neutral and signs of increased mucus production, the proportion of goblet cells
acidic glycoprotein in bronchial mucus changes to one that is largely being increased at the expense of the ciliated cells (Fig. 3.9).99 Also,

99
 Pathology of the Lungs

Figure 3.9  Chronic bronchitis. In the surface epithelium, goblet cells are
increased at the expense of the ciliated cells.

the surface epithelium may undergo patchy squamous metaplasia.

The accompanying loss of cilia, which ordinarily clear bacteria
and dust particles from the lower respiratory tract, predisposes to
infection.
The fall in the proportion of serous to mucous acini in the bron­
chial glands may also be expected to promote infection as the serous
cells are a major source of the antibacterial agents lysozyme and
lactoferrin100,101; however, these antibacterial agents continue to be
detectable in patients’ sputum.102 The serous cells also contribute the
secretory piece to immunoglobulin A, so protecting it from proteo­
lytic degradation. Reduced expression of this secretory piece has been
demonstrated in severe COPD.103 The serous cells are also a major
source of secretory leukocyte protease inhibitor.104 This factor can be
Figure 3.10  Chronic bronchitis with superadded infection. The
identified in the sputum of patients with chronic bronchitis but
submucosal glands are enlarged, a gland duct is plugged by mucus,
normal values have not been established: a diminution could help mucus has accumulated in the bronchial lumen and as a consequence
explain why chronic bronchitis and emphysema are so commonly of secondary infection there is also pus in the lumen and chronic
associated. inflammation of the bronchial wall.
Mucus accumulates in the airways and may completely fill their
lumen. With infection, neutrophil leukocytes are added to the mucus
and the airway wall is swollen by oedema and an acute inflammatory purely bronchitic subjects and the increased amount found in atopic
infiltrate; between acute attacks, the wall of the airways is infiltrated asthmatics.112
by lymphocytes and macrophages and its blood vessels are congested. Constitutional factors, in particular bronchial hyperactivity, may
The lymphocytes are largely CD8-positive (cytotoxic/suppressor) T contribute to airflow limitation in certain cigarette smokers who
cells, in contrast to the CD4-positive Th2 cells found in asthma.99,105,106 develop ‘chronic asthmatic bronchitis’.113 This concept is embodied
Thus, although essentially hypersecretory, chronic bronchitis is also a in what has become known as the ‘Dutch hypothesis’ – that smokers
truly inflammatory disease (Fig. 3.10).107 Furthermore, it appears that with progressive airflow limitation have increased bronchial reactivity
the inflammation in turn promotes hypersecretion,108,109 a process and atopic features similar to, but less marked than, those observed
envisaged by an older generation of pathologists when they spoke of in asthma.114 The observation that cigarette smokers have elevated
catarrhal inflammation. A vicious cycle is thus set in motion in chronic serum immunoglobulin E levels raises the possibility that some of the
bronchitis, as in bronchiectasis (see p. 119). In contrast to bron­ adverse effects of smoking might be immunologically mediated.115
chiectasis, however, the musculature and cartilage of the bronchial However the elevated serum immunoglobulin E in smokers does not
walls remain intact in chronic bronchitis.90 appear to be specific for the common seasonal aeroallergens. Chronic
bronchitis and asthma are compared in Table 3.1.116

‘Wheezy’ bronchitis
Small-airway disease (chronic
Hyperplasia of bronchial muscle in chronic bronchitis is reported by
obstructive bronchiolitis)
some observers110 but not by others.111 The explanation for this dis­
crepancy may be that some patients have features of both asthma and The aetiological differences between chronic bronchitis and small-
bronchitis. The amount of muscle in the airways of these ‘wheezy airway disease are as yet unclear but cigarette smoking is undoubtedly
bronchitics’ is intermediate between the normal amounts found in important in both. The latter condition is met more often in those

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 Diseases of the conductive airways Chapter |3|

Table 3.1  Comparison of chronic bronchitis and asthma116

Chronic bronchitis Asthma

Age Over 35 years Any

Smoking history Almost invariable Possible
Cough Persistent and Intermittent and
productive non-productive
Breathlessness Progressive and Intermittent and
persistent variable
Nocturnal Uncommon Common
symptoms
Family history Uncommon unless Common
family members also
smoke Figure 3.11  Peribronchiolitis and fibrosis in small-airway disease.
Concomitant Uncommon Common
eczema or
allergic rhinitis
patients whose breathlessness steadily increases with the years and in
Airflow Fixed and irreversible Variable and reversible
obstruction whom there is progressive deterioration in exercise tolerance leading
to inability to continue working.
Sputum Macrophages Eosinophils Postmortem studies have shown that in chronic obstructive lung
Neutrophils Charcot–Leyden crystals disease the major site of airflow obstruction is in airways of about
Creola bodies 2 mm diameter or less.117 Airways of this calibre, which correspond
Curschmann’s spirals to those of approximately the eighth generation, have subsequently
Postmortem Excess mucus Mucous plugs become generally known as ‘small airways’. They include both small
appearances Bronchial dilatation Hyperinflation but no bronchi and proximal bronchioles.
Associated emphysema emphysema Such small-calibre airways are numerous and in health they have a
large collective cross-sectional area so that they normally contribute
Airway CD8+ T cells CD4+ T cells
little to total airflow resistance (see Fig. 1.8, p. 7). Many may be lost
inflammation Neutrophils periodically Eosinophils
before there is any appreciable impairment of airflow. It is likely
Mast cells
therefore that many cigarette smokers are progressively developing
Airway Present Present obstructive airway disease long before they notice any significant
congestion reduction in their respiratory capabilities. For this reason the periph­
and oedema ery of the lung has become known as its ‘silent zone’.
Airway Intact Fragile with stripping
epithelium Goblet cell hyperplasia Goblet cell hyperplasia Histopathology
Squamous metaplasia Squamous metaplasia
Small-airway disease is characterised by bronchiolar goblet cell hyper­
Basement Mild-to-moderate Marked plasia.118 This takes place at the expense of Clara cells,119 which,
membrane together with the serous cells of the bronchial glands, secrete an air­
reticular layer way-specific low-molecular-weight protease inhibitor (antileukopro­
thickening tease), which is a potent protective factor against the development
Bronchial glands Marked enlargement Moderate enlargement of emphysema.104,120–123 There is also inflammation in the smaller
of the mucous acini of both mucous and bronchi and bronchioles. Similar chronic inflammatory changes to
serous acini those affecting the larger airways in chronic bronchitis are observed
in the walls and adjacent tissues of bronchioles and small bronchi,
Mucin Shift from neutral to Unchanged the predominant cell again being the CD8-positive T lymphocyte.124
histochemistry acid and within the
Wall thickening125 and fibrosing peribronchiolitis126 (Fig. 3.11) lead
acid mucins from
to the lumen becoming severely reduced: this causes irreversible
sialo- to sulpho-
obstruction and severe airflow limitation. The narrowing takes the
Airway muscle May show hypertrophy Marked hypertrophy form of focal stenoses.127 Proximal to the stenoses the bronchioles are
often dilated. Bronchographic medium pools in the dilated segments,
Major Cor pulmonale Allergic
giving what has been described as a ‘mimosa flower’ effect,128 and
complications bronchopulmonary
aspergillosis
there is an absence of peripheral filling.129 The focal stenoses are dif­
ficult to identify in random sections but are well demonstrated in
plastic casts of the airways (Fig. 3.12).130,131 Alternatively, quantitative
methods may be employed: these show both organic narrowing and
mucus plugging of small airways.132 It is likely that cases of small-
airway disease were included among the patients with chronic lung
diseases studied by McLean.133–135 In many smokers peribronchiolar

101
 Pathology of the Lungs

Airways may be normal in emphysema. Alternatively, they may be

atrophic and dilated but prone to collapse prematurely,91,92 unless
there is also chronic bronchitis with its characteristic thickening of the
airway wall by glandular hyperplasia and inflammatory oedema.

Definition
Emphysema was defined in 1959 as a condition of the lung charac­
terised by increase beyond the normal in the size of air spaces distal
to the terminal bronchiole either from dilatation or from destruction
of their walls.73 Subsequently, this was modified by excluding purely
distensive forms of pulmonary enlargement so that the definition
became: ‘an abnormal increase in the size of air spaces beyond the
terminal bronchioles with destruction of air space walls’.139 This seems
to be the most sensible definition. However, in some patients the
destruction is secondary to scarring and it has been suggested that this
type of air space enlargement should also be excluded from the defini­
Figure 3.12  Small-airway disease. Plastic cast of some small airways of a tion. The American Thoracic Society accepted this recommendation
patient dying of chronic obstructive bronchiolitis, showing a focal and adopted the following definition: ‘abnormal, permanent enlarge­
stenosis. (Courtesy of Professor J Bignon, Creteil, France.) ment of the air spaces distal to the terminal bronchioles, accompanied
by destruction of their walls and without obvious fibrosis’.140,141 The
exclusion of fibrosis is unfortunate for two reasons. Firstly the term
‘scar emphysema’ is a useful one and secondly those forms of emphy­
inflammation and fibrosis involve the more distal respiratory bron­ sema that are not secondary to scarring do entail some degree of
chioles and thicken the walls of adjacent alveoli so that there is restric­ fibrosis, albeit slight.142–144 More severe centriacinar fibrosis is being
tive as well as obstructive lung disease. This so-called respiratory increasingly recognised in smokers in association with what is
bronchiolitis-associated interstitial lung disease overlaps with yet described as air space enlargement, a term that is used in place of the
another effect of cigarette smoking, namely desquamative interstitial term ‘emphysema’ because of the fibrosis. This combination
pneumonia, and is dealt with on page 313. of centriacinar air space enlargement and fibrosis is often termed
smoking-associated interstitial lung disease and is considered again
under this title on page 373.
Complications
Patients with small-airway disease are prone to develop cor pulmo­ Pathology
nale, mainly as a result of widespread hypoxic pulmonary vasocon­ Early emphysematous changes can only be detected microscopically:
striction and the consequent rise in pulmonary vascular resistance. these include an increase in the size and number of fenestrae (pores
Hypoxic pulmonary hypertension is dealt with on page 424. A further of Kohn) in the alveolar walls.145 When the destruction is moderate
consequence of the hypoxia is a compensatory polycythaemia, the in degree, there is loss of alveolar walls, resulting in fewer alveolar
resultant haemoconcentration adding to the increased cardiac burden. attachments to bronchioles and the consequent premature closure of
Whilst death from small-airway disease is usually due to right-sided these airways on expiration.72,146–148 Quantitation of the microscopic
heart failure, obstructive respiratory failure and bron­chopneumonia changes in the lung substance can best be achieved by the application
also contribute. These conditions are often present in combination. of an image analyser set to calculate factors such as mean linear inter­
cept149,150 or the air space wall surface area per unit volume.151,152 More
severe changes are characterised by complete loss of most of the wall
of the air spaces, bronchiolar as well as alveolar, leaving only a
Emphysema
network of blood vessels and some interlobular septa.
Emphysema denotes pathological inflation of the affected tissue. Two These gross changes are better appreciated by the macroscopic study
fundamentally different forms are recognised, vesicular and interstitial of whole lung slices rather than microscopy. If the lungs are fixed by
(or surgical). The first affects spaces that normally contain air whilst distension with aqueous formalin at a pressure of 25–30 cm of water
the second represents the ingress of air into the normally airless inter­ before slicing, the emphysema can be appreciated much better than
stitial planes of the lung and contiguous connective tissues outside in the collapsed fresh lung. Fixation overnight is adequate and if time
the lung. The distinction between vesicular and interstitial emphy­ presses a few hours’ fixation is beneficial. If the fixed slices are impreg­
sema was first made by Laennec in 1819 but pathological descriptions nated with barium sulphate, deficiencies in the lung substance are
of the condition have been traced back to as early as 1679.136 The highlighted and the amount of destruction and the type of emphy­
adjective vesicular has fallen into disuse and may be inferred when sema can be better appreciated.153 Barium sulphate impregnation is
the term ‘emphysema’ is used without qualification. Although inter­ simply achieved by gently squeezing a slice of lung in a saturated
stitial emphysema does not fall within current definitions of emphy­ solution of sodium sulphate and then immersing it in one of barium
sema the term ‘interstitial (or surgical) emphysema’ persists and the nitrate. Paper-mounted whole lung sections can be prepared if a per­
condition is described as such on pp. 48 and 108. manent record is desired.154 Various ways of quantitating the gross
Vesicular emphysema is a common condition. A consecutive series changes have been recommended155 but none is as accurate or as easy
of 50 male necropsies in London identified emphysema in more than as computerised image analysis.156
trace amounts in 37, although few of the patients had respiratory Several morphological types of emphysema are distinguished
symptoms.137 Similar findings have been reported in other English according to the part of the acinus that is affected, as observed in
cities.138 whole lung slices or paper-mounted whole lung sections. Three of

102
 Diseases of the conductive airways Chapter |3|

Pleura or AS
Paraseptal emphysema
septum This form of emphysema affects air spaces adjacent to septa or to the
AD AS
AS
RB3 AS pleura, thus involving only the periphery of the lung lobules (Fig.
AS AD
AD RB3 RB3 AS 3.16B). It may result from forces pulling on the septa and perhaps
RB3
RB3 RB2
AS
also from inflammation. It may occur alone or in association with
AD
RB2
TB
RB2
RB3 other forms of emphysema.
RB1 RB1 AS
TB
Particularly large solitary bullae are apt to form in paraseptal
emphysema (Fig. 3.16A). On inspiration, emphysematous portions of
Bronchiolitis the lung in general and large bullae in particular are preferentially
inflated, in accordance with Laplace’s law, which states that a distend­
AS
ing force is proportional to surface tension and inversely proportional
RB3 AD AS

RB3
AS
to diameter. Inflation of these large useless air sacs prevents the expan­
AD
RB2 RB3 AS
AS
sion of adjacent normal lung and their excision may be beneficial.
RB3 AD
RB1
AD
AS
RB3
Subpleural bullae that are liable to rupture and cause pneumothorax
TB RB2
RB3
AD AS
TB RB1
RB2 AS are also particularly common in paraseptal emphysema. Giant bullae
may be multilocular or crossed by fibrous bands containing the rem­
nants of blood vessels.
Figure 3.13  Morphological types of emphysema in relation to the acinar Some bullae have oedematous papillary infoldings which bear a
architecture of the lung. Upper left: The normal acinus. Upper right: superficial histological resemblance to chorionic villi and this has
Centriacinar emphysema, in which third-order respiratory bronchioles are given rise to the somewhat bizarre terms placental transmogrification
predominantly involved. Lower left: Panacinar emphysema in which there of the lung and bullous placentoid lesion or, if fat is also present,
is destructive enlargement of all air spaces distal to the terminal pulmonary lipomatosis (see p. 703).
bronchiole, and the acinus is affected uniformly. Lower right: Paraseptal
emphysema. TB, terminal bronchiole; RB, three orders of respiratory
bronchioles; AD, alveolar duct; AS, alveolar sac. For simplicity only one Irregular, scar or cicatricial ‘emphysema’
order of alveolar duct and one of alveolar sac are drawn and they are
not to scale. This term has been used to describe permanent enlargement of air
spaces distal to terminal bronchioles caused by fibrosis, a category of
enlargement that is specifically excluded from the latest definitions of
emphysema (see above). This type of air space enlargement does not
these types, centriacinar, paraseptal and panacinar, are illustrated dia­
affect the lungs in any regular pattern in relation to the acini or
grammatically in Figure 3.13. The fourth type, scar or irregular emphy­
lobules, but occurs in focal areas near scars. It is a consequence of the
sema, bears no relation to the acinar architecture of the lung.
scars and is therefore often known as scar or cicatricial ‘emphysema’.
Diffuse pulmonary fibrosis is often accompanied by widespread irreg­
Centriacinar emphysema ular ‘emphysema’, which together with bronchiolectasis gives a char­
This form of emphysema is characterised by focal lesions confined to acteristic gross appearance known as ‘honeycombing’ that reflects
the centres of the acini (Fig. 3.14). They are often pigmented with end-stage fibrosis, typically in idiopathic pulmonary fibrosis (see Fig.
dust. The changes are more marked in the upper lobes, a feature that 6.10A). Apical foci of cicatricial ‘emphysema’ with bulla formation are
has been attributed to the greater gravitational forces there, conse­ found in 6% of healthy young adults and are the probable cause of
quent upon our upright posture, and also upon the support afforded many cases of spontaneous pneumothorax (see p. 711).
to the lower lobes by the diaphragm. Spaces that exceed 1 cm in size
are known as bullae and may be seen in severe cases. The alveolar
Aetiology and pathogenesis of emphysema
walls are lost; only some pulmonary vessels survive to cross the spaces
as seemingly bare strands radiating outward from their parent arteries Better knowledge of the anatomical types of emphysema has improved
to supply the alveoli of the periphery of the acini (see Fig. 3.14). our understanding of its aetiology. So too have discoveries concerning
Although centriacinar emphysema affects the upper lobes of the lungs the control of tissue proteolysis.
more severely than the lower, any part may be involved and centri­ Centriacinar emphysema is related to cigarette smoking157 and has
acinar emphysema is quite often accompanied by panacinar emphy­ long been thought to be the result of airway inflammation.126,158
sema. Severe centriacinar emphysema may be difficult to distinguish Particular blame is attached to elastases released by neutrophil leuko­
from the panacinar form but an upper-lobe predominance suggests cytes during episodes of acute inflammation. That proteases can have
that the lesions were originally confined to the centres of the acini, as this effect is shown by the experimental induction of a non-inflam­
does the presence of an obviously centriacinar form of emphysema in matory panacinar form of emphysema by the intratracheal injection
the less severely affected portions of the lung. of the proteolytic enzyme papain.159
Panacinar emphysema, in contrast, is recognised as being that form
associated with an inherited deficiency of α1-antitrypsin, which is
Panacinar emphysema normally the chief component of plasma α1-globulin.160–161a Deficiency
Panacinar emphysema involves all the air spaces beyond the terminal of this protein results in leukocyte elastases acting unopposed on the
bronchiole more or less equally (Fig. 3.15). Most classic descriptions connective tissues of the lungs.
of emphysema refer to this variety. It affects all zones or is worse in α1-Antitrypsin deficiency is inherited through an autosomal-reces­
the lower lobes. There may be a remarkable degree of parenchymal sive gene which exhibits polymorphism, the variants being classified
destruction. The lungs have a doughy feel, pit on pressure, do not alphabetically in a Pi (protease inhibitor) nomenclature according to
collapse when the chest is opened and overlap the heart because of their electrophoretic mobility. For example, PiBB is the homozygote
their great size. They appear very pale because of loss of substance; for an anodal variant and PiZZ for a cathodal variant, with PiMM
air-filled bullae, several centimetres across, may be seen. representing the homozygote for the normal M allele. There are over

103
 Pathology of the Lungs

Figure 3.14  Centriacinar emphysema. (A) Paper-mounted whole lung section. (B) Inflation fixation and barium sulphate precipitation. Dust-pigmented
deficiencies in the lung substance are confined to the centres of the acini. As well as using barium sulphate to emphasise the emphysema, the
pulmonary arteries have been injected with a barium gelatine preparation for angiography.

70 different variants. Those of particular medical relevance are the Z

Table 3.2  Serum α1-antitrypsin concentrations (expressed as
and S mutants.162–164 The frequency of Pi types in England and Wales
percentage of normal level) and frequencies of the commoner
and the corresponding serum levels of α1-antitrypsin are shown in
phenotypes in the UK162,163
Table 3.2. Although α1-antitrypsin deficiency was first identified in
Sweden, subsequent studies have shown that it affects all races.165
Phenotype Serum concentration Frequency
Madeira is reputed to have the highest prevalence.166
PiZZ homozygotes are prone to suffer hepatitis, cirrhosis or emphy­ MM 100 86
sema, the liver being the site of synthesis of the enzyme and the lung
an important site of its action.167 α1-Antitrypsin deficiency accounts MS 75 9
for about 6% of all clinically significant emphysema (PiZZ 5%, PiSS MZ 57 3
and PiSZ 1%). It is debatable whether PiM heterozygotes (PiMS and
PiMZ) have an increased risk of emphysema but it appears unlikely, SS 52 0.25
particularly if they do not smoke.168,169 SZ 37 0.2
The emphysema associated with α1-antitrypsin deficiency develops
unusually early in life, typically in the third or fourth decade. The ZZ 16 0.03
condition is familial and patients may have seen an older relative die
of the same disease. The probability of survival to age 50 years is
estimated to be 52% and to age 60 years 16%.170 Mortality is reported gesting bronchiectasis are also described.172 Rarely, several family
to be 2% a year.171 The bases of the lungs are particularly affected members suffer from either α1-antitrypsin deficiency or idiopathic
because their greater blood flow, which is attributable to gravity, pulmonary fibrosis.173
brings more leukocytes to these regions.167 Although emphysema is α2-Macroglobulin is another antiprotease that is synthesised in the
the predominant respiratory abnormality, radiographic changes sug­ liver but it is of too large a molecular size to leave the circulation.

104
 Diseases of the conductive airways Chapter |3|

Figure 3.15  Panacinar emphysema. The whole of lung acinus is affected uniformly. (A) Paper-mounted whole lung section. (B) Barium sulphate
precipitation.

However, as well as antiproteases that reach the lungs from the Neutrophils are an even richer source of proteases than macrophages
blood, antiproteases specific to the lung have been identified, notably and large numbers of these cells enter the lungs in the acute exacerba­
in the serous acini of the bronchial glands and in the Clara cells of tions that characterise chronic bronchitis. An imbalance between pro­
the bronchioles.104,120–122 A reported increase in Clara cells in small- teases and antiproteases is therefore considered to underlie the
airway disease123 possibly represents a compensatory response to aetiology of emphysema.184 The various factors contributing to this
inactivation of antiproteases by irritants such as cigarette smoke174,175 imbalance are represented in Figure 3.17. This protease–antiprotease
and to the increased release of proteases that cigarette smoke elicits theory may be invoked to explain both centriacinar and panacinar
from phagocytic cells.176 Others report that the bronchiolar goblet emphysema, which frequently coexist.
cell proliferation seen in smokers takes place at the expense of Clara The inflammatory component of emphysema is often maintained
cells.119 long after the patient gives up smoking,185 possibly because peptides
Cigarette smokers have a constant increase in alveolar macro­ derived from degraded connective tissue are chemotactic for inflam­
phages,177,178 particularly in the central part of the lung acini.179 During matory cells.186 This suggests that the disease is sometimes self-
phagocytosis these cells release proteolytic enzymes180 and a neu­ perpetuating, which may explain the progressive clinical deterioration
trophil-chemotactic factor,181 and this process is enhanced by cigarette that is seen in some ex-smokers with obstructive airway disease.
smoking.182 The role of cigarette smoking in the development of A check-valve mechanism is often envisaged to explain the forma­
emphysema was demonstrated in a radiological study of persistent tion of bullae, but pressure measurements at thoractomy show that
smokers during which foci of ground-glass attenuation probably rep­ the air in bullae is at the same negative pressure as that in the rest
resenting bronchiolocentric aggregates of alveolar macrophages pro­ of the lungs, except when they are subjected to positive-pressure
gressed to emphysema over a 5-year period in about 25% of cases.183 ventilation.187 It would appear that bullae originate in the same way

105
 Pathology of the Lungs

Smoke

Macrophage

Neutrophil

Oxidants
a Norm (inactivation)
hysem a
Emp l

Anti-proteases

Elastase

A Elastin framework

Figure 3.17  The pathogenesis of emphysema, envisaged as a

consequence of imbalance between proteases and antiproteases
in the lung.

as smaller emphysematous foci, namely by a process of unchecked

proteolysis rather than through undue distensive forces.
Cadmium is a further factor involved in the pathogenesis of emphy­
sema. It has been found that occupational exposure to cadmium
fumes over long periods can cause emphysema,188 and this clinical
observation has experimental support from the production of emphy­
sema through the introduction of cadmium into the trachea of
animals or its inhalation in the form of an aerosol.189 In humans, the
emphysema that is attributable to inhalation of cadmium affects the
upper lobes severely and is mainly of the centriacinar type.190 Cigarette
smoke is an important source of inhaled cadmium and there is a
significant correlation between the degree of emphysema and the
concentration of cadmium in the lungs at necropsy, even in the case
of patients who have not been exposed to cadmium fumes at work.191
A combination of occupational cadmium exposure and cigarette
smoking appears to be particularly dangerous.192

B
Functional effects of emphysema
Figure 3.16  Paraseptal emphysema. (A) Giant bulla formation. Although much emphasis is placed on elastin digestion in the patho­
(B) Barium sulphate precipitation. genesis of emphysema, it is debatable whether the amounts of
elastin are reduced in this disease.143,144,193 Nevertheless, if a piece of
elastic material such as a rubber band is cut at merely one point its
functional integrity is completely destroyed: focal digestion of alveolar
elastin may be expected to have a similar effect without there neces­
sarily being much overall loss of this protein. Experiments inducing

106
 Diseases of the conductive airways Chapter |3|

emphysema with elastase show that losses in elastin can be made been introduced. In addition, there is potential in techniques that
good but that the structural derangement is irreversible.194 enhance expiratory air flow by inserting bronchial valves or injecting
Although elastic recoil is often attributed to the connective tissue polymers, producing bronchopulmonary fenestrations and the thora­
framework of the lung it is markedly reduced when alveolar air is coscopic plication or compression of emphysematous lung.201–206
replaced by water, showing that it is surface tensive forces at the tis­ In the future there is also the possibility of genetic manipulation to
sue–air interface that underlies recoil. These forces are, of course, also correct α1-antitrypsin deficiency.
weakened when there is loss of alveolar tissue.
Diminished elastic recoil and severance of alveolar attachments to
bronchioles result in premature closure of these airways on expiration
(Fig. 3.18).72,146–148 The resultant air trapping is responsible for the
overinflation of the lungs and ‘barrel chest’ that are characteristic of
emphysema. Respiration is conducted near maximal lung volume,
which severely compromises inspiratory muscle function. Some adap­
tation to this is achieved by an increase in the proportion of slow
(‘endurance’) fibres in the inspiratory muscles.195
Emphysema also results in there being less alveolar surface available
for gas exchange but the extent of this is seldom appreciated when
lung slices are examined. The relationship of diameter to surface area
is logarithmic so that for a given increase in air space diameter there
is a much greater loss in surface area. Normal alveoli are about
0.25 mm in diameter, which corresponds to an alveolar surface area
of about 24 mm2/mm3, whereas by the time emphysema is just visible
to the naked eye at an alveolar diameter of 1 mm, three-quarters
of the surface area of the lung has been lost, the alveolar surface
area being reduced to 6 mm2/mm3. Emphysema that is easily recog­
nisable in the postmortem room has air spaces that measure about
4 mm in diameter, when the alveolar surface is less than 10% of
normal (Fig. 3.19).
Emphysema is often accompanied by the small-airway disease dealt
with in the preceding section. In their different ways, emphysema and
small-airway disease both contribute to the airflow limitation that
these patients suffer, one permitting premature bronchiolar closure
and the other narrowing the bronchioles, but there has been much
debate as to which of these mechanisms is the more important.

Treatment of emphysema
The cessation of smoking is essential to minimising progression of
the disease but apart from bullectomy there has, until recently, been
no effective treatment for emphysema. However, in recent years, the
intravenous infusion of α1-antitrypsin,196 lung transplantation197 and Figure 3.18  Emphysema showing bronchiolar collapse due to loss of
lung volume reduction surgery (reduction pneumoplasty)198–200 have alveolar attachments.

Figure 3.19  Relationship between alveolar diameter

and surface area. The normal alveolar diameter
is about 0.25 mm. Emphysema is just detectable
when the diameter is increased fourfold (to 1 mm),
at which time there is a 75% loss of alveolar
surface area. At autopsy the emphysematous
air spaces commonly have a diameter of 4 mm,
representing a loss of alveolar surface of
approximately 90%.

Diameter 0.25 0.50 1.00 2.00 4.00

(mm)

Surface area 24 12 6 3 1.5

(mm2 mm-3)

107
 Pathology of the Lungs

Bullectomy is practised to reduce the risk of pneumothorax and to Infantile lobar ‘emphysema’
eliminate tissue which, in accordance with Laplace’s law is preferen­
Infantile lobar ‘emphysema’ is described on page 72. It is the result
tially aerated and compresses comparatively normal adjacent tissue.
of valvular obstruction to a lobar bronchus and is characterised by
In contrast to bullectomy, lung volume reduction surgery often
extreme distension without destruction.
involves the resection of much comparatively normal lung tissue as
well as the most severely diseased portions, a seemingly paradoxical
way to treat someone who has already lost considerable lung tissue. Compensatory ‘emphysema’
The undoubted success of this operation probably stems from the This is another condition characterised by distension without destruc­
improved efficiency of the inspiratory muscles when they are no longer tion. It occurs when parts of the lung collapse or are removed.
operating at maximal stretch.207,208 Pathological examination of the Pneumonectomy leads to distension of the remaining lung rather
resected tissue is worthwhile as it occasionally reveals unexpected than true (destructive) emphysema. Lung cancer is a common reason
diseases such as fibrosis, inflammation, lymphangioleiomyomatosis for pneumonectomy, and with cigarette smoking underlying both
and even carcinoma that adversely affect the postoperative course.209,210 lung cancer and emphysema, the remaining lung may well show true
Early attempts at treating emphysema by unilateral lung transplan­ emphysema: the relationship between the pneumonectomy and the
tation were unsuccessful and at the time this was attributed to a poor emphysema is not then a causal one.
understanding of Laplace’s principles, which dictate that the inspired
air will enter the large-volume diseased lung rather than the unilateral
implant. In retrospect, rejection was the probable cause of the failure. Focal ‘emphysema’
Today, transplantation of one or both lungs is firmly established in Focal ‘emphysema’ and simple pneumoconiosis of coalworkers are
the treatment of emphysema; the success of the unilateral procedure terms applied to a distensive bronchiolectasis that closely simulates
probably depends partly upon the improved efficiency of the inspira­ the milder degrees of centriacinar emphysema.212 It may represent an
tory muscles, as in lung volume reduction surgery. early form of centriacinar emphysema but is said to affect more proxi­
Intervention at the molecular level has great potential in the preven­ mal respiratory bronchioles and to be non-destructive. Until recently,
tion of emphysema in groups particularly at risk, such as those with the UK pneumoconiosis medical panels have restricted their attention
α1-antitrypsin deficiency, and replacement or supplemental therapy to fibrosis, not attempting to distinguish focal and centriacinar
using either natural or recombinant antiproteases is being attempted. emphysema and attributing both to social factors rather than occupa­
Unfortunately the half-life of natural α1-antitrypsin is only 4 days, so tion. Others did not accept this and believed that mine dust causes
weekly infusions are needed. Recombinant α1-antitrypsin has an even chronic bronchitis, obstructive bronchiolitis and true emphysema,
shorter half-life but aerosol trials are in progress. Bronchial anti­ and in addition to this, focal dilatation of respiratory bronchioles.213–215
leukoprotease has also been produced by recombinant methods This view has now prevailed so that British miners are now compen­
and trials of this are under way. Work is also in progress on the pro­ sated financially if they have these diseases (see also p. 340).
duction of synthetic antiproteases.
Interstitial emphysema
Emphysema-like conditions The fundamental difference between this condition and those
The term ‘emphysema’ has been applied to several other conditions, described above is outlined on page 102 and may be summarised thus:
none of which falls strictly within the limits of the current definition whereas all other forms of emphysema affect spaces that normally
which requires destruction of respiratory tissue as well as the abnor­ contain air, interstitial emphysema represents the ingress of air into
mal enlargement of air spaces. tissues that are normally airless.
Air reaches the interstitial tissues of the lung when abnormal pres­
sure ruptures the alveolar walls. Interstitial emphysema is therefore a
Senile ‘emphysema’ form of barotrauma. The rupture may be due to excessively high pres­
The condition that has been known as senile ‘emphysema’ is not a sure caused by violent artificial respiration, exposure to the blast of
true form of the disease because the alterations are neither destructive explosions, sudden decompression, or tearing of alveolar walls by
nor beyond the limits of normal age change. After a developmental fractured ribs or by instruments.
period of alveolar multiplication that terminates in adolescence, there At operation or necropsy, interstitial emphysema is seen as small
is a gradual alteration in the shape of the lungs coupled with progres­ bubbles of air in the connective tissue immediately beneath the vis­
sive diminution in elastic recoil and alveolar surface area, the latter ceral pleura (see Fig. 2.16, p. 49). Large interstitial air bubbles are
reducing by about 4% in each decade after the age of 30 years.211 Total termed blebs, as distinct from bullae, which represent enlargement of
lung capacity remains constant throughout adult life but with pre-existent air spaces (see Fig. 13.4, p. 711).139 Air in the interstitial
in­creasing age the lungs change shape, increasing in height and par­ tissues may track along the connective tissue sheaths about the pul­
ticularly in anteroposterior distance. There is also a gradual shift in monary vessels to the hila of the lungs, producing mediastinal emphy­
the distribution of air from the alveoli to the alveolar ducts and bron­ sema; it may then reach the neck and present subcutaneously as
chioles. The alveolar ducts gradually enlarge and the mouths of alveoli surgical emphysema. Systemic air embolism may complicate intersti­
opening from them dilate so that the alveoli become more shallow. tial emphysema.
All these changes may be regarded as part of the normal ageing process Microscopically, minute air bubbles appear as seemingly empty
and therefore outwith the definition of emphysema. Although the interstitial spaces, particularly in the abundant connective tissue that
ageing lungs lose some elastic recoil, this is not so great as in true surrounds the pulmonary artery and airway and forms the interlobu­
emphysema, and they generally collapse when the chest is opened. lar septa. The differential diagnosis on microscopy is from congenital
This gave rise to the term ‘atrophic emphysema’ as an alternative lymphangiectasia and this can be extremely difficult, not least because
to senile emphysema and in contrast to ‘hypertrophic emphy­ the air tracks within lymphatics as well as through the surrounding
sema’ which was formerly used for true emphysema. The definition connective tissues. It is therefore helpful if the nature of the contents
of emphysema given on page 102 renders the terms atrophic, senile of the spaces, gaseous or fluid, is ascertained at necropsy. If the
and hypertrophic emphysema redundant. emphysema has been present for a few days before death, the diag­

108
 Diseases of the conductive airways Chapter |3|

Table 3.3  A comparison of mucoid impaction and plastic

bronchitis

Mucoid Plastic bronchitis

impaction

Clinical features Aggravation of Expectoration of stringy

underlying asthma. sputum
Progression to
hilar bronichectasis
Cause Atopy: allergic Unknown. Numerous
bronchopulmonary associations of
aspergillosis questionable causal
complicating relationship, e.g. heart
asthma disease, lymphatic
abnormalities,
hypogammaglobulinaemia
Gross A short stubby A long stringy bronchial cast
appearance of mucoid plug of up to eight airway
expectorate generations
Microscopic Alternating layers of Alternating layers of mucus
appearance of mucus and and fibrin with variable
plug/cast inspissated numbers of lymphocytes.
eosinophils with No eosinophils. No fungi
numerous
Charcot–Leyden
crystals and scanty
Aspergillus hyphae

Figure 3.20  A 15-cm-long bronchial cast from a patient with plastic

bronchitis. Compare with the short, stubby plugs characteristic of allergic
bronchopulmonary aspergillosis shown in Fig. 5.4.17, p. 230.

CHRONIC IDIOPATHIC COUGH

A chronic cough, defined as one lasting for more than 8 weeks, is very
nosis is simplified by the development of a foreign-body giant cell common. Usually there is an identifiable cause but this is not always
reaction to the air (see Fig. 2.18, p. 49),216–218 similar to that found in the case and it is postulated that such patients have an intrinsic syn­
pneumatosis coli and following the experimental injection of gases aptic excitability in the brainstem, spine or airway innervation that
into the subcutaneous tissues.216 enhances the normal cough reflex and persists after the resolution of
the initiating event.229 Bronchial biopsy shows non-specific changes
including goblet cell hyperplasia, increased vascularity and sub-
basement membrane fibrosis but nothing that distinguishes these
PLASTIC BRONCHITIS patients from those with cough of known cause.230

Patients with plastic bronchitis are generally well but complain of fits
of coughing that often result in them involuntarily expectorating long
stringy pieces of sputum, which causes them much social embarrass­ BRONCHIAL ASTHMA
ment.219–221,223–224 The expectorate represents a bronchial cast of up to
eight airway generations (Fig. 3.20). Microscopically the cast is seen Bronchial asthma is to be distinguished from the aetiologically dis­
to consist of alternating bands of fibrin and mucus, with the fibrin tinct condition of cardiac asthma. The latter represents pulmonary
containing variable numbers of lymphocytes.220,221 The appearances oedema consequent upon a failing left heart. Bronchial asthma, here­
suggest that the cast represents an inspissated fibrinous exudate and after called simply asthma, is a condition in which breathing is peri­
the term ‘fibrinous bronchitis’ is sometimes applied to the condition. odically rendered difficult by widespread narrowing of the bronchi
Several associated conditions have been described220,222,224–225 and it is that changes in severity over short periods of time, either spontane­
possible that some of these have a causal relationship, notably heart ously or under treatment.73 The difficulty becomes particularly appar­
failure and lymphatic abnormalities. Plastic bronchitis is often con­ ent during expiration because the airways normally collapse during
fused with the mucoid impaction of allergic bronchopulmonary that phase of respiration, and because the expiratory muscles are less
aspergillosis,226 which is characterised by the expectoration of short powerful than those that act during inspiration. Clinically, the disease
stubby gobbets of mucus (see Fig. 5.4.17, p. 230). The two conditions is characterised by episodic attacks of wheezing, tightness of the chest,
are quite different. They are compared in Table 3.3.220,227,228 shortness of breath and cough.

109
 Pathology of the Lungs

Extrinsic and intrinsic forms of asthma

Asthma is said to be ‘extrinsic’ if allergy to exogenous substances
is recognised, and ‘intrinsic’ if no such exogenous factors can be iden­
tified. Extrinsic asthma is the commoner; it usually begins in child­
hood and is generally paroxysmal, the attack starting suddenly and
lasting a few hours or days. Boys are affected about twice as commonly
as girls. Extrinsic asthma tends to become less severe as the child
grows older, and often ceases during adolescence. However, about
30% of asthmatic children continue to have symptoms in adult life.
Extrinsic asthma is often familial and some of the genes responsible
have been identified.231–234 This form of asthma is frequently preceded
by flexural infantile eczema and succeeded in adult life by perennial
vasomotor rhinitis, although in such families any one of these three
diseases may affect some members much more than others. In con­
trast, intrinsic asthma more often has its onset in adult life, is chronic,
with exacerbations and remissions less evident, and tends to worsen Figure 3.21  Charcot–Leyden crystals in sputum from an asthmatic
with age; also the symptoms are apt to become more severe in winter, patient.
when the asthmatic disabilities are likely to be complicated by infec­
tion of the respiratory tract. In both types of the disease, the dyspnoea
is characteristically accompanied by cough, wheezy breathing, some
cyanosis and expectoration. Blood eosinophilia is more prominent in thought to have contributed.250 The prognosis is worse in late-onset
extrinsic asthma but eosinophils are found in the airways in both. intrinsic asthma. Most asthma deaths occur in the elderly, although
Serum immunoglobulin E is often raised in extrinsic asthma and asthma accounts for a greater proportion of deaths in the young (0.9%
normal or low in intrinsic asthma. There is an increased incidence of of those under 25 against 0.3% overall).
nasal polyps in both forms of asthma, but especially in the intrinsic
variety and in certain asthmatic patients in whom bronchospasm is The sputum in asthma
triggered by aspirin. Despite these differences the pathological features
The sputum is viscous251 and yellow in asthma. The colour should not
are similar and an immunological basis may be envisaged in both.235,236
be taken as evidence that the sputum is infected. It is due to myelo­
peroxidase, which is found in both eosinophils and neutrophils. In
asthma, the sputum is rich in eosinophils, but not neutrophils unless
Epidemiology
there is also infection. As well as eosinophils, microscopy shows
Over the past few decades the prevalence of asthma has increased the presence of certain formed elements: Charcot–Leyden crystals,
considerably in most developed countries, where it now stands at Curschmann’s spirals and Creola bodies.
about 10%. The reason for this is unclear but it is notable that it has Charcot–Leyden crystals are found when there are large numbers of
been paralleled by similar increases in the prevalence of allergic rhini­ eosinophils. They have the shape of a pair of long, narrow, six-sided
tis and eczema. pyramids placed base to base (Fig. 3.21). Their hexagonal shape can
General atmospheric pollution has been widely incriminated but often be seen when they are cut across in histological preparations.
there is little to support this: the increase has been experienced in Chromatographic studies suggested that they consisted of lysophos­
countries such as New Zealand which have little atmospheric pollu­ pholipase derived from the cell membranes of eosinophils252 but
tion and in Philadelphia at a time when atmospheric pollution molecular analyses indicate that they represent a β-galactose-binding
declined.237 Atmospheric pollution is more likely to aggravate asthma lectin, galectin-10.253
than cause it. Changes in the home that encourage the growth of the A Curschmann spiral (Fig. 3.22) is a corkscrew-shaped twist of
principal allergen, the house dust mite (higher temperature and condensed mucus several millimetres long that is usually surrounded
humidity and extensive carpeting), are more likely environmental by an elongated mass of clear or opalescent material. Curschmann
factors.238,239 spirals are widely believed to represent bronchial casts, but their
Another possibility is the decline in childhood infections in the calibre is more commensurate with that of a bronchial gland duct or
developed countries. Infection induces a Th1 response rather than the of a peripheral bronchiole. Furthermore they have also been observed
Th2 reactions responsible for atopy (see aetiology, below).240 Indirect in uterine cervical smears, and in peritoneal and pleural effusions,
support for this possibility comes from studies of family size and birth where they have been attributed to myxoid degeneration of the sub­
order. Atopy is less common in children belonging to large families serosal connective tissue.254
and, within such families, in the younger children – the ones that are Creola bodies (see Fig. 3.22) are compact clumps or strips of colum­
most likely to be exposed in infancy to infections brought home by nar epithelial cells shed from the bronchus. They are sometimes found
their siblings.241,242 More direct evidence comes from studies showing in the sputum of asthmatics and care must be taken not to mistake
less atopy in those who had previously had measles,243 were seroposi­ them for exfoliated adenocarcinoma cells.255
tive for hepatitis A244,245 or gave a strong tuberculin reaction.246 This
raises the attractive possibility of preventive immunisation using
harmless bacteria.247
Morbid anatomy
Mortality figures have fluctuated over the past few decades, appar­ No differences are recognised between the structural changes in extrin­
ently being influenced adversely on occasion by the introduction of sic and intrinsic asthma, but most of our knowledge has come from
new drugs, particularly β-agonists.248,249 The mechanism underlying necropsies in cases of status asthmaticus. This has tended to overem­
these fluctuations is not fully understood but overdosage, cardiac phasise the terminal features and the complications of the condition,
dysrhythmia, refractoriness to the bronchodilatory effect of the drug but from the few biopsy specimens obtained from asthmatics or
and a false sense of security afforded by carrying an inhaler are all autopsies performed on asthmatics dying of other diseases, it seems

110
 Diseases of the conductive airways Chapter |3|

Figure 3.22  A Curschmann spiral and two Creola bodies in sputum from
an asthmatic patient. Methylene blue stain.

Figure 3.24  Status asthmaticus. Tenacious plugs of mucus occlude the

airways. (Reproduced by permission of Dr GA Russell, Tunbridge Wells, UK.)

mucus that can be made to protrude from the lumen by compressing

the lungs. Bronchography shows that air can pass the plugs only on
inspiration.256
Patches of subpleural fibrosis and honeycombing are common,
particularly in the upper lobes; these are possibly the sequel of eosi­
nophilic pneumonia which is often most marked in the periphery of
the upper lobes. It is notable in asthma that, although the lungs may
be fully distended with air at necropsy, very little emphysema is
found. Some patients have right ventricular hypertrophy but this is
uncommon in the absence of associated bronchiectasis or chronic
bronchitis.
The above changes are typically found in patients dying hours after
Figure 3.23  The lungs of a patient dying of status asthmaticus. After the onset of an asthmatic attack but they have also been found after
their removal from the chest and exposure to atmospheric pressure the death in asthmatic patients who have been well seconds earlier.257,258
lungs fail to collapse owing to mucus obstructing the airways. (Reproduced Rarely, a patient with asthma dies suddenly and the airways are
by permission of Dr GA Russell, Tunbridge Wells, UK.) found to be empty of mucus.259 Myocardial contraction bands that
have been described in such patients260 are possibly connected with
the overuse of β-adrenergic drugs, which may have contributed to
that qualitatively similar but less severe lesions are present between these deaths.261,262 Other such patients have been found to have
attacks: during non-fatal attacks it is assumed that similar lesions of inflammation of their cardiac conduction system.263
intermediate severity are present. Bronchography has shown that Mucous plugging of airways and hyperinflation of the lungs are not
airway plugging is widespread between asthmatic attacks as well as confined to patients with a history of asthma. They are also found in
being prominent in patients dying of asthma.256 patients dying of anaphylaxis initiated by factors such as wasp or bee
The gross appearances are characteristic. When the chest is opened venom, foodstuffs and drugs.264
in cases of death in status asthmaticus, the lungs are found to be
greatly distended: they fail to retract as normal lungs do when the
negative intrapleural pressure is replaced by atmospheric pressure on Histopathology
opening the pleural cavities (Fig. 3.23). Contrasting with the general Microscopically, three major processes are seen to contribute to the
distension, small foci of collapse may sometimes be seen as dark, airway narrowing: increased amounts of mucus, inflammatory oedema
airless, firm areas, depressed below the level of the surrounding lung. and muscular hypertrophy. These are found principally in bronchi but
The airways are occluded by plugs of thick, tenacious mucus (Fig. may also be found in smaller airways, including bronchioles.265–269
3.24). These are found in airways of all sizes beyond the second-order The inflammation may even involve alveoli.270
bronchi256 but the most striking changes are seen in airways of about The airway lumen is compromised by the accumulation of mucus
5 mm diameter. When the cut surface of the lung is exposed, the and an exudate of eosinophils and desquamated epithelial cells mixed
bronchi of this size are seen to be filled with grey plugs of viscous with components derived from the plasma but not including fibrin

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 Pathology of the Lungs

Figure 3.26  Asthma showing epithelial desquamation, hypersecretion of

mucus, thickening of the epithelial basement membrane and infiltration
of the bronchial wall by lymphocytes and eosinophils.

ally numerous in asthma, making up half the inflammatory

cells.275,276,282 Mast cells are not usually identified in appreciable
numbers, but this is only because of degranulation, which can some­
times be recognised in appropiately stained sections by the presence
of clusters of free metachromatic granules.274 Staining for mast cell
tryptase shows that these cells are increased in number.283 Eosinophil
degranulation is also evident and degranulation of both eosinophils
and mast cells is confirmed by electron microscopy.284
The eosinophil inflammation of the airways is accompanied by
marked congestion and oedema, and separation and detachment of
B the more superficial columnar epithelial cells from the underlying
basal cells.285,286 Where such exfoliation has occurred, regeneration
Figure 3.25  Asthma showing bronchial plugging by mucus. may be evident in the form of mitotic division of the basal cells of
(A) Haematoxylin and eosin, (B) Alcian blue-periodic acid–Schiff. the epithelium. The loss of ciliated cells contributes to the impaired
bronchial clearance. Between attacks, patchy exfoliation of the epithe­
lium may still be recognized,287 and electron microscopy shows bleb­
bing of the apical cell membrane and bizarre cilia.288 During the
(Figs 3.25 and 3.26).271,272 The mucus commonly has a concentric or regenerative process the epithelium may show evidence of cell prolif­
spiral pattern in cross-section, and includes cells that are often aggre­ eration and squamous metaplasia.286,289
gated in a corresponding distribution. These cells are mostly eosi­ Loss of the surface epithelial cells also exposes intraepithelial nerves
nophils and desquamated epithelium. There is goblet cell hyperplasia to inflammatory mediators released in the bronchial lumen: stimula­
in the surface epithelium and the bronchial glands are enlarged, but tion of these nerves is thought to lead to an axon reflex that is respon­
not as much as in chronic bronchitis111,112,265; in contrast to chronic sible for much of the vasodilatation, oedema, mucus secretion and
bronchitis, the serous elements in the submucosal glands are as smooth-muscle contraction that characterises an asthmatic attack.290
numerous as the mucous acini.273 The mucus is consequently less The epithelial basement membrane is often thickened in asthma.
acidic than that in chronic bronchitis.274 Changes in the bronchioles This may be a reflection of the repeated shedding of epithelial cells,
are less obvious than those in the larger airways but there may be for basement membrane thickening is well known in other situations
muscle hypertrophy and an increase in goblet cells.265,268 The bronchi­ where the cells it supports are rapidly replaced. However, electron
oles may also contain mucous plugs and mucus may even be seen in microscopy shows that the thickening is confined to the deepest layer
alveolar ducts. How much of this mucus is derived from bronchiolar of the basement membrane, the collagen and fibronectin-rich lamina
goblet cells and how much is aspirated from the more proximal reticularis (Figs 3.27 and 3.28),291–293 which is probably produced by
airways is unknown. myofibroblasts derived from the epithelium by a process of epithelial–
A characteristic feature of the airways in status asthmaticus is mesenchymal transition.294,295 Tenascin, a glycoprotein concerned in
infiltration of the walls of bronchi and proximal bronchioles by repair, has been identified in the bronchial basement membrane in
eosinophils (Fig. 3.26).265 It has been shown immunocytochemically asthma but not in controls296 whereas although plasma proteins,
that the eosinophils are activated to secrete major basic protein.275–277 including immunoglobulins, can be demonstrated in the thickened
Neutrophils are generally uncommon and when numerous suggest basement membrane they are also present in the bronchial basement
secondary bacterial infection. However, more attention is now being membrane of many non-asthmatic patients.291 Although basement
paid to the pathogenetic role of these cells in asthma.278,279 It is membrane thickening is frequently emphasised as being characteristic
reported that in fatal asthma of sudden onset neutrophils outnumber of asthma, it is by no means specific for this disease274,287,297; lesser
eosinophils,280 or even that they are the only polymorpho­nuclear degrees are often seen in biopsy specimens from non-asthmatic
leukocyte present.281 Lymphocytes (mainly T-helper cells) are gener­ patients, taken for example because of suspected cancer. Much atten­

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 Diseases of the conductive airways Chapter |3|

Figure 3.27  Asthma showing heavy eosinophil infiltration and marked

basement membrane thickening.

tion is paid to the thickening of the basement membrane, with the

implication that it makes a considerable contribution to airway nar­
rowing but, as shown in Figure 3.29, its role in this is insignificant A
compared to that of muscular hypertrophy and inflammatory oedema.
A prominent increase in the amount of airway muscle is a major
feature of bronchial asthma and presumably reflects sustained mus­
cular contraction (Fig. 3.29).110–112,267,298–300 The increase involves
airways of all sizes but is most apparent in small bronchi of about
0.5 cm diameter.110,267,268,298,301 It is attributable to hyperplasia as well
as hypertrophy.110,300 The bronchial smooth muscle is hyperactive in
asthma and the peptidergic (non-adrenergic, non-cholinergic) bron­
chial innervation is probably important here as fatal asthma is char­
acterised by depletion of vasoactive intestinal peptide from bronchial
nerve terminals.302 Hyperplasia of the myoepithelial cells of the bron­
chial glands is also seen.303
The major changes in the airways act together and enhance the
effect of each other on airway calibre. Mathematical modelling
suggests that a moderate degree of inflammatory thickening of the
mucosa, which by itself would have little effect on baseline resistance
to gas flow, can profoundly affect the airway narrowing caused
by normal smooth-muscle shortening: the various processes narrow­
ing the airways are more than additive in their effect on airway
responsiveness.266,304–306
It will be evident from the above that asthma and chronic bronchi­
tis have features in common but that there are notable differences.
The two diseases are compared in Table 3.1 (p. 101). A possible
overlap condition known as ‘wheezy bronchitis’ is described on
page 100.
B
Pathogenesis and aetiology of asthma
Figure 3.28  Bronchial asthma. (A) Transmission electron micrograph
Two major mechanisms operate in both extrinsic and intrinsic asthma, showing that the epithelial basement membrane dividing epithelium
one neurological and the other inflammatory.290,307,308 The two mecha­ (above) from connective tissue (below) is greatly thickened. Immediately
nisms may interact. Thus, inflammatory mediators are prone to trigger beneath the basement membrane there is a lymphocyte and a mast
nerve reflexes whilst nerve stimuli, or loss of inhibitory activity, cell. (B) Higher magnification shows that the lamina rara and lamina
may, in addition to causing secretion and contraction, affect vascular densa (arrows) are normal and that the thickening involves the deepest
layer of the basement membrane, the lamina reticularis (LR). (A) ×2500;
permeability and promote oedema.
(B) ×30 000.
In both extrinsic and intrinsic asthma there are many non-specific
trigger factors. For example, many asthmatics are overresponsive to
irritant dusts and to respiratory infection, reacting to either with
marked bronchial narrowing. Emotional stress is another non-specific
triggering factor in asthma. Exercise has a similar effect in many
asthmatic patients, the large amount of cold dry air inhaled during

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 Pathology of the Lungs

were found to coincide with the unloading of soybean.316 Occupational

factors can be identified as contributing to asthma in about 2% of
adult cases (see p. 357). Such asthma occurs in many industries and
over 200 aetiological agents have been identified (see Table 7.1.8,
p. 356).
Intrinsic asthma usually affects people older than those afflicted
with extrinsic asthma. IgE levels are lower than in extrinsic asthma
and skin tests are often negative or only weakly positive. It is therefore
widely presumed that, in intrinsic asthma, airway inflammation is
triggered by non-immunological mechanisms. However, IgE levels
and the prevalence of positive skin tests to common allergens decline
throughout adult life and some workers find that a high age-corrected
IgE level is as good a marker of asthma in the elderly as in the
young.317,318 When these age-related changes are taken into account
the traditional separation of intrinsic and extrinsic asthma is less clear.
The reaginic antibodies are largely fixed to cells, particularly to the
Fc receptors on the surface of mast cells.319 Inhalation of the appropri­
ate allergen then leads to an antigen–antibody reaction on the surface
of the mast cells; the consequent degranulation releases various chem­
ical mediators from these cells.
The mast cell and the eosinophil leukocyte are central to the patho­
genesis of asthma, the former cell being responsible for many of the
acute manifestations of the disease and the latter for more of its
chronic features. In response to both immunological and non-specific
stimuli, the mast cell secretes a range of bioactive substances, whilst
the eosinophil secretes substances antagonistic to mast cell mediators
but also releases others that are detrimental to the integrity of the
respiratory epithelium.
Mast cells are most numerous in relation to airway muscle and
glands,320 but they are also present within the surface epithelium288,321
and can be recovered in bronchial washes.322 Inhaled antigens first
Figure 3.29  Asthma. The bronchial muscle is greatly hypertrophied. react with immunoglobulin E bound to mast cells free in the bron­
chial lumen, and this causes release of mediators from these mast cells
and consequent weakening of the tight junctions binding together
outdoor exercise probably being the non-specific bronchial irritant. surface epithelial cells, so facilitating access of the antigen to mast cells
Exercise-induced asthma is rare in the warm, humid atmosphere of in the epithelium. The degranulation of these mast cells further
an indoor swimming bath. Eosinophilia is not a feature of exercise- augments epithelial permeability. Penetration of antigen into the rest
induced asthma.309 of the bronchial wall is thus facilitated as successive mast cells are
Up to 10% of asthmatic patients are unduly sensitive to aspirin rapidly triggered. Differences between mucosal and connective tissue
and other non-steroidal anti-inflammatory drugs310,311: non-atopic mast cells are described: the former are smaller and contain heparin
patients with nasal polyps whose asthma is difficult to control are and tryptase rather than chymase.323,324 Both types have been identi­
particularly sensitive to aspirin.312 Aspirin-induced bronchial narrow­ fied in human airways.323
ing is attributed to inhibition of arachidonic acid metabolism by Various mediators are released when the mast cell degranulates.
the cyclo-oxygenase pathway and its diversion to the lipoxygenase Some of these cause immediate effects whilst others are responsible
pathway with the production of bronchoconstrictor leukotrienes C4 for reactions that come on hours later. Preformed mediators include
and D4 (formerly known collectively as slow releasing factor of histamine, exoglycosidases, tryptase, and eosinophil and neutrophil
anaphylaxis). chemotactic factors. Histamine causes dilatation and increased perme­
Extrinsic asthma is usually associated with atopy, this being a lia­ ability of blood vessels, triggers irritant nerve receptors causing cough­
bility to develop excessive amounts of immunoglobulin E (so-called ing, and stimulates smooth-muscle contraction and mucus secretion,
reaginic antibodies) in response to commonplace antigens that the whilst exoglycosidases such as glucuronidase, hexosaminidase and
individual repeatedly meets in everyday life. Cutaneous prick tests galactosidase together with neutral proteases disrupt the integrity of
usually result in an immediate wheal and flare response to a range of the bronchial submucosa through their actions on connective tissue
allergens. Specific allergens are found in many pollens, feathers, horse ground substance. Histamine release also stimulates the generation
dander, fur and, especially, house dust. The most important asthma- and release of newly formed mediators, including prostaglandin D2,
causing allergen is probably the house dust mite, Dermatophagoides platelet-activating factor and leukotrienes C4 and D4, that are respon­
pteronyssinus, which is found worldwide. It feeds on shed human sible for the later effects. Prostaglandin D2 and leukotriene C4 res­
epidermal squames and for this reason is particularly numerous in pectively enhance vasodilation and vascular permeability, while
dust from bedding, especially mattresses. Warm damp houses favour platelet-activating factor and the leukotrienes C4 and D4 cause smooth
the growth of the mites more than cold dry ones, but very few samples muscle to contract. Collectively these contribute greatly to the inflam­
of house dust are completely free of them. A reported increase in matory oedema, muscular contraction and hypersecretion of mucus
asthmatic attacks during thunderstorms may be due to pollen counts that characterise an asthmatic attack. Mast cells also produce a variety
rising at such times.313–315 Many environmental allergens causing of cytokines, notably interleukins-1, 2, 3, 10 and 13, granulocyte–
asthma probably go undetected but one such agent was identified macrophage colony-stimulating factor, interferon-γ and tumour
when periodic outbreaks of asthma in the vicinity of Barcelona’s docks necrosis factor-α.325

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 Diseases of the conductive airways Chapter |3|

Allergen

Mast cell Th2 cell

Smooth muscle Bone marrow
IgE IL-5
spasmogens eosinophil release

IL-4 IL-4
IL-13 IL-13
TNFα
Epithelial cells,
smooth muscle cells
fibroblasts

EOTAXINS

Airway
Microvessel

Eosinophils

Figure 3.30  Diagrammatic representation of eosinophil production and bronchopulmonary infiltration in response to allergen inhalation. (Reproduced
from Respiration Research by permission of Professor TJ Williams, London, UK and BioMed Central Ltd.326)

Eosinophil leukocytes are produced in the bone marrow under the eosinophil infiltration of the airways and bronchial hyperresponsive­
control of cytokines secreted by type 2 helper lymphocytes, notably ness is seen in the separate condition of eosinophilic bronchitis,
interleukin-5 (Fig. 3.30).326 They are released into the blood and are which is considered below.
drawn into the tissues by chemotactic agents known as eotaxins,326 of There is increasing evidence that cellular hypersensitivity is impor­
which three are now recognised. These agents are small proteins pro­ tant in asthma, indicating that the T lymphocyte plays an important
duced by a variety of cells, which in the lung include bronchial epi­ role in initiating an asthmatic attack (Fig. 3.31). Activated T-helper
thelial cells, smooth-muscle cells and fibroblasts, acting under the lymphocytes may be demonstrated in the airways276,277,333–337 and
influence of interleukins derived from type 2 helper lymphocytes and selective activation of the Th2 subgroup has been identified, resulting
mast cells.326–328 in interleukin 4, 5, 9, 10 and 13 secretion.247,275,338–345 Interleukins-4
Eosinophils counter the action of many of the mast cell mediators and 13 cause plasma cells to form IgE rather than IgG, while inter­
described above by secreting degradative enzymes: these include his­ leukin-5 is responsible for increased eosinophil production by the
taminase and aryl sulphatase, which destroy histamine and leuko­ bone marrow and interleukin-10 inhibits the development of Th1
trienes respectively. However, further substances secreted by the cells. Conversely, Th1 cells produce interferon-γ, which is a potent
eosinophil aggravate the disease. In helminthic infestation, major inhibitor of IgE production.
basic protein and eosinophil cationic protein derived from the Both genetic and environmental factors appear to influence the
eosinophil are probably beneficial in promoting elimination of the relative activity of Th1 and Th2 cells. Certain infections are character­
parasites but in asthma they appear to be responsible for the epi­ ised by the production of large amounts of interferon-γ but the
thelial disintegration that characterises the disease.329 In vitro, low children of atopic parents have fewer interferon-γ-producing cells in
concentrations of major basic protein impair ciliary motility and cause their peripheral blood. It is plausible therefore to envisage repeated
epithelial disruption, cell shedding and lysis.329,330 In vivo, there is viral infections, particularly in early life, selectively enhancing the
vacuolation of epithelial cells and the degree to which this occurs development of Th1 cells and inhibiting the proliferation of Th2
correlates with the number of eosinophils.282 Major basic protein is clones and allergic sensitisation – the so-called hygiene hypothesis
normally confined to the core of eosinophil granules331 (see Fig. 9.1, that is also touched upon above, under epidemiology. This hypothesis
p. 461) but in patients dying of status asthmaticus, it is present within has led to suggestions that vaccines designed to stimulate Th1 cell
mucous plugs and on damaged epithelial surfaces.332 Epithelial fragil­ development could be beneficial in preventing asthma and allied
ity is likely to enhance the access of allergens and non-specific irritants allergic diseases.247
to mast cells, lymphocytes and nerves in the bronchial wall, thereby Asthma is also characterised by infiltration of the bronchial surface
aggravating the condition. Nevertheless, a clear disassociation between epithelium by Langerhans cells.338 These non-phagocytic histiocytes

115
 Pathology of the Lungs

Allergen event as hyperinflation of the lungs increases abdominal pressure and

thus promotes reflux. Reflux may be asymptomatic355 and some
asthmatics report symptomatic improvement on medical antireflux
therapy, but their lung function is generally unchanged.353 Surgical
IL4 intervention is currently considered inappropriate.
B
Some intriguing observations concerning asthma have emanated
Th2
from transplantation centres. It is reported that the lungs of an asth­
matic donor confer asthma on a non-atopic recipient and conversely
IgE
that an asthmatic recipient receiving lungs from a non-asthmatic
donor experiences no further attacks of asthma.356
IL5
IL3 Treatment of asthma
Asthma is largely treated quite successfully by the avoidance of recog­
M nised trigger agents coupled with bronchodilator drugs and corticos­
teroids as required, supplemented on occasion by desensitisation to
ECF E specific allergens and breathing exercises. Other treatments that have
been developed more recently include leukotriene and leukotriene
receptor antagonists and antibodies directed against IgE while several
asthma genes have recently been identified, suggesting that gene
therapy may be introduced at some future date.

Complications of asthma
H, L, PAF MBP, ECP Asthma is sometimes complicated by allergic bronchopulmonary
aspergillosis: it is also a frequent manifestation of the latter (see
Figure 3.31  Cellular interrelationships in asthma. Allergens stimulate Th2
lymphocytes to release interleukins which activate B lymphocytes, mast p. 228). Aspergillus fumigatus is the species most commonly concerned
cells and eosinophils. Interleukin-5 promotes eosinophil activation while in the UK, but other species appear to be relatively more frequent
interleukin-4 is responsible for B-lymphocyte maturation, which results in causes in other parts of the world. It is important to note that in this
immunoglobulin E production; the adherence of immunoglobulin E to condition the fungus does not invade the tissues. Inhalation of fungal
mast cells primes the latter to degranulate on contact with the same spores sets up a reaction in the sensitised bronchial tree that is char­
allergen. The eosinophil modulates some of the effects of the mast cell acterised by bronchospasm, accumulation of eosinophils and out­
by releasing histaminase and aryl sulphatase, which inactivate histamine pouring of abundant, very viscid mucus. The mucus forms a cast
and leukotrienes respectively, but also damage adjacent tissue by which distends the affected segment of the bronchial tree. The cast is
secreting major basic protein and eosinophil cationic protein. Th2,
colonised by the fungus and the preparation of histological sections
T-helper 2 lymphocyte; B, B lymphocyte; M, mast cell; E, eosinophil;
of these mucous plugs, expectorated at the end of the acute episode
IL, interleukin; IgE, immunoglobulin E; H, histamine; L, leukotrienes;
PAF, platelet-activating factor; MBP, major basic protein; ECP, eosinophil of the illness, permits demonstration of the characteristic hyphae
cationic protein; ECF, eosinophil chemotactic factor. within their substance: silver impregnation methods are very satisfac­
tory for this purpose. It should be noted that the hyphae are usually
scanty. Immunological tests have largely superseded histological
investigation in the diagnosis of this condition, although the latter is
are rich in surface receptors and are responsible for the presentation a valuable confirmatory measure and in cases with equivocal immu­
of antigenic information to T lymphocytes: very few Langerhans cells nological results may be the only means of recognising the disease.
are found in the normal lung, although there is a rich network of the Immunological tests include the demonstration of precipitating anti­
dendritic cells that are their probable precursors.338,346–348 bodies to Aspergillus in the blood, and skin testing with Aspergillus
The bronchial epithelium also contributes actively to the develop­ antigen which causes both immediate and delayed reactions. Some
ment of asthma.307 For example, epithelial expression of the broncho­ atopic individuals develop allergic aspergillosis of the paranasal
constrictor substance endothelin is increased in asthma.349 Other sinuses similar to that in the bronchi.357
bronchoconstrictor agents, such as prostacyclins, are also released Bronchocentric granulomatosis (see p. 464) is a further manifesta­
when bronchial epithelium is damaged. tion of allergic bronchopulmonary aspergillosis. So too is eosinophilic
The association of asthma with nasal polyps and paranasal sinusitis pneumonia (see p. 459). In this latter condition, radiological exami­
has been ascribed to aspiration of upper respiratory tract secretions nation of the chest during an attack of asthma reveals scattered opaci­
but radionuclide tracer studies do not support this.350 Furthermore ties which biopsy shows to be foci of eosinophil exudation in the
asthmatic patients’ minor salivary glands show inflammatory changes alveoli, with similar infiltration of the bronchiolar and alveolar walls.
similar to those in their airways,351 suggesting that there is generalised Such foci appear to be transient but healing of them by fibrosis may
mucosal disease affecting both upper and lower airways. The polyps contribute to the subpleural honeycombing and bronchiectasis men­
themselves have an oedematous stroma infiltrated by eosinophils. tioned above.
Nasal polyps are common in certain other airway diseases, notably
cystic fibrosis and primary ciliary dyskinesia, but in these non-allergic
conditions the polyps lack the tissue eosinophilia seen in asthma.
Non-eosinophilic asthma
Asthma is also associated with gastro-oesophageal reflux but it is Some patients with the clinical features of asthma lack the distinctive
uncertain whether the relationship is causal.352,353 Contact of the sputum eosinophilia of the disease and on biopsy their airways show
oesophagus or the trachea with hydrochloric acid induces reflex bron­ a non-specific neutrophilic rather than eosinophilic infiltrate and an
chial constriction354 but it is unclear whether the reflux is the primary absence of the usual basement membrane thickening seen in asthma.

116
 Diseases of the conductive airways Chapter |3|

They respond poorly to inhaled corticosteroids.358 The cause is gener­

ally unknown and the pathogenesis poorly understood, apart from a Box 3.2  Causes of bronchiectasis
possible link to smoking.359 However, in what has become known as • Infection: measles, pertussis, adenovirus
irritant-induced asthma (or reactive airways dysfunction), a similar
• Chemical damage: gastric acid, toxic gases
situation is encountered in non-atopic individuals exposed to a single
• Diffuse pulmonary fibrosis
heavy concentration of a severely irritant gas, fume, smoke or
• Obstruction: tumour, foreign body, enlarged hilar nodes
vapour.360 These patients develop cough, wheezing and dyspnoea
within 24 hours of such exposure and their symptoms persist for at • Impaired local defence: cystic fibrosis, ciliary dyskinesia, Young’s
least 3 months. They have airflow obstruction and give a positive syndrome
challenge test but display no eosinophilia. Thus, there are patients • Impaired systemic immunity: hypogammaglobulinaemia
who are categorised clinically as having asthma who would not be so • Autoimmunity: ulcerative colitis, rheumatoid disease, Sjögren’s
recognised by a pathologist. syndrome, ankylosing spondylitis, relapsing polychondritis,
systemic lupus erythematosus, Marfan’s syndrome, lung transplant
rejection, graft-versus-host disease
Eosinophilic bronchitis • Allergy: allergic bronchopulmonary aspergillosis
Eosinophilic bronchitis is characterised by corticosteroid-responsive • Congenital: Mounier-Kuhn’s syndrome, Williams–Campbell
cough and eosinophilia but not the variable airflow obstruction, syndrome
airway hyperresponsiveness or bronchial muscle hypertrophy seen in
asthma.361,362 The inflammatory changes are similar except that mast
cells are reportedly better represented in the bronchial muscle in
asthma whereas they are best seen in the epithelium in eosinophilic
bronchitis.363,364 Both conditions show thickening of the reticular
basement membrane.362 Exposure to certain occupational allergens
Bacteriology
has been reported to cause eosinophilic bronchitis.365 In the earlier stages of bronchiectasis, Haemophilus influenzae is much
the commonest bacterium to be recovered from the sputum. Later,
a wide variety of different organisms becomes established in the
infected air passages. As well as H. influenzae, Pseudomonas aeruginosa,
BRONCHIECTASIS Streptococcus pneumoniae and Mycobacterium avium may be found.
Sometimes, various spirochaetes and anaerobes are found and it is
In literal terms, bronchiectasis means no more than dilatation of the through the activities of these organisms that the smell of the sputum
bronchi and it is legitimately used in this restricted sense to describe, is so often offensive. Probably all these bacteria are secondary colon­
for instance, the distensive changes that are commonly encountered isers rather than the primary causative agent. P. aeruginosa is a parti­
distal to a bronchial tumour. More often, however, it is understood cularly difficult bacterium to eradicate as it secretes an alginate
to indicate a characteristic clinical condition that has bronchial dilata­ coating that enables it to live on the mucosal surface esconced within
tion and suppuration as its pathological basis. Although such dilata­ a biofilm where it is protected against phagocytosis and humoral
tion is traditionally considered to be permanent, radiologists are or chemical attack.379
familiar with early cases reverting to normal with treatment.
Structural changes366,371
Aetiology and clinical features The terms ‘cylindrical’ and ‘saccular’ (Fig. 3.32), alluded to above, are
Prior to the advent of antibiotics and immunisation against the self-explanatory. Follicular is another descriptive term, one that refers
common exanthems of childhood, bronchiectasis usually followed a to an abundance of lymphoid follicles in the walls of the affected
severe respiratory infection. It was characterised by a chronic cough bronchi (Fig. 3.33) which are usually dilated in a cylindrical fashion.
productive of abundant foul sputum that originated in localised sac­ The terms ‘follicular’ and ‘cylindrical’ are therefore often used inter­
cular lesions, which were typically located in the lung bases. This form changeably. Apart from the association of saccular disease with pre­
of the disease is now uncommon and has been replaced by, or its ceding infection and cylindrical/follicular with idiopathic cases, the
reduction has uncovered, an insidious progressive type of bron­ distribution of the disease within the lungs also gives a clue to the
chiectasis, which is usually more extensive and cylindrical. This is also aetiology. Thus, postinfective bronchiectasis tends to be basal, whilst
characterised by persistent purulent sputum production but patients in cystic fibrosis and ciliary dyskinesia the bronchiectasis is general­
with this form of the disease often give a history of wheezy bronchitis ised but with upper-lobe preponderance and in allergic broncho­
in childhood and have chronic rhinosinusitis.366 The cause of this pulmonary aspergillosis hilar bronchi are particularly affected.
form of bronchiectasis is not easily identified and it is often termed Bronchiectasis confined to the right middle lobe is a major feature of
idiopathic. Immunological dysfunction is suspected.367 The idiopathic the middle-lobe syndrome (see p. 92).
form has been identified in 14–53% of cases.368–370 These studies also The affected bronchi are most frequently those of the third or fourth
identified 29–32% of cases as being postinfectious, as well as several order, the first orders being spared because their more substantial
rarer causes (Box 3.2).371–377 A further possible cause is the dysfunction cartilage prevents dilatation. By counting the number of generations
of primary cilia that underlies autosomal-dominant polycystic kidney of the bronchial tree from the hilum it has been shown that subpleural
disease, as discussed on page 65). bronchiectatic cavities of the cystic type usually represent dilated
An unexplained association of bronchiectasis is that with lymphatic proximal airways.380
obstruction and pleural effusions in the yellow-nail syndrome (see The dilated airways are usually filled with a purulent exudate and
p. 709). It is also uncertain whether an observed association their mucosal surfaces are deeply congested. Many of the normal
between bronchiectasis and antitrypsin deficiency is attributable components of the bronchial wall are partly destroyed, particularly
to impaired defence against infection or protease–antiprotease the fibromuscular and elastic framework. The bronchial walls may be
imbalance.378 thin, but more often they are thickened by fibrosis, inflammatory

117
 Pathology of the Lungs

A B

C D

Figure 3.32  (A) In a patient with cystic fibrosis there is widespread saccular bronchiectasis; almost all segments of the lung are affected. The lung is
largely replaced by saccules with thick fibrous walls, sometimes showing the remains of the mucosal folds of the bronchi from which they were
derived. (B) In a patient with idiopathic bronchiectasis, the changes are cylindrical. (C and D) In a further patient with bronchoectasis a peanut was
identified obstructing the lumen.

oedema and a heavy infiltrate of lymphocytes and plasma cells. licular bronchiectasis, there may be extensive chronic interstitial pneu­
Lymphoid follicles may be prominent (see Fig. 3.33). The mucosa monia. Organising pneumonia may be found in relation to the
may show polypoid hyperplasia and there may be squamous bronchiectasis but this is not an invariable association and when
metaplasia. Thin-walled pus-filled bronchiectatic cavities may be mis­ present it is generally difficult to tell whether it has preceded or fol­
taken for abscesses: the essential difference is that the latter entail lowed the bronchiectasis.
destruction of lung tissue and consequently several airways may com­ As with many diseases of the lung, bronchiectasis derives its blood
municate with one abscess cavity (Fig. 3.34). supply chiefly from the bronchial arteries, leading to the development
The dilated airways often end blindly, the more distal airways being of large bronchopulmonary anastomoses.381
obliterated by fibrosis (Fig. 3.35). Unless inflation is maintained by The airway neuroendocrine cells are often increased in bronchiecta­
collateral ventilation the distal lung then shows absorption collapse. sis, sometimes leading to the formation of multiple tumourlets (see
The adjacent lung may be substantially normal or, particularly in fol­ p. 598).

118
 Diseases of the conductive airways Chapter |3|

Figure 3.33  Follicular bronchiectasis. Lymphoid follicles are evident in the

wall of this dilated airway, which also contains mucopus. A

A B

B
Figure 3.34  Diagrammatic representation of (A) bronchiectasis and (B)
lung abscess. In bronchiectasis each space represents a dilated airway Figure 3.35  Bronchiolitis in long-standing bronchiectasis (A) shows
that communicates only with its parent and daughter airways, in contrast widespread peribronchiolar inflammation; (B) shows peribronchiolar
to an abscess cavity brought about by ‘cross-country’ necrosis forming a fibrosis.
newly formed cavity that communicates with several separate airways.
(Redrawn after Liebow.)

The normal tractive forces that operate on the airways in inspiration

may then be enough to stretch their walls unduly. Distal to an obstruc­
Pathogenesis
tion, dammed-up secretions exert distensive forces, whilst outside the
The pathogenesis of bronchiectasis is complex and several mecha­ inflamed airways, increased tractive forces are brought to bear on their
nisms have been proposed. It is likely that some of these act in con­ weakened walls by processes such as absorption collapse and post­
junction, establishing a ‘vicious cycle’ of events.382,383 This involves pneumonic fibrosis (Fig. 3.36). Coughing may be dismissed as a
initial damage to the bronchial epithelium permitting heavy second­ possible pathogenetic factor because it entails the sudden closure of
ary bacterial colonisation which in turn inhibits ciliary clearance and airways rather than their distension.
so promotes continued infection and inflammation. Evidence for
this comes from the isolation of a heat-labile bacterial product that
attacks ciliated cells and slows ciliary motility. Other bacterial prod­
Complications
ucts capable of perpetuating obstructive lung disease include pro­ Notable local complications of bronchiectasis include the develop­
teinases that stimulate the secretion of mucus into the airways.108,384 ment of lung abscess and empyema, the latter being the less common
Pseudomonas aeruginosa is a particularly troublesome coloniser because adhesions often form early and obliterate the pleural cavity.
because it survives within a biofilm on the mucosal surface where it Bronchiectasis is seldom widespread enough to cause severe pulmo­
is protected against cellular and humoral attack but is nevertheless nary hypertension but cor pulmonale is common in the generalised
responsible for strong antigen–antibody reactions that attract form of the disease that develops in cystic fibrosis. Old bronchiectatic
neutrophils. cavities may be colonised saprophytically by fungi (see p. 231). Distant
An undoubtedly important pathogenetic mechanism is inflamma­ complications of bronchiectasis include metastatic abscesses, particu­
tory weakening of the walls of the bronchi, largely stemming from larly in the brain, generalised amyloidosis and immune complex
proteolytic enzymes and toxic oxygen radicals released by neutrophils. vasculitis.385,386

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 Pathology of the Lungs

A
Box 3.3  Causes of bronchiolitis
1. Disorders in which the bronchioles are primarily involved
A. Non-specific features
i. Cellular changes (acute, acute on chronic or chronic)
ii. Fibrotic changes (peribronchiolar/intraluminal/constrictive)
B. Features suggestive of specific diseases
iii. Follicular bronchiolitis
iv. Eosinophilic bronchiolitis
v. Granulomatous bronchiolitis
vi. Mineral dust airway disease
C. Diseases with specific features
vii. Diffuse panbronchiolitis
viii. Respiratory bronchiolitis
ix. Diffuse idiopathic neuroendocrine cell hyperplasia
B (DIPNECH)
x. Neuroendocrine cell hyperplasia of infancy
2. Disorders in which the bronchiolitis is secondary to other
lung disease
A. Associated with proximal airway disease
xi. Bronchiectasis
xii. Asthma
xiii. Chronic obstructive pulmonary disease
B. Associated with diffuse parenchymal lung disease
xiv. Extrinsic allergic alveolitis
xv. Organising pneumonia
xvi. Sarcoidosis
xvii. Langerhans cell histiocytosis
xviii. Wegener’s granulomatosis
Figure 3.36  Pathogenesis of bronchiectasis. Top: bronchopneumonia.
Bottom: the peribronchiolar consolidation has healed by fibrosis, xix. Airway-centred interstitial fibrosis, centrilobular fibrosis
contracture of which exerts a tractive force on airway walls weakened by and idiopathic bronchiolocentric interstitial pneumonia,
inflammation. (Redrawn after Liebow.) peribronchiolar metaplasia and fibrosisa
Other
a
It is uncertain whether these patterns represent separate entities.
(Adapted from Rice & Nicholson (2009).393)
Treatment and outcome
Bronchiectasis can be treated by pharmacological and non-pharma­
cological means, the former including antibiotics, mucolytics and
anti-inflammatory agents, and the latter physiotherapy and, if the
disease is localised, surgical resection. In one group of patients There is also a variety of conditions characterised by small free
followed for 13 years, 30% died: mortality correlated with the degree bodies, calcified or otherwise, that may be detected in sputum or lung
of restrictive and obstructive disease, poor gas transfer and chronic tissue. These are mainly found free in the air spaces and are dealt with
Pseudomonas infection.387 under alveolar filling defects on pp. 320–322.

BRONCHOLITHIASIS CHRONIC BRONCHIOLITIS

Occasionally the laboratory is presented with a stony hard object that Bronchiolitis may be acute, chronic or acute on chronic. The more
a patient has coughed up. Such sputum ‘liths’ (or broncholiths) may acute forms have been dealt with earlier in this chapter and this
derive from many conditions characterised by bronchopulmonary section is concerned with the chronic forms, particularly that in which
calcification. Analytical electron microscopy and X-ray diffraction may the lumen is compromised, for which the term ‘obliterative bronchi­
give information on their elemental composition and crystalline struc­ olitis’ (or bronchiolitis obliterans) is used, in contrast to cellular
ture that can be helpful in identifying the underlying disease.388 bronchiolitis, which term is sometimes used when the bronchiole is
Generally the cause is a heavily calcified bronchial lymph node, rep­ inflamed but the lumen remains patent.391
resenting healed tuberculosis, sarcoidosis or histoplasmosis, that It is useful to separate those disorders in which bronchiolar disease
presses upon and gradually ulcerates the wall of a bronchus until it is is the predominant feature from those in which it represents a distal
free in the lumen (see Fig. 3.2B, p. 93). Bronchial obstruction or extension of what is primarily a bronchial disorder and those in which
bleeding may necessitate intervention before the broncholith works it represents a proximal extension of an essentially parenchymal con­
itself free.389 Broncholiths may also cause obstructive pneumonia, dition (Box 3.3).392,393 Attention here is confined to the disorders in
mediastinal abscess or broncho-oesophageal fistula.390 which bronchiolar disease is the predominant feature.

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 Diseases of the conductive airways Chapter |3|

Chronic bronchiolitis is often non-specific but some forms have

distinctive histological patterns. These are dealt with separately: see
follicular bronchiolitis (see p. 654), respiratory bronchiolitis (see p.
313) and diffuse panbronchiolitis (see p. 124). Obliterative bronchi­
olitis is also encountered in diffuse idiopathic neuroendocrine cell
hyperplasia (see p. 599) and chronic obstructive bronchiolitis (‘small-
airways disease’) is an important facet of chronic obstructive pulmo­
nary disease (see p. 100).

Clinical features
Chronic bronchiolitis is characterised by cough, wheeze and shortness
of breath of varying severity. It becomes life-threatening when there
is widespread luminal obliteration. Widely differing orders of bron­
chioles may be affected, the disease sometimes extending proximally
into small bronchi and in other patients extending distally to involve
alveoli. For this reason the functional effects are not uniform: whereas
obliteration of proximal bronchioles causes an obstructive pattern of
impairment, scarring in the region of respiratory bronchioles causes
restrictive functional impairment.
A

Imaging
Imaging shows centrilobular nodules, extending from which there are
short branching lines, the so-called ‘tree in bud’ pattern. This repre­
sents thick-walled bronchioles filled with mucus or mucopus. There
may also be patchy centrilobular ground-glass opacification represent­
ing spread of the bronchiolar inflammation into adjacent alveoli.
Focal air-trapping, best seen on expiratory scans, is a further feature.
Loss of the normal lung markings may also be observed. This
represents vascular shutdown in response to hypoventilation (see
ventilation-perfusion matching, p. 22), which in this case is due to
obliterative bronchiolitis. Although this is generally patchy, resulting
in a mosaic pattern, it may affect a whole segment, lobe or lung.
The Swyer–James or Macleod syndrome of unilateral hypertrans­
radiancy (or hyperlucency) of the lungs394–397 was once thought to
represent congenital unilateral atresia of pulmonary vessels but it is
now recognised that arterial constriction in response to hypoventila­
tion underlies the condition. The condition is an acquired one with
obliterative bronchiolitis as its pathological basis. The hypertransra­
diancy (see Fig. 2.62, p. 73) appears soon after an attack of bronchi­ B
olitis and is initially due to vascular constriction; later, structural
obliteration of the vessels supervenes. Absorption collapse, which Figure 3.37  Lambertosis. (A) Centriacinar scarring with bronchiolar
would render the lung radiopaque rather than radiolucent, is pre­ epithelial metaplasia. (B) The appearances differ from those of atypical
vented by collateral ventilation (see p. 92). The syndrome is consid­ adenomatous hyperplasia in that the cells are mainly of ciliated type,
ered further on page 73. closely abut each other and there is no atypia.

Pathological features
The bronchiolar wall is thickened by non-specific lymphoplasmacytic cells contribute directly to the fibrosis by participating in a process of
inflammation, oedema and a varying degree of fibrosis. All compo­ epithelial–mesenchymal transition.399,400
nents of the wall are affected – mucosa, muscularis and adventitia. If the mucosal fibrosis encroaches upon the bronchiolar lumen the
Sometimes the inflammation and fibrosis extend out to affect the changes are described as obliterative bronchiolitis (or bronchiolitis
adjacent alveoli, resulting in a bronchiolocentric interstitial pneumo­ obliterans). Two major pathological patterns of bronchiolar oblitera­
nia and fibrosis. This may be accompanied by a centrifugal extension tion are recognised: one characterised by polypoid intraluminal buds
of the bronchiolar epithelium through the canals of Lambert (see of granulation tissue, which is sometimes termed proliferative or
p. 4) so that peribronchiolar alveolar septa thickened by fibrosis intrusive, and a constrictive type. Both forms are the result of epithe­
are lined by tall columnar epithelial cells, a process termed bron­ lial damage but whereas the polypoid type represents healing of
chiolisation of alveoli, peribronchiolar metaplasia or lambertosis damage inflicted at one point in time, the constrictive type is the result
(Fig. 3.37).398 The epithelial cells are generally ciliated and closely abut of chronic attrition from continuing damage. Thus, the polypoid form
each other, in contrast to atypical adenomatous hyperplasia, which is typically seen soon after viral and chemical attack on the bronchi­
involves non-ciliated, low columnar or cuboidal Clara cells and type oles and the constrictive type with autoimmune disease, lung trans­
II pneumocytes separated by gaps representing type I pneumocytes plant rejection and graft-versus-host disease (Box 3.4). However, with
(see Fig. 12.1.3, p. 538). It has become apparent that the epithelial time the intraluminal buds of granulation tissue seen in the former

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 Pathology of the Lungs

Box 3.4  Morphological forms of obliterative bronchiolitis

and their aetiological associations

Intraluminala
Organising infectious exudates
Chemical fume inhalation, e.g. silo-filler’s disease
Constrictiveb
Rheumatoid and other connective tissue disease
Inflammatory bowel disease
Lung transplant rejection
Bone marrow transplantation (graft-versus-host disease)
Sauropus androgynus ingestion
Idiopathic (including diffuse idiopathic neuroendocrine cell
hyperplasia)
a
This pattern is seen early in the healing phase. With time the intraluminal buds
of granulation tissue may be incorporated into the airway wall resulting in
appearances indistinguishable from those of the constrictive type.
b
Drugs such as gold and penicillamine are often incriminated as a cause of this
pattern without considering the possibility that the disease for which they are
administered, which is often rheumatoid, may be the true cause.

type may become incorporated into the airway wall, resulting in

appearances indistinguishable from those of the constrictive type.
The polypoid type of obliterative bronchiolitis results from the
organisation of luminal inflammatory exudates and entails the devel­
opment of granulation tissue polyps that protrude into and obstruct
much of the bronchiolar lumen (Fig. 3.38). These are akin to the
Masson bodies (bourgeons conjonctifs) of organising pneumonia,
which may also be present in the distal lung. Alternatively, alveoli
beyond the bronchiolar obstruction may contain abundant foamy
macrophages, the hallmark of endogenous lipid pneumonia, which
should prompt the pathologist to examine the bronchioles.
In the constrictive pattern of obliterative bronchiolitis401,402 the Figure 3.38  Bronchiolitis due to intraluminal organisation complicating
mucosa is concentrically thickened by chronic inflammatory granula­ viral infection. A granulation tissue polyp protrudes into and occupies
tion tissue (Figs 3.39 and 3.40) and in active cases the surface epithe­ most of the bronchiolar lumen.
lium is destroyed (Fig. 3.39). Sometimes the bronchiole is totally
replaced by scar tissue. In this case, the presence of small fibrous scars
next to pulmonary arteries that lack their usual accompanying airways
should suggest that there has been bronchiolar destruction. Elastin obstruction may also be found beyond chronic suppurative bronchial
stains may support this by showing a remnant of the bronchiolar wall diseases, such as bronchiectasis or cystic fibrosis, and in immuno­
in the scar, a feature that is often difficult to identify on haematoxylin compromised patients.405,406
and eosin staining (Fig. 3.41). The disease is often patchy and may Intraluminal organisation is again seen when the bronchiolitis is
affect only short segments of the bronchioles. More distal airways may caused by the inhalation of noxious gases, fume or smoke, whether
therefore appear structurally normal, although they are in fact non- the exposure is occupational, environmental or encountered in war.
functioning continuations of completely obliterated bronchioles, The pathogenesis is identical to that which follows infective bronchi­
something that may only be appreciated by studying serial sections. olitis. Examples are provided in Chapters 7.1 and 7.2. They include
As with the intraluminal pattern peripheral accumulations of foamy silo-filler’s disease due to oxides of nitrogen (see p. 356), diacetyl,
alveolar macrophages may be found, suggesting that there is an which is encountered by popcorn workers (p. 355) and thionyl chlo­
obstructive pneumonitis and that the bronchioles may therefore be ride used in the manufacture of lithium batteries (see p. 356). War
worthy of more detailed examination (Fig. 3.42). gases such as phosgene and sulphur mustard and indeed many irritant
gases or fumes that are inadvertently inhaled are liable to cause a
chemical bronchiolitis that may be complicated by luminal organisa­
Aetiology tion.407 When due to inhaled chemicals this is generally indistinguish­
Bronchiolar infection is a major cause of the classic polypoid pattern able from that caused by infections but nylon flock worker’s lung has
of obliterative bronchiolitis. The organisation of an acute inflamma­ a distinctive lymphoid pattern (see p. 354). Ingested chemicals may
tory exudate caused by viral infection complicated by bacterial super­ also cause obliterative bronchiolitis: Sauropus androgynus, described on
infection results in the polypoid intraluminal buds of granulation page 376, is a notable example; here the damage is perpetuated by
tissue.133,135,403,404 The viruses responsible include adenoviruses, respi­ repeated ingestion and the resultant obliterative bronchiolitis is con­
ratory syncytial virus and influenza virus. This pattern of bronchiolar sequently of the constrictive variety.

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 Diseases of the conductive airways Chapter |3|

Figure 3.39  Active constrictive obliterative bronchiolitis obliterative in a

rheumatoid patient. The epithelium is under constant attack and is
consequently unable to regenerate, leading to the build-up of Figure 3.40  Constrictive obliterative bronchiolitis in a rheumatoid
granulation tissue. patient. Internal to the muscle coat there is a thick layer of pale-staining
granulation tissue which severely compromises the airway lumen.
Surviving bronchiolar epitheium is reduced to a small central nidus.
Bronchiolar involvement is often evident in the pneumoconioses. (Reproduced from Geddes et  al. (1977)402 by permission of the editor of the
The clearance mechanisms of the alveolus result in inhaled dust being Quarterly Journal of Medicine.)
concentrated in and around the terminal bronchiole and its accomp­
anying lymphoreticular aggregates (see Macklin’s dust sumps, pp. 27
and 329 and Figs 1.7, p. 7 and 7.1.12, p. 339). This is therefore a site wise clinically similar ‘cryptogenic’ cases have been reported in
where pneumoconiotic nodules are particularly likely to develop, with patients free of connective tissue disease.415,416 In some cases the
inevitable distortion of the bronchiole.408–410 Peribronchiolar fibrosis is changes have been attributed to drugs used to treat the underlying
also an early feature of asbestosis,409,411 probably because much inhaled disease (e.g. penicillamine) but the bronchiolar narrowing is recorded
fibrous dust initially penetrates no further than the bronchioles. in patients who have not been so treated and conversely bronchiolitis
Cigarette smokers are at risk of two forms of bronchiolitis: respira­ obliterans is not recorded in patients who have received these drugs
tory bronchiolitis and chronic obstructive bronchiolitis (small-airway in the treatment of other diseases (e.g. Wilson’s disease). It is therefore
disease). The former predominantly affects the peribronchiolar alveoli more likely to be a manifestation of the connective tissue disease than
and is therefore dealt with in Chapter 6.2 (see p. 313) while the latter an effect of the drug. Similarly, some cases of obliterative bronchiolitis
is considered above under chronic obstructive lung disease (see attributed to chemical fumes have involved rheumatoid patients and
p. 100). may represent rheumatoid airway disease rather than chemical
Obliterative bronchiolitis of constrictive pattern has been described damage.417 The association of bronchiolar disease and connective
in such autoimmune disorders as rheumatoid disease,402,412 ankylosing tissue disease is discussed further in Chapter 10.
spondylitis, systemic sclerosis413 and paraneoplastic pemphigus.414 Obstructive pulmonary disease has been recorded in several patients
The disease affects small bronchi as well as bronchioles and is rapidly with ulcerative colitis.418,419 Airways of any size from the trachea to
progressive: affected patients may die of obstructive respiratory small bronchioles may be affected and there is a spectrum of disease
impairment within a year of the onset of dyspnoea. Milder but other­ ranging from sclerosing tracheobronchitis to obliterative bronchiolitis

123
 Pathology of the Lungs

Figure 3.42  Chronic bronchiolitis. A small airway shows chronic

inflammation and intraluminal accumulation of macrophages suggesting
proximal obstruction.

DIFFUSE PANBRONCHIOLITIS

B The cause of this disease is unknown but it is prevalent in Japan, and,

to a lesser extent, Korea and China.422–426 Only a few cases have been
Figure 3.41  Constrictive obliterative bronchiolitis. (A) At low power there described in the west,427–430 possibly because of genetic differences.
are no obvious abnormalities but an elastin stain (B) highlights that what The affected Asians show an increase in certain HLA antigens that do
might have been interpreted as an interlobular septum is a bronchiole not occur in other races, notably B54 in Japan and A11 in Korea.431,432
wholly obliterated by fibrosis. (Courtesy of Dr G Taylor, Auckland, New However, environmental factors also appear to be important since
Zealand.)
the disease is uncommon in persons of Japanese ancestry living
abroad. The identification of diffuse panbronchiolitis in a Hispanic
man who had visited Japan raises the possibility that a transmissible
agent may be involved.433 As diffuse panbronchiolitis mimics several
of constrictive type, similar to that seen in autoimmune connective other obstructive airway diseases,424 it is possibly masquerading as one
tissue disease. As in rheumatoid disease, the airway narrowing is or other of these elsewhere and chest physicians and pathologists
progressive and may prove fatal. The temporal relationship of disease outside Japan need to be more conversant with the features of this
activity in the bowel and airways is a weak one. Indeed, the pulmo­ disease.
nary disease may appear years after the patient has undergone colec­
tomy. The changes in the airways are comparable to those that develop
in the biliary tree in sclerosing cholangitis, another extraintestinal
Clinical features
complication of ulcerative colitis. The association of lung and bowel The disease has a wide age distribution with a peak age incidence
disease is dealt with further in Chapter 10. between the fourth and seventh decades of life. It does not appear to
Patients who have undergone lung transplantation are at risk of be related to smoking. Men are affected twice as commonly as women.
both forms of obliterative bronchiolitis. In the early posttransplant Long-standing sinusitis generally precedes the onset of lower respi­
period they are subject to infection or aspiration, either of which is ratory tract disease, which in its early stages is characterised by a
likely to result in obliterative bronchiolitis of classic polypoid pattern, productive cough and obstructive respiratory impairment. The term
whereas later they are at risk of graft rejection, a major feature of which ‘sinobronchial syndrome’ is often applied. Wheezing may lead to a
is obliterative bronchiolitis of constrictive pattern.420,421 resemblance to chronic bronchitis or asthma.

124
 Diseases of the conductive airways Chapter |3|

Early in the course of the disease sputum cultures are unrevealing.

Infection and/or colonisation follows and, in the advanced stages,
large amounts of purulent sputum infected by Haemophilus influenzae
and Pseudomonas aeruginosa are produced and dilatation of proximal
bronchioles develops. The disease then resembles bronchiectasis, par­
ticularly the idiopathic variety, which is also associated with sinusitis.
Cold haemagglutinins frequently develop after the disease is estab­
lished but Mycoplasma antibodies are generally lacking. Rheumatoid
factor is often present but few patients with diffuse panbronchiolitis
have overt rheumatoid disease.

Imaging
Chest radiographs show numerous small nodular opacities scattered
throughout both lung fields and, in late cases, bronchiolectasis and
bronchiectasis may be demonstrated. High-resolution computed tom­
ography is characteristic but not pathognomonic. The nodular opaci­
ties are centrilobular and often extend as short linear opacities (‘tree
in bud’ pattern). Expiratory scans usually show focal air-trapping.

Pathological features
As its name suggests, diffuse panbronchiolitis is an inflammatory
disease of small airways that is widely disseminated throughout both
lungs, but it especially affects the bases. Numerous yellow nodules
measuring up to 4 mm in diameter are seen on the cut surfaces of the Figure 3.43  Diffuse panbronchiolitis. The bronchiolar wall is thickened
lungs. Microscopically, the walls of membranous and respiratory by a chronic inflammatory infiltrate and the surrounding alveoli contain
bronchioles are thickened by a lymphoplasmacytic infiltrate and there many foam cells, which also infiltrate the alveolar walls. (Reproduced by
is prominence of the bronchus-associated lymphoid tissue. The permission of Dr M Kitaichi, Kyoto, Japan.)
inflammatory changes extend into the peribronchiolar tissues and
there is obstructive lipid pneumonia, corresponding to the fine yellow
nodules observed grossly (Fig. 3.43).423,434 Interstitial as well as air
space accumulation of foamy macrophages is a striking histological the changes of diffuse panbronchiolitis were identified in 20 (1.5%)
feature. of 1336 patients with a variety of other lung diseases, notably cystic
fibrosis, bronchiectasis and bronchiolitis.436 However, diffuse pan­
bronchiolitis is a clinicopathological diagnosis and Japanese physi­
Differential diagnosis
cians are reluctant to make the diagnosis if the patient does not exhibit
Diffuse panbronchiolitis bears some resemblance to several diseases the appropriate clinical features, especially sinusitis.
familiar to non-Japanese practitioners, notably idiopathic bron­
chiectasis, chronic bronchitis and obliterative bronchiolitis, but
whereas these have their major impact on the bronchi or membranous
Course of the disease
bronchioles, diffuse panbronchiolitis is centred on the respiratory Death from respiratory failure and cor pulmonale was formerly
bronchioles.435 Nevertheless, the pathological changes of diffuse pan­ common but erythromycin treatment has improved the
bronchiolitis are not specific. In a review of American archival material prognosis.437,438

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– lessons from lung transplantation. Chronic bronchial suppuration and et al. Calcite sputum lith. Characterization
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recognised form of sinusitis. J Allergy Clin Pulmonary involvement in ulcerative 389. Nollet AS, Vansteenkiste JF, Demedts MG.
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390. Studer SM, Heitmiller RF, Terry PB. 407. Dompeling E, Jobsis Q, Vandevijver NMA, 424. Izumi T. Diffuse panbronchiolitis. Chest
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gas. Eur Resp J 2004;23:343–6. panbronchiolitis. In: Sharma OP, editor.
Chronic bronchiolitis 408. Churg A, Wright JL. Small-airway lesions Lung Disease in the Tropics. New York:
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1998;109:101–9. 1983;14:688–93. and distribution of bronchiolar
392. Ryu JH, Myers J, Swenson SJ. Bronchiolar 409. Churg A, Wright JL. Small airways disease obstruction in lungs with chronic
disorders. Am J Resp Crit Care Med and mineral dust exposure. Pathol Annu obstructive pulmonary disease –
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393. Rice A, Nicholson AG. The pathologist’s 410. Churg A, Wright JL, Wiggs B, et al. Small three-dimensional reconstruction of
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transradiancy. Thorax 1962;17:230–9. 411. Wright JL, Churg A. Morphology of small- panbronchiolitis observed in an Italian.
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The development of unilateral exposure. Hum Pathol 1984;15:68–74. 428. Randhawa P, Hoagland MH, Yousem SA.
hypertransradiancy of the lung. Br J Dis 412. Devouassoux G, Cottin V, Liote H, et al. Diffuse panbronchiolitis in North-America
Chest 1967;61:190–2. Characterisation of severe obliterative – report of three cases and review of the
396. Stokes D, Sigler A, Khouri NF, Talmo RC. bronchiolitis in rheumatoid arthritis. Eur literature. Am J Surg Pathol 1991;15:
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pneumoniae infection. Am Rev Respir Dis Association of bronchiolitis with Diffuse panbronchiolitis in the United
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397. Avital A, Shulman DL, Bar-Yishay E, et al. Dis 1986;45:656–62. 1996;154:497–503.
Differential lung function in an infant 414. Hasegawa Y, Shimokata K, Ichiyama S, 430. Fisher MS, Rush WL, Rosado-de-
with the Swyer–James syndrome. Thorax et al. Constrictive bronchiolitis obliterans Christenson ML, et al. Diffuse
1989;44:298–302. and paraneoplastic pemphigus. Eur Resp J panbronchiolitis: Histologic diagnosis in
398. Fukuoka J, Franks TJ, Colby TV, et al. 1999;13:934–7. unsuspected cases involving North
Peribronchiolar metaplasia: a common 415. Turton CW, Williams G, Green M. American residents of Asian descent. Arch
histologic lesion in diffuse lung disease Cryptogenic obliterative bronchiolitis in Pathol Lab Med 1998;122:156–60.
and a rare cause of interstitial lung disease: adults. Thorax 1981;36:805–10. 431. Sugiyama Y, Kudoh S, Maeda H, et al.
clinicopathologic features of 15 cases. Am 416. Kraft M, Mortenson RL, Colby TV, et al. Analysis of HLA antigens in patients with
J Surg Pathol 2005;29:948–54. Cryptogenic constrictive bronchiolitis. diffuse panbronchiolitis. Am Rev Respir
399. Guarino M, Tosoni A, Nebuloni M. Direct A clinicopathologic study. Am Rev Respir Dis 1990;141:1459–62.
contribution of epithelium to organ Dis 1993;148:1093–101. 432. Park MH, Kim YW, Il Yoon H, et al.
fibrosis: epithelial–mesenchymal 417. Murphy DMF, Fairman RP, Lapp NL, et al. Association of HLA class I antigens with
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2009;40:1365–76. fumes from cleansing agents. Chest patients. Am J Respir Crit Care Med
400. Borthwick LA, Parker SM, Brougham KA, 1976;69:372–6. 1999;159:526–9.
et al. Epithelial to mesenchymal transition 418. Wilcox P, Miller R, Miller G, et al. Airway 433. Homer RJ, Khoo L, Smith GJW. Diffuse
(EMT) and airway remodelling after involvement in ulcerative colitis. Chest panbronchiolitis in a hispanic man with
human lung transplantation. Thorax 1987;92:18–21. travel history to Japan. Chest
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419. Rickli H, Fretz C, Hoffman M, et al. Severe
401. Gosink BB, Friedman PJ, Liebow AA. inflammatory upper airway stenosis in 434. Sato A, Chida K, Iwata M, et al. Study of
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1973;117:816–32. Rev Respir Dis 1992;146:473–8.
420. Abernathy EC, Hruban RH, Baumgartner
402. Geddes DM, Corrin B, Brewerton DA, WA, et al. The two forms of bronchiolitis 435. Homma S, Sakamoto S, Kawabata M, et al.
et al. Progressive airway obliteration in obliterans in heart–lung transplant Comparative clinicopathology of
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421. Sato M, Keshavjee S. Bronchiolitis
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Part II: The repair phase. Aust Ann Med dependent and -independent injury with panbronchiolitis: diagnosis and distinction
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adenovirus type 21 infection in young Diffuse panbronchiolitis 1994;25:357–63.
children. J Clin Pathol 1971;24:72–82. 422. Homma H, Yamanaka A, Tanimoto S, 437. Ichikawa Y, Hotta M, Sumita S, et al.
405. Diaz F, Collazos J, Martinez E, et al. et al. Diffuse panbronchiolitis. A disease of Reversible airway lesions in diffuse
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406. Ito M, Nakagawa A, Hirabayashi N, et al. 423. Maeda M, Saiki S, Yamanaka A. Serial
Bronchiolitis obliterans in ataxia- section analysis of the lesions in diffuse 438. Koyama H, Geddes DM. Erythromycin and
telangiectasia. Virchows Arch panbronchiolitis. Acta Pathol Jpn diffuse panbronchiolitis. Thorax
1997;430:131–7. 1987;37:693–704. 1997;52:915–18.

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 Chapter 4 

Acute alveolar injury and repair

common condition, which carries a high mortality, about 50%

CHAPTER CONTENTS
overall. Estimations of incidence show considerable international
Acute respiratory distress syndrome 135 variability but one American study reported it to be 79 per 100 000
Diffuse alveolar damage 136 population.4
ARDS is a fulminant form of respiratory failure characterised by
Shock 142
refractory hypoxaemia (Pao2/FIo2 < 200) and bilateral radiographic
Infection 145 opacification in the absence of any evidence of an elevated left atrial
Aspiration of gastric contents 145 pressure.5 These features indicate widespread alveolar collapse and
Irradiation 146 exudation that cannot be attributed to left heart failure or other cause
of pulmonary venous hypertension. There is generalised ground-glass
Idiopathic acute alveolar injury 146
opacification of the lungs, which is most pronounced in the depend-
Treatment of acute respiratory distress 146 ent parts of the lungs. The opacification rapidly becomes increasingly
Outcome 147 dense until there is frank consolidation (Fig. 4.2).6 Air is then confined
Pulmonary fibrosis 147 to the bronchi, which therefore appear black on plain radiographs
Intra-alveolar fibrosis (organising pneumonia) 147 where they stand out against the alveolar ‘white-out’ (so-called air
bronchograms).7
Obliterative fibrosis 148
Functional studies confirm that little of the lung substance is
Interstitial fibrosis 148 ventilated. There is initially mild pulmonary hypertension but the
‘Honeycomb lung’ 149 pulmonary arterial constriction responsible for this is succeeded
Dystrophic calcification and ossification 149 by vascular non-responsiveness so that the normal vasoconstrictor
response to hypoxia is diminished. The consequent ventilation/per-
References 149
fusion mismatching aggravates the hypoxaemia. Other organs suffer
both hypoxia and the effects of inflammatory mediators initiated by
the pulmonary injury once these gain access to the general circulation.
The end stages of ARDS are therefore frequently associated with
ACUTE REPIRATORY DISTRESS SYNDROME multiple organ failure.8
Despite the variety of causes, most patients with ARDS show the
Acute alveolar injury may be caused by a wide range of pulmonary same pattern of pathological changes, one that is termed diffuse alveo-
insults that at their most severe result in what is termed the acute lar damage (DAD). Much of this chapter is devoted to this pattern of
respiratory distress syndrome (ARDS). This was formerly known as injury but occasionally patients presenting with ARDS show other
the adult respiratory distress syndrome,1–3 a term introduced to changes when subjected to biopsy or coming to autopsy. These are
emphasise its similarity to that seen in premature babies suffering listed in Box 4.1 and are considered in other chapters but their chief
from the effects of deficient pulmonary surfactant production, i.e. the pathological features are compared with those of DAD in Table 4.1.
infantile respiratory distress syndrome (see p. 43), but following the Recognition of these other patterns may lead to a change in the
recognition that the causes of the adult respiratory distress syndrome patient’s management. In that they include infection it is essential that
may also operate in children, ‘adult’ has given way to ‘acute’. The some of the specimen goes to the microbiology department. Lung
causes of the syndrome differ markedly in infants and adults but biopsy is also undertaken to assess the reversibility of the changes.9,10
whatever the cause, a common cycle of events is initiated (Fig. 4.1) The process is potentially reversible in its exudative phase whereas
so that the end-result is the same regardless of the cause. It is a widespread fibrosis with loss of the lung architecture is not.

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00004-5 135
 Pathology of the Lungs

Viruses
NOx, O3
Paraquat
Irradiation
Prematurity Shock

Surfactant Epithelial and

deficiency endothelial damage

Figure 4.2  Acute respiratory distress syndrome. High-resolution

computed tomography shows dense consolidation of both lungs,
Shear forces especially the dependent regions.

Collapse
and oedema

Figure 4.1  The cycle of events in the infantile and acute (formerly adult) Box 4.1  The pathological basis of the acute respiratory
respiratory distress syndromes. The infantile syndrome is initiated by the
distress syndrome
immature fetal lungs being unable to replenish spent surfactant whereas
in the acute syndrome the cycle is initiated by a variety of causes that 1. Diffuse alveolar damage (the typical pattern, considered in this
damage the delicate alveolar epithelium. chapter)
2. Other causes (considered elsewhere):
• Pulmonary oedema due to high-altitude, rapid lung
re-expansion or cerebral injury
• Unusual manifestations of bacterial pneumonia, e.g.
DIFFUSE ALVEOLAR DAMAGE streptococcal pneumonia, leptospiral pneumonia
• Acute fibrinous organising pneumonia
DAD represents a non-specific pattern of acute alveolar injury caused • Capillaritis/diffuse alveolar haemorrhage
by a variety of noxious agents.11–14 It is the chief pathological basis of • Acute eosinophilic pneumonia
ARDS. The pathological changes of DAD can be divided into the • Unusual forms of malignant disease that affect the lungs
overlapping phases of exudation, regeneration and repair.15 diffusely, e.g. adenocarcinoma, intravascular lymphoma,
‘lymphangitis carcinomatosis’

Exudative phase
To facilitate gas exchange the alveolar wall is highly specialised in
structure. Unfortunately this specialisation renders it susceptible to
injury by a wide variety of agents. The principal cells of the air–blood
barrier, the type I alveolar epithelial cell and the capillary endothelial there is widespread collapse, intense congestion of the capillaries,
cell are exceptionally thin (see Fig. 1.27, p. 16) and this makes them interstitial oedema and distension of the lymphatics, a pattern that is
particularly vulnerable to non-specific damage. Injury to these two sometimes known as congestive atelectasis (Fig. 4.4). Alternatively,
cells underlies the development of DAD. At an early stage of alveolar there may be haemorrhagic oedema (Fig. 4.5). At the air–tissue inter-
injury the type I epithelial cells show cytoplasmic blebbing, which is face, which in these collapsed lungs is at the respiratory bronchiole
soon followed by necrosis resulting in denudation of the basement or alveolar duct level, respiratory movements compact a fibrin-
membrane (see Fig. 7.2.5, p. 376).16,17 Similar blebbing is seen in the rich exudate mixed with necrotic epithelial debris into a thin
alveolar capillary endothelium but denudation of the endothelial layer that covers an otherwise denuded epithelial basement mem-
basement membrane is seldom observed, probably because of differ- brane (Fig. 4.6), leading to the formation of hyaline membranes
ences in the ways epithelial and endothelial cells regenerate (see (Fig. 4.7)11–13,21,22: these are identical to those that paediatric
below). The consequences of this damage include the escape of fibrin- pathologists recognise as the hallmark of the infantile respiratory
rich exudates into the interstitial and air spaces, loss of the surface- distress syndrome (compare Fig. 4.3 with Fig. 2.8, p. 44). Similar
active alveolar lining film and pulmonary collapse. changes are also seen in acute eosinophilic pneumonia but here the
The exudative phase lasts about 1 week, during which the lungs are hyaline membranes contain eosinophils, possibly in small focal col-
heavy, often weighing over 1 kg each, dark and airless. The changes lections that are easily overlooked (see p. 462).
are often patchy, with the dorsal and basal regions being most severely The congested alveolar capillaries sometimes contain increased
affected (Fig. 4.3).18–20 Slicing shows that they are wet, the cut surface numbers of platelets or neutrophil leukocytes. This selective sequestra-
exuding blood or heavily blood-stained watery fluid. Microscopically tion of formed blood elements in the microvasculature of the lungs

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 Acute alveolar injury and repair Chapter |4|

Table 4.1  Histological patterns associated with the acute respiratory distress syndrome

Diffuse alveolar Acute eosinophilic Acute fibrinous Capillaritis/diffuse

damage pneumonia organising pneumonia alveolar haemorrhage

Hyaline membranes ++ + − +/−

Eosinophils − + − −
Fibrin knots +/− +/− ++ +/−
Type II cell hyperplasia ++ +/− +/− −
Interstitial fibrosis + +/− +/− −
Capillaritis/haemorrhage − − − ++

Figure 4.4  Congestive atelectasis in septic shock. There is severe capillary

congestion and alveolar collapse.

Figure 4.3  Shock lung. The lower lobe shows large irregular areas of
collapse and congestion. (Reproduced from Corrin (1980)18 by permission of the
editor of the Journal of Clinical Pathology.)

Figure 4.5  Haemorrhagic pulmonary oedema in septic shock. The

is particularly noticeable in shock, and is considered in more detail alveolar capillaries are congested and the alveolar spaces are filled by
under that heading below. oedema fluid in which there are free erythrocytes.

Regenerative phase The regenerative (or proliferative) phase becomes prominent

As with any exudative process, healing may be by resolution, which 1–2 weeks after the initial injury. It involves proliferation of both
involves fibrinolysis and permits the lungs to return to normal, or epithelial and connective tissue cells. The stem cell concerned in
repair, which involves fibrosis and leaves the lungs permanently epithelial regeneration is the type II alveolar epithelial cell.23,24 These
scarred. Resolution and repair are both accompanied by epithelial and cells first proliferate and then differentiate into type I cells, thereby
endothelial regeneration. re-epithelialising the denuded basement membranes. The dividing

137
 Pathology of the Lungs

Figure 4.7  Diffuse alveolar damage, exudative phase. Hyaline

membranes are a conspicuous feature. They often outline alveolar ducts.
From a pregnant woman who suffered respiratory arrest due to
angioneurotic oedema. She needed to be ventilated for 2 weeks before
death and the oxygen concentration in the inspired air constantly
increased to prevent hypoxaemia, reaching 70% for the last 8 days of
her life. (Courtesy of Dr D Melcher, Brighton, UK.)

effete endothelial cell is first undermined by its healthy neighbours

and only cast off when these have completely covered the basement
membrane.31 Therefore, although segments of bare basement mem-
brane have been described on the vascular side of the air–blood
barrier,32,33 they are not seen to the same extent as on the epithelial
side. Nevertheless, thrombosis may complicate such endothelial
damage21,32 and subsequent organisation of such thrombi is probably
responsible for some of the vascular remodelling that is seen in the
repair phase of DAD. This remodelling consists of fibrocellular intimal
thickening that narrows the lumen of small vessels throughout
Figure 4.6  Diffuse alveolar damage. The alveolar epithelium terminates the lung and can be visualised as decreased background filling on
just above centre and from this point (arrow) upwards a mixture of
postmortem arteriograms.34
electron-dense fibrin and cell debris (seen at the light microscopic level  
as a hyaline membrane) is closely applied to the denuded basement
membrane. Part of a necrotic cell is seen within the alveolus. Repair phase
Transmission electron micrograph. (Courtesy of Miss A Dewar, Brompton, UK.)
If healing is by repair, interstitial connective tissue cells proliferate
and, as in any scarring, myofibroblasts are involved at an early stage.35
Whilst myofibroblast contracture is beneficial when it promotes early
type II cells form a simple cuboidal epithelium (Fig. 4.8), or the closure of an open wound, in the lungs it largely results in harmful
alveoli may be lined by plump pleomorphic spindle cells that repre- distortion of the bronchioloalveolar architecture and shrinkage of
sent cell forms intermediate between types II and I epithelial cells the lungs. Possible sources of the proliferating interstitial connective
(Figs 4.9 and 4.10). Eosinophilic cytoplasmic inclusions indicative of tissues include resting interstitial connective tissue cells, the bone
cell damage (see Fig. 7.1.25, p. 348) are often present,25,26 and some- marrow and the alveolar epithelium. Epithelial–mesenchymal transi-
times there is squamous metaplasia instead of orderly differentiation tion is being increasingly recognised throughout the body and in the
into type I cells, a change that the unwary pathologist may mistake lung in conditions such as idiopathic pulmonary fibrosis, asthma and
for neoplasia.27 obliterative bronchiolitis.36–38
The regenerating epithelium usually grows beneath the exudates Whatever the source of the proliferating connective tissue cells,
lining the denuded basement membrane, casting the hyaline mem- those with a fibroblastic phenotype lay down collagen, leading to the
branes off into the air space (Fig. 4.11), but it may grow over them development of interstitial fibrosis.39,40 Interactions between fibro­
so that they are incorporated into the interstitium (Figs 4.12 and blasts and the alveolar epithelium through gaps in the basement
4.13),11–13 where their subsequent organisation contributes to the membrane have been described,41–45 suggesting that the regenerating
fibrosis.22 The regenerating epithelial cells may also bridge the mouths epithelial cells play a further role in the underlying process of fibrosis.
of collapsed alveoli so that these air spaces never re-expand and there It is known that these cells synthesise fibrogenic cytokines such as
is permanent shrinkage of the lung, a process termed atelectatic indu- tumour necrosis factor-α; the secretion of tumour necrosis factor-α
ration (Figs 4.14 and 4.15).28–30 into the underlying connective tissue would further promote intersti-
In contrast to the type I epithelial cells, which have no regenerative tial fibrosis.46,47
powers and are replaced by differentiation of proliferating type II cells, Fibroblasts also migrate into the alveolar exudates through defects
endothelial cells are replaced by lateral spread of their own kind. An in the epithelial basement membrane to lay down collagen within the

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 Acute alveolar injury and repair Chapter |4|

Figure 4.9  Diffuse alveolar damage, regenerative phase. Regenerating

alveolar epithelial cells are atypical, consisting of plump, elongated forms
that represent type II pneumocytes differentiating into type I.

Figure 4.8  Diffuse alveolar damage, regenerative phase. (A) The alveoli
have a simple cuboidal epithelial lining. (Courtesy of Dr D Melcher, Brighton,
UK.) (B) Electron microscopy shows that such cells represent hyperplastic
type II pneumocytes, which form a continuous row rather than being
scattered singly in the corners of the alveoli. They are readily recognisable
by their surface microvilli and the osmiophilic lamellar secretory vacuoles
of alveolar surfactant. (Courtesy of Mrs D Bowes, Midhurst, UK.)
Figure 4.10  Diffuse alveolar damage, regenerative phase. An alveolar
epithelial cell having the squamous form of a type I cell but the microvilli
and lamellar vacuoles of a type II cell. Such intermediate cells are
indicative of epithelial regeneration.

139
 Pathology of the Lungs

Figure 4.11  Diffuse alveolar damage, regenerative phase. The

regenerating alveolar epithelium grows underneath the hyaline
membranes, casting them off into the air space.

Figure 4.13  Diffuse alveolar damage, repair phase. Hyaline membranes,

which are stained red, are in the process of being incorporated into the
alveolar interstitium. Martius scarlet blue stain.

hyaline membranes.48,49 As epithelial cells grow over the newly formed

connective tissue, a new basement membrane is formed, thereby
incorporating the collagen into the interstitium,49 a process known as
fibrosis by accretion. Involvement of the alveolar ducts results in these
structures being lined by a ring of granulation tissue (Fig. 4.16). Less
frequently, the organised exudates retain a predominantly intra-
alveolar position, resulting in loose buds of granulation tissue similar
to those seen in organising pneumonia due to other causes (see
Box 6.2.1, p. 309). However, here they are more widespread and there
is more prominent type II cell hyperplasia, interstitial fibroblastic
proliferation and interstitial inflammation (Fig. 4.17). Nevertheless,
such an organising pneumonia pattern is worth recognising as it
carries a better prognosis than interstitial fibrosis.50 It is claimed that
this intra-alveolar pattern of repair is particularly found when gener-
Figure 4.12  Diffuse alveolar damage, regenerative phase. The
alised sepsis is the cause of the initial damage whereas interstitial
regenerating alveolar epithelium may also grow over the hyaline
fibrosis is more characteristic of injury caused by cytotoxic drugs and
membranes to incorporate them into the alveolar wall. In this electron
micrograph the hyaline membranes are largely represented by electron- the idiopathic cases.51
dense fibrin which is closely applied to previously denuded alveolar An increase in lung collagen can be detected in patients with ARDS
epithelial basement membrane and are in turn covered by regenerating who survive longer than 14 days and this progressively increases with
epithelium laying down a new basement membrane. (Courtesy of Miss A the duration of the disease.52 The identification of pulmonary fibrosis
Dewar, Brompton, UK.) on transbronchial biopsy is closely related to mortality.53 Fibrosis can

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 Acute alveolar injury and repair Chapter |4|

Figure 4.16  ‘Ring’ fibrosis, representing the organisation and

incorporation of exudates lining the alveolar ducts into the walls of these
airways.

be well established by 2 weeks, at which time the lungs may be con-

tracted and firm with a fine sponge-like pattern on their cut surfaces,
representing bronchiolectasis and irregular microcystic distortion of
the alveolar architecture (Figs 4.18 and 4.19).54–57 The changes are
similar to those seen in any fibrotic process but are reached remark-
ably quickly (see Fig. 4.19).22 However, at this early stage the fibrosis
differs from that seen in chronic fibrosis in being more cellular and
less collagenous: extensive fibroblast proliferation is evident. With
small air cysts alternating with solid areas of fibrosis and foci of squa-
mous metaplasia there is a resemblance to the bronchopulmonary
Figure 4.14  Atelectatic induration. Denuded alveolar epithelial basement dysplasia seen in the late stages of the infantile respiratory distress
membranes are closely apposed (centre). The regenerating alveolar syndrome.55,56 In survivors the granulation tissue undergoes progres-
epithelium (top) bridges the mouth of the alveolus, which consequently
sive collagenisation and such patients may suffer from debilitating
has little chance of ever re-expanding. (Courtesy of Miss A Dewar,
fibrotic lung disease. The pattern is then that of fibrotic non-specific
Brompton, UK.)
interstitial pneumonia,58 making it important to determine whether
there has been an episode of acute lung injury in such patients.

Causes
The causes of DAD are quite diverse (Box 4.2). So too are the pathways
by which the injurious agents reach the lungs. Some enter the lungs
directly via the airways, e.g. oxygen in high concentrations, poisonous
gases such as phosgene and metallic fumes such as those of mercury
and cadmium. Other agents responsible for DAD penetrate the chest
wall to damage the lungs (e.g. ionising radiation) and some reach the
lungs via the blood stream, having been ingested or injected (e.g.
paraquat and cytotoxic chemotherapeutic agents). The blood stream
also conveys many of the endogenous factors that underlie the DAD
of shock. In numerical terms, septic shock is the most important cause
of DAD.59,60
Multiple causes may operate in one patient. For example, trauma
may be combined with blood loss, fat embolism and sepsis, whilst
therapeutic efforts to correct these may themselves be hazardous. The
transfusion of stored blood is not without danger, whilst to prevent
hypoxaemia, damaged lungs that require rest often have to be forcibly
ventilated and subjected to injurious concentrations of oxygen,
Figure 4.15  Atelectatic induration. Silver staining of the basement although it is known that this can only aggravate the injury to the
membranes shows that what appear to be thickened single alveolar walls lungs.22 The damaged lung also appears to be unduly susceptible to
represent the closely apposed walls of several collapsed alveoli. infection,61 partly because of impaired neutrophil migration into the

141
 Pathology of the Lungs

Figure 4.18  Diffuse alveolar damage, repair phase. The repair process
has resulted in interstitial fibrosis.

Figure 4.17  Diffuse alveolar damage, repair phase. (A) A lower lobe Figure 4.19  Suicidal ingestion of kerosene resulting in advanced
seen at autopsy shows diffuse consolidation, with occasional lobules pulmonary fibrosis and honeycombing within 2 weeks of the initial injury.
showing more exudative appearances. (B) Microscopy shows diffuse
intra-alveolar organisation with abundant interstitial inflammation.
Shock
Shock is a state of prolonged hypotension, generally attributable to
air spaces.62 It is therefore common in clinical practice for the lungs trauma, hypovolaemia, cardiac failure, sepsis or anaphylaxis.63,64 The
to be subjected to several injurious agents and since these all contrib- hypotension leads to inadequate tissue perfusion and, if this is not
ute to a non-specific pattern of disease it may be difficult for the corrected, multiorgan failure is inevitable. At necropsy, the lungs are
pathologist to distinguish the initiating factor from the effects of treat- the organs most commonly affected.65–67
ment. Consideration of events in the intensive care unit is essential Severe pulmonary injury was well described in patients suffering
in these circumstances. Many of the causes of DAD listed in Box 4.2 from shock in the Second World War68 but it was not until the war in
are dealt with elsewhere, leaving only a few to be considered here. Vietnam that the importance of respiratory failure as a complication

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 Acute alveolar injury and repair Chapter |4|

Gram-negative, which are slightly commoner than polymicrobial.

Box 4.2  Causes of diffuse alveolar damage The role of lipopolysaccharide derived from the cell walls of
Gram-negative bacteria has been particularly well studied in the
Via the airways pathogenesis of septic shock.73–77 The many effects of this endotoxin
Infection, especially viral include the release of tumour necrosis factor from monocytes, mac-
Inhaled smoke, fume and toxic gases, including oxygen in high rophages and polymorphonuclear leukocytes,74–76,78,79 the production
concentrations of cytokines such as interleukin-1 and interferon-γ that act synergisti-
Aspiration of gastric contents cally with tumour necrosis factor,80 the widespread induction of nitric
oxide synthesis81–83 and the activation of both the coagulation and
Through the chest wall
complement cascades.84 Exotoxins released by Gram-positive bacteria
X-irradiation appear to act similarly. Some of the most fulminant forms of shock
Via the blood stream are seen with group A streptococci causing puerperal sepsis and necro-
tising fasciitis, meningococci, Staphylococcus aureus related to tampon
Various mediators generated in shock
retention and a meticillin-resistant strain that secretes an exotoxin
Reperfusion of ischaemic tissue known as Panton–Valentine leukocidin.85
Acute pancreatitis Tumour necrosis factor has been demonstrated on the luminal
Cardiopulmonary bypass surface of pulmonary endothelium in endotoxin-induced shock.86 It
Transfusion of stored blood causes vascular smooth muscle to relax but this action is reduced if
Fat embolism the endothelium is removed,87 indicating that tumour necrosis factor-
Paraquat ingestion induced vasodilatation is partially dependent upon the integrity of the
Cytotoxic chemotherapeutic agents endothelium. A factor that causes vascular dilatation has been detected
as coming from the vascular endothelium and acting on the medial
muscle coat of the vessel. At first termed endothelium-derived relaxing
factor, this factor is now known to be nitric oxide, a remarkably simple
chemical that has long been recognised to be poisonous.88 Fortunately,
of shock was fully appreciated.69,70 By this time there had been major
its half-life in the vessel wall is very short, timed in seconds rather
improvements in medical care. Casualties could be transported rapidly
than minutes. The enzyme responsible for its production (from
by helicopter to well-equipped field hospitals where intensive care
l-arginine) is nitric oxide synthase, which is found in endothelium
with mechanical ventilatory support was available. Despite this,
and can be induced in the vascular medial smooth muscle. Both the
injured patients often developed fatal respiratory insufficiency, typi-
constitutive and inducible forms of the enzyme are activated by bacte-
cally after an interval of between 48 and 72 hours. A number of terms
rial lipopolysaccharide and it therefore seems likely that in septic
graphically described this syndrome – ‘shock lung’, ‘posttraumatic
shock bacterial products act directly on the vessel wall resulting in the
respiratory insufficiency’, ‘traumatic wet lung’ and ‘Da Nang
production of excess amounts of nitric oxide. Even momentarily
lung’. Pathological examination showed congestive atelectasis or
increased levels of nitric oxide might be expected to cause arterial
haemorrhagic oedema proceeding to fully developed DAD, as
dilatation and hence capillary congestion. It would appear that in
described above.
septic shock circulating bacterial products such as lipopolysaccharide
The pathogenesis of ‘shock lung’ is complex and requires special
cause vascular dilatation and possibly increased permeability by direct
consideration. In hypovolaemic and cardiogenic shock, compensatory
action on the blood vessels and indirectly through the induction of
mechanisms such as peripheral vasoconstriction initially maintain
nitric oxide synthase and the release of the cytokines mentioned in
cerebral oxygenation, but if the underlying cause is untreated, there
the preceding paragraph. Pulmonary endothelial upregulation is indi-
follows a state of decompensation characterised by vascular unrespon-
cated by widespread expression of intercellular adhesion molecule-1
siveness: vasodilatation develops, the blood pressure plummets and
(ICAM-1: CD54) in septic shock. Indeed, positive immunostaining
there is widespread hypoxic cell death. Anaphylactic and septic shock
for CD54 is proving to be a useful marker of shock.89
are characterised from the outset by such vasodilatation, which is
Nitric oxide is a powerful vasodilator but it also mediates many
caused by a variety of mediators that are released from inflammatory
other processes throughout the body. In host defence nitric oxide
and other cells.71 The identification of the same mediators in experi-
plays a very different and more aggressive role. It enables macrophages
mental hypovolaemia72 suggests that the pathogenesis of shock may
to generate free oxygen radicals, the principal means by which these
be similar regardless of the cause.
cells eliminate both bacteria and cancer cells, but which, if not inac-
In numerical terms, septic shock is the most important cause of
tivated, also damage healthy host cells.90 Macrophages release much
diffuse damage.59,60 It represents the culmination of a clinicopatho-
more nitric oxide than endothelial cells but, as in the blood vessels,
logical continuum of infection-driven sepsis syndromes:
the amounts released are generally inactivated within seconds.
1. Sepsis – the systemic inflammatory response to infection However, overwhelming bacterial infections result in the release of
characterised by normal heart rate, temperature, respiratory rate very large amounts of nitric oxide and the overproduction of toxic
and white blood cell count oxygen radicals. Although the oxygen radicals are countered by the
2. Severe sepsis – sepsis, as defined in 1, plus multiorgan protective action of enzymes such as superoxide dismutase,91 their
dysfunction excessive release results in oxidation of lipids and protein sulphydryl
3. Septic shock – severe sepsis, as defined in 2, plus refractory groups, and DNA damage.92 Damaged cell membrane phospholipids
hypotension. release free arachidonic acid which in turn is degraded to produce
These terms have replaced ‘septicaemia’, which proved difficult to leukotrienes, such as prostaglandins and thromboxane, that are
define and has now been abandoned. The multiorgan dysfunction is capable of altering vessel calibre and permeability.
due to inflammatory cytokines released into the circulation from the The direct vasodilatory action of nitric oxide and the toxic action
site of infection, the common sites of which are, in decreasing fre- of the free oxygen radicals that nitric oxide generates account for most
quency, lung, blood, intestine and peritoneum, urinary tract and sur- of the pathological features of shock but there are other processes in
gical wounds. Gram-positive infections are slightly commoner than the microvasculature of the lung that contribute to the pulmonary

143
 Pathology of the Lungs

Figure 4.20  Shock lung. In shock, the alveolar walls are sometimes
hypercellular due to the accumulation of neutrophil polymorphonuclear
leukocytes.

damage. The vascular engorgement characteristic of shock lung is

occasionally accompanied by sequestration of neutrophil polymor-
phonuclear leukocytes in the pulmonary microvasculature (Figs 4.20
and 4.21).18,18,93,94 Acting through the complement cascade,84,95,96
endotoxin activates these cells within the systemic circulation so that Figure 4.21  Shock lung. Electron microscopy shows that the neutrophil
they lose their normal deformability and aggregate into microemboli, leukocytes are sequestered in the alveolar capillaries. (Courtesy of Professor
with the result that they cannot traverse the alveolar capillaries.73,97,98 PK Jeffery, Brompton, UK.)
Their arrest there is promoted by activated endothelial intercellular
adhesion molecules.99–103 The unique position of the pulmonary capil-
laries in the circulation is probably responsible for the lungs being
the organs most severely affected in shock.65–67 Trapped in the alveolar
capillaries, activated neutrophils damage the alveolar wall by produc- postmortem (Fig. 4.22).18,112–116 It is uncertain whether intravascular
ing reactive oxygen radicals and releasing enzymes such as elastase, coagulation initiates lung injury,73,117,118 but histamine released from
collagenase and cathepsins that are able to degrade protein constitu- platelets is likely to increase vascular permeability whilst fibrin degra-
ents of the wall.104–110 Impairment of neutrophil migration into the air dation products, which are elevated in patients with the respiratory
spaces has been referred to above.62 distress syndrome,119 are known to induce pulmonary oedema.120
Patients suffering from ARDS frequently have haematological Larger pulmonary thrombi, formed in situ or embolic, are common
evidence of disseminated intravascular coagulation111 and it is then in patients with ARDS.34 Any infarction they cause increases the risk
generally possible to demonstrate platelet and fibrin thrombi and of interstitial emphysema and pneumothorax, forms of barotrauma
increased numbers of megakaryocytes in their alveolar capillaries to which all patients on ventilators are prone.

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 Acute alveolar injury and repair Chapter |4|

Figure 4.23  Aspiration of gastric acid (Mendelson’s syndrome). There is

haemorrhagic oedema and centrally the extravasated blood is discoloured
due to the production of brown acid haematin.

The changes of DAD are not typically seen in bacterial pneumonia,

but may occur in fulminating infection with organisms such as
Streptococcus pyogenes. In pneumonic plague and anthrax pneumonia,
the overwhelming alveolar damage leads to intensely haemorrhagic
pulmonary oedema similar to that sometimes seen in shock. DAD
may also accompany miliary tuberculosis and Pneumocystis pneumo-
nia, particularly the non-reactive forms seen in the severely
immunocompromised.

B Aspiration of gastric contents

Figure 4.22  Shock lung. Shock is often accompanied by disseminated Pulmonary aspiration of gastric contents is a frequent event in
intravascular coagulation, consumptive coagulopathy and the release of un­conscious or semiconscious patients. If the aspirated material is
megakaryocytes from the bone marrow. (A) Platelets fill the alveolar infected it is likely to cause pneumonia and lung abscess but if sterile
capillaries. (B) Megakaryocytes released from the bone marrow are and highly acid the consequences are liable to be even more dire.
arrested in the pulmonary capillary bed, from whence they release their Mendelson reported 66 instances of patients aspirating stomach con-
platelets. Occasional megakaryocytes may be observed in normal lung tents during obstetric anaesthesia. The aspiration of abundant solid
but they are more noticeable in shock. They are seen as clumps of material resulted in suffocation but Mendelson was more interested
basophilic nuclear material within alveolar capillaries (centre). To the right
in the larger number of patients who aspirated liquids and developed
a blood vessel contains a globular hyaline microthrombus.
pulmonary oedema. He suspected that the pH of the aspirate was
important and confirmed this in experiments on rabbits.121 The
aspiration of gastric acid is now known as Mendelson’s syndrome.
The mortality is high,122,123 reaching 94% in some series.124
Infection
Ultrastructural studies on experimental animals in which fluids of
In assessing the role of infection in causing DAD it is important to differing pH and osmolarity have been instilled into the lungs show
distinguish between primary infection of the lung and infection else- features of alveolar injury that are most severe when the fluid is
where in the body. Septic shock has been dealt with above and atten- strongly acid, but even distilled water or saline is able to produce
tion has been drawn to the increased risk of secondary lung infection minor damage. Disturbance of the osmotic gradient across the alveo-
when the lungs are already damaged.62 This section is confined to lar capillary membrane may therefore be an additional factor. Damage
consideration of some primary pneumonias that can produce DAD. occurs to both epithelial and endothelial cells, which separate from
DAD is characteristic of some viral infections, most recently the their basement membranes.125 The most severe changes include necro-
severe acute respiratory syndrome (SARS)-related coronavirus (see sis and neutrophil exudation. Pulmonary haemorrhage is generally
p. 163). Some patients with viral pneumonia succumb during the found and often shows a brown discoloration microscopically, due to
acute exudative phase and are found to have prominent hyaline mem- the production of acid haematin (Fig. 4.23). The alveolar changes are
branes, whilst others suffer less severe damage, allowing regeneration accompanied by acute bronchitis and bronchiolitis with sloughing of
and fibrosis. Indications that the disease is viral include the presence the mucosa. The pathological changes after acid aspiration may be
of specific inclusions, such as those seen in cytomegalovirus infection, described as those of a severe chemical burn.
or of syncytial giant cell formation, most typically seen in measles Preventive measures include the administration of antacids to post-
pneumonia. operative or obstetric patients, but this often results in colonisation

145
 Pathology of the Lungs

of the stomach by Gram-negative bacteria and a bacterial rather than consequently reduced. Irradiation also impairs the bactericidal prop-
a chemical pneumonia if there is aspiration.126 erties of pulmonary macrophages and predisposes to infection.

Irradiation Idiopathic acute alveolar injury

Radiation may be environmental, occupational or employed as a In some cases of rapidly progressive DAD no cause is evident. Such
weapon of war and is of course also part of the therapeutic armamen- patients were described by Hamman and Rich,134 since when these
tarium. Environmental and occupational exposure carries an increased authors’ names have often been applied eponymously to rapidly pro-
risk of lung cancer and is dealt with on page 533 while the iatrogenic gressive idiopathic pulmonary fibrosis.135 Others favour the term
effects of radiation treatment are dealt with on page 391. This section ‘acute interstitial pneumonia’ for such cases and emphasise the differ-
is concerned with the high-level radiation experienced by the victims ences from chronic interstitial pneumonia,135,136 but all intermediate
of nuclear attack or accident. stages are encountered. Furthermore, some patients with idiopathic
Nuclear explosions cause significant acute and long-term damage pulmonary fibrosis that for the most part has run a typically chronic
to the victims. The immediate mortality is high and in such cases course exhibit acute exacerbations. If they die of such a flare-up of
it is difficult to separate the direct effects of radiation from those of their disease autopsy shows the hyaline membranes of DAD superim-
thermal injury and the secondary effects of bone marrow failure. posed upon long-established collagenous fibrosis (see Fig. 6.1.10, p.
Nevertheless, by studying the victims of the atomic bombs dropped 274).137,138 In a series of 58 patients with DAD diagnosed by surgical
on Japan in 1945 much was learnt of the effects of large doses of biopsy, 21% had no identifiable cause or predisposing condition (i.e.
whole-body irradiation. The lungs of victims dying within 2 weeks acute interstitial pneumonia) and in 12% the changes represented an
showed focal collapse and oedema, while those dying between 2 and acute exacerbation of idiopathic pulmonary fibrosis.139 Patients with
6 weeks after exposure had centriacinar areas of necrosis and haemor- idiopathic pulmonary fibrosis of non-specific interstitial pneumonia
rhage; and those dying more than 6 weeks afterwards showed broader pattern may similarly experience acute exacerbations characterised by
areas of necrosis with a heavy infiltrate of neutrophils.127 DAD, while patients with connective tissue disease may develop DAD
ab initio or have it complicate pre-existent interstitial fibrosis.140–142

Pathogenesis
Treatment of acute respiratory distress
Radiation generates free radicals in the tissues and its effects are
potentiated by the presence of oxygen. Free radicals result in DNA The treatment of ARDS is based upon minimising whichever of the
damage and chromosomal abnormalities.128 At the cellular level, several causes of the condition are deemed to be operating and achiev-
alveolar capillary endothelial cells and type I epithelial cells are most ing a balance between maintaining blood oxygen levels and affording
susceptible. the lungs the rest that all tissues recovering from injury require.4,143
Endothelial injury is believed to be of prime importance in radia- Ideally, the lungs would be rested completely and the blood oxygen-
tion pneumonitis.129 Severe or prolonged endothelial damage disturbs ated in some other way. Indeed, this is occasionally attempted by a
the normal endothelial–mesenchymal relationships and allows process of extracorporeal oxygenation in which the systemic blood is
un­coordinated fibroblast proliferation. Endothelial changes are diverted through an artificial lung in the form of a membrane oxy-
detectable within days of exposure. In rats they are seen within 48 genator that sits alongside the patient.143a–c This is a major procedure
hours after 1100 rads and within 5 days after 650 rads.130 Endothelial that generally occupies a surgical operating theatre and is often
cells become swollen and vacuolated and separate from the basement attended by problems with haemostasis and, if prolonged, haemoly-
membrane, resulting in increased capillary permeability and intersti- sis. Lesser procedures involve the insertion of an intravenous oxygena-
tial oedema. Adhesion of platelets to the denuded basement mem- tor or the use of an extracorporeal device that removes carbon dioxide
brane initiates thrombosis and occlusion of the vascular lumen. from the blood passing through a cannula connecting a femoral artery
Proliferation of endothelial cells follows and endothelial basement to its vein, but these only treat a fraction of the blood leaving the
membrane is reduplicated.128,130,131 By light microscopy the early vas- heart.
cular changes are evident as thrombosis, which is followed by cellular More often, blood oxygenation is maintained by artificial ventila-
intimal thickening or even complete occlusion of small arteries and tion, sacrificing the optimal conditions for lung recovery in favour of
arterioles. In the later fibrotic stage vessels are thick-walled and supplying other organs, particularly the brain, with oxygen. Simply
hyaline.132 allowing the mechanically expanded lung to collapse again several
Epithelial cell damage is also well described in radiation injury. times a minute would establish a pattern of respiration quite unlike
Within 10 days of exposure type I cells become swollen and undergo the normal and one that would incur further damage to the lungs.
necrosis and sloughing with the formation of hyaline membranes. With a normal lining of surfactant the alveoli do not collapse com-
Type II cells proliferate and appear swollen and vacuolated.131 pletely at the end of expiration. A considerable residual volume of gas
Pleomorphism of regenerating alveolar lining cells is apparent and is normally retained but, when the alveolar lining film is lost, as in
similar changes are seen in bronchial and bronchiolar epithelium.133 DAD, the alveoli collapse completely at the end of each respiratory
In many respects therefore the appearances closely resemble those due excursion and the inspiratory phase commences from a much lower
to cytotoxic drugs (see p. 385). baseline. It is now recognised that this exerts considerable mechanical
stress upon the delicate alveolar epithelial lining,144 the integrity of
which is already severely compromised in ARDS. These purely
Pathology mechanical forces result in the generation and release of a variety of
Early radiation changes in human lung include oedematous thicken- injurious cytokines (e.g. tumour necrosis factor-α) and reactive oxygen
ing of the alveolar walls, hyperplasia and swelling of type II cells, and species without necessarily involving any inflammation.145,146 To mini-
alveolar exudates. The changes are essentially those of DAD, as mise this, positive pressure is usually maintained throughout the res-
described above. Fibrosis develops later and is typically interstitial. piratory cycle, a form of ventilation termed positive end-expiratory
Type II cells and fibroblasts are often atypical, with large nuclei and pressure, frequently referred to as PEEP.147 If, despite PEEP, hypox­
prominent nucleoli. Blood vessels are sclerosed and the vasculature aemia approaches dangerous levels the intensivist has no choice but

146
 Acute alveolar injury and repair Chapter |4|

to raise the concentration of oxygen in the inspired air, although it is With more widespread pulmonary fibrosis, elastin stains often
recognised that high concentrations of oxygen are themselves injuri- show that the framework of the alveolar walls is maintained,156
ous to the lung. With severe lung damage a situation is often reached and one of three patterns of fibrosis may then be recognised: intra-
where to prevent cerebral injury increasingly higher concentrations of alveolar, interstitial and obliterative.157,158 These patterns are not
oxygen have to be employed. The initial damage to the lung is then mutually exclusive. For example, interstitial fibrosis may result from
compounded by a combination of mechanical and chemical injury, the incorporation of organising air space exudates into the alveolar
resulting in an aggravated form of DAD to which the term ‘respirator wall,159,160 as described above in the proliferative phase of DAD. This
lung’ is often applied. is particularly likely if the epithelium is lost on a broad front and its
Nitric oxide, a selective pulmonary vasodilator with anti- regeneration is delayed. Whether the fibrosis has an intra-alveolar,
inflammatory properties, has been used in acute lung injury but a interstitial or obliterative pattern largely depends on the severity and
meta-analysis found that despite limited improvement in oxygenation duration of the initial injury. To some extent therefore these patterns
it confers no mortality benefit and may cause harm.147a are of prognostic significance.
A promising technique that is now under experimental investiga-
tion follows the recent recognition that bone marrow stem cells are
capable of differentiating into a variety of mature cell types, including
Intra-alveolar fibrosis (organising
those that constitute the alveolar epithelium.148 The successful appli- pneumonia)
cation of this would hasten the healing process and minimise the Intra-alveolar fibrosis represents organisation of an alveolar exudate.161
likelihood of the damaged lung developing irreversible fibrosis. It is characterised by the presence within the alveoli of polypoid knots
of myxoid granulation tissue, rich in glycosaminoglycans, fibroblasts
Outcome and myofibroblasts162 but containing little polymerised collagen.
These intra-alveolar knots of granulation tissue are known as Masson
DAD carries a high mortality rate, around 50% overall but reaching bodies163 or bourgeons conjonctifs (see Figs 4.17B, p. 142, 5.2.4, p. 180
94% when aspiration of gastric acid is the cause.124 The DAD associ- and 6.2.2, p. 310). This is the classic pattern of postpneumonic carni-
ated with septic shock also carries a particularly high mortality rate.149 fication, found particularly when bacterial pneumonia fails to re­­
Certain polymorphisms of the vascular endothelial growth factor solve. It is familiar to all pathologists conducting autopsies and
(VEGF) gene have been associated with a higher mortality.150 Survivors must have been well known to the great morbid anatomists of
may appear to recover completely but tests of lung function often the nineteenth century. Twentieth-century descriptions date back at
show that they have a mild restrictive or diffusion defect.151,152 least to 1912.164–166
Organising pneumonia may also represent incomplete resolution
of eosinophilic pneumonia or the fibrin-rich transudate of severe left
PULMONARY FIBROSIS ventricular failure, or be caused by inhaled irritants,167 viral infection,
including human immunodeficiency virus,168 drugs,169,170 radia-
tion171–173 and connective tissue disease.174,175 Organising pneumonia
The healing of DAD by fibrosis leads to a consideration of pulmonary is also found in transplanted lungs176 and is commonly seen around
fibrosis in general. This is not an inevitable consequence of injury for, tumours or other localised lung lesions. It is also one of the minor
if the damaged tissue is capable of regeneration, healing by resolution features of extrinsic allergic alveolitis (Box 4.3). Although organising
is possible and normality is regained. However, if tissue is irretrievably pneumonia is readily recognisable in trans­bronchial biopsies, such
lost, healing can only take place by repair, entailing the replacement specimens may not include these under­lying lesions, which may
of the lost tissue by fibrous tissue and resulting in scar formation. therefore remain undetected unless a surgical biopsy is obtained.
Various patterns of fibrosis are encountered in the lungs and these There is also an idiopathic variety of organising pneumonia, known
will now be described. as cryptogenic organising pneumonia (formerly known as idiopathic
Focal scars are quite commonly found in the lungs at necropsy, bronchiolitis obliterans-organising pneumonia). This is described in
particularly at the apices of the upper lobes where they consist of Chapter 6.2 (p. 308).
narrow bands of contracted, often blackened, lung covered by thick-
ened pleura, the so-called apical cap.153–155a When such apical scars are
accompanied by calcification and pleural adhesions, they have
probably followed tuberculosis, but this is now unusual in developed
countries. Most apical scars in these countries are probably attribut-
Box 4.3  Causes of intra-alveolar fibrosis
able to the relative ischaemia of the apices of the lungs, which, due
to our upright posture, are barely perfused at all for much of the day. Bacterial pneumonia
Quite minor apical scars are often associated with bullae and rupture Aspiration pneumonia
of these underlies many spontaneous pneumothoraces (see p. 711). Eosinophilic pneumonia
Apical scarring also develops in ankylosing spondylitis (see p. 478). Severe left-sided cardiac failure (‘congestive consolidation’)
In other parts of the lungs, a focal subpleural scar may be the result Inhaled irritants
of a primary tuberculous lesion or the corresponding primary lesions
Viral infection
of fungal infections such as histoplasmosis. Focal scars also result
Drugs
from embolic infarction and pneumonia. In such scars combined
Radiation
stains for elastin and collagen (such as the elastin-van Gieson stain)
often show that the alveolar framework of the lung is completely lost, Connective tissue disease
reflecting total destruction of the affected area. Such scars are generally Inflammatory bowel disease
rich in elastin, a feature common to organs such as the lungs and the Extrinsic allergic alveolitis
heart that are subject to repeated movement and one that is not seen Adjacent lesions such as tumour, abscess, Wegener’s granulomatosis
to the same degree in scars of organs such as the liver and kidneys Idiopathic (cryptogenic organising pneumonia)
that are subjected to less movement.

147
 Pathology of the Lungs

Figure 4.25  Interstitial pulmonary fibrosis.

Box 4.4  Causes of predominantly interstitial

pulmonary fibrosis
A ‘transudate/exudate’ group A ‘granulomatous’ group
that affects the dependent that tends to spare the bases
parts of the lung
Organising diffuse alveolar damage Sarcoidosis
Idiopathic pulmonary fibrosis (usual Extrinsic allergic alveolitis
interstitial pneumonia) Langerhans cell histiocytosis
Chronic oedema Silicosis
Asbestosis Chronic berylliosis
B The conditions in the left-hand column are ranked on a time scale from
organising diffuse alveolar damage, which may progress to fibrosis within  
Figure 4.24  Accidental paraquat poisoning. The patient died from 10 days, to asbestosis, which evolves over many years.
pulmonary fibrosis within 10 days of ingesting a relatively small amount
of the chemical. The fibrosis is of the obliterative pattern, resulting from
organisation of exudate that flooded many alveoli so that the air spaces
are completely obliterated although the alveolar walls can still be
alveolar walls but it may also be brought about by an accretive
identified. (A) Haematoxylin and eosin. (B) Masson stain.
process involving incorporation into the interstitium of exudates or
connective tissue first formed in air spaces.159,160,177 The causes are
Obliterative fibrosis varied but may be divided into two broad groups, one involving the
formation of exudates and transudates and the other involving
Pulmonary fibrosis sometimes effaces the lumen of several adjacent the formation of what may be loosely termed granulomas (Box 4.4).
alveoli completely, rendering them totally airless (Fig. 4.24). This It is particularly notable that the ‘exudate and transudate’ group of
obliterative pattern of fibrosis is the result of severe lung injury due diseases predominantly affects the basal portion of the lungs and the
to any of the causes of DAD considered above. Intra-alveolar and ‘granulomatous’ group more the upper parts. The reason for this is
obliterative pulmonary fibrosis have many causes in common. The not well understood but it can be a helpful diagnostic pointer in
pattern of fibrosis depends not so much on the nature of the damage advanced disease. It requires no great skill in interpreting chest radio-
as its severity. With very severe injury the alveolar lumen is flooded graphs to assign a patient with widespread reticulonodular opacities
with a fibrin-rich exudate, organisation of which completely to one or other of these two broad groups on the basis of the distribu-
obliterates the air spaces over broad tracts of lung. Within these tion of the disease. This criterion is also useful when assessing wide-
areas, however, the framework of the alveolar walls can often still be spread pulmonary fibrosis postmortem.
appreciated, particularly with elastin or basement membrane stains. In the ‘exudate and transudate’ group many cases are unexplained
It is as if the architecture has undergone a form of petrification. The but some represent the outcome of DAD caused by agents that range
parts of the lung affected by obliterative fibrosis are completely non- from fumes to viruses, irradiation, the aspiration of regurgitated
functioning. This pattern of fibrosis is unlikely to resolve. gastric acid and the ingestion of various chemicals (see Box 4.1,
p. 136). These causes may also lead to an obliterative pattern of pul-
monary fibrosis (see above) but in the present context, instead of
Interstitial fibrosis
exudates flooding alveoli, they line the denuded alveolar walls as
This pattern of pulmonary fibrosis involves the interstitial compart- hyaline membranes, organisation of which leads to their incorpora-
ment of the alveolar walls and largely spares the air spaces (Fig. 4.25). tion into the alveolar interstitium (see Figs 4.12 and 4.13). This
It often entails the laying down of connective tissue within the augments the activity of interstitial fibroblasts, the two processes com-

148
 Acute alveolar injury and repair Chapter |4|

bining to cause fibrosis of the alveolar walls. A similar process, albeit 269 and 274). ‘Honeycomb lung’ is not a specific disease but repre-
at a slower tempo, is envisaged in idiopathic pulmonary fibrosis sents the final result of many, being an end-stage pattern of injury
(usual interstitial pneumonia), which is dealt with in Chapter 6.1. comparable to the granular contracted kidney and cirrhosis of the
Most of these conditions entail damage to the delicate lining cells of liver. Idiopathic pulmonary fibrosis is its commonest cause, particu-
the alveoli and capillaries with consequent exudation. It is perhaps larly those cases with the pattern of usual interstitial pneumonia, and
because of this that the subsequent interstitial fibrosis is most marked pathologists may see this remodelling microscopically in the absence
in the dependent parts of the lungs. This distribution is also seen in of changes on high-resolution computed tomography. Other causes
the interstitial fibrosis that follows long-standing interstitial oedema include extrinsic allergic alveolitis, Langerhans cell histiocytosis, sar-
in conditions such as mitral stenosis and pulmonary veno-occlusive coidosis and berylliosis. Lymphangioleiomyomatosis also produces
disease. widespread cystic change but generally lacks the extensive fibrosis and
The other major group of causes of interstitial fibrosis may be bronchiolisation seen in these other conditions.
termed ‘granulomatous’ because focal collections of activated macro-
phages are involved in the development of the fibrosis. This group
includes sarcoidosis, extrinsic allergic alveolitis and Langerhans cell
Dystrophic calcification and ossification
histiocytosis (eosinophilic granuloma), all of which are described in Dystrophic calcification is very common in pulmonary scars, particu-
Chapter 6. The fibrosis they cause is predominantly mid- or upper larly those resulting from tuberculosis, chickenpox and histoplasmo-
zonal. sis. Pulmonary calcification in the absence of hypercalcaemia also
The pneumoconioses constitute an important group of diseases occurs in the tracheobronchial cartilages of the elderly, the cartilagi-
causing interstitial pulmonary fibrosis. They are dealt with separately nous nodules of tracheobronchopathia osteochondroplastica and
in Chapter 7.1 but it is possible to allocate individual pneumoconi- bronchopulmonary amyloid tumours. Pulmonary calcification also
oses to one or other of the above two groups (see Box 4.2). Thus, accompanies haemosiderin deposition in the lungs and is therefore
asbestosis resembles the idiopathic cases in having a predominantly found in chronic haemorrhagic conditions such as idiopathic
basal distribution, whereas others, e.g. silicosis and chronic beryllio- haemosiderosis and the postcapillary pulmonary hypertension of
sis, resemble the granulomatous diseases morphologically (given that mitral stenosis, lymphangioleiomyomatosis and veno-occlusive
early silicotic nodules resemble granulomas) and in their upper zone disease. Pulmonary calcification secondary to hypercalcaemia (meta-
distribution. static calcification) is described on page 489.
Dystrophic pulmonary ossification takes place in similar circum-
stances to dystrophic pulmonary calcification: it is found with
‘Honeycomb lung’
scarring, ageing of the bronchial cartilages, tracheobronchopathia
In advanced cases of pulmonary fibrosis the normal alveolar architec- osteochondroplastica and amyloid tumour formation. Lamellar bone,
ture is lost and the three patterns just described can no longer be readily recognisable as such, is laid down, and marrow spaces are
distinguished. At this stage the lung is replaced by a series of cystic often evident. Sometimes branching spicules of bone extend through
spaces giving an appearance that has been termed ‘honeycomb lung’. the lung in a racemose or dendriform manner.178–183 Isolated foci of
The spaces represent a combination of disrupted alveoli showing laminated bone may also be found within alveoli of otherwise normal
bronchiolisation and bronchiolectasis (see Figs 6.1.5 and 6.1.10A, pp. appearance (see Fig. 6.2.25, p. 322).

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162. Kuhn C, McDonald JA. The roles of the 172. Bayle JY, Nesme P, Bejui-Thivolet F, et al. 1998;92:887–9.
myofibroblast in idiopathic pulmonary Migratory organizing pneumonitis 183. Lara JF, Catroppo JF, Kim DU, et al.
fibrosis – ultrastructural and ‘‘primed’’ by radiation therapy. Eur Respir J Dendriform pulmonary ossification, a
immunohistochemical features of sites of 1995;8:322–6. form of diffuse pulmonary ossification:
active extracellular matrix synthesis. Am J 173. Stover DE, Milite F, Zakowski M. A newly report of a 26-year autopsy experience.
Pathol 1991;138:1257–65. recognized syndrome – Radiation related Arch Pathol Lab Med 2005;129:348–53.

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 Chapter 5 

Infectious diseases
5.1  Viral, mycoplasmal and rickettsial infections

viruses are of course also responsible for non-respiratory disease. The

CHAPTER CONTENTS
role of papillomavirus in neoplasia of the respiratory tract is discussed
Viral infections 155 on page 535 and parvovirus is mentioned as a cause of hydrops fetalis
Influenza 156 on page 43. The role of herpes-like viruses in Kaposi’s sarcoma and
body cavity-based lymphomas is discussed on pages 635 and 734
Parainfluenza 159
respectively.
Respiratory syncytial virus 159 Viral infection of the lower respiratory tract occurs in three general
Metapneumovirus 160 situations: infections confined to the respiratory tract, systemic infec-
Measles 160 tions that involve the lung and opportunistic infection of the lungs
in the immunocompromised (Box 5.1.1).
Adenovirus 161
Respiratory viruses may strike any part or all the respiratory tract
Severe acute respiratory syndrome 163 but on the whole each tends to affect particular parts and thereby elicit
Herpes simplex 164 characteristic clinical effects (Fig. 5.1.1). This pattern varies however
Cytomegalovirus 164 if there is some predisposing cause. Thus, the rhinoviruses, which
HIV and AIDS 165 usually cause nothing more serious than a cold, are the commonest
viral trigger of acute exacerbations of chronic bronchitis, while in the
Chickenpox (varicella) and herpes zoster 167
immunodeficient herpes simplex virus and cytomegalovirus are
Smallpox (variola) 167 serious pathogens in the lower respiratory tract.
Hantavirus pulmonary syndrome 168 The frequency of these various infections also differs in children and
Mycoplasmal pneumonia 169 adults. In children, respiratory syncytial virus is the most important
viral cause of lower respiratory tract disease, typically causing an
Rickettsial infection 170
obstructive bronchiolitis. Parainfluenza viruses are the most frequent
Coxiella burnetti pneumonia (Q fever) 170 cause of viral pneumonia in children, and the influenza virus in adults.
Bacillary angiomatosis 171 These are followed by the measles and adenoviruses in children
References 171 and varicella virus in adults, whilst the immunocompromised are
also susceptible to cytomegalovirus and herpes simplex virus. A
viral aetiology is responsible in 7–15% of adults admitted to hospital
with community-acquired pneumonia (see Table 5.2.2, p. 178).
The virus responsible can be cultured from sputum or nasopharyn-
VIRAL INFECTIONS geal washings and evidence of infection by particular viruses may be
provided by the demonstration of a rising titre of specific antibodies
Many viruses infect the lower respiratory tract. They include the in the patient’s serum. The advent of monoclonal antibodies has
orthomyxoviruses (influenza virus), paramyxoviruses (parainfluenza provided specific sensitive and reproducible probes that can be directly
viruses, measles virus and respiratory syncytial virus), adenoviruses, conjugated to a fluorescent tag so that the examination of exfoliated
herpesviruses (cytomegalovirus, varicella-zoster virus and herpes cells for viral antigen by immunofluorescent techniques is now the
simplex virus) and formerly variola virus (smallpox). Many of these method of choice for the rapid identification of most respiratory

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00005-7 155
tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

complication. Few bacterial species have developed mechanisms for

Box 5.1.1  Classification of viruses that infect the lower attachment to normal, intact human respiratory epithelium (notable
respiratory tract exceptions being Bordetella pertussis and Mycoplasma pneumoniae) but
viral injury to the epithelium permits bacterial attachment to take
Normal host place and is associated with a greatly increased incidence of bacterial
Primary respiratory infection pneumonia.
Respiratory syncytial virus From the occasional postmortem studies that have been undertaken
Parainfluenza in uncomplicated cases of viral pneumonia it is apparent that the
Influenza inflammatory reaction in the lung is mainly lymphocytic and intersti-
Adenovirus tial. Neutrophils are numerous only when there is a complicating
Secondary to systemic infection bacterial infection. At the alveolar level viruses cause an atypical
Measles pneumonia characterised by a chronic inflammatory interstitial
Varicella-zoster virus infiltrate rather than the acute inflammatory exudates that fill the air
Adenovirus spaces in the bacterial pneumonias.
The pathology is modified to some extent by the type of virus
Immunocompromised host
responsible but infections caused by different viruses have many
Cytomegalovirus features in common.8 In the lungs, as in other organs, some viruses
Herpes simplex virus
have a cytopathic effect and kill the infected host cells, whilst others
Varicella-zoster virus
stimulate proliferative activity. Thus, influenza, adenovirus, varicella
Adenovirus
and herpes simplex pneumonia are all characterised by epithelial cell
necrosis (Figs 5.1.2 and 5.1.3), whilst respiratory syncytial virus and
measles virus stimulate mitotic division and cause characteristic
proliferative changes in the bronchioles and alveoli respectively. The
distribution of the changes is often characteristic of a particular virus,
Tracheobronchitis
Common colds

but not specific. Thus, within the alveoli, influenza tends to affect the
Feverish colds

Broncholitis

Pneumonia

epithelium diffusely. The effects of adenovirus, on the other hand, are

Sore throat
Laryngitis
Influenza

generally maximal in the region of the terminal bronchioles, whilst

varicella pneumonia is also focal but lacks any particular relationship
to the acinar architecture. Viral inclusions are evident in certain viral
pneumonias, notably measles, adenovirus, cytomegalovirus, varicella
and herpes simplex pneumonia, but not in others.
Alveolar epithelial necrosis is a feature of severe viral pneumonia.
Rhinovirus It causes the formation of hyaline membranes (Fig. 5.1.3) and the
pathology of such viral pneumonia is essentially that of diffuse alveo-
lar damage (see Chapter 4). The regenerative changes seen in diffuse
alveolar damage may be evident, possibly involving epithelial
Corona
metaplasia.
Much of the damage caused by respiratory viruses is due to a direct
cytopathic effect on the infected cells but there may also be indirect
Influenza injury. The latter may be due to normal immune mechanisms such as
cytotoxic T lymphocytes attacking infected host cells, depression of
immunity by the virus (facilitating secondary infections) or the
development of autoimmunity initiated by the virus.
Parainfluenza The possible threat of bioterrorism is a feature of life today
and, because of the ease with which they may be widely dispersed,
respiratory pathogens figure large in the thinking of defence forces. The
US Centers for Disease Control have classified six agents as category A
Respiratory
threats. Several of these will be considered in this infectious disease
syncytial virus
section. The six category A agents are Bacillus anthracis (anthrax),
Variola major (smallpox), Yersinia pestis (plague), Francisella tularensis
Adenovirus (tularaemia), viral haemorrhagic agents and Clostridium botulinum
toxin. Category B and C agents, which are seen as posing less of a
threat, include the repiratory pathogens Coxiella burnetti (Q fever),
Measles Hantavirus and multidrug-resistant Mycobacterium tuberculosis.

Figure 5.1.1  Clinical features of the common respiratory virus infections. Influenza
Microbiology and epidemiology
viruses. In tissue, the particular virus may be identified by immuno- Influenza is epidemic almost annually in the winter months in many
cytochemistry, electron microscopy or gene probes.1–7 parts of the world and at long intervals the disease occurs in pandemic
Most respiratory viral infections end in recovery. In fatal cases, the form, notably in 1889–92, 1918–19, 1957–58, 1968 and 2009. It is
pathological changes in the lungs are often dominated by the estimated that in the pandemic that followed the world war of 1914–
effects of secondary bacterial infection, which is a very frequent 18, some 20–30 million people died from the disease in little more

156
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 Infectious diseases Chapter |5|

Antigenic lability involves changes in the principal surface antigens

of the virus, haemagglutinin and neuraminidase. Minor changes
(‘antigenic drift’) are seen progressively from season to season. Major
changes (‘antigenic shift’) due to acquisition of a new haemagglutinin
occur periodically and are responsible for the emergence of new sub-
types to which populations have little immunity and which therefore
cause epidemics or pandemics. Influenza epidemics generally occur
in the winter months and often start in countries south of the equator
or in the east, giving northern and western countries time to prepare
and distribute appropriate vaccines to those most at risk, notably the
infirm. Influenza A viruses are named after their haemagglutinins (H1,
H2, etc.), their neuraminidases (N1, N2, N3, etc.), and the place
where and year when the strain was first identified. Thus, the 1968
pandemic virus was H3N2 influenza A/Hong Kong/68.
The haemagglutinin molecule enables the virus to attach to host
cells prior to infecting them and neuraminidase permits new virus
particles to bud from the cell membrane. Although there are consider-
Figure 5.1.2  Necrotising viral bronchiolitis. The bronchiolar epithelium is able differences between the influenza viruses that infect different
partly destroyed and the lumen is largely filled with pus due to secondary species, the haemagglutinin molecule’s lability occasionally permits
bacterial infection. its virus to switch from one host species to another, in which the
disease is likely to spread in epidemic form. It appears that all the
devastating influenza pandemics of the twentieth century, such as
Spanish flu in 1918, Asian flu in 1957 and Hong Kong flu in
1968, were caused by viruses that made such a switch from birds to
humans.11
Recent genomic studies of the H1N1 virus responsible for the 1918
pandemic suggest that it was an avian virus that adapted to humans,
rather than developing by a reassortment of avian and human viruses,
as in the 1957 and 1968 pandemics.12
The switch from animals to humans in the ‘wet markets’ of the Far
East is also relevant to the severe acute respiratory syndrome (SARS),
described on page 163.
In 2004, the H5N1 strain of the influenza A virus devastated flocks
of poultry in Asia and was responsible for the deaths of some humans
from what was termed ‘Asian bird flu’.13,14 This strain was not very
infective to humans, possibly because the temperature of the human
nose (32°C) is too cold for a virus whose natural host is the avian
intestine (temperature 40°C).15,16 However, when the virus succeeded
in infecting humans it was particularly virulent for two reasons. First,
it was resistant to the antiviral effects of human interferons and
Figure 5.1.3  Viral pneumonia causing necrosis of the alveolar epithelium tumour necrosis factor-α, a property acquired by a simple mutation
with the formation of hyaline membranes. The virus responsible in this in the non-structural gene resulting in a change from aspartate to
patient was that of measles but many respiratory viruses have a similar glutamate at position 92.17 Second, it preferentially targeted the
effect, as do several other cytotoxic factors: see diffuse alveolar damage,
alveolar rather than the tracheobronchial epithelium.18
in Chapter 4. (Courtesy of Dr V Chrystal, Durban, South Africa.)
The year 2009 saw swine influenza A/H1N1 virus switch to humans
and exhibit the ability to spread from case to case, rapidly assuming
pandemic proportions. Pigs are unusual in that their respiratory epi-
than a year, more than were killed in the war itself. Until 1933 it thelium has receptors for both avian and human influenza viruses so
was widely believed that the disease was caused by the bacterium that they can be infected with these viruses simultaneously, providing
Haemophilus influenzae. The discovery in 1933 that the disease could the ideal environment for genetic reassortment. This appears to have
be transmitted to ferrets by intranasal inoculation of filtered washings taken place as the 2009 swine influenza virus shows a novel reassort-
from the noses of patients established its viral nature.9 ment of genes derived from swine, avian and human influenza viruses,
There are several types of influenza virus. All are originally bird a feature that is probably responsible for this virus being able to infect
viruses, some crossing from birds to species such as humans, pigs, both pigs and humans. Unlike seasonal influenza, the disease made
horses and seals. Once established in the new species they undergo its first appearance in the northern hemisphere, apparently originating
constant changes in their antigenic makeup, a feature that necessitates in Mexico, and its first impact was during the summer months. There
the constant manufacture of new vaccines. The strains involved in was much mild disease but again, in contrast to seasonal influenza,
most serious human infections belong to types A and B, with the severe respiratory failure was seen in young, previously healthy
former much the more virulent. Outbreaks of infection with influenza persons, as is often the case in influenza pandemics. This feature is
A occur most years, with epidemics every 5–15 years. Influenza B also not well explained but it is possible that the healthy mount a more
causes epidemics, but less frequently. Influenza C does not appear to vigorous immune response that is in some way detrimental to the
cause epidemics. Successive epidemics appear to be decreasing in host. Older people were less susceptible but more likely to die when
severity, possibily due to natural selection involving evolutionary infected.19 However, one year later it was apparent that the pandemic
changes that favour transmissibility over pathogenicity.10 had not proved as severe as first thought.

157
 Pathology of the Lungs

Clinical features a fibrin-rich oedema fluid, which is often frankly haemorrhagic.

Macrophages may be numerous in the exudate and hyaline mem-
The severity of influenza varies from one epidemic to another and
branes are often found lining the alveoli. T lymphocytes are often
from case to case. In its uncomplicated form it is relatively mild, with
prominent in the alveolar interstitium while focal necrosis of alveolar
fever, coryza, headache and body aches as its main features, and
walls and thrombosis of capillaries are conspicuous features in the
recovery after a few days. When the viral infection is followed by
parts most severely affected.26
invasion of the lungs by staphylococci, pneumococci, streptococci or
Postmortem examination of two victims of the H5N1 virus
Haemophilus influenzae, the condition assumes a much graver form
showed similar evidence of diffuse alveolar damage but it was also
and the fatality rate may rise alarmingly. Infection rates are highest
found that viral replication in the respiratory tract had resulted in
among schoolchildren and decrease with age but death is commonest
particularly high levels of cytokines such as interferons and tumour
in infants, the elderly and those with underlying lung or heart disease,
necrosis factor-α, which, with the resultant haemophagocytic syn-
and is generally due to complications.
drome, was considered to be the chief cause of death.27 Generally,
Primary influenzal pneumonia is generally rare but figured promi-
however, H5N1 viral pneumonia shows no special features and it may
nently in the 1918–19 pandemic. It carries a high case fatality rate
be difficult to distinguish the changes brought about by the H5N1
and in the 1918–19 pandemic it was notable that mortality was
virus from those caused by viruses such as that responsible for
highest in adults aged 25–34, possibly because older people had been
SARS or by factors such as acid aspiration or oxygen toxicity. More
exposed earlier to a similar strain of the virus.20,21 Primary influenzal
specific tests such as viral isolation, in situ hybridisation and reverse
pneumonia may be fulminant, leading to the death of a previously
transcription-polymerase chain reaction (RT-PCR) are required to
healthy person within a few hours of the onset of symptoms.22
confirm H5N1 infection.
Recent years have seen the development of effective antiviral agents
Fulminant uncomplicated influenzal pneumonia is often associated
such as the drugs oseltamivir (Tamiflu) and zanamivir (Relenza)
with changes in other parts of the body that indicate the occurrence
which inhibit viral neuraminidase (in contrast to anti-influenza vac-
of influenzal viraemia14: among these are haemorrhagic encephalo-
cines, which target viral haemagglutinin).
myelitis, which is an acute infective condition distinct from postinflu-
enzal encephalomyelopathy, rhabdomyolysis and placentitis.28,29
Pathology of uncomplicated influenza In the healing phase of influenzal pneumonia there is conspicuous
swelling of the alveolar lining cells, which proliferate and in places
The cytopathic effect of influenza virus is seen microscopically in
may virtually fill the lumen. The proliferation of alveolar lining cells
characteristic degenerative changes in the epithelial cells of the bron-
may be so marked as to produce appearances somewhat resembling
chial and bronchiolar mucosa. These changes involve all cells of the
a neoplastic state. The changes reach their peak on about the third
surface epithelium and often the cells lining the bronchial glands:
to fifth day of the disease and then regress, eventually subsiding
swelling of the cells, vacuolation of their cytoplasm and degeneration
completely. Also during the phase of recovery, regeneration of the
of the nucleus proceed to cell loss and frank necrosis (Fig. 5.1.4). Viral
bronchial epithelium may involve squamous metaplasia, but this
inclusions are not evident but the virus can be identified in tissue
soon gives place to normal ciliated pseudostratified respiratory tract
sections by immunocytochemistry and in situ hybridisation.23,24 The
epithelium.
deeper tissues show oedema, hyperaemia and a moderate to marked
accumulation of lymphocytes; neutrophils are present but account for
only a small proportion of the cellular infiltrate. Bacterial superinfection in influenza
Alveolar involvement is unusual but cases of fulminating influenzal
Although pneumonia is the usual cause of death in epidemics of
viral pneumonia are occasionally encountered, particularly with the
influenza, it is often a secondary bacterial pneumonia that is respon-
1918 and more recent H5N1 and H1N1 strains.14,24,25 Autopsy in such
sible. Neutrophilic exudates, organising pneumonia and bronchiolitis
cases shows that the lungs are bulky and deeply congested.14,22,24a
obliterans are then added to or replace the changes seen in uncom-
Blood-stained, frothy fluid oozes freely from the cut surface. Areas of
plicated cases.22,24,30–33 The impact an influenza epidemic has on
haemorrhage are present and may be extensive. The mucosa of the
respiratory death rates in general is shown in Figure 5.1.5.
bronchial tree is very hyperaemic. Microscopically, the alveoli contain
Before the discovery of the influenza virus in 1933, the changes that
are now known to be due to the viral infection were often confused
with those of complicating infections, mainly caused by bacteria.
Haemophilus influenzae was first isolated in the 1889–90 pandemic and
so named because its discoverer, Pfeiffer, recovered it from a large
proportion of cases and mistook it for the cause of influenza. In
the 1918–19 pandemic H. influenzae was again found, along with
Streptococcus pneumoniae and Staphylococcus aureus.32 With the advent
of antibiotics, resistant strains of Staphylococcus aureus emerged and in
the 1957–58 pandemic staphylococcal superinfection of the lungs was
the major fatal complication of influenza. In the 1968 epidemic
Streptococcus pneumoniae was the principal bacterial pathogen in the
elderly and Staphylococcus aureus in the young.30
The relationship of the staphylococcus and the influenza virus has
been much studied and there is evidence that each promotes the
growth of the other.34 Thus, certain staphylococci have a protein in
their cell wall that binds to the Fc region of immunoglobulin G. In
the presence of anti-influenzal serum this protein enhances staphylo-
coccal binding to cells infected by the influenza virus35 and in this
Figure 5.1.4  Influenza. This cytopathic virus has totally destroyed the way the staphylococcus takes advantage of the host’s immune reaction
bronchial epithelium, predisposing to bacterial superinfection. to the influenza virus. In turn, the staphylococcus aids entry of the

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 Infectious diseases Chapter |5|

5,000 Figure 5.1.5  Weekly deaths from respiratory disease

in England and Wales 1987–92, showing the impact
Other respiratory causes of an influenza epidemic in 1989/90 on deaths from
4,000 Pneumonia other respiratory diseases. (Data supplied by the Lung and
Asthma Information Centre.)
Influenza
Number of deaths

3,000

2,000

1,000

0
1988 1989 1990 1991
Year

virus into the host’s cell. It does this by secreting a protease that
activates a viral surface protein necessary for penetration of the host’s
cells36: normally such proteases are in short supply, so limiting the
rate at which influenza virus can infect cells and reproduce. The rela-
tionship of influenza and Streptococcus pneumoniae infection has been
studied in less detail but there is evidence of similar enhancement
of bacterial adherence to tracheal epithelium following influenza
infection.37

Parainfluenza
Parainfluenza is caused by the parainfluenza viruses, not by
Haemophilus parainfluenzae. It is commoner in children and particu-
larly affects the larynx, causing croup. There may be necrosis of the
mucosa as in influenza (Fig. 5.1.6A), and quite frequently small poly-
poid growths of the bronchial and bronchiolar epithelium develop, A
similar to those associated with infection by respiratory syncytial virus
(see below). In the lung there is hyperplasia of the alveolar epithelium
and a serous exudate containing increased numbers of macrophages
is seen. In immunosuppressed individuals, parainfluenza type III virus
may result in a giant cell pneumonia that is indistinguishable from
that of measles except that the inclusion bodies typical of measles
pneumonia are not a feature (Fig. 5.1.6B).38–41

Respiratory syncytial virus

Epidemiology
Respiratory syncytial virus was first isolated in 1956 from an outbreak
of coryza in a colony of chimpanzees and its infectivity for Man was
shown when one of the investigators of this epizootic illness con-
tracted the disease. It has since been shown that the virus frequently
infects the lower respiratory passages of Man, particularly the young.42
B
Specific neutralising antibodies indicative of an earlier infection are
found in the serum of almost all children over the age of 5 years in
Figure 5.1.6  Parainfluenza in an immunosuppressed patient. (A) The
Britain. Most children merely develop a cold but a few suffer from
epithelium of the bronchiole seen upper left has been destroyed and
severe bronchiolitis, which in the developing world is an important
giant multinucleate epithelial cells are seen in adjacent alveoli. (B) Higher
cause of death in the very young.42a,b Those that recover are prone to magnification of the giant cell pneumonia.
develop recurrent wheeze later in childhood.42c The immunity infec-
tion conveys is incomplete and reinfections may occur throughout life.
Respiratory syncytial virus infection shows a marked seasonal
pattern, producing annual epidemics each winter in temperate
climates and in the hot rainy season in tropical countries. During
an incubation period of 3–6 days the virus replicates in the upper

159
 Pathology of the Lungs

respiratory tract, causing fever, cough and coryza. Spread from the
upper to the lower respiratory tract may occur, with consequent bron-
chiolitis and pneumonia.
Particularly important is the bronchiolitis that respiratory syncytial
virus is prone to cause in infants. The conductive airways of small
infants are quite narrow and easily blocked by relatively small amounts
of inflammatory exudate: because of this, fatal asphyxia is liable to
follow respiratory syncytial virus infection. This is particularly the case
in those who have airflow obstruction as a consequence of prematu-
rity and its treatment. Several epidemics of acute bronchiolitis due to
this virus have been described among infants. These outbreaks are
often remarkably focal in distribution, affecting only a comparatively
small area or community. Infants with bronchopulmonary dysplasia
and those who have congenital heart disease or are immuno­
compromised are particularly at risk and units specialising in these
underlying conditions have to guard against nosocomial spread of
infection.43–45 However, most children with respiratory syncytial virus
infection have no predisposing factors and even previously healthy Figure 5.1.7  Respiratory syncytial virus infection in which the patency of
the bronchioles is compromised by epithelial proliferation forming
children may suffer fatal infection.42,46
micropolypoid intrusions into the lumen. The bronchiolar lumen is further
narrowed by a neutrophil exudate in response to secondary bacterial
infection.
Pathogenesis
It is notable that infants under six months of age are particularly prone
to respiratory syncytial virus infection. Although this is a period when
the infant benefits from the presence of maternal antibodies, placental Metapneumovirus
antibody transmission is selective, being better for immunoglobulin Metapneumovirus was only discovered in 200157 but is now recog-
G than A. Breast-feeding protects against respiratory syncytial virus nised to be ubiquitous; serological evidence of past infection is uni-
infection,47 presumably by virtue of breast milk being rich in immu- versal by the age of 5 years. Much of this goes unrecognised but
noglobulin A. It has been noted that infants immunized against the metapneumovirus infection is nevertheless a leading cause of lower
virus and subsequently infected naturally, suffer a more severe illness respiratory tract illness in young children. In one investigation the
than those not so immunised,48 suggesting that the damage is medi- virus or its DNA was found in 20% of nasal-wash specimens previ-
ated immunologically.49,50 This is supported by the finding that the ously declared virus-negative that had been collected from otherwise
typical bronchiolitis is characterised by scanty virus whereas in the healthy infants and children suffering from a lower respiratory tract
rarer pneumonic form of the disease the virus is abundant. This is illness: the infection was associated with bronchiolitis in 59% of cases,
compatible with the bronchiolitis representing an adverse immune pneumonia in 8%, croup in 18% and exacerbation of asthma in 14%,
reaction and the pneumonia being the result of direct viral damage a spectrum of disease similar to that found with respiratory syncytial
to the lungs.51 The cytokine profile suggests that the reaction involved virus.58 The pathological changes are not well described.
in the bronchiolitis involves a predominantly type 2 response charac-
terised by high interleukin-10/interleukin-12 and interleukin-4/γ-
interferon ratios.52 Suspicion has fallen upon the formaldehyde Measles
inactivation of the vaccine creating reactive carbonyl groups on the
antigen.52a Passive immunisation, conferred by monthly injection, is
Clinical features and epidemiology
free of the hazards induced by active immunisation and is recom- Measles (rubeola) is highly infectious and most children are infected
mended for high-risk babies.53 soon after their maternal antibodies have waned, the peak incidence
being between 1 and 5 years of age. After an incubation period of 1–2
weeks the patient develops coryza, cough and fever. The subsequent
development of small red spots with a white centre (Koplik’s spots)
Histopathology on the buccal mucosa followed by an erythematous maculopapular
The virus infects the bronchiolar epithelium and usually leads to its rash first involving the face and then the rest of the body facilitates
destruction.54,55 Occasionally cytoplasmic inclusion bodies may be the diagnosis. The infection resolves in about a week, following which
seen in degenerating bronchiolar epithelial cells or the virus may be the patient enjoys lifelong immunity.
demonstrated by immunocytochemistry.1,55 Regeneration involves In those parts of the world where measles has been prevalent for
the proliferation of poorly differentiated cells which form a stratified centuries the disease is almost invariably mild and, unless compli-
non-ciliated epithelium. Occasionally micropolypoid epithelial pro- cated by bacterial pneumonia, it has a very low mortality. In contrast,
trusions are evident (Fig. 5.1.7).8 The bronchioles are occluded by the mortality from measles may be appallingly high in lands to which
plugs of mucus, fibrin and epithelial cell debris, and cuffed by an the virus is newly introduced. When the disease was carried to Fiji
infiltrate of lymphocytes, plasma cells and histiocytes. Except in the from Australia in 1875, almost the whole population contracted it
immediate vicinity of the bronchioles, alveoli are generally not and a quarter of them succumbed. Similar outbreaks have occurred
involved in the inflammatory process. If, however, infection is on a in more recent times, when the infection first reached Greenland for
major scale there may be pneumonia with the general features of a instance.
viral pneumonia, as described above.46 In severe immunodeficiency, Measles has been regarded as one of the inevitable infections of
respiratory syncytial virus may cause giant cell pneumonia,56 a condi- childhood but with an effective safe vaccine now available this is no
tion that is more often caused by measles virus. longer necessary (Fig. 5.1.8).59 In the developed countries first and

160
 Infectious diseases Chapter |5|

Notifications Vaccine coverage both adenovirus and herpesvirus pneumonia.65,66 Secondary pulmo-
800 100 nary infection is responsible for about half the mortality in measles.67
Other causes of death include measles pneumonia and measles
Measles vaccine 80 encephalitis.
Notifications (000s)

600 Measles may also be very severe when it affects immunodeficient

60 patients, whether they are suffering from primary immunological
400 Measles and rubella defects, acquired diseases such as leukaemia or conditions which
campaign 40 require treatment with cytotoxic or immunosuppressant drugs.68 Such
MMR vaccine patients may have unpredictable responses to measles virus. They may
200 20 have a rash but fail to produce antibodies, or they may fail to develop
a rash although infected with the virus. Fatal measles pneumonia in
0 0 a previously healthy adult is very rare.69
1950 1960 1970 1980 1990 2000
Year
Figure 5.1.8  Annual measles notifications and vaccine coverage in
Pathology of measles pneumonia70,71
England and Wales 1950–1999. (Adapted by permission from BMJ Publishing Death from measles pneumonia occurs typically about 2 weeks after
Group Limited.56) the appearance of the rash. At necropsy, the lungs are heavy and of
rubbery consistency, and their cut surface is pale pink. Close examina-
tion may show that the small bronchi are cuffed by a greyish zone.
more recently in the developing world, immunisation against measles Extensive vascular thrombosis has been a feature of some cases.
has been promoted vigorously, with spectacular success. Between Microscopically, there are degenerative changes in the epithelium
2000 and 2007 mortality from measles fell by 74% worldwide and of the bronchi and bronchioles, often accompanied by hyperplasia,
by 89% in Africa, where it was formerly a major cause of death in particularly in the small airways. As in influenzal pneumonia,
childhood. The Americas were declared free of endemic measles trans- squamous metaplasia may occur and mitotic figures may be numer-
mission in 2002 and cases there now occur only as a result of its ous. Measles pneumonia may take the form of diffuse alveolar damage
importation from other countries.60,61 The disease has not yet been with hyaline membrane formation (see Fig. 5.1.3), or, more charac-
eradicated in the UK, partly because unfounded claims that the teristically, multinucleate giant cells may line the alveolar ducts and
vaccine is responsible for autism led to declining vaccine uptake with alveoli (Fig. 5.1.9). Electron microscopy shows that the giant cells are
consequent focal outbreaks of measles.62 Other European countries formed from type II alveolar epithelial cells.71,72 The giant cells contain
still experiencing large outbreaks include the Ukraine, Switzerland prominent cytoplasmic and nuclear viral inclusion bodies that are
and Austria. clearly evident in eosin-stained sections. Being epithelial, the pulmo-
Where measles is prevalent, the incidence is usually highest in the nary giant cells are quite different from the Warthin–Finkeldey giant
early spring, when droplet infections are particularly rife. The epidem- cells that are found in lymphoid tissue throughout the body in
ics have a remarkably consistent biennial character (see Fig. 5.1.8) and measles, particularly in the immediately pre-exanthematous stage.
the explanation of this has been the subject of several interesting As well as the epithelial changes, there is a heavy accumulation of
hypotheses. The one most favoured envisages waning immunity over macrophages, lymphocytes and plasma cells in the alveolar walls. This
the succeeding 2 years in those children who had only a subclinical cellular infiltrate extends into the connective tissue surrounding the
illness in the last epidemic. With the influx of two further entries into bronchioles and small bronchi, accounting for the pale cuff that is
infant schools, a new population of susceptible children is formed seen around them on naked-eye examination. Neutrophils are not
that is liable to contract overt disease when the seasonal conditions numerous unless there is a secondary bacterial infection. The appear-
are again favourable for the spread of the virus. In this way a fresh ances are closely comparable to those found in the lungs of dogs that
epidemic develops. Overt clinical disease, on the other hand, confers have died of distemper (Carre’s disease), which is also caused by a
lifelong immunity. paramyxovirus.
If the lower respiratory tract is infected, the measles virus propagates
in the epithelial cells of the main respiratory passages, leading to the
Differential diagnosis
destruction of many of the infected cells. In time there is recovery and
multiplication of surviving cells, but at the height of the disease the Measles is the commonest cause of giant cell pneumonia but occa-
natural defences of the lower respiratory tract are greatly compromised sionally other viruses such as parainfluenza, respiratory syncytial and
and secondary invading bacteria can successfully establish themselves varicella-zoster viruses are responsible, especially in the immunocom-
in the lungs, causing bronchiolitis and pneumonia. promised (see Fig. 5.1.6).38,56,73 The diagnosis is usually evident clini-
Pneumonia is a rare complication of measles in the western world cally or is made serologically but immunohistochemistry can be
but is common in malnourished African children, in whom it fre- performed on tissue sections. Hard-metal disease is also characterised
quently proves fatal.63 That pneumonic foci may develop in prosper- by the presence of alveolar epithelial polykaryons but these are more
ous countries in the course of severe but non-fatal attacks of measles focal than those of measles, lack viral inclusion bodies and are not
is shown by the demonstration in some such cases of patchy opacities accompanied by such severe interstitial pneumonia (see Fig.7.1.25,
on chest radiography; in almost all these cases the condition resolves p. 354).
rapidly. The cause is usually one of the common bacterial pathogens
but it can be another virus taking advantage of the patient’s debility
and impaired cellular immunity. Measles virus infection is character-
Adenovirus
ised by both the development of a strong antiviral immune response Like measles, adenovirus causes a febrile rash and infects the upper
and abnormalities of immune regulation: there is often a poor skin respiratory tract much more commonly than the lungs. However,
response to common antigens and helper/suppressor T-cell ratios may adenovirus may infect the lower respiratory tract at all levels and it is
be low in both the blood and bronchoalveolar lavage, suggesting that a relatively common cause of pneumonia in malnourished children
cellular immunity is impaired.64 Thus, measles has predisposed to throughout the world.

161
 Pathology of the Lungs

Figure 5.1.9  Measles giant cell pneumonia. There is a syncytial

proliferation of type II pneumocytes containing eosinophilic cytoplasmic
and nuclear viral inclusions. This response is typical of measles
pneumonia but is occasionally encountered with other forms of viral
pneumonia (see Fig. 5.1.6).

Adenovirus pneumonia occurs sporadically and in epidemics, par-

ticularly in children and young adults, and occasionally complicates
measles.65,66 Adenovirus pneumonia is usually combined with bron-
chiolitis and the lesions are most severe at the centres of the acini,
C
being concentrated on the bronchioles. The virus causes necrosis of
the bronchioles, many of which are totally destroyed or are recognis-
Figure 5.1.10  Adenovirus pneumonia. (A) Bronchioles bear the brunt of
able only by their muscle coat: hyaline membranes replace the necrotic
the damage and here show necrosis of their lining epithelium.
epithelium (Fig. 5.1.10A). Surviving epithelial cells show nuclear (B) Viable alveolar lining cells contain basophilic nuclear inclusions while
inclusions of varying staining reaction: some are diffusely basophilic others are necrotic, having been reduced to eosinophilic ‘smudge cells’
or amphiphilic and fill the entire nucleus apart from a rim of chro- by the viral inclusions disrupting the nucleus. (A and B from sections
matin (Cowdry type B) while others are eosinophilic and surrounded provided by the late Dr N Rossouw, Tygerberg, South Africa and Dr V
by a clear halo (Cowdry type A). The bronchioles are cuffed by a Chrystal, Durban, South Africa.) (C) Electron microscopy shows that
lymphoid infiltrate and may show proliferative epithelial activity, adenovirus particles measure 70–100 nm and have a naked icosahedral
variously interpreted as being the result of viral stimulation or of structure. (Courtesy of Miss A Dewar, Brompton, UK.)
regeneration.54,74 The alveolar tissue shows a mononuclear interstitial
pneumonia.
The intranuclear viral inclusions measure up to 5 µm and eventu-
ally disrupt the nucleus, leaving so-called smudge cells (Fig. 5.1.10B,
C). Healing may be by complete resolution or the pneumonia may
be complicated by bronchiolitis obliterans or bronchiectasis.75

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 Infectious diseases Chapter |5|

Severe acute respiratory syndrome

SARS first appeared in southern China in 2002, from where it quickly
traversed the globe, facilitated by air travel and coming to interna-
tional attention particularly after an outbreak in Hong Kong in
2003.76–81 Cases were subsequently identified in many countries and
about 10% of those affected died.82–85 The cause was a previously
unknown coronavirus that had switched from civet cats encountered
in Asian food markets and adapted to human transmission.86,87
Transmission is air-borne but requires close person-to-person contact.
There is no evidence of transmission following casual contact. The
virus has subsequently been identified in Chinese horseshoe bats and
it is likely that these animals represent the natural reservoir of the
virus, with the civets merely acting as carriers.88,89

Clinical features
The incubation period ranges from 1 to 10 days, following which there
is a prodromal fever, cough and dyspnoea. Less common symptoms A
include headache, diarrhoea, dizziness, myalgia, chills, nausea, vomit-
ing and rigor.90 There is no apparent sex predilection and the age
distribution is wide. Common laboratory features include lympho­
penia involving both CD4 and CD8 lymphocytes, thrombocytopenia,
prolonged thromboplastin time, elevated alanine transminase, lactate
dehydrogenase and creatinine kinase. Positive viral recovery rates from
urine, nasopharyngeal aspirate and stool specimen have been reported
to be 42%, 68% and 97% respectively on day 14 of illness, whereas
serological confirmation may take 28 days to reach a detection rate
above 90%. However, quantitative measurement of blood SARS
coronavirus RNA using real-time RT-PCR techniques has a detection
rate of 80% as early as day 1 of hospital admission.91
Radiographic abnormalities include focal, multifocal or diffuse
opacities. Computed tomography is more sensitive, sometimes
showing extensive consolidation in patients with normal chest radio-
graphs. However, the radiological features are not specific and need
to be correlated with the clinical and histological findings.92

Pathogenesis
B
Although pulmonary involvement is the dominant clinical manifesta-
tion, extrapulmonary features are common and the virus can often be
Figure 5.1.11  Severe acute respiratory syndrome. (A) The features of
recovered from faeces and urine, indicating that it is widely distributed early diffuse alveolar damage are seen, consisting of extravasation of red
in the body. The identification of a specific receptor for the virus is blood cells, desquamation, an acute and chronic interstitial inflammatory
relevant to its tissue distribution. The receptor, a metallopeptidase infiltrate and a few hyaline membranes. (B) Regenerating epithelial cells
known as angiotensin-converting enzyme 2, is expressed particularly show nuclear atypia.
strongly by pulmonary alveolar and small intestinal epithelia and
vascular endothelia.93–95

Treatment and prognosis

Pathology Treatment with corticosteroids, broad-spectrum antibiotics and anti-
The histology varies according to the duration of illness but the pre- viral agents has been beneficial.98,102 Interferon-α may also have a
dominant pattern is diffuse alveolar damage.96–100 Cases of less than role.103 However, infection control is as important as pharmacological
10 days’ duration show air space oedema and hyaline membranes therapy in this disease.
whereas those of longer duration exhibit type II pneumocyte hyper- In the acute phase, SARS is associated with considerable morbid-
plasia, squamous metaplasia, multinucleated giant cells and acute ity and mortality, with a global case fatality rate ranging from 7
bronchopneumonia succeeded by intra-alveolar organisation.26,96 The to 27% (average about 11%). Adverse prognostic factors include
alveolar pneumocytes may also show striking cytomegaly with granu- advanced age, coexistent disease, high lactose dehydrogenase levels
lar amphophilic cytoplasm (Fig. 5.1.11), that sometimes contains and high initial neutrophil counts. CT data on the extent of the
eosinophilic inclusions akin to the Mallory bodies of alcoholic hepa- disease are also useful in assessing prognosis.104 Clinical follow-up
titis.96,97 Less common features include haemophagocytosis and of patients who recover has demonstrated residual abnormalities
thrombosis.97,99 The virus can be identified by RT-PCR in fresh or of varying degree, including abnormal lung function and patchy
formalin-fixed, paraffin-embedded lung tissue. Electron microscopy fibrosis.105,106 Many survivors also experienced transient pituitary
may reveal the viral particles in the cytoplasm of epithelial cells.97–99 dysfunction.107

163
 Pathology of the Lungs

Herpes simplex108,109 debris rather than exudation of neutrophils. Occasionally herpes

simplex infection takes the form of a focal necrotising pneumonia
Virology and predisposing causes more typical of varicella infection (see below). Alternatively there
Herpes simplex virus typically causes mucocutaneous vesiculation, may be arterial involvement in herpes simplex pneumonia with a
serotype 1 (HSV1) generally affecting the oronasal area and serotype necrotising vasculitis affecting small and medium-sized pulmonary
2 (HSV2) the genital mucosae. As with all herpesviruses, infection is arteries.120 Sometimes the pneumonia is diffuse: it is suggested that
lifelong; the virus remains dormant until immunity weakens, which focal disease represents extension of oral mucocutaneous herpesvirus
may be triggered by a variety of factors. In these circumstances either infection down the tracheobronchial tree into the lung whereas
serotype may involve the lower respiratory tract. Respiratory infection diffuse pneumonia is the result of haematogenous spread.108
by HSV1 is more commonly encountered in adults, the infection
spreading from the oropharynx, whereas neonatal respiratory infec-
tion is usually due to HSV2 as a component of generalised haema­ Cytomegalovirus
togenous disease.110,111 Infection of the lower respiratory tract takes Virology and epidemiology
the form of tracheobronchitis or pneumonia. Herpes simplex tracheo-
bronchitis is predisposed to by damage to the respiratory epithelium, Cytomegalovirus is the largest of the herpesviruses and is widespread
especially factors that lead to squamous metaplasia, such as endo­ in most communities, persisting for life, like all herpesviruses. It is
tracheal intubation and burns.112–116 Risk factors for herpes simplex transmitted in saliva and blood and by sexual contact and organ
pneumonia include transplantation,117 cytotoxic chemotherapy and transplantation. Seropositivity, taken to indicate carriage of the virus,
human immunodeficiency virus (HIV) infection118: herpes simplex steadily increases with age. The prevalence of seropositivity in adults
pneumonia is rare in the immunocompetent.119 is generally over 50% and approaches 100% in homosexual men.
However, carriage of the virus does not necessarily equate with disease.
The immunocompetent host is unlikely to experience any recognis­
Pathology able clinical effects of cytomegalovirus infection.
In herpes simplex tracheobronchitis there is extensive mucosal Symptomatic cytomegalovirus infection is seen in newborn chil-
ulceration and pseudomembrane formation. Viral inclusions are most dren infected before birth by virus carried by their mother, and in
prominent at the periphery of the ulcers and may be identified in adults who have undergone organ transplantation or have been
exfoliated cells (Fig. 5.1.12). If they are not well developed an immu- infected with HIV. In the newborn the disease presents as an acute
nostain may establish the diagnosis. Long-standing airway infection fatal infection with jaundice and leukoerythroblastic anaemia.
leads to luminal narrowing and obstructive features. In the lungs the Cytomegalovirus is a serious pathogen in transplantation recipi-
changes are very similar to those of adenovirus pneumonia, including ents,121 possibly because the virus replicates best in cells that are
the presence of Cowdry type B ground-glass intranuclear viral activated, as in a transplanted organ. The risk is greatest with bone
in­clusions, although these are more eosinophilic than those of adeno- marrow transplantation, intermediate with heart, lung and liver trans-
virus. Both adenovirus and herpes simplex pneumonia bear a super- plantation and lowest with renal transplantation. However, donor
ficial resemblance to bacterial bronchopneumonia but the similarity and recipient matching for cytomegalovirus status has reduced the
is in the distribution of the lesions rather than their character: the incidence of transmission from the donor. Before the introduction of
bronchioles and centriacinar alveoli are mainly affected but the this policy, fatal cytomegalovirus pneumonia or systemic infection
lesions are characterised by necrosis and the accumulation of nuclear was common. Today reactivation of latent infection is a more common
problem but it is important to distinguish the mere presence of viral
inclusions from pneumonitis. When a lymphoid infiltrate accompa-
nies the viral inclusions it is also important to distinguish an infective
pneumonitis from lung allograft rejection: generally, the infiltrate of
cytomegalovirus pneumonia lacks the perivascular lymphocyte distri-
bution seen in rejection. As well as causing a pneumonitis that has to
be distinguished from rejection, cytomegalovirus may be involved in
chronic lung rejection.122 It has been speculated that cytomegalovirus
could promote allograft rejection by stimulating the production of
proinflammatory cytokines or increasing the expression of major
histocompatibility complex molecules.
The position of cytomegalovirus in regard to pulmonary disease in
acquired immunodeficiency syndrome (AIDS) can also be difficult to
determine. Cytomegalovirus inclusions are frequently encountered
in AIDS but it is often difficult to determine whether pathological
changes are due to the virus or to accompanying bacterial or
Pneumocystis infection. Only occasionally is cytomegalovirus the only
pathogen identified in severe pneumonia in AIDS patients.123 Some
investigators claim that cytomegalovirus contributes to the high mor-
tality from pneumonia in AIDS patients124 while others view it merely
as a bystander rather than the primary pathogen in these patients.125
Sometimes, replication of the virus is unaccompanied by any signifi-
cant degree of pulmonary inflammation or damage,126 indicating a
Figure 5.1.12  Herpes simplex virus. Bronchial brushings from an ulcer in poor host response, which, as in other viral infections, largely involves
the lower trachea show multinucleate epithelial cells with glassy nuclear T lymphocytes, cells that are particularly defective in AIDS. The
features. From a patient with oral herpes who had started steroid differing roles of cytomegalovirus in AIDS and transplant recipients
therapy for asthma. have led to the view that the pathological changes are not a direct

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 Infectious diseases Chapter |5|

effect of the virus but an immunopathological condition attributable of virus in the blood and body fluids are particularly high around the
to the T-cell response to the virus.127 time of seroconversion and when AIDS develops.

Pathological features Epidemiology

The pneumonia may be unilateral or bilateral, and generally involves AIDS was first recognised in 1981 in Haiti, since when it has spread
the lower lobes; advanced lesions may appear as reddish purple widely and few countries are now spared its ravages. A quarter of a
nodular areas. Two patterns of pulmonary involvement have been century after its first recognition AIDS had killed about 25 million
described in bone marrow transplant recipients: a fulminant systemic people and about 65 million had been infected with HIV. Many of
infection characterised by a miliary pattern of disease and a more those harbouring HIV do not know they are infected. The number of
insidious disease with a more diffuse distribution in the lungs.121 people infected with HIV is rising, because of population growth and
Histologically, there is a chronic interstitial pneumonitis and some because drug treatment is prolonging life. The epidemic is worst in
of the alveolar epithelial cells are enlarged and contain characteristic sub-Saharan Africa and next the Caribbean but it is growing fastest in
inclusions. These measure up to as much as 10 µm in diameter and eastern Europe and central Asia. Worldwide, women make up about
are surrounded by a clear zone inside the nuclear membrane (Fig. half of those infected with HIV, with the largest number in sub-
5.1.13). These Cowdry type A intranuclear inclusions have been Saharan Africa. Since the introduction of highly active antiretroviral
likened to an owl’s eyes. The inclusions represent clumped chromatin therapy (HAART) mortality rates have declined and life expectancy
and the clear zone the virus. Cytoplasmic inclusions up to 2 µm in improved amongst those so treated, but these benefits have so far been
diameter are often also present. Severe cases may show a necrotising largely confined to the industrialised countries.
pneumonia or tracheobronchitis without the inclusions being well
developed, in which case immunocytochemistry or in situ hybridisa-
tion may be used to advantage as these techniques show that many
Pathology
more cells are infected than those containing the characteristic inclu- Few organs escape the ravages of fully developed AIDS but the lungs
sions (see Fig. 5.1.13D).6,7,128 Diffuse alveolar damage is a further are those most frequently involved in many series.130,131 AIDS has
pattern of disease that is occasionally seen in cytomegalovirus many pulmonary manifestations, all of which are described in detail
pneumonia. under their relevant headings. Most are secondary to the immuno­
deficiency but it is possible that certain lymphocytic infiltrates reflect
HIV infection of the lung. These are generally non-specific T-cell infil-
HIV and AIDS trates, which are largely CD8+ and milder than those that characterise
lymphoid interstitial pneumonia132–136; HIV has been identified in the
Virology and means of spread
lung tissue by in situ hybridisation in a minority of cases.135 The
The HIVs belong to the lentivirus subfamily of the retroviruses and heavier lymphoid infiltrates of lymphoid interstitial pneumonia seen
are thought to have originated from chimpanzees, which harbour the in HIV-infected children largely comprise CD8+ HIV-specific lympho­
closely related simian immunodeficiency virus. They are the cause of cytes. Such children have fewer opportunistic infections and survive
AIDS and are transmitted primarily through sexual contact, by anal longer than other HIV-positive children, suggesting that in this setting
or vaginal intercourse with an HIV-positive person. Other routes of lymphoid interstitial pneumonia reflects an effective immune
transmission are by exposure to infected blood, generally through the response.137 Experiments in mice suggest that viral persistence and
use of contaminated needles and syringes by drug addicts. Infected interferon-γ production are involved.138,139
blood products and donor tissues are other potential sources of The commonest pulmonary manifestations of AIDS are listed in
in­fection. An infected woman can pass the virus to her child in utero, Table 5.1.1.140–150 Rarer pulmonary manifestations include infection
at delivery or through breast-feeding. Occupational acquisition of HIV by herpes simplex118,151 and varicella-zoster152 viruses, Blastomyces der-
is unusual but has occurred, chiefly through needlestick injuries. In matitidis,153 Candida species,152 cryptosporidia,154 microsporidia155 and
histopathology departments, particular care is required in handling Strongyloides stercoralis.152 There is also an increased incidence of res-
unfixed tissues, as in preparing frozen sections and conducting piratory infection by common pyogenic organisms,143,156,157 especially
autopsies. Fixed tissues do not present a risk of infection. Most Streptococcus pneumoniae and Haemophilus influenzae,152 sometimes
national bodies have produced guidelines for safe laboratory practice resulting in obliterative bronchiolitis158 or unusual diseases such as
in the AIDS era.129 HIV infection is not always recognisable and a bacterial tracheitis159 where the trachea is narrowed by pus or necrotic
practical approach is therefore to treat every cadaver and all unfixed material containing colonies of mixed bacteria. Tuberculosis has also
tissue as if it were infectious. made an unwelcome resurgence since the advent of AIDS.160–162
Opportunistic mycobacterial infection,163 malakoplakia,164,165 bacil-
lary angiomatosis,166 secondary alveolar lipoproteinosis,167 follicular
Pathogenesis of AIDS bronchitis and bronchiolitis149 are also encountered in AIDS patients.
Following entry into the body and the development of neutralising However, there are marked geographical differences in the incidences
antibodies, HIV is found in highest concentration within the germinal of these manifestations of AIDS: tuberculosis is particularly common
centres of lymphoid tissue where it can be demonstrated by immu- in poor countries whereas Pneumocystis, non-tuberculous myco­
nohistochemistry attached to a follicular dendritic cell.129a The virus bacteriosis and lymphoma are commoner in richer communities.
attacks both the follicular dendritic cells and the CD4+ helper T lym- Since the 1990s there has been a trend towards multiple infections,
phocytes and blood levels of these latter cells below 200/µL are associ- more mycobacterial disease and less Pneumocystis infection and
ated with the development of a variety of AIDS-defining conditions. Kaposi’s sarcoma.130,142,168
The interferon-γ-secreting Th1 cells that are central to immune defence In most cases the secondary pulmonary infections can be diagnosed
against a variety of other infections are particularly vulnerable to from material obtained through the fibreoptic bronchoscope (brush-
attack. Once HIV infection has occurred, antibody develops, generally ings, washings, lavage or biopsy)169 or from sputum170 but occasion-
within a month, and after a period that is usually measured in years ally a particular pulmonary manifestation of AIDS is not revealed until
CD4 counts drop and manifestations of AIDS develop. Concentrations open biopsy is undertaken or examination is made postmortem.

165
 Pathology of the Lungs

A B

Figure 5.1.13  Cytomegalovirus pneumonia. (A) There is a prominent nuclear inclusion in the centre of the field. (B) Electron micrograph of an alveolar
epithelial cell infected by cytomegalovirus. Numerous viral particles are evident in both nucleus (above) and cytoplasm (below). As the viral particles
leave the nucleus and enter the cytoplasm they acquire a coating derived from the nuclear envelope and consequently enlarge. (C) Low-power electron
micrograph of the cell seen in (B), showing that it is greatly enlarged compared with its neighbours. Coated viral particles are evident in the cytoplasm
but uncoated particles in the nucleus are too small to be recognised at this magnification. However, characteristic central clumping of the chromatin is
evident. (B and C courtesy of Miss A Dewar, Brompton, UK.) (D) Immunocytochemistry shows abundant virus in the cytoplasm as well as the nucleus
(immunoperoxidase stain).

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 Infectious diseases Chapter |5|

than those in the general population.179–181 All these tumours may

Table 5.1.1  The varieties of pulmonary disease described in 131
present as endobronchial lesions, as may tuberculosis and aspergil-
patients with AIDS.137,138 The opportunistic invaders are often
losis in AIDS patients.182 The lymphomas include diffuse large B-cell
present in combination and the inflammatory reaction to them
lymphomas that take the form of mass lesions within the lungs and
is often atypical: for example, the reaction to mycobact­erial
infection (frequently Mycobacterium avium-intracellulare) is primary effusion lymphomas affecting the pleura.
often non-granulomatous, whilst Pneumocystis jirovecii may
provoke a granulomatous response or diffuse alveolar Drug toxicity
damage, rather than the usual foamy alveolar exudate
HAART drug toxicity contributes up to 2% of deaths among HIV-
Patients (%) infected patients so treated. The toxicity is mainly hepatic but sarcoid-
like nodules have been reported in the lungs,183 probably reflecting
Opportunistic infection immune restoration.184 Recovery of immune status may give rise to
an active and often dramatic inflammatory response to previously
Pneumocystis jirovecii pneumoniaa 63
indolent infections, which has been termed the immune recon­
Cytomegalovirus pneumonia 19 stitution syndrome (IRIS).185 It is also suggested that it is HAART
rather than HIV that is responsible for the pulmonary hypertension
Mycobacterial pneumonia 13
referred to above.186
Bacterial pneumoniaa 8
Invasive candidiasis 2 Chickenpox (varicella) and herpes zoster
Toxoplasmosis 2 The manifestations of chickenpox and herpes zoster are generally
Cryptococcosis 1 confined to the skin but visceral involvement occurs on rare
occasions.187,188 Since chickenpox is so common in childhood, most
Invasive aspergillosis 1 adults are immune. However when chickenpox affects adults, espe-
Histoplasmosis 1 cially pregnant women, it carries a risk of fulminating varicella pneu-
monia, which can be rapidly fatal. The fetus is also at risk: in the first
Non-infectious diseases two trimesters of pregnancy chickenpox may result in embryopathy
and in the last trimester it may cause neonatal pneumonia. The
Diffuse alveolar damage 15
im­munocompromised, including those receiving systemic corticoster-
Kaposi’s sarcoma 9 oids, are particularly prone to suffer severe infections, including pneu-
a monia.189 The severe forms of chickenpox sometimes encountered in
Non-specific interstitial pneumonitis 5
otherwise healthy adults may involve the lungs but recognition of this
Pulmonary haemorrhage 3 is often retrospective; the healed lesions may produce characteristic
b radiographic changes, namely innumerable small foci of calcifica-
Pulmonary lymphoid hyperplasia 0
tion.190,191 Such patients are generally cigarette smokers.192
Lymphoid interstitial pneumonia 2
Lymphoma a
2 Pathological features
a
Since the introduction of highly active antiretroviral therapy (HAART), P. The pneumonias of varicella and herpes zoster pneumonia are identi-
jirovecii pneumonia has become less common while bacterial pneumonia and cal.193 They represent a focal necrotising condition that lacks any
lymphoma have increased.139–141 apparent relation to the acinar architecture (Fig. 5.1.14A). It starts as
b
Pulmonary lymphoid hyperplasia is seen particularly in children suffering from a fibrinous exudate, involving several adjacent alveoli, and goes on to
acquired immunodeficiency syndrome (AIDS)142–145 but is also recorded in destroy the intervening alveolar walls. Eosinophilic intranuclear viral
occasional adults.146 Together with lymphoid interstitial pneumonia, pulmonary inclusions may be evident in bronchiolar or alveolar epithelial cells.
lymphoma and the sicca syndrome,147 it forms a spectrum of pulmonary
Giant cell pneumonia is a rare manifestation of varicella-zoster
lymphoproliferative disease in AIDS and other conditions.
infection.73
Healing results in circumscribed fibrous nodules that measure up
to 5 mm in diameter and are prone to calcify (Fig. 5.1.14B, C).190,191
Numerous calcified opacities scattered throughout the lung fields
Rapidly progressive plexogenic pulmonary hypertension is also present a radiographic appearance that, outside the USA and other
reported in persons infected by HIV but generally not evincing countries where histoplasmosis is endemic, is virtually diagnostic of
AIDS.171–176 The lungs are often otherwise normal. The virus has not previous chickenpox pneumonia.
been identified in the pulmonary vessels but tubuloreticular structures
suggestive of cytokine accumulation have been identified there by
electron microscopy in HIV-positive individuals.177 Less frequently,
Smallpox (variola)
veno-occlusive disease or thrombotic arteriopathy is the basis of HIV- In 1980 the world was declared free of smallpox and it is to be hoped
associated pulmonary hypertension. Emboli of foreign particulate that this section is only of historical interest. Severe smallpox was
material may also be found in the lungs of patients who have acquired often accompanied by acute ulcerative tracheobronchitis and pneu-
their HIV infection through the intravenous injection of drugs formu- monia. The latter was ordinarily due to secondary bacterial infection,
lated for oral use, while a variety of vasculitides affecting various but interstitial lesions of viral type were also found.
organs including the lungs is described.178 A condition described as ‘smallpox handler’s lung’ was also
As well as the neoplastic manifestations of AIDS listed in Table observed. This affected nursing and medical staff attending patients
5.1.1 (Kaposi’s sarcoma and lymphoma), the incidence of carcinoma with smallpox. It was characterised by high fever and prostration:
of the lung is increased in AIDS and the affected patients are younger radiological examination showed widespread mottling of the lungs

167
 Pathology of the Lungs

B C

Figure 5.1.14  Chickenpox pneumonia. (A) Lung showing a focus of necrosis similar to that more commonly encountered in the skin. (B) Healed
chickenpox pneumonia showing central dystrophic calcification. (C) Healed chickenpox pneumonia evident macroscopically as numerous hard, pale
micronodules scattered through the lungs. (Courtesy of Dr GA Russell, Tunbridge Wells, UK.)

with shadows up to several millimetres across. Typically, there were of dried mouse excreta. Further cases have subsequently been identi-
no catarrhal symptoms and recovery appeared to be the rule. These fied in other parts of the USA and retrospective studies of archival
patients were well immunised by previous vaccination against small- material have shown that cases existed before 1993, the earliest in
pox and did not develop a rash. The pulmonary changes may have 1978.197 The name Muerto Canyon virus was initially proposed for
represented an allergic reaction to smallpox virus inhaled in the dust the hantavirus responsible for the pulmonary syndrome but this has
of scales desquamated by their patients, but it was never possible to given way to Sin Nombre virus. It is now know to be a member of
study the pathological changes. the Bunyaviridae family of RNA viruses.
Cases of hantavirus pulmonary syndrome have subsequently been
identified in several South American countries, with one outbreak in
Hantavirus pulmonary syndrome southern Argentina being unusual in that there appeared to be person-
Hantaviruses are best known as the cause of haemorrhagic renal fever to-person transmission,198 a feature that has so far not been observed
but they also cause a (non-haemorrhagic) pulmonary syndrome. This in any other form of hantavirus infection.
was first recognised in 1993 when an unusual respiratory illness was
noted in rural communities in the south-west of the USA and soon
identified as a previously unrecognised hantavirus infection.194–196 As
Clinical features
with the previously recognised hantaviruses, that responsible for the The hantavirus pulmonary syndrome commences with a prodromal
pulmonary syndrome is maintained in the wild in a single species of illness characterised by fever and myalgia, and perhaps nausea, vomit-
rodent, in this case the deer mouse, Peromyscus maniculatus, which is ing, abdominal pain, headache and dizziness.194,195 After a few days,
widely distributed across North America. Like other mice they are a cardiopulmonary phase is heralded by progressive cough and short-
inclined to impinge on humans in their hunt for food and there had ness of breath. Common physical findings at this stage are tachyp-
been a marked increase in the number of deer mice in the south-west noea, tachycardia, hypotension and fever. Radiographic findings
USA in 1993. Transmission of the virus is believed to be by inhalation include the rapid development of pulmonary oedema. Most of the

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 Infectious diseases Chapter |5|

original 17 patients with laboratory-confirmed disease required intu- development of bronchiectasis, pneumonia, lung abscess and em­­
bation and mechanical ventilation and this led to large volumes of pyema, unless specific pathogen-free strains are used.
clear proteinaceous fluid being obtained by endotracheal suction. In For a time, M. pneumoniae was regarded as the L form of Streptococcus
13 cases (76%) intractable hypotension terminated in cardiac dys- MG, a non-haemolytic streptococcus that is agglutinated by the serum
rhythmia and death within 2–16 (median 7) days of the onset of of some 10% of patients with Mycoplasma pneumonia and that was
symptoms. isolated originally from a case of the latter at necropsy: comparative
studies of the nucleic acids of the two organisms have shown that they
are in fact unrelated. The explanation of the presence of agglutinins
Pathological features against Streptococcus MG is probably a matter of shared antigens. In
about half the cases the patient’s serum agglutinates group O red
Autopsy shows heavy oedematous lungs and large, serous pleural effu- blood cells at a temperature between 0 and 5°C (cold haemagglutina-
sions. Microscopy confirms the oedema and shows interstitial lym- tion test), but the diagnosis is best established by demonstrating
phocytic infiltrates.195,196,199 Hyaline membranes have been described antibodies to M. pneumoniae in the patient’s serum or more recently
in some studies.200,201 Neutrophils are scarce and viral inclusions are by PCR assay.204,205
not found. Despite the profound circulatory failure the heart is normal.
Lymphocytosis is evident in the liver, spleen and lymph nodes.
Immunocytochemistry shows viral antigen in pulmonary endothelial Clinical features
cells and virus-like particles are evident in these cells on electron
microscopy. The target of infection appears to be the capillary endo­ The organism generally follows a 4-yearly epidemic cycle and pre-
thelium in all organs with particularly heavy involvement of those in dominantly affects younger patients. There is a wide spectrum of
the lung, resulting in increased pulmonary vascular permeability. respiratory disease, including sore throat, otitis media, sinusitis, laryn­
The diagnosis is now made by serological tests that detect specific gitis, bronchitis, bronchiolitis and pneumonia. The chief clinical
IgM antibodies or a fourfold rise in IgG antibodies. Immuno­ features are cough, fever, headache and malaise, sometimes associated
cytochemistry and PCR are used to detect the virus in tissue. The with rashes, arthritis and haemolytic anaemia. Pneumonia develops
danger to mortuary and laboratory staff is unknown but in view of in about 10% of cases and is characterised by a more gradual onset
the high mortality rate, full precautionary measures are advocated.202 than acute bacterial pneumonia. Chest radiography shows irregular,
Treatment is supportive. Prevention is based on methods that mini- ill-defined opacities, usually in the hilar region and sometimes bilat-
mise contact with the rodent vectors. eral. It is characteristic of the disease that the radiological changes are
much more extensive than the comparatively mild clinical manifesta-
tions indicate. The case fatality rate is low, of the order of 1 in 1000
patients, and the pulmonary opacities that are conspicuous during the
Mycoplasmal pneumonia 10 days or so that the illness lasts gradually resolve during the ensuing
Epidemiology and microbiology days of convalescence.

During the 1930s, cases of a mild form of pneumonia were reported

that clinically were unlike those attributable to bacterial infection. Pathogenesis
None of the bacteria known to cause pneumonia could be recovered
from the sputum, and as long as the condition was uncomplicated by The pathogenesis of M. pneumoniae infection has been studied in
secondary bacterial infection the leukocyte count in the blood showed animal models and organ cultures of human respiratory epithelium.
little tendency to rise. Cases often occurred in small community The organisms adhere to the respiratory epithelial cells and inhibit
epidemics in schools, colleges and camps, although even under these ciliary activity. Infected cells show cytoplasmic vacuolation and
conditions, which are usually conducive to the spread of respiratory nuclear swelling, with progression to complete loss of cilia.206,207 The
infections, the disease was not highly contagious. It became known loss of cilia predisposes the more distal lung to secondary bacterial
as primary atypical pneumonia. superinfection but the Mycoplasma may also affect the distal paren-
The aetiology of primary atypical pneumonia attracted much inter- chyma directly.
est and the first advance came in 1944 with the isolation of an organ- Immunodeficient animals show reduced severity of mycoplasmal
ism that became widely known as the ‘Eaton agent’ after its discoverer. pneumonia and it is likely that immune mechanisms are involved in
That this agent is specifically concerned with the clinical disease is the pathogenicity of the disease. Autoantibodies are produced in
indicated by the rise in specific antibodies that occurs during the response to Mycoplasma infection, probably as a result of mycoplasmal
course of the illness. The infection, mainly in subclinical form, has antigens being shared by host cells; such antibodies could account for
become widely prevalent, as is shown by the frequency with which many of the bronchopulmonary and extrapulmonary manifestations
specific antibodies can be detected in the serum of healthy people in of the disease.
the general population. The clinical disease accounts for 18% of all
community-acquired pneumonia requiring admission to hospital, a
frequency second only to that of pneumococcal pneumonia.203 Histopathology
Because the disease could be transmitted to both experimental There have been few opportunities for histological study of the lesions
animals and human volunteers by filtrates of sputum from cases of in primary atypical pneumonia but when undertaken it generally
primary atypical pneumonia, the Eaton agent was at first regarded as discloses widespread bronchiolitis and chronic interstitial pneumonia
a virus. Later studies indicated instead that it belongs to the group of similar to that caused by many respiratory viruses.208,209 The bronchi-
‘pleuropneumonia-like’ organisms (PPLO) – the mycoplasmas which olitis sometimes progresses to epithelial ulceration. Lymphocytic infil-
can pass through a coarse bacterial filter. The organism is now known tration of the walls of alveolar ducts and alveoli characterises the
as Mycoplasma pneumoniae: it is one of the considerable number of interstitial pneumonia whilst oedema fluid, red blood cells and mac-
mycoplasmas that have been recognised in humans, animals, plants rophages are found in many groups of alveoli, and an occasional
and soil. Because of their ubiquity in rats and mice, any experiments alveolus may contain hyaline membranes. Neutrophils are generally
involving the lungs of these animals are soon bedevilled by the less numerous, both in the bronchioles and the alveoli, than in the

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 Pathology of the Lungs

bacterial forms of pneumonia, but bacterial superinfection is a The organism can generally be recovered during the height of the
common complication.208 The more heavily involved parts may disease by inoculation of the patient’s blood or sputum into guinea
become fibrotic and pleural adhesions may develop. There is nothing pigs but few laboratories offer this test because of the danger of labora-
pathognomonic about any of these changes. Rarely, M. pneumoniae is tory infection. The detection of specific antibodies is the laboratory
responsible for fatal respiratory disease, in which case the histological test of choice.
appearances are those of diffuse alveolar damage.210
Pathology
The case fatality rate in acute Q fever is very low, and few necropsies
RICKETTSIAL INFECTION on cases uncomplicated by bacterial superinfection have been
recorded. In these, the lungs show nodular or confluent areas of grey
Rickettsia are rod-like or coccobacillary organisms that are similar to consolidation. The development of an inflammatory pseudotumour
but smaller than bacteria. However, rickettsial pneumonia is dealt is recorded but is a very rare complication.217
with in this chapter rather than with the bacterial pneumonias because Microscopically, the changes in the lungs resemble those seen in
its clinical and pathological features more closely resemble those of viral or mycoplasmal pneumonias. There is a diffuse interstitial infil-
mycoplasmal pneumonia. Of the tribe rickettsiae, three genera contain trate of lymphocytes and plasma cells and an alveolar exudate of
organisms pathogenic to humans: Rickettsia, Bartonella (formerly fibrinous oedema fluid containing mainly macrophages and only a
Rochalimaea) and Coxiella. Rickettsia species are responsible for typhus few neutrophils. Lymphocytic cuffing is seen about the bronchioles
and certain spotted fevers, and whilst pneumonia may occur in several and small pulmonary arteries. The bronchioles contain an exudate
of these,211–213 the most frequent rickettsial pneumonia is that which similar to that in the alveoli and often lose their epithelial lining.
occurs in Q fever, the causative organism of which is Coxiella burnetti. Organisation of the exudates may lead to obliterative bronchiolitis
Respiratory disease is rarely caused by Bartonella, but bacillary angi- and organizing pneumonia.218
omatosis is one example. The causative organisms may be demonstrable: they usually measure
about 0.25 × 0.45 µm but bacillary forms measuring up to 1.5 µm in
length also occur. The organisms form microcolonies in infected cells,
Coxiella burnetti pneumonia (Q fever)214,215
Q fever (‘query fever’) was so named because of its ‘questionable’
nature prior to the isolation of the causative organism, now recog-
nised to be a Rickettsia known as Coxiella burnetti. The disease was first
recognised in a meat-packing plant in Queensland, Australia, in 1937
and is now known to have a virtually global distribution. It is essen-
tially an infection of cattle, sheep and goats that is transmitted to
humans, probably more frequently than is apparent from the inci-
dence of the disease, for many people who have never had Q fever
possess circulating antibodies against C. burnetti. Among cattle, the
disease is sometimes transmitted by ticks, but possibly more fre-
quently by the inhalation of contaminated dust from the floor of
milking sheds. The organisms are excreted in milk, urine and faeces,
and particularly during calfing when amniotic fluid and placentae are
a rich source of infection. In humans, the disease may be acquired by
the inhalation of infected dust through close contact with cattle, as in
dairy farms, abattoirs and hide factories, or through drinking milk that
has been inadequately pasteurised. C. burnetti is resistant to drying A
and may survive exposure to a temperature of 60°C, an important
characteristic in regard to the pasteurisation of milk.

Clinical features
Q fever is a disease of sudden onset marked by general malaise, severe
frontal or retro-orbital headache, high fever and muscle pain. Men are
more often symptomatic than women, despite equal seroprevalence,
and there is evidence that sex hormones such as 17β-oestradiol play
a protective role.216 Pneumonia develops in only a very small propor-
tion of those infected. In these patients, chest radiographs at the
height of the disease disclose numerous relatively small, but widely
distributed, opacities. The symptoms generally subside after about a
week and most patients recover completely within a few months
without treatment. Chronic Q fever, characterised by infection that
persists for more than 6 months, is uncommon but more serious. This B
form of the disease may also represent a recrudescence of acute Q
fever years after apparent recovery. It generally takes the form of Figure 5.1.15  Bacillary angiomatosis. (A) There are many capillaries lined
endocarditis, usually developing in patients with pre-existent valvular by plump endothelial cells, neutrophils and prominent cell debris.
heart disease, transplant recipients or those with cancer. Q fever (B) Warthin–Starry staining reveals clumps of rickettsial coccibacilli.
responds to treatment with doxycycline, quinolones or macrolides. (Courtesy of Dr I Abdalsamad, Creteil, France.)

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 Infectious diseases Chapter |5|

such as alveolar epithelium, and this facilitates their recognition in trench foot and bacillary peliosis hepatis and are responsible for some
Giemsa-stained preparations. C. burnetti may also be identified in cases of cat scratch disease (which is also caused by the related bacillus
infected tissues by immunohistochemical staining and DNA detec- Afipia felis).226
tion. If the organisms are not demonstrable the changes are non- Histologically, the lesions are likely to be mistaken for granulation
specific and, therefore, in suspected cases, coming to necropsy, blood tissue or Kaposi’s sarcoma. Capillaries lined by plump endothelial
should be taken for serology. It should be noted that there is a real cells are separated by neutrophils and cell debris, often surrounding
risk of pathologists and postmortem room staff contracting the disease clumps of bacilli (Fig. 5.1.15). The bacilli are easily overlooked in
if precautions to avoid splashing and drying of body fluids are not haematoxylin and eosin-stained sections and do not stain well with
taken. This infectivity has raised its profile as a potential agent in conventional stains for bacteria. However, aggregates of them are
bioterrorism.219 evident in sections stained by the Warthin–Starry or Dieterle silver
techniques, predominantly in the extracellular tissue surrounding
blood vessels. It should be remembered that these techniques stain
Bacillary angiomatosis many different types of microorganisms and a positive result is only
Bacillary angiomatosis is a reactive vascular proliferation that was meaningful if conventional methods for bacteria fail to stain the
originally described in the skin and regional lymph nodes of patients bacilli.
infected by HIV.220,221 Mucosal surfaces may also be involved, some- The lesions lack the spindle cells of Kaposi’s sarcoma and the
times in the absence of cutaneous disease. In the respiratory tract this endothelial cells are more readily recognisable as such, carrying a wide
results in polypoid endobronchial lesions.166,222 Chest wall involve- variety of endothelial markers (CD34, factor VIII-related antigen and
ment with intrathoracic spread is also recorded.223 The disease has Ulex europaeus lectin positivity) rather than the more restricted CD34
subsequently been described in other forms of immunodeficiency and positivity of Kaposi’s sarcoma. Similarly, Weibel–Palade bodies are
even in immunocompetent patients, implying that unrecognised readily identified on electron microscopy, which is not the case with
cases preceded the AIDS epidemic. The organisms involved have Kaposi’s sarcoma.227 Bacillary angiomatosis responds well to treat-
been identified as the rickettsial coccobacilli Bartonella (formerly ment with erythromycin and its distinction from Kaposi’s sarcoma is
Rochalimaea) henselae and B. quintana,224,225 These microbes also cause therefore important.

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5.2  Acute bacterial pneumonia

CHAPTER CONTENTS distri­bution, an aetiological classification facilitates the choice of an

appropriate antibiotic, and will be followed here as far as possible.
Bronchopneumonia 179 Consideration of the clinical situation provides important clues to the
Pneumococcal pneumonia 180 likely bacterium responsible (Table 5.2.1), and so aids the initial treat-
Staphylococcal pneumonia 182 ment. Most bacterial pneumonia is endogenous, caused by microor-
ganisms that make up the flora of the pharynx. Cultures taken at
Streptococcal pneumonia 183
autopsy have identified similar bacterial species in lung and
Haemophilus pneumonia 184 pharynx.1–3
Moraxella pneumonia 184 Of outstanding importance is the Gram-positive diplococcus
Legionella pneumonia (legionnaire’s disease) 184 Streptococcus pneumoniae, which is generally known as the pneumo­
coccus. This bacterium is responsible for almost all cases of lobar
Klebsiella pneumonia 185
pneumonia and for most cases of bronchopneumonia. Other varieties
Pseudomonas pneumonia 185 of bacteria that may produce pneumonia, almost always in its bron-
Burkholderia infection 186 chopneumonic form, include Staphylococcus aureus, Streptococcus pyo-
Acute melioidosis 186 genes, Haemophilus influenzae (Pfeiffer’s bacillus), Klebsiella pneumoniae
Burkholderia cepacia pneumonia 186 (Friedlander’s bacillus), and Legionella pneumophila.
Streptococcus pneumoniae is much the commonest cause of adult
Pneumonic plague 187
cases of community-acquired pneumonia requiring admission to hos-
Tularaemic pneumonia 187 pital (Table 5.2.2).4–10 However, the situation is very different in
Anthrax pneumonia (woolsorter’s disease) 187 patients who develop pneumonia after admission to hospital (noso-
Leptospiral pneumonia 188 comial pneumonia), in whom Gram-negative enteric bacilli such as
Pseudomonas aeruginosa and members of the Enterobacteriaceae family
Chlamydophila pneumonia (psittacosis, ornithosis) 188
(Escherichia coli, Proteus and Klebsiella species) are most commonly
C. pneumoniae pneumonia 189 responsible.11–15 This is largely due to the administration of wide-
Aspiration pneumonia 189 spectrum antibiotics. Soon after such antibacterial drugs are adminis-
Lung abscess 191 tered, the oral flora changes and the upper respiratory tract commonly
Secondary lung abscess 191 becomes colonised by bowel organisms.16,17 Acid suppressants also
increase the risk of nosocomial pneumonia.18 They act by countering
Primary lung abscess: an aspiration lesion 191
an important natural defence mechanism against bacterial growth in
Botrymycosis 191 the stomach and upper small intestine. The problem has been particu-
References 192 larly seen in intensive care units where acid suppressants may be
administered to minimise the risk of gastric stress ulceration.12
Sometimes the lungs are infected by way of the blood stream and on
rare occasions an exogenous source such as a contaminated ventilator
Acute bacterial infection of the lungs is still one of the commonest or nebuliser has been identified.19,20 The mechanisms involved in
causes of death, especially in the young and the aged, but very often nosocomial pneumonia are summarised in Figure 5.2.1.
it is merely a terminal event secondary to some other debilitating Bacteriological diagnosis is usually made from the direct examina-
process. Primary pneumonia is one that develops in a previously tion or culture of expectorated sputum. Sputum is prone to be con-
healthy individual. Whilst it is still possible to classify pneumonia taminated by upper respiratory tract commensals and bronchoscopic
on the classic basis of its lobar, bronchial (lobular) or interstitial or transcutaneous tracheal aspirates free of this problem have much

177
 Pathology of the Lungs

Table 5.2.1  Acute pneumonia: inference of the bacterium Infected ventilators

responsible from the clinical situation Endotracheal tubes
Suction catheters
Clinical situation Likely bacterium
Hospitalisation Broad spectrum
Previously healthy individual Streptococcus pneumoniae antibiotics
Immobility and debility
Complication of viral infection Staphylococcus aureus
Reduced consciousness
Streptococcus pneumoniae Swallowing difficulty
Gram-negative bacilli colonise Vomiting
Chronic bronchitis Streptococcus pneumoniae
nasopharynx
Haemophilus influenzae
Cystic fibrosis Staphylococcus aureus
Haemophilus influenzae
Pseudomonas aeruginosa Nasopharyngeal Gastro-oesophageal
Burkholderia cepacia aspiration aspiration

Immunosuppression Streptococcus pneumoniae

Staphylococcus aureus
Impaired cough
Pseudomonas aeruginosa
reflex and
Klebsiella pneumoniae
mucociliary clearance
Anaerobes
Hospital inpatient Pseudomonas aeruginosa
Enterobacteriaceae spp.
Staphylococcus aureus (often
methicillin-resistant)
Bronchial tumour Streptococcus pneumoniae
Staphylococcus aureus
Anaerobes
Aspiration Anaerobes Blood spread from infected
intravenous cannula etc.
Alcoholism Streptococcus milleri
Haemophilus influenzae Figure 5.2.1  Mechanisms involved in the development of nosocomial
Anaerobes pneumonia. Other risk factors include older age, underlying diseases such
Klebsiella pneumoniae as cancer and diabetes mellitus, obesity and cigarette smoking.

Table 5.2.2  Microbial diagnoses (%) in adults admitted to hospital with community-acquired pneumonia

UK4 New Zealand5 Spain6 Netherlands7 North Americaa,8 Chile9 Australia10

Streptococcus pneumoniae 34 27 39 20–60 11 24 5

Mycoplasma pneumoniae 18 6 16 1–6 4 2 9
Viruses 7 8 – 2–15 14 12 15
Haemophilus influenzae 6 8 11 3–10 0.4 3 5
Chlamydia 3 3 – 4–6 9 2 2
Legionella pneumophila 2 2 11 2–8 2 2 3
Staphylococcus aureus 1 – – 3–5 – 1 1
Microbiologically negative 33 45 27 – 57 54 45
a
Based on 15 separate reports.

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to commend them. At autopsy, bacterial contamination is un­­

avoidable and microbiological sampling of a consolidated area of
lung should be through a surface sterilised by searing with a hot iron
rod. A more elegant method entails the in situ culture of bacteria in
the whole frozen organ using large Petri dishes.21 By this method
bacteria can be matched topographically to foci of consolidation, and
contaminants recognised as being on the pleural surface of the lung.

BRONCHOPNEUMONIA

Although it has been resolved to follow an aetiological classification

as far as possible, many bacteria cause a common morphological
pattern of disease and this will be described before proceeding to
specific aetiological agents. This pattern of pneumonia results from
the successive infection of conductive airways and is therefore called
bronchopneumonia.

Predisposing causes
Bronchopneumonia occurs most frequently in infants, debilitated
young children and elderly people, and in such patients often proves
fatal. The disease is particularly likely to complicate a condition that
predisposes to infection by weakening either the local or general
defence mechanisms. Local predisposing conditions include other
acute infections of the respiratory tract, such as influenza, measles,
pertussis and Mycoplasma infection, and chronic infective conditions
such as chronic bronchitis and cystic fibrosis. Bronchopneumonia
may also follow inhalation of irritant gases, aspiration of food or
vomit, and obstruction of a bronchus by a foreign body or tumour.
Bronchopneumonia is also common after surgical operations.
Figure 5.2.2  Bronchopneumonia. There are focal areas of pale
The pathogenesis of postoperative bronchopneumonia is complex.
consolidation surrounding small airways.
Tracheal intubation bypasses the nose, which normally warms and
moistens the inspired air, whilst ether or other irritant vapours may
further impair the ciliary defence mechanism of the bronchial tree.
The unconscious patient may inhale infected material from the mouth numerous in the lower lobes, where they may be several millimetres
or nose, and the temporary depression of the cough reflex may allow across. In the freshly cut lung they are commonly seen as pale, solid,
microorganisms to establish themselves in the lungs. Once the effect centriacinar foci, often somewhat raised above the surface of the sur-
of the anaesthetic has worn off, the pain associated with movement, rounding lung substance (Fig. 5.2.2). These consolidated areas can be
particularly of the abdominal wall, may restrict the normal aeration felt as well as seen. Small beads of yellow mucopus can often be
of the lower parts of the lungs. The haemorrhage and shock that may expressed from the bronchioles on the cut surface of the lung. In
accompany any major surgical operation also result in some general severe cases, the patches of consolidation may become confluent
depression of resistance to infection. but even when this happens the affected area seldom presents the
Other factors predisposing to bronchopneumonia include general- uniformity of texture and colour that is characteristic of lobar pneu-
ised metabolic disorders such as diabetes mellitus. Finally, broncho­ monia, in which all parts of the lobe are involved almost
pneumonia is a very common terminal event in patients debilitated simultaneously.
by cancer. Once the organisms are established in the small bronchioles, they
spread partly by the aspiration of pus and partly by penetrating the
inflamed bronchiolar walls. When the bacteria reach the alveoli they
Clinical features excite an acute inflammation, with copious exudation of fluid and
The onset of bronchopneumonia is insidious but once established it migration of neutrophils into the alveoli (Fig. 5.2.3). The air spaces
may have serious effects on respiratory function. The filling of many nearest to the bronchioles show the most advanced degree of inflam-
air spaces with exudate excludes air from much of the lungs and may mation; those at a greater distance may be filled merely with fluid
lead to serious peripheral hypoxia. Healing is slow and the patient’s exudate.
temperature, which is seldom as high as in lobar pneumonia, subsides The point at which neutrophils interact with the pulmonary vascu-
only gradually: resolution is said to be ‘by lysis’ rather than ‘by crisis’. lature is unusual. In contrast to other tissues where neutrophil migra-
tion takes place in postcapillary venules, in the lungs neutrophils leave
the circulation through the thin walls of the alveolar capillaries, a
Pathological features difference that may serve to localise the inflammation to the alveoli.22
Bronchopneumonia is characterised by widespread patchy areas of When recovery from bronchopneumonia takes place the exudate
inflammation that begin as a widely dispersed bronchitis and liquefies and is expectorated or absorbed and respiratory function
bronchio­litis: focal areas of pneumonia then develop in the centres is restored. However, healing by fibrosis rather than resolution is
of the acini. The consolidated areas are generally larger and more commoner in bronchopneumonia than in lobar pneumonia.

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 Pathology of the Lungs

Host resistance is very dependent upon the development of opsonic

anticapsular antibodies because the polysaccharide capsule of the
pneumococcus impairs phagocytosis. The identification of the sero-
logical type of the pneumococcus responsible for each case of pneu-
monia was of great importance when effective treatment depended on
the prompt administration of the appropriate type-specific antiserum
but the introduction of sulphonamides and then antibiotics made
serum therapy obsolete. Unfortunately, penicillin-resistant strains
have now emerged. Serological typing is based on the Quellung reac-
tion, an easily recognisable swelling of the bacterial capsule when the
specific antiserum is applied.

Pathogenesis
The widespread distribution of all types of pneumococcus in the
throats of healthy people is relevant to the pathogenesis of pneumo-
Figure 5.2.3  Bronchopneumonia. Pus fills a bronchiole (centre) and some coccal pneumonia, the development of which must be regarded as
of the adjacent alveoli. attributable to circumstances that sharply lower resistance to a poten-
tially pathogenic strain of pneumococcus that has been carried in the
nose or throat, perhaps over a long period. Pneumococcal pneumonia
is, essentially, an endogenous infection, due to failure of the natural
defences of the respiratory tract to prevent the spread of a potentially
pathogenic strain of pneumococcus from the nasopharynx to the
lungs, where it causes acute inflammation. Pneumococci may also
cause bacteraemia and meningitis.
Although most cases of pneumococcal pneumonia occur sporadi-
cally, minor epidemics sometimes occur as a result of the spread of
newly introduced pathogenic strains into a community, such as a
school or military camp, where personal contacts are especially close.28
Under these circumstances, a rise in the carrier rate for the responsible
type generally precedes the outbreak.
In temperate climates, pneumococcal infections of the lungs, espe-
cially in infants and the elderly, are much commoner in winter than
in summer. Low external temperature probably has the greatest
bearing on the seasonal occurrence of pneumonia, partly by impairing
the natural defences of the respiratory tract through cold air chilling
its mucosa and partly indirectly, by aggravating the overcrowding that
Figure 5.2.4  Organising pneumonia. Micropolypoid buds of pale, occurs in inclement weather. Both these mechanisms also promote
myxoid, granulation tissue (Masson bodies) are seen in three alveoli.
viral infections of the respiratory tract that predispose to subsequent
pneumococcal infection. The carrier rate for pneumococci in the
Bronchopneumonia healing by fibrosis is the commonest cause of general population also tends to rise considerably during the winter
organising pneumonia. It takes the form of granulation tissue polyps, and thus to increase dispersal of the more pathogenic strains by
which are often known as ‘Masson bodies’, protruding into the alveoli droplet spread.
and bronchioles (Fig. 5.2.4). An absent or non-functioning spleen (perhaps removed because of
trauma or destroyed by sickle cell disease) also predisposes to pneu-
mococcal infection. Other contributory conditions include alcoholic
binge-drinking, chronic chest disease, respiratory-depressant drugs,
PNEUMOCOCCAL PNEUMONIA debilitating metabolic diseases such as diabetes mellitus, cirrhosis, the
nephrotic syndrome, carcinomatosis, immunodeficiency or immuno-
In 1880 Sternberg and Pasteur independently recovered pneumococci suppression due to treatment or disease, including human immuno-
from saliva of ill patients23,24 and it was soon recognised that this deficiency virus infection, and any condition, such as coma, that
bacterium was an important cause of lobar pneumonia. At least 90 depresses the cough reflex and so impairs clearance of the respiratory
types of pneumococcus are distinguished serologically on the basis of tract.27,29 Chronically high-risk individuals and elderly people in resi-
antigenic differences between their capsular polysaccharides.25 Any dential nursing homes benefit from a polyvalent vaccine containing
serological type may be found from time to time in sputum from purified capsular polysaccharide that is now available.30
normal people and most, if not all, are capable of causing serious Pneumococcal infection of the lungs may result in either lobar
disease in humans. However, some types are more pathogenic than pneumonia or bronchopneumonia. These two forms of pneumonia
others. Type 3 is particularly pathogenic and is commonly isolated differ greatly in their clinical and pathological features but the con-
from patients with acute respiratory illness26 and pneumococcal tributory conditions outlined above underlie both.31 Whether the
bacteraemia.27 The distribution of the various serotypes differs from pneumonia has a lobar or bronchial distribution appears to depend
country to country and between different age groups but overall type more on the virulence of the particular serotype than on host defence.
14 is the commonest, particularly in young children, followed by However, host factors involving hypersensitivity have been implicated
types 4, 1, 6 and 3.25 in the development of lobar pneumonia, largely because of the

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 Infectious diseases Chapter |5|

Structural changes in the lungs

As the name lobar pneumonia implies, it is usual for the typical
changes to be uniform throughout the affected lobe. Sometimes two
or even three lobes may be involved simultaneously or after brief
intervals, in which case 2 or 3 days may separate the onset of involve-
ment of the different lobes. The lower lobes are most commonly
affected; there is no significant difference in the frequency of involve-
ment of the two lungs. Before the introduction of effective treatment,
the morphological alterations in the lungs generally followed a classic
sequence which, following Laennec’s original description, comprised
four stages:
1. congestion
2. red hepatisation
3. grey hepatisation
4. resolution.
It should be realised that these terms apply to typical appearances,
and that each stage shades into the next. Antibiotic treatment has
curtailed and modified the natural course of lobar pneumonia, and
reduced both its incidence and its mortality so that the classic morbid
anatomical appearances are now rare.

Congestion
The stage of congestion generally lasts less than 24 hours. It is excep-
tional for patients to die so early in the disease, but when such cases
are seen at necropsy, the affected lobe is more or less uniformly
involved and appears disproportionately large in comparison with the
other lobes, which collapse in the usual way when the pleural sacs are
opened. The pneumonic lobe is heavy and congested with blood. A
blood-stained, frothy fluid oozes freely from the cut surface.
Histological examination shows that alveolar capillaries are much
dilated, and the air spaces are filled with pale eosinophilic fluid in
Figure 5.2.5  Temperature chart (Fahrenheit) of a patient spontaneously which there are a few red cells and neutrophils. The uniformity of the
recovering from pneumococcal lobar pneumonia.
appearances throughout the lobe is taken to indicate widespread,
rapid dissemination of the bacteria through the pores of Kohn by
a flood of oedema fluid. In Gram-stained sections, the paired,
lanceolate pneumococci can often be seen, mainly free, in the alveolar
rapidity with which the disease spreads to involve a whole lobe. fluid. At this stage, little fibrin has formed, and the affected lobe has
Bronchopneumonia is dealt with above and only lobar pneumonia not yet acquired the firm consistency typical of hepatisation.
will be considered here.
Red hepatisation
Clinical features The feature that led Laennec to popularise Morgagni’s term ‘hepatisa-
tion’ is the consistency of the affected lobe, which resembles that of
The onset of lobar pneumonia is typically abrupt. The patient feels ill, the liver. The cut surface of the lung is dry and there is a serofibrinous
complains of a sharp pain in the side of the chest that is made worse pleurisy. Small rough tags of fibrin cover much of the visceral pleura
by deep breathing, coughs up ‘rusty’ sputum, and quickly develops a of the affected lobe. Congestion persists and the lung remains red.
fever of about 40°C. The respiration is shallow and its rate becomes The changes in the gross features of the affected lobe are readily
fast, sometimes reaching 50 breaths/min or more: the ratio of pulse explained by the histological changes that have taken place during the
to respiration may fall from its usual 4 : 1 to 2 : 1. Cyanosis usually preceding few hours. The copious fluid exudate, which at the time of
appears as the disease advances. A leukocytosis of 15–20 × 109/l, its formation contained abundant fibrinogen, has clotted in the alveo-
mainly neutrophils, is frequently found. In many cases, pneumococci lar spaces and interlacing strands of fibrin now occupy each air space
can be cultured from the blood during the height of the fever. The and can often be seen connecting with those in neighbouring alveoli
patient is delirious and before effective treatment became available through the pores of Kohn. At the same time, more and more
the death rate was high. Before the days of chemotherapy, resolution neutrophils have migrated from the congested capillaries into the
generally began on about the eighth or ninth day of the illness, if fibrin meshwork. Usually, at this stage, the pneumococci are numer-
the patient survived that long. Quite frequently, the fever fell suddenly, ous, and many of them have been ingested by neutrophils.
sweating was profuse, respiration became deeper and less rapid, the
delirium abated and the temperature quickly returned to normal
(Fig. 5.2.5). The healing was said to be ‘by crisis’, as opposed to Grey hepatisation
the gradual abatement of symptoms seen in bronchopneumonia, After 2–3 days, the affected lobe gradually loses its red colour and
which was described as healing ‘by lysis’. This rapid recovery followed assumes the grey appearance that it retains for the next few days (Fig.
the appearance of specific antibodies against the pneumococcus 5.2.6). This change in colour, which starts at the hilum and spreads
responsible. towards the periphery, is brought about by a lessening of the capillary

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 Pathology of the Lungs

Table 5.2.3  Pneumonia as a cause of septic shock

Number of Source of infection (%)

patients
Lung Abdomen Urinary Other
tract

Warren 2314 34 27 7 31
et al.
200134
Abraham 1754 51 28 13 8
et al.
200335

apoptotic neutrophils are ingested by macrophages and excessive lyso-

somal enzyme release is thereby avoided.32
The now fluid contents of the alveoli are removed, partly by expec-
toration but mainly through the lymphatics, resulting in the hilar
lymph nodes being soft, moist and swollen. By the end of the stage
of resolution, completion of which is shown by chest radiographs to
require several weeks, the lung has recovered its normal structure.

Complications
Lobar pneumonia may be complicated by dissemination of the pneu-
mococci throughout the lungs and to other organs. In some patients
acute pneumococcal bronchitis and foci of bronchopneumonia may
be present in lobes other than that mainly involved. These accessory
lesions, if severe, may exacerbate the disease by further impairing the
respiratory exchange in the lungs. In many cases of lobar pneumonia
there is a bacteraemia at the height of the infection. Acute endocarditis
may then develop, and this is sometimes followed by the formation
of an abscess in the brain after lodgement of an infected embolus.
Pneumococcal meningitis, peritonitis and arthritis are rarer manifesta-
tions of the dissemination of the organisms by the blood but septi-
Figure 5.2.6  Lobar pneumonia in the stage of grey hepatisation. The caemia with consequent septic shock are important complications in
lower lobe is uniformly consolidated. patients requiring hospital admission.33 Pneumonia is the commonest
cause of septic shock (Table 5.2.3).34,35
Although, in patients who recover, the area of lobar consolidation
usually resolves completely, several complications may interfere with
congestion and by the migration of very large numbers of leukocytes, the healing process. Resolution may be delayed through incomplete
at first mainly neutrophils but later macrophages, into the fibrin in digestion of the fibrin in the exudate within the alveoli, and organisa-
the alveoli. An almost complete shutdown of the vasculature of the tion, followed by fibrosis (‘carnification’), may develop. The fibrosis
affected lobe can be demonstrated in radiographs of the lungs after is essentially intraluminal, taking the form of micropolypoid buds of
their injection at necropsy with radiopaque material. The temporary granulation tissue (Masson bodies) that largely fill alveoli and extend
virtual cessation of blood flow through the unventilated lobe lessens into alveolar ducts and respiratory bronchioles (organising pneumo-
the liability to systemic hypoxia that might otherwise develop, a good nia), as described above under bronchopneumonia (see Fig. 5.2.4).
example of ventilation/perfusion matching (see p. 22). The contracting fibrous tissue may exert traction on the airways,
The cut surface of the lung is now moist as the fibrin has contracted, leading to bronchiectasis, which may affect the whole or part of the
expelling serum. Toward the end of the stage of grey hepatisation, lobe. Alternatively, part of the affected tissue may break down, espe-
pneumococci are less numerous and appear in degenerate forms, cially in cases of infection by pneumococci of serotype 3, and a lung
varying much in size, and often no longer Gram-positive. abscess may form.36 On the pleural surface, the serofibrinous exudate
may develop into empyema (see Fig. 13.6, p. 713) or be complicated
Resolution by suppurative pericarditis.
Resolution proceeds in a patchy yet progressive manner by liquefac-
tion of the previously solid, fibrinous constituent of the exudate in
the air spaces. Soon the affected lobe becomes more crepitant as the
air spaces reopen. Liquefaction of the fibrin is thought to be due to a STAPHYLOCOCCAL PNEUMONIA
fibrinolytic enzyme liberated from senescent neutrophils. However,
excessive neutrophil breakdown would probably damage the lung and Staphylococcus aureus pneumonia is a serious but relatively uncommon
an alternative form of cell death is also utilised, namely apoptosis: disease with a high case fatality rate. It often complicates influenza.

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 Infectious diseases Chapter |5|

The special relationship of staphylococci and influenza virus has been

dealt with on page 158. In children, staphylococcal pneumonia may
follow measles or whooping cough. In infants a primary staphylococ-
cal bronchopneumonia is known, with a case fatality rate as high as
80% in the pre-antibiotic era. The infection is generally endogenous,
the bacteria frequently being derived from the patient’s skin or nose
and the infection air-borne. However, staphylococcal pneumonia or
lung abscess sometimes follows bacteraemia or septicaemia,37 particu-
larly in drug addicts with right-sided bacterial endocarditis.
Although the mortality from most forms of pneumonia has been
reduced by modern drugs, many strains of Staphylococcus now widely
distributed in the population are resistant to the generally used anti-
biotics. Even relatively new antibiotics such as meticillin are inactive
against some of these staphylococci, which have become known as
meticillin-resistant S. aureus or MRSA. Such strains periodically
become prevalent in hospitals,15 carried in the nose by staff and
patient, and fatalities from staphylococcal infection, often with pneu-
monia, have occurred among surgical patients who otherwise should
have recovered from their operation. In addition, although MRSA
is primarily viewed as the prototype of multiresistant nosocomial
(hospital-acquired) infections, new lineages have emerged that
cause community-acquired infections in individuals without risk
factors, including rare cases of necrotising pneumonia.38–40
S. aureus owes its pathogenicity to a series of necrotising exotoxins
that induce a marked neutrophil response resulting in suppurative
tissue necrosis.41 Particularly potent is a strain of meticillin-resistant
S. aureus that secretes an exotoxin known as Panton–Valentine leuko-
cidin. As well as complicating influenza,42–44 this strain has resulted
in fatal septic shock in previously healthy persons.38
At necropsy, the bronchi are acutely inflamed and the lungs contain
many bright yellow centrilobular foci of suppuration (Fig. 5.2.7),
which in the more advanced cases may have enlarged and coalesced
to form abscesses 1 cm or more in diameter. Adjacent air spaces
contain a purulent exudate. A superficial abscess may rupture into Figure 5.2.7  Staphylococcal bronchopneumonia. The pneumonic foci
the pleura and cause empyema, which is a common complication show early suppuration.
of staphylococcal pneumonia. If the patient survives, there may be
permanent damage to the lungs in the form of pulmonary fibrosis,
bronchiectasis or large air-filled cysts known as pneumatoceles
(Fig. 5.2.8).

STREPTOCOCCAL PNEUMONIA

In the pre-antibiotic era, up to 5% of all acute pneumonias were

caused by group A β-haemolytic streptococci but Streptococcus pyogenes
is now a rare cause of serious pulmonary infection; nevertheless,
occasional cases of streptococcal pneumonia are still encountered,45
and infective pulmonary embolism is recorded in streptococcal toxic
shock.46 Streptococcal pneumonia typically follows viral infections of
the respiratory tract and is thought to have been a prominent bacterial
superinfection during the 1919 influenza pandemic. Patients present
with abrupt fever, dyspnoea and pleuritic chest pain. They often
develop haemoptysis and cynosis. Death may take place within 2–3
days of the onset, in which case the lungs show haemorrhagic oedema
and pneumonic consolidation is not well developed. In subacute cases
there is bronchopneumonic consolidation, which is characteristically
accompanied by early pleural involvement and effusion.
The anaerobic Streptococus milleri is now recognised to be an
important cause of necrotising lung disease, causing lung abscess and
empyema. Patients are often elderly men with periodontal disease,
excessive alcohol consumption, malignant disease or recent thoracic Figure 5.2.8  Pneumatoceles in a child’s lung, the consequence of
surgery.47 staphylococcal pneumonia.

183
 Pathology of the Lungs

Although Legionella pneumonia occurs in epidemics, the bacterium

HAEMOPHILUS PNEUMONIA is seldom transmitted from person to person. Spread is usually due
to atmospheric contamination. It is ironic that a bacterium so hard
The Gram-negative bacillus Haemophilus influenzae is a frequent isolate to grow in the laboratory can succeed so well in air-conditioning
from the upper respiratory tract of healthy individuals and can often plants. These provide the necessary warm, moist conditions that the
be cultured from the sputum of patients with pneumonia due to other bacterium requires, drawing it in from the outside, fostering its growth
organisms, the true pathogen being identified by lung aspiration or and dispersing it around a building. The contaminated buildings are
blood culture. It was first isolated in the 1889–90 influenza pandemic therefore generally modern, but with neglected engineering plants.
and so named because its discoverer, Pfeiffer, recovered it from a large Colonisation of the plant by certain free-living amoebae may also
proportion of cases and mistook it for the cause of influenza. promote the growth and survival of legionellae for these bacteria are
Occasionally however H. influenzae is itself the cause of pneumonia.48 resistant to amoebic digestion and may survive exposure to disinfect-
Patients are often elderly or predisposed to pneumonia by alcoholism ants when the amoeba encysts.63
or chronic bronchitis. The consolidation may take the form of either Passers-by as well as those within the building may be infected. In
lobar pneumonia or bronchopneumonia. The changes in the lung are 1985, the 2-year-old Stafford General Hospital in the UK was the
similar to those in pneumococcal pneumonia (see above). Pleural setting of one of the biggest outbreaks: 46 people died there of legion-
effusion is a common feature. naire’s disease, mostly patients rather than staff. It is no coincidence
that outbreaks affect hospitals or conventions of ex-servicemen, for
the old, the infirm, heavy smokers and those who drink to excess are
at particular risk. Hospital-acquired infection is particularly likely to
affect immunocompromised patients, such as transplant recipients.62
MORAXELLA PNEUMONIA
Also, mixed infections involving legionellae may be commoner than
previously thought.64
The Gram-negative diplococcus Moraxella catarrhalis, previously
known as Branhamella catarrhalis or Neisseria catarrhalis, is usually a
harmless pharyngeal commensal but in the immunodeficient it Bacteriology
can cause many serious infections, including pneumonia.49–51 M. Legionellae are aerobic, 1–2-µm, Gram-negative bacilli that differ
catarrhalis is one of the bacteria that colonise the bronchi in chronic from other such bacilli in the fatty acid profile of their cell wall. They
bronchitis and are responsible for acute exacerbations of this disease.52 fail to grow on standard media and require buffered charcoal yeast
Chronic bronchitis and lung cancer both predispose to M. catarrhalis extract, which is also useful for isolating Nocardia. The number of
pneumonia.53–55 Other conditions predisposing to M. catarrhalis infec- species has been continually increasing since the original isolation of
tion include old age, heart failure, diabetes mellitus and corticosteroid L. pneumophila and now exceeds 50, of which about half are patho-
treatment. The incidence of M. catarrhalis colonisation and infection genic to humans. In the USA L. pneumophila accounts for about 85%
is highest in winter. The pathological appearances are those of acute of Legionella infections, L. micadadei for about 8% and L. longbeachae
bronchitis and bronchopneumonia. for 1–3%. The legionellae are facultative intracellular organisms that
Acinetobacter is another genus belonging to the family Moraxellaceae, are able to proliferate within phagocytic cells. They are also able to
one species of which (A. baumannii) has emerged as a potential cause invade and proliferate within alveolar epithelial cells.65
of pneumonia in intensive care units. Acinetobacter are generally
regarded as harmless soil-living commensals but they may colonise
hospitals and cause serious respiratory illness in severely immuno- Host defence
compromised patients. Acinetobacter species are innately resistant to Humoral mechanisms of defence appear to be limited to opsonic
many classes of antibiotics. enhancement of phagocytosis. The role of neutrophils is unclear:
neutropenic patients are not particularly susceptible to legionnaire’s
disease. Macrophages activated by T-cell lymphokines appear to be
more important.66
LEGIONELLA PNEUMONIA
(LEGIONNAIRE’S DISEASE)56–58 Clinical features
Legionnaire’s disease is heralded by a vague prodromal illness that
Aetiology and epidemiology lasts about 5 days. Malaise and muscle pain are followed by rapidly
The legionellae were only discovered after prolonged investigations rising fever, rigors, cough, chest pain and dyspnoea. There may also
into the deaths of 34 of some 4500 members of the American Legion be confusion, diarrhoea and proteinuria. There is usually a moderate
attending a convention in a Philadelphia hotel in 1976.59,60 The inves- leukocytosis. Thus, the clinical features of legionnaire’s disease are
tigations took so long because the responsible bacterium, subse- similar to those encountered in other bacterial pneumonias. The
quently named Legionella pneumophila, is resistant to conventional radiographic findings are similarly non-specific but detection of
stains and fastidious in its culture requirements. Once identified, it Legionella antigen in urine provides a reliable diagnostic test.67
was possible to recognise retrospectively from stored sera that Macrolides, fluoroquinolones and rifampin (rifampicin) are the most
Legionella had been responsible for pneumonia in the past. Sporadic widely used drugs in treatment.
cases were subsequently recognised.61,62 These are commoner than
those encountered in epidemic outbreaks but nevertheless only form
a small proportion of community-acquired pneumonia (see Table
Pathology56,57,61,68–72
5.2.2). In addition to causing pneumonia (legionnaire’s disease), The gross appearances of the lungs are those of a confluent or multi­
Legionella is responsible for a less severe, non-pneumonic, acute febrile focal lobular pneumonia with a fibrinous pleurisy and a serosanguin­
illness known as Pontiac fever. The term ‘legionellosis’ embraces both eous pleural effusion. If confluent, the boundaries of the consolidation
diseases. generally fail to match the interlobar fissures (Fig. 5.2.9). There may

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 Infectious diseases Chapter |5|

be abscess formation73 but this is not typical. A miliary distribution paraffin sections.75 Electron microscopy of the bacteria shows features
is another atypical manifestation.74 that are indistinguishable from those of Gram-negative bacilli.76 In
Microscopically, airways do not appear to be particularly involved practice, most cases are diagnosed without recourse to pathology.
in the inflammatory process, so the disease is not a bronchopneumo- The hilar lymph nodes are often infected and there is haemato­
nia. An acute, leukocytoclastic, fibrinopurulent pneumonia is charac- genous dissemination to sites such as the spleen and bone marrow
teristic (Fig. 5.2.10) but sometimes macrophages are more prominent in 27% of cases.61
than neutrophils. The legionellae resist digestion and multiply within The process generally resolves completely but healing by organisa-
the phagocytes, which they eventually destroy so that intense necrosis tion may be recognised in fatal cases as buds of connective tissue
of the inflammatory cells is often observed. At low magnifications, (Masson bodies) in the lumen of alveoli, alveolar ducts and respira-
alveolar walls may be difficult to recognise but even when there is tory bronchioles. Such postpneumonic fibrosis presumably accounts
extensive necrosis of the exudate, close inspection, perhaps aided by for the permanent impairment of lung function that has been noted
reticulin stains, shows that the alveolar architecture is generally intact. in some patients.
Occasionally however there are breaks in the alveolar walls or more
widespread destruction may be seen. This may be due to vasculitis and
thrombosis, which is sometimes evident in small blood vessels.
Demonstration of the organisms is difficult; the fickle and non- KLEBSIELLA PNEUMONIA
specific Dieterle silver impregnation method is the best of the non-
immunological techniques used to stain the small coccobacilli.
Klebsiella pneumoniae (Friedlander’s bacillus) is a rare cause of com-
Fortunately the bacterial antigens withstand formalin fixation and
munity-acquired pneumonia but accounts for a higher proportion of
routine processing, permitting immunostaining to be applied to
pneumonia acquired in hospital, where patients are more likely to be
treated with antibiotics that permit this bacterium to dominate the
pharyngeal flora.77 K. pneumoniae is also a particularly common inhab-
itant of the oral cavity in those with poor dental hygiene and such
persons are accordingly at increased risk of Klebsiella pneumonia.
Alcoholics are also particularly susceptible to Klebsiella pneumonia,
constituting about half the patients dying of Klebsiella infection.78
Others at particular risk are the elderly and diabetics. The mortality
of Klebsiella pneumonia is much higher than that of pneumococcal
pneumonia: 21% in the general population and 64% in alcoholics.78,79
Bacteraemia is a particularly adverse prognostic factor.78
Klebsiella pneumonia has a predilection for the upper lobes. There
is often uniform diffuse consolidation but, with only part of the lobe
involved, a sharply demarcated edge abutting interlobular septa rather
than interlobar fissures: the part of the lobe affected by such consoli-
dation enlarges by the progressive involvement of adjacent lobules
(Fig. 5.2.11). The abundant mucoid coat of the klebsiellae gives the
pneumonic lesions a distinctively slimy appearance and feel. This
material is mucicarminophilic, a characteristic that is often helpful in
identifying the infection in histological sections. Klebsiella pneumonia
Figure 5.2.9  Legionnaire’s disease, represented by a confluent lobular is particularly liable to suppurate and form lung abscesses (Fig.
pneumonia that does not show the uniform involvement of the affected 5.2.12). These may progress to massive pulmonary gangrene.80
lobe seen in lobar pneumonia. Chronic Klebsiella pneumonia may mimic tuberculosis by presenting
with cavitating upper-lobe disease.

PSEUDOMONAS PNEUMONIA

The species of Pseudomonas involved in lung infections is usually

Pseudomonas aeruginosa, which is the commonest bacterium isolated
in hospital-acquired pneumonia.15 Infection may be inhalational or
blood-borne. Infection via the airways generally follows colonisation
of the pharynx, especially in patients on antibiotics that destroy the
normal flora of the upper respiratory tract. As with many bacterial
infections, prior viral injury promotes adhesion to the bronchial
mucosa,81,82 for it is difficult for P. aeruginosa to adhere to normal
epithelial cells. Adhesion of the bacteria is dependent upon the tran-
sient expression of a sialoganglioside at the apex of the regenerating
epithelial cells.83 Inhalational Pseudomonas pneumonia has also
developed in patients treated by tracheostomy and mechanical
ventilation due to contamination and inadequate disinfection of the
Figure 5.2.10  Legionnaire’s disease, showing widespread alveolar filling ventilators.19 Several outbreaks in the USA were attributable to faulty
by fibrin and necrotic neutrophils. bronchoscopes.84,85

185
 Pathology of the Lungs

usually readily apparent at high magnification but the Sandiford

modification of the Gram stain is especially useful for demonstrating
Gram-negative bacteria in tissue sections (Fig. 5.2.13A).90 The bacte-
rial colonisation causes a vasculitis with resultant thrombosis and
ischaemic necrosis (Fig. 5.2.13B). Such necrotising arteritis is not
found in non-bacteraemic Pseudomonas pneumonia.91 Meningitis,
arthritis and jaundice are further manifestations of Pseudomonas sep-
ticaemia. There may also be striking skin lesions, including vesicles
and sharply demarcated foci of cellulitis that enlarge rapidly and
become haemorrhagic and necrotic.

BURKHOLDERIA INFECTION

Acute melioidosis
Melioidosis is a generalised infection caused by Burkholderia (formerly
Pseudomonas) pseudomallei, a Gram-negative bacillus found in watery
environments in certain tropical areas, notably south-eastern Asia and
northern Australia.92 However, isolated cases have been described in
many other countries.93,94 The route of infection is most often through
the skin but may be through the respiratory tract, where cystic fibrosis
appears to be a predisposing factor.95 Early studies were made during
the British occupation of Burma, whilst French and American service-
men were infected in Vietnam.96 The prognosis was initially thought
to be very poor but improved serological testing indicated that sub-
Figure 5.2.11  Friedlander’s (Klebsiella) pneumonia showing diffuse clinical and mild forms of the disease are common in certain tropical
consolidation of the upper part of the upper lobe. The unaffected lower
areas.96 The bacterium may lie dormant in an infected person for many
portion has collapsed on slicing but the consolidated, airless upper
portion has retained its shape. years before causing disease and it is estimated on the basis of high
antibody titres that many thousands of American veterans of the
Vietnam war are at risk. Acute and chronic forms are recognised, and,
in both, lesions are commonest in the lungs. Melioidosis is very
similar clinically (but not epidemiologically) to the equine disease,
glanders, which is caused by infection with Malleomyces mallei, with
which B. pseudomallei shares certain antigenic determinants. Chronic
melioidosis is described on page 213.
Acute melioidosis is characterised by the sudden onset of severe
diarrhoea, overwhelming pneumonia and septicaemia, and if
untreated is rapidly fatal. Numerous abscesses are found throughout
the body. In chest radiographs these are seen as disseminated
nodules.97 The early lesions take the form of small foci of neutrophils
surrounded by haemorrhagic zones. As the abscess enlarges, fibrin
becomes more prominent and necrosis ensues. Cases with prominent
pulmonary features are characterised by a confluent necrotising pneu-
monia which has a bronchitis element that is not evident when there
are only discrete abscesses. Vasculitis, a feature of P. aeruginosa pneu-
monia, is not seen in melioidosis. Bacilli are generally quite numerous
and often form distinct collections within multinucleate macrophages
Figure 5.2.12  Abscess formation complicating Friedlander’s (Klebsiella) that are scattered amongst the numerous neutrophils.98 They have
pneumonia. been shown to survive and multiply within cells, including neu-
trophils.99 The bacteria are most easily identified by the Giemsa stain,
Pseudomonas pneumonia is often characterised by well-demarcated which can then be supplemented by a Gram preparation. Staining is
pale areas of necrosis, which histologically are composed of an strongest at the ends of the bacilli, which therefore have a bipolar
amorphous coagulum containing many bacteria, the nuclear debris of appearance that has been likened to that of a closed safety pin.
necrotic neutrophils and small numbers of lymphocytes and macro-
phages.86,87 Pseudomonas appears to be able not only to resist, but also
Burkholderia cepacia pneumonia
to destroy neutrophils.88 It is debatable whether the tissue necrosis is
due to bacterial toxins or an immunological response. Burkholderia cepacia (formerly Pseudomonas cepacia) is an important
Pseudomonas septicaemia may complicate Pseudomonas pneumo- pathogen in cystic fibrosis100 but is seldom isolated in the immuno-
nia87 or abdominal infection. It results in further changes, notably competent. The few pathological studies of B. cepacia pneumonia have
prominent colonisation of blood vessels. So pronounced is this feat­ shown necrotising granulomatous inflammation merging with areas
ure that the vessels exhibit a distinctive blue haze with haematoxylin, of more conventional necrotising bronchopneumonia, occasionally
or a red one with a Gram stain.89 The rod-like form of the bacteria is with necrotising granulomas in the mediastinal lymph nodes.101

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 Infectious diseases Chapter |5|

PNEUMONIC PLAGUE

In humans, infection with the Gram-negative bacillus Yersinia pestis

takes two main forms: bubonic plague, in which the bacillus is trans-
mitted to humans by the bite of infected rat fleas, and pneumonic
plague, in which the organism is usually spread from person to person
by infected sputum droplets. Before the era of effective antibiotics
both forms had a high case fatality rate: indeed, the plague bacillus
has been the cause of some of the most widespread and devastating
epidemics in human history.
In the pneumonic form the lungs show many areas of broncho­
pneumonia: these are sometimes confluent but the course of the
untreated disease is generally too short for massive consolidation
to develop. The pulmonary lesions are often haemorrhagic and they
A
are usually accompanied by serofibrinous pleurisy and great enlarge-
ment of the hilar lymph nodes. Histologically the alveolar capillaries
are engorged and the air spaces are full of fluid exudate containing
few leukocytes but many bacilli. In successfully treated cases, pro­
gression to consolidation and rarely cavitation has been noted
radiologically.102

TULARAEMIC PNEUMONIA

Tularaemia is caused by Francisella (formerly Pasteurella) tularensis,

a Gram-negative coccobacillus that infects many wild animals in
North America and, to a lesser extent, Scandinavia, Japan and else-
where, including the UK.103 The bacterium was named after Tulare
county in California where human infection was first identified.
The infected animals include rabbits, hares, muskrats and ground
squirrels. Humans are infected when handling these animals or when
bitten by ticks that act as vectors of the disease. Direct infection takes
place through skin abrasions, mucous membranes, the conjunctivae,
and, less commonly, the lungs. The bacterium is highly virulent and
its handling poses an extreme hazard to microbiology staff. It is a
facultative intracellular pathogen with its primary target being the
macrophage.
Pulmonary involvement is usually by septicaemic spread from a
lesion in the skin or eyes, via the local lymph nodes, but may be
primary. Many patients show neither septicaemia nor pulmonary
involvement but in fatal cases the incidence of pneumonia rises
to 70%.
At necropsy, the lungs show necrotising bronchiolitis, broncho­
pneumonia, pleurisy and pleural effusions. The consolidation tends
to become confluent and undergo necrosis.104 The alveoli then contain
abundant fibrin and necrotic macrophages, resembling the changes
seen in Legionella pneumonia. Vasculitis and thrombosis may lead to
necrosis of the alveolar walls. The bacteria are difficult to demonstrate
in sections with conventional stains but can be identified by immu-
nocytochemistry. Culture is important and the demonstration of a
rising titre of antibodies is also helpful in establishing the diagnosis.
B

Figure 5.2.13  Blood-borne Pseudomonas aeruginosa pneumonia. (A) A

Gram–Sandiford stain shows heavy colonisation of arterial walls by
ANTHRAX PNEUMONIA  
Gram-negative bacilli. (B) The consequent vasculitis has led to extensive (WOOLSORTER’S DISEASE)
infarction of the lower part of the lung.
Anthrax occurs in many species of domestic animals, especially her-
bivores. Spores of the causative organism, Bacillus anthracis, occasion-
ally infect humans, most commonly by skin inoculation, where they
cause a ‘malignant pustule’, least commonly by ingestion, or with
devastating effect by inhalation, resulting in ‘woolsorter’s disease’.

187
 Pathology of the Lungs

Woolsorter’s disease was formerly seen in the Yorkshire textile The pulmonary lesions are foci of haemorrhagic pneumonia or, in
towns, where it was acquired by inhalation of dust from imported some cases, of simple haemorrhage.116 In the pneumonic foci there
wool contaminated with anthrax spores. Others at risk include those is a haemorrhagic fibrinous exudate that contains a few neutrophils
exposed to infected hides, hair, bristle, bonemeal and animal car- and occasional macrophages; the exudate is most conspicuous within
casses. The spores are very resistant to drying but effective measures the alveoli but is seen also in the interalveolar septa, which are
are now directed to their destruction by exposure of imported materi- correspondingly thickened. Diffuse alveolar damage is occasionally
als to antiseptics before they are handled; as a result anthrax is now observed. In cases of simple pulmonary haemorrhage, the bleeding is
very rare in Great Britain. In 1979 there was a major epidemic of often associated with the profound thrombocytopenia that is an
anthrax resulting in over 60 deaths in a narrow corridor of land occasional accompaniment of leptospirosis but electron microscopy
downwind of a military establishment near Sverdlovsk, Russia, which reveals that there is also profound capillary damage, culminating in
was suspected of conducting microbiological warfare research.105,106 endothelial necrosis118: a paucity of bacteria near the lesions supports
Anthrax spores were also used as a bioweapon by terrorists operating the suggestion that they are due to toxins released elsewhere.119
in the USA in 2001: of 11 people who were infected, 5 died. Screening
procedures and plans to deal with the possibility of similar attacks
have subsequently been put in place.107–109
If inhaled, the spores are rapidly transmitted to the mediastinal
lymph nodes. It is here that the bacilli form and the disease starts.
CHLAMYDOPHILA PNEUMONIA
From the lymph nodes the bacilli reach the blood stream and are (PSITTACOSIS, ORNITHOSIS)
distributed in large numbers throughout the body. The septicaemia is
often so severe that the organisms are recognisable in films of the The chlamydophilae, formerly known as the chlamydiae or bedsoniae
circulating blood. Although the lungs may have provided the portal and once considered to be viruses, are obligate, intracellular organ-
of entry, they are affected secondarily as part of a systemic blood- isms, 0.25–0.50 µm in diameter, that are now classed as bacteria. The
borne disease.110,111 genus includes three species pathogenic for humans: Chlamydophila
The course of inhalational anthrax is dramatic. Non-specific psittaci, C. trachomatis and C. pneumoniae.
influenza-like symptoms rapidly progress to cardiopulmonary failure C. psittaci pneumonia is contracted from infected birds, particularly
and death within a few days.112 Necropsy shows haemorrhagic necrosis parrots imported from South America, where the disease is enzootic.
of the infected tissues. The process is most advanced in the lymph In contrast, C. trachomatis is almost exclusively confined to humans,
nodes draining the site of primary infection.106 Thus, in woolsorter’s causing trachoma, lymphogranuloma venereum and other genital
disease a haemorrhagic mediastinal mass is one of the principal find- diseases, and, in infants, pneumonia, which is usually accompanied
ings at necropsy. Other changes commonly encountered at necropsy by ocular infection.120,121 C. pneumoniae was described as a separate
include a large, dark, soft spleen, haemorrhagic effusions, haemor- pathogen in 1986 and in some communities is responsible for as
rhagic intestinal ulceration, haemorrhagic meningitis (which is often many as 10% of pneumonia admissions to hospital,122–125 although
limited to the top of the cerebral hemispheres in a so-called ‘cardinal’s generally causing milder disease than C. psittaci.
cap’), haemorrhagic bronchitis and widespread, often confluent, areas Organisms similar to C. psittaci are found in many species of wild
of haemorrhagic pneumonia. As in other organs, the haemorrhagic and domesticated birds in various parts of the world and at least some
inflammatory oedema that constitutes the exudate in the alveoli of these are pathogenic for humans. For this reason, the more gener-
contains large numbers of the characteristic large Gram-positive ally applicable name, ornithosis, is more appropriate to this group of
bacilli, which are readily seen in haematoxylin and eosin prepara- diseases rather than psittacosis (parrot’s disease). Budgerigars are now
tions.105,111,113 However, immunohistochemistry is proving more relia- the commonest source of ornithosis in the UK.126 Outbreaks have also
ble than Gram staining in identifying the bacteria.108,109 been associated with ducks, chickens and turkeys.127,128
Infected birds, which may show no signs of disease, excrete the
organisms in droppings that eventually form a highly infected dust.
It is usually through the inhalation of such dust while attending to
LEPTOSPIRAL PNEUMONIA the birds that individuals become infected, but the disease may
also be contracted in poultry-processing plants or pillow-filling fact­
Leptospirosis is a zoonosis of worldwide distribution with many wild ories.127 The infectivity of ornithosis is high and numerous instances
and domestic animal reservoirs. Human infection occurs through have been recorded of nurses and relatives contracting the disease
direct contact with infected animals or, more commonly, through while caring for patients. The disease has also been acquired through
contact with water or soil contaminated with the urine of infected exposure to the organism in the laboratory and in the performance of
animals. Sewage workers, farmers, animal handlers and veterinarians necropsies.
are at particular risk. Pulmonary disease may be seen in cases of infec-
tion by leptospires of various serogroups: they are severest in cases of
infection by Leptospira icterohaemorrhagiae, which is acquired from rats,
but have been a conspicuous feature in a small proportion of cases of Clinical features
canicola fever (infection by L. canicola, acquired from dogs) and of The clinical presentation of ornithosis varies from a mild influenza-
infection by L. bataviae, which occurs in parts of south-eastern Asia. like illness to fulminating pneumonia complicated by lesions in
The spirochaetal leptospires can be demonstrated in the lesions by other systems. Fulminating cases carry a high mortality. Symptoms
Levaditi’s silver impregnation method, immunocytochemistry or in usually start within 1–2 weeks of exposure. The organism may be
situ hybridisation. cultured from the patient’s blood, but more usually the diagnosis is
Pulmonary involvement is manifest as cough and haemoptysis in established by demonstrating a rising titre of complement-fixing
association with patchy consolidation of the lungs.114,115 Occasionally, antibodies. Cross-reactions with other organisms of the psittacosis–
severe pulmonary haemorrhage is the predominant or only manifesta- lymphogranuloma–trachoma group occur but should not be con­
tion of the infection.116,117 but provided the disease is recognised, and fusing in practice. Many patients with ornithosis give a positive skin
treated early and efficiently, the case fatality rate is low. reaction to Frei (lymphogranuloma venereum) antigen.

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 Infectious diseases Chapter |5|

Figure 5.2.14  The effect of posture on the distribution of aspirated material. When the patient is fully supine (left) aspirated material is preferentially
distributed by gravity to the apical segment of the lower lobe, whereas when tilted to one side (right) the lateral portions of the anterior and posterior
basal segments of the upper lobe are affected. (Reproduced from Brock et  al. (1942)139 courtesy of the Editor of The Guy’s Hospital Reports.)

Pathology C. pneumoniae infection has a bimodal age distribution, affecting

schoolchildren and the elderly. C. pneumoniae pneumonia is not fatal
At necropsy, the lungs are bulky and patchily consolidated. The con-
and there have consequently been few histopathological studies in
solidated areas, which are usually haemorrhagic, are more numerous
humans. Experimental studies suggest that the bacterium causes a
in the lower lobes than elsewhere. Where they abut the pleura there
non-specific acute pneumonia.125 C. pneumoniae has been linked to
is local fibrinous pleurisy but pleural effusion is uncommon.
chronic obstructive lung disease125,132,133 and an intriguing relationship
Microscopically, the changes are appropriate to a bacterial rather
between C. pneumoniae and atheroma has been identified.124,134,135
than to a viral pneumonia, for exudation within the alveoli is more
marked than interstitial changes. However, the inflammatory cells are
a mixture of those found in bacterial and viral pneumonia, macro-
phages predominating in the air spaces and a mixed lymphocytic and
neutrophil infiltrate being seen in the interstitium. The changes are ASPIRATION PNEUMONIA136
concentrated on the terminal bronchioles, from which they spread to
involve adjacent alveoli and then the whole lobule, by which time
there is often necrosis of the bronchiolar and bronchial epithelium.129 Causes of aspiration pneumonia
There is engorgement and often thrombosis of capillaries that can Aspiration lesions include infective processes such as pneumonia and
result in foci of alveolar necrosis. Later, the alveoli develop a conspicu- lung abscess, which are dealt with here, and non-infective processes
ous lining of swollen epithelial cells. The chlamydophilae are just such as exogenous lipid pneumonia and the chemical pneumonias or
visible with the light microscope as cytoplasmic inclusion bodies pulmonary fibrosis that result from the aspiration of gastric acid and
(known as Levinthal–Coles–Lillie bodies, LCL bodies, or Levinthal other irritants. Aspiration is promoted by loss of consciousness and
bodies) that range from about 0.25 to 0.50 µm in diameter. They suppression of the cough reflex, particularly the latter.137 It is therefore
are to be seen in the cytoplasm of a variable proportion of the likely to complicate drunkenness, general anaesthesia, cerebrovascular
alveolar lining cells. They are basophilic and may most easily be accidents, drug overdosage or other causes of coma. Aspiration is also
found in preparations stained by the prolonged Giemsa method. As promoted by dysphagia, whether it be neurological or due to
with many bacterial pneumonias, healing may be by repair rather oesophageal diseases such as achalasia, stricture, diverticulum or
than resolution, resulting in bronchiolitis obliterans organising involvement in systemic sclerosis.138 Aspiration pneumonia and lung
pneumonia.130 abscess are also promoted by poor oropharyngeal hygiene: they are
rare in the edentulous.

C. pneumoniae pneumonia
C. pneumoniae is spread from person to person rather than from birds, Anatomical location
infecting both upper and lower respiratory tracts and causing pro- Aspiration lesions affect the dependent parts of the lungs so that their
longed bronchitis and mild pneumonia of rather non-specific charac- anatomical location is dictated by the position of the individual when
ter, somewhat similar to that caused by Mycoplasma pneumoniae.125 aspiration occurs. Common sites of aspiration pneumonia include the
Retrospective studies of stored sera have shown that many patients apical segment of the lower lobe and the lateral parts of the basal
diagnosed as having psittacosis on the basis of a positive serological segments of the upper lobe because gravity carries the aspirated mate-
test were actually infected with C. pneumoniae. Antibodies to rial into these lung segments when the patient is in the prone and
C. pneumoniae have also been identified in many persons who give no lateral positions respectively (Figs 5.2.14, 5.2.15).139 Conversely, the
history of respiratory disease.131 right middle lobe is affected when gasoline is accidentally aspirated

189
 Pathology of the Lungs

Figure 5.2.16  Aspiration pneumonia showing a bronchiole filled with

pus in which there is a spicule of foreign material with attendant
foreign-body giant cells.

Figure 5.2.15  Aspiration pneumonia showing necrotizing foci of

consolidation in the apical segment of the lower lobe.

while it is being syphoned from a motor vehicle, a procedure that Figure 5.2.17  Aspiration pneumonia characterised by florid foreign-body
necessitates the person bending forward so that the right middle lobe granulomas.
and the lingula become the most dependent parts of the lungs.140

venous drug abusers and are described in the section on foreign-body

Pathological findings emboli on page 411.

Aspiration pneumonia is a bronchopneumonia in that the conductive

air passages as well as the alveoli are filled with pus and the consolida-
tion is peribronchiolar. The consolidation is particularly florid; indi- Clinical features
vidual foci are often much larger than those encountered in the more Fever, consolidation of the lung and leukocytosis may develop soon
usual type of bronchopneumonia. The lesions also tend to undergo after the aspiration. Alternatively, the precipitating episode may not
necrosis (see Fig. 5.2.15). Microscopically, particles of undigested food be recognised and the onset of the pneumonia may be insidious.
may sometimes be observed in the pus. These are generally attended Cavitation and the production of foul purulent sputum are common
by foreign-body giant cells (Fig. 5.2.16) and a florid granulomatous late manifestations of aspiration pneumonia.
reaction may be provoked, sometimes termed ‘pulse granuloma’ (Fig.
5.2.17).141–143 In such cases, the surgeon palpitating the lung at thora-
cotomy may suspect metastatic carcinoma but the pathologist is more
likely to mistake the microscopic changes for a specific infective granu-
Bacteriology
lomatous disease, such as miliary tuberculosis, if the aspirated debris The bacteria responsible for aspiration pneumonia are the dominant
goes unrecognised. Less frequently, the granulomas may contain com- components of the indigenous flora of the upper respiratory tract and
ponents of pharmaceutical tablets such as starch, talc, microcrystalline mouth. Because of this, specimen contamination bedevils the inter-
cellulose and crospovidone used as fillers, or kayexalate, which is a pretation of sputum samples. Cultures of blood, pleural fluid or
polystyrene sulphonate used in the treatment of hyperkalaemia.143 The transcutaneous tracheal aspirates are more informative. Facilities for
fillers may also gain access to the lungs via the blood stream in intra- anaerobic culture are essential as anaerobes outnumber aerobes by 10

190
 Infectious diseases Chapter |5|

to 1, as they do in the mouth and pharynx. Mixed infections are the

rule, comprising either a variety of different anaerobes or mixed anaer-
obes and aerobes. The commonest isolates are Bacteroides melanino-
genicus, Fusobacterium necrophorum, anaerobic or microaerophilic cocci
and Bacteroides fragilis.144 It is fortunate that all except the last of these
are sensitive to penicillin. B. fragilis is sensitive to the cephamycin,
cefoxitin. A predilection for opportunistic mycobacteria to infect lungs
containing aspirated lipids, such as those in milk, is referred to on
page 212.

LUNG ABSCESS

An abscess is a focus of suppuration consisting of a collection of pus

that is walled off by chronic inflammatory granulation tissue and
fibrous tissue. Although abscesses are very familiar lesions, in the lung
they are often confused with other pus-filled cavities, particularly
those of bronchiectasis. Similarly, when a lung abscess discharges into
the air passages, as it is prone to do, the air-filled space that results is
often confused with an empty bronchiectatic cavity. Lung abscess and Figure 5.2.18  Bilateral aspiration abscesses. High-resolution computed
bronchiectasis are fundamentally different diseases. The essential tomography scan shows bilateral consolidation and cavitation. Culture
structural difference between them is that several airways communi- grew anaerobic bacteria.
cate with an abscess cavity, whereas if multiple airways are ectatic, they
only communicate at their normal branching points (see Fig. 3.34,
page 119). This is because the formation of an abscess entails ‘cross- Primary lung abscess: an aspiration lesion
country’ destruction of lung tissue, something that is unique to an The development of a secondary lung abscess is easily understood and
abscess, regardless of its aetiology. clearly dependent upon some other underlying disease. On occasion,
Spontaneous rupture of an abscess into a bronchus is a likely event however, a lung abscess has no apparent cause and is therefore termed
and if the patient survives this by coughing up the pus instead of dis- primary. The available evidence indicates that primary lung abscesses
seminating it throughout the bronchial tree, a marked improvement are nearly always a consequence of the aspiration of infected oropha-
in the patient’s general condition can be expected. With time, the ryngeal secretions. First, there is usually some condition predisposing
granulation tissue bordering the now empty cavity may become epi- to aspiration or impairing the cough reflex, for example, alcoholic
thelialised. Also, the many airways cut across when the abscess formed stupor, general anaesthesia, head injury or neurological disease
may be sealed off by scar tissue. The cavity may then resemble a con- causing loss of consciousness, dysphagia or primary oesophageal dys-
genital cyst. A congenital bronchogenic cyst is distinguished by the function. Second, dental hygiene is usually poor, and there is often
presence of cartilage and glands in its wall, but a simple congenital periodontitis or gingivitis. Third, primary lung abscesses are usually
cyst may be indistinguishable morphologically from a cavity that found in the dependent parts of the lungs. They are commoner on the
started as an abscess. Other congenital cysts (dealt with in Chapter 2) right, probably because the right main bronchus is a more direct
have their own special features (see Table 2.2, p. 56). continuation of the trachea than the left, and in the apical segment
Sometimes the airways leading into a postinfective cavity only open of the lower lobe and the lateral parts of the basal segments of the
in inspiration so that they act as check valves. The fibrous wall is then upper lobe, these being the most dependent parts in the prone and
stretched progressively, resulting in a very thin-walled air sac that is lateral positions respectively (Figs 5.2.14, 5.2.18 and 5.2.19).139
often termed a pneumatocele. This process is seen particularly after Fourth, the bacteria responsible are usually the mixed anaerobes that
staphylococcal infection (see Fig. 5.2.8). Pneumatoceles resemble predominate in the oropharynx, particularly in people with bad teeth
emphysematous bullae but, although they are often multiple, the (Fusobacterium, Bacteroides and Peptostreptococcus species), and aerobes
remainder of the lung tissue is generally free of emphysema, some- such as Streptococcus milleri.47,150,151 Thus, primary lung abscess has
thing that is unlikely with bullae. much in common with aspiration pneumonia and it is for this reason
that it is dealt with here, rather than in Chapter 5.3, the chapter on
Secondary lung abscess chronic bacterial infection, which its indolent nature would justify.
The bacteriology of empyema is similar to that of aspiration pneu­
Abscesses develop in the lungs as a complication of several condit­ monia and primary lung abscess but this condition is dealt with
ions. Pneumococcal pneumonia was formerly a common cause but in Chapter 13, the chapter on pleural disease.
pneumonia due to staphylococci, klebsiellae (see Fig. 5.2.12) and
anaerobic bacteria is now more important in this respect.145 Local
predisposing conditions include bronchial cancer and the presence of
a foreign body. Septic embolism and multiple pyaemic abscesses of BOTRYOMYCOSIS
the lung were formerly common complications of such staphylococcal
infections as osteomyelitis and carbuncle but antibiotics have rend­ The term ‘botryomycosis’ is used to describe colonies of pyogenic
ered these rare. Still seen on occasion is necrobacillosis (Lemierre’s bacteria growing within tissues such as the skin, muscle, bone and
disease), a severe septicaemic illness in which pharyngitis caused by various viscera, including the lungs.152–154 The colonies generally exist
the anaerobe Fusobacterium necrophorum is complicated by throm- within pus-filled cavities and are often enclosed within sheaths of
bophlebitis of the internal jugular vein and multiple metastatic eosinophilic hyaline material (Splendore–Hoeppli reaction – see p.
abscesses, particularly in the lungs.146–149 214) (Fig. 5.2.20). They are indistinguishable from the granules of

191
 Pathology of the Lungs

Figure 5.2.20  Botryomycosis. A colony of mixed bacteria is seen within a

purulent exudate.

The size of the bacterial colonies varies. They may only be identifi-
able with the aid of a microscope or they may form visible flecks
within the pus, similar to the sulphur granules of actinomycosis.
Figure 5.2.19  Primary lung abscess straddling the fissure and involving Rarely the colonies are considerably larger; sometimes a single mass
the lateral parts of the basal segments of the upper lobe and the apical
of bacteria may attain a size of 5 cm in diameter. One such colony
segment of the lower lobe.
simulated an aspergilloma and was called a ‘botryomycoma’.155
The bacteria involved are often of mixed species but generally
include anaerobes such as Bacteroides or peptostreptococci.155 These
actinomycosis in sections stained by haematoxylin and eosin but are normal inhabitants of the pharynx and are generally found in
Gram stains show cocci or bacilli rather than filamentous bacteria. aspiration pneumonia and primary lung abscess, thus relating
The bacteria are viable but the growth of the colonies is slow and there botryomycosis to these aspiration lesions. Botryomycosis is also a
is no invasion of the adjacent tissues: something approaching a state complication of cystic fibrosis,156 acquired immunodeficiency
of balance exists between the body defences and the bacteria. syndrome (AIDS)157 and tracheopathia osteochondroplastica.158

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5.3  Chronic bacterial infections

demonstration, as in the Ziehl–Neelsen stain. Once stained in this

CHAPTER CONTENTS
way, they are difficult to decolorise, even with strong acids and alcohol,
Tuberculosis 197 hence references to the acid- and alcohol-fast bacilli. Mycobacteria
Primary and postprimary types of tuberculosis 199 also show some resistance to formalin: of 138 tissue specimens from
autopsy lungs fixed in formalin and showing histological evidence of
Primary tuberculosis 199
acid-fast bacilli, 12 grew mycobacteria, including three Mycobacterium
The immunity and hypersensitivity that result from tuberculosis isolates.3
tuberculous infection 205 The bacilli are normally scanty in tuberculous tissue and their iden-
Postprimary tuberculosis 207 tification with the Ziehl–Neelsen stain may require tedious examina-
Infection by opportunistic mycobacteria 211 tion of many sections.4 They are easier to identify in rhodamine-
Brucellosis 212 auramine-stained sections examined by fluorescence microscopy.5–7
Tissue containing necrotising granulomas is most likely to give posi-
Chronic melioidosis 213 tive results whereas specimens showing only non-necrotising granu-
Actinomycosis 213 lomas, poorly formed granulomas or acute inflammation are less
Nocardiosis 215 likely to reveal acid-fast bacilli.8,9 Culture is no more likely to identify
Rhodococcus pneumonia 215 the mycobacteria than the examination of tissue sections.9,10 Failure
to demonstrate them does not exclude a diagnosis of tuberculosis. The
Malakoplakia 216
future lies in immunohistochemistry11 or molecular techniques such
Syphilis 216 as the polymerase chain reaction, which can be adapted for applica-
Congenital pulmonary syphilis 217 tion to paraffin sections.12–15a The detection of mycobacterial RNA
Acquired pulmonary syphilis 217 indicates that the bacilli are viable and is therefore preferable to tests
References 217 for mycobacterial DNA. Molecular techniques are also useful in iden-
tifying drug resistance, distinguishing mycobacterial species and iden-
tifying specific strains of M. tuberculosis.16–18
The mycobacteria that cause tuberculosis in humans are sometimes
listed as M. tuberculosis, M. bovis, M. africanum and M. microti, the so-
TUBERCULOSIS called tuberculosis complex, although these four organisms are prob-
ably just variants of a single species. The first two correspond to the
human and bovine tubercle bacilli while M. africanum includes a
Bacteriology heterogeneous group of strains, with properties intermediate between
Tuberculosis is caused by certain mycobacteria. In the laboratory these the former two, isolated from humans in equatorial Africa and from
microbes are difficult to stain and in the body they are difficult to kill. African immigrants in Europe. The features and management of tuber-
Their comparative resistance to the normal body defences is due to culosis in humans caused by these three variants are very similar. M.
an ability to inhibit phagosome–lysosome fusion, permitting them to microti, the vole tubercle bacillus, is of attenuated pathogenicity for
survive within the host’s phagocytes.1,2 Their resistance to ordinary humans and has been used as a vaccine.
stains is attributed to their cell walls being rich in mycolic acid waxes. M. tuberculosis is largely responsible for the disease and the infection
This necessitates the use of hot concentrated carbol fuchsin for their is predominantly pulmonary, acquired through inhalation of this

197
 Pathology of the Lungs

organism into the lungs. Formerly, intestinal tuberculosis, acquired by Other routes of infection which may have operated in pulmonary
drinking milk infected with M. bovis, was much commoner, but the mycobacteriosis in the past include haematogenous dissemination
eradication of mycobacteriosis from cattle and the widespread pas- from a primary focus of M. bovis infection in the intestine, acquired
teurisation of milk brought about a virtual disappearance of this form by drinking infected milk, and similar spread from a primary focus in
of disease in developed countries. the skin acquired by traumatic inoculation (a rare occupational hazard
In addition to the human, bovine and vole types, the term ‘tubercle of pathologists and butchers, hence the old term ‘butcher’s wart’), but
bacillus’ includes the avian and the ‘cold-blooded’ types. The avian these have never been as important as droplet spread.
tubercle bacillus is a distinct species, M. avium, while the ‘cold-
blooded’ group includes the fish, turtle and frog tubercle bacilli, which
Epidemiology
are known as M. marinum, M. chelonei and M. fortuitum respectively.
All these other ‘tubercle bacilli’ can cause opportunistic infections in In most developed countries there has been a considerable fall in the
humans and, together with a number of other opportunistic species, incidence of tuberculosis and its mortality over the last century (Fig.
are often referred to as the atypical, anonymous or opportunistic 5.3.1). This is attributable to a variety of factors that began to operate
mycobacteria. M. intracellulare is no longer distinguished from M. among the prosperous classes and subsequently extended to all strata
avium, and the collective M. avium-intracellulare is often used. Similarly, of society. During almost the whole of this period an amelioration in
reference is sometimes made to M. fortuitum-chelonei. The opportun- social conditions took place in an almost uninterrupted, unspectacu-
istic mycobacteria are dealt with separately later in this chapter lar manner and it is to these unspecific factors that for many years the
(see p. 211). progressive fall in mortality was essentially due, although it was aided
by public health measures such as the eradication of tuberculous cattle
and mass radiography screening. After 1950, the decline in mortality
Route of infection in pulmonary tuberculosis from tuberculosis was hastened by the introduction of effective antitu-
In the past, there was much speculation about the possible routes of berculosis drugs. By bringing about a great fall in the number – often
infection in tuberculosis. Today, there is little doubt that when the even the complete disappearance – of bacilli in the sputum in cases
lesions are present in the lungs the infection has taken place as a result of active respiratory tuberculosis, these drugs have much reduced the
of inhalation of tubercle bacilli. That the respiratory tract should be hazard of infection that was formerly incurred by those who inadvert-
the chief portal of entry is scarcely surprising in view of the great ently or by obligatory associations were brought into contact, at work
preponderance of the pulmonary form of chronic tuberculosis in or at home, with an infectious case of the disease.
humans and of the enormous numbers of tubercle bacilli that are The reduced incidence of the disease in developed countries led to
eliminated daily in the sputum of most untreated active cases. Those changes in the ages of the affected patients. Whereas it was formerly
in close contact with such patients are liable to inhale the bacilli and a disease of the young, tuberculosis came to be largely limited to the
acquire the infection in their lungs. Although the smaller droplets of elderly in these countries, the disease representing recrudescence of
expectorated sputum, which may remain for many minutes suspended quiescent infection acquired in youth. Many of these elderly patients
in the air after a cough, are probably the chief vehicle for the trans­ suffered from an insidiously progressive form of the disease and this
mission of tubercle bacilli, it should be realised that the organisms is still the case today (see p. 210).
are resistant to desiccation, and that in consequence, dried The situation remained very different elsewhere. Much of the world
‘droplet nuclei’, or the dust that they ultimately contaminate, may has still not shared the economic and health benefits enjoyed in the
long remain as potential carriers of the infection. Tuberculosis trans- west and in many countries tuberculosis remains one of the most
mission can be reduced however by hospitalising patients with posi- important specific communicable diseases. Furthermore, the consider-
tive sputa in isolation rooms equipped with ultraviolet light and able gains that have slowly been achieved are now in peril because of
exhaust ventilation.19 the acquired immunodeficiency syndrome (AIDS) and other factors.

180 Figure 5.3.1  Deaths from tuberculosis in

England and Wales in the twentieth century.
160 The decline in mortality, temporarily checked
by two world wars, was established well
140 before specific chemotherapy became
Deaths per 100,000 per year

available, and is largely attributable to

120 improved living standards.

100

80

60

40

20

0
1900 1905 1910 1915 1920 1925 1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000

Years

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 Infectious diseases Chapter |5|

There has been a resurgence of tuberculosis recently, even in groups 456 000 deaths, one in four deaths from tuberculosis being HIV-
where AIDS has yet to make a major impact, possibly due to new related.34 In sub-Saharan Africa, the AIDS epidemic is having a devas-
levels of urban deprivation and the influx of immigrants and refugees tating effect on tuberculosis control programmes, with up to 100%
from countries with a high incidence of the disease.20 In the UK, for increases in reported tuberculosis cases. The annual risk of active
example, immigrants from the Indian subcontinent have rates of tuberculosis in those who are doubly infected is 10%, compared with
tuberculosis about 25 times as high as that of the white population.21 a 10% lifetime risk in those who harbour the tubercle bacillus but are
The decline in the incidence of tuberculosis in the UK slowed towards HIV-negative.35 The situation in richer countries may not be so bad
1987 and has subsequently reversed: since that date case numbers because HIV-infected persons tend to be young and those harbouring
have risen, particularly in inner London. The situation is similar in tuberculosis old, rendering recrudescence unlikely.35 However, within
many other developed countries. Tuberculosis can therefore be HIV units, cross-infection is being reported.31 Such nosocomial trans-
regarded once more as a worldwide problem. It is estimated that mission has involved patients and hospital staff who are immuno-
about one-third of the world’s population (approximately 2000 competent as well as other HIV-positive patients.36
million people) have latent tuberculosis while the prevalence of active The mechanism whereby HIV infection promotes tuberculosis is
disease is put at more than 20 million worldwide. In 2006 there were probably related to the pattern of cytokines produced by T-lymphocyte
9.2 million new cases and 1.7 million deaths, which makes tubercu- subsets. T-helper-1 lymphocytes produce interferon-γ and are central
losis the largest cause of death from a single pathogen in the world. to antimycobacterial immune defence. However, when peripheral
Despite the prevalence of tuberculosis, the human response to blood lymphocytes from HIV-infected patients with tuberculosis are
infection is good. In the absence of immunosuppressive disorders exposed to tubercle bacilli in vitro they produce less interferon-γ than
such as human immunodeficiency virus (HIV) infection, only about lymphocytes from HIV-negative patients with tuberculosis, suggesting
10% of those infected develop clinically evident disease. The basis of that a reduced T-helper-1 response contributes to HIV-infected
these patients’ susceptibility is not well understood but tobacco patients’ susceptibility to tuberculosis.37 It is also noteworthy that
smoking is a predisposing cause22 and genetic factors appear to be there is a reciprocal relationship between tuberculosis and HIV infec-
involved.23 tion: tuberculosis appears to promote the course of HIV infection,
probably by inducing macrophages to secrete cytokines that increase
HIV replication.38–40
The impact of HIV infection
Not surprisingly in view of the interrelationship of HIV and the
Following the advent of AIDS the downward trend in tuberculosis tubercle bacillus, the tuberculosis associated with HIV infection is
stabilised or was reversed.24,25 An alarming resurgence of the disease particularly aggressive, being characterised by widespread dissem­
is being witnessed, particularly in the poorer communities where drug ination throughout the body and a poor host response.41 This non-
abuse is prevalent (Table 5.3.1).26–28 Furthermore, multidrug-resistant reactive form of tuberculosis is similar to the insidious disease of
strains have emerged and now represent a global problem.29–33 The elderly patients referred to above and described on page 210.
mortality is high with such strains, even in patients who are not
immunodeficient, but it is particularly high in AIDS.
It is estimated that worldwide more than 6 million people are Primary and postprimary types  
dually infected with the tubercle bacillus and HIV, the majority in 10 of tuberculosis
sub-Saharan African countries. In 2007, there were an estimated 1.37
million new cases of tuberculosis among HIV-infected people and Although the morbid anatomical changes that develop in tuberculosis
assume a variety of forms, the great majority of cases fall into one or
other of two distinctive types. The first type was formerly found
mainly in children and became known as the ‘childhood type’ of
tuberculosis. Further experience has shown that it is not so much the
Table 5.3.1  The effect of human immunodeficiency virus (HIV) youth of these patients as the fact that they are infected for the first
infection on the global toll of tuberculosis27,28 time that accounts for the distinctive structural features of their
lesions. In consequence, this form of tuberculosis is now known as
Region People New Deaths HIV- the ‘primary type’, and as the incidence of the disease in the general
infected cases attributed population has declined and the age of first infection has correspond-
(millions) ingly risen, it is now met with increasing frequency in adults. The
second morphological form – previously known as the ‘adult type’ of
Western Pacifica 574 2 560 000 890 000 19 000 the disease – occurs in those patients who have been sensitised by an
earlier exposure to tuberculosis: this type of disease is now generally
South-East Asia 426 2 480 000 940 000 66 000
termed ‘postprimary tuberculosis’. Postprimary tuberculosis is due to
Africa 171 1 400 000 660 000 194 000 either fresh infection or reactivation of a dormant primary lesion (Fig.
5.3.2). Reinfection is common in countries in which tuberculosis is
Eastern 52 594 000 160 000 9000
prevalent but in the developed countries reactivation of infection
Mediterranean
acquired decades earlier is commoner. The various patterns of tuber-
The Americasb 117 560 000 220 000 20 000 culous infection are summarised in Box 5.3.1.
The industrialized 382 410 000 40 000 6000
countriesc
Primary tuberculosis
Total 1722 8 004 000 2 910 000 315 000
The very early stages of a tuberculous lesion in the human lung have
a
Excluding Japan, Australia and New Zealand. seldom been seen, and our ideas on its pathogenesis have been
b
Excluding USA and Canada. derived almost wholly from study of lesions in experimental animals.42
c Initially, the presence of tubercle bacilli in an alveolus excites little
Western Europe, USA, Canada, Japan, Australia and New Zealand.
immediate reaction, and for the first day or two the only change may

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 Pathology of the Lungs

Primary infection Re-infection

Resolution Latency
Progressive
primary
tuberculosis
Re-activation

Endogenous or Exogenous
Post-primary tuberculosis

Figure 5.3.2  Possible events following infection by tubercle bacilli.

Box 5.3.1  Summary of patterns of tuberculous infection

of the lungs

Primary tuberculosisa
Ghon focus + regional lymph node = primary complex
Reparative
Quiescent
Progressive
Pleural involvement Figure 5.3.3  A tuberculous granuloma consisting of a central collection
Airway dissemination (tuberculous bronchopneumonia, laryngeal of epithelioid macrophages surrounded by lymphocytes. A Langhans
giant cell is seen amongst the epithelioid cells.
lesions)
Epituberculosis (segmental tuberculosis)
Haematogenous (miliary tuberculosis, meningitis, solitary lesions in
organs with a rich systemic blood supply and therefore a high
oxygen tension, e.g. kidney. Also the lung apices because of their are mixed with the epithelioid and giant cells and outside these,
high ventilation/perfusion ratio) further lymphocytes form a dense outer mantle. This localised collec-
Postprimary tuberculosisa (reactivation or reinfection) tion of epithelioid macrophages, Langhans giant cells and lym-
phocytes constitutes a tuberculous granuloma (Fig. 5.3.3).
Fibrocaseous apical cavitation (high oxygen tension)
Immunocytochemistry shows that the lymphocytes in the inner zone
Reparative of the granuloma are mainly T-helper (CD4) and memory (CD45RO)
Quiescent cells whereas the outer zone includes both CD4 and CD8 (T-suppressor)
Progressive lymphocytes, while immediately adjacent to the outer zone and dif-
Local extension ficult to distinguish from it without immunocyto­chemistry there is a
Pleural involvement secondary centre composed of B lymphocytes and active (Ki-67+)
Airway dissemination (tuberculous bronchopneumonia) antigen-presenting cells (Fig. 5.3.4).45
Haematogenous (miliary tuberculosis) By the third week, the granuloma has usually grown sufficiently to
Non-reactive tuberculosis (immunocompromised be visible to the naked eye as a small, grey nodule, or tubercle, which
or elderly) gives the disease its name. As the tubercle enlarges, its centre turns
yellow. Microscopical examination at this stage shows that the granu-
a
Primary tuberculosis usually heals but if it progresses there is a greater chance loma has undergone necrosis (Fig. 5.3.5). A ring of satellite tubercles
of widespread dissemination than in postprimary disease, in which progression
then develops and as these undergo central necrosis they fuse together
is more often local.
(Fig. 5.3.6). In this way the original granuloma gradually increases in
size. The growth of a tuberculous lesion by the progressive develop-
ment and subsequent incorporation of satellite tubercles is also seen
in postprimary tuberculosis (see Fig. 5.3.19, p. 210).
be a small amount of exudate and a few neutrophils round the organ- It is characteristic of the classic active tuberculous lesions that the
isms. Within the next few days, macrophages collect in increasing tubercle bacilli are scanty, probably reflecting a state of relatively
numbers, and ingest most of the bacilli. strong immunity/hypersensitivity (see below). Also characteristic of
Gradually, the macrophages, with living bacilli in their cytoplasm, tuberculosis is prolonged survival of the tubercle bacilli within the
aggregate to form microscopical nodules. The macrophages also tissues, despite a vigorous host reaction. This is attributable to the
develop an abundant eosinophilic cytoplasm and are described as tubercle bacillus inhibiting the fusion of macrophage lysosomes
‘epithelioid’. This represents a switch from their basic phagocytic and phagosomes and so avoiding the bactericidal contents of the
function to a secretory one (see sarcoidosis, p. 286), modulated by lysosomes.1,2
lymphokines from T lymphocytes, notably interferon-γ.23,43,44 This The type of necrosis found in a classic tuberculous lesion is distinc-
change promotes the antibacterial properties of the macrophage but tive, being dry, crumbling and cheesy (hence the term ‘caseous’ as a
also contributes to tissue necrosis, as outlined below. After about 2 macroscopic description). It is of the coagulative rather than lique­
weeks some of the more centrally placed macrophages fuse to form factive type, probably because of the relative dearth of polymorpho-
multinucleate cells of Langhans type. Small numbers of lymphocytes nuclear leukocytes. The necrosis is a hypersensitivity phenomenon; no

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Figure 5.3.4  Diagrammatic representation of a

tuberculous granuloma. The central necrosis,
which harbours mycobacteria, is surrounded by
an inner layer of antigen-presenting cells and
CD4+ T lymphocytes, within which CD8+ cells are
Active centre: scarce. The outer lymphocyte infiltrate contains
B cells large numbers of CD8+ T cells and active (Ki-67+)
Antigen presenting cells centres with mycobacteria-containing antigen-
presenting cells and B cells surrounded by both
CD4+ and CD8+ T cells. (Redrawn from Ulrichs
et  al.45 by permission of the Journal of Pathology.)

Blood vessel/
lymphatic
Inner layer:
CD4,
CD8 low
Necrosis
CD8
(which harbours mycobacteria)
CD4
B cell
Outer layer:
Antigen presenting cells CD8 high

mycobacterial toxins have been identified. It represents apoptosis

brought about by cytotoxic T cells and macrophages activated by
subsets of T-helper cells. The epithelioid cells show strong immuno­
expression of the proapoptotic proteins Bax and Fas, with the anti­
apoptotic protein Bcl-2 being notably absent.46,47
The elastic tissue of the lung persists for a long time in necrotising
tuberculous lesions. When stained appropriately, its distribution and
pattern give information about the position of blood vessels and of
alveolar walls within the necrotic centre that cannot be recognised
clearly, if at all, in haematoxylin and eosin preparations. Ultimately,
however, all trace of the lung’s elastin framework is lost.
In the comparatively small number of human cases in which there
is an opportunity to examine the lungs while the lesion of primary
tuberculosis is still active, the latter – often known as the ‘Ghon
focus’48 – is generally visible as a pale yellow, caseous nodule, a few
millimetres to a centimetre or two in diameter. Characteristically, it
is situated in the peripheral part of the lung underlying a localised
Figure 5.3.5  A tuberculous granuloma showing central caseous necrosis. area of chronic inflammation and thickening of the pleura. Usually,
only one such focus is present, but if the lungs are searched carefully,
preferably with the help of postmortem radiography, it will be found
that there is more than one focus in a small proportion of cases. It is
a point of importance in the distinction between primary and post­
primary tuberculosis of the lungs that in the latter the lesions are
almost invariably in the apical region of an upper lobe, whereas in
the former they are found most frequently in the periphery of the
lower lobes, where airflow is greatest.
Studies on primary tuberculosis in both humans and experimental
animals show that within a few days of their deposition in subpleural
alveoli some of the bacilli are carried centripetally in the lymphatics
to establish infection in hilar lymph nodes. Thereafter, the granu­
lomatous changes in the lung and lymph nodes, and the smaller foci
that may have formed along the course of the intrapulmonary lym-
phatics, all develop at about the same rate but the caseating lesions
in the lymph nodes tend to be larger than the primary focus in the
lung. This combination of a peripheral Ghon focus with the corre-
sponding focus of caseation in the regional lymph nodes is known as
Figure 5.3.6  Tuberculous granulomas clustered around more extensive the primary complex of Ranke (Figs 5.3.6 and 5.3.7). The complex is
areas of coagulative necrosis. the typical result of a primary tuberculous infection of the lungs.

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 Pathology of the Lungs

Figure 5.3.7  Primary complex of tuberculosis with miliary spread. A small

Ghon focus in the lower lobe of the lung is accompanied by prominent
caseating tuberculous lymphadenitis. The infection has spread from one
of the lymph nodes into a branch of a pulmonary artery, resulting in
miliary haematogenous tuberculosis of the lower lobe. (Courtesy of the
Curator of the Pathology Museum, Charing Cross and Westminster Medical School,

The primary complex may undergo a series of reparative changes,

or it may continue to enlarge and in so doing implicate further struc-
tures and thus promote dissemination of the infection. The pathologi-
cal features of healing and progressive primary complexes and the Figure 5.3.8  Tuberculous empyema. The lung is compressed by a large
relative frequency of these processes will be considered next. cavity that was originally filled by caseous material, loculated collections
of which persist at the apex. The walls of the cavity are formed by the
thickened parietal and visceral layers of the pleura. (Courtesy of the curator
Reparative changes of the Gordon Museum, Guy’s Hospital, London, UK.)

The slow enlargement of the caseating primary complex is accompa-

nied by the development of a fibrous capsule that impedes further
centrifugal dispersal of the bacilli should any still remain alive. Later,
there is often dystrophic calcification and even ossification, within survive and multiply in the surviving zone of granulation tissue that
which fatty and sometimes haemopoietic marrow may form. Diffuse borders the lesion, leading to its peripheral extension. As a result of
racemose (dendriform) ossification (see p. 149) has also been reported this, a caseous mass, several centimetres in diameter, may form either
in association with pulmonary tuberculosis.49 in the lung itself or in the now much enlarged and generally matted
These old foci of caseous necrosis, walled off by fibrous tissue, may regional lymph nodes. If the lesion erodes into a bronchus, loss of
contain viable bacilli, despite an absence of inflammation. Such latent the necrotic material through the airway leads to the creation of a
lesions, which are known as quiescent tuberculosis, are potential sites cavity, often of a size little less than that of the parent caseous mass,
of recrudescence. Active disease is denoted by granulomatous and surrounded by a ragged lining of partly necrotic tuberculous
inflammation. granulation tissue. If the necrotic focus breaks through the pleura, the
result is pleural effusion, pneumothorax, tuberculous empyema (Fig.
5.3.8) or pyopneumothorax. Sometimes this is the presenting mani-
Progressive changes festation of the disease, and occasionally the only clinical evidence of
In a small proportion of cases of primary tuberculosis, the reparative the disease. In tuberculous empyema the matter in the pleural sac is
changes fail to stem the progress of the disease. As the infected tissues caseous and not purulent, despite the traditional terminology, unless
undergo caseation, the bacilli tend to die in the central areas but to there is a secondary infection by pyogenic organisms.

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Figure 5.3.10  Dissemination of caseous material via the airways has led
to widespread focal consolidation. (Courtesy of Dr Max Millard, formerly of
Florida, USA.)

Figure 5.3.9  Primary complex of tuberculosis comprising a large

caseating Ghon focus and marked enlargement of the infected
mediastinal lymph nodes. A caseating lymph node to the right of the
lower end of the trachea has become adherent to the latter, and the
tuberculous process has extended through the tracheal wall to form a
sinus. Aspiration of infective material from this sinus has led to the
development of the tuberculous bronchopneumonia, represented by
multiple small foci of consolidation scattered throughout the lung.
(Courtesy of the curator of the Gordon Museum, Guy’s Hospital. London, UK.)

Dissemination through the airways

Caseous material that enters the main respiratory passages is largely
expectorated but some is dispersed to other parts of the lungs by the
deep inspiration that usually accompanies coughing. Such dispersion
of large numbers of organisms within the bronchial tree may lead to
widespread tuberculous bronchopneumonia (‘galloping consump-
tion’), an often fatal condition (Figs 5.3.9–5.3.11). Smaller numbers
of bacilli may infect the bronchial, tracheal or laryngeal mucosa, or,
by being swallowed, the intestine. Infection of a bronchus causes
ulceration, mucosal thickening or concentric scarring which may be
complicated by collapse of the distal lung. Figure 5.3.11  Tuberculous bronchopneumonia. Almost the whole of the
Caseous hilar nodes may compress a bronchus and lead to lung shows pale, confluent areas of caseation. (Courtesy of the curator of
absorption collapse (see middle-lobe syndrome, p. 92).50–52 Partial the Gordon Museum, Guy’s Hospital. London, UK.)

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 Pathology of the Lungs

obstruction may lead to air trapping and severe distension of a lobe, the establishment of blood-borne tuberculosis. The reason for this is
proper ventilation of which may be obtainable only by surgical evacu- described below under ‘Postprimary tuberculosis’.
ation of the caseous contents of the nodes responsible. Massive When many bacilli enter the circulation simultaneously and a
enlargement of paratracheal nodes, particularly those of the right side, massive haematogenous dissemination ensues, generalised miliary
may result in compression of the trachea, causing stridor and some- tuberculosis develops. In this condition, as in all forms of bacter­
times cyanosis. aemia, the organisms are removed from the circulating blood by
A caseating hilar lymph node may also erupt into a bronchus. phagocytic cells lining sinusoids in the liver, spleen, bone marrow and
Very rarely, so much matter escapes suddenly that the patient, usually elsewhere. Although, to judge from experimental tuberculous
a child, is quickly asphyxiated. More often there is progressive bacillaemias, most of the circulating bacilli are promptly destroyed
change in the affected segment. This is the condition known as by the phagocytes, enough survive ingestion to set up innumerable
epituberculosis. small metastatic foci of infection.
The massive blood stream invasion by tubercle bacilli necessary to
produce miliary tuberculosis is often brought about by a caseating
Epituberculosis (segmental tuberculosis) tuberculous focus involving the wall of a neighbouring blood vessel.
This condition53 is a fairly frequent radiological finding in cases of This is particularly likely to complicate the hilar lymph node compo-
primary pulmonary tuberculosis. The radiographic picture is that of a nent of a primary complex, for these caseous masses are not only
segmental opacity. It is associated with little clinical disturbance and larger than those in the lungs, but they develop in proximity to the
usually resolves completely over a period of months. It was once com- large veins in the mediastinum (see Fig. 5.3.7). The wall of the affected
monly assumed to represent absorption collapse due to compression blood vessel becomes replaced by tuberculous granulation tissue. In
of the segmental bronchus by the lymph node component of the time, caseation develops, the lesion ulcerates through the intima and
primary complex, but this explanation is now recognised to be in­­ tubercle bacilli escape into the blood stream. In exceptional cases, the
adequate in many cases. The great majority of these lesions represent aorta may be eroded, with consequent rupture and rapidly fatal bleed-
inflammatory consolidation caused by the lymph node component ing. However, it is not always possible to demonstrate vascular erosion
of the complex perforating into the segmental bronchus so that and it seems likely that the organisms may on occasion reach the
infected caseous material is disseminated throughout the distal air blood by way of the lymphatics.
passages. Generalised miliary tuberculosis is usually fatal unless treated
The affected segment is pale grey and the lobular markings are quickly and appropriately, particularly if the infection has involved
accentuated by thickening of the interlobular septa. There is exudation the central nervous system and given rise to tuberculous meningitis.
of both fluid and macrophages into the alveoli, and lymphocytic Necropsy in such cases shows enormous numbers of small, grey tuber-
infiltration of the alveolar walls. That the lesion is not merely a non- cles, a millimetre or less in diameter, most notably in the liver, spleen,
specific obstructive pneumonitis is clear from the constant presence bone marrow, lungs and meninges, and more sparsely in other organs
of numerous epithelioid cell granulomas. Initially the granulomas are (Fig. 5.3.12). The term ‘miliary’ derives from a supposed likeness of
non-necrotising but quite extensive caseation may develop. Tubercle the tubercles to millet seeds. The preponderant distribution and typi-
bacilli are to be found in the caseous node but are usually very sparse cally uniform dispersal of tubercles in the parts affected may be
in the consolidated lung. ascribed partly to the particularly large number of phagocytic cells in
The lesion can be reproduced experimentally by introducing either the walls of the blood sinusoids of the tissues, and partly to the situ-
killed tubercle bacilli or the purified protein derivative of tuberculin ation of the vessel invaded: if it is a systemic vein in the mediastinum,
into previously sensitised animals. The condition is therefore consid- or the main thoracic duct, the bacilli are first carried to the lungs,
ered to represent a local hypersensitivity reaction to the aspiration of where many are filtered out in the pulmonary capillaries to give origin
caseous material from the perforated hilar nodes. This is supported to a preponderance of the miliary tubercles in the lungs; if it is a
by the acceleration of the resolution that is achieved by adding tributary of the pulmonary veins, they are carried to other organs
corticosteroids to the usual specific antituberculous drugs, and by in the systemic arterial circulation.
the dramatic reappearance of the disease if the corticosteroids are Histologically, miliary tubercles have a characteristic structure. A
withdrawn. Langhans multinucleate giant cell commonly forms the centre and is
The natural outcome of epituberculosis is variable. There may be enclosed by a zone of epithelioid macrophages and an outer shell of
complete resolution or patchy fibrosis with contracture and perhaps lymphocytes. If the patient survives for a month or more, the tubercles
bronchiectasis. The perforation of the bronchus usually heals with will be larger and their centres show early caseation. These more
only minor scarring, but occasionally it causes fibrous constriction of advanced lesions consist of small groups of satellite tubercles that
the bronchus similar to that caused by aerogenous spread to the have a general resemblance to the original one and surround the
bronchus from a lesion in the lung, as described above. A rare sequel, central caseous area that has taken its place.
comparable in pathogenesis to the traction diverticula of the Today, when many of those patients who develop generalised hae-
oesophagus, is the formation of a bronchial diverticulum. matogenous dissemination of the infection are successfully treated,
the progressive changes in the tubercles in the lungs can sometimes
be followed in serial radiographs and the findings compared with
Haematogenous dissemination those in histological preparations of the lungs of patients who died
Tuberculous bacillaemia is a common early event in primary tubercu- at the corresponding stage. Gradually, during the weeks following the
losis. Strom provided evidence of this when he used radiolabelled institution of the treatment the finely dispersed opacities can be seen
tubercle bacilli to induce the disease experimentally.54,55 The bacilli to regress until their presence is no longer detectable radiologically.
are generally destroyed by phagocytes throughout the body but occa- At this stage, microscopical examination of the tubercle shows merely
sional organisms may escape this fate and – after their lodgement in a minute scar composed almost wholly of hyaline collagen with no
a kidney, bone or joint, the central nervous system, an adrenal gland trace of the former distinctive cellular structure. If a cure follows at a
or some other organ favourable to their growth – set up an isolated more advanced stage of the disease, after caseation has occurred, the
focus of tuberculosis that may either remain latent for years or caseous material becomes calcified. This results in a fine mottling of
progress. The apices of the lungs are amongst the tissues that favour the lung fields that may be seen radiologically for years after.

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 Infectious diseases Chapter |5|

successful therapeutically but von Pirquet used Koch’s ‘old tuberculin’

as a skin-testing agent after showing that reactivity to it indicates that
a person has been infected by the tubercle bacillus. In the original test,
a drop of old tuberculin was placed on the skin and a scratch was
made through the drop, but reagents are now administered by intra-
dermal injection (the Mantoux method) or by use of multiple-pronged
devices (Heaf and tine tests). Old tuberculin has given way to purified
protein derivative but the principle of the test remains unchanged and
it provides a useful indication of the extent of transmission of tuber-
culosis in countries where tuberculin reactivity has not been artificially
induced by bacillus Calmette–Guérin (BCG) vaccination (see below)
or there is not heavy exposure to the opportunistic environmental
mycobacteria. To circumvent the problem of opportunistic
mycobacteria causing such spurious reactions, blood tests have been
developed that measure T-cell interferon release in vitro in response
to antigens unique to the tubercle bacillus.56
The tuberculin skin test becomes positive within a few weeks of
Figure 5.3.12  Miliary tuberculosis. The lung is studded with numerous tuberculous infection being acquired and remains so in the great
tubercles, each the size of a millet seed. (Courtesy of Dr M Kearney, Tromso, majority for many years. Confidence in the reliability and specificity
Norway.) of the test is based mainly upon evidence from two sources. The first
comes from surveys made on cattle just before slaughter: the result of
the test correlated very closely with the presence or absence of tuber-
Subclinical primary tuberculosis culous lesions in the carcass. The second is derived from tests on
The true prevalence of tuberculous infection in the general population clinically tuberculous and clinically non-tuberculous children under
is very much higher than overt clinical manifestations suggest. This 5 years of age: 94% of the former, and only 12% of the latter, were
inference is based on two main sources of evidence: first, identification positive.
of healed tuberculous lesions in necropsy studies on long series of Tuberculin surveys have given incontestable support to the general
consecutive cases of patients dying from all causes in large general conclusion drawn from necropsy studies that tuberculosis has been
hospitals; and second, immunological surveys on large samples of the widespread in urban populations. In a tuberculin survey in London
population employing the tuberculin skin test as an indicator of between the two world wars the percentage of positive reactors was
previous infection. found to rise progressively from well below 10 in children under 2
The realisation that primary tuberculosis is followed by recovery years to 90 in adults. Yet despite the great frequency of infection and
in the great majority of those infected was the most important the large number of deaths from the disease, the case fatality rate –
outcome of a pioneer study by Naegeli at the end of the nineteenth the only numerical indicator of the probable outcome of an infection
century in the postmortem room of the Zurich General Hospital. – is comparatively low. This is exemplified by the figures set out in
Employing acceptable anatomical criteria for the identification of Table 5.3.2, which shows that even in 1931 only one out of several
healed and active tuberculous lesions, he reached two very significant thousand children who became infected actually died from the
conclusions: first, that practically all the adults who had died in that disease: a fatal outcome is even less frequent today.
hospital from diseases of all kinds had, at some site in their body,
recognisable tuberculous foci that, in the great majority, had healed;
and second, that in only a minority of these patients could death be The immunity and hypersensitivity that
attributed to tuberculosis. Forty years later, a similar study was made result from tuberculous infection
at the same hospital, and again traces of a previous tuberculous infec-
tion were detected in the bodies of 80–90% of all adult patients. The frequency with which a primary tuberculous infection is over-
The interest and surprise aroused by Naegeli’s work stimulated come, usually without the patient being aware of its presence, roused
numerous similar studies elsewhere: his general conclusions were interest in the possibility that in tuberculosis, as in many other infec-
fully confirmed and it was recognised that signs of past tuberculous tious diseases, recovery from an attack might leave a heightened resist-
infection, notably calcified mediastinal and mesenteric lymph nodes, ance to infection in the event of subsequent exposure to the same
were common in any population studied. Although in elderly people organism. Further, as some degree of immunity generally results from
the frequency of evidence of such healed infections changed little over a natural infection, the question was raised whether similar protection
the ensuing half-century, in children and young adults it showed a could be conferred by some controllable prophylactic procedure. An
decline that reflected the diminished incidence of clinical tuberculosis affirmative answer has been given to both these questions.
in western countries. A much larger fraction of the population than The first study that disclosed convincingly that a primary infection
formerly became liable to reach adult life without a primary infection conferred some protection was made by Heimbeck in Oslo. His con-
and, as a corollary, also without the valuable, if partial, immunity that clusions were based on studying follow-up records of positive and
results from an infection that has been overcome. Prophylactic immu- negative tuberculin reactors among probationer nurses entering the
nisation in childhood was therefore instituted and is now widely municipal hospital in that city. Through a comparative study of the
practised. findings on enrolment and the subsequent medical history while
nursing, it became apparent that, although all were equally exposed
to the same general hospital environment and its hazards, the inci-
The tuberculin skin test dence of overt tuberculosis was significantly less in those girls who
As well as first identifying the tubercle bacillus in 1882, Robert Koch were positive reactors at the time of their entry.
went on to develop a vaccine against the disease based upon the Heimbeck’s conclusions have since been scrutinised and confirmed
subcutaneous injection of a sterilised extract of the bacteria. It was not in many studies elsewhere. The most extensive of these – the Prophit

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 Pathology of the Lungs

environment as these confer some protection against tuberculosis but

Table 5.3.2  Comparison by age of positive tuberculin reactors
also reduce the effectiveness of BCG.59a Table 5.3.4 shows that BCG is
in a sample London population with deaths from tuberculosis
most effective when administered soon after birth, i.e. to the immu-
for England and Wales in 1931
nologically naïve.
In developing countries, where the prevalence of tuberculosis is
Age group Positive Deaths from
high, BCG immunisation of the newborn is recommended to prevent
(years) reactors (%) tuberculosis (%)
the dangerous forms of childhood tuberculosis, but elsewhere it is
0–5 12 0.076 only recommended for the Mantoux-negative members of certain
high-risk groups – health workers, including mortuary and laboratory
6–10 30 0.026 staff, veterinarians, case contacts, immigrants from countries with a
11–20 61 0.060 high prevalence of tuberculosis together with their children and
infants wherever born, and those intending to stay in Asia, Africa or
Central or South America for longer than a month.
Although BCG inoculation is generally harmless, disastrous dis-
Table 5.3.3  Incidence of clinical tuberculosis among positive semination of the infection has been known to occur.60 Impaired host
and negative reactors to tuberculin in London, 1934–4457 immunity may be presumed to account for these rare instances as the
dose and batch of the vaccine used in these exceptional cases have not
Tuberculin Number of Cases of Incidence differed from those used successfully in other children. Cases have
reaction people tuberculosis (%) been reported in the context of AIDS and inherited immunodeficiency
at outset examined recorded states such as severe combined immunodeficiency and chronic granu-
lomatous disease. However, in half the cases reported no well-defined
Positive 7130 95 1.33 inherited immunodeficiency state has been recognised. Some of these
Negative 1745 69 3.95
patients have been able to mount a good granulomatous response
against the infection but others have developed disease similar to
lepromatous leprosy, characterised by florid proliferation of the bacilli
and an apparently ineffective non-granulomatous macrophage
Fund Tuberculosis Survey – was carried out on nearly 10 000 young
response.61 It follows that any form of immunosuppression is a
people, mainly nurses and medical students, in London over the
contraindication to BCG immunisation: this includes corticosteroid
period from 1934 to 1944.57 The results of this investigation are sum-
treatment and HIV infection.
marised in Table 5.3.3, which shows that there was about three times
BCG immunisation confers advantages other than protection
as high an incidence of clinical tuberculosis among young adults who
against tuberculosis as it has heterologous effects on the immune
were negative reactors at the start of the study as among similarly
response to many organisms and thereby exerts a beneficial influence
exposed positive reactors in London. This is almost the same as the
on several human infections.61a It has also been suggested that
average ratio derived from nearly 30 comparable surveys elsewhere in
children so immunised suffer less leukaemia and other malignancies
Europe and in America. It establishes the conclusion that, although a
but such claims are somewhat tenuous.62 However, BCG has
primary infection does not confer absolute immunity, it does give a
been injected into the pleural cavity or the bladder of patients
valuable degree of protection against developing the disease in a clini-
with inoperable cancer of these regions in the hope that it would
cal form after subsequent exposure to the same organism.
have a non-specific adjuvant effect on the immune reaction to the
cancer and, as with its use in preventing tuberculosis, there are rare
Specific prophylactic immunisation instances of the bacillus being disseminated widely throughout the
body.63,64
Numerous efforts have been made to confer immunity to tuberculosis
through prophylactic inoculation, many by veterinary surgeons who
The relationship of immunity to hypersensitivity
hoped to free cattle from the disease. The most significant conclusion
from their work was that, unlike what had been found for many other in tuberculosis
infectious diseases, killed organisms were relatively impotent as The rapid translocation of tubercle bacilli to the regional lymph
immunising agents. Protection could be conferred only through an nodes, and perhaps beyond, on first infection, is less likely in post­
infection that had been overcome. In consequence of this, the search primary tuberculosis, indicating some degree of acquired immunity,
for an effective prophylactic agent became one for strains of the bacil- while the development of caseation at a time when cellular immune
lus that were of such low natural virulence, or that had been so attenu- mechanisms may be expected to take effect suggests that hypersensi-
ated by appropriate methods of culture, that they could be inoculated tivity accompanies the immunity. Long ago, Rich showed that guinea
safely while still alive. Such strains, it was hoped, would produce only pigs made allergic by the injection of non-virulent tubercle bacilli still
a self-limiting infection. Of those that have been found, the organism retained resistance after gradual desensitisation with tuberculin, sug-
now widely known, after those who developed it, as bacillus Calmette– gesting that hypersensitivity and immunity were distinct,65 a proposi-
Guérin or BCG has established itself as the agent of choice, and is now tion for which there is now considerable support.66,67 Hypersensitivity
widely employed in antituberculosis schemes in many parts of the and specific acquired immunity are both cell-mediated, but T-cell
world. Yet, although the effectiveness of BCG has been demonstrated characterisation indicates that different T-cell subsets are involved.
on many occasions (Table 5.3.4), in other studies it appears to have Antigens are processed by specific cells, such as dendritic cells, and
conferred no protection whatsoever.58 The reason for these marked are presented in association with products of the major histocompat-
differences is poorly understood but may be connected with the fact ibility complex genes to T lymphocytes. Cytotoxic (CD8-positive) T
that, since its introduction, numerous daughter strains of varying cells are activated by products of the class I major histocompatibility
antigenicity have developed, which is not surprising as being a live genes (HLA-A and -B), which are expressed on the surface of antigen-
bacterium it has had to be passaged in vitro over 1000 times.59 Another presenting cells if microbial proliferation proceeds unchecked within
possible reason is the variable prevalence of other mycobacteria in the phagocytes, the bacteria-containing phagocytes then being eliminated

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 Infectious diseases Chapter |5|

Table 5.3.4  The protective effect of bacillus Calmette–Guérin (BCG) found in nine major studies58

Group studied Date of commencement Duration (years) Age range Protection (%)

Native North American 1935–38 9–11 0–20 years 80

Chicago, USA 1937–48 12–23 3 months 75
Georgia, USA 1947 20 6–17 years 0
Illinois, USA 1947–48 19–20 Young adults 0
Puerto Rico 1949–51 5–7.5 1–18 years 31
Georgia/Alabama, USA 1950 14 Over 5 years 14
Great Britain 1950–52 15 14–15 years 78
South India (Bangalore) 1950–55 9–14 All ages 30
a
South India (Madras) 1969–71 7.5 All ages 0
a
15-year follow-up has revealed some protection amongst those administered BCG as neonates.

by the T cells. On the other hand, effective processing of the bacteria M. tuberculosis
results in the antigen-presenting cells expressing class II major histo-
compatibility genes (HLA-D), the products of which activate (CD4-
positive) T-helper cells, so enhancing bacterial elimination.68
Two types of T-helper cells are recognised, one concerned mainly ThO
in immunity and the other with hypersensitivity. Type 1 T-helper
lymphocytes (Th1) secrete interleukin-2 and the macrophage-
activating cytokine interferon-γ, resulting in enhanced bacterial elimi-
nation; however, it also results in the secretion of tumour necrosis
factor by the macrophage, which contributes to the hypersensitivity Th1 Th2
that derives from the activation of type 2 helper T cells (Th2).69 Th2
cells secrete interleukins-4, -5, -6 and -10, which prime tissue cells to
the necrotising action of tumour necrosis factor secreted by macro- IFN-L IL4, 5, 6, 10
phages activated by Th1 cells. Thus, type 1 reactions are essentially
protective but also contribute to the type 2 cell-mediated hypersensi-
tivity (Fig. 5.3.13).43,44,68,70 Many chronic infections are first character- Macrophage Primed
ised by a Th1 response which then shifts to a Th2 response, with tissue
detriment to the host. Animal models suggest that necrosis occurs in TNF-F cell
T-cell-dependent granulomas when Th2 involvement is superimposed
on a Th1 reaction.71

Postprimary tuberculosis
Bacillary
In contrast to primary tuberculosis of the lungs, where the Ghon focus growth Necrosis
may develop in any lobe, the early lesions in the postprimary disease contained
are almost invariably found near the apex of one of the upper lobes.
Postprimary pulmonary tuberculosis obviously involves considerable Figure 5.3.13  Types of T-helper cell (Th-) reactions. IFN, interferon-γ ;
spread of the infection. The dissemination is believed to be IL, interleukin; TNF-α, tumour necrosis factor-α. (Redrawn after Grange.68)
blood-borne. Using radiolabelled bacilli, Strom provided experimen-
tal evidence that tuberculous bacillaemia is a common and early event
in primary tuberculosis.54,55 In the great majority of people, both the apices of the lungs are poorly perfused, but the pulmonary arteries
primary complex and its haematogenous dissemination are quickly bring deoxygenated blood. Ventilation on the other hand promotes
overcome, but in some the distant foci progress or remain latent. If oxygen tension, but the apices are also the most poorly ventilated
tributaries of the pulmonary veins are involved in the spread of the parts of the lungs. The oxygen tension in the lungs is in fact dependent
infection, the bacilli pass out of the thorax, but if the blood stream is upon the ventilation/perfusion ratio. In the upright position, this
colonised via the lymphatics, the pulmonary capillaries are the first declines from the apices to the bases of the lungs (Fig. 5.3.14),72–75
to be reached, and so the infection returns to the lungs. and the oxygen tension is therefore highest at the top of the lungs,
Oxygen tension governs the predilection for blood-borne tubercu- thus favouring the development of postprimary tuberculosis at the
losis to favour the apical regions of the lungs and also sites such as apices.
the kidneys, meninges and metaphyses. These extrapulmonary sites If the disease progresses, radiological opacities appear in the apex
are well vascularised and therefore have a relatively high oxygen of one or both of the upper lobes. They may resolve or progressively
tension. The tubercle bacillus is a strict aerobe and thrives in such enlarge and ultimately cavitate. Necropsy studies indicate that such
organs. In the lung, more complex factors govern oxygen tension. The lesions represent areas of caseating granulomatous inflammation that

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 Pathology of the Lungs

.15
3
Litres / min / unit lung voulme

VA / Q
.10 Blood flow
2

VA / Q
Ventilation
.05 1

Base 5 4 3 2 Apex
Rib number
Figure 5.3.14  Regional differences in pulmonary blood flow, ventilation
and ventilation/perfusion ratios (VA/Q), consequent upon gravitational
forces. These result in a higher oxygen tension and poorer lymphatic
drainage at the apices, thereby promoting the development of
tuberculosis at this site. (Redrawn after West.74)

ultimately develop large central areas of necrosis. It is through the

expulsion of this dead tissue through the regional bronchi that the
cavities so typical of the advanced lesions originate.
If the liquefying contents of a cavity escape into the bronchial tree,
the bacilli become widely dispersed to other parts of both lungs, as
in progressive primary tuberculosis. This diffuse bronchogenic infec-
tion gives rise to innumerable small areas of caseous pneumonia,
mostly in the lower lobes, and occasionally, a rapidly developing
confluent tuberculous bronchopneumonia involves almost the whole
lower lobe. Microscopical examination may show tubercle bacilli
and macrophages in very large numbers in the consolidated areas.
Figure 5.3.15  Postprimary tuberculosis. The upper lobe is consolidated
Occasionally, such regions undergo caseation. They may become so
and several large foci of caseous necrosis are evident. Smaller foci are
confluent as to involve a whole lobe. also seen in the lower lobe. (Courtesy of the Curator of the Gordon Museum,
At necropsy, the lungs of a patient with long-standing, progressive, Guy’s Hospital, London, UK.)
postprimary tuberculosis have a characteristic appearance. Large cavi-
ties may replace much of an upper lobe and one or more smaller, but
otherwise similar, cavities may be present in the apical part of the zone may also contain many neutrophils. Outside this zone there is
lower lobe. The cavities may be filled with caseous material (Fig. generally a mantle of satellite tubercles. Still deeper in the wall are
5.3.15) or the contents may have been evacuated through communi- traces of residual parenchyma, often with alveoli obliterated by com-
cating bronchi (Figs 5.3.16–5.3.18). The cavities may be several cen- pression and fibrosis. The cavities enlarge by incorporation of the
timetres in diameter, with walls formed by tuberculous granulation satellite tubercles, more of which are constantly forming more periph-
tissue in which the fibrotic remains of the larger bronchi and of erally (see Fig. 5.3.19). In this way tuberculous granulation tissue
branches of the pulmonary arteries form coarse, irregular bands. extends into the surrounding lung substance as its lining progressively
Usually the disease is bilateral, with similar, but often less advanced, caseates, liquefies and is expectorated. Eventually the process of cavita-
changes in the opposite lung. As in progressive primary tuberculosis, tion may reach the pleura, but perforation into the sac hardly ever
satellite nodules are evident at the advancing edge (Fig. 5.3.19). takes place, for the chronic pleurisy that accompanies the changes
The hilar lymph nodes are less obviously involved in the post­ within the lungs results in the formation of firm adhesions between
primary form of tuberculosis than in the primary form of the disease the visceral and parietal layers, with obliteration of the pleural sac.
but, on histological examination, tuberculous foci, often with small Although the formation of a cavity is a serious development in the
areas of caseation, can generally be seen in them. progress of a postprimary tuberculous infection of the lung, it does
Histological examination of the wall of a cavity usually discloses not represent an irreversible stage in the course of the disease. As long
several zones, each grading into the next. The yellowish-grey lining is as it is small, a cavity may heal by scarring. Ultimately, such a lesion
formed largely of granulation tissue that has undergone caseation but may only be recognisable as an area of fibrosis that stands out from
not yet liquefied. Acid-fast bacilli can generally be seen in this zone: the surrounding parenchyma because of its black pigmentation and
their multiplication there and subsequent escape into the cavity the radiating pale strands of fibrous tissue that pucker the neighbour-
largely account for the high infectivity of the sputum expectorated by ing lung substance. Alternatively, a balance may be achieved whereby
patients with advanced pulmonary tuberculosis. Just deep to this is a the tubercle bacilli are not destroyed but their spread is halted and
zone of granulation tissue containing a profusion of macrophages and the process is held in check, typically by a fibrous capsule forming.
lymphocytes and occasional multinucleate giant cells. If the cavity has Such an encapsulated mass of caseous material is sometimes termed
been infected secondarily by other organisms, as often happens, this a tuberculoma (Fig. 5.3.20). In such quiescent tuberculosis there is no

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 Infectious diseases Chapter |5|

Figure 5.3.16  Postprimary tuberculosis. The caseous contents of this

cavitating upper-lobe lesion have been partially evacuated through
communicating airways. (Courtesy of Dr M Kearney, Tromso, Norway.)

Figure 5.3.17  Postprimary tuberculosis. The upper lobe is replaced by a

inflammation but viable bacilli may survive in the central caseation, large air-filled cavity, its caseous contents having emptied into the lobar
ready to reactivate the disease should host defence weaken. Any bronchus with which the cavity communicates.
granulomatous inflammation in the vicinity of such a lesion indicates
active tuberculosis.
In some cases the cavity acquires an epithelial lining: the epithelial
lining may be of modified respiratory type or squamous. A squamous
Local complications of postprimary lining may be simple or stratified; sometimes keratinisation develops,
pulmonary tuberculosis and the lumen of the cavity may become filled by compressed de­­
squamated cells, the appearances then being reminiscent of an epi-
Pulmonary tuberculosis is often attended by minor episodes of
dermoid cyst. Squamous carcinoma occasionally arises from such
haemoptysis. That the involvement of blood vessels is not more fre-
areas of metaplasia.
quently accompanied by haemoptysis is accounted for by the fact that
Chronic tuberculosis of the lungs is usually accompanied by pleu-
the destructive process usually advances slowly, so that obliterative
risy. Although this begins in the neighbourhood of the most active
endarteritis leads to the closure of the lumen of the pulmonary and
lesions, in time it may extend to involve the whole surface of the lung.
bronchial arteries before their walls have been penetrated. However,
The condition advances slowly, generally without the formation of
caseation sometimes advances too quickly for the artery to become
much exudate; by the time of necropsy the pleural lesions have usually
completely blocked, and an aneurysm may form where the muscular
undergone fibrosis. The damaged lung becomes firmly attached to the
and elastic coats are destroyed on the side nearer the cavity. It is
chest wall – indeed, the fibrosis may be so firm and extensive that the
through the rupture of such aneurysms (Rasmussen’s aneurysms) that
lung can be removed from the body only by dissection outside the pari-
sudden and sometimes fatal haemorrhages occur.
etal pleura. Occasionally, the entire lung may be enclosed by a dense
Large tuberculous cavities may persist indefinitely once the tuber-
white layer of hyaline connective tissue, several millimetres thick.
culous infection has been overcome. If the cavity is not able to drain
freely into the bronchial tree, secretion may accumulate in it and
Extrapulmonary complications of postprimary
predispose to secondary bacterial infection, sometimes with the
formation of a lung abscess. Fungal colonisation may also take respiratory tuberculosis
place, leading to the formation of an aspergilloma or other variety of The proliferation of tubercle bacilli that takes place in the caseating
intracavitary ball colony76 (see p. 231). lining of cavities in the lungs is often so great that it leads to heavy

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 Pathology of the Lungs

Figure 5.3.20  Quiescent tuberculosis forming a ‘tuberculoma’. Growth

of this apical focus of tuberculosis has been halted and its caseous
contents walled off by a fibrous capsule. However, the infection has not
necessarily been overcome as viable bacilli may persist in the caseous
material and reactivate the disease if immunity wanes.

pulmonary tuberculosis via the airways. Occasionally it may mimic a

neoplasm but generally there is just slight destruction of tissue and
the ulceration amounts to little more than loss of epithelium; occa-
sionally, it may extend more deeply and expose one or more rings of
Figure 5.3.18  Postprimary tuberculosis. Tuberculous bronchopneumonia tracheal cartilage. Such tracheobronchial disease was identified in
is seen throughout the lower lobe, the result of aerogenous 42% of cases in the preantibiotic era.77 Subsequently, it was rarely
dissemination of infection from the cavitating focus at the apex of this encountered, until AIDS appeared, since when there have been several
lobe. A further focus of cavitating tuberculosis is seen in the midzone of reports of endobronchial tuberculosis.78–81 Similar infection may
the upper lobe. involve the larynx, particularly the glottis and the aryepiglottic folds;
the subsequent injury to the vocal cords leads both to hoarseness and
to frequent stimulation of the cough reflex.
The passage through the mouth of sputum teeming with tubercle
bacilli may also lead to infection of the oral mucous membrane. Most
commonly, the lesions appear as ulcers on the margin of the tongue:
these are probably initiated by some minor damage to the mucosa
such as results from abrasion by a nearby carious tooth, the resulting
breach in the epithelial surface giving access to the organisms. Once
these ulcers form, they may penetrate deeply into the muscle.
Sometimes, the organisms gain entry to the tonsils and there produce
typical changes.
Unless trained not to do so, many patients with respiratory tuber-
culosis swallow much of their sputum and thus maintain a constant
infection of the alimentary canal. Since tubercle bacilli are relatively
resistant to acid in the concentrations found in gastric juice, they
escape destruction in the stomach and enter the small intestine. The
most typical lesions occur in the lowest 2 m of the ileum; these are
chronic, circumferentially oriented ulcers that begin in, and finally
destroy, Peyer’s patches, and then extend towards the mesentery along
Figure 5.3.19  Postprimary pulmonary tuberculosis progressing by the the mucosal lymphatics.
incorporation of satellite tubercles. Satellite tubercles are evident at Amyloidosis is prone to develop in many cases of slowly progressive
the advancing edge of a chronic caseating focus of infection.
pulmonary tuberculosis. Although many organs become infiltrated
with the amyloid material, renal involvement is the commonest
serious manifestation and the lungs are seldom involved. As in other
infection of the exudate and secretions, most of which are expelled by
forms of secondary amyloidosis, the amyloid is a polymer of the
coughing, sometimes aided by the adoption of a posture that
hepatic acute-phase protein A.
promotes gravitational drainage. These organisms form a potent
reservoir for infection of the upper respiratory tract and of the
Tuberculosis in the elderly and immunodeficient:
alimentary canal.
In advanced cases of chronic respiratory tuberculosis small ulcers, non-reactive tuberculosis
each a few millimetres in diameter, often develop in the tracheobron- In developed countries, miliary tuberculosis is now a commoner cause
chial mucosa,77 as described above under the dissemination of primary of death in the elderly than the young.82 It is thought to result from

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 Infectious diseases Chapter |5|

It is to be remembered that the tissues in this form of tuberculosis

are highly infective. Several cases of tuberculous infection in
laboratory staff, including those working in mortuaries, have been
traced to this source.

Postmortem recognition of pulmonary tuberculosis

It is estimated that many cases of active tuberculosis of the lungs go
unrecognised until necropsy. This is particularly true of the elderly,
whose resistance to the infection is lowered as an accompaniment of
ageing: dormant lesions become active, and spread of the disease
follows, often with little in the way of clinical manifestations to indi-
cate the seriousness of the danger. Similarly, at any age, patients,
whose resistance is lowered by conditions such as lymphoma and
poorly controlled diabetes mellitus, are prone to reactivation of
dormant tuberculosis and vulnerable to exogenous reinfection: often
the presence of the infection is overlooked, even when it is the
Figure 5.3.21  Non-reactive tuberculosis in acquired immunodeficiency immediate cause of death, until disclosed in the postmortem room.
syndrome (AIDS). There is extensive necrosis but no granulomatous Now that the necropsy rate is falling markedly in so many countries,
reaction. Such lesions teem with tubercle bacilli. many cases of active tuberculosis must go unrecognised. The danger
that persists after the patient’s death is that the infection may have
been passed to relatives or associates without awareness of the
need for treatment.

activation of old tuberculous foci, primary or postprimary, as a con- Treatment of tuberculosis

sequence of waning of the immunological defences. In many cases the
disease takes a ‘cryptic’ form,82–84 characterised by insidious onset The treatment of tuberculosis is based on a combination of drugs
and progression, and often lacking any evidence of miliary mottling (classically triple therapy) but is bedevilled by the emergence of
in the chest radiograph. The diagnosis is usually not made until drug-resistant strains, an inability of many countries to provide the
necropsy. Both cryptic and overt miliary tuberculosis in the elderly drugs and poor compliance on the part of the patient.88–91
may be accompanied by changes in the blood, including pancyto­
penia and leukaemoid reactions: these may be the first manifestation
of the illness, and their significance in such cases is sometimes over-
looked. In the elderly, and especially in the immunodeficient, the INFECTION BY OPPORTUNISTIC
disease may be non-reactive. Non-reactive tuberculosis differs from MYCOBACTERIA
ordinary tuberculosis in lacking the usual giant cell granuloma
formation.
At necropsy, disseminated miliary tuberculous lesions are found to Bacteriology
be widespread. Microscopy shows that the lesions comprise foci of The organisms responsible for tuberculosis and leprosy are only two
virtually structureless necrotic matter, sharply defined from the sur- of about 40 species of mycobacteria, most of which live freely in the
rounding tissue, which shows little or no abnormality (Fig. 5.3.21). environment, particularly where water abounds, and seldom infect
There is little or no granulomatous response. Appropriate staining humans. Occasionally, however, especially when resistance is low,
shows that they teem with tubercle bacilli, and, unlike the caseation several of these environmental mycobacteria cause serious disease.92,93
of classic tuberculosis, the necrotic material may contain much Their distinction from M. tuberculosis is important because they require
nuclear debris.41,85,86 Neutrophil polymorphonuclear leukocytes are special drug regimens; they do not respond to antituberculosis treat-
commonly seen. ment. Formerly dismissed as ‘atypical’ or ‘anonymous’, these species
Other forms of non-reactive tuberculosis include diffuse alveolar are better described as the opportunistic mycobacteria. They include
damage and vasculitis. In the former tubercle bacilli are generally M. marinum and M. ulcerans, the causes of swimming-pool granuloma
demonstrable in the hyaline membranes86 while in the latter they and Buruli ulcer respectively, and a group that causes disease that is
teem within the vessel walls. very like tuberculosis. In infection by members of the latter group, as
Non-reactive tuberculosis is the result of a deficiency in the body’s in tuberculosis itself, the lungs are the organs most often involved and
cellular defences. In some cases it develops as a complication of there may be spread to lymph nodes, bone, meninges, kidneys and
lymphoid neoplasia, particularly Hodgkin’s disease and leukaemia. elsewhere, or massive dissemination throughout the body akin to
In other cases it has followed treatment with immunosuppressant miliary tuberculosis. The similarity to tuberculosis is also seen in that
drugs. More recently it has been seen in patients suffering from the gastrointestinal tract is another important portal of entry.94
AIDS.41,87 Often, however, no predisposing cause is found; such The commonest opportunistic mycobacteria infecting the lungs are
patients are generally elderly. M. avium-intracellulare, M. kansasii and M. xenopi. Less frequent causes
If the diagnosis of non-reactive tuberculosis is suspected during life, of tuberculosis-like disease are M. scrofulaceum, M. malmoense, M.
tubercle bacilli should be looked for in films of bone marrow. Biopsy szulgai, M. simiae, M. chelonei, M. fortuitum and M. gordonae. M. avium-
may be helpful; any suggestion of a tuberculous reaction is potentially intracellulare and M. scrofulaceum are often said to comprise the MAIS
an important diagnostic guide. When any biopsy section includes complex. They are all acid-fast but, unlike M. tuberculosis, many of
unexplained areas of necrosis, particularly when there is little in the them can also be demonstrated with periodic acid–Schiff and Grocott’s
way of a related cellular reaction, it is imperative to look for tubercle stains. M. kansasii has a distinctive shape, being long, broad, beaded
bacilli. and bent.95 Species-specific probes are available.96,97

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 Pathology of the Lungs

Infection with these organisms comes from the environment, in

contrast to tuberculosis, which is always transmitted from an infected
individual. The infection rate of tuberculosis in the community bears
a direct relation to the number of infectious cases but this is not
the case with the opportunistic mycobacteria. The prevalence of
opportunistic mycobacterial infection in a community is independent
of that of tuberculosis and is not controlled by public health
measures aimed at reducing the spread of tuberculosis.

Interpretation of cultured isolates

The interpretation of cultured isolates must always take account of the
possibility that specimens may be contaminated with opportunistic
mycobacteria from the environment. Whereas M. tuberculosis is an
obligate parasite and its isolation indicates tuberculosis, the culture
of opportunist mycobacteria does not necessarily indicate that they
are the cause of the disease being investigated. Their isolation from
granulomatous tissue strongly suggests that they have played a
causative role, but sputum isolates need to be obtained consistently
over a period of weeks, and other causes of granulomatous disease,
especially tuberculosis, thoroughly excluded before a clinical Figure 5.3.22  Mycobacterium avium-intracellulare infection. There is
diagnosis of opportunistic mycobacterial infection can be advanced necrotising granulomatous inflammation similar to that seen in
with confidence. tuberculosis.

Predisposing causes
5.3.22), but there is more airway involvement leading to bronch­
Factors predisposing to opportunistic mycobacterial infection may be
iectasis117–119 and a higher proportion of cases that lack the classic
general or local.98 General factors include any congenital or acquired
granulomatous response.120 In one study, four histological features
immunodeficiency, but especially AIDS,94,99,100 therapeutic immuno-
were identified that favoured non-tuberculous mycobacterial infec-
suppression and autoimmune disease. Local factors include pneumo-
tion: the presence of microabscesses, the granulomas being ill defined,
coniosis, chronic bronchitis, cystic fibrosis, bronchiectasis and old
an absence of necrosis and a comparatively small number of giant
tuberculosis. The virulence of mycobacteria is enhanced by lipid101 and
cells,121 but these are not absolute points of distinction.
the growth of opportunistic mycobacteria, especially M. fortuitum-
Granulomatous disease indicates a strong immune response and
chelonei, appears to be promoted by lipid pneumonia.102–104 The aspira-
the mycobacteria are then scanty, as in classic tuberculosis. However,
tion of milk may explain an observed association between achalasia
in very severe immunodeficiency, as for example AIDS, the lesions
and M. fortuitum-chelonei infection.105,106
may consist of numerous swollen macrophages, all of which contain
Only rarely is no predisposing cause recognised.107,108 Although
large numbers of acid-fast bacilli (Fig. 5.3.23). Necrosis is not seen
some impairment of host defence is generally necessary for these
and granulomas are poorly formed or absent. The changes then resem-
bacteria to establish themselves in humans, heavy exposure may result
ble those of lepromatous leprosy94 or, if the macrophages are spindle-
in healthy individuals being infected. An example of this is the
shaped, inflammatory myofibroblastic tumour (see p. 620).122–125 A
increasingly frequent presentation in affluent, non-immunocompro-
leproma-like pattern has also been described in disseminated BCG
mised individuals of diffuse lung disease due to the inhalation of
infection but is unusual in non-reactive tuberculosis126 which is char-
aerosols from hot tubs and showers heavily infected by these bacteria.
acterised by sheets of necrosis unattended by the usual granulomas,
However, there are suggestions that this may represent extrinsic
the tubercle bacillus being more toxic to the macrophage than the
allergic alveolitis rather than infection.96,109–114
opportunistic mycobacteria.127
Despite the above, there appears to be an increasing incidence of
infection by opportunistic mycobacteria in persons who are not obvi-
ously immunodeficient or heavily exposed. These individuals are Treatment
often women and it has been suggested that their infection may be The treatment of opportunist mycobacteriosis is less well defined than
due to them suppressing their cough reflex for reasons of societal for tuberculosis, there being few large clinical trials. However, the
etiquette, an unlikely scenario but one that has nevertheless entered British Thoracic Society has published a set of guidelines.97
the medical argot as the Lady Windermere syndrome, a term taken
from the fastidious character of the same name in Oscar Wilde’s play
Lady Windermere’s Fan.115 A survey of such patients found that they
were taller and leaner than controls, had high rates of scoliosis, pectus BRUCELLOSIS
excavatum, mitral valve prolapse and mutation of the cystic fibrosis
transmembrane conductance regulator gene. This categorised the Pneumonia is a rare form of brucellosis but has been reported in
condition as one of women with a complex pre-existing morpho­ countries such as Kuwait and Arabia128,129 where this zoonosis is
type, suggesting that there was an underlying genetic defect.116 endemic, and in farmers and meat packers in North America and
Europe.130,131 Cattle, sheep, goats and camels are common sources of
Pathological changes infection, which is usually acquired by consuming unpasteurised milk
or milk products. Close contact with infected animals or their
The pathological changes produced by opportunistic mycobacteria are carcasses may also be responsible for transmission of the disease to
generally very similar, if not identical, to those of tuberculosis (Fig. humans, either orally or, in the case of pneumonia, by inhalation.

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Patients with Brucella pneumonia develop a cough productive of

mucopurulent sputum or present with fever of unknown cause.132
Perihilar or peribronchial infiltrates, or less frequently coin lesions,
are evident radiographically. Pleural effusion with a predominance of
monocytic or lymphocytic infiltrates is also described.133
Histology shows necrotising epithelioid and giant cell granulomas,
very similar to those of tuberculosis.128,134,135 Diagnosis is dependent
upon excluding tuberculosis and identifying brucellae by culture or
brucellar DNA by polymerase chain reaction in blood or tissue.135
Examination of sputum and bronchial washings is generally
unrewarding.

CHRONIC MELIOIDOSIS
A
The general features and acute form of melioidosis have been described
on page 186. Chronic melioidosis is acquired in the same way as the
acute form and may represent persistence or recrudescence of acute
disease or arise insidiously in someone unknown to have had acute
disease. The disease progresses gradually over months or years. It takes
the form of localised lesions that may affect any organ but most
commonly involve the lungs, where chronic cavitatory melioidosis
may closely mimic tuberculosis apart from relative sparing of the
apices.136–138 Pleural effusion and empyema are less common in
chronic than acute disease. Before cavitation takes place, microscopy
shows areas of necrosis surrounded by granulomatous inflammation.
The central necrotic zones are often stellate, and may be suppurative
or caseous. The surrounding granulomatous reaction consists of
epithelioid and Langhans giant cells and is itself encompassed by a
fibrous mantle. When necrosis is suppurative, the histological features
mimic those of cat scratch disease or lymphogranuloma venereum,
and, especially in the lungs, tularaemia (see p. 187) or sporotrichosis
B (see p. 244). When the necrosis is caseous, the histological picture is
very similar to that of tuberculosis. In contrast to the acute form of
the disease, the causative bacterium (Burkholderia pseudomallei) can be
difficult to demonstrate in tissue sections (see p. 186 for staining
methods). The diagnosis is then largely dependent upon serological
techniques.

ACTINOMYCOSIS

Bacteriology
Actinomycetaceae (which include the genera Actinomyces, Nocardia
and Rhodococcus) and Mycobacteriaceae (which include the genus
Mycobacterium) are both families of the order Actinomycetales.
Although Actinomycetales are classed as bacteria and mycobacterial
diseases are invariably considered among bacterial infections, some
C of the pathogenic Actinomycetaceae are often mistakenly referred to
as fungi and the diseases they cause are commonly grouped with those
Figure 5.3.23  Mycobacterium avium-intracellulare/M. scrofulaceum caused by the true fungi under the general heading of mycoses. It will
(MAIS complex) infection in a patient with acquired immunodeficiency be difficult to correct this misconception, particularly in view of such
syndrome (AIDS). Whereas the tissue reaction to opportunistic entrenched nosological nomenclature as actinomycosis, which by
mycobacteria is usually identical to that seen in tuberculosis, in the virtue of the ending ‘-mycosis’ – its etymology is usually mis­
immunodeficient it resembles the lepromatous form of leprosy, consisting interpreted – is unlikely to be displaced from its common association
of numerous macrophages with abundant pale cytoplasm (A); Ziehl–
with the true mycoses, in spite of other well-understood termino­
Neelsen staining demonstrates that this contains innumerable acid-fast
bacilli (B). (C) Alternatively, the macrophages may be spindle-shaped and
logical paradoxes and pitfalls such as mycosis fungoides and mycotic
the cytoplasm eosinophilic, resulting in an appearance simulating aneurysm. However, as well as differing from fungi in size, structure
inflammatory myofibroblastic tumour. and metabolism, the Actinomycetaceae are susceptible to anti­
bacterial agents and resistant to specifically antifungal drugs.
Actinomyces israelii is by far the most frequent cause of actinomy­
cosis in humans. A. bovis, the cause of actinomycosis in cattle, is an

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 Pathology of the Lungs

exceptionally rare cause of the disease in humans. Other species that

occasionally cause actinomycosis in humans include A. eriksonii,
A. meyerii and A. naeslundii. A. propionicus (Arachnia proprionica), an
organism closely related to Actinomyces israelii, also causes disease
indistinguishable from actinomycosis.
A. israelii is a strictly anaerobic, Gram-positive bacterium, formed
of branching filaments 0.5–1.0 µm wide. The filaments readily break
into bacillus-like fragments. They are not acid-fast. Like those of the
nocardiae (see below), fragments of the Actinomyces may be mistaken
for contaminant corynebacteria.
A. israelii is a common commensal or saprophyte in the human
mouth and intestine and it is probable that most infections by this
organism are endogenous. About 60% of cases of actinomycosis
present with lesions in the region of the mouth, face or neck, the
portal of entry being dental or tonsillar. About 25% of cases of actino-
mycosis involve the ileocaecal region and in the remaining 15% of
cases the infection is in the lungs. It is presumed that pulmonary
actinomycosis is the outcome of aspiration of infected matter from
the tonsillar crypts or mouth, apart from the very small proportion of
cases in which the disease has extended from known foci of infection A
in the abdomen. The diagnosis should therefore be particularly sus-
pected in patients with dental caries or a history of unconsciousness
with aspiration. The incidence of actinomycosis is in decline, probably
due to a combination of improved dental hygiene and the early initia-
tion of antibiotic therapy, the bacterium being highly sensitive to
penicillin.
Most cases of actinomycosis are of mixed microbial aetiology, the
pathogenicity of Actinomyces being enhanced by the synergistic action
of other bacteria, notably microaerophilic streptococci, other anaer-
obes such as Bacteroides and Fusobacterium, and aerobic streptococci
and staphylococci. Actinobacillus actinomycetem comitans is another
constituent of the mouth flora – one that is seldom recovered in pure
culture139 but is often found in association with Actinomyces israelii in
actinomycotic lesions. It secretes a powerful leukotoxin which prob-
ably contributes to the virulence of these mixed infections.

Clinical features
Pulmonary actinomycosis is promoted by poor dental hygiene, B
smoking and heavy drinking140 and is recorded in AIDS.141 It is usually
a disease of adults, though may rarely occur in children.142,143 It is Figure 5.3.24  Actinomycosis. (A) Computed tomography shows a mass
characterised by fever and expectoration of mucopurulent sputum. in the right middle lobe extending through the chest wall and mimicking
Contrary to a common belief, ‘sulphur granules’ – the yellow colonial an invasive carcinoma. (B) The lobectomy specimen shows colonies of
granules of the organisms – are not often to be found in the sputum. Actinomyces (arrow) within abscesses that extend into the fat of the
Haemoptysis is a significant complication and may require surgical chest wall.
treatment.144 The diagnosis depends on recognition of the fine, Gram-
positive, sometimes branching filaments in films, and isolation of the should be confirmed by culture and, because A. israelii is a strict
organism. It has to be remembered that the organism may be present anaerobe and will die on exposure to atmospheric oxygen, prompt
in sputum only in short bacillary forms that are liable to be mis­ delivery to the laboratory for appropriate processing is imperative.
interpreted. The chest radiograph may show opacities of various sizes
scattered through both lungs, particularly in the middle and lower
zones. Alternatively, there may be a large pneumonic area, sometimes Pathological findings
associated with an empyema: this type of disease may be accompanied Actinomycosis of the lungs typically affects the lower lobes but may
by new bone formation on the inner aspects of several contiguous ribs involve any part. Characteristically, the affected tissue is riddled with
due to elevation of the periosteum by the inflammatory infiltrate. chronic abscesses that range in diameter from a few millimetres to 3
Occasionally, infiltration of the chest wall suggests malignancy (Fig. cm. These lesions may communicate with one another, drain into
5.3.24). The presence of discharging sinuses on the chest wall is char- the bronchial tree or extend to the pleural surface and open into the
acteristic of advanced thoracic actinomycosis145 but this stage is pleural sac. ‘Sulphur granules’ are often to be found within the
seldom encountered today.146,147 It is in the pus discharging from these abscesses. These colonies of Actinomyces consist of numerous radiating
sinuses that the ‘sulphur granules’ referred to above are to be found. bacterial filaments that often terminate in a prominent cap of eosi-
Recent series have been characterised by less specific features that have nophilic material that represents immune material, a reaction known
suggested tuberculosis or cancer.140,141,148 The diagnosis has often been as the Splendore–Hoeppli phenomenon (Fig. 5.3.25). Fibrosis sur-
made only after lung tissue has been resected, but may be possible by rounds the suppurative foci and extends more widely through the
biopsy, particularly when the process involves major airways.141,149 It lungs, particularly involving the septa. The infection may spread to

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N. asteroides does not form macroscopically evident colonial granules

in infected tissues.

Clinical features
Nocardiosis is typically acquired by inhalation but may extend beyond
the respiratory tract. Infection may develop in a previously healthy
person,153 but in most cases there are predisposing factors, particularly
those that compromise cellular immunity.154–157 The disease is ordi-
narily chronic but may progress rapidly in the severely immuno­
compromised. Predisposing factors include diseases such as leukaemia
and AIDS that interfere with resistance, therapeutic agents such as
corticosteroids and cytotoxic drugs that similarly suppress immunity
and underlying pulmonary diseases, including alveolar lipoprotein­
osis.158,159 The overall incidence of nocardiosis appears to be rising,
probably in the main because of the increasing use of the drugs that
predispose to its occurrence. The disease is commoner in adults than
Figure 5.3.25  Actinomycosis. Pus containing a colony of Actinomyces children.
surrounded by an eosinophilic mantle of immune material. The Pulmonary nocardiosis causes fever and cough productive of thick,
eosinophilic mantle is known as the Splendore–Hoeppli phenomenon, sticky, purulent sputum that may be streaked with blood. The radio-
although neither of these workers recognised its true nature. Splendore logical findings vary from minor infiltrates to extensive consolidation,
described the eosinophilic material around Sporotrichum in 1908 and
sometimes with abscess formation or empyema.160,161 Less commonly,
erroneously assumed that it was a new species, while Hoeppli described
nocardiosis results in bronchial obstruction.162–164
the same material around schistosomes in 1932 and erroneously
suggested that it was secreted by the parasite. The material is now
considered to consist of immunoglobulin, complement and cellular
debris. It is especially striking in actinomycosis, botryomycosis and various Pathological findings
fungal infections, but may also be seen around parasites such as
schistosomes and helminths, and even around foreign material. In general, the picture of nocardiosis is that of suppuration, with the
development of multiple abscesses. The lesions have a notable ten-
dency to confluence. Pulmonary nocardiosis may affect one or both
lungs widely, with extensive consolidation round the suppurative foci:
the pleura and on into the spine and ribs, whether or not there is an the exudate in the alveoli of these pneumonic foci initially contains
actinomycotic empyema: the latter may be loculated or involve the much fibrinogen, and a fibrin coagulum forms, often with relatively
entire pleural sac. Obliteration of the sac prevents empyema forma- little leukocytic involvement. The organisms are present in the exudate,
tion but does not present a barrier to the infection as it spreads out- and may be very numerous. Their number is often only inadequately
wards to involve not only the thoracic skeleton but also the soft tissues disclosed by Gram or Ziehl–Neelsen stains: the Grocott–Gomori
and skin of the chest wall, often with the establishment of the draining method is generally more reliable (Fig. 5.3.26).165 Healing may result
sinuses that are a classic, if rare, feature of the disease. Actinomycotic in extensive organising pneumonia.166 Rarely, pulmonary nocardiosis
bacteraemia is uncommon but arises more frequently from pulmo- may take the form of an intracavitary nocardioma167 or invade con-
nary foci than from any other form of actinomycosis; it may give rise tiguous vertebrae and compress the spinal cord.168 N. asteroides has a
to metastatic abscesses in other viscera, the skeleton or soft tissues. particular affinity for the central nervous system; nocardial brain
Actinomycosis is occasionally complicated by amyloidosis. abscess and nocardial meningitis are frequent complications of
pulmonary infection. Coexisting microbial agents are commonly
identified. Treatment of nocardiosis is generally medical, typically
employing sulphonamides or co-trimoxazole. Abscesses and empyema
NOCARDIOSIS may require additional surgery.

Bacteriology
Nocardiosis is caused by several genera of aerobic Actinomycetaceae.
Nocardia asteroides is the usual cause: N. brasiliensis and N. caviae are RHODOCOCCUS PNEUMONIA
less common human pathogens. None of these is part of the normal
human flora. They are soil saprophytes that are often found in decay- Rhodococcus equi (formerly Corynybacterium equi) is an aerobic, Gram-
ing organic matter and human infection is exogenous. Nocardia were positive and acid-fast bacillus belonging to the order Actinomycetales,
first identified in cattle suffering from farcy in 1888.150 Human disease and is therefore closely related to the mycobacteria and Nocardia. Its
was described shortly afterwards.151,152 natural habitat is the soil and its transmission is aerogenous. It is best
In contrast to A. israelii, N. asteroides is an aerobic bacterium. It is known as a pathogen in foals, cattle, swine and sheep, where it is a
formed of filaments measuring 0.5–1.0 µm in width, which are so lethal cause of suppurative granulomatous pneumonia, lympha­
highly branched that they have been likened to Chinese characters. denitis, mediastinitis and pyometra. It has only recently been recog-
They often break into bacillus-like fragments during preparation of nised as pathogenic to humans. Human infection often follows
films of infected exudate. They are Gram-positive but often weakly so, exposure to farm animals or to stockyards contaminated with animal
and although commonly acid-fast, they are seldom as strongly so as excreta. Virtually all Rhodococcus-infected patients have been severely
tubercle bacilli and they are not alcohol-fast; silver impregnation immunocompromised, typically suffering from AIDS, of which it is
methods offer the best means of demonstrating this organism in tissue an infrequent complication.169 The clinical presentation is often in­­
sections. In contrast to A. israelii, and to N. brasiliensis and N. caviae, sidious, consisting of fatigue, fever and a non-productive cough.

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 Pathology of the Lungs

Figure 5.3.27  Malakoplakia. A mass lesion composed of histiocytes with

abundant eosinophilic cytoplasm. Occasional Michaelis–Gutman bodies
are evident (arrows).

in the lungs Rhodococcus equi (formerly Corynebacterium equi) is gener-

ally involved, although rare cases associated with other infections are
described.184 Rhodococci are Gram-positive coccobacilli that may be
mistaken for commensal diphtheroids in sputum. They are sometimes
acid-fast. R. equi has been recognised as an agent causing broncho­
pneumonia in horses and other domesticated animals since its first
isolation from infected foals in 1923. Its habitat is the soil. Infection
of both humans and beasts is thought to be acquired through the
lungs. Human infection almost always involves patients who have
B defects in cell-mediated immunity. A history of exposure to animals
is not invariably obtained.
Figure 5.3.26  Nocardiosis. Pus containing colonies of basophilic nocardia
(A), which are better demonstrated by Grocott staining (B).
Pathological and clinical features
Malakoplakia of the lungs may form solitary or multiple bilateral
lesions, mimicking either primary or metastatic neoplasms radiologi-
R. equi infection causes pneumonic consolidation with abscesses. cally. The gross appearances also mimic neoplastic disease. The lesions
The disease typically affects the upper lobes and may simulate are well demarcated, firm and either solid or cavitating. Microscopically,
tuberculosis radiologically.170–172 Spread to sites such as the brain and the lung tissue is replaced by sheets of swollen macrophages with
bone may occur. The inflammation is histiocytic in nature and may abundant eosinophilic, granular or vacuolated cytoplasm that stains
result in pulmonary malakoplakia. well with periodic acid–Schiff reagents and is diastase-resistant. The
appearances may suggest a granular cell tumour (see p. 640). A char-
acteristic feature is the presence of Michaelis–Gutman bodies in the
Malakoplakia macrophage cytoplasm or free between the cells. These are faintly
Malakoplakia is a rare inflammatory disorder characterised by tumour- basophilic, round, target-like structures that measure up to 20 µm
like accumulations of swollen macrophages. It usually affects im­­ diameter (Fig. 5.3.27). They contain calcium and are therefore well
munocompromised persons and is due to a defect in macrophage shown by von Kossa’s stain. The Michaelis–Gutman bodies represent
function.173 Bacteria are ingested normally but are not killed within mineralised bacteria-containing phagolysosomes.183 Aggregates of
the cell, suggesting that the fault lies in the lysosomes. Malakoplakia bacteria can sometimes be demonstrated within macrophages by
usually affects the lower genitourinary or gastrointestinal tracts and Gram stains.
until recently few cases had been described with lung involvement.
However, several cases of malakoplakia confined to the lungs have
now been described, chiefly in the setting of AIDS but also associated
with general debilitation, organ transplantation, haematopoietic
SYPHILIS
malignancy and alcoholism.170,171,174–183
Syphilitic lesions have never been particularly frequent in the lungs,
and congenital pulmonary syphilis (‘pneumonia alba’) has probably
Bacteriology always been the commonest manifestation. However, there has
Malakoplakia is associated with infection by various bacteria and recently been an increase in syphilis and its protean manifestations
fungi. In the urinary tract the organism is usually Escherichia coli but should not be forgotten.185,186

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 Infectious diseases Chapter |5|

Congenital pulmonary syphilis small or large. They may occur in the trachea and bronchi as ulcerative
lesions, with a tendency to destroy the cartilage of the wall. These
The pallor and firmness of the lungs, which are larger than normal, cause cough and haemorrhage whereas gummas in the lung substance
account for this condition’s old name, pneumonia alba. It is usually may be clinically silent.
seen in stillborn syphilitic babies or those who die within a few hours Bronchopulmonary gummas have the structure that is common to
of birth: in the latter, the aerated lobules stand out above the indu- these lesions wherever they occur in the body. They consist of a
rated parts. Microscopically, there is widespread thickening of the necrotic core surrounded by granulation tissue that is heavily
alveolar walls by fibroblastic connective tissue accompanied by an infiltrated by plasma cells and lymphocytes with scanty giant cells.
accumulation of plasma cells with some lymphocytes. In places there Satellite lesions, as seen in tuberculosis, are not a feature. As
are microscopical foci of necrosis, maybe with histiocytic proliferation elsewhere, gummas tend ultimately to produce dense scars that
round them, as well as some accumulation of neutrophils: these contract and produce deep cicatricial fissures in the surface of the
lesions occasionally merge to form gummatous foci that may be lungs, an appearance comparable to that of the classic hepar lobatum
evident macroscopically. Usually there is a conspicuous lining of of tertiary syphilis.
cuboidal type II alveolar epithelial cells and many alveoli may be filled It is very important to consider and exclude other types of infection,
with macrophages. Silver impregnation methods show the presence particularly mycobacterioses and mycoses, before a diagnosis of
of great numbers of treponemes in the tissues. The bacteria may also gumma can be sustained, even when the patient’s serological tests
be demonstrated immunohistochemically.187 Imaging may show indicate the presence of syphilis. Moreover, primary and secondary
diffuse pulmonary infiltrates, which persist long after adequate tumours are commoner causes of discrete shadows in chest radio-
antibiotic treatment.188 graphs than gummas, even in patients with syphilis. The necrotic
Somewhat similar macroscopical and microscopical changes may pulmonary lesions of Wegener’s granulomatosis and even pulmonary
result from viral infections in the neonatal period. Also, Pneumocystis infarcts are among other conditions to be considered in the differ­
pneumonia may be mistaken for syphilitic pneumonia in those cases ential diagnosis.
in which interstitial accumulation of plasma cells is particularly Other thoracic manifestations of acquired syphilis include diffuse
marked (see p. 226). pulmonary fibrosis of non-specific character, hilar lymphadenopathy
and pleural fibrosis.185,186
Acquired pulmonary syphilis
Gummas and interstitial fibrosis are the manifestations of acquired
syphilis in the lungs. The gummas may be solitary or multiple, and

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5.4  Fungal infections

CHAPTER CONTENTS Rare pulmonary mycoses 243

Torulopsosis 244
Pneumocystosis 223
Sporotrichosis 244
Aspergillosis 226
Adiaspiromycosis 244
Predisposing causes and types of pulmonary
Malasseziosis 244
aspergillosis 228
Pseudallescheriosis (monosporiosis) 244
Saprophytic aspergillosis 231
Penicillium marneffei infection 245
Aspergilloma 231
Microsporidiosis 245
Obstructive aspergillosis 233
References 245
Invasive and septicaemic aspergillosis 233
Invasive aspergillosis 233
Septicaemic aspergillosis 233
Chronic necrotising Aspergillus pneumonia In certain regions of the world, environmental soil conditions
(acute cavitary pulmonary aspergillosis) 233 support the saprophytic phase of pathogenic fungi such as Histoplasma
Pseudomembranous Aspergillus capsulatum, Blastomyces dermatitidis, Coccidioides immitis and
tracheobronchitis 234 Paracoccidioides brasiliensis that are able to cause disease in previously
Mucormycosis 234 healthy people. Other fungi invade the tissues only because of lower-
Candidosis (moniliasis) 235 ing of the patient’s resistance by some other disease or as a side-effect
of treatment. Some of the fungi that cause these so-called opportun-
Cryptococcosis 236
istic infections are seldom, if ever, responsible for illness in healthy
Histoplasmosis 238 individuals: this is particularly so of mucormycetes. Others cause
Primary pulmonary histoplasmosis 239 disease in healthy individuals of a type very different from the progres-
Histoplasmoma 239 sive, destructive, disseminated infection that they set up in those
whose resistance has been reduced: asthma from sensitisation to
Cavitary histoplasmosis 239
aspergilli and saprophytic growth in previously formed cavities are
Acute (‘epidemic’) pulmonary histoplasmosis 240 examples of such disease.
Progressive disseminated histoplasmosis 240 Many fungi that infect humans are dimorphic – that is, they grow
Fibrosing mediastinitis 240 as yeast-like organisms at certain temperatures and in mycelial form
African histoplasmosis 240 at others. Sporulating conidiophores (or ‘fruiting heads’) form on the
mycelial hyphae when oxygen is plentiful and release spores into the
Coccidioidomycosis 241 atmosphere. The spores are particularly likely to be inhaled and
Blastomycosis (‘North American’ blastomycosis) 242 germinate into hyphae in the lungs. The size and shape of the fungus
Paracoccidioidomycosis (’South American in its various forms often enable the histopathologist to identify
blastomycosis’) 243 the genus (Box 5.4.1) but speciation generally requires culture.

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Czechoslovakia in the years immediately after the war.4,5 Subsequently

Box 5.4.1  Microscopical differentiation of common fungi it has been recognised that the human pathogen is a separate species,
in lung tissue P. jirovecii. Although pneumocysts were long thought to be protozoal,
they are now regarded as a primitive fungus in which the mycelium
Yeasts is reduced to a unicellular state but is still able to sporulate.6–8 Despite
Small this, various forms of the fungus are still referred to as sporozoa or
Pneumocystis trophozoites, as if it was a protozoa.
Histoplasma Electron microscopy6,9–12 provides an insight into the structure of
Torula the organism and the pathogenesis of Pneumocystis pneumonia. It
Medium-sized shows that the organism forms cysts measuring 3–6 µm in diameter,
Candida which have a thick wall or pellicle (Fig. 5.4.1). The pellicle is particu-
Cryptococcus larly thick at one point, a feature that is evident by light microscopy
Blastomyces in silver-stained preparations as a peripheral dot on the cyst wall. The
Paracoccidioides pellicle is triple-layered, consisting of an outer electron-dense zone
about 75 nm thick, an electron-lucent intermediate zone 250 nm
Large
thick and an inner 7-nm membrane. Numerous small tubular struc-
Coccidioides
tures are associated with the inner layer. Up to eight nucleated
Hyphae intracystic bodies or sporozoa are also probably derived from this
Short membrane. These are released when the cyst ruptures (Fig. 5.4.2).
Candida (pseudohyphae) Collapsed cysts are largely empty and the innermost membrane of the
Long and regular wall is either detached or absent. The released sporozoa grow from
about 1.5 to 6 µm, have a thin pellicle and are highly irregular in
Aspergillus
shape (Fig. 5.4.3). They are now known as trophozoites and possibly
Long and irregular undergo binary fission before entering a precyst stage in which their
Mucormycetes pellicles thicken (Fig. 5.4.4).
Cysts tend to be sparse near the alveolar walls, which are bordered
chiefly by trophozoites, suggesting that limitation of some nutritional
factor promotes cyst formation. In successfully treated cases only
empty cysts are found, indicating that all viable forms of the parasite,
whether free-living or encysted, are vulnerable to chemotherapy.
The ease and frequency of international travel make many hitherto Although there is not a heavy cellular reaction within the alveoli, cysts
‘exotic’ diseases the immediate practical concern of doctors who have and trophozoites may fill these air spaces.
no personal experience in their recognition and management. The fact Electron microscopy also shows that the trophozoites attach to type
that fungi which are frequently the cause of disease in other parts of I alveolar epithelial cells, eventually causing these cells to slough away
the world are not indigenous where the doctor is in practice is no from the alveolar walls.13 Tracer studies show that there is increased
longer an excuse for not considering the possibility that a patient may permeability in the lung, even before epithelial cells are lost.14 In
have acquired infection while visting another country or through severe cases, trophozoites are observed within the alveolar inter­
exposure to contaminated, imported materials. Neither histo­ stitium. From here they may gain access to the blood stream and
plasmosis nor coccidioidomycosis, for instance, occurs naturally in disseminate widely.15
western Europe, yet every year in countries such as the UK patients
are seen whose symptoms are due to these diseases: the cardinal
importance of the patient’s geographical history, and of the doctor’s
knowledge of geographical medicine, is self-evident.
Epidemiology
The epidemic Pneumocystis pneumonia mentioned above as a feature
of malnourished children is no longer seen in Europe but is still
encountered in parts of the world where poverty and malnutrition are
PNEUMOCYSTOSIS1,2 rife. Pneumocystis pneumonia is also recognised as a complication of
immunodeficiency states, both congenital and acquired. Until the
appearance of the acquired immune deficiency syndrome (AIDS),
Microbiology such immunodeficiency was generally due to lymphoproliferative
Pneumocystosis is caused by organisms discovered in the early twen- disease or immunosuppressive therapy but interest now centres on
tieth century by Chagas and soon after by Carini. They both thought Pneumocystis pneumonia as being by far the commonest opportunistic
the organism to be a stage in the life cycle of trypanosomes as they infection in AIDS (see Table 5.1.1, p. 167). P. jirovecii is kept in check
found it in the lungs of rats experimentally infected with trypano- by T lymphocytes and suppression of these cells, as in AIDS, allows
somiasis. The Delanoës recognised that it was a distinct species, the parasite to proliferate and cause pneumonia. In very severe
Pneumocystis carinii. Pneumocystis organisms were first identified as a T-lymphocyte depletion extrapulmonary dissemination is found (see
cause of human disease in 1942, in Belgium, in association with cases below). Patients who have undergone heart/lung transplantation are
of the condition, previously of unknown causation, that had been also at risk of developing Pneumocystis pneumonia,16 as are those with
described in 1937 as interstitial plasma cell pneumonia. Outbreaks of cancer.17 Whatever the cause of the immunoparesis, Pneumocystis
the latter occurred during the Second World War, and for some years pneumonia in immunodeficient individuals lacks the intense plasma
after, in orphanages and other institutions that housed malnourished cell infiltration seen in malnourished children.
children, particularly in eastern Europe and the Middle East.3 The Antibodies to P. jirovecii can be detected in most of the population
causative role of the Pneumocystis in this type of pneumonia in young by the age of 4 years18 but the absence of the organism from normal
children was generally recognised following work of Jirovec in lungs suggests that the pneumonia represents reinfection rather than

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 Pathology of the Lungs

Figure 5.4.1  Pneumocystis jirovecii. Cyst form. The cyst wall has three Figure 5.4.3  Pneumocystis jirovecii. Trophozoites. These are irregular in
layers: an outer electron-dense zone about 75 nm thick, an electron- shape and have a thin unit membrane wall. Electron micrograph.
lucent intermediate zone 250 nm thick and an inner 7-nm membrane. (Reproduced from Corrin & Dewar 1992.12)
Numerous small tubular structures are associated with the inner layer,
which also spawns up to eight intracystic bodies or sporozoites, one of
which is visible here. Electron micrograph. (Reproduced from Corrin & Dewar
B
(1992).12)

A
C

F D

E
Figure 5.4.2  Pneumocystis jirovecii. Collapsed cyst releasing its contents.
Electron micrograph (Reproduced from Corrin & Dewar (1992).12)

reactivation.8,19,20 Infection is presumed to be by inhalation from an

as yet poorly characterised environmental source. Although P. jirovecii Figure 5.4.4  Proposed life cycle of Pneumocystis jirovecii. (A) Cystic form
has been found in a wide range of animals it shows host specificity containing two intracystic bodies. Note the focal thickening of the
pellicle. (B) Discharge of cyst contents and collapse of the cyst.
and is the species prevalent in humans.
(C–E) Trophozoites, which possibly undergo binary fission. (F) Trophozoite
Autopsy in cases of Pneumocystis pneumonia presents no danger in precystic stage.
except in AIDS where there is a possibility of mortuary staff being
infected by the HIV virus.
with mounting tachypnnoea, hypoxaemia and cyanosis. Radiographs
typically show widespread bilateral opacification. Late features include
Clinical features calcification, cavitation and pneumothorax. Diagnosis requires dem-
Pneumocystis pneumonia is characterised by breathlessness, cough and onstration of the organisms, for which sputum production is generally
fever, generally of insidious onset. Untreated, the disease progresses induced by the inhalation of a saline aerosol or bronchoalveolar

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Figure 5.4.6  Pneumocystis jirovecii pneumonia. The alveoli are filled by a

foamy exudate and the alveolar walls are thickened by a lymphoid
infiltrate.

Figure 5.4.5  Pneumocystis jirovecii pneumonia. The lung shows diffuse Figure 5.4.7  Pneumocystis jirovecii demonstrated by Grocott’s
methenamine silver stain. The smaller group includes crescentic forms
consolidation. (Courtesy of the late Dr AA Liebow, San Diego, USA and Dr T
representing collapsed cysts and other cysts that show a characteristic
Jelihovsky, Sydney, Australia.)
dot representing focal thickening of the cyst wall.

lavage is undertaken.21 The organisms may be demonstrated with have not been successfully differentiated in the staining procedure,
toluidine blue, Giemsa stain, Grocott’s methenamine silver stain or especially if bronchial washings or bronchoalveolar lavage fluids are
by immunofluorescence, but detection of Pneumocystis DNA by the being examined and the topographical features provided by a biopsy
polymerase chain reaction is much more sensitive.22–28 cannot be studied. Another helpful feature is a dot, generally seen on
the edge of the cyst (see Fig. 5.4.7); this represents a focal thickening
of cyst wall.31 Various quick modifications of fixation and processing
Morbid anatomy and of the Grocott stain have been introduced to speed the diagno-
sis,32–34 but the importance of fixation in killing any concomitant
Fatal Pneumocystis pneumonia is generally characterised by widespread
human immunodeficiency virus (HIV) should not be overlooked.
bilateral consolidation with relative sparing of the bases and apices of
Other special stains that find favour include the Gram Weigert and
the lungs (Fig. 5.4.5). Rarely, the disease takes the form of solid or
Giemsa methods35,36 and those using monoclonal antibodies (Fig.
cavitating pulmonary nodules.29,30
5.4.8).22 The last two methods stain the trophozoite as well as the
encysted form of the parasite, but as the cysts are invariably present
in Pneumocystis pneumonia (and are shown by Grocott’s stain),
Histological appearances this is a dubious advantage: the Grocott stain is clearer and has the
Microscopically, the alveoli are filled by a foamy, pale, eosinophilic advantage of staining any other fungi that may also be present.37
exudate (Fig. 5.4.6). The parasite is unstained in haematoxylin and However, in sputa and other cytological specimens where the pneu-
eosin preparations but with Grocott’s methenamine silver stain the mocysts may be sparse the greater sensitivity of immunochemical
alveoli are seen to contain numerous round cysts that measure about stains and molecular techniques is advantageous.23–27 In situ hybrid­
5 µm across. Crescent-shaped forms (Fig. 5.4.7) represent collapsed isation has also been used to demonstrate pneumocysts in tissue
cysts and their presence is helpful if there is concern that erythrocytes sections.38

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 Pathology of the Lungs

litis.30 The invasion of the interstitium and pulmonary blood vessels

probably causes the necrosis that underlies the cavitating nodules.30,53,54
The cavities develop into air cysts, which are prone to rupture into the
pleural cavities, resulting in both pneumo­thorax and Pneumocystis
infection of the pleura.55,56 Alternatively, there may be interstitial
spread and infection of the pleural cavities in the absence of any direct
fistulous communication.52
In view of the vascular invasion it is not surprising that
widespread blood-borne dissemination is also reported, particularly
in AIDS.15,39,57–61 The fact that this sometimes develops in the absence
of obvious pneumonia has been attributed to the prophylactic use of
inhaled pentamidine which reduces the risk of Pneumocystis pneumo-
nia but does not prevent the organism spreading to other organs.
Restitution of the immune response following effective antiviral
therapy is sometimes accompanied by an ‘immune reaction inflam-
mation syndrome’ (IRIS)62 and this may ultimately result in wide-
spread interstitial pulmonary fibrosis.
Figure 5.4.8  Immunocytochemical staining of Pneumocystis jirovecii Although opportunistic infections are often multiple, there appears
demonstrates the trophozoites as well as the cysts. to be a special relationship between P. jirovecii and cytomegalovirus
because these two organisms coexist particularly frequently in the
infected lung (Fig. 5.4.10). It has been suggested that P. jirovecii acts
as an intermediate host for cytomegalovirus.63
Table 5.4.1  Pneumocystis jirovecii pneumonia: atypical
histological features43
Differential diagnosis
No. of cases %
The differential diagnosis of classic Pneumocystis pneumonia is from
Fibrosis 77 63 pulmonary oedema and alveolar lipoproteinosis. These three condi-
tions are all characterised by the alveoli being filled by a largely acel-
  Interstitial 44 36 lular material, but whereas in oedema the material is amorphous, in
  Intraluminal 23 19 lipoproteinosis it is granular and in Pneumocystis pneumonia it has a
foamy appearance. Alveolar lipoproteinosls is further distinguished
Absence of typical exudates 11 9 from Pneumocystis pneumonia by the presence of cholesterol crystal
Numerous alveolar macrophages 6 5 clefts and a few foamy fat-filled macrophages in the alveolar deposit
and by the strong periodic acid–Schiff-positivity of the deposit
Granulomatous inflammation 5 4 (compare Fig. 5.4.6 with Fig. 6.2.18A, p. 319).
Hyaline membranes 4 3
Marked interstitial pneumonitis 3 2
Parenchymal cavities 3 2
ASPERGILLOSIS
Interstitial microcalfication 2 2
Mycology
Minimal histological reaction 1 1
Aspergilli are common saprophytes found throughout the world in
Vascular permeation 1 1 decaying organic matter where their spores may be so numerous that
they can be seen as a dense dust cloud when piles of such material
are disturbed. Several species have been identified as causes of human
disease but Aspergillus fumigatus is by far the most frequent, particu-
The alveolar exudate in which the parasites are found is virtually larly in European cases of pulmonary disease and septicaemia. Other
free of host cells except for a mild increase in the number of alveolar species responsible for disease in humans include A. flavus and A.
macrophages. The reaction to the parasite is largely an interstitial niger, the latter more common in the USA.
infiltrate of lymphocytes and plasma cells (see Fig. 5.4.6). In most Definitive diagnosis requires culture but this is not always success-
immunodeficient patients the infiltrate is generally mild but in mal- ful. In histological preparations an aspergillus has a characteristic
nourished children it is intense, warranting the original descriptive appearance and can be generically identified by the morphology of its
term interstitial plasma cell pneumonia. hyphae (Fig. 5.4.11). Aspergillus hyphae are usually visible in haema-
Changes other than the classic one of foamy alveolar exudates may toxylin and eosin preparations, and sometimes are so intensely hae-
be found in Pneumocystis pneumonia, particularly in AIDS (Table 5.4.1 matoxyphil that they are immediately evident at low magnifications.
and Fig. 5.4.9),29,30,39–46 demonstrating that pathological changes in Although the periodic acid–Schiff stain and the Gridley stain for fungi
infective disorders are dependent on host factors as well as the facilitate their recognition, the Grocott–Gomori methenamine silver
parasite. In addition to the cavitating nodules mentioned above,29,30 nitrate method is very much more reliable. The hyphae are septate and
necrotising granulomatous inflammation,26,39,42–44,47 diffuse alveolar their hyphal diameter, which varies from 3 to 6 µm, is fairly regular.
damage,41 calcification,40,45,48 lymphoid interstitial pneumonia (par- Typically, the hyphae branch dichotomously at relatively narrow
ticularly in children)49–51 and interstitial52,53 and vascular invasion have angles (35–45°), the branches then tending to orient themselves
been described, the latter sometimes resulting in a necrotising vascu- parallel to each other. Rare fungi of similar morphology, such as

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A B

C D

Figure 5.4.9  Atypical reactions to Pneumocystis jirovecii in severely immunodeficient patients. (A, B) Necrotising, granulomatous inflammation.
(C) Necrosis, cavitation and dystrophic calcification. (D) Invasion of the interstitium, evident from the foamy exudate expanding alveolar walls as well as
occupying alveoli. (Courtesy of Dr R Steele, Brisbane, Australia; and Professor F Capron and Dr I Abdalsamad, Paris, France.)

Chaetomium globosum, can be distinguished by immunocyto­chemistry,

culture or molecular methods.64–67
The conidiophores (or fruiting heads), that are so striking a feature
of aspergilli when growing as saprophytes, are seen in infected tissues
only when the fungus is exposed to air: they are never found within
the solid structure of colonised organs and tissues, but may occasion-
ally be seen in the lung if the lesion communicates with a bronchus
(Fig. 5.4.12). Species identification is based on colonial characteristics
and on the structure of the conidiophores, which is best studied in
culture (Figs 5.4.13 and 5.4.14).

Oxalate crystal deposition

Crystals of calcium oxalate have been identified in tissues infected by
aspergilli, particularly A. niger, of which oxalic acid is a fermentation
product. In some cases local tissue injury and even generalised acute
Figure 5.4.10  Pneumocystis jirovecii and cytomegalovirus pneumonia. As oxalosis and renal failure have resulted from the production of oxalic
well as the foamy exudate of Pneumocystis pneumonia there are acid by the fungus.68,69 Its widespread deposition as insoluble calcium
prominent viral inclusions (centre). oxalate may be accompanied by sudden hypocalcaemia.70 Tissue tox­
icity is attributed to calcium oxalate complexing with iron, resulting
in the production of free oxidants.71 Oxalosis is commonest with
saprophytic aspergillosis but is also recorded with the allergic and

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 Pathology of the Lungs

Figure 5.4.11  Aspergillus hyphae are septate, of fairly uniform thickness

(3-6 µm diameter) and branch dichotomously. Grocott’s methenamine
silver stain.

invasive varieties of the infection (described below). The demon­

stration of oxalate crystals in biopsy and cytology specimens can
be a useful aid in the diagnosis of pulmonary aspergillosis.72–74 The
crystals are birefringent (Fig. 5.4.15), stain with alizirin red75 and can
be confirmed as oxalate by crystallography and X-ray diffraction.76

Predisposing causes and types of

pulmonary aspergillosis77,78
Although exposure to Aspergillus spores is common, the fungus is not
a frequent pathogen. Only if the individual is atopic, or the lungs have B
been previously damaged, or general resistance is lowered by other
conditions are ill-effects likely to occur. Bronchopulmonary disease Figure 5.4.12  The fruiting heads or conidiophores of Aspergillus in a
caused by aspergilli may accordingly be classified respectively as aller- pulmonary cavity that communicated with the bronchi, so affording
gic, saprophytic and invasive.77,79 Rarely, different forms of pulmonary the fungus the oxygen that stimulates this form of reproduction.
aspergillosis occur in the same patient. For example, an aspergilloma (A) Grocott’s methenamine silver stain; (B) lactophenol cotton blue stain.
may be complicated by allergic aspergillosis,80,81 even in a non-atopic
patient, whilst an aspergilloma may develop within the bronchiectasis
resulting from allergic aspergillosis.82,83
centration of the serum may be necessary to detect them for they are
often not present in the high concentrations found in association with
Allergic bronchopulmonary aspergillosis an aspergilloma. Poor antigens may give false-negative results and
Persons suffering from this form of aspergillosis are generally atopic corticosteroids may depress the antibody response and thus both
and give a history of asthma.84–87 There is also an increased incidence skin and serological reactions. Culture of the sputum is not always
of allergic aspergillosis in patients with cystic fibrosis, but nearly half positive and on occasion the diagnosis of allergic bronchopulmonary
those so affected are also atopic.88 It is important to reiterate that this aspergillosis is first made by the histopathologist after surgery has
form of aspergillosis is not characterised by invasion of the tissues by been undertaken for a suspected malignancy (Fig. 5.4.16 and see
the fungus: it is an allergic response to Aspergillus that remains con- Fig. 9.8, p. 464).89
fined to the airways. Furthermore, as the disease is a hypersensitivity The term ‘allergic bronchopulmonary aspergillosis’ is generally
phenomenon, hyphae are very sparse and have to be searched for limited to a syndrome that is chiefly characterised by the
diligently, in contrast to both the other main forms of aspergillosis expectoration of mucous plugs or the impaction of such plugs and
(saprophytic and invasive) in which hyphae are numerous. the consequent development of bronchiectasis. However, allergy to
The allergic reaction in the lung is frequently reflected in a raised Aspergillus may have further bronchopulmonary consequences,
blood eosinophil count: eosinophilia is also seen in lung tissue and notably bronchocentric granulomatosis and eosinophilic pneumonia,
sputum. Circulating precipitating antibodies to Aspergillus antigens both of which are dealt with elsewhere (see pp. 461 and 464).
may be demonstrable and immunoglobulin E, both total and specific, Attention here will be limited to mucoid impaction.
is generally raised; indeed, these immunological tests, together with
the demonstration of immediate (and late) skin reactions to Aspergillus Mucoid impaction
antigens, are now the main means of confirming the clinical diagnosis In some asthmatic individuals particularly large mucous plugs
of allergic aspergillosis. There is, however, a wide range of specific develop, typically 1–2 cm thick and 2–5 cm long. They generally form
antibodies to various antigenic components of the fungus, and con- in proximal bronchi (see Fig. 5.4.16) and can be clearly seen in plain

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 Infectious diseases Chapter |5|

Figure 5.4.14  Aspergillus conidiophores. The structure of the

conidiophores shows marked species variation. (A) Diagrammatic
appearances of A. fumigatus on the left and A. flavus on the right.
(B) A conidiophore in culture.

Figure 5.4.13  Aspergillus colonies in culture. The hyphal mycelium

is white in all species but the conidiophores’ colour is distinctive.
(A) A. fumigatus; (B) A. niger.

radiographs as finger-like opacities near the hilum of the lung. They

are frequently expectorated spontaneously (Fig. 5.4.17). The airway
involved is dilated and its wall shows non-specific chronic inflamma-
B
tory changes which vary from a mild infiltrate to a severe reaction that
includes many eosinophils. The affected airway may be merely dis-
Figure 5.4.15  Calcium oxalate crystal deposition in the tissues bordering
tended and therefore returns to normal after the plug is expectorated, an aspergilloma viewed with (A) non-polarised and (B) polarised light. As
or its wall may be largely destroyed by the inflammation so that there is usually the case, much of the fungal colony is dead but here the
is permanent bronchiectasis (Fig. 5.4.18). The proximal distribution adjacent host tissue is also necrotic; this change is attributable to oxalic
of this form of bronchiectasis contrasts with that of the postinfective acid secretion by the fungus. The oxalic acid combines with free calcium
form, which generally affects the bases. ions in the tissues to precipitate as insoluble, birefringent crystals.

229
 Pathology of the Lungs

Figure 5.4.16  Allergic bronchopulmonary aspergillosis identified as the

cause of a pulmonary opacity thought to be neoplastic. (A) Several bronchi
are distended by plugs of viscous mucus. (B, C) Microscopy shows
alternating eosinophilic bands, the pink ones representing mucus and the
red conglomerations of eosinophils. In (C) the walls of the bronchi also
show chronic inflammation, which weakens them and leads to proximal
bronchiectasis. (Courtesy of Professor DH Wright, Southampton, UK.)

Figure 5.4.17  A mucous plug spontaneously expectorated by a patient

with allergic bronchopulmonary apergillosis. Such plugs are short and
stubby, very different from the long, many-tailed plugs expectorated in
plastic bronchitis (compare with Fig. 3.20, p. 109). (Courtesy of Dr T
Jelihovsky, Sydney, Australia.)

The mucous plugs undergo inspissation and often have the consist-
ency of hard rubber. Although they may form casts of several genera-
tions of bronchi, they tend to be shorter and stubbier than the long
B
stringy casts expectorated in plastic bronchitis (see p. 109). The micro-
scopic appearances also differ. Mucous plugs characteristically consist
of bands of agglutinated eosinophils alternating with layers of mucus
(see Fig. 5.4.16). The bands of eosinophils are arranged parallel to the
airway wall and frequently diminish in length towards the centre of
the lumen so that wedges of alternating cellular and mucous bands
point inwards, presenting an appearance that has been likened to fir
trees.90 Sparse Aspergillus hyphae are generally to be found in the
mucous plugs.
In exceptional cases other fungi are responsible for similar changes,
resulting in reports of allergic bronchopulmonary stemphyliosis,
curvulariosis, drechsleriasis, candidosis, helminthosporiosis,
penicilliosis, torulopsosis, fusariosis and pseudallescheriosis.91–96 and
the term ‘allergic bronchopulmonary fungal disease’ is therefore
sometimes preferred.97

Extrinsic allergic alveolitis

C Extrinsic allergic alveolitis may also be a manifestation of allergy to
Aspergillus, but here it is heavily exposed non-atopic individuals who
are affected. One example is ‘malt worker’s lung’, which occurs in

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 Infectious diseases Chapter |5|

Figure 5.4.18  Allergic bronchopulmonary aspergillosis. The proximal

bronchi (top) are dilated and some contain mucous plugs. More
peripherally there is coagulative necrosis representing bronchocentric
granulomatosis and beyond that pale foci of eosinophilic pneumonia are
seen. (Courtesy of the late Dr AA Liebow, San Diego, USA.)
Figure 5.4.19  Aspergilloma. Computed tomography shows a cavity in
the apical segment of the right lower lobe, containing an intracavitary
body consistent with an aspergilloma, which was confirmed following
lobectomy.
brewery staff working with mouldy barley; the species of Aspergillus
involved here is usually A. clavatus. Extrinsic allergic alveolitis may
also develop in patients harbouring an aspergilloma.81 These forms of
allergy to Aspergillus are similar, both clinically and pathologically,
to the extrinsic allergic alveolitis that develops in response to other type of fungal granuloma that is characterised by the formation of
allergens (see p. 279). multiple sinuses and is usually the outcome of penetration of the soft
tissues by a thorn, or the like, contaminated by the causative organism.
Such lesions are most frequent on the extremities and ‘Madura foot’
is the type example. In this sense a mycetoma represents a lesion
SAPROPHYTIC ASPERGILLOSIS caused by invasion of the tissues by the organism concerned, in con-
trast to an intracavitary fungal ball, which is essentially outside the
Aspergilli may grow saprophytically within stagnant secretions in the tissues and does not, except in unusual circumstances, lead to exten-
bronchi in cases of chronic bronchitis and, less often, bronchiectasis. sion of the infection into the wall of the cavity itself. Many varieties
In certain circumstances this may be very marked, resulting in of fungus cause mycetomas: most of them seldom, if ever, cause other
obstructive aspergillosis (see below). Other varieties of saprophytic disease.
aspergillosis include the colonisation of an infarct,98 a tumour,99 the While most intracavitary fungal ball colonies are formed by A.
bronchial anastomosis following transplantation100,101 and a prefor­ fumigatus, other species of Aspergillus have been identified in some
med cavity, resulting in the last case in the formation of an aspergil- cases and, exceptionally, fungi such as Pseudallescheria (Petriellidium)
loma (intracavitary Aspergillus ball colony).102 boydii,104 Cladosporium cladosporidioides105 and species of Penicillium,
Candida or Syncephalastrum106 have been responsible. Also, ball colo-
nies similar to an aspergilloma may on rare occasions consist solely
Aspergilloma of bacteria (see nocardioma on p. 215 and botryomycoma on p. 192).

In an aspergilloma the fungus grows in the lumen of a cavity in the

lung without invading the tissues to any appreciable extent, drawing
its nutriment from such exudate as may be present. The ball usually Radiology
forms in an existing cavity, particularly an old tuberculous cavity,102 The radiological appearances of an aspergilloma are often character-
but sometimes in a cavity resulting from conditions such as sarcoid­ istic. The fungal ball appears as a sharply demarcated radiopaque
osis (see Fig. 6.1.37, p. 289), bronchiectasis, abscess or emphysema, spheroid that rests on the wall of the dependent part of the cavity and
or in a congenital cyst. Aspergilloma formation has been observed is separated from it elsewhere by a crescent of air (Fig. 5.4.19). In cases
both in the bronchiectatic lung distal to an obstructing carcinoma and of long standing the colony may fill the cavity completely but the
within the cavity resulting from necrosis at the centre of a peripheral fungal ball is often able to move within the cavity in accordance with
carcinoma.103 Although usually single, aspergillomas may be present the patient’s posture. However, although these features are character-
in cavities in both lungs, and in some cases there are several such istic of an aspergilloma, they may also be given by an indolent necro-
lesions. tising form of invasive aspergillosis which is considered below. A true
The term ‘mycetoma’ is frequently misapplied to intracavitary aspergilloma is often demonstrated in radiographs over a period of
fungal balls, such as aspergillomas. The term is correctly limited to a several years, sometimes with little or no detectable change in its

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 Pathology of the Lungs

Figure 5.4.21  Aspergilloma. (A) The centre of the fungus ball consists of
a dense feltwork of dead fungal hyphae. Only at the periphery is the
fungus viable. (B) The edge of the fungus ball is coated by a layer of
Figure 5.4.20  An Aspergillus fungal ball (an aspergilloma) filling an eosinophilic immune material (Splendore–Hoeppli phenomenon).
apical cavity. In its fresh state the fungal ball forms a soft, brown,
pultaceous mass but as seen here after fixation, it is more friable.

there may be so much calcification that the ball becomes stony and
may be classified among the so-called ‘pneumonoliths’.
appearance, sometimes with appreciable phases of shrinkage and
enlargement. Histological appearances
Microscopically, an aspergilloma consists of a dense feltwork of
hyphae, most of which are dead. Only the hyphae at the surface are
Antibody production well preserved. The tips of these may be abundantly coated with
Most patients with an aspergilloma have strong serum precipitins hyaline eosinophilic material of probable immune origin (Splendore–
against Aspergillus antigens but, unless allergy with asthma has devel- Hoeppli phenomenon; see Fig. 5.3.25, p. 215), giving the edge of
oped, skin tests against extracts of the fungus are negative. Occasionally the aspergilloma a distinctive appearance (Fig. 5.4.21). The lining of
the circulating precipitins combine with fungal antigen disseminated the cavity that contains an aspergilloma varies according to the nature
via the airways to produce the changes of extrinsic allergic alveolitis of the condition that has given rise to it. The wall of an old tubercu-
elsewhere in the lung or there may be immune complex-mediated lous cavity may consist of dense, hyaline fibrous tissue, sometimes
vasculitis elsewhere in the body. devoid of an epithelial covering; in other cases there may be a lining
zone of chronic inflammatory granulation tissue, which usually is
without specific features of tuberculosis or other former disease. When
present, an epithelial lining may be of either respiratory or squamous
Morbid anatomy type.
The fungal colony appears macroscopically as a grey or reddish brown, Chronic inflammatory changes in the lining of the cavity that are
rarely white or green-tinged mass, sometimes firm or rubbery in con- attributable to the fungal ball are variable but their presence underlies
sistency but often friable or pultaceous (Fig. 5.4.20). Old colonies may any enlargement of the cavity. It is mentioned above that numerous
have a gritty feel, from deposition of calcium salts, and exceptionally calcium oxalate crystals are occasionally present. These are found in

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the cavity lining, particularly near the surface and in relation to the
sides of blood vessels that face the fungus ball (see Fig. 5.4.15). The
toxic nature of oxalic acid contributes to the progressive enlargement
of the cavity but proteinases secreted by the fungus are probably more
important in this respect.107 Sometimes non-specific chronic inflam-
mation is due to secondary bacterial infection.
It is exceptional for the fungus to invade the tissues, although this
has been observed. Such a change from saprophytosis to invasive
growth is more likely to occur when the patient’s resistance is lowered,
particularly by immunosuppressant and cytotoxic therapy and less
often by administration of corticosteroids.

Haemorrhage
Haemoptysis is a common feature of aspergilloma. Usually it causes
no more than anaemia, but in some cases it has been massive and
death has resulted. It often accompanies the development of further
excavation of the lung tissue round the colonised lesion. The rich Figure 5.4.22  Invasive aspergillosis. The fungal hyphae grow through all
capillary bed of a granulation tissue lining is generally the source of constituents of the lung tissue, including blood vessels, which thrombose,
the haemorrhage,108 but larger vessels are occasionally involved; the resulting in infarction.
endarteritis obliterans usually found in chronic inflammation fails to
seal them completely. The blood supply to the wall of an aspergilloma
cavity ultimately derives from the bronchial circulation and the
haemoptysis can sometimes be controlled by cannulation of the
bronchial arteries concerned under radiographic control and Invasive aspergillosis
the introduction of occlusive synthetic emboli (see Fig. 8.1.15, p. 412).
In neutropenic patients invasive aspergillosis is characterised by
star-like clusters of radiating hyphae that extend widely throughout
Obstructive aspergillosis the lung tissue (Fig. 5.4.22). There is vascular invasion leading
to thrombosis, infarction and generalisation of the infection through
This form of aspergillosis was first described in patients with AIDS109
the body. Non-neutropenic patients are more likely to show neu-
and subsequently in the recipients of organ transplants.110 It is char-
trophilic and monocytic exudates and inflammatory necrosis.125
acterised by a progressive cough, which is sometimes productive of
bronchial casts composed entirely of Aspergillus hyphae, in contrast to
the mucous plugs of allergic bronchopulmonary aspergillosis in
which hyphae are scanty. There is no wheezing or eosinophilia but
Septicaemic aspergillosis
the patient rapidly develops hypoxaemia. Chest radiographs show Septicaemic aspergillosis is commonly first recognised at necropsy,
areas of collapse and at bronchoscopy some airways are found to be and often not until the tissues are examined with the microscope. In
completely obstructed by fungal casts. When these are removed the many cases the portal of invasion of the blood stream by the fungus
bronchial mucosa appears normal. The condition therefore represents is not apparent. In others it is a recognisable local infection such as
saprophytic infection. Nevertheless, it is probably a precursor of the Aspergillus pneumonia. There may be a rapidly overwhelming septi-
locally invasive pseudomembranous Aspergillus tracheobronchitis, caemia, with little to show in the way of focal lesions, or there may
described below. be many large foci of necrosis, most frequently in the brain, heart and
kidneys. The lesions are often so heavily colonised by the Aspergillus
that, very soon after exposure to the air at necropsy, condiophores
INVASIVE AND SEPTICAEMIC develop and colour the necrotic tissue – green in the case of A. fumiga-
tus and A. flavus and black if the fungus is A. niger. There may even be
ASPERGILLOSIS an obvious growth of the pigmented mould on the surface.
Microscopical examination often shows that the hyphae of the invad-
Excluding saprophytic colonisation of pulmonary infarcts and ing fungus are surrounded by a spreading zone of necrosis in advance
superficial invasion round an aspergilloma – each a relatively rare of their progress through the tissues: this is probably a result of dif-
occurrence – most instances of Aspergillus pneumonia are due to the fusion from the infected part of toxins and degradative enzymes pro-
patient’s resistance being undermined by factors that cause prolonged duced by the Aspergillus.68,107 Occasionally, the lesions are suppurative.
granulocytopenia, such as lymphoproliferative disease, leukaemia and Infection by other fungi may be present at the same time.
corticosteroid therapy.111–115 Less often, invasive pulmonary aspergil-
losis complicates influenza or other viral infection116,117 or chronic
obstructive pulmonary disease.117a,118 AIDS is another predisposing Chronic necrotising Aspergillus pneumonia
cause119–121 but the incidence of invasive aspergillosis is nevertheless
(acute cavitary pulmonary aspergillosis)
lower than that of many other opportunistic infections in this group
of patients,109,122,123 probably because the HIV attacks lymphocytes This is a localised form of invasive aspergillosis in which the
rather than granulocytes. Rarely, the patient is apparently immuno- necrotic lung tissue may separate away as a sequestrum and mimic
competent.124 In severely immunodeficient patients the infection an aspergilloma both radiographically and macroscopically
spreads quickly and often disseminates via the blood stream, whereas (Fig. 5.4.23)126–134; microscopically, however, infected lung tissue is
in less debilitated patients infection results in more indolent localised easily distinguishable from an intraluminal ball colony of fungus,
lesions. even though both are largely necrotic.

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 Pathology of the Lungs

Figure 5.4.23  Chronic necrotising Aspergillus pneumonia. The lung

contains a cavity partly lined by a plaque of Aspergillus nigra. The
appearances simulate those of an aspergilloma but the cavity is newly
formed and its contents consist of necrotic lung tissue heavily infiltrated
by the fungus. Compare the colour of this non-sporing mycelium with
the cultured colony of the same species, which is exposed to oxygen and
is therefore producing black conidiophores (Fig. 5.4.13b). (Reproduced
from Wiggins et  al. (1989) by permission of the editor of Thorax.130)

Pseudomembranous Aspergillus
tracheobronchitis
Pseudomembranous Aspergillus tracheobronchitis involves only a B
narrow zone of tissue bordering the major airways; the intervening
lung parenchyma is spared.135–140 In this form of invasive aspergillosis Figure 5.4.24  Pseudomembranous Aspergillus bronchitis. Many airways
the airways are occluded by a mixture of necrotic debris and fungal are plugged by fungal hyphae and necrotic debris. Invasion is generally
hyphae (Fig. 5.4.24). It may be preceded by the obstructive form limited but in this patient the process has already affected the adjacent
of saprophytic aspergillosis, described above. A granulomatous pulmonary artery. (A) Gross appearances; (B) microscopy.
response to the fungus may develop, mimicking bronchocentric
granulomatosis.141,142
phytes on decaying organic matter. It is quite exceptional for one
of these moulds to set up progressive infection in a patient who is
MUCORMYCOSIS otherwise in good health.145
The Mucorales that cause pulmonary infection are recognisable as
such in histological sections by their characteristic morphology (Fig.
Mycology 5.4.25A) but this does not allow identification of genus or species,
Mucormycosis (formerly zygomycosis or phycomycosis) is the name which requires immunohistochemistry.66 The hyphae are characteristi-
most widely familiar for any infection caused by a fungus that is a cally of variable but generally broad diameter, ranging from 3 to
member of the class Zygomycetes (formerly Phycomycetes). This class 20 µm. They tend to branch perpendicularly, and septation of the
includes the orders Mucorales and Entomophthorales. They are found hyphae is absent or at most very infrequent. A false impression of
in soil, dung and dust throughout the world and are common causes septum formation may be given by folds that result from shrinkage.
of food spoilage. The classic form of mucormycosis is rhinocerebral, Because of their irregular appearance and the sometimes striking
where the fungi grow from an infected ulcer in the nasal space to effects of shrinkage during histological processing the hyphae have
invade the cranial cavity, cerebral blood vessels and the contents of been likened to lengths of crushed ribbon. Although visible in haem­
one or both orbits.143,144 Some of the mucormycoses are primary sub- atoxylin and eosin preparations, the mucoraceous fungi are best
cutaneous or orificial mucosal infections, occurring without predis- shown by special methods: the methenamine silver stain is often
posing disease. Very rarely, dissemination of the fungus from these useful, but better results may be obtained by the silver impregnation
primary sites results in visceral infection, including pulmonary methods used in the demonstration of reticulin fibres. As in the
mucormycosis due to the Entomophthorales Basidiobolus haptosporus case of aspergilli, such morphologically specific structures as
(B. meristosporus) and Conidiobolus coronatus (Entomophthora coronata). sporangiophores develop only when the mould is growing in air:
Much more commonly, pulmonary mucormycosis is direct and attrib- they are seldom, if ever, seen in pulmonary lesions in the fresh state,
utable to lowering of resistance to invasion of the tissues by Mucorales but they may form if a specimen has inadvertently been left exposed
of the species Absidia, Mucor and Rhizopus which ordinarily are sapro- before being placed in fixative solution. Culture often fails and

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 Infectious diseases Chapter |5|

histology may then be the first means of identification, supplemented

if required by molecular techniques.67 The distinction from aspergilli
is important because the treatment differs.

Predisposing causes
Conditions predisposing to visceral mucormycosis include AIDS,
leukaemia, pancytopenia, myelomatosis, diabetes mellitus and im­­
munosuppression to prevent graft rejection.142,146,147 Certain thera­
peutic measures also predispose to these infections, particularly
desferrioxamine and the administration of cytotoxic and immunosup-
pressant drugs, including corticosteroids. Cannulation of blood
vessels, when long continued, is a further occasional factor, being a
potential portal of infection. Burns, too, have repeatedly become not
merely a site of superficial infection but the source of haematogenous
dissemination. The predisposing factors to some extent determine the
site of predominant infection. For instance, the syndrome of naso-
orbitomeningingocerebral mucormycosis occurs usually as a compli-
A
cation of diabetes mellitus or renal failure: these metabolic disorders
are comparatively seldom responsible for the development of pulmo-
nary or primarily septicaemic mucormycosis, which in most cases
occur as complications of severe blood disease or of the resistance-
lowering side-effects of drugs. Similarly, severe malnutrition predis-
poses to mucormycosis of the stomach or intestine.

Pathological findings
Mucormycotic lesions in the lungs vary greatly in size and number.
Multiple lesions are usually the result of haematogenous dissemin­
ation, as may occur in cases of naso-orbitocerebral mucormycosis,
whereas lesions that are single or few may be the result of direct infec-
tion of the lungs by way of the airways. The lesions are firm, hyper­
aemic or haemorrhagic, and often necrotic. If they extend to the
pleura, a fibrinous exudate is found over them and there are often
petechial or larger foci of bleeding. Central lesions tend to be spherical
B and peripheral ones wedge-shaped,148 the former resembling chronic
necrotising pulmonary aspergillosis (see above) and the latter
representing infarcts.
Microscopically, the most significant finding is fungal invasion of
blood vessels of all sizes, with thrombosis and colonisation of the
thrombus by the fungus, and infarction (Fig. 5.4.25B, C). It is clear
that many strains of these fungi are thrombogenic, and staining the
lesions with phosphotungstic acid haematoxylin or by other appro­
priate methods clearly demonstrates the formation of fine radiating
threads of fibrin on the surface of the hyphae within the blood vessels.
Perineural invasion is also commonly seen.144 The hyphae may be
present in great number, not only in the thrombi but throughout the
resulting infarcts. The latter soon liquefy, and there may be secondary
bacterial infection. Calcium oxalate crystal deposition, as described in
aspergillosis (see above), is rarely reported in mucormycosis.149
As with other fungal infections occurring as a consequence of pre-
disposing illnesses and drug-induced failure of resistance, mucor­
mycosis is often accompanied by one or more other opportunistic
C
infections, even of the same part. Frequent associations are of
mucormycosis with aspergillosis or candidosis but bacterial, viral and
Figure 5.4.25  Mucor. (A) Mucor hyphae have few septa and are protozoal infections may also be present.
irregular in outline. The rounded structures that resemble spores are
hyphae cut transversely. (B) Mucormycosis in a lung excised because of
massive haemoptysis. Haemorrhage surrounds a partially thrombosed
ruptured blood vessel. (C) The wall of the ruptured vessel shows
necrotising granulomatous angiitis. CANDIDOSIS (MONILIASIS)

Candida is a yeast-like fungus that forms round or oval budding cells

(blastospores), septate hyphae and intermediate structures called
pseudohyphae (Fig. 5.4.26). Candidosis generally represents infection

235
 Pathology of the Lungs

AIDS.119 In sections, Candida may be seen within a pseudomembrane

consisting of purulent exudate on the surface of a bronchus, or very
rarely in lung tissue as a cause of pneumonia or even lung abscess. In
agranulocytic patients there is necrosis with minimal inflammation.
Candida pneumonia may represent a peripheral extension of Candida
bronchitis or result from haematogenous dissemination complicating
diseases or therapeutic measures that lower resistance. Pulmonary
vascular candidosis may complicate endocarditis or infection of
central venous catheters inserted for prolonged parenteral feeding (see
Fig. 5.4.26).151,152 Features that distinguish Candida from P. jirovecii
and other yeast-forming fungi such as Histoplasma include the mixture
of budding yeast cells with pseudohyphae and the pyogenic or necro-
tising host reaction. The invariable presence of yeasts distinguishes
candidosis from aspergillosis and mucormycosis.

CRYPTOCOCCOSIS
A

Mycology
Cryptococcosis, a disease of worldwide distribution, is caused by the
monomorphic yeast-like fungus, Cryptococcus neoformans. This organ-
ism was formerly known as Torula histolytica, and the disease as toru-
losis. Because it was first recognised in Europe, and is caused by a
fungus the cells of which reproduce by budding, cryptococcosis was
also sometimes known as European blastomycosis, in contrast to the
so-called North and South American blastomycoses (now blasto­
mycosis and paracoccidioidomycosis respectively).
Although perhaps most familiar as a complication of leukaemia or
lymphoma, in which the infection typically presents as a progressive
meningoencephalitis, cryptococcosis is also known as a primary
disease of the lungs without predisposing conditions, particularly
when Cryptococcus neoformans var. gattii is involved.153,154 The lung is
the principal portal of entry and infection of the lungs is probably
much commoner than at present recognised. The primary pulmonary
lesion of cryptococcosis is comparable to the initial lesion of
histoplasmosis and coccidioidomycosis and to the Ghon focus of
tuberculosis. Other diseases predisposing to secondary pulmonary
cryptococcosis include alveolar lipoproteinosis and AIDS.119,155,156
Cryptococcal inflammatory pseudotumours are recorded in HIV-
positive patients.157
B C. neoformans is a spheroidal or ovoid organism (Fig. 5.4.27). A
characteristic feature is variability in size, the cell body measuring
from 3 to 20 µm in diameter, although in many instances it is within
Figure 5.4.26  ‘Mycotic’ candidal aneurysm of a pulmonary artery
complicating surgery for complex congenital heart disease. (A) Severe the range of 6–9 µm. Another prominent feature is single, narrow-
inflammation of the artery has led to mural necrosis (below) and based budding, as opposed to the single, broad-based budding of
thrombosis. (B) Grocott staining reveals Candida spores and hyphae Blastomyces dermatitidis and the multiple narrow-based budding of
within the thrombosed vessel. Note: the term ‘mycotic’ is applied to any Paracoccidioides brasiliensis (Fig. 5.4.27A). The organism has a mucoid
aneurysm caused by infected emboli regardless of whether the infection capsule that usually stains with mucicarmine, a reaction that is
is fungal or bacterial. not given by any other pathogenic yeast-like fungus. Cryptococci can
be seen in haematoxylin and eosin preparations because they
are refractile and, in polarised light, birefringent. They can also be
by Candida albicans (formerly known as Monilia albicans) but other demonstrated by any of the special methods for staining fungi
species may be involved.150 Speciation requires culture as the species (Fig. 5.4.27B). The capsule is sometimes deficient, in which case the
are morphologically identical. C. (Torulopsis) glabrata is dealt with fungus is not mucicarminophilic.158 However, in most cases of
separately (see p. 244). capsule-deficient cryptococcosis some carminophilic capsular mat­
The commonest form of candidosis is oral thrush, but the organism erial can be identified around a few yeasts. A Masson–Fontana stain
can attack any mucous or moist cutaneous surface. The fungus is often can also help in the recognition of capsule-deficient cryptococci
found in the sputum but its presence there generally represents no because, unlike other yeasts, cryptococci produce a melanin-like
more than saprophytic growth. The diagnosis of bronchopulmonary pigment.159 Alternatively, capsule-deficient strains may be identified
candidosis therefore often depends on finding the organism histologi- by immunohistochemistry.
cally. It is found as a secondary invader of the lower respiratory tract The cryptococci may be found in the sputum in cases of pulmonary
in cases of chronic bronchitis, bronchiectasis and bronchial carci- involvement. They may be seen on microscopical examination of wet
noma, and in severely ill patients with immunosuppression, including films, particularly when the sputum has been mixed with India ink or

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 Infectious diseases Chapter |5|

A B

C D

Figure 5.4.27  Cryptococcosis. (A) A single Cryptococcus exhibiting single narrow-based budding (haematoxylin and eosin stain). (Courtesy of Dr A
Paiva-Correia, formerly of Oporto, Portugal.) (B) Cryptococci demonstrated by periodic acid–Schiff staining. (C) A necrotising 4-cm cryptococcoma excised
after its chance radiographic discovery. (Courtesy of Dr M Jagusch, formerly of Auckland, New Zealand). (D) Fungal spores (arrows) are seen amongst
neutrophils in an immunosuppressed patient with disseminated disease. (B and D courtesy of Dr PM Cury, Rio Preto, Brazil.)

nigrosin to display the capsule. In dry films the fungal cells ings, particularly during demolition. The infection in such patients is
disintegrate or become smudged and usually cannot be recognised, slow to appear, in contrast to the acute pneumonic form of histoplas-
although sometimes staining with mucicarmine is conclusive. Cultures mosis. It is clear that exposure to cryptococci must occur very fre-
are generally the preferred means of confirming the diagnosis, but quently: equally, the great majority of people must have a high
some strains of the cryptococcus do not grow well and several immunity, for cryptococcosis is rare in any population.
attempts may have to be made before the organism is isolated. It is It is important to remember that any patient with active crypto­
notable that the cryptococcus is only exceptionally, if ever, found in coccosis is at risk of developing infection of the central nervous
sputum in the absence of infection, in spite of its near ubiquity system because of the peculiar affinity of the organism for the brain
in our environment. and meninges and the frequency of its dissemination in the blood.
The fungus is often found in the dried droppings of birds, particu-
larly pigeons and starlings; these provide a good culture medium and
pathogenic cryptococci can often be isolated from buildings on which Clinical features
these birds roost.160 Isolation from soil is less frequent, probably Clinical features range from asymptomatic pulmonary involvement to
because of the avidity with which cryptococci are phagocytosed by soil life-threatening meningitis and overwhelming cryptococcaemia.
amoebae. As in the case of histoplasmosis, cryptococcosis has been Imaging shows single or multiple well-circumscribed masses, poorly
known to develop in people who have worked in bird-infested build- demarcated opacities or segmental consolidation.

237
 Pathology of the Lungs

Morbid anatomy the disease that it causes differs significantly from that caused by H.
capsulatum, an organism that is geographically far more widespread.
Pulmonary cryptococcosis takes several forms: primary, crypto­
In general, when the word histoplasmosis is used without elaboration
coccoma, cavitary, pneumonic, miliary and inflammatory pseudo­
it refers to disease caused by H. capsulatum.
tumour.153,155–157,161–163 Isolated, discrete, encapsulated, subpleural
The histoplasmas are dimorphic fungi, growing as ovoid, yeast-like
granulomas are occasionally seen at necropsy: these are healed or
organisms in cultures at 37°C and in infected tissues (parasitic phase),
healing lesions, and the implication of their presence is that they are
and in mycelial form, producing characteristic tuberculate macroco-
a manifestation of a primary and non-progressive infection. Less
nidia, in cultures at laboratory temperature (about 18°C) and in their
rarely, there are one or more focal lesions in the lungs, up to several
free-living state in the soil (saprophytic phase). Spores released by the
centimetres in diameter, that prove to be foci of progressive crypto­
macroconidia are inhaled and at body temperature germinate into
coccal infection. These are known as cryptococcomas (formerly toru-
yeasts that grow by binary fission.
lomas) (Fig. 5.4.27C). They are firm, pale tan and rather sharply
Histoplasmas can rarely be demonstrated in sputum, even by
defined but are encapsulated only when healing. Their cut surface may
culture, but complement fixation and precipitin tests may be helpful.
be dry or gelatinous: the latter is the case when there is less inflam-
However, on occasion, biopsy may be necessary. When this is under-
matory reaction to the organisms, which, packed closely in great
taken, the opportunity to set up cultures must not be lost, although
numbers, account for the mucoid appearance and consistence of such
histology is more sensitive than culture.164 The fungi may be quite
lesions. Cryptococcal inflammatory pseudotumours are solid, firm
focal in their distribution, and therefore difficult to find, but within
and grey. Progressive cavitary disease occurs in about 10% of cases.
these foci the spores are usually present in large numbers within the
Confluence and continuing enlargement of multiple foci may produce
cytoplasm of macrophages or in areas of necrosis. They are readily
a gelatinous pneumonia involving a segment or the greater part of
seen in haematoxylin and eosin preparations, but only if recently
one or more lobes. In cases of generalised haematogenous dissemina-
viable. They measure 1–3 × 3–5 µm and may contain a distinct
tion of cryptococcosis both lungs may be studded with miliary or
nucleus. Histoplasmas that have been dead for some time may escape
larger foci: close inspection of these discloses their gelatinous nature;
detection in such preparations, although sometimes birefringence,
they tend to be sharper in outline than miliary tubercles or pyaemic
induced by histological processing, may make a proportion of them
abscesses. The gelatinous collection of cryptococci at the centre of the
visible in polarised light. Fortunately, the methenamine silver stain
lesion may be washed out during examination of the tissue, leaving a
commonly demonstrates histoplasmas very clearly, even when they
minute cavity.
have long been dead. Unfortunately, they are difficult to distinguish
from other budding yeasts but a granulomatous reaction, their intra-
Histological appearances cellular location and an absence of pseudohyphae help separate them
from Candida species and P. jirovecii.
Microscopically, the lesions may be composed largely of the crypto-
cocci themselves, with little cellular reaction: the alveoli and intersti-
tial tissue contain the closely packed organisms, their cell bodies Epidemiology
separated by the variable extent of their mucoid capsule. In other
cases, particularly those involving capsule-deficient strains, there may H. capsulatum is a soil-inhabiting fungus that requires organic nitrates
be a tuberculoid reaction, the fungal cells being found within the for growth. These are generally provided by bird droppings. Histo­
cytoplasm of multinucleate giant cells and of mononuclear macro- plasmosis results from inhalation of infective spores and the geo-
phages as well as free in the tissue spaces. In lesions of long standing, graphical distribution of the disease is determined by environmental
lymphocytes and plasma cells may be present in large numbers, and conditions. In regions where the fungus cannot survive to complete
fibrosis may be a feature, although not often conspicuous. Occasionally, its saprophytic phase in soil or other organic debris, histoplasmosis
neutrophils accumulate in considerable numbers (Fig. 5.4.27D), par- does not occur naturally – infection does not ordinarily take place
ticularly in miliary haematogenous lesions, but in the absence of from person to person, the tissue form of the fungus being in general
bacterial infection frank suppuration is not found. Caseation is unable to convey the disease. In those parts of the world where the
a rare development, and has to be distinguished from the somewhat soil or the climate is unsuitable for the saprophytic phase of H. cap-
similar appearance that may result when large numbers of cryptococci sulatum, the disease is found only among those who have acquired
have died and disintegrated into an amorphous, finely granular, the infection in lands where the fungus is present in the environment,
eosinophile mass. Cryptococcal inflammatory pseudotumours are or, much more rarely, as a result of exposure to imported materials
composed of plump spindle cells mixed with lymphocytes, plasma contaminated by the infective spores165 or to laboratory cultures of the
cells and the yeast forms of the fungus. saprophytic phase, which develops when the tissue form is grown at
laboratory temperature.
Histoplasmosis is endemic in many parts of North, Central and
South America, Asia and Africa. In North America, infection is particu-
HISTOPLASMOSIS larly common in the basin of the Ohio and Mississippi river valleys,
where as many as 90% of the population give a positive reaction to
The first report of Histoplasma infection was in 1905 by Samuel the histoplasmin skin test. The histoplasmin test has the same signifi-
Darling, a US Army pathologist stationed in Panama around the time cance in relation to histoplasmosis as the tuberculin test in relation
of the building of the canal. Darling observed the organisms in histio- to infection by Mycobacterium tuberculosis. In Africa, infection by H.
cytes (hence the prefix ‘histo’), likened them to plasmodia (hence capsulatum is endemic over an area far greater than that in which infec-
‘plasma’) and incorrectly assumed that an artefactual clear space tion by the ‘African histoplasma’, H. duboisii, occurs. Histoplasmosis
around each organism was a capsule (hence ‘capsulatum’). is also endemic in India and South-east Asia but it has not been
recognised as an indigenous infection in Australia. Its occurrence in
Europe, other than as a result of travel to an endemic area or accidental
Mycology exposure to the fungus, is exceptionally rare.
Two species of Histoplasma are pathogenic in humans, H. capsulatum Most people who acquire histoplasmosis have no more than a
and H. duboisii. The latter is found exclusively in tropical Africa and subclinical infection. It has been estimated that clinical manifestations

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 Infectious diseases Chapter |5|

Figure 5.4.29  Histoplasmoma representing quiescent disease.

Figure 5.4.28  Histoplasmosis. A chest radiograph shows multiple

bilateral calcific nodules in a patient with quiescent histoplasmosis. culosis, there is spread of the infection to the hilar lymph nodes,
which undergo comparable changes. It is a characteristic of calcified
lesions of histoplasmosis that they have a massively chalky appear-
ance and often show a peculiar stippled pattern in radiographs, par-
ticularly lesions in lymph nodes. Occasionally, the calcified foci in the
occur in only about 1% of cases and that few of these patients develop lungs have a target-like radiographic shadow because of concentric
serious illness. Histoplasmosis is seen in rural communities exposed zones of greater and lesser transradiancy.
to bird droppings and in urban dwellers exposed to demolition
and building sites. Bat guano is rich in organic phosphates and histo-
Histoplasmoma
plasmas and the likely cause of an acute illness of cave explorers.
Several forms of histoplasmosis are desribed, which will now be The name histoplasmoma is given to any circumscribed, persistent
considered. focus of Histoplasma infection in a lung. The lesion is an outcome of
a primary focus, akin to a tuberculoma rather than an aspergilloma.
It occurs typically just under the pleura, and is roughly spherical and
Primary pulmonary histoplasmosis from 1 to 4 cm, sometimes more, in diameter (Fig. 5.4.29). Both in
The primary focus of histoplasmosis resembles that of tuberculosis. radiographs and when examined with the naked eye it has a charac-
As with mycobacteria, the main line of host defence is the macro- teristically concentric pattern of closely set laminae, which may
phage. Specific T-cell immunity appears about 10–14 days after infec- contain appreciable amounts of calcium salts, although by no means
tion and macrophages so activated usually terminate the infection. If invariably. This laminar structure is so characteristic of chronic caseous
not, the organisms continue to grow within the macrophage cyto- granulomas of fungal origin that in some centres it is regarded as
plasm. The disease is spread during its primary stage by infected proof of the non-neoplastic nature of ‘coin shadows’: this is not neces-
macrophages migrating to the regional lymph nodes and beyond to sarily justified, for it has been known for carcinoma to arise in the
disseminate by the blood stream to all organs, but being filtered out fibrotic capsular zone round such a long-standing mycotic lesion. In
particularly well by those rich in reticuloendothelial cells so that the general, histoplasmomas are altogether benign in outlook, and may
liver and spleen are commonly involved. be left in situ with little chance that the infection will be activated and
The primary lesion may be solitary or there may be two or more, progress; they may become more heavily calcified as the years pass. If
sometimes many, primary lesions in the lungs, the number depending resected, they usually prove to be sterile on culture. The causative
on the heaviness of the exposure to the infecting spores. Primary organism may then be demonstrated most reliably by the
lesions may occur in any part of the lungs. Generally, and especially methenamine silver stain, even though it is no longer viable.
when solitary, it is larger than the corresponding lesion of primary
tuberculosis but otherwise similar, showing epithelioid and giant cell
Cavitary histoplasmosis
granulomatous inflammation. Caseation develops within a few weeks
of infection and its appearance is believed to coincide with the devel- Histoplasmosis may closely reproduce the clinical and radiological
opment of skin reactivity to histoplasmin, an observation comparable picture of cavitating pulmonary tuberculosis. Moreover, if such
to the corresponding events in tuberculosis. Early calcification and the patients are exposed to a substantial risk of infection by Mycobacterium
formation of a fibrous capsule are common (Fig. 5.4.28). As in tuber- tuberculosis, as may occur if they are nursed in company with

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 Pathology of the Lungs

tuberculous patients, tuberculosis may be superimposed on the histo­

plasmic lesions, with detriment to the chances of successfully treat­­
ing either infection. In general, cavitary histoplasmosis is seen most
frequently in older patients, particularly men with emphysema or
other chronic lung disease.166 It is attributed to a local breakdown in
immunity at the site of dormant subapical histoplasmic granulomas.
In some cases it is possible that the condition is due to reinfection,
thus adding to the similarities between histoplasmosis and tubercu-
losis. Like the cavities of chronic pulmonary tuberculosis, the lesion
of cavitary histoplasmosis may become the site of an aspergilloma.
Tuberculoid granulomatous tissue in the lining and vicinity of the
cavities contains typical intracellular histoplasmas.

Acute (‘epidemic’) pulmonary

histoplasmosis
The condition that has been described as ‘epidemic’ pulmonary his-
A
toplasmosis is a form of acute histoplasmosis characterised by a severe
influenza-like illness that occurs as a result of a particularly heavy
inhalational infection in an unprotected individual.167 The epithet
‘epidemic’ has been applied because such cases are commonly seen
in several patients simultaneously, all of them exposed on the same
occasion to a massive contamination of the air by infective spores. It
is an unfortunate name, for such cases may occur singly when indi-
viduals are so unfortunate as to stir up large numbers of spores when
working alone in a contaminated environment. These outbreaks have
occurred when infected dust is disturbed in the course of cleaning or
demolishing buildings, ranging from hen houses to city halls, that
have harboured birds that over years have left the droppings that so
perfectly favour the growth of the saprophytic phase of H. capsulatum.
Similarly, those who enter caves where bat and bird droppings have
encouraged the Histoplasma to proliferate may suffer comparable
group outbreaks of acute histoplasmic pneumonia. The multiple foci
of histoplasmosis that form in the lungs of heavily infected patients
have the same structure and run the same course as the solitary
primary foci described above. However, in some cases the infection is
so heavy, and the resulting changes in the lungs are so widespread,
that death occurs. Those who have not previously had a histoplasmic B
infection tend to suffer the severest illness in these outbreaks, but even
those already known to have had a primary infection may develop Figure 5.4.30  Progessive disseminated histoplasmosis in a patient dying
fatal pneumonic lesions under such conditions of massive reinfection. of acquired immunodeficiency syndrome (AIDS). (A) A pulmonary vessel
Fatal opportunistic Histoplasma pneumonia is recorded168 but im­­ shows only slight granulomatous inflammation but (B) Grocott staining
munosuppression is by no means necessary. shows extensive infiltration of the vessel by histoplasmas. (Courtesy of Dr
PM Cury, Rio Preto, Brazil.)

Progressive disseminated histoplasmosis

Mention has been made above of haematogenous dissemination of Fibrosing mediastinitis
the infection during its primary stage. In most such cases the wide-
spread lesions heal without ill effects. However, there is another form In those countries where histoplasmosis is prevalent mediastinal
of disseminated histoplasmosis in which the disease progresses and fibrosis with obstruction of some, or all, of the mediastinal contents
eventually kills the patient. In some cases of this sort there are no is recorded as a complication of such infection.172
obvious predisposing causes but in most the patient’s resistance is
lowered by the presence of serious underlying disease leading to de­­
African histoplasmosis
fective T-cell function.169 AIDS is now an important cause of such
progressive disease (Fig. 5.4.30).170,171 Histoplasma duboisii, an organism larger than H. capsulatum, has been
Fatal disseminated histoplasmosis is characterised by heavy parasi- recognised as a cause of disease throughout much of Africa between
tisation of the reticuloendothelial cells resulting in hepatospleno­ the Sahara and the Zambesi. Its distribution overlaps that of H. cap-
megaly and leukoerythroblastic anaemia. Painful ulcers develop at sulatum, which, however, is much more widespread on the continent.
mucocutaneous junction zones or within the orifices of the body or The source of the infection and the portal of entry of the fungus
in the pharynx and larynx. Organising pneumonic exudates and thin- remain debatable. There is growing evidence that the organism has a
walled cavities may be found in the lungs. Well-formed granulomas saprophytic phase, probably in soil, and that it may enter the body
are not usually found. Fatal adrenal cortical insufficiency is another either through the lungs or, in certain cases, by inoculation into the
important manifestation. skin. Pulmonary disease as one of its manifestations has attracted less

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 Infectious diseases Chapter |5|

attention than cutaneous and skeletal involvement, but it is possible

that in many cases the lesions in the skin, like those in bones, are the 1 6
result of dissemination in the blood from inapparent pulmonary foci.
A feature typical of African histoplasmosis is that the fungal cells
provoke a foreign-body giant cell reaction, not a simple histiocytosis
with or without tuberculoid metamorphosis, as occurs in cases of
infection by H. capsulatum. The organism is ovoid, has a distinct cell
wall and some internal structure, and measures 5–12 µm in its longer
dimension. It stains well with all the fungal stains, but is unlikely to
be overlooked by the careful microscopist in haematoxylin and eosin 2 5
preparations.

COCCIDIOIDOMYCOSIS173–175

Epidemiology
3 4
This disease is endemic in certain parts of North and South America,
occurring especially in hot semiarid regions such as Arizona and the
San Joaquin valley of California, but also in other such areas of the
Americas down to Argentina. It is caused by the fungus Coccidioides
immitis, the saprophytic, free-living form of which requires special Figure 5.4.31  Life cycle of Coccidioides immitis. 1–3: Saprophytic phase
environmental conditions of soil and climate for its survival: these in soil; 4–6: parasitic phase in lungs. Mycelial strands (1) growing in soil
determine its geographical distribution. C. immitis grows best in soils mature into chains of barrel-shaped arthroconidia (2), which disarticulate
free of competing microflora, losing out to competitors when the soil (3), become air-borne, and are returned to the soil or are inhaled. The
parasitic phase in the lungs begins with the enlargement of the inhaled
is irrigated. Upsurges of infection may follow dust storms that release
arthroconidia and their development into thick-walled spherules (4),
the fungus into the air. The fungus may also be transported on in­­ within which endospores form (5). Released spores (6) can initiate the
animate objects such as crops or native artefacts and infect persons development of a new spherule in the lungs or if infected material
outside endemic areas, and of course patients may travel to non- returns to the soil, mycelia (1), so completing the cycle.
endemic regions while incubating the disease.176 For example, the
2001 model airplane-flying world championship was held in an
endemic region of California and several of those attending from
other areas were found to have contracted coccidioidomycosis when
they returned home.177

Mycology
C. immitis is a dimorphic fungus. Saprophytically, it grows as a mould
that produces highly infective arthroconidia: these, inhaled in soil
dust, establish the disease. As a parasite, the organism is found almost
exclusively in the form of spherules: hyphae develop occasionally in
the wall of coccidioidal cavities when air is admitted by them
communicating with an airway, but this is exceptional: only spherules
and their released spores are usually present, even when air is
admitted (Figs 5.4.31 and 5.4.32).
Coccidioides is one of the most dangerous of all organisms in terms of
risk of accidental infection of laboratory personnel. It is imperative that
clinicians communicate to the laboratory any suspicion that a speci-
men may contain C. immitis. Laboratories dealing with coccidioidal
cultures must operate with stringent precautions, including the exclu- Figure 5.4.32  Coccidioidomycosis. Spherules discharging their spores
sion of staff not known to have acquired some natural immunity within lung tissue. Grocott methenamine silver stain. (Courtesy of Dr JT
through previous infection. The coccidioidin skin reaction is an in­­ Gmelich, formerly of Pasadena, USA.)
valuable screening test.
Once in the lungs, the arthroconidia develop into endosporulating
spherules. These range from 30 to 60 µm or more in diameter and become transformed into further spherules, thus repeating the cycle
contain from scores to hundreds of endospores (see Fig. 5.4.32). The and leading to extension of the infection.
maturing spherule is usually accompanied by a histiocytic reaction, The fungal cells are usually well seen in haematoxylin and eosin
with the formation of many multinucleate giant cells: the parasite may preparations, except in the early stages when only a few, newly released
be enclosed by the latter or lie free in the tissues. The mature spherule spores are present, which may be so inconspicuous as to escape detec-
attracts neutrophils, which collect to form microabscesses at the centre tion. The methenamine silver and other stains for fungi demonstrate
of the histiocytic granulomatous foci. When the spherule ruptures, the all forms of the organism very clearly. Whilst the mature or even
freshly released spores, which range from 5 to 10 µm in diameter, at ruptured spherule is diagnostic, immature spherules or free spores are
first lie free in the purulent exudate but soon are engulfed by mono- not: the former may be confused with Blastomyces or Paracoccidioides
nucleate or multinucleate macrophages. They grow, and eventually and the latter with cryptococci or histoplasmas.

241
 Pathology of the Lungs

Figure 5.4.33  Coccidioidomycoma representing quiescent disease.

Clinical features
The initial coccidioidal infection is symptomless in about 60% of
persons.178 When disease develops, there is usually an influenza-like
fever, which characteristically may be accompanied by erythema
nodosum – hence its popular name of ‘the bumps’ in the San Joaquin
valley, where it is also called ‘valley fever’. In most cases there is spon-
taneous recovery from the primary infection. When the disease is
more severe, which is likelier to be the case in patients of African or
Asian ethnic origin, it may mimic tuberculosis in any of its mani­
festations. In severe infections generalisation through the blood is
a frequent and particularly grave complication. Meningitis is
another common complication. Many patients are left with quiescent
pulmonary foci. B

Figure 5.4.34  Blastomycosis. There is a neutrophil and giant cell reaction

Pathological findings to Blastomyces dermatitidis yeasts, several of which have been ingested
At necropsy, the lungs may show focal consolidation, necrotic haem- by giant cells. (A) Haematoxylin and eosin; (B) Grocott stain.
orrhagic areas or extensive necrotic excavating granulomatous nodules.
Histologically, there may be a suppurative exudate in the alveoli, or
necrotic haemorrhagic and fibrinous lesions, or a tuberculoid granu-
lomatous reaction. Granulomatous inflammation is in general associ- In North America, the greatest prevalence is in the south-eastern
ated with good resistance, and purulent inflammation with poor and north central USA, the area drained by the Mississippi, Missouri
resistance. However, when a spherule ruptures to release its spores (see and Ohio rivers, the Great Lakes region and the eastern provinces of
Fig. 5.4.32), there may be a transient neutrophil response whatever Canada.179,180 The natural habitat of the fungus is soil, particularly that
the underlying pattern of inflammation. Also, the type of reaction is subjected to flooding. Infection is believed to occur by inhalation.
partly determined by the maturity of the developing fungal cells. In Africa, lung disease is not so predominant. Many patients present
Patients whose resistance is lowered by other diseases may develop with bone lesions or skin disease. Also, the antigenic make-up of the
generalised haematogenous coccidioidomycosis as a consequence of fungus differs from that encountered in North America, suggesting
activation of a dormant pulmonary focus. The lesion of quiescent that there are at least two variants of blastomycosis, one seen in North
pulmonary coccidioidomycosis is typically a fibrocaseous nodule America and in scattered foci in other countries (Mexico, Lebanon,
containing a few viable organisms (Fig. 5.4.33). Israel, Saudi Arabia and India), the other restricted to Africa.

Mycology
BLASTOMYCOSIS (‘NORTH   Like the histoplasmas, B. dermatitidis is a diphasic fungus.181 In tissues
AMERICAN’ BLASTOMYCOSIS) and in cultures at 37°C it grows as a yeast whereas in cultures at labo-
ratory temperature, and presumably in nature, it grows as a mycelium
from which project special slender hyphae known as conidiophores
Epidemiology which bear conidia, the infective agents. The yeasts are rounded and
It is now recognised that infection with Blastomyces dermatitidis occurs usually within the range of 7–15 µm in diameter, although some cells
very widely throughout Africa and that the geographical designation may be as much as 30 µm across (Fig. 5.4.34). They have a thick wall,
‘North American’, intended to distinguish this disease from ‘European which may give them a double-contoured appearance, but they differ
blastomycosis’ (cryptococcosis) and ‘South American blastomycosis’ from the spores of Cryptococcus neoformans, which they otherwise
(paracoccidioidomycosis), is inappropriate. resemble, in lacking a capsule and therefore failing to stain with

242
 Infectious diseases Chapter |5|

mucicarmine. It is a special feature of B. dermatitidis that it reproduces

in tissues by the formation of a single broad-necked bud that pro-
trudes from the surface of the parent cell, enlarging even until it has
reached as much as half the diameter of the latter, or more, before the
two separate.

Clinical features
As with several other fungi, Blastomyces causes a variety of clinical
syndromes, including primary, progressive and disseminated disease.
Asymptomatic disease is rarely documented, probably because there
are no reliable skin or serological tests of infection. The disease is
generally first identified on cytology or histology with subsequent
positive culture.181,182 Most patients are immunocompetent.
Primary blastomycosis is characterised by the abrupt onset of chills
and cough accompanied by patchy radiographic opacities. Such illness
may be self-limiting or followed by progressive disease, which is some-
times first manifest many months or years later, affecting either the
lung or extrapulmonary sites. Some patients who have no history of
pulmonary involvement develop blastomycosis in tissues such as the
skin, the fungus probably having spread there during the course of Figure 5.4.35  Paracoccidioides brasiliensis. The larger of the organisms
asymptomatic primary lung infection. illustrated is forming multiple buds. Grocott’s methenamine silver stain.
(Courtesy of Dr PM Cury, Rio Preto, Brazil.)

Pathological features
The lungs are the usual portal of entry and within the lungs the upper
lobes are predominantly involved.183 The histological reaction to the A characteristic feature is that they reproduce by the development of
fungus is characterised by necrotising granulomas that are typically multiple buds over the surface of the parent cell. The buds have been
suppurative, the fungal cells either lying free in the purulent exudate likened to the handles of a ship’s wheel or Mickey Mouse’s ears (Fig.
or engulfed by phagocytes. Although neutrophils are generally con- 5.4.35). The presence of buds distinguishes Paracoccidioides from
spicuous, tuberculoid granulomas also form. A characteristic feature Coccidioides and their multiplicity from Blastomyces.
is the so-called ‘suppurating pseudotubercle’, in which a central
microabscess is enclosed within a complex of epithelioid histiocytes Clinicopathological features
and multinucleate giant cells (see Fig. 5.4.34). Alternatively, an over-
Both pulmonary and disseminated forms of the disease are described.187
whelming infection may cause diffuse alveolar damage.184,185 The
After the establishment of a primary complex in the lung and hilar
infection is usually confined to the lungs and hilar lymph nodes but
lymph nodes there may be haematogenous dissemination. Primary
dissemination by the blood stream may occur, particularly if immu-
infection occurs in childhood and generally heals spontaneously. The
nity is impaired.186 However, blastomycosis is not a common mani-
sexes are affected equally in childhood but the development of the
festation of AIDS.
yeasts is inhibited by oestrogens and in adults the disease is largely
limited to male agricultural workers. It is also described in patients
with AIDS.191 Disseminated disease tends to be acute and generalised
PARACOCCIDIOIDOMYCOSIS (’SOUTH in children and chronic and localised in adults. Chronic disseminated
AMERICAN BLASTOMYCOSIS’)187,188 disease may take the form of lymphadenopathy, painful oro­
pharyngeal ulceration or destruction of tissues such as the adrenal
glands. Progressive pulmonary paracoccidioidomycosis is character-
Epidemiology ised by multiple cavities that mimic tuberculosis, or by progressive
Infection with Paracoccidioides brasiliensis is limited to Latin American fibrosis of the lower lobes with traction bronchiectasis and paracica-
countries from Mexico to Argentina but does not occur in all countries tricial emphysema in a bilaterally symmetrical distribution.192 The
in this area. The endemic regions are the tropical and subtropical tissue response is generally granulomatous but may be purulent (Fig.
forests, particularly those of Brazil, Venezuela and Colombia. 5.4.36). Calcification is not a prominent feature. The diagnosis is
Paracoccidioidomycosis has not been proved to occur in any other established by recognising the spores in smears or culture of sputum
part of the world. Cases reported from North America189 and England190 or pus, or in tissue sections, or by serology. Biopsy is an excellent
had all lived in South or Central America. The fungus is thought to diagnostic procedure. The spores are best recognised with silver stains.
live in the soil but its exact ecological niche is still unknown. Humans
are the only known naturally infected animal host. Person-to-person
transmission is of little importance in the epidemiology of the disease, RARE PULMONARY MYCOSES
which is thought to be acquired by inhalation.

Fungi responsible for extrinsic allergic alveolitis are listed in Table

Mycology 6.1.4 (p. 279) and the occurrence of intracavitary colonies of various
P. brasiliensis is a dimorphic fungus that grows as a mould at ambient fungi is mentioned on page 231. Allergic bronchopulmonary
temperatures and as a yeast at 37°C. Infection is acquired by inhala- candidosis, helminthosporiosis, penicilliosis and curvulariosis, similar
tion of conidia produced in the mycelial phase. The spores that form to the more familiar allergic aspergillosis, have all been described on
its tissue form are round or ovoid and vary in size from 5 to 30 µm. rare occasions.97

243
 Pathology of the Lungs

round or ovoid budding yeast forms, 2–4 µm in size, in the areas

of necrosis. Hyphae bearing sessile budding yeasts are found
infrequently.

Adiaspiromycosis204–212
Adiaspiromycosis is caused by a remarkable fungus, Emmonsia (also
known as Chrysosporium), which is a dimorphic filamentaous soil
saprophyte of worldwide distribution. Its principal species are E.
crescens and E. parva. The term ‘adiaspiromycosis’ derives from the
conidia of this fungus, which are quite small but at 37°C exhibit the
unique property of progressive enlargement, perhaps a million-fold
in volume, without replication, when they are known as adiaspores.
The disease is ordinarily limited to wild rodents but has been seen
exceptionally in humans. It is characterised by the formation of tuber-
culoid granulomas around the inhaled adiaspores, which are usually
solitary. The adiaspores have a prominent yellowish wall, up to about
Figure 5.4.36  Paracoccidioidomycosis. There is a giant cell and 8 µm in thickness, surrounding a central mass of amorphous cyto-
neutrophil reaction to numerous spores of Paracoccidioides brasiliensis. plasm in which there is a single nucleus. The adiaspores are remark-
able for the great size that they may reach – as much as 600 µm
in diameter. They are too large to be effectively mobilised by the
host cells and the granulomatous response usually maintains a
Pulmonary mycoses not dealt with above are rare and ordinarily bronchiolocentric distribution indicative of inhalational infection.
occur as a result of lowering of the body’s resistance by other diseases Dissemination is unusual but is recorded in AIDS.210 Diagnosis relies
or their treatment.193 Some examples are dealt with below. Others on recognition of the fungus in tissue sections, as serology and culture
include infection by the common saprophytic mould Geotrichum can- are unreliable.
didum, Trichosporon cutaneum, the organism of white piedra (tinea Light infection may result in a solitary adiaspiromycotic granuloma
alba),194,195 Chaetomium globosum,65 Paecilomyces lilacinus,196 Dactylaria which would only be found incidentally in an asymptomatic indi-
gallopava197 and Ochroconis galloparvum.198 Chromomycosis (caused by vidual. Widespread adiaspiromycotic granulomas are indicative of
species of Phialophora or Cladosporium) and rhinosporidiosis (caused heavy infection and patients so affected may complain of fever, cough
by Rhinosporidium seeberi) are very occasionally found as infections of and dyspnoea and show a diffuse, micronodular pattern on chest
the lungs; in most cases such infection has spread, by the airways or radiographs.207 Death is very unusual.208 Healing is by progressive
in the blood, from a site elsewhere in the body. fibrosis and calcification.

Torulopsosis Malasseziosis
Torulopsis glabrata, also known as Candida glabrata, is a common yeast Malassezia furfur, the causative organism of tinea versicolor (pityriasis
on the body surface, and is frequently isolated as a contaminant of versicolor), is dependent for its growth on high concentrations of
urine cultures. Human infection is usually opportunistic, taking the fatty acids and is normally limited to the skin. Systemic infection
form of pneumonia, septicaemia, pyelonephritis or endocarditis in has however complicated prolonged lipid infusions through central
debilitated or immunocompromised patients, particularly those with venous catheters, in which circumstances the small yeast-like organ-
AIDS or advanced cancer or being treated with wide-spectrum anti­ isms have been noted infiltrating the walls of pulmonary arteries
biotics.199,200 Pulmonary infection is often by aspiration. Unlike and in small pulmonary thromboemboli.213,214 As is so often the
Candida albicans it does not form hyphae. Its cells are nearly invisible case with fungi, identification of the species depends upon cultural
in haematoxylin and eosin sections but are easily seen in Grocott characteristics.
preparations. They are difficult to distinguish from those of
Histoplasma capsulatum but are rounded rather than ovoid.
Pseudallescheriosis (monosporiosis)
Pseudallerscheria boydii (syn. Petriellidium boydii, Allescheria boydii) is a
Sporotrichosis
fungus of worldwide distribution in soils, and is of low pathogenicity.
Sporotrichosis is usually seen as an indurated ulcer of the finger It is the commonest cause of mycetoma in Europe and North America,
acquired from the prick of a thorn. Pulmonary involvement is rare gaining access to the subcutaneous tissues through cuts and abrasions
and when present is generally secondary to disseminated lympho­ in the skin. Pulmonary involvement may occur through the inhalation
cutaneous sporotrichosis. Primary pulmonary sporotrichosis (involve- of airborne spores, taking the form of an intracavitary fungal ball,
ment of the lung in the absence of cutaneous disease) is distinctly comparable to an aspergilloma, or in conditions such as leukaemia it
unusual.201–203 However, because it mimics tuberculosis, its incidence may be invasive and disseminate widely.104,215–218 Allergic broncho­
may be greater than is generally recognised. The causative agent, pulmonary pseudallescheriosis is also described.96
Sporothrix schenckii, is a yeast-like fungus that occurs worldwide on Pseudallerscheria boydii usually grows in hyphal form within the
decaying vegetation, contaminated soil and living plants, especially body but within air-filled cavities conidia may develop. The conidial
roses. Primary pulmonary sporotrichosis is acquired by inhalation of state is known as Monosporium (syn. Scedosporium) apiospermum and
the spores and usually presents as a chronic, cavitary, bilateral, apical infection showing such growth may be termed monosporiosis. The
disease, most often in a clinical setting of alcoholism and chronic hyphae are slender, thin-walled and of fairly constant diameter with
obstructive airway disease: less often it forms a solitary, necrotising, numerous septa and branching points. The hyphae are slightly
peripheral pulmonary nodule.202 Fungal stains demonstrate many indented at the septa. They are more slender and their branches less

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 Infectious diseases Chapter |5|

clearly dichotomous than those of aspergilli but the differences are infect many animals and have emerged as important opportunistic
insufficient to discriminate between them with confidence morpho- pathogens in AIDS.221,222 They are also being increasingly recog­
logically. This requires immunohistochemistry.66 The distinction of nised in HIV-negative individuals.223 Four microsporidian genera,
these two fungi is important because their drug sensitivities differ.217 Enterocytozoon, Encephalitozoon, Pleistophora and Nosema, have been
reported to infect humans. Infection generally involves the gastro­
intestinal tract but may become generalised.223,224 Pulmonary involve-
Penicillium marneffei infection ment is unusual but heavy infestation of the tracheobronchial mucosa
Penicillium marneffei is a dimorphic fungus endemic in South-east is recorded.225–229 The infected respiratory epithelium may show focal
Asia.219 At room temperature it grows as a mould with red to black proliferation with little inflammation or there may be a lymphocytic
conidia whereas in tissue it forms a 3–5-µm yeast-like cell that divides infiltrate of the airway epithelium similar to that seen in the bowel;
by binary fission. The yeasts therefore display clear central septation, heavy infestations cause sloughing and ulceration of the tracheobron-
unlike H. capsulatum and other fungi that divide by budding. Infection, chial mucosa and severe subacute inflammation. In haematoxylin and
which is highest after the rainy season, is by inhalation but the pul- eosin-stained sections the parasite appears as a supranuclear ‘blue
monary changes are usually overshadowed by systemic features such body’ but the staining is weak and it is easily overlooked, even when
as hepatosplenomegaly, skin lesions and bone marrow involvement. infestation is heavy. It is ovoid or spherical, and measures approxi-
However, there may be diffuse infiltration, mass lesions or cavities in mately 2 µm in length, and is Gram-positive. Microsporidia differ
the lungs. While it can affect the immunocompetent, infection is from cryptosporidia, which attach to the outer surface of infected
mainly associated with AIDS, for which it is a clinical marker in the epithelial cells, in being obligate intracellular parasites. Immuno­
endemic areas.220 cytochemistry, electron microscopy and in situ hybridisation are
useful for confirming the diagnosis.230 Antiretroviral therapy has been
shown to improve gastrointestinal symptoms, presumably through
Microsporidiosis restoring immunity,231 and albendazole has also been effective in
Microsporidia, once thought to be protozoa, are now regarded as some patients.
extremely reduced fungi. They are obligate intracellular parasites that

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detection of Histoplasma in surgically Blastomycosis. Infect Dis Clin North Am 194. Saul SH, Khachatoorian T, Poorsattar A,
excised pulmonary granulomas. Arch 2003;17:21–40, vii. et al. Opportunistic Trichosporon
Pathol Lab Med 2007;131:780–3. 181. Taxy JB. Blastomycosis: contributions of pneumonia. Arch Pathol Lab Med
165. Symmers WStC. Histoplasmosis contracted morphology to diagnosis: a surgical 1981;105:456–9.
in Britain: a case of histoplasmic pathology, cytopathology, and autopsy 195. Ito T, Ishikawa Y, Fujii R, et al.
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166. Goodwin RA, Loyd JE, Des Prez RM. 182. Lemos LB, Guo M, Baliga M. leukaemia. Cancer 1988;61:585–8.
Histoplasmosis in normal hosts. Medicine Blastomycosis: organ involvement and 196. Ono N, Sato K, Yokomise H, et al. Lung
(Baltimore) 1981;60:231–66. etiologic diagnosis. A review of 123 abscess caused by Paecilomyces lilacinus.
167. Lehan PH, Furculow ML. Epidemic patients from Mississippi. Ann Diagn Respiration 1999;66:85–7.
histoplasmosis. J Chronic Dis Pathol 2000;4:391–406. 197. Mazur JE, Judson MA. A case report of a
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Thorax 1987;42:698–9. cases. South Med J 1999;92:289–95. Multiple lung abscesses due to Ochroconis
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large urban outbreaks. Medicine distress syndrome. N Engl J Med 199. Aisner J, Schimpff SC, Sutherland JC, et al.
1983;62:263–70. 1993;329:1231–6. Torulopsis glabrata infections in patients
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clinical findings, diagnosis and treatment, and review of the literature. Ann Diagn 200. Srivastava S, Kleinman G, Manthous CA.
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202. England DM, Hochholzer L. Primary in premature infants. Am J Clin Pathol an Italian AIDS patient: a retrospective
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203. England DM, Hochholzer L. Sporothrix Pathology of hyalohyphomycosis caused et al. Disseminated microsporidiosis
infection of the lung without cutaneous by Scedosporium apiospermum (Encephalitozoon hellem) and acquired
disease. Primary pulmonary sporotrichosis. (Pseudallescheria boydii): An emerging immunodeficiency syndrome – autopsy
Arch Pathol Lab Med 1987;111:298–300. mycosis. Hum Pathol 1998;29:1266–72. evidence for respiratory acquisition. Arch
204. Watts JC, Callaway CS, Chandler FW, et al. 216. Nonaka D, Yfantis H, Southall P, et al. Pathol Lab Med 1992;116:660–8.
Human pulmonary adiaspiromycosis. Arch Pseudallescheriasis as an aggressive 226. Weber R, Kuster H, Keller R, et al.
Pathol 1975;99:11–5. opportunistic infection in a bone marrow Pulmonary and intestinal microsporidiosis
205. Schwarz J. Adiaspiromycosis. Pathol Annu transplant recipient. Arch Pathol Lab Med in a patient with the acquired
1978;13:41–53. 2002;126:207–9. immunodeficiency syndrome. Am Rev
206. Rippon JW. Medical Mycology: The 217. Raj R, Frost AE. Scedosporium apiospermum Respir Dis 1992;146:1603–5.
Pathogenic Fungi and the Pathogenic fungemia in a lung transplant recipient. 227. Schwartz DA, Visvesvara GS, Leitch GJ,
Actinomycetes. 3rd ed. Philadelphia: W.B. Chest 2002;121:1714–16. et al. Pathology of symptomatic
Saunders; 1988. p. 718–21. 218. Jayamohan Y, Ribes JA. Pseudallescheriasis: microsporidial (Encephalitozoon hellem)
207. Filho JVB, Amato MBP, Deheinzelin D, a summary of patients from 1980–2003 in bronchiolitis in the acquired
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219. Deng Z, Ribas JL, Gibson DW, et al. biopsy, bronchoalveolar lavage, sputum,
208. Peres LC, Figueiredo F, Peinado M, et al.
Infections caused by Penicillium marneffei and tissue culture. Hum Pathol
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adiaspiromycosis in humans. Am J Trop
Med Hyg 1992;46:146–50. eighteen published cases and report of 228. Cowley GP, Miller RF, Papadaki L, et al.
four more Chinese cases. Rev Infect Dis Disseminated microsporidiosis in a patient
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1988;10:640–52. with acquired immunodeficiency
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220. McShane H, Tang CM, Conlon CP. syndrome. Histopathology 1997;30:
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infection presenting as a right upper lobe 229. Scaglia M, Sacchi L, Croppo GP, et al.
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mass in an HIV positive patient. Thorax Pulmonary microsporidiosis due to
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pathology of microsporidiosis. Arch Pathol 230. Velasquez JN, Carnevale S, Labbe JH, et al.
211. Nuorva K, Pitkanen R, Issakainen J, et al.
Lab Med 1993;117:1215–19. In situ hybridization: A molecular
Pulmonary adiaspiromycosis in a two year
222. Schwartz DA, Sobottka I, Leitch GJ, et al. approach for the diagnosis of the
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212. Denson JL, Keen CE, Froeschle PO, et al. bieneusi. Hum Pathol 1999;30:54–8.
Adiaspiromycosis mimicking widespread parasitic infections in patients with
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malignancy in a patient with pulmonary
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microsporidiosis. Ultrastruct Pathol patients infected with human
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in patients receiving intralipid therapy. 224. Tosoni A, Nebuloni M, Ferri A, et al.
Hum Pathol 1988;16:852–4. Disseminated microsporidiosis caused by
214. Shek YH, Tucker MC, Viciana AL, et al. Encephalitozoon cuniculi III (Dog type) in
Malassezia furfur – Disseminated infection

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5.5  Parasitic infestations

are responsible for hydatid disease and cysticercosis respectively,

CHAPTER CONTENTS
whilst nematodes found in the lung include immature forms of
Protozoa 252 Ascaris, Strongyloides, Ancylostoma, Necator, Wuchereria and Brugia and
Toxoplasmosis 252 the adult forms of heartworm (Dirofilaria) and gapeworm (Syngamus).
Arthropods include the ticks and mites (arachnids), adult forms of
Amoebiasis 252
which may cause pulmonary acariasis. Pulmonary pentastomiasis is a
Malaria 253 manifestation of infestation by larvae of Linguatula or of Armillifer.
Leishmaniasis 253 The mode of transmission is variable. Some of these parasites are
Cryptosporidiosis 253 transmitted by an insect bite e.g. those causing tropical pulmonary
Trichomoniasis 254 eosinophilia, dirofilariasis and malaria, while some penetrate the skin
directly e.g. Strongyloides, hookworms and schistosomes, and others
Helminths 254 are ingested e.g. Paragonimus, Entamoeba and Echinococcus.
Trematodes 254 The human lungs may be involved in the life-cycle of these parasites
Cestodes 256 in various ways:
Nematodes 257 1. The lungs may be the natural location of the parasite, for
Hookworm infestation 258 example Paragonimus and Syngamus.
2. The larval form of the parasite may encyst in the lungs, for
Arthropods 259
example Echinococcus.
Pulmonary acariasis 259 3. The lung may be a migratory route for the larvae of the parasite:
Pentastomiasis 260 this includes most of the nematodes listed above and the larvae
Myiasis 260 responsible for pentastomiasis.
References 260 4. The parasite may reach the lungs as an embolus: most
schistosomal ova and the dead adult canine heartworm,
Dirofilaria, are examples of this.
5. The parasite may invade the lung through the diaphragm from
This chapter describes infestation of the lungs by certain parasitic the liver, for example Entamoeba histolytica and the liver fluke
protozoa, helminths and arthropods, of which man may be either the Opisthorchis.
natural or the accidental host. 6. The lungs may be involved in disseminated parasitosis, for
Protozoal diseases of the lungs include toxoplasmosis, leishman­ example microsporidiosis in the acquired immune deficiency
iasis and amoebic abscess while severe malaria may be complicated syndrome.
by acute respiratory failure. Also, parasites usually confined to other Although immunodeficient patients are particularly prone to
organs may be identified in the lungs, for example cryptosporidia in parasitic infestation, most of these pulmonary parasites are capable of
AIDS and trichomonas in aspiration lesions. infecting and causing disease in the immunocompetent; only a few
Helminths of all three major classes may infest the lung. Trematodes are opportunists (e.g. Cryptosporidium spp.). Many of them have a
include the blood flukes (genus Schistosoma), the lung flukes (genus characteristic distribution, often in tropical or subtropical countries.
Paragonimus) and certain liver flukes (genus Opisthorchis). The cestodes In the developed world parasitic diseases of the lung mainly affect
are represented by the larval forms of Echinococcus and Taenia, which immigrants and tourists.

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 Pathology of the Lungs

PROTOZOA

Protozoa are unicellular eukaryotic microbes that reproduce vegeta-

tively (as trophozoites) but encyst when conditions are unfavourable.
Some are parasitic to man. A comprehensive review of those that affect
the human lungs, including their taxonomy and treatment, has
recently been provided.1

Toxoplasmosis
Toxoplasmosis represents infection with the coccidian parasite
Toxoplasma gondii, this name deriving from the crescentic bow shape
of the parasite’s tachyzoites and its discovery in the gondi, a North
African rodent used as a laboratory animal. The domestic cat is the
usual definitive host from which man is infected but the disease occurs
in many species of wild and domestic birds and mammals, all of
which provide a ready source of human infection. Ingestion of infected
animal material is the usual route of infection of adults but neonatal
disease generally reflects placental transmission. Toxoplas­mosis is one
Figure 5.5.1  A Toxoplasma cyst exciting little inflammatory reaction in
of the most prevalent protozoal infections of man but the parasite
the surrounding lung.
rarely harms its host and the vast majority of human infections remain
occult throughout life, causing damage only when cellular immunity
is impaired. Gametogenesis and oocyst formation take place in the and proliferate within host cells to form distinctive collections known
intestine of animals such as cats; outside the body, sporozoites are as pseudocysts. These resemble true cysts in size and appearance but
liberated which can infect other species, including man. Only asexual are intracellular and lack an outer membrane. Cysts and pseudocysts
cysts containing dormant bradyzoites are formed in normal accidental are easier to recognise than individual tachyzoites but both are gener-
hosts but if immunity fails the cysts liberate motile tachyzoites and it ally very rare.
is these that swarm through the host tissues causing cell damage and Treatment with pyrimethamine and sulfonamides is effective if
inflammation. initiated promptly.10 The mortality for toxoplasma pneumonia is
Pulmonary toxoplasmosis is rare and most cases have been in 55%, although survival is much better in the immunocompetent.11
patients suffering from generalised disease attributable to immuno­
deficiency from diseases such as lymphoma and AIDS. Transplant
recipients are also liable to develop toxoplasmosis. Because many of
these patients undergo toxoplasma sero-conversion after they receive
Amoebiasis
new organs, it is likely that the parasite is introduced in the donor Entamoeba histolytica, the causative organism of amoebic dysentery, is
tissues in which it presumably lay dormant. In lung transplant a protozoon with a trophozoite and a cystic stage that is endemic in
patients, recognition of the parasites in transbronchial biopsies is much of sub-Saharan Africa, South America and southern Asia.
important in distinguishing infection from the changes of graft rejec- Infection is acquired by the ingestion of food or water contaminated
tion. Because of the size of the parasite relative to the thickness of by amoebic cysts. Trophozoites develop in the small intestine and are
tissue sections, many laboratories involved in transplantation work carried to the large bowel, which they ulcerate. From there they may
cut serial sections through these small biopsies. spread in the blood, giving rise to metastatic foci of infection. These
Pulmonary infection is initially non-specific. There is an interstitial are found most frequently in the liver, lungs and brain, in that order.
infiltrate of lymphocytes, and alveolar macrophages are increased. Although the lesions in these organs are conventionally described as
Hyaline membranes may develop, indicating necrosis of the alveolar abscesses, they are not accompanied by suppuration unless there is
epithelium, and the changes are then those of diffuse alveolar damage. secondary bacterial infection.
Alveoli adjacent to those lined by hyaline membranes show type II If there is amoebic ulceration of the lower part of the rectum,
pneumocyte hyperplasia. Up to this stage the parasites are scanty amoebae may reach the rectal venous plexus and, bypassing the liver,
but if immunity is sufficiently impaired, enormous numbers of make their way directly in the systemic circulation to the lungs. More
tachyzoites develop. These cause necrosis on a major scale. Air spaces often, amoebic pulmonary abscesses are secondary to those in the
may be filled with necrotic debris or broad tracts of the lung under­ liver: the amoebae pass though the diaphragm to infect the lungs and
go coagulative necrosis.2–7 In one case macrophages filled with are therefore commoner in the right lung. Whether the pleural cavity
toxoplasma trophozoites formed a mass lesion.8 becomes infected in the course of this extension of the disease from
Individual tachyzoites are very difficult to recognise in histological liver to lung depends on whether adhesions have formed that bind
sections but their identification is facilitated by immunocyto­ the apposed pleural surfaces sufficiently to protect the cavity from
chemistry,6,7 which is superior to the Giemsa stain formerly used. The invasion. Pleuropulmonary complications develop in less than 5% of
tachyzoites are crescentic in shape and measure within the range 4–7 patients with intestinal amoebiasis but in 50% of those with liver
× 2–3 µm with a prominent central nucleus.9 The intracystic abscesses. They may include bronchohepatic fistulas.12
bradyzoites tend to be shorter and more rounded. The cysts, which An amoebic abscess in the lung, like one in the liver, is essentially
represent the latent form of the parasite, lie free in the intercellular a focus of localised destruction in which part of the lung is converted
tissues and provoke no inflammatory response (Fig. 5.5.1). They vary into a cavity filled with reddish-brown, viscous fluid. There is little
considerably in size but are commonly of the order of 60 µm in inflammatory reaction in the surrounding tissues but amoebae with
diameter. Single tachyzoites are difficult to identify but they invade their characteristic ingested erythrocytes may be seen in the zone

252
 Infectious diseases Chapter |5|

bordering the cavity or on aspiration cytology.13 Often the area of

destruction extends to involve one of the bronchi, and much of the
contents, often blood-stained, may then be expectorated. Should this
happen, there may be secondary bacterial infection of the cavity.
Metronidazole is the treatment of choice.12
In addition to E.histolytica, certain free-living amoebae have
occasionally caused disease in man, of which two, Acanthamoeba spp.
and Balamuthia mandrillaris have been responsible for pulmonary
disease.14

Malaria
Severe Plasmodium falciparum malaria may be complicated by acute
respiratory failure.15–17 This is usually due to non-cardiogenic oedema,
reflecting increased permeability of the alveolar capillaries.18
Alternatively, patients may display the acute respiratory distress
syndrome, which as usual has diffuse alveolar damage as its path­
ological basis.
It is suggested that the various cytokines that have been identified
in the general circulation in complicated forms of malaria19–21 may be
more important than the ischaemia occasioned by heavy erythrocyte
parasite burdens rendering the red blood cells less deformable and so Figure 5.5.2  Pulmonary involvement in disseminated leishmaniasis. The
protozoa are seen within macrophages in alveoli and capillaries. (Courtesy
inclined to occlude capillaries. However, blood sludging undoubtedly
of Dr J DeGaetano, Malta.)
takes place in the lungs as well as the brain and elsewhere. The pul-
monary capillaries are engorged with parasitised erythrocytes, pig-
ment-laden macrophages and neutrophils. This is contributed to by
endothelial activation and increased expression of intercellular ad­­
hesion molecule-122 as well as the non-deformability of the parasit-
ised cells. The alveoli are filled with protein-rich or haemorrhagic
oedema fluid, often containing pigment-laden macrophages, or
show the hyaline membranes of diffuse alveolar damage.
The parasites in the lung are largely early trophozoites or ring forms
rather than the later schizonts that predominate in cerebral vessels,
possibly because the higher oxygen levels in the lung inhibit plasmo-
dium maturation.23 Therapeutic measures resulting in fluid overload
and oxygen toxicity may aggravate the respiratory distress. Even after
treatment, altered pulmonary function in malaria is common, with
airflow obstruction, impaired ventilation, impaired gas transfer, and
increased pulmonary phagocytic activity. This occurs in both vivax and
falciparum malaria suggesting common underlying inflammatory
mechanisms.24

Leishmaniasis Figure 5.5.3  Cryptosporidia (arrows) are seen in the bronchial lumen of
a patient suffering from acquired immunodeficiency syndrome (AIDS).
Visceral leishmaniasis, which is contracted by the bite of an infected (Courtesy of Dr M Antoine, Paris, France.)
sandfly, is characterised by fever, weight loss, splenomegaly and
hepatomegaly. Most patients also complain of cough but there are few
reports of pulmonary involvement. As in the spleen and liver, the faecal–oral transmission of an encysted form and generally involves
leishmania are contained within macrophages (Fig. 5.5.2) but are drinking contaminated water. A small number of immunocompro-
difficult to find. One study identified chronic interstitial pneumonitis mised patients show respiratory as well as enteric infection, complain-
in 10 of 13 cases of visceral leishmaniasis, accompanied in 7 by focal ing of cough and chest pain (Fig. 5.5.3).28–31
interstitial fibrosis.25 Leishmania donovani were identified in only 3 Cryptosporidia are extracellular protozoan parasites which adhere
cases but leishmanial antigenic material was recognised immuno­ to the surface of lining epithelia. They are seen as faintly haema­
cytochemically in all cases showing pneumonitis and in none of toxyphil dots measuring up to 5 µm arrayed along the mucosal
the others. surface. In the respiratory tract they have been identified on the surface
and glandular epithelium of the trachea and bronchi and in the
lung parenchyma, associated with extensive squamous metaplasia of
Cryptosporidiosis
the conductive airways.29 The superficial location of cryptosporidia
Cryptosporidia species cause diarrhoea in many species.26 In man, helps distinguish them from microsporidia, which are found within
enteric cryptosporidiosis was first recognised in an immunodeficient the cytoplasm of epithelial cells. Electron microscopy shows that
patient and the disease has now become a serious problem in AIDS.27 cryptosporidia occupy a vacuole that communicates with the cell
It also affects the immunocompetent and is a common cause of surface: they lie just beneath the level of cell membrane but are nev-
short-term diarrhoea in day nurseries and in travellers. Infection is by ertheless extracellular.

253
 Pathology of the Lungs

Treatment may require immune reconstitution as well as the admin-

istration of drugs such as paromomycin, azithromycin and nitazoxa-
nide, for which varying success is reported.26,32,33

Trichomoniasis
The finding of trichomonads in human lungs is rare. Trichomonas
hominis, the intestinal trichomonas, has spread to the pleura via an
enteropleural fistula, and T.vaginalis has been isolated from the respi-
ratory tracts of newborn babies, but pulmonary trichomoniasis is
usually caused by aspirated T.tenax.34–36 Trichomonads cannot persist
without associated bacterial infection and T.tenax is generally found
as a harmless commensal in patients with poor oral hygiene, surviving
in carious teeth where it feeds on the bacteria responsible for the
dental decay. Pulmonary trichomoniasis is usually found as part of a
mixed infection in adult men with chronic purulent or necrotic lung
disease such as lung abscess or bronchiectasis. The flagellated proto-
zoan may be identified by microscopic examination of wet-smear,
Gram-stained or Papanicolaou-stained preparations but cultural iden-
tification is reputed to be superior to these methods.34 Aspirated pul-
monary trichomoniasis is an opportunistic infection of dubious
pathogenicity, but it seems advisable that it be treated appropriately
(with metronidazole).

Figure 5.5.4  Schistosomiasis. Schistosomal ova are evident (centre)

within the alveolar interstitium, which also shows a lymphocytic infiltrate.
HELMINTHS

Trematodes
Schistosomiasis
Pulmonary schistosomiasis (bilharziasis) may be due to any of
the three most important species of human blood fluke, Schistosoma
haematobium, S.mansoni and S.japonicum. Although involvement of
the lung is relatively infrequent as a cause of clinical disease in com-
parison with the major locations of schistosomal infestation, it is
recognised wherever schistosomiasis is endemic. However, with
increased international travel, it seems that the non-endemic pop­
ulation has a higher incidence of pulmonary involvement once
infected.37,38 Specific changes are found in the lungs in a third of cases
of clinically evident schistosomiasis in Egypt but contribute to death
in only about 2% of these patients.39,40 The frequency of pulmonary
involvement is least in the Far East where schistosomiasis is due to
S.japonicum.
The schistosomal cercariae thrive in fresh water and penetrate the Figure 5.5.5  Schistosomiasis. Lodgement of the schistosomal eggs in the
skin to to transform into immature adults, which are transported in pulmonary microcirculation has provoked a vigorous granulomatous
the blood to mature in venous plexuses around the bladder or rectum, response.
where they reproduce. Pulmonary infestation generally comes from
ova being carried to the lungs in the blood, either bypassing the portal
venous circulation or having been produced by flukes inhabiting consequent angiomatoid lesions are attributable to vascular obstruc-
plexuses that drain directly into the inferior vena cava. Alternatively, tion by the ova, to an allergic response to the parasite, or to the ‘pip-
if adult parasites are present within the pulmonary vasculature itself, estem’ hepatic fibrosis that is commonly found in schistosomiasis
ova are produced locally. permitting vasoconstrictive substances that normally are metabolised
The ova, which measure from 70 to 170 µm in length by 50 to in the liver to reach the pulmonary arteries.41 Cor pulmonale may
70 µm in breadth, according to the species, are bound by their dimen- complicate pulmonary schistosomiasis and aneurysmal dilatation of
sions to lodge in blood vessels of corresponding calibre; local throm- the pulmonary trunk has been observed in long standing cases.
bosis and organisation result, with the formation of a characteristic The ova also pass through the walls of the pulmonary vessels and
tuberculoid granuloma round the egg itself (Figs 5.5.4 and 5.5.5).39 initiate parenchymal lesions characterised by a similar granulomatous
Medial hypertrophy, intimal fibrosis, thrombosis, necrotising angiitis reaction and more widespread lymphocytic infiltrate and interstitial
and angiomatoid lesions (see p. 422) develop in the obstructed fibrosis. Although the ova may be much distorted during tissue
arteries.39,41 Eosinophils may be conspicuously numerous in the vicin- processing, they are readily seen and recognised, particularly if they
ity of the ova. It is uncertain whether the necrotising arteritis and were viable at the time when the specimen was obtained (see Fig.

254
 Infectious diseases Chapter |5|

5.5.4). Dead ova often become heavily calcified but may long retain
identifiable traces of the contained embryo. Eosinophilic infiltration
and necrotising angiitis are only seen in the presence of viable ova.
The presence of eggs, viable or dead, is generally the clue to the
diagnosis, but in some cases pulmonary arterial lesions, including
thrombosis and arteritis, develop where no ova are demonstrable.
Occasionally, ova reach the respiratory bronchioles and cause a
local tuberculoid bronchiolitis. Sometimes a tumour-like mass forms
in the lungs, abutting and obstructing a bronchus: this proves to be a
confluent growth of granulomatous tissue and scarring around great
numbers of schistosome ova.
When adult flukes reach the lungs they appear to cause no reaction
while alive, any associated lesions being caused by the presence of
their ova. However, when the flukes die, thrombosis and arteritis
result, and there is commonly an accompanying focal consolidation
of the adjacent parenchyma. This gives rise to nodules up to 1 cm and A
more in diameter that show as small ‘coin’ shadows in chest
radiographs.

Katayama fever
As well as the classic chronic form of schistosomiasis described above,
pulmonary symptoms such as cough feature in the severe form of
acute schistosomiasis known as Katayama disease.15 This systemic
illness signifies seroconversion and develops about 3–6 weeks after
penetration of the skin by water-borne cercariae. It is almost
exclusively a disease of non-immune visitors to endemic areas and
has been reported in several groups of tourists returning from such
areas, especially those participating in water sports. The disease is self-
limiting but recognition and treatment are important to avoid the
sequelae of chronic infection.

B
Paragonimiasis
Infestation by lung flukes is endemic in the Far East, and to a lesser Figure 5.5.6  Paragonimiasis. (A) A ‘worm cyst’ including several
extent in central Africa and parts of the Americas. 42–44 In its early stages Paragonimus eggs in the chronic inflammatory granulation tissue that
the disease is characterised by chest pain or discomfort. Later, when borders the central necrosis. (B) Paragonimus eggs removed from the
it has become chronic, there is persistent cough and recurrent haemop­ lung (scale divisions = 10 µm).
tysis. Characteristic operculate eggs can then be found in the sputum;
they are golden-brown and measure about 90 µm in length. In some
cases the presence of the parasite is borne well; in others it leads to cooked, that man becomes infested. Pickling the crabs does not
anorexia and debility. As long as the flukes remain in the lungs the destroy the parasite. The disease may also be acquired by eating the
disease is rarely fatal, but should they reach the brain, as happens in flesh of another host, such as a pig, that has eaten infected crabs or
a minority of cases, the prognosis is grave. Occasionally the disease crayfish. On reaching the duodenum of the human host, the parasite
mimics lung cancer.45 Rapid and reliable immunodiagnostic methods penetrates the gut wall and thence passes by way of the peritoneal
are now available, and there are PCR techniques that distinguish cavity and diaphragm to the pleura and the lungs. It grows to a length
individual species.46,47 of 12 mm and attains maturity about five weeks after reaching the
The species most frequently responsible are Paragonimus westermani lungs and so completing its life cycle.
in the Far East and P.kellicotti in the Americas.44 Morphologically these In man the flukes often lie singly in the connective tissue ‘worm
differ from each other only slightly. The adults infest the lungs of cysts’, the number of which rarely exceeds ten, each about 1 to 2 cm
many predatory animals: P westermani in the dog, cat and pig, and across. They may excite an eosinophilic pneumonia, give rise to a
P.kellicotti in the mink. Small groups of them become sexually mature pleural effusion or cause pneumothorax.48 Sometimes the young
within the lung tissue, where necrosis and the formation of a fibrous worms go astray and reach the liver, spleen, kidneys or brain.
capsule produce characteristic ‘worm cysts’ (abscess cavities) that Occasionally dead worms in the lungs are associated with distant
eventually enlarge and break into the bronchial lumen (Fig. 5.5.6). tissue reactions that probably have a hypersensitivity basis. The
The ova that thus escape pass up the respiratory tract and are either diagnosis is based on the demonstration of the eggs in bronchial
expectorated or swallowed, to be eventually excreted in the stools. The secretions, pleural fluid or faeces.
life cycle of the fluke is a complex one: after several weeks in water or
moist earth, the ovum hatches into a miracidium, a free-swimming
form that eventually enters and parasitises water snails of the genus Opisthorchiasis
Melania. After its larval life in the snail, the fluke emerges as a cercaria, Liver flukes generally remain within the hepatic bile ducts but in
which in turn parasitises small fresh-water crabs and crayfish. It is Thailand Opisthorchis viverrini has on rare occasions made its way from
through the consumption of these crustaceans, raw or insufficiently the liver through the diaphragm to the right lung.49

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 Pathology of the Lungs

Figure 5.5.8  Hydatid cyst. The encysted larva of the Echinococcus

granulosus tapeworm has died and the parasite’s capsule has collapsed
away from the fibrous capsule formed by its human host.

Figure 5.5.7  Hydatid cyst, the encysted larval form of the Echinococcus
granulosus tapeworm, filled with numerous ‘daughter’ cysts.

Cestodes
Hydatid disease (larval echinococcosis)
This disease has long been endemic in sheep-raising countries, notably
Australia, New Zealand, Wales, parts of South Africa and South
America, and the Middle East.50 Control measures are steadily lessen-
ing its incidence. The dog is the usual host of the mature tapeworm,
Echinococcus granulosus, and sheep the commonest host of its larval
stage. The ova in the faeces of the dog reach sheep or man in contami-
nated food or water and, after hatching in the small intestine, larvae Figure 5.5.9  Hydatid cyst. The convoluted chitinous layer of a collapsed
penetrate the gut wall and enter the portal circulation. Most are dead hydatid cyst.
retained in the liver, but some negotiate the hepatic barrier to reach
the systemic venous circulation and the lungs. The larval forms of this
helminth thus tend to occur most frequently in the liver and the lungs. potential to develop into secondary cysts if released by cyst rupture.
They take the form of hydatid cysts (Fig. 5.5.7). If a hydatid cyst is They also form daughter cysts within the mother cyst, each daughter
demonstrated in the lung, others are almost always present in the liver. cyst being an exact true replica of the mother cyst. The daughter cysts
Pulmonary hydatid cysts are usually solitary but bilateral instances are may be packed together in the mother cyst or float freely in the mother
recorded.50–52 cyst cavity. In older cysts, the contents degenerate into gelatinous
The wall of a hydatid cyst is formed of a semipermeable laminated material known as the matrix, which may be mistaken for pus. The
capsule, which is composed of chitin, and an inner germinal layer. cysts are usually bacteriologically sterile but they may become infected,
Outside these is the pericyst, formed of a layer of chronic inflamma- resulting in true suppuration. Calcification commonly develops in the
tory granulation tissue or a fibrous capsule, these representing the host pericyst without affecting the viability of the parasite but calcification
reaction to the parasite (Figs 5.5.8 and 5.5.9). The germinal layer gives of the endocyst indicates that it is dead.
rise to brood capsules and from the germinal layer of these arise Because the parasite has evolved mechanisms to avoid host immu-
scolices. Free brood capsules and scolices form the hydatid ‘sand’ that nity, the infection is often asymptomatic until a mechanical complica-
can be seen as minute white grains in the otherwise clear cyst fluid tion occurs.53 Thus, most cases of pulmonary hydatid disease are
(Fig. 5.5.10). When sheep tissues containing hydatid cysts are eaten discovered on routine chest radiography. Symptoms stem from com-
by a dog, the scolices attach to the intestinal mucosa and develop into pression, infection or rupture into a bronchus. The sudden escape of
the adult worms, thus completing the life cycle. Scolices also have the a large amount of its fluid contents may give rise to a grave, even fatal,

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days after ingestion of the eggs. In the lungs, the larvae pierce the
alveolar wall to reach the air space, whence they are cleared to the
pharynx to be swallowed. Maturation, copulation and ovulation occur
in the small intestine.
Toxocara canii and cati are respectively the corresponding round-
worms of dogs and cats, human infection by which is acquired
through close contact with these animals or with soil contaminated
by their faeces. Toxocarae do not complete their life-cycle in man but
dissemination of their larvae simulates visceral ascariasis, resulting in
what is known as visceral larva migrans.
Migration of these worms through the lungs may cause self-limiting
pulmonary eosinophilia (Löffler’s syndrome, see p. 460) during which
eosinophils and Charcot–Leyden crystals are often conspicuous in the
sputum, although the larvae themselves are rarely seen. The illness is
usually over within three weeks but in exceptional cases respiratory
distress becomes so severe that the patient may die.60
Microscopical studies of the pulmonary lesions have been infre-
quent except in the rare fatal cases, or when the parasites are present
by chance in lungs examined as a result of other disease. The larvae
may be found in capillaries, the interstitial tissues, or air spaces,
accompanied by eosinophils and neutrophils. When a larva dies, an
Figure 5.5.10  Hydatid cyst. An echinococcal scolex from a ruptured intense reaction may develop, with dense local accumulation of
hydatid cyst is surrounded by pus. eosinophils, lesser numbers of macrophages and neutrophils, and
fibrin. Identifiable remnants of larvae may be seen, sometimes in
multinucleate giant cells. There may be local haemorrhage.
The larvae of A.lumbricoides, the ascarid parasite of man, are difficult
anaphylactic reaction. Rupture of a hydatid cyst into a bronchus may to distinguish from those of other ascarids, such as species of
also cause bronchocentric granulomatosis54 or lymphoid hyperplasia. Toxocara, that may also be found in human lung tissue or pleural
Aspiration of the cyst contents should not be undertaken because of fluid.61 Morphological differentiation of these larvae in histological
the risk of spillage and a consequent hypersensitivity reaction. The preparations is commonly beyond the ability even of professional
treatment of choice for compressive cysts is surgical resection, with parasitologists but investigation by means of specific immuno­
particular care being exercised to avoid rupture of the cyst, and post- cytochemical staining may be decisive. The larvae of the toxocarae
operative drug therapy using albendazole.55–57 have a greater tendency than those of A.lumbricoides to die in the lungs
when they infest man: they then cause pulmonary eosinophilia and
tuberculoid granulomas that eventually lead to fibrous encapsulation
Cysticercosis (larval taeniasis) of the remains of the parasites.
Cysticercosis occurs when man becomes the intermediate host of the
porcine tapeworm, Taenium solium, through the ingestion of the
Strongyloidiasis
worm’s eggs present in faecally contaminated water or food or on
soiled hands, or by the eggs hatching within the intestine of those Strongyloides stercoralis is another intestinal parasite that at one stage
harbouring the adult worm.58,59 The disease is common in Africa, in its development passes through the lungs. Infection is endemic in
China, south east Asia and South America. Once hatched, the embryo much of the tropics and subtropical regions. The filariform larvae of
penetrates the intestinal wall and is disseminated by the blood stream, strongyloides, like those of hookworms and schistosomal cercariae,
giving rise to an encysted larva. Such cysticerci may form anywhere have the ability to penetrate intact human skin, following which they
but the brain is particularly vulnerable. The lungs are seldom affected are carried to the lungs where they penetrate the alveoli and migrate
but may be the seat of either solitary or multiple lesions, the latter via the airways and upper gastrointestinal tract to the small intestine.
generally as part of disseminated disease, which probably reflects Here they mature into parthenogenetic adult females, the eggs of
immune impairment. The larva has an inverted scolex and lies within which release rhabditiform larvae within the intestine, unlike the eggs
clear fluid bounded by a thin fibrous capsule. Little inflammation is of other intestinal helminths which are passed intact in the faeces to
induced while the larvae are alive but after their death a variable embryonate in the soil. The rhabditiform larvae of Strongyloides may
response is seen, often culminating in calcification. pass with the faeces to complete a free-living sexual cycle in the soil
or differentiate within the intestine into filariform larvae, which are
capable of penetrating the bowel wall or the perianal skin to repeat
Nematodes their parasitic asexual cycle, an endogenous process known as auto­
infection. This difference between Strongyloides and other intestinal
Ascariasis and toxocariasis (‘visceral larva migrans’) helminths is important in maintaining the infection and, in immuno­
Although essentially an intestinal parasite, the large roundworm compromised hosts, leading to potentially fatal hyperinfestation.
Ascaris lumbricoides passes through the lungs during one phase of its Chronic strongyloidiasis has been well described among individu-
complex life cycle. Infection is endemic in much of Africa, Asia and als who were prisoners of the Japanese during the second world war:
South America. The infestation is acquired by ingesting food or water decades later, it affected a fifth of the survivors of those who worked
contaminated with ova passed in the faeces of an earlier host. The ova on the notorious Burma railway.62,63 Most infestations cause at most
hatch in the small intestine, where the larvae quickly penetrate the a creeping skin eruption (larva migrans) or chronic diarrhoea but
mucosa and are carried either to the liver in the portal bloodstream there is a real danger of fatal hyperinfestation if the individual becomes
or in lymph to the systemic veins, reaching the lungs about five or six immunosuppressed. This may happen when corticosteroid drugs are

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 Pathology of the Lungs

Filariasis: tropical eosinophilia

Filariasis is endemic in the tropics. The adult nematodes, Wuchereria
bancrofti, Brugia malayi, Brugia pahangi and Onchocerca volvulus inhabit
lymphatics where they produce eggs from which are released embryos
known as microfilariae. These circulate in the blood and disseminate
widely in the tissues, to be transmitted to others by mosquitoes.
Some of those infected present with ‘tropical eosinophilia’, a name
that was given to a condition that was initially described from the
coast of southern India but is now known to have a far wider distribu-
tion in the tropics.72 The clinical signs are fever, loss of weight, dys­
pnoea and asthmatic attacks; there is marked blood eosinophilia and
radiographs show nodular shadows in the lungs. The condition is
benign and little is known of the changes in the lungs. Such reports
as have been published describe whitish nodules 3 to 5 mm in diam-
eter, scattered irregularly throughout the lungs. Histologically, the
nodules are composed of groups of alveoli consolidated by eosino­
phils enmeshed in fibrin. In the centre of some of the nodules, the
alveolar walls are destroyed and the area becomes an ‘eosinophil
abscess’. In others, a central collection of epithelioid cells becomes
arranged in a palisade manner round deeply eosinophilic hyaline
material that probably represents inspissated granules of eosinophil
leukocytes. Giant cells and fibrosis are seen in some lesions and
microfilariae are sometimes observed.73,74 The condition is thought to
represent an immunopathological response to the parasite rather than
direct damage by the microfilariae because it is confined to those
individuals who are highly sensitised to filarial antigens.
Figure 5.5.11  Strongyloides stercoralis filaria in the lung in a case of Tropical eosinophilia is readily distinguished from other forms of
strongyloides superinfection. (Courtesy of the late Professor BE Heard, eosinophilia (which are described in Chapter 9) by the patient’s
Brompton, UK.) history of residence in the tropics, by the presence of extraordinarily
high levels of both serum IgE and antifilarial antibodies, and by a
dramatic therapeutic response to the filaricide diethylcarbamazine.

administered, particularly in the treatment of unrelated conditions

but also because of resistant asthma caused by unrecognised strongy- Dirofilariasis (heartworm infestation)
loidiasis. In cases of such asthma the dose of corticosteroids may be Pulmonary dirofilariasis occurs when man becomes an alternative
progressively increased when the patient would have been better host of the canine heartworm, Dirofilaria immitis, after being bitten by
treated with anti-helminthic drugs.64 Worsening asthma as the steroid a mosquito or sandfly infested with the microfilariae. Early develop-
dosage is increased should alert the clinician to the possibility of ment occurs in a subcutaneous nodule, whence after a few weeks’
hyperinfestation. Heavy infestation is often associated with blood development the young adult worm migrates to the right side of the
eosinophilia and fleeting pulmonary opacities that represent eosino­ heart and the pulmonary arteries. In man, the adult worm typically
philic pneumonia but these features may be absent in those who are dies while it is immature and is carried from the heart to the lungs as
immunosuppressed. Other risk factors include advanced age, chronic a parasitic embolus to occlude a small pulmonary artery. This gener-
lung disease and altered cellular immunity, particularly that found in ally causes no symptoms. A necrotising granuloma forms about the
adult T-cell leukaemia complicating human T-lymphotropic retrovirus dead worm and this is seen as an incidental ‘coin’ lesion in chest
(HTLV-1) infection.65–68 radiographs,75 often prompting a needless thoracotomy as carcinoma
The respiratory features in hyperinfestation may be those of the is the principal differential diagnosis. The diagnosis is almost always
acute respiratory distress syndrome. At necropsy in such cases, the made only when resected tissue is submitted to microscopy. The
larvae are seen in huge numbers within the lumen and walls of airways granuloma is rounded rather than wedge-shaped and is not haemor-
of all sizes down to the alveoli and within interlobular septa (Fig. rhagic, appearances favouring an immune reaction to the worm rather
5.5.11). They excite an inflammatory response, chiefly of plasma cells than infarction. The young adult worm in the centre of the granuloma
with smaller numbers of lymphocytes and eosinophils. Diffuse alveo- is about 3cm in length but the mature female measures up to 30cm
lar haemorrhage may be seen.69 More chronic infestation may result x 2mm with the male about 20cm x 2mm. Very rarely an embolic
in restrictive lung disease due to interlobular septal fibrosis70 or a mass tangle of worms results in major pulmonary infarction (Fig. 5.5.12A).
lesion.71 Heartworm is enzootic in the Gulf states of America but since the
first report of human infestation in 1961 it has become recognised in
dogs throughout the United States and in southern parts of Canada.
Human cases have now been reported also from Japan, Australia,
Hookworm infestation Brazil and various other countries.76–81 The smaller D.repens, which is
The larval forms of the hookworms Ancylostoma duodenale and Necator common in Italy, may result in a similar pulmonary nodule but the
americanus, like those of Ascaris lumbricoides and Strongyloides stercora- lung is a relatively rare locus for this species.82–84
lis, migrate through the heart, lungs and trachea to reach the intestine The lesions in man are usually solitary, peripheral and lower lobar
where they mature. On their way through the lungs, they may simi- in distribution (Fig. 5.5.12B), but multiple bilateral nodules have
larly cause fleeting eosinophilic pneumonia. been reported. They range in size from 1 to 4 cm. Most patients are

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 Infectious diseases Chapter |5|

D
B

Figure 5.5.12  Dirofilaria immitis, the dog heart worm. (A) A tangle of Dirofilaria worms that was removed surgically from the pulmonary artery of a
merchant seaman. Magnification ×1.8. (Courtesy of Professor F Ho, Hong Kong.) (B–D) Dirofilaria immitis causing a 3-cm, rounded, necrotising nodule in
the lung of a man who had lived rough in tropical countries. (B) Gross appearances; (C) microscopy; (D) elastin stain showing the worm situated within
a pulmonary artery. (B–D courtesy of Dr M Jagusch, Auckland, New Zealand.)

asymptomatic but some complain of cough, chest pain, haemoptysis Indies, Brazil, the Philippines and Korea.87–90 Affected patients com-
and fever, with up to 20% showing eosinophilia. Microscopically, a plain of dyspnoea, cough, wheeze and pain or a feeling of tightness
large central area of coagulative necrosis is surrounded by a thin band in the chest. Ova and adult worms may be found in the sputum or
of chronic inflammatory granulomatous tissue containing occasional on bronchoscopy. The adults live off the host’s blood and are there­
giant cells (Fig. 5.5.12C).80,85,86 Eosinophils may be numerous but are fore bright red. The female measures up to 2 cm and the male a
often absent. The diagnosis is made by identifying the dead worm quarter of this. They live in permanent copulation and since the vulva
within a thrombosed artery in the central area of necrosis (Fig. opens in the mid region of the female’s body, each pair forms
5.5.12D). This may require step sections, which are therefore advisa- a characteristic Y shape. It must be disconcerting to see the paired
ble when examining any necrobiotic nodule of obscure aetiology. worms wriggling away from the bronchoscopy forceps.87
Methenamine silver and elastin stains aid the identification and loca­
lisation of the parasite (Fig. 5.5.12D), which has a thick cuticle and
in man seldom measures more than 300 µm in diameter.
ARTHROPODS
Syngamiasis (gapeworm infestation)
Pulmonary acariasis
Gapeworms of the Syngamidae family infest domestic mammals,
rodents and birds, producing in domestic fowl a disease known as ‘the Adult ticks and mites are occasionally found in the sputum of those
gapes’, which is characterised by dyspnoea and an asphyxial death due exposed to organic dust in tropical climates, probably representing
to the worms obstructing the bird’s trachea and bronchi. Human bronchial saprophytes. This is known as pulmonary acariasis. Mites
infection is rare but isolated cases have been reported from the West were found in the sputum of 5% of Chinese grain workers.91

259
 Pathology of the Lungs

Pentastomiasis Myiasis
The upper or lower respiratory passages of some dogs, birds and Myiasis is caused by parasitic dipterous fly larvae feeding on the host’s
snakes are inhabited by certain arthropods of debatable taxonomic necrotic or living tissue. The disease is a serious problem in the
standing, the so-called ‘tongueworms’ or pentastomes, which include livestock industry and is fairly common in rural human populations
Linguatula and Armillifer. 92,93 The eggs of Armillifer may be transmitted in tropical and subtropical regions. The insect that attacks man
to snake handlers in Africa and the Far East and those of Linguatula is Dermatobia hominis, the human bot-fly. The infestation is usually
are transmitted to dog handlers worldwide. Larvae develop in the cutaneous but many other parts of the body may be affected, includ-
human intestine and penetrate the wall to reach many viscera, ing the respiratory tract on rare occasions. Respiratory involve­
including the lungs, where in their natural host they mature to ment is usually identified when a patient complaining of cough or
adults but where in man they die. A recognisable larva is occasionally haemoptysis coughs up a recognisable maggot.
encountered in human lungs but more often, barely recognisable
parasitic remnants are observed within encapsulated, partly calcified,
necrotic debris. Their identification from other metazoal remnants
may be impossible, even for professional parasitologists.

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41. Harris P, Heath D. The Human Pulmonary 1982;126:344–347. infection by Strongyloides stercoralis. Am J
Circulation. Its Form and Function in 55. Dakak M, Genc O, Gurkok S, et al. Surgical Respir Crit Care Med 1995;151:205–9.
Health and Disease. 3rd ed. Edinburgh: treatment for pulmonary hydatidosis (a 71. Mayayo E, Gomez-Aracil V, Azua-Blanco J,
Churchill Livingstone; 1986. review of 422 cases). J R Coll Surg Edinb et al. Strongyloides stercolaris infection
2002;47:689–92. mimicking a malignant tumour in a
Paragonimiasis 56. Kabiri e, Caidi M, al Aziz S, et al. Surgical non-immunocompromised patient.
42. Mukae H, Taniguchi H, Matsumuto L, et al. treatment of hydatidothorax. Series of 79 Diagnosis by bronchoalveolar cytology.
Clinicoradiologic features of cases. Acta Chir Belg 2003;103: J Clin Pathol 2005;58:420–2.
pleuropulmonary Paragonimus westermani 401–4.
on Kyusyu Island, Japan. Chest 57. Ayed AK, Alshawaf E. Surgical treatment Filariasis: tropical eosinophilia
2001;120:514–20. and follow-up of pulmonary hydatid cyst. 72. Udwadia FE. Tropical eosinophilia – a
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paragonimiasis – Case report of a severe 73. Webb JGK, Job CK, Gault EW. Tropical
clinical infection. Chest 2002;121:1368–72. Cysticercosis (larval taeniasis) eosinophilia : demonstration of
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kellicotti infection – North American 59. Mauad T, Battlehner CN, Bedrikow CL, et al. The etiology and pathology of
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lung cancer on FDG-PET imaging. Ascariasis and toxocariasis 75. Kido A, Ishida T, Oka T, et al. Pulmonary
Anticancer Res 2003;23:3437–40. (‘visceral larva migrans’) dirofilariasis causing a solitary lung mass
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76. Awe RJ, Mattox KL, Alvarez BA, et al. 83. Pampiglione S, Rivasi F, Angeli G, et al. 89. Delara TDC, Barbosa MA, Deoliveira MR,
Solitary and bilateral pulmonary nodules Dirofilariasis due to Dirofilaria repens in et al. Human syngamosis – two cases of
due to Dirofilaria immitis. Am Rev Respir Dis Italy, an emergent zoonosis: report of 60 chronic cough caused by Mammomonogamus
1975;112:445–9. new cases. Histopathology 2001;38: laryngeus. Chest 1993;103:264–5.
77. Merrill JD, Otis J, Logan WD, et al. The dog 344–54. 90. Kim HY, Lee SM, Joo JE, et al. Human
heartworm (Dirofilaria immitis) in man. An 84. Pampiglione S, Rivasi F, Gustinelli A. syngamosis: the first case in Korea. Thorax
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1980;243:1066–8. attributed to Dirofilaria immitis: a critical
78. Tsukayama C, Manabe T, Miura Y. appraisal. Histopathology Acariasis
Dirofilarial infection in human lungs. Acta 2009;54:192–204. 91. Li C, Li L. Human pulmonary acariasis in
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79. Chesney TM, Martinez LC, Painter MW. dirofilariasis: A clinicopathologic study of Zhongguo Ji. Sheng Chong. Xue Yu Ji.
Human pulmonary dirofilarial granuloma. 41 lesions in 39 patients. Hum Pathol Sheng Chong. Bing. Za Zhi 1990;8:41–4.
Ann Thorac Surg 1983;36:214–17. 1999;30:251–6.
80. Nicholson CP, Allen MS, Trastek VF, et al. 86. Hiroshima K, Iyoda A, Toyozaki T, et al. Pentastomiasis
Dirofilaria immitis – a rare, increasing cause Human pulmonary dirofilariasis: report of 92. Guardia SN, Sepp H, Scholten T, et al.
of pulmonary nodules. Mayo Clin Proc six cases. Tohoku J Exp Med Pentastomiasis in Canada. Arch Pathol Lab
1992;67:646–50. 1999;189:307–14. Med 1991;115:515–17.
81. deCampos JRM, Barbas CSV, Filomeno LTB, 93. Morsy TA, El Sharkawy IM, Lashin AH.
et al. Human pulmonary dirofilariasis: Syngamiasis (gapeworm infestation) Human nasopharyngeal linguatuliasis
Analysis of 24 cases from São Paulo, Brazil. 87. Basden RDE, Jackson JW, Jones EI. (Pentasomida) caused by Linguatula serrata.
Chest 1997;112:729–33. Gapeworm infestation in man. Br J Dis J Egypt Soc Parasitol 1999;29:787–90.
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pulmonary dirofilariasis. Histopathology 88. Grell GAC, Watty EI, Muller RL. Syngamus
1996;29:69–72. in a West Indian. BMJ 1978;2:1464.

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 Chapter 6 

Diffuse parenchymal disease of the lung

Some diseases that affect the periphery of the lung largely involve the with predominant histological pattern so that there is often dual
alveolar interstitium whereas others encroach upon, or preponderate terminology (Table 6.1).1 It brings together clinical, imaging and
within, the alveolar lumen. Until the advent of modern imaging tech- histological criteria and is of undoubted prognostic and therapeutic
niques this distinction was not fully appreciated by clinicians, with value. However, it is not above criticism, particularly in its retention
the result that many diseases have been termed interstitial, irrespective of terms such as ‘interstitial pneumonia’ for a group of parenchymal
of the lung compartment predominantly involved. A classification diseases that may be either interstitial or intra-alveolar. The term
formulated by a joint committee of the American Thoracic Society and ‘desquamative interstitial pneumonia’ (DIP) is retained, although it
the European Respiratory Society in 2002 (the ATS/ERS classification) is now well established that this process is not desquamative but
corrects this anomaly by referring to them as the diffuse parenchymal exudative and has only a minor interstitial component. Cryptogenic
lung diseases.1 organising pneumonia is a further condition listed under the idio-
The parenchyma of an organ is the part concerned with function. pathic interstitial pneumonias despite it affecting the alveolar space
In most viscera, function resides in the epithelium, and the interstitial rather than the interstitium. Furthermore, DIP and respiratory bron-
connective tissue merely acts in a supporting role. This is not the case chiolitis are largely caused by smoking and are therefore not strictly
in the lungs. The function of the lungs is of course gas exchange, which idiopathic. Similarly, lymphoid interstitial pneumonia (LIP) is virtu-
takes place in the alveoli. It is unlikely that gas exchange could take ally never idiopathic and it is questionable whether it should be
place if any component of the alveolus or its wall was lacking. The regarded as an interstitial pneumonia or a lymphoproliferative disease.
lung parenchyma is therefore to be regarded as all the tissue of the The prime reason for assembling the seven disparate entities listed
gas-exchanging region, which is that portion beyond the terminal in Table 6.1 under the heading idiopathic interstitial pneumonias is
bronchiole – the pulmonary acinus (see p. 4 and Fig. 1.4, p. 5). An that, although they differ in their prognosis and treatment, they may
earlier term synonymous with diffuse parenchymal lung disease is enter the differential diagnosis of idiopathic pulmonary fibrosis (IPF)
acinar lung disease.2 The lung acinus includes the alveolar interstitium at initial presentation. These patterns are also of considerable prog-
and endothelium as well as its epithelium and air space. Thus the term nostic value.1,3–8 The ATS/ERS classification provides pathological
‘diffuse parenchymal (or acinar) lung disease’ is highly appropriate criteria that allow these patterns to be distinguished in a fairly repro-
for a group of diseases that includes some which are truly interstitial ducible manner.9 However, pathologists should be aware that they are
and others that represent alveolar filling defects. only identifying a particular histological pattern, not a specific disease,
The idiopathic interstitial pneumonias form a major subgroup of subsequent correlation with clinical and imaging data being required
the diffuse parenchymal lung diseases, and represent one in which to reach a final diagnosis.1 Mixed patterns may be encountered. For
there have been several recent advances. Of particular importance is example, diffuse alveolar damage, the pathological basis of acute inter-
the recognition that ongoing fibrosis is a better prognostic indicator stitial pneumonia (AIP), may be superimposed on UIP in acute exac-
than inflammation. Histopathological patterns such as usual intersti- erbations of IPF,10 different lobes may concurrently show different
tial pneumonia (UIP) have therefore been defined more precisely and histological patterns in the same patient11 and different histological
separated from less specific patterns, leading to the introduction of patterns may be seen in successive samples of the same lung.12
terms such as non-specific interstitial pneumonia (NSIP). Considerable However, there is nothing to stop pathologists reviewing all the data
work has gone into correlating histopathological patterns with clinical and coming to a final diagnosis themselves.13
course and radiological detail, as revealed by modern imaging tech- It is also worth noting that, whereas a UIP pattern is typical of IPF,
niques. The result has been an intensification in clinicopathological conditions other than IPF may show UIP on occasion, while diffuse
correlation and a better appreciation of the likely clinical outcome. alveolar damage has many recognisable causes besides being the basis
The ATS/ERS classification concentrates upon the idiopathic inter- of AIP (see Box 4.2, p. 143) and NSIP is seen in a variety of unrelated
stitial pneumonias and in this area seeks to match disease diagnosis conditions.3 One review estimated that 68% of cases showing NSIP

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00006-9 263
 Pathology of the Lungs

monia, the pathologist should consider the possibility that the

Table 6.1  Classification of diffuse parenchymal lung disease1
changes may represent inactive forms of such centriacinar diseases as
1. Of known cause, e.g. drugs (Chapter 7.3) or of known association, extrinsic allergic alveolitis. Having done so, one group suggested that
e.g. collagen vascular disease (Chapter 10) the changes were the result of gastric aspiration.18
2. Idiopathic interstitial pneumonias The term cryptogenic fibrosing alveolitis (CFA) was introduced in
Diagnosis Predominant histological the 1960s to link IPF to the pulmonary fibrosis that is occasionally
pattern seen in association with the collagen vascular disorders, the prefixes
Idiopathic pulmonary fibrosis Usual interstitial pneumonia ‘lone’ and ‘system’ being used to distinguish the two.21–23 However,
(cryptogenic fibrosing alveolitis) the prefixes are now seldom used and the unqualified term CFA has
Non-specific interstitial pneumonia Non-specific interstitial become an unnecessary synonym for IPF1 or is used as a general
(provisional)a pneumonia umbrella term for pulmonary fibrosis of uncertain aetiology.24
Desquamative interstitial pneumonia Desquamative interstitial Antedating all these terms but now largely abandoned are those
pneumonia applied by nineteenth-century morbid anatomists who were evidently
Respiratory bronchiolitis-associated Respiratory bronchiolitis
familiar with the pathological changes seen in IPF and applied graphic
interstitial lung disease
descriptive terms such as muscular cirrhosis of the lung25 and cirrhosis
Acute interstitial pneumonia Diffuse alveolar damage
cystica pulmonum.26
Cryptogenic organising pneumoniab Organising pneumonia
Lymphoid interstitial pneumonia Lymphoid interstitial
pneumonia
3. Granulomatous, e.g. sarcoidosis DIFFUSE PARENCHYMAL LUNG DISEASE  
4. Environmental or occupational (Chapters 7.1 and 7.2) IN CHILDHOOD
5. Others, e.g. lymphangioleiomyomatosis, Langerhans cell
histiocytosis
Diffuse parenchymal lung disease in children is very different from
a
A heterogeneous group of diseases with poorly characterised clinical and that seen in adults. IPF with its characteristic pattern of UIP is virtually
radiological features that need further study. unknown in children,27,28 most reports antedating the ATS/ERS con-
b
Synonymous with idiopathic bronchiolitis obliterans organising pneumonia. sensus classification. When the criteria recommended in this classifica-
tion are applied to the paediatric cases it is found that patterns other
than UIP are more common. AIP is also very rare in children, although
its histological pattern of diffuse alveolar damage was first recognised
in premature babies dying of the infantile respiratory distress syn-
were idiopathic, 22% were associated with connective tissue disease, drome. On the other hand, LIP is common in childhood, where it is
8% represented atypical cases of extrinsic allergic alveolitis and 2% nearly always associated with either connective tissue disease or immu-
followed the acute respiratory distress syndrome.14 Another group nodeficiency, both congenital and acquired.27,28 It is a well-described
estimated that 88% of patients classified as idiopathic NSIP had what complication of paediatric acquired immunodeficiency syndrome
they termed unclassified connective tissue disease.15 (AIDS), occurring in over 30% of children infected perinatally by
The terms ‘acute interstitial pneumonia’ (AIP) and NSIP are rela- human immunodeficiency virus (HIV). NSIP is also increasingly rec-
tively new and when the adjective ‘usual’ was originally introduced it ognised in children and some cases are a result of surfactant gene
was to contrast UIP with four other patterns of idiopathic interstitial mutations. DIP is rare and its outcome is worse in children compared
pneumonia, namely DIP, LIP, a pattern occurring in association with to adults. Some childhood cases of DIP represent inborn errors of
bronchiolitis obliterans (BIP) and one marked by the presence of metabolism such as surfactant B deficiency and lipid storage dis-
giant cells (GIP).16 It was hoped that this histopathological classifica- eases.29–31 Cryptogenic organising pneumonia is exceptionally rare in
tion would facilitate a better understanding of aetiology, pathogenesis children and respiratory bronchiolitis has not been reported. Disorders
and clinical features. This hope has been partly realised in that many such as extrinsic allergic alveolitis and eosinophilic pneumonia are
cases of GIP are now known to be caused by hard-metal alloys. uncommon in children but have to be considered in the differential
The term BIP is no longer used, having been superseded initially by diagnosis, as do infections and their sequelae, which tend to be diffuse
idiopathic bronchiolitis obliterans organising pneumonia and now by in this age group. Langerhans cell histiocytosis is seen in children with
cryptogenic organising pneumonia. the systemic forms of the disease, especially Letterer–Siwe disease, but
A further pattern, described since the ATS/ERS classification was the type confined to the lung is largely a disease of cigarette smokers.
formulated, is one that has been termed bronchiolocentric interstitial After all these conditions have been considered there remain diffuse
pneumonia.17–20 This lacks any specific features and is of unknown parenchymal diseases that feature in the perinatal period: these are
cause but before using the term bronchiolocentric interstitial pneu- considered in Chapter 2 (see Table 2.2, p. 51).32,33

REFERENCES

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Respiratory. Society international 277–304. interstitial pneumonia/fibrosis – histologic
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the idiopathic interstitial pneumonias. Am of the pulmonary acini. Br J Dis Chest Pathol 1994;18:136–47.
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4. Bjoraker JA, Ryu JH, Edwin MK, et al. interstitial pneumonias: progress and 23. Scadding JG. Diffuse pulmonary alveolar
Prognostic significance of histopathologic controversies. Histopathology fibrosis. Thorax 1974;29:271–81.
subsets in idiopathic pulmonary fibrosis. 2009;54:90–103. 24. Wells AU, Hansell DM, Nicholson AG.
Am J Respir Crit Care Med 14. Cottin V, Loire R, Chalabreyesse L, et al. What is this thing called CFA? Thorax
1998;157:199–203. Pneumopathie interstitielle non specifique: 2007;62:3–4.
5. Katzenstein ALA, Myers JL. Idiopathic une nouvelle entité anatomoclinique au 25. Buhl VL. Muscular Zirrhose der Lungen.
pulmonary fibrosis: Clinical relevance of sein des pneumopathies interstitielles Lungenentzundung, Tuberkulose und
pathologic classification. Am J Respir Crit diffuses idiopathiques. Rev Mal Respir Schwindsucht. Munich: R. Olderburg; 1873.
Care Med 1998;157:1301–15. 2001;18:25–33. p. 169.
6. Nicholson AC, Colby TV, Dubois RM, et al. 15. Kinder BW, Collard HR, Koth L, et al. 26. Rindfleisch GE. Ueber Cirrhosis Cystica
The prognostic significance of the histologic Idiopathic nonspecific interstitial Pulmonum. Zentralbl Pathol 1897;8:864–5.
pattern of interstitial pneumonia in patients pneumonia: lung manifestation of
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Crit Care Med 2000;162:2213–17. 691–7.
27. Fan LL, Kozinetz CA, Wojtczak HA, et al.
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Idiopathic pulmonary fibrosis – pulmonary disease. In: International thoracoscopic, and open lung biopsy in
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Care Med 2001;164:1025–32. 1967. p. 332–65. 1997;131:565–9.
8. Flaherty KR, Toews GB, Travis WD, et al. 17. Yousem SA, Dacic S. Idiopathic 28. Nicholson AG, Kim H, Corrin B, et al. The
Clinical significance of histological bronchiolocentric interstitial pneumonia. value of classifying interstitial pneumonitis
classification of idiopathic interstitial Modern Pathol 2002;15:1148–53. in childhood according to defined
pneumonia. Eur Resp J 2002;19:275–83. 18. deCarvalho MEP, Kairalla RA, Capelozzi VL, histological patterns. Histopathology
9. Nicholson AG, Addis BJ, Bharucha H, et al. et al. Centrilobular fibrosis: A novel 1998;33:203–11.
Inter-observer variation between histological pattern of idiopathic interstitial 29. Amir G, Ron N. Pulmonary pathology in
pathologists in diffuse parenchymal lung pneumonia. Pathol Res Pract Gaucher’s disease. Hum Pathol
disease. Thorax 2004;59:500–5. 2002;198:577–83. 1999;30:666–70.
10. Kondoh Y, Taniguchi H, Kawabata Y, et al. 19. Churg A, Myers J, Suarez T, et al. Airway- 30. Stillwell PC, Norris DG, O’Connell EJ, et al.
Acute exacerbation in idiopathic pulmonary centered interstitial fibrosis – A distinct Desquamative interstitial pneumonitis in
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findings in three cases. Chest J Surg Pathol 2004;28:62–8.
31. Tal A, Maor E, Bar-Ziv J, et al. Fatal
1993;103:1808–12. 20. Fukuoka J, Franks TJ, Colby TV, et al. desquamative interstitial pneumonia in
11. Flaherty KR, Travis WD, Colby TV, et al. Peribronchiolar metaplasia: a common three infants siblings. J Pediatr
Histopathologic variability in usual and histologic lesion in diffuse lung disease and 1984;104:873–6.
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32. Deutsch GH, Young LR, Deterding RR, et al.
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Diffuse Lung Disease in Young Children:
12. Katzenstein ALA, Zisman DA, Litzky LA, Surg Pathol 2005;29:948–54.
Application of a Novel Classification
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Histologic study of biopsy and explant 1964;2:686. 2007;176:1120–8.
specimens. Am J Surg Pathol 22. Scadding JG, Hinson KFW. Diffuse fibrosing 33. McFetridge L, McMorrow A, Morrison PJ,
2002;26:1567–77. alveolitis (diffuse interstitial fibrosis of the et al. Surfactant metabolism dysfunction
13. Myers JL, Katzenstein ALA. Beyond a lungs): correlation of histology at biopsy and childhood interstitial lung disease
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6.1  Interstitial lung disease

lates clinically with idiopathic pulmonary fibrosis (IPF). However, it

CHAPTER CONTENTS
may also, on rare occasions, be encountered in drug reactions, colla-
Usual interstitial pneumonia and idiopathic gen vascular diseases and hypersensitivity pneumonia, and IPF can
pulmonary fibrosis (IPF) 266 only be diagnosed when these possibilities have been excluded.1–3
Cancer in IPF 275 Some regard UIP as the only acceptable pattern in IPF,1 but others
report fibrotic non-specific interstitial pneumonia (NSIP) in a minor-
Non-specific interstitial pneumonia 276
ity of patients with this disease.4–7 Occasionally, UIP is observed in
Acute interstitial pneumonia (idiopathic diffuse one lobe and NSIP in another, in which case the prognosis is that of
alveolar damage) 278 UIP.4,7 Although abundant macrophages may accompany UIP, de­­
Idiopathic bronchiolocentric interstitial pneumonia 278 squamative interstitial pneumonia (DIP) is now considered to
Extrinsic allergic alveolitis (hypersensitivity represent a separate process, which is dealt with on page 311.5,8–11
pneumonia) 279
‘Hot tub lung’ 283 Epidemiology
Sarcoidosis 283 IPF shows a wide age spectrum. The mean age at presentation is 71
Pulmonary Langerhans cell histiocytosis (pulmonary years,12 somewhat older than earlier studies that possibly included
histiocytosis X, eosinophilic granuloma of the lung) 288 patients with DIP.13,14 The disease affects twice as many men as women
Lymphangioleiomyomatosis 293 and there is a strong association with smoking.14–16 Prevalence is
References 297 between 1 and 5 per 100 000 population.17 In the UK the reported
incidence doubled between 1990 and 2003 while in the USA age-
adjusted death rates over a similar period increased 28% in men and
The diseases described in this section predominantly involve the 41% in women.12,18 There is no predilection for specific countries,
alveolar interstitium, which constitutes the connective tissue frame- ethnic groups or urban/rural locations.1 Occasionally, several members
work of the alveolar walls. Its boundaries are the epithelial and of a family are affected.19,20
endothelial basement membranes (see Fig. 1.28, p. 17). Many of the
diseases considered here involve the interstitial fibroblasts and
progress to interstitial fibrosis and ultimately ‘honeycombing’ (see p. Clinical features
149). They represent examples of restrictive lung disease, the other Most patients with IPF complain of breathlessness on exertion, dry
major cause of which is interstitial oedema, which is dealt with in cough and loss of weight.16 Bilateral basal crackles are heard on inspi-
Chapter 8.1 (p. 401). Lymphangioleiomyomatosis is an exception in ration and digital clubbing is commonly found. Functional studies
that it progresses to severe cystic change without any appreciable show a restrictive respiratory defect, the lungs being small and stiff.
degree of fibrosis. Chest X-rays may show a ‘ground-glass’ pattern or fine linear mottling,
predominantly affecting the subpleural region of the lung bases.
Progressive elevation of the diaphragm and ‘honeycombing’ accom-
USUAL INTERSTITIAL PNEUMONIA AND pany the shrinkage of the fibrotic lung tissue (Fig. 6.1.1A). On high-
resolution computed tomography (HRCT), the dominant pattern
IDIOPATHIC PULMONARY FIBROSIS comprises irregular lines forming a reticular pattern, mainly involving
the bases of the lungs. As the disease progresses, the reticular pattern
Usual interstitial pneumonia (UIP) is the commonest histological becomes coarser and ‘honeycombing’ and ‘traction bronchiectasis’
pattern seen in idiopathic interstitial pneumonia. It generally corre- develop (Fig. 6.1.1B). Serological abnormalities and changes detect-

266
 Diffuse parenchymal disease of the lung Chapter |6|

A B

Figure 6.1.1  (A) Chest radiograph of a patient with idiopathic pulmonary fibrosis. Note the predominantly basal distribution with involvement of the
costophrenic angles, which is characteristic of this disease. (B) High-resolution computed tomography scan of usual interstitial pneumonia. The lung
bases show subpleural honeycombing. (Courtesy of Dr I Kerr and Professor DM Hansell, Brompton, UK.)

able on bronchoalveolar lavage (outlined below under pathogenesis) interferon-γ, which initially showed promise34 but has since shown no
contribute to a distinctive clinical picture. advantage.35 In recent trials neither etanercept (a tumour necrosis
The disease is generally diagnosed on the above clinical and imaging factor-α antagonist) nor imatinib (a tyrosine kinase inhibitor) influ-
features; indeed, the diagnostic accuracy of HRCT in identifying enced the primary study endpoint, although both showed some evi-
patients with a UIP pattern and hence IPF is now such that many dence of decreasing disease progression.36,37 More promising was a
patients do not have a biopsy.1,21 In the UK only 40% of patients with study with N-acetyl cysteine in combination with steroids and aza-
IPF undergo any form of biopsy: 28% have a transbronchial biopsy thioprine that achieved its primary endpoint in showing a significant
and 12% a surgical lung biopsy.16 Transbronchial biopsy may establish slowing of disease progression,38 and initial trials of both bosentan
an alternative diagnosis, but a surgical biopsy is nearly always required (an endothelin-1 receptor antagonist)39 and pirfenidone40,41 have sug-
to determine the pattern of interstitial pneumonia, and is now usually gested a positive effect. Another agent to show a positive treatment
obtained at video-assisted thoracoscopy. In these instances, it is the effect, notably a reduction in mortality, has been warfarin.42 The intro-
presence of UIP that establishes the diagnosis (of IPF) and dictates duction of these drugs reflects advances in our understanding of the
prognosis.22 pathogenesis of IPF that have in part arisen from the more precise
definition of the disease within the consensus classification.43–47
Currently however, the only treatments that can be recommended
Course of the disease
outside a drug trial are oxygen therapy and transplantation.3
Early studies showed a mean survival of about 4 years14 but in later
series limited to patients with UIP this figure was reduced to about 2
years (Fig. 6.1.2).1,5,8,22,23 The later stages of the disease are character-
ised by cyanosis and dyspnoea at rest. These features presage death Morbid anatomy
from respiratory failure, cor pulmonale or lung cancer, this last being In a typical case, the lungs are shrunken and firm when removed at
an important complication that is dealt with below. Although IPF is autopsy or in preparation for transplantation. The lower lobes are
typically characterised by a steady, predictable decline, some patients most severely affected, with the pleura having a finely nodular ‘cob-
experience more rapid deterioration, either episodically or as a termi- blestone’ pattern, resembling that of a cirrhotic liver (Fig. 6.1.3).
nal event.3,24–32 These acute exacerbations are defined as clinically Pleural fibrosis is uncommon, in contrast to asbestosis which IPF
significant deteriorations in patients with underlying IPF, character- otherwise resembles macroscopically. The cut surface of the lung
ised by subjective worsening over 30 days or less, new bilateral radio- shows fibrosis and a variable degree of ‘honeycombing’, which is most
graphic opacities and the absence of infection or another identifiable marked beneath the pleura (Figs 6.1.4 and 6.1.5). The posterior basal
aetiology.31 segment is maximally affected and from here the process extends
Until recently, treatment was largely based on immunosuppression upwards, involving particularly the subpleural lung tissue. This rind
but this has seldom proved effective23,33 and in the last decade several of contracted fibrous tissue prevents the lungs from expanding and is
other drugs have either been or are being assessed.3 These include an important factor contributing to the restrictive respiratory defect.

267
 Pathology of the Lungs

100 100
DIP / RBILD

80
75
Survival (%)

60

Survival (%)
50
NSIP
40

25
20
UIP
0 0
0 3 6 9 12 15 17 0 20 40 60 80 100
A Time (years) B Time (months)
Figure 6.1.2  The survival curve of two groups of patients treated for idiopathic pulmonary fibrosis at the Brompton Hospital. (A) In a group antedating
the distinction of usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) the median survival was about 4 years from the onset
of symptoms whereas in a later group (B) categorised according to their histological pattern, those with a UIP pattern had a median survival nearer to
2 years. DIP, desquamative interstitial pneumonia; RBILD, respiratory bronchiolitis-associated interstitial lung disease.

Figure 6.1.4  Idiopathic pulmonary fibrosis. The lung shows basal

subpleural ‘honeycombing’.

Figure 6.1.3  Idiopathic pulmonary fibrosis. The visceral pleura shows

a ‘cobblestone’ pattern, reflecting changes in the underlying lung
parenchyma. The pleura itself is not affected by the fibrotic process.
(Courtesy of Dr RVP Dissanayake, Ilford, UK.)

268
 Diffuse parenchymal disease of the lung Chapter |6|

termed ‘fibroblastic foci’, can be highlighted by staining the abundant

acidic proteoglycans present in such granulation tissue with alcian
blue or Movat’s stain (see Fig. 6.1.7C). They are thought to represent
the sites of repeated lung damage.13 Their progression is characterised
by weakening alcianophilia and increasing collagenisation.48 Most
studies suggest that a profusion of these foci predicts poor survival
whereas the more traditional feature of disease activity, interstitial
mononuclear cell infiltration, is of only limited prognostic value.49–52
Despite the term ‘interstitial pneumonia’, chronic inflammatory cell
infiltration is generally only mild to moderate in intensity. Lymphoid
follicles are not usually prominent in idiopathic disease and when
present suggest collagen vascular disease.53 As the process becomes
more advanced, there is increased loss of alveolar architecture with
remodelling and eventual formation of cysts separated by bands of
fibrosis, so-called honeycombing.
This full constellation of histological features permits the patholo-
gist to recognise a UIP pattern with confidence but in some cases only
some of these features are evident, in which case only an opinion of
probable or possible UIP can be offered. However, histological assess-
ment is also of value in that it sometimes permits the confident exclu-
sion of UIP (Table 6.1.1, p. 272).3
Although widespread ‘honeycombing’ usually represents advanced
IPF, attempts to differentiate end-stage UIP from end-stage NSIP
have shown poor reproducibility5 and it is preferable to classify these
changes merely as end-stage lung rather than assign a particular his-
tological pattern.5,54 Such areas can often be avoided if the surgeon
discusses the cases with radiologist and pulmonologist before taking
the biopsy to ascertain the probable sites of active disease.2 Many
centres now biopsy two sites to reduce the possibility of sampling
error.4,7
A variety of secondary changes that are not specific to UIP and are
of limited diagnostic value may also be observed:
• The residual air spaces are often lined by hyperplastic
bronchiolar or cuboidal alveolar epithelium (Fig. 6.1.8A),
Figure 6.1.5  Idiopathic pulmonary fibrosis. Paper-mounted whole-lung sometimes showing squamous metaplasia (Fig. 6.1.8B) or goblet
section. Note the predominance of the disease in the basal parts of  
cell proliferation. Dysplasia and neoplasia may also develop (see
the lung.
below).
• The distorted air spaces often contain mucin, cellular debris,
cholesterol crystal clefts, macrophages and other inflammatory
cells.
• Blood vessel walls are usually thickened by intimal fibrosis in
Histological changes the affected areas but are normal elsewhere, unless there is
The cardinal features of UIP2 are: secondary pulmonary hypertension.
• subpleural and paraseptal predominance • Reactive smooth-muscle hyperplasia is often very marked
• patchy parenchymal involvement (Fig. 6.1.8C), contributing to the archaic term ‘muscular
• established (i.e. collagenous) fibrosis leading to loss of cirrhosis of the lung’. The hyperplastic muscle is probably
architecture (‘honeycombing’) derived from bronchioles and small blood vessels rather than
• fibroblastic foci adjacent to the established fibrosis, indicative of the myofibroblasts of young fibrous tissue, but its origin is
progressive disease seldom evident.
• only mild to moderate chronic interstitial inflammation • Occasionally, eosinophilic pneumonia-like areas may
• an absence of any causal feature such as inorganic dust, be seen.55
granulomas or accumulations of Langerhans cells. • Other non-specific features include focal alveolar macrophage
accumulation (sometimes mimicking DIP), mild pleuritis and
As noted above, the disease is most marked immediately beneath
pleural fibrosis, subpleural fatty metaplasia, dilated lymphatics,
the pleura and characteristic low-power feature is that the changes
neutrophil accumulation (especially within areas of honeycomb
are patchy. Areas of chronic interstitial inflammation and fibrosis
change), osseous metaplasia, focal alveolar fibrin, and hyaline
alternate with foci of relatively normal lung (Fig. 6.1.6). Much of the
cytoplasmic inclusions in pneumocytes.2
fibrosis is well established, consisting of poorly cellular hyaline col-
lagen, but lying immediately adjacent to this older fibrous tissue are Patients with IPF frequently smoke and it is therefore not surprising
localised areas of granulation tissue consisting of plump fibroblasts that a variety of further changes commonly found in smokers may be
set in a slightly haematoxyphilic myxoid stroma (Fig. 6.1.7). This seen in addition to UIP, namely centriacinar emphysema, respiratory
variation in the age of the fibrosis is sometimes described as evidence bronchiolitis, DIP-like changes and what has been termed air space
of ‘temporal heterogeneity’. The foci of immature fibrous tissue, enlargement with fibrosis.56

269
 Pathology of the Lungs

A B

Figure 6.1.6  Usual interstitial pneumonia. Patchy subpleural and paraseptal

fibrosis is characteristic of this pattern of interstitial pneumonia. In all cases,
C the fibrosis is interspersed with unaffected normal lung. Arrows pleura.

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 Diffuse parenchymal disease of the lung Chapter |6|

Figure 6.1.7  Usual interstitial pneumonia. (A) A fibroblastic focus

consisting of granulation tissue adjacent to more collagenous interstitial
fibrosis. (B) A fibroblastic focus showing a greater degree of
collagenisation and overlying epithelialisation as it becomes incorporated C
in the interstitium. (C) Granulation tissue rich in alcianophilic
proteoglycans (top) covers older, more mature fibrous tissue (Alcian blue
stain). Figure 6.1.8  Secondary changes commonly associated with usual
interstitial pneumonia but not essential to its recognition. (A) Type II cell
hyperplasia. (B) The regenerating alveolar epithelium has undergone
marked squamous metaplasia. (C) An area of advanced interstitial fibrosis
shows marked smooth-muscle hyperplasia and hypertrophy.

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 Pathology of the Lungs

Table 6.1.1  Histopathological criteria for usual interstitial pneumonia (UIP)3

UIP (all four criteria Probable UIP Possible UIP (all three Not UIP (any of the six
present) criteria present) criteria present)

Marked fibrosis with Marked fibrosis with architectural distortion in Patchy or diffuse parenchymal Hyaline membranesa
architectural distortion in a a predominantly subpleural and paraseptal fibrosis, with or without Organising pneumoniab
predominantly subpleural and distribution interstitial inflammation Granulomasb
paraseptal distribution Absence of either patchy involvement or Absence of other criteria for Marked interstitial
Patchy involvement fibroblastic foci, but not both UIP (see UIP pattern column) inflammatory cell infiltrate
Fibroblast foci Absence of features suggesting an alternative Absence of features suggesting away from honeycombing
Absence of features suggesting diagnosis (see fourth column) an alternative diagnosis (see Predominance of airway-
an alternative diagnosis (see or fourth column) centred changes
fourth column) Honeycomb changes onlyc Other features suggestive of
an alternative diagnosis
a
Can be superimposed upon UIP in acute exacerbations of idiopathic pulmonary fibrosis.
b
An isolated or occasional granuloma or a little organising pneumonia may rarely coexist with UIP.
c
End-stage fibrotic lung disease, which is usually evident on high-resolution computed tomography (HRCT) and can be avoided by preoperative HRCT targeting of biopsy
sites away from these areas.

Electron microscopy myomatosis by the different nature of the smooth muscle, which is
atypical and differs markedly from that seen as reactive hyperplasia in
Ultrastructural studies support the view that the alveolar epithelium
IPF (compare Figs 6.1.8C and 6.1.48).
is the target tissue, identifying foci of bare epithelial basement mem-
Extrinsic allergic alveolitis can also usually be excluded by the pres-
brane as an early feature of the disease (Fig. 6.1.9).57–59
ence of granulomas, but chronic cases may be difficult to distinguish
from UIP.65,66 This again emphasises the need to correlate the biopsy
findings with clinical and imaging data.67
Differential diagnosis If the vascular changes are so severe that primary pulmonary hyper-
IPF was formerly categorised as either ‘cellular’ or ‘fibrotic’ and, tension enters the differential diagnosis, attention should be paid to
although this was of prognostic value,14,60,61 the ‘cellular’ cases would the vessels in the comparatively normal areas of the biopsy, when it
now be recognised as having a different histological pattern, such as will generally be appreciated that the abnormal blood vessels are
cellular NSIP, DIP or respiratory bronchiolitis. It is important to dis- limited to areas of diseased parenchyma, unlike the generalised
tinguish UIP from these other patterns of interstitial pneumonia vascular hypertrophy seen in primary pulmonary hypertension.
because IPF differs radically from the other interstitial lung disease in Pulmonary hypertension can of course complicate IPF, when it is an
its prognosis and treatment (see Fig. 6.1.2). The most problematic adverse prognostic indicator.68
area is the distinction of UIP from fibrotic NSIP.62 The key features in Occasionally, lung biopsy reveals fibrosis that does not conform to
this are a relatively diffuse pattern of interstitial fibrosis and an absence the pattern of either UIP or any other idiopathic interstitial pneumo-
or dearth of fibroblastic foci (lack of temporal heterogeneity) in NSIP.2 nia and for these cases the term ‘non-classifiable fibrosis’ is recom-
In reality, this can be very difficult and diagnostic confidence is often mended.3 Table 6.1.2 summarises the pertinent features of UIP and
low,62 not helped by the fact that, as well as areas showing UIP and the other interstitial lung diseases and may be used as part of a diag-
normal lung, foci indistinguishable from NSIP are often seen.6 In nostic algorithm.
these difficult cases, consideration of the clinical and imaging features
may be of great help.62a
Sometimes there are abundant macrophages, resulting in a DIP-like Aetiology and pathogenesis69,70
pattern, but attention to the alveolar walls reveals the characteristic The histological features of IPF suggest that the disease results from
fibroblastic foci and patchy subpleural distribution of UIP.2,63,64 Any repeated episodes of focal damage to the alveolar epithelium but
fibrosis found in DIP is mild, diffuse and non-fibroblastic. provide no clue to the nature of the injurious agent. However, IPF has
Diffuse alveolar damage (DAD) is easily distinguished by its char- many features in common with the so-called collagen vascular dis-
acteristic hyaline membranes but may be superimposed upon UIP in eases and the concept of lone versus systemic cryptogenic fibrosing
acute exacerbations of IPF (Fig. 6.1.10).25,27–31 alveolitis (CFA) links the two (see p. 264).71 Hyperglobulinaemia is
Organising pneumonia may progress to interstitial fibrosis and common and circulating non-organ-specific autoantibodies such as
when the polypoid foci of granulation tissue are closely applied to the rheumatoid factor and antinuclear factor are often present in IPF.61,72
alveolar wall they may resemble the fibroblastic foci of UIP, but the In a national British survey of patients with ‘lone CFA’, rheumatoid
subpleural distribution of UIP is not seen and the intra-alveolar tufts factor was positive in 19% and antinuclear factor in 26%.16 Antibodies
of granulation tissue are generally evident elsewhere in the biopsy. In directed against the alveolar epithelium have also been identified.73,74
such cases, previous scans will usually show features more character- Immune complexes have been demonstrated in the serum75 and occa-
istic of organising pneumonia progressing to fibrosis. Clinical review sionally in the wall of pulmonary capillaries, particularly in early
also helps exclude an acute exacerbation of IPF. cases.76,77 It seems likely therefore that IPF has in part an autoimmune
UIP differs from asbestosis by the absence of asbestos bodies, from basis, with the alveolar epithelium being the target tissue (see Fig.
granulomatous diseases such as Langerhans cell histiocytosis and sar- 6.1.9). The initiating cause remains unknown although environmen-
coidosis by the absence of granulomas, and from lymphangioleio- tal and occupational pollutants,15,16,78,79 gastric reflux,80 viruses81–86 and

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 Diffuse parenchymal disease of the lung Chapter |6|

Table 6.1.2  A diagnostic algorithm for usual interstitial

pneumonia and the other interstitial lung diseases

Collagenous or Histology Diagnosis

inflammatory?

A predominance Patchy subpleural and Usual interstitial

of collagen paraseptal distribution, pneumonia
loss of architecture, (idiopathic
and presence of pulmonary fibrosis
fibroblastic foci in most cases)
With chronic Chronic extrinsic
peribronchiolar allergic alveolitis
inflammation and
possibly granulomas or
isolated giant cells
Stellate peribronchiolar Burnt-out
scars (often masked by Langerhans cell
excess macrophages) histiocytosis
No significant Fibrotic non-specific
architectural disruption interstitial
or consistent zonal pneumonia
distribution
None of the above Unclassified fibrosis
A predominance Peribronchiolar with Extrinsic allergic
of inflammation granulomas alveolitis
Peribronchiolar with Langerhans cell
eosinophils and histiocytosis
Langerhans cells
Peribronchiolar with Respiratory
intraluminal pigmented bronchiolitis
macrophages
Diffuse with hyaline Diffuse alveolar
membranes and damage
fibroblast proliferation
No consistent zonal Cellular non-specific
distribution – mild interstitial
intensity pneumonia
No consistent zonal Lymphoid interstitial
Figure 6.1.9  Idiopathic pulmonary fibrosis. Electron microscopy shows distribution – marked pneumonia
patchy loss of the alveolar epithelium (bottom right), remnants of which
intensity
are shrunken and electron-dense (upper right). Between these
cytoplasmic remnants, denuded epithelial basement membrane is Non-necrotising Sarcoidosis
exposed to alveolar air. (Reproduced from Corrin et al.58 by permission of the granulomas in a
editor of the Journal of Pathology.) lymphatic distribution

drugs87 have all been incriminated from time to time. However, there Other genes identified include ones encoding for surfactant protein C
is no firm evidence that any of these plays a causative role.88 and telomerase.94,95 HRCT of the asymptomatic relatives of patients
Against IPF having an immune basis is the ineffectiveness of thera- with familial IPF identified abnormalities in 22%, with diverse pat-
peutic immunosuppression3,23,33 and the accelerated rate of progres- terns being found on lung biopsy.96 Several subtypes of idiopathic
sion of the disease seen in the native lung of patients who have interstitial pneumonia may occur within the same family,90 which
undergone single-lung transplantation despite the profound im­­ suggests that there may be an interaction between a specific environ-
munosuppression necessary to prevent rejection of the donor lung.89 mental exposure and a predisposing gene (or genes) such that the
The fact that the disease is occasionally familial19,20,90 suggests insult predicates the pattern of fibrosing lung disease rather than the
that genetic susceptibility may be important. There is evidence that gene itself.
in some families, susceptibility to the disease is inherited in an Following recognition of the alveolar epithelium as the site of initial
autosomal-dominant manner.90,91 One gene that is potentially respon- injury, from which dysregulated repair and eventual fibrosis ensue,
sible for such susceptibility is situated on chromosome 14q32, close considerable attention has been paid to the cytokines associated with
to the alleles responsible for α1-antitrypsin deficiency.92 Rarely, several the regenerating epithelial cells. These cells express numerous
family members suffer from either IPF or α1-antitrypsin deficiency.93 profibrotic cytokines, including transforming growth factor-β

273
 Pathology of the Lungs

A B

Figure 6.1.10  Terminal acute exacerbation of idiopathic pulmonary fibrosis in which diffuse alveolar damage is superimposed upon a background of
usual interstitial pneumonia. (A) Extensive honeycombing affects the peripheral parts of the lung while the non-fibrotic central part is deeply
congested. (B) Microscopically, the hyaline membranes that characterise diffuse alveolar damage are evident, superimposed upon the interstitial
fibrosis.

(Fig. 6.1.11),97–99 interleukin (IL)-10,99 endothelin,100 tumour necrosis the mouths of collapsed alveoli (atelectatic induration).59,109 This is at
factor-α,101 insulin-like growth factor-1,102 transcription factor GATA- its most extreme in relation to acute exacerbations when hyaline
3,103 gremlin104 and connective tissue growth factor.105 Receptors for membranes are seen (see Fig. 6.1.10).29,110–113
these profibrotic cytokines such as CCR7 have been localised to the The fibrosis that follows the epithelial injury is initially fibroblastic
interstitial compartment in UIP.106 Other factors identified in the and in advanced disease the most recent injury is recognisable as
regenerating epithelium include proteinases,107 tenascin98 and foci of granulation tissue rich in these cells. The number of these
cytokines that inhibit cell migration and further re-epithelialisation, fibroblastic foci correlates with the rate of disease progression and
which may be important in the delayed or defective re-epithelialisa- mortality.49,114,115 The fibroblasts show an altered phenotype, typically
tion that has been held responsible for fibroblast recruitment, activa- myofibroblastic, that reflects activation and the production of extra­
tion and sustained proliferation.108 Poor re-epithelialisation may be cellular matrix proteins. This is part of normal tissue repair but
due in part to increased pneumocyte apoptosis, promoted by some the persistence of an activated fibroblast phenotype probably contrib-
of the above cytokines, for example, transforming growth factor-β. utes to the chronic progression to fibrosis and remodelling. This is
Epithelial loss with resultant surfactant deficiency would also enhanced by a reduced capacity for degradation of extracellular matrix
explain the focal collapse with apposition of bare basement mem- proteins, through imbalances between matrix metalloproteinases and
branes that has been described by electron microscopists, a change their tissue inhibitors. Myofibroblasts also produce cytokines that
that is rendered permanent by regenerating epithelial cells bridging induce epithelial cell apoptosis, thereby contributing to reduced re-

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 Diffuse parenchymal disease of the lung Chapter |6|

lymphocyte is the predominant interstitial inflammatory cell. Focal

collections of B lymphocytes cluster about the airways while the
diffuse infiltrate largely comprises T lymphocytes, particularly of the
suppressor/cytotoxic (T8) variety.122,123 The alveolar epithelial cells
show aberrant expression of HLA-DR antigen, suggesting that the
epithelium may be recognised as autoantigenic by the cytotoxic T8
cells.124,125 However T4 (helper) lymphocytes are also found and a shift
from their type I to type II cytokine profile may be important in the
progression of inflammation to fibrosis, type II cytokine (IL-4 and
IL-13) receptors being overexpressed in IPF126 and type I cytokines,
particularly interferon-γ, being antifibrotic.108
Other inflammatory cells that may contribute to disease activity
include macrophages and neutrophils, both of which are increased in
lavage fluid in IPF (see Table A2, p. 759).127 Suitably stimulated, these
cells secrete a variety of proteases and toxic oxygen and hydroxyl radi-
A cals.128–130 Proteases may so disturb the healing process as to per­
petuate it, whilst the toxic radicals may be responsible for damage
to the capillary endothelium and alveolar epithelium128–130 that is
evident on electron microscopy (see Fig. 6.1.9).57–59
Bronchoalveolar lavage also highlights a potential role for mast cells
in IPF131 and when mast cells are sought by appropriate staining in
tissue sections they are seen to be numerous in the interstitial tissues
of the lungs in this disease, and undergoing degranulation.132 Electron
microscopy demonstrates that they are frequently in close apposition
to fibroblasts.133 A variety of cytokines, including those that stimulate
fibroblasts, are known to be released by mast cells and immuno­
phenotyping indicates that these cells are highly activated in a variety
of interstitial lung diseases.134–136
Endothelial damage and interstitial oedema, which are evident on
electron microscopy,58 are probably also important since it is known
that chronic interstitial oedema contributes to interstitial fibrosis in
other circumstances, e.g. the ‘brown induration’ of the lungs seen in
long-standing mitral stenosis (see p. 403).137 Various mechanisms
B
contributing to microvascular injury have been identified.138 However,
although likely to play a role in the development of pulmonary
Figure 6.1.11  Usual interstitial pneumonia. (A) Immunocytochemistry
fibrosis in IPF, the exact role and relative importance of angiogenesis
demonstrates the intracellular form of transforming growth factor-β
and vascular remodelling remain uncertain at present.139
within the hyperplastic alveolar epithelium. (Reproduced from Corrin et al.97
with permission of the editor of Histopathology.) (B) The extracellular form of
In conclusion, a combination of environmental and genetic factors,
transforming growth factor-β is seen within the alveolar interstitium age and other unknown agents appear to cause an initial injury to the
immediately beneath the alveolar epithelium, compatible with it having alveolar epithelium that progresses to a state of persistent dysregulated
been secreted by these cells. repair, eventually leading to irreversible architectural remodelling. The
mechanisms involved in this process are represented diagrammati-
cally in Figure 6.1.12.108

epithelialisation.108 Direct signalling between epithelial cells and

fibroblasts may also be possible in view of the contacts that have been
Cancer in IPF
described between these cells through gaps in the epithelial basement
membrane.116,117 A further role for the epithelium involves a direct A notable complication of IPF is the development of lung cancer,
contribution to the fibrosis in a process of epithelial–mesenchymal which has been reported in up to 13% of fatal cases.140,141 In an early
transition.118,119 study, in which the patients were matched for age and smoking habit,
Eicosanoids, which are lipid metabolites that play a role in it was claimed that IPF contributed a 14-fold increased risk of lung
many inflammatory processes, have also been suggested as playing cancer.142 However, although a later study confirmed the association
a role in patients with IPF, with an imbalance of molecules leading to the authors were not convinced that the association was causal.143
increased profibrotic leukotrienes and a decrease of the antifibrotic The tumour may be of any histological type. Reports on the relative
prostaglandin PGE2.108 prevalence of the various histological types vary but overall their dis-
It is noticeable from the above that the emphasis on pathogenesis tribution does not appear to depart significantly from that found in
has shifted away from a process driven primarily by inflammation to the general population. The epithelial hyperplasia–metaplasia–dys-
one initiated by epithelial cell injury coupled with aberrant wound plasia sequence found in IPF (see Fig. 6.1.8B) is thought to represent
healing.120 This view gains support from genetic profiling, IPF being the starting point of the cancer. Mutations of the p53 oncogene
characterised by genes concerned with tissue remodelling rather than have been demonstrated therein144 and a high proportion of the
inflammation.121 Nevertheless, it is likely that inflammatory cells play cancers arise in the periphery of the lower lobes where the fibrosis and
a contributory role. Histological studies show that the severity of the dysplasia are most severe.141 Non-small cell carcinoma complicating
interstitial inflammation correlates with disease progression.49 The IPF may be resectable but operative mortality is high.145 A few cases

275
 Pathology of the Lungs

Age
Genetic factors
Environmental factors
Nature of injury

Repetitive alveolar
epithelial injury

Oxidative Profibrotic
stress cytokines

TIMPs-MMPs Altered alveolar Chemokines

imbalance microenvironment

Fibrosis
Impaired Eicosanoid
fibrinolysis imbalance Figure 6.1.13  Non-specific interstitial pneumonia. High-resolution
computed tomography shows ground-glass and faint reticular opacities.

Dysregulated repair
Loss of epithelial cells sometimes of extrinsic allergic alveolitis and occasionally of IPF.157
Accumulation of mesenchymal cells Genetic profiling also supports a multifactorial aetiology, some cases
Figure 6.1.12  Pathogenesis of idiopathic pulmonary fibrosis. Progressive of NSIP expressing genes associated with IPF (such as those concerned
pulmonary fibrosis results from dynamic alterations in the alveolar with remodelling), some with extrinsic allergic alveolitis (such
microenvironment that eventually promote loss of alveolar epithelial cells as inflammation and immune processes) and yet others that defy
and accumulation of activated fibroblasts/myofibroblasts. TIMPs, tissue characterisation.121
inhibitors of matrix metalloproteinases; MMPs, matrix metalloproteinases. NSIP may also represent connective tissue disorders that as yet lack
(Redrawn from Thannickal et al.108 with permission of The Annual Review of systemic features, it being a common histological pattern in fully
Medicine.) developed cases of systemic sclerosis, polymyositis, Sjögren’s syn-
drome and, to a lesser extent, rheumatoid disease.155,158–161 One group
reported that 10% of patients originally diagnosed as having idio-
of IPF have been complicated by the development of pulmonary pathic NSIP subsequently developed collagen vascular disease.152
lymphoma.146 Patients with such early connective tissue disease tend to be young,
female non-smokers and in one centre constituted 88% of cases with
NSIP.162 There is also indirect evidence that some cases of fibrotic NSIP
may be smoking-related.163
NON-SPECIFIC INTERSTITIAL PNEUMONIA A histological pattern of NSIP should therefore be viewed as no
more than a category from which the clinician can return to the
The term NSIP was first used in the context of human immunodefi- patient to look for these potential associations, rather than a ‘waste-
ciency virus (HIV) infection147 and only later applied to a pattern of basket’ diagnosis.156 Thus, the clinical disease ‘idiopathic NSIP’ should
supposedly idiopathic interstitial pneumonia that lacked specific fea- only be diagnosed after all these possible associations have been
tures and could not be classified as one of the better-defined subsets.148 excluded.151
The cause was unclear but clinical correlation suggested that it was
multifactorial, some cases showing evidence of connective tissue
disease, exposure to environmental allergens or previous acute lung Clinical features
injury. This uncertainty is reflected in the American Thoracic Society In patients with idiopathic disease, symptoms and signs are similar to
and European Respiratory Society classification in that the diagnosis those seen in IPF. The patients complain of breathlessness, cough and
allocated to a histological pattern of NSIP is merely given as NSIP fever and are found to have crackles on auscultation. Clubbing
(provisional). However, the term is of value in that patients with a is frequently evident. Some bronchoalveolar lavage studies record
histological pattern of NSIP have consistently been shown to respond increased numbers of lymphocytes,164 but others have shown no
better to treatment and have a more favourable prognosis than difference from UIP in this respect.165 Functional studies generally
patients with UIP (see Fig. 6.1.2).2,4,5,8,9,148–150 show restrictive impairment.151 HRCT shows varying patterns
Subsequent studies have provided further support for the multifac- but a common one is of ground-glass opacities and reticular changes
torial nature of NSIP and shown that only a minority of cases are which may be diffuse but mainly involve the lower lobes (Fig.
idiopathic.151,152 An NSIP pattern has been reported in further cases of 6.1.13).151,157,162,166,167 Volume loss and traction bronchiectasis may
extrinsic allergic alveolitis66,67,153 and it is now realised that some drug also be seen.151 Honeycombing is less prevalent than in UIP but may
reactions result in a pattern of NSIP.154 Similarly, it is now clear that be encountered.166,167
organising pneumonia and DAD may progress to NSIP.148,155 Foci of
NSIP may also be seen in IPF, with the classic UIP pattern evident
Histopathology
elsewhere in the lung.4–6,156
Imaging provides further support that NSIP is multifactorial. HRCT NSIP is characterised by expansion of the interstitium by variable
scans of NSIP are sometimes suggestive of organising pneumonia, amounts of chronic inflammation and fibrosis, the distribution of

276
 Diffuse parenchymal disease of the lung Chapter |6|

Figure 6.1.15  Non-specific interstitial pneumonia. The interstitium

is infiltrated by lymphocytes, histiocytes and plasma cells, whilst the
fibrosis is collagenous and lacks the fibroblastic foci of usual interstitial
pneumonia.

Table 6.1.3  Major histological features of cellular and fibrotic

forms of non-specific interstitial pneumonia

Cellular Fibrotic

B Diffuse involvement of Diffuse involvement of affected

affected parenchyma parenchyma
Figure 6.1.14  Non-specific interstitial pneumonia. (A) The changes are Moderate chronic interstitial Mild to moderate chronic interstitial
more diffuse than in usual interstitial pneumonia. (B) The cellular variant inflammation inflammation
shows mild uniform expansion of the interstitium by a non-specific Little or no fibrosis Variable degree of interstitial fibrosis
chronic inflammatory cell infiltrate. Preservation of alveolar Little loss of alveolar architecture (no
architecture honeycombing)

Any features that suggest a specific aetiology, such as inorganic dust,

granulomas, eosinophils and Langerhans cells, exclude non-specific interstitial
pneumonia.
which is diffuse and usually lacks evidence of being either centriacinar
or subpleural/paraseptal (Fig. 6.1.14). Foci of organising pneumonia
may be seen but they are not the dominant component. At high
power, the inflammatory cell infiltrate is seen to comprise small lym-
phocytes with occasional plasma cells, whilst the fibrosis may be may show mild to moderate fibrosis and overlap histologically with
predominantly collagenous or fibroblastic in nature (Figs 6.1.15 and fibrotic NSIP.
6.1.16). However, the fibrotic process is all of the same age (i.e. tem- The exudative and organising phases of DAD are easily distinguish-
porally homogeneous) with fibroblastic foci being absent or, at most, able from NSIP as neither hyaline membranes nor diffuse organising
scanty.2 pneumonia is present, but in long-term survivors of DAD the histo-
NSIP was initially divided into inflammatory, mixed and fibrotic logical features may be indistinguishable,148 again emphasising the
types (grades 1–3) but subsequent studies showed that the survival importance of clinical correlation.
for the mixed and fibrotic patterns is similar.5,9 NSIP is therefore now Extrinsic allergic alveolitis may also simulate fibrotic NSIP, in which
divided only into cellular and fibrotic, the latter having the worse case the presence of even a single granuloma or a suggestion of
prognosis. Table 6.1.3 summarises the histological features of bronchiolocentricity should raise the suspicion of hypersensitivity.
NSIP. The distinction of cellular NSIP from lymphoid interstitial pneu-
monia (LIP – see p. 655) is subjective, being primarily based upon
the intensity of the interstitial chronic inflammatory cell infiltrate,
Differential diagnosis which is much more marked in LIP than in NSIP. Again imaging is of
The principal differential diagnosis is between fibrotic NSIP and UIP, value as LIP more frequently shows cystic changes superimposed on
the key features of which are described on page 269 and in Table 6.1.2. the ground-glass opacities. From a clinical perspective, the distinction
The separation of cellular NSIP from DIP is facilitated by the relative between LIP and cellular NSIP is not particularly important as their
dearth of alveolar macrophages in NSIP but rare cases of DIP prognoses are similar.

277
 Pathology of the Lungs

UIP,2,4,5,8,9,148–150 82% in one study and 74% in another.151,152 Rare

patients experience acute exacerbations.168 The prognosis of NSIP in
the connective tissue diseases is similar to that in idiopathic cases.169

ACUTE INTERSTITIAL PNEUMONIA

(IDIOPATHIC DIFFUSE ALVEOLAR DAMAGE)

Acute interstitial pneumonia (AIP) differs from the other idiopathic

interstitial pneumonias in that it presents as acute respiratory failure
rather than chronic lung disease. The pathological basis is DAD, which
has many well-recognised causes as well as the idiopathic variety now
under discussion (see Box 4.2, p. 143).

Clinical features
As opposed to other interstitial lung diseases, AIP has an acute
A presentation and shows a rapid clinical progression.170 The clinical
features are very similar to those described by Hamman and
Rich171–173 but minor differences have been described.174 AIP starts
with a flulike episode, which is succeeded by rapidly progressive
severe dyspnoea, often leading to death from respiratory failure. The
age range is wide but the mean is approximately 50 years and there
is no sex predilection. By definition, patients are previously healthy
and have no underlying disease.170,174 HRCT shows bilateral ground-
glass opacification and dependent consolidation while in the organis-
ing phase there is reticular opacification with traction bronchiectasis
and ultimately cystic change.

Histopathology
The histological features are those of DAD, as described in Chapter 4
(p. 136). DAD differs from UIP in its lack of established fibrosis and
the presence of hyaline membranes in most cases, while long-term
survivors lack the temporal heterogeneity of UIP. The organising phase
of DAD may resemble organising pneumonia175 and the late features
may be indistinguishable from fibrotic NSIP.148 It is important to
exclude infection and special stains should be applied accordingly.
B Indeed, most biopsies come from the intensive care unit, with a view
to confirming the presence of DAD and excluding infection, acute
Figure 6.1.16  Cellular and fibrotic non-specific interstitial pneumonia. eosinophilic pneumonia and occult malignancy.
(A) Cellular non-specific interstitial pneumonia (NSIP) shows mild
interstitial chronic inflammation without fibrosis. (B) Fibrotic NSIP  
shows variably intense interstitial chronic inflammation in association   Prognosis
with established fibrosis. Mortality in AIP is reported as varying between 12 and 70%,26,170,174
with survivors showing either complete recovery or residual fibrosis.

IgG4-related systemic sclerosing disease is a further condition that IDIOPATHIC BRONCHIOLOCENTRIC

may be confused with cellular NSIP. It is characterised by a heavy
INTERSTITIAL PNEUMONIA
infiltrate of IgG4-bearing plasma cells, the recognition of which is key
to the diagnosis (see p. 485).
Mixed patterns should alert one to the possibility of an adverse drug Centriacinar inflammation and fibrosis are features of many lung
reaction or a collagen vascular disease. diseases, being seen for example in viral infections, bronchiectasis,
aspiration, respiratory bronchiolitis-associated interstitial lung disease,
extrinsic allergic alveolitis, Langerhans cell histiocytosis, rheumatoid
disease and pneumoconiosis. Several of these conditions abate to
Prognosis leave only non-specific centriacinar scarring and reports of an idio-
Patients with cellular NSIP show a good response to steroid therapy pathic form of bronchiolocentric interstitial pneumonia may there-
and have an excellent prognosis, their 5-year survival being close fore engender initial scepticism. However, a few workers have reported
to 100%.5,9,150 Data on fibrotic NSIP are less consistent but it is small groups of patients with such pathological changes and distinc-
universally reported that the 5-year survival is better than with tive demographic and clinical features.176–178 The majority of these

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 Diffuse parenchymal disease of the lung Chapter |6|

patients were middle-aged women with restrictive respiratory impair-

Table 6.1.4  Some aetiological agents in extrinsic allergic
ment and bilateral, predominantly lower-lobe interstitial infiltrates,
alveolitis. Although this list is far from complete, byssinosis
airway thickening and traction bronchiectasis. No cause was apparent.
and humidifier fever are omitted intentionally, being dealt
Many of the patients died of their disease within a few years of pres-
with on page 358
entation. At present it is uncertain whether these features represent a
new pattern of idiopathic interstitial pneumonia or the end-result of
Antigen Source Disease
a variety of previously described conditions, not least as several so-
described patients had possible environmental exposures.178 Thermophilic bacteria
Micropolyspora faeni Mouldy hay Farmer’s lung

EXTRINSIC ALLERGIC ALVEOLITIS Thermoactinomyces vulgaris Mouldy grain Grain handler’s

lung
(HYPERSENSITIVITY PNEUMONIA)
M. faeni, T. vulgaris Mushroom Mushroom
compost worker’s lung
The synonymous terms ‘extrinsic allergic alveolitis’ and ‘hypersensitiv-
ity pneumonia’ are applied to a chronic granulomatous disease of the T. sacchari Mouldy sugar Bagassosis
lungs that results from the inhalation of any of a wide variety of cane (bagasse)
organic substances that are capable of acting as a foreign antigen and
T. vulgaris, T. thalpophilus Contaminated Air conditioner
triggering a local hypersensitivity reaction.179 Farmer’s lung180 is the
water lung
archetypal example but there are numerous different circumstances
and allergens, frequently designated by exotic names such as paprika Other bacteria
pod splitter’s lung, maple bark stripper’s lung and the like (Table
Bacillus subtilis Biological Detergent
6.1.4). Budgerigar-fancier’s lung and summer-type hypersensitivity
washing packer’s lung
pneumonitis are respectively the commonest varieties of extrinsic powder
allergic alveolitis in the UK and Japan.181,182 In the USA farmer’s lung
is the commonest nationally183 but at the Mayo Clinic avian proteins Cryptostroma corticale
accounted for 34% of cases, ‘hot tub’ mycobacteria (see below) for Bacillus subtilis
21%, farmer’s lung for 11% and household moulds for 9%, with the
causative agent unidentified in 25%.184 No matter what the antigen, Mycobacterium avium Hot tubs Hot tub lung
the pathology is identical in them all and a more meaningful division complex
is into those of sudden onset (acute), those which come on gradually Fungi
(subacute) and those with long-standing disease (chronic). Thus, the
pigeon fancier with a large flock is likely to relate the onset of his Cryptostroma corticale Mouldy maple Maple bark
symptoms to mucking out his loft a few hours previously, whereas the bark stripper’s lung
owner of a single budgerigar will probably not suspect that her gradu- Aspergillus clavatus Mouldy malt or Malt worker’s
ally increasing breathlessness is attributable to the pet she has suc- barley lung
coured without ill-effect for many years. In each case the allergen
consists of avian protein in the bird droppings. Aureobasidium pullulans Mouldy redwood Sequoiosis
dust

Clinical features Penicillium casei Cheese mould Cheese washer’s

lung
Atopy is not a prerequisite for extrinsic allergic alveolitis. Anyone may
develop this disease but certain alleles of the major histocompatibility Penicillium frequentans Mouldy cork dust Suberosis
complex (MHC) appear to increase genetic susceptibility. Conversely, Trichosporon asahii House dust, bird Summer-type
smoking appears to confer protection as the disease is unusual in droppings pneumonitis
smokers.185 Patients with low constant exposure to the relevant aller-
gen complain of slowly progressive breathlessness and are more likely Animal proteins
to undergo lung biopsy than those with acute forms of the disease, Avian serum and excreta Pigeons, Bird fancier’s lung
which can generally be diagnosed from the occupational and clinical budgerigars
histories. Farmer’s lung provides a typical example. This disease is
liable to develop if hay has to be gathered when it is still damp, as Feathers, serum Chickens, turkeys Chicken/turkey
often happens after a wet summer, in which circumstances ther- handler’s lung
mophilic bacteria grow on it during storage. Subsequent handling in Rat urine and serum Rats Rodent handler’s
late winter may raise a fine dust which, if inhaled, can produce acute lung
respiratory disease. This usually begins a few hours after exposure,
Sitophilus granarius Infested wheat Wheat weevil
with fever and a rigor, followed by cough, dyspnoea and, perhaps,
flour lung
expectoration of blood-stained sputum. About half such patients
show transient pulmonary opacities on X-ray examination. Mild Porcine or ovine protein Pituitary snuff Pituitary
attacks clear up in 2–3 weeks but further attacks may be more severe snuff-taker’s
and protracted, and recovery may never be complete. Occasional lung
patients develop jejunal villous atrophy and suffer from intestinal
Drugs, including methotrexate, procarbazine,
malabsorption, as in coeliac disease.186 The slowly progressive
trimethoprim, gold thiomalate
dyspnoea that results from constant low exposure is the result of a

279
 Pathology of the Lungs

Figure 6.1.17  Extrinsic allergic alveolitis. In the acute phase of the

Figure 6.1.18  Extrinsic allergic alveolitis. A poorly formed non-
disease high-resolution computed tomography shows a generalised
necrotising giant cell granuloma (bottom right) is associated with
increase in the density of the lung parenchyma and faint nodularity. In
widespread interstitial pneumonitis.
this example, several thin-walled cystic air spaces are also evident, an
occasional feature of the disease.

restrictive respiratory defect with decreased lung compliance and

reduced gas diffusion.
Radiologically, acute disease is characterised by generalised ground-
glass opacification with small centrilobular nodules whereas in
chronic cases the process often affects the upper lobes and HRCT
shows a reticular pattern, reflecting the development of fibrosis (Fig.
6.1.17).187 A mosaic pattern of attenuation may also be seen reflecting
the bronchiolitic component of the disease. As with many diffuse
diseases of the pulmonary parenchyma the advent of HRCT has
resulted in many cases being diagnosed without recourse to biopsy.
Bronchoalveolar lavage shows a lymphocytosis with a predominance
of CD8 suppressor/cytotoxic T cells (see Table A2, p. 759). Skin
tests and serology may provide further evidence in support of the
diagnosis but there are many more antigens in nature than in the
immunologist’s armamentarium and often the responsible antigen is
never identified.65

Figure 6.1.19  Extrinsic allergic alveolitis showing a collection of

Histological appearances65,66,153,188–191 Schaumann bodies. (Courtesy of Dr Nassif Ibrahim, Bristol, UK.)
The lung is seldom biopsied in the acute forms of the disease and
there are consequently few descriptions of the pathological features
in these patients but the authors have encountered prominent necro-
tising granulomas in such a case. Others have reported capillaritis in
an early acute fatal case192 and following provocation tests.193 DAD
was reported in a further fatal case.188
Lung biopsies taken during the first few months of extrinsic allergic
alveolitis show poorly formed non-necrotising granulomas. These are
generally smaller and less frequent than those seen in sarcoidosis and
are accompanied by widespread thickening of the alveolar walls by a
diffuse lymphocytic infiltrate (Fig. 6.1.18). No fungal elements are
found, but small fragments of foreign material may be present.
Schaumann bodies may also be observed (Fig. 6.1.19). Isolated giant
cells with cytoplasmic clefts are frequently observed: these are sugges-
tive of the diagnosis but not specific (Fig. 6.1.20). In contrast to
sarcoidosis, the hilar lymph nodes are unaffected. The diffuse back-
ground interstitial inflammation is another feature distinguishing the
condition from sarcoidosis as it is only seen in the latter if biopsy is
undertaken very early in the course of the disease. A further difference Figure 6.1.20  Extrinsic allergic alveolitis. To the right a giant cell contains
is the presence of knots of granulation tissue within alveoli and res- two acicular crystal clefts while Masson bodies (bourgeons conjonctifs)
piratory bronchioles (see Fig. 6.1.20), evidence of organisation of representing organisation of luminal exudates are seen  
luminal exudates and responsible for the accumulation of lipid-laden centre left.

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 Diffuse parenchymal disease of the lung Chapter |6|

Table 6.1.5  Biopsy findings in 60 patients with farmer’s lung189

Interstitial pneumonitis 60 (100%)

Interstitial fibrosis 39 (66%)
Intra-alveolar fibrosis 39 (66%)
Foam cells 39 (66%)
Bronchiolitis obliterans 30 (50%)
Granulomas 42 (70%)
Solitary giant cells 32 (53%)
Vasculitis 0

Figure 6.1.21  Extrinsic allergic alveolitis. The inflammatory infiltrate is

maximal around bronchioles. Table 6.1.6  A comparison of the histological features of
pulmonary sarcoidosis, extrinsic allergic alveolitis (EAA) and
lymphoid interstitial pneumonia (LIP)

Sarcoid EAA LIP

Granulomas Persistent, well Evanescent, Persistent, poorly

formed poorly formed formed
Interstitial Inconspicuous Prominent, Very prominent,
pneumonitis peribronchiolar diffuse
Intraluminal Minimal Moderate Absent
fibrosis
Lymph node Prominent Absent Absent
involvement
Fibrosis Dense in Dense in Slight
advanced advanced
cases cases

Progression and distribution of the lesions

within the lungs
Figure 6.1.22  Lung biopsy in a chronic case of extrinsic allergic alveolitis The granulomas resolve within about 6 months, unless there is further
shows cystic change and patchy bronchiolocentric inflammation (arrows). exposure, but the inflammation may progress to irreversible scarring,
which in biopsy material is an adverse prognostic factor.194 The
fibrosis may show a histological pattern of either UIP or fibrotic
macrophages (endogenous lipid pneumonia) which may also be NSIP.65,66,191,195 In advanced cases, the lungs show end-stage features
evident. such as honeycombing. The upper lobes are affected more than
The granulomas tend to resolve with time but the diagnosis may the bases, although in acute cases chest radiographs show a basal
still be suggested by the inflammatory process being peribronchiolar preponderance. Whereas UIP is basal and affects a peripheral sub­
(Figs 6.1.21 and 6.1.22), these airways being the portal of entry of the pleural rim of lung, burnt-out extrinsic allergic alveolitis affects the
aetiological agent. The peribronchiolar distribution of the inflamma- upper lobes more than the lower and is patchy and irregular in its
tion also helps to distinguish extrinsic allergic alveolitis from NSIP distribution, with central portions affected as much as the periphery
and LIP. LIP is a condition that may also show poorly formed granu- (Fig. 6.1.23). Also, the fibrosis is often more bronchocentric in
lomas but it is characterised by a more diffuse, intense infiltrate that distribution, rather than being predominantly subpleural and
is seldom accompanied by any appreciable degree of fibrosis. The paraseptal as in UIP.
differential diagnosis also includes mycobacterial and fungal infection
and adverse drug reactions to agents as diverse as methotrexate, inter-
feron and tumour necrosis factor-α antagonists (see p. 389). Aetiology196,197
The histological features of extrinsic allergic alveolitis are summa- The role of an inhaled agent in provoking extrinsic allergic alveolitis
rised in Table 6.1.5 and contrasted with those of sarcoidosis and LIP has been demonstrated with inhalation tests. For example, extracts of
in Table 6.1.6. Although they are characteristic of extrinsic allergic mouldy hay produced characteristic reactions in 12 of 15 patients with
alveolitis and permit a confident histological diagnosis, exhaustive farmer’s lung compared with none of 20 control individuals,198 but
environmental and serological investigations quite commonly fail to such testing would now be regarded as unethical due to the danger of
identify the cause.65,184 permanent lung damage.

281
 Pathology of the Lungs

Figure 6.1.23  Farmer’s lung. Honeycombing is maximal in the upper lobe. (Courtesy of Dr RME Seal, Cardiff, UK.)

A feature of all forms of extrinsic allergic alveolitis is the presence

of serum precipitins against extracts of the substances known to
produce symptoms of the disease and because of this the disease is
widely believed to represent an immune complex disorder, with the
antigen–antibody complexes forming locally rather than being filtered
from the circulation. The precipitins are well demonstrated by double
diffusion (Ochterlony) testing or by immunoelectrophoresis, whereby,
for example, avian antigens give a pattern of precipitin arcs with serum
from cases of bird fancier’s lung (Fig. 6.1.24). However, it should be
noted that many exposed persons have circulating precipitins but few
show evidence of disease. In support of an immune complex aetio­
logy, biopsies from patients with farmer’s lung subjected to provoca-
tion tests have shown immunoglobulin and complement around
blood vessels.193 The peribronchiolar/periarterial preponderance is Figure 6.1.24  Extrinsic allergic alveolitis. Immunoelectrophoresis showing
explained by the antigen diffusing from the airways meeting anti­ precipitation arcs where antibodies from the patient’s serum have
bodies diffusing from the blood at this site. Although granulomas are encountered the test antigen. (Courtesy of Dr J Longbottom, Brompton, UK.)
better known in cellular hypersensitivity states, they are quite compat-
ible with immune complex disease, as it has been shown that they
form when antigen and antibody are present in a particular ratio that
renders them insoluble.199 asymptomatic pigeon breeders, lymphocyte stimulation by pigeon
On the other hand, there is considerable evidence to support cel- serum extracts was only obtained in the first group, regardless of the
lular immune mechanisms playing an important role in extrinsic presence or absence of precipitins, thus supporting a direct role
allergic alveolitis. In addition to the granulomas, most of the lym- of T-cell-mediated immunity in the aetiology of pigeon breeder’s
phocytes recovered by alveolar lavage are T-suppressor/cytotoxic cells disease.200 Further support for this comes from experiments producing
(see Table A3, p. 760). Furthermore, in a study of symptomatic and hypersensitivity pneumonitis in athymic mice.201

282
 Diffuse parenchymal disease of the lung Chapter |6|

Thus there is evidence that immune complexes and cellular hyper- Epidemiology
sensitivity are both involved179 and it is probably naive to conceive
Sarcoidosis occurs worldwide but is more prevalent in the higher
any immune process as being wholly humoral or wholly cellular.
latitudes; northern Europe and North America have prevalence rates
Furthermore, non-immunological mechanisms involving activation
in the range of 10–40 per 100 000. The incidence and severity of
of complement by the alternate pattern have also been implicated in
the disease vary considerably between different racial groups living in
the pathogenesis of extrinsic allergic alveolitis.196 Impaired lung
the same geographical area. West Indian and Asian immigrants living
immunity may explain the apparent protection against extrinsic aller-
in London have a 10-fold higher incidence than the native white
gic alveolitis observed in smokers.185
population.211 Similarly, black Americans have more sarcoidosis than
whites, whilst the disease is quite rare in native Americans. It is also
‘Hot tub lung’ rare in Eskimos, Arabs and the Chinese. Negroes are affected more
acutely and more severely than other races.
‘Hot tub lung’ is caused by the inhalation of Mycobacterium avium-
cellulare from an infected spa pool and, although this bacterium can
often be isolated from the patient’s lungs, the condition is widely Aetiology
believed to represent extrinsic allergic alveolitis rather than infection.
This is largely because it frequently resolves with corticosteroids, or The aetiology of sarcoidosis is obscure; no single factor is known. The
even by avoiding exposure to the infected hot tub; antimycobacterial racial differences referred to above have generally been attributed to
treatment does not appear to be required.202 Patients complain of genetic factors,212–215 Associations have been shown with the major
dyspnoea, cough, weight loss and fever while HRCT demonstrates histocompatibility complex (MHC), in particular the class II MHC
centrilobular nodules and ground-glass opacification. The pathologi- alleles, several of which confer susceptibility (HLA-DR11,12,14,15,17)
cal changes consist of florid, non-necrotising granulomatous disease while others appear to be protective (HLA-DR1, DR4 and possibly
centred on the conducting airways. The granulomas are well formed HLA-DQ*0202).216–218 Familial sarcoidosis has also been described,
and are frequently situated within the airway lumina. They are more and variably ascribed to either genetic or shared environmental
prominent than is usually the case in extrinsic allergic alveolitis and factors.219–222 A comparison of monozygotic and dizygotic twin pairs
the widespread interstitial inflammation characteristic of such alveo- suggests that genetic factors account for two-thirds of the susceptibility
litis is not a feature – on the other hand, neither is the prominent to sarcoidosis and environmental factors for one-third.223
necrosis that is commonly seen in mycobacterial infection. Culture Environmental factors are also suspected of playing a role in the
and a history of exposure are necessary for the diagnosis as the bacteria aetiology of sarcoidosis, probably involving the uptake and processing
are seldom identified on special stains of tissue sections. Sarcoidosis of as yet unknown antigens, particularly by the respiratory system.
is the principal differential diagnosis, the distinction from which is Granulomas are of course found in a variety of conditions, notably
often determined by the environmental history and culture.202–208 tuberculosis, some fungal infections and chronic berylliosis. They may
also be found in the vicinity of tumours. The granulomas of primary
biliary cirrhosis resemble those of sarcoid and occasional patients
have features of both these diseases.224 Pulmonary granulomas have
SARCOIDOSIS also been reported in HIV-infected patients receiving antiretroviral
therapy225 and in leukaemic patients being treated with interferon-α.226
Some authors regard sarcoidosis as an anomalous form of tubercu-
Sarcoidosis is a multisystem granulomatous disease of unknown cause
losis for occasional cases seem to swing from one of these conditions
that is characterised by enhanced cellular hypersensitivity at sites
to the other and back again.227,228 Acid-fast bacterial L forms have been
of involvement. Elsewhere in the body cellular hypersensitivity is
cultured from the blood of patients with sarcoidosis,229 and the appli-
depressed so that reactions to common allergens such as tuberculin
cation of molecular probes for mycobacterial nucleic acids to granu-
are consistently negative.
lomatous tissue from patients with sarcoidosis has given positive
The lesions of sarcoidosis may be confined to one organ or dis-
results in a variable proportion of cases.230–232 However, positive cul-
seminated widely. Autopsy studies show that asymptomatic sarcoid­
tures are very rare, antituberculous treatment is ineffective and there
osis is much commoner than is realised clinically.209 Lymph nodes,
are notable differences in the distribution of the two diseases: for
the lungs, liver, spleen, skin and eyes are the organs most commonly
example, there is a high incidence of uveitis in sarcoidosis that is not
affected but virtually any part of the body may be involved. The dis-
seen in tuberculosis. Another bacterium for which there is similar
tribution of the lesions is consistent with the lungs being the portal
genomic but negative cultural evidence in sarcoid tissue is the epider-
entry of the unknown causative agent, the lymph nodes being affected
mal agent Propionibacterium acnes.233,234 Other agents suggested as
by lymphatic spread from the lungs, and other organs being involved
having a role in the aetiology of sarcoidosis are listed in Table 6.1.7.
by a combination of lymphatic and blood spread, a situation entirely
As noted above, sarcoidosis is characterised by anomalous immu-
analogous with that in tuberculosis.
nological reactions. For example, the intracutaneous tuberculin reac-
The minimal criteria for an established diagnosis of sarcoidosis210
tion is generally negative, despite contact with tubercle bacilli, a
are:
phenomenon known as anergy. An explanation for this is provided
• consistent clinicoradiological features by study of T-lymphocyte subsets.235 In the blood, the suppressor cell
• histological evidence of non-necrotising epithelioid cell (CD8):helper cell (CD4) ratio is increased in sarcoidosis whereas in
granulomas bronchoalveolar lavage fluid the ratio alters in the opposite direction
• exclusion of agents known to cause granulomatous disease (see Table A3, p. 760). Analysis of lymphocyte subsets within the
but the diagnosis may be made in biopsy-negative patients if there are granuloma (see below) is in accordance with the lavage findings. The
appropriate clinical features and other supportive investigations. increase in CD4 helper T cells is seen especially in acute disease. When
The Kveim test has been largely abandoned because of fears of prion suitably stimulated these cells show a type I cytokine response, releas-
transmission: the inoculum consists of supposedly sterilised human ing cytokines such as IL-2, interferon-γ and IL-16 that attract other
splenic tissue affected by sarcoidosis. mononuclear cells into the granulomas. Cytokine profiles also cor-

283
 Pathology of the Lungs

Table 6.1.7  Sarcoidosis: proposed causative agents

Infective agents Inorganic Organic

agents agents

Mycobacterium tuberculosis
Other mycobacteria Aluminium Pine pollen
Propionibacterium acnes Zirconium
Borrelia burgdorferi Talc
Mycoplasma
Herpes virus
Epstein–Barr virus
Coxsackie B virus
Cytomegalo virus

Figure 6.1.25  Sarcoidosis. High-resolution computed tomography shows

numerous small nodules, some of which involve the interlobular septa
(arrow). Note the enlarged lymph node immediately anterior to the
trachea.

relate with disease progression. For example, increased IL-2 secretion

is associated with a poor prognosis, whilst transforming growth
factor-β is associated with spontaneous remission.236

Clinical features
Sarcoidosis usually appears early in adult life.210 It affects the sexes
equally.12 Cigarette smokers appear to be less likely to develop sar-
coidosis.237 The presenting features are extremely varied, as may be
expected of a disease so varied in its distribution. Most commonly,
patients complain of fatigue, weight loss and a dry cough. Dyspnoea
usually indicates more advanced disease. About one-third of patients
develop erythema nodosum and this may be the presenting feature.
Other extrapulmonary features include visual disturbances, neurolog­
ical manifestations, arthralgia, parotid enlargement, hepatomegaly
Figure 6.1.26  Sarcoidosis. On the left granulomas have coalesced to
and cardiac dysrhythmia. Disfiguring indurated lesions on the cheeks
form a mass lesion while the right side shows a more typical lymphatic
and nose, known as lupus pernio, may develop. The onset of sarcoido-
distribution.
sis is sometimes first evident in old tattoos or in scars containing
foreign material such as road gravel that gained access years previ-
ously. Serum levels of calcium, angiotensin-converting enzyme and
gamma-globulin levels are often elevated.
In the lungs, a multiplicity of small nodules comparable in size to Pathological findings249,250
miliary tubercles develops (Fig. 6.1.25). As with other granulomatous The histological hallmark of sarcoidosis is the granuloma, many of
diseases of the lungs, the upper lobes are more severely affected than which are generally seen scattered throughout otherwise unremark­
the lower lobes. The mediastinal lymph nodes often form large masses able lung tissue (Figs 6.1.26 and 6.1.27). They are generally confined
readily detectable by chest radiograph238 and increasingly accessed by to the interstitium and only rarely involve air spaces. The granulomas
ultrasound-guided transbronchial needle aspiration.239,240a Sometimes are preceded by a lymphocytic infiltrate251 but this is transient and is
the pulmonary lesions form large masses in what is known as a seldom evident by the time lung biopsy is undertaken. Indeed, in
nodular or conglomerate form of the disease.238,241 Occasionally the contrast to extrinsic allergic alveolitis, the histopathology of pulmo-
disease is centred on the airways and the patient has obstructive rather nary sarcoidosis is generally notable in that it lacks a diffuse lym-
than restrictive respiratory impairment.242,243 phocytic infiltrate (Fig. 6.1.27).
Some degree of pulmonary hypertension is found in most patients Sarcoid granulomas closely resemble early tubercles microscopi-
whose sarcoidosis has progressed to irreversible pulmonary fibro- cally; they differ from tubercles in that they do not undergo caseation,
sis.244,245 However, fibrosis cannot be the only mechanism as pulmo- although a little central necrosis is occasionally seen microscopically
nary hypertension is sometimes found in the absence of such advanced (Fig. 6.1.28). Epithelioid cells and multinucleate giant cells of
disease.246 The granulomatous impingement on pulmonary blood Langhans or foreign-body type are found in the centres of the granu-
vessels described below offers an alternative explanation.247,248 lomas. The giant cells often contain Schaumann and asteroid bodies
Compression of pulmonary arteries by enlarged mediastinal lymph (Figs 6.1.29 and 6.1.30) but these are not pathognomonic of sarcoid­
nodes, sarcoid-related mediastinal fibrosis and left ventricular failure osis, for they may be found in other forms of granulomatous inflam-
due to cardiac involvement are further mechanisms by which sar- mation. Schaumann bodies represent lysosomal residual bodies,252,253
coidosis may cause pulmonary hypertension.248a whilst asteroid bodies are aggregates of vimentin microfilaments

284
 Diffuse parenchymal disease of the lung Chapter |6|

Figure 6.1.29  Pulmonary sarcoid showing an asteroid body within a

giant cell.

Figure 6.1.27  Pulmonary sarcoidosis. The lung is studded with discrete

non-necrotising epithelioid and giant cell granulomas. Intervening
alveolar walls are unaffected. Two granulomas are closely applied to a
bronchiole.

Figure 6.1.30  Pulmonary sarcoidosis in an advanced stage. The

granulomas have healed, leaving only the central calcified Schaumann
bodies and extensive fibrosis that has destroyed the pulmonary
parenchyma.

and microtubules derived from the cytosphere, the radial arrangement

of which determines the bodies’ stellate form.254 Lymph nodes
draining sarcoid tissue often contain small brown Hamazaki–
Wesenberg bodies, which represent lysosomal ceroid pigment formed
Figure 6.1.28  Sarcoid granulomas occasionally show a little central through the oxidation and polymerisation of unsaturated fatty acids.
necrosis. More often the follicular architecture of the hilar lymph nodes is
completely effaced by numerous non-necrotising sarcoid granulomas
(Fig. 6.1.31).

285
 Pathology of the Lungs

Figure 6.1.31  Nodal sarcoidosis. The lymph node contains numerous

sarcoid granulomas.

Epithelioid cells are derived from macrophages but such is the

transformation they undergo during this development that there
are few ultrastructural similarities: gone are the phagosomes and
lysosomes of a macrophage, replaced by cytoplasmic organelles more
in keeping with a secretory cell. The immature epithelioid cell is rich
in rough endoplasmic reticulum, as seen in cells synthesising a pro-
teinaceous secretion. Golgi apparatus and storage vesicles then appear,
and in the mature epithelioid cell these organelles predominate (Fig.
6.1.32).255 These cells secrete a variety of proinflammatory cytokines
B
and fibrogenic cytokines, for example, transforming growth factor-β,
tumour necrosis factor-α, RANTES and nitric oxide synthase.256–261 The
Figure 6.1.32  Electron micrographs of epithelioid cells in a pulmonary
enzyme dipeptidyl carboxypeptidase (EC3.4.15.1), which acts as a
sarcoid granuloma. (A) An immature epithelioid cell showing abundant
kininase but is best known by its trivial name angiotensin-converting rough endoplasmic reticulum. The lysosomal dense bodies that
enzyme, has been localised to the cytoplasm of the epithelioid cells,262 characterise a macrophage are not evident. The electron-dense structures
which would therefore appear to be the source of the high serum are mitochondria. (B) A mature epithelioid cell showing an abundance of
levels of this enzyme that characterise granulomatous disease in vesicles and Golgi apparatus. (Courtesy of Dr C Danel and Miss A Dewar,
general and sarcoidosis in particular. The granulomas are also respon- Brompton, UK.)
sible for the final hydroxylation and hence activation of vitamin D,263
thereby accounting for the hypercalcaemia that is so frequently found
in sarcoidosis.264
Closely associated with the centrally situated epithelioid cells are
T-helper lymphocytes. T-suppressor lymphocytes are fewer in number veins and quite frequently involve all coats of these vessels in a granu-
and more peripherally situated.265,266 Cytokine studies suggest that the lomatous angiitis (see Fig. 6.1.33).250,272,273 All sizes of vessel, from
T-helper lymphocytes are mainly of the Th1 phenotype, producing large elastic arteries to venules and lymphatics, may be affected, but
IL-2 and interferon-γ.267,268 Tissue gene expression analysis has shown veins are the vessels most commonly involved.273 Indeed, sarcoidosis
a gene network engaged in Th1-type responses to be significantly can sometimes cause veno-occlusive disease.274 Right heart strain has
overexpressed in pulmonary sarcoidosis, with proteins MMP-12 and been attributed to this vascular involvement.247,248 Rarely, sarcoidosis
ADAMDEC1 emerging as likely mediators of lung damage and re­­ is combined with disseminated visceral giant cell angiitis (see p. 445).
modelling.269 A switch to predominantly Th2 lymphocytes may under- The granulomas may be so numerous that they become confluent,
lie a change from healing by resolution to healing by fibrosis. and rarely, large masses of sarcoid tissue are formed, the so-called
Antigen-presenting reticular cells are found at the periphery of the nodular or conglomerate form of sarcoidosis (see Fig. 6.1.26).238,241
granulomas and B lymphocytes between the granulomas.270 Spontaneous resolution is common, suggesting that the granulomas
At first sight the granulomas appear to be scattered haphazardly in often resolve but in other patients healing is by fibrosis, often with
the lung but in fact they are most numerous along the lymphatics and ‘honeycombing’ (Figs 6.1.35 and 6.1.36). The latter process involves
are therefore particularly well seen in relation to the centriacinar progressive hyalinisation and Schaumann bodies may provide the
bronchioloarterial bundles (Fig. 6.1.33) and in the interlobular septa. only indication that extensive scarring is the result of granulomatous
The bronchi are richly supplied with lymphatics and the granulomas disease (see Fig. 6.1.30). However, active and healed granulomas are
are accordingly well developed there, so this is a condition in which often seen together, suggesting that the unknown stimulus to the
small fibreoptic bronchial biopsies frequently provide sufficient tissue disease is a continuing one. Furthermore, early clinical disease may
for diagnostic purposes (Fig. 6.1.34).271 Also, because of their distribu- show fibrosis histologically, indicating that the disease may be quite
tion along lymphatics, the granulomas come very close to arteries and advanced before it causes symptoms.

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 Diffuse parenchymal disease of the lung Chapter |6|

Figure 6.1.34  Sarcoidosis. Bronchoscopy shows yellow nodules studding

the mucosa of the distal trachea and both main stem bronchi.
(Reproduced from Häussinger et al. (2003)433 with permission of Elsevier.)

organs such as the lung and may even mask the tumour.275 Overlooking
lymphoma in a lymph node showing florid secondary granulomas is
a notorious trap for the unwary. Reports of sarcoidosis being associ-
ated with lymphoma should only be accepted if the two diseases affect
anatomically distinct sites and the appropriate clinical, radiographic
and serological features of each disease are present.276
B Sarcoid-like granulomas characterise extrinsic allergic alveolitis but
are generally more poorly formed, scanty, and seen on a background
Figure 6.1.33  Pulmonary sarcoidosis. (A) The granulomas are clustered of diffuse chronic interstitial pneumonia, in contrast to sarcoidosis in
around small pulmonary blood vessels, where lymphatics are found.   which well-formed granulomas are usually studded throughout
(B) Granulomas within and alongside a small vein, the lumen of which   otherwise normal alveolar tissue. Even in very late sarcoidosis, lesions
is occluded and the wall partly destroyed. Elastin-van Gieson stain. are generally recognisable as burnt-out granulomas, whereas in extrin-
sic allergic alveolitis the granulomas resolve without trace within a
few months of last exposure to the responsible antigen. In both condi-
Differential diagnosis tions, lymphocytes are increased in bronchoalveolar lavage fluid but
in sarcoid the helper-cell:suppressor-cell ratio is high, whereas in
Infections such as tuberculosis always have to be considered in the
extrinsic allergic alveolitis it is low (see Table A3, p. 60).
differential diagnosis of sarcoidosis. The only conclusive histological
distinction is the identification of Mycobacterium tuberculosis by Ziehl–
Neelsen staining but features that favour sarcoidosis include granulo- Course and prognosis
matous involvement of blood vessels and the presence of Schaumann
The course of the disease is unpredictable. In about 60% of cases the
bodies.271 Necrotising sarcoid granulomatosis resembles tuberculosis
lesions regress over a period of 2–5 years and the patient recovers.
in showing large tracts of necrosis but is widely considered to repre-
After spontaneous improvement relapse is unusual. Sometimes,
sent a form of conglomerate sarcoidosis (see p. 443).
however, the lungs become progressively infiltrated and there is exten-
Sarcoidosis also has to be distinguished from a giant cell reaction
sive fibrosis resulting in upper-lobe volume loss and traction bron-
to foreign material, for which polarising filters are indispensable
chiectasis. Based on the radiographic changes, four stages of thoracic
(not forgetting that fragmented Schaumann bodies are usually bi­­
sarcoidosis have been described:
refringent). However, as noted above, the onset of sarcoidosis is some-
times first evident in old scars containing foreign material, such as 1. bilateral hilar lymphadenopathy (Löfgren’s syndrome)
road gravel that gained access years previously. In general, sarcoid 2. bilateral hilar lymphadenopathy and lung involvement
granulomas are more florid than the ordinary reaction to foreign 3. lung involvement without hilar lymphadenopathy
material. 4. irreversible pulmonary fibrosis.
Sarcoid granulomas are also a well-known phenomenon in lymph However, except that stage 4 is obviously preceded by stages 2
nodes draining tumours. They may also be seen close to a tumour in or 3, these are modes of presentation rather than successive

287
 Pathology of the Lungs

Figure 6.1.35  Late-stage pulmonary sarcoidosis. A whole lung slice

showing fibrosis maximal in the upper lobe. (Courtesy of Dr N Gubbay,
Cheltenham, UK.)

stages: lung involvement is not necessarily preceded by hilar

lymphadenopathy.
An acute onset with erythema nodosum or asymptomatic bilateral
hilar lymphadenopathy usually heralds a self-limiting course, whereas
an insidious onset, especially with multiple extrapulmonary lesions,
is more likely to be followed by relentless pulmonary fibrosis. Older
patients and blacks do less well than the young and whites. Advanced
pulmonary sarcoidosis is characterised by ‘honeycombing’, which
may be complicated by life-threatening saprophytic aspergillosis (Fig.
6.1.37). An increased risk of pulmonary lymphoma and carcinoma
Figure 6.1.36  Late-stage pulmonary sarcoidosis. A paper-mounted
has been identified in some studies277,278 but not others.279
whole-lung section showing fibrosis and ‘honeycombing’ maximal at the
Because limited disease often resolves spontaneously the decision apex of the lung. Solid nodules at the upper end of the interlobar fissure
to treat must be weighed against the risks of drug side-effects. In those are enlarged hilar lymph nodes, also involved by sarcoidosis.
patients who require therapy, corticosteroids are the drugs of choice.
Patients with progressive disease may require additional therapy with
drugs such as chloroquine, azathioprine and cyclophosphamide.
Drugs that suppress tumour necrosis factor-α may also be of benefit PULMONARY LANGERHANS CELL
in steroid-refractory disease.280 HISTIOCYTOSIS (PULMONARY
The disease carries a mortality of about 5%, most of the deaths HISTIOCYTOSIS X, EOSINOPHILIC
being attributable to either cardiac involvement or pulmonary fibrosis
causing respiratory failure.281–283 Rare causes of death include chronic GRANULOMA OF THE LUNG)286–290
renal failure due to nephrosclerosis and the cerebral effects of
meningovascular sarcoidosis. If transplantation is undertaken the During the 1940s it became clear that three previously described
disease may develop in the new lungs and there is evidence that it clinical conditions, Hand–Schüller–Christian disease, Letterer–Siwe
derives from recipient immune cells.284,285 disease and eosinophilic granuloma, had much in common patho-

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 Diffuse parenchymal disease of the lung Chapter |6|

Figure 6.1.38  The ultrastructural marker organelle of the Langerhans cell

(the Birbeck granule) is a pentalaminar structure with regularly spaced
cross-striations. (Reproduced from Corrin and Basset (1979)287 with permission
from Investigative Cell Pathology.)
Figure 6.1.37  Pulmonary sarcoidosis complicated by saprophytic
aspergillosis. An irregular fungus ball occupies a cavity just above  
the interlobar fissure. Elsewhere the lung shows irregular pale fibrosis,
the result of long-standing sarcoidosis. Table 6.1.8  The different forms of Langerhans cell histiocytosis

Clinical form Age Organs Prognosis

commonly
logically, and in 1953 the term ‘histiocytosis X’ was introduced to involved
encompass all three.291 This grouping subsequently derived support
from the electron microscopic identification of a distinctive cytoplas- Generalised diffuse Infancy Bone, bone Usually lethal
mic marker organelle in all forms of the disease, the Birbeck granule (Letterer–Siwe marrow, skin,
(Fig. 6.1.38).292 In normal tissues this marker organelle has been disease) lymph nodes,
described only in Langerhans cells, the implication of this being that liver, spleen,
histiocytosis X represents a pathological proliferation of Langerhans thymus, lung
cells. Accordingly, the term ‘Langerhans cell histiocytosis’ (or gran­ Generalised multifocal Childhood, Bone, skin, lung Chronic
ulomatosis) is now preferred (Table 6.1.8). However, a distinction is (Hand–Schüller– young disabling
drawn between pulmonary and extrapulmonary Langerhans cell his- Christian disease) adults disease
tiocytosis. The latter mainly affects children and is thought to be
Localised (eosinophilic Childhood, Bone Variable. May
neoplastic whereas pulmonary Langerhans cell histiocytosis is largely
granuloma of bone) young stabilise or
confined to young adult cigarette smokers and is thought to be
adults remit
reactive despite evidence of clonality in some of the pulmonary
nodules.293,294 Localised (eosinophilic Young Lung Variable. May
Langerhans cells are a constant feature of the normal epidermis and granuloma of lung) adult stabilise or
are occasionally found in the dermis. They are believed to be involved smokers remit
in delayed hypersensitivity reactions, particularly the transport of
antigen from the skin to the draining lymph nodes (see p. 28).
Langerhans cells are rarely identified in completely normal lung but Langerhans cells,295,298 which appear to be attracted by the altered
they appear there in response to cigarette smoke.295 They have also airway epithelium expressing granulocyte–macrophage colony-
been observed in the lung in various pulmonary diseases, both reac- stimulating factor.299 IL-2 has an inhibitory effect on Langerhans cells
tive296 and neoplastic.297 Epithelial hyperplasia and metaplasia and it is notable that tobacco smoke constituents impair IL-2 produc-
induced by tobacco smoke are particularly likely to be targeted by tion.300,301 In pulmonary Langerhans cell histiocytosis electron micro-

289
 Pathology of the Lungs

scopy shows that the Langerhans cells are in close contact with
lymphocytes that have been previously characterised as T-helper cells:
it is therefore suggested that the disease represents a hyperimmune
response in which the Langerhans cells serve as accessory cells.302
Langerhans cells and their pathological counterpart have a moder-
ate amount of light eosinophilic cytoplasm that is devoid of pigment,
and a single nucleus with an indented cerebriform outline and a finely
dispersed chromatin pattern. They carry surface receptors for Fc and
C3 but are poorly phagocytic. Electron microscopy shows that they
have few lysosomes but contain elongated pentalaminar structures of
constant width (40–45 nm) with a longitudinal periodicity (10 nm)
in their central laminae, the Birbeck granules (see Fig. 6.1.38).292,303
Interdigitating dendritic cells are functionally related and morpho-
logically similar to Langerhans cells but lack this marker organelle.292
Both these cells express S-100 protein but CD1a, fascin and langerin
are specific immunocytochemical markers of Langerhans cells.304–308

Clinical features
Figure 6.1.39  Langerhans cell histiocytosis. High-resolution computed
The lungs may be involved in the disseminated forms of Langerhans tomography shows irregular cystic changes and scattered nodules.
cell histiocytosis but they are most often affected in isolation. Young
adults are affected most frequently but there is a wide age distribution.
The great majority of patients are cigarette smokers.237,309 Males out-
number females in most series but the more recent literature suggests Table 6.1.9  Evolution of the disease in 67 patients with
a trend to a more equal sex distribution, reflecting the increasing pulmonary Langerhans cell histiocytosis286
number of women who smoke.
Non-specific chest complaints such as cough and dyspnoea are Evolution No. of patients %
often accompanied by multiple pneumothoraces and sometimes by
general symptoms such as weight loss and fever.286 Some patients are Improved 9 14
asymptomatic despite radiographic evidence of lung disease. One Stabilised 27 40
previously asymptomatic patient presented with bilateral pneumo­
thoraces and rapidly succumbed.310 Chest radiographs typically show Deteriorated 14 21
bilateral reticulonodular shadowing, most marked in the mid-zones311 Died 17 25
with sparing of the costophrenic angles, this last forming a useful
point of distinction from IPF. HRCT shows features that reflect the
stage of disease, ranging from nodules in the early stages to cysts at a
later stage, again sparing the costophrenic angles. The cysts vary in Cytotoxic drugs have only been beneficial in Letterer–Siwe disease.
shape, size and wall thickness (Fig. 6.1.39).312 In a smoker, these fea- Claims that steroids are beneficial are not substantiated in other
tures are highly specific and often obviate the need for biopsy.313 series.286 Generalised disease has been treated by bone marrow trans-
Rarely, the disease may present as a solitary pulmonary nodule or with plantation320 and advanced pulmonary disease by lung transplanta-
tracheal obstruction.314,315 With advancing disease, the cysts enlarge tion, but some patients undergoing transplantation have developed
and all zones of the lung become involved. Lung function tests usually the disease in their new lungs.321 It seems sensible to advise patients
show restrictive impairment. Pulmonary hypertension is a common with pulmonary Langerhans cell histiocytosis to stop smoking and
feature and is often severe.316 Blood eosinophilia is never found and, there is anecdotal evidence that this is helpful. An infant with osseous
if present, should suggest alternative diagnoses such as eosinophilic Langerhans cell histiocytosis is reported to have responded well to
pneumonia. Extrapulmonary involvement occurs in up to 15% of IL-2 therapy; the relevance of IL-2 therapy to Langerhans cell pro­
cases, when features such as lytic bone lesions or diabetes insipidus liferation is referred to above.300
may give a clue to the diagnosis. Rare cases have been reported in which Langerhans cell histiocytosis
has been associated with malignant lymphoma or leukaemia, the
association following various patterns: the histiocytosis may
Course of the disease and response to therapy
follow, precede or develop at the same time as the lymphoma or
The natural history of Langerhans cell histiocytosis of the lungs varies leukaemia.322,323 The basis of this association is unclear and may be
considerably (Table 6.1.9).286,317–319 A few patients follow a rapidly multifactorial.289 In one study of 102 adults with pulmonary
downhill course and die early, while others improve spontaneously Langerhans cell histiocytosis, six haematological cancers were
and become symptom-free with disappearance of the radiological identified.319 A hypothetical relationship between Langerhans cell his-
changes. Others experience spontaneous remissions and relapses and tiocytosis of the lung and pulmonary carcinoma may be explained by
slowly deteriorate, but the disease may arrest at any stage. Such the sharing of an aetiological agent, such as cigarette smoking, rather
patients are left with residual functional incapacity but suffer no than there being a direct cause-and-effect relationship.324
further progression of the disease. Unfavourable prognostic features
include generalised multisystem disease, prolonged fever and weight
loss, widespread involvement of the lungs, multiple pneumothoraces,
Pathological findings286,287,325–327
poor lung function, pulmonary hypertension and extremes of Microscopically, early lesions show a focal interstitial infiltrate of
age.286,316,317,319 In one study the overall median survival was 12.5 years, mitotically active Ki51- and Ki67-positive Langerhans cells intermin-
considerably shorter than expected.319 gled with eosinophils (Fig. 6.1.40). The lesions are centred on the

290
 Diffuse parenchymal disease of the lung Chapter |6|

A
Figure 6.1.41  Langerhans cell histiocytosis. The lesions are focal,
peribronchiolar and interstitial.

Figure 6.1.42  Langerhans cell histiocytosis. A mixed mononuclear

interstitial infiltrate has destroyed part of the bronchiolar wall. (Reproduced
from Corrin and Basset (1979)287 with permission from Investigative Cell Pathology.)

bronchioles (Figs 6.1.41 and 6.1.42), which are often weakened so

that small cavities develop (Fig. 6.1.43). The cavitation may ultimately
progress to gross cystic change (Fig. 6.1.44), which is responsible for
the repeated pneumothoraces that are such a prominent clinical
feature of the disease.
As the lesions heal, their appearances alter and they assume the
form of stellate fibrous scars (Figs 6.1.45 and 6.1.46) in which
Langerhans cells and eosinophils are no longer readily apparent,
having been replaced by pigment-laden macrophages, lymphocytes,
plasma cells and fibroblasts. The pigment in the macrophages is
C partly exogenous, and is largely derived from the cigarette smoke to
which these patients have almost always been exposed, and partly
Figure 6.1.40  Langerhans cell histiocytosis. (A) The Langerhans cells endogenous – this component is generally Perls- and periodic
have vesicular nuclei and a moderate amount of pale cytoplasm that is acid–Schiff-positive and diastase-resistant. Old and active lesions are
devoid of phagocytosed material. Numerous eosinophils are also present. often found in the same specimen. At autopsy, interstitial fibrosis is
Immunostaining for S-100 (B) and CD1a (C) highlights the Langerhans widespread and there may be marked ‘honeycombing’: nevertheless,
cells. the predilection for the mid- and upper zones with sparing of the
costophrenic angles, evident in life radiographically, is often still
apparent after death (see Fig. 6.1.44). The fibrosis may be attributable

291
 Pathology of the Lungs

Figure 6.1.43  Langerhans cell histiocytosis showing microcystic change. Figure 6.1.45  Pulmonary Langerhans cell histiocytosis. Older lesions
often have a characteristically stellate outline.

Figure 6.1.46  Pulmonary Langerhans cell histiocytosis. Small stellate

scars on the cut surface represent healed lesions.

Figure 6.1.44  Langerhans cell histiocytosis of the lung at autopsy. Severe nary circulation is involved independently of the airway and paren-
fibrocystic change is seen at the apex of the upper lobe. chymal changes.316

to fibroblast-stimulating cytokines such as platelet-derived growth Differential diagnosis

factor, transforming growth factor-β, tumour necrosis factor-α and Differential pathological diagnoses include eosinophilic pneumonia
IL-197,328,329 and the cavitation to collagenolytic activity mediated by (see p. 461), reactive eosinophilic pleuritis (see p. 711) and various
matrix metalloproteinases,330,331 all of which have been demonstrated patterns of interstitial pneumonia. The interstitial rather than intralu-
in Langerhans cells within active lesions. minal location of the eosinophils should indicate Langerhans cell
The pulmonary hypertension is reflected in a proliferative vascu- histiocytosis (eosinophilic granuloma) rather than eosinophilic pneu-
lopathy involving both arteries and veins. It is suggested that this monia, whereas an associated blood eosinophilia would favour the
represents intrinsic pulmonary vascular disease, in which the pulmo- latter condition. HRCT patterns for these two disorders are also

292
 Diffuse parenchymal disease of the lung Chapter |6|

notably different. Reactive eosinophilic pleuritis is caused by pneu- abdominal lymph nodes.341 However, either the lungs or the lymph
mothorax and is limited to the pleura and subpleural lung tissue. IPF/ nodes may be affected in isolation. A notable feature is that the disease
UIP and fibrotic NSIP lack the focal centriacinar distribution of the is largely confined to women in the reproductive years. Onset is rare
lesions of eosinophilic granuloma. When Langerhans cell histiocyto- before the menarche342 and after the menopause,343–345 although it is
sis is completely inactive and the lung has reached an end stage of being increasingly recognised in older women.346 Very few men have
widespread ‘honeycombing’ common to many diseases, a definite been affected.347–349 Of 243 patients enrolled in a national registry over
histological diagnosis may no longer be possible but before this the a 3-year period, all were women. Their ages ranged from 18 to 76 years
focal distribution and stellate outline of the scars are very suggestive and the average age at onset of symptoms was 39 years.350 Tuberous
of burnt-out Langerhans cell histiocytosis. sclerosis was evident in 15%.
The characteristic lesions are focal and may be obscured by
other changes attributable to cigarette smoking, particularly smokers’
macrophages filling the adjacent alveoli. DIP and respiratory
Aetiology
bronchiolitis-associated interstitial lung disease (see pp. 311 and The fact that lymphangioleiomyomatosis is largely confined to
313) often accompany Langerhans cell histiocytosis and hinder its women in the reproductive years suggests that it has a hormonal
recognition in this way.332 basis and this is supported by reports of exacerbations of the disease
The immunocytochemical demonstration of CD1a, S-100 protein during pregnancy351,352and the menses,353and following oestrogen
or fascin may be used to augment routine light microscopy304–306 but therapy.354,355 Further support comes from the identification of oestro-
positive results are only of significance in the right pathological gen or progesterone receptors in the diseased lung tissue, and this
setting. Langerhans cells and the related S-100-positive interdigitating presumably is responsible for the peculiar sex distribution.356
dendritic cells are widely distributed and increased in a variety of Lymphangioleiomyomatosis has long been recognised as having an
reactive and neoplastic diseases296,333: CD1a, fascin and langerin are intriguing relationship to tuberous sclerosis341,357 and this has now
more specific than S-100 and can be detected in paraffin sections.304–308 been substantiated by molecular studies identifying mutation of a
Negative results for these markers raise the possibility of histiocytic tuberous sclerosis gene in lung tissue showing lymphangioleiomyo-
sarcoma which is exceptionally rare in the lung. However, it is recorded matosis.358–362 Stemming from these studies, two forms of tuberous
there, closely resembling Langerhans cell histiocytosis both clinically sclerosis are now recognised (Table 6.1.10).341,363–372 One is a domi-
and histologically.334 Langerhans cell sarcoma is quite different.335 This nant hereditary condition caused by mutation of the TSC1 gene situ-
sarcoma is also exceptionally rare in the lung but cases complicating ated on chromosome 9. In these patients, the brain, skin and kidney
pulmonary Langerhans cell histiocytosis are recorded.336 It is distin- are chiefly affected. Pulmonary lymphangioleiomyomatosis is clini-
guished from Langerhans cell histiocytosis histologically by the overt cally evident in only 2.3% of such patients367 (but accounts for 10%
malignancy of its Langerhans cells, the nature of which may only be of deaths).364 In the second form of tuberous sclerosis, attributable to
recognized by the characteristic staining reactions described above. mutation of the TSC2 gene located on chromosome 16, lymphangio-
Erdheim–Chester disease (see p. 492) is a further systemic histiocytic leiomyomatosis is the dominant clinical manifestation and is respon-
proliferation that may involve the lung. The cells are morphologically sible for most deaths.
identical to those of Langerhans cell histiocytosis but, although they The products of the TSC1 and TSC2 genes, respectively known as
stain for S-100, they do not stain for CD1a and they lack Birbeck hamartin and tuberin, form a coiled complex that functions in mul-
granules on electron microscopy. The distribution of disease is also tiple tumour suppressor roles in cell cycle control.373 It is therefore not
different, following the path of the lymphatics rather than being pri- surprising that mutation of either gene results in increased cell growth.
marily bronchiolocentric and partly cystic.337,338 The TSC2 form of tuberous sclerosis is often termed the sporadic form
The diagnosis has been made on transbronchial biopsy but surgical of pulmonary lymphangioleiomyomatosis. It would appear that the
lung biopsy is generally required for a definite tissue diagnosis. TSC2 mutation is confined to certain somatic cells as this form of
Histological diagnosis is most difficult in the healing phase when tuberous sclerosis is not hereditary: there is as yet no record of a
Langerhans cells are poorly represented. At this stage immunocyto- woman suffering from sporadic pulmonary lymphangioleiomyoma-
chemistry is least helpful. The optimal applications of immunocyto- tosis giving birth to an affected child.
chemistry are probably in the examination of small fibreoptic The demonstration of identical TSC2 mutations in the pulmonary
specimens, in which the valuable architectural features evident in a and renal lesions of a patient with sporadic lymphangioleiomyoma-
surgical lung biopsy cannot be assessed, and in the evaluation of tosis indicated that their constituent cells were derived from the same
bronchoalveolar lavage cells.339,340 Electron microscopy may also be source and led to the suggestion that those comprising the pulmonary
used to identify Langerhans cells in lavage specimens but immuno­ lesions had metastasised from the renal angiomyolipoma.360 Metastatic
cytochemistry is more suited to the enumeration of lavage cells that spread (from lung to lung) also appears to be the explanation for
is necessary for diagnosis. Patients with pulmonary Langerhans cell recurrent lymphangioleiomyomatosis following transplantation,
histiocytosis have an increased but variable number of Langerhans identical mutations being identified in the native and donor lungs,
cells in their lavage fluid (1–25%) compared to normal non-smokers and angiomyolipoma being excluded at autopsy.374,375 Clusters of the
(fewer than 1%) and to normal smokers and patients with lesional cells enveloped by lymphatic endothelial cells have been
other interstitial lung diseases (up to 3%) (see Table A3, p. 760).339,340 identified within distant lymphatics and within chylous pleural and
Thus, the sensitivity is low and lavage is therefore of limited peritoneal fluid, suggesting that dissemination of the disease is by
diagnostic use.313 means of these smooth-muscle/lymphoendothelial cell packets.376
Tuberous sclerosis is referred to again on page 488 where further
pulmonary manifestations are described.

LYMPHANGIOLEIOMYOMATOSIS
Clinical features
Lymphangioleiomyomatosis is a rare but distinctive disease that in its Early studies indicated that patients with pulmonary lymphangioleio-
fully developed state combines widespread proliferation of unusual myomatosis presented at an average age of 32–34 years.344,377–380 but
smooth muscle in the lungs with lymphangioleiomyomas in thoraco- with increasing recognition of the condition in older women the

293
 Pathology of the Lungs

Table 6.1.10  A comparison of the two forms of tuberous sclerosis341,363–371

TSC1 TSC2 (sporadic lymphangioleiomyomatosis)

Family history Common Absent

Sex incidence Equal Almost exclusively female
Cerebral ‘gliomas’ Present Absent
Facial angiofibromas Frequent Absent
Cardiac rhabdomyomas Occasionally present Absent
Angiomyolipomas Frequent Frequent
Lymph node angioleiomyomatosis Occasionally present Occasionally present
Pulmonary lymphangioleiomyomatosis Occasionally present Present – the dominant feature
Multifocal type II pneumocyte hyperplasia Occasionally present Absent

If attention is concentrated on the occasional patients with classic (TSC1) tuberous sclerosis who have pulmonary involvement it is found that neurological disorders are
rare and the sex incidence is overwhelmingly female. Clinically evident pulmonary lymphangioleiomyomatosis is initially found in only 2.3% of patients with classic
(TSC1) tuberous sclerosis367 but may be detected by computed tomography in 34–39% of women with this form of the disease370,371 and accounts for 10% of deaths.

average age at presentation has shifted to 39–43 years.346,350 Patients

complain of breathlessness of insidious onset and are liable to develop
any of three complications: repeated pneumothoraces, chylous effu-
sions and pulmonary haemorrhage, all of which are satisfactorily
explained by the pathological features of the disease, as outlined
below.341 The functional features are variable and may indicate obstruc-
tive, restrictive or mixed disease, generally with markedly reduced
diffusing capacity, and a normal or mildly increased total lung capac-
ity.369,379,381–384 Bronchoalveolar lavage typically recovers haemosiderin-
laden macrophages. Radiographically, the lungs show a reticular
pattern but unlike fibrotic lungs they appear enlarged and ultimately
show gross cystic change.382 Septal lines (Kerley B) may be seen as a
result of the lymphatic obstruction. The appearance on computed
tomography is virtually diagnostic in the appropriate clinical
context.369,385 Thin-walled, well-defined cysts of fairly uniform size are
evenly distributed throughout all lung zones: nodules are not a feature
(Fig. 6.1.47).
The natural course of the disease is one of inexorable decline in
respiratory function over a period of several years, inevitably culminat-
ing in death except in patients who reach the menopause, when the Figure 6.1.47  Pulmonary lymphangioleiomyomatosis. Computed
clinical state stabilises.341,377,386 However, the rate of decline is very tomography shows thin-walled cystic spaces with no zonal distribution
variable. Survival figures have progressively improved, probably due and no accompanying nodules.
to a combination of improved patient management and early radio-
graphic identification of the disease in asymptomatic women. Thus,
10-year survival figures of 20% were reported in 1975, 40% in 1995
and 79% in 1999.341,352,387 Severe cystic change indicates advanced them to have all the features of smooth muscle.389 Immunostaining
disease and a correspondingly worse prognosis.387 Conversely, those is in accord with this, both cell types being strongly positive for
patients in whom the lungs are spared and only extrapulmonary smooth-muscle actin.390 However, an unusual feature is that 17–67%
lymphatics are affected have a relatively good prognosis.386,388 of the proliferating cells also react for the melanoma-related marker
Treatment possibilities are discussed below. human melanin black-45 (HMB-45) (Fig. 6.1.49).369,391–395 Electron
microscopy shows the HMB-45 immunoreactivity to be localised
to cytoplasmic inclusions similar to premelanosomes.391 HMB-45
Pathological findings reactivity is a feature that lymphangioleiomyomatosis shares with the
The essential pathological feature is a proliferation of unusual smooth- angiomyolipomas of tuberous sclerosis, benign clear cell tumour of
muscle cells that involves all parts of the lungs,341,381,382 often in a focal the lung (see p. 625) and certain clear cell tumours at other sites, both
manner. The smooth-muscle nature of the cells is not immediately benign and malignant.396 The term ‘perivascular epithelioid cell’ has
apparent and they may be mistaken for fibroblasts. They are generally been applied as an encompassing term for the cell type from which
plump and spindle-shaped with pale eosinophilic cytoplasm (Fig. these entities derive, although there is no normal counterpart; it is
6.1.48) but the cytoplasm may be clear and the cells polygonal in described as a mesenchymal cell that is either spindle-shaped or
outline so that they appear epithelioid. Electron microscopy shows has a plump, glycogen-rich epithelioid phenotype, and variably

294
 Diffuse parenchymal disease of the lung Chapter |6|

Figure 6.1.48  Pulmonary lymphangioleiomyomatosis. Spindle cells

infiltrate the alveolar walls.

A
368,397–401
co­­expresses actin, HMB-45, S-100, CD1a and cathepsin-k. It
is reported that HMB-45 and the receptors for oestrogen and proges-
terone are confined to the plump epithelioid cells whereas metallo-
proteases and proliferating-cell nuclear antigen are confined to the
spindle cells.368,391,402,403
The alveolar walls are infiltrated by the unusual smooth-muscle
cells and consequently thickened, often in nodular fashion. Narrow
lymphatic channels are often evident within these cell collections.404
At the periphery of the lesions the walls of bronchioles may be simi-
larly infiltrated.341 The interstitial connective tissue is increased405 and
structurally abnormal,389,406 probably due to the protease activity
exhibited by the spindle cells.403,407 Consequent breakdown of the
alveolar walls leads to focal cystic change, which ultimately culminates
in gross ‘honeycombing’ throughout the lungs (Fig. 6.1.50). Airway
collapse consequent upon this cystic change is the principal mecha-
nism contributing to airflow limitation.408 Rupture of the cysts explains
the frequent pneumothoraces which are one of the distinctive com-
plications of this disease. A histological score based on the severity of
the cystic change and the degree of smooth-muscle infiltration has
been shown to be of prognostic value.409 B
The proliferating cells also infiltrate blood vessels and the use of
elastic stains demonstrates that small veins are often totally obliter-
Figure 6.1.49  Pulmonary lymphangioleiomyomatosis. (A) Spindle cells
ated (Fig. 6.1.51).341 This veno-occlusive process and perhaps direct evident in the walls of cystic spaces (arrows) stain for HMB-45(G). (Case of
capillary damage cause pulmonary haemorrhage, so explaining the Dr D. Schneider Coventry, UK.)
haemoptyses that complicate the breathlessness. They also cause
haemosiderosis (Fig. 6.1.52) and occasionally this is sufficiently
severe to encrust the elastic laminae of pulmonary blood vessels with
iron and calcium. Fragmentation of the encrusted elastin elicits a Variant forms of the disease
foreign-body giant cell reaction (so-called endogenous pneumo­ In rare cases the lesional cells have a clear, glycogen-rich cytoplasm
coniosis; see p. 449). reminiscent of those comprising another form of ‘PEComa’, namely
Involvement of lymphatics in the myoproliferative process the clear cell tumour of the lung described on page 625.411 Another
and the development of lymphangioleiomyomas in mediastinal unusual patient showed both a clear cell tumour and lymphangioleio-
lymph nodes explain the frequent chylothoraces (Fig. 6.1.53).341,410 myomatosis limited to the right upper and middle lobes.412
Chyloptysis, chylous ascites and even chyluria may also develop.353 Occasionally pulmonary lymphangioleiomyomatosis is associated
The chylous effusions contain free-floating clumps of the lesional with micronodular type II pneumocyte hyperplasia (see p. 701) but
cells, so providing a useful source of these cells for special studies, this is to be regarded as an independent manifestation of tuberous
but it is notable that mesothelial seedlings are not a feature of sclerosis rather than a component of lymphangioleiomyomatosis.
lymphangioleiomyomatosis.
The focal nature of the disease means that it may be difficult to
identify the lesions in small biopsies, in which case the immuno­ Differential diagnosis
markers described above can be helpful, particularly smooth-muscle One of the conditions that histologically enters the differential diag-
actin, HMB-45 and cathepsin-k.400 nosis is IPF showing reactive hyperplasia of bronchiolar and vascular

295
 Pathology of the Lungs

Figure 6.1.51  Pulmonary lymphangioleiomyomatosis. Elastin staining

reveals that small postcapillary blood vessels are infiltrated and their
lumen markedly narrowed.

Figure 6.1.52  Pulmonary lymphangioleiomyomatosis. Occlusion of

postcapillary blood vessels results in capillary rupture and haemosiderosis.

Figure 6.1.50  Pulmonary lymphangioleiomyomatosis. Infiltration of

the alveolar walls weakens them, causing focal cystic change (A) and
ultimately gross honeycombing (B). (B courtesy of the late Dr AA Liebow,
San Diego, USA.)

Figure 6.1.53  Lymphangioleiomyoma of a mediastinal lymph node.

296
 Diffuse parenchymal disease of the lung Chapter |6|

smooth muscle (so-called muscular cirrhosis of the lung, see Fig. tomy, ovarian ablation with X-rays and hormonal manipulation.418–423
6.1.8C). However, the reactive smooth-muscle hyperplasia that Response has been varied and sometimes unrelated to sex steroid
accompanies fibrosis is quite mature and readily recognisable as such, receptor analysis.424 The oestrogen antagonist, tamoxifen, has often
whereas this is not the case in lymphangioleiomyomatosis. IPF also been employed but is probably best avoided as it may have agonist
has an inflammatory component, which is not seen in lymphangio- activity. Progesterone has also been widely employed but without
leiomyomatosis, and the reactive smooth muscle of IPF does not significant benefit and few specialist centres now recommend hormo-
express HMB-45 or cathepsin-k. If doubt remains, HRCT will probably nal therapy.425,426
establish the diagnosis. Indeed, few cases now come to biopsy because For patients with progressive disease, lung transplantation offers an
of the high specificity of the imaging features, those that do often alternative treatment. It has been successfully performed in several
being smokers with a differential diagnosis of emphysema, which may patients427 but recurrence in the allograft has been encountered, even
coexist with lymphangioleiomyomatosis. with lungs obtained from male donors.374,428,429 The source of the
A further condition to be distinguished is that of so-called benign recurrent disease is discussed under aetiology.
mestastasising leiomyomas (see p. 686).413,414 This also affects women The elucidation of the molecular mechanisms underlying tuber-
in the reproductive years and both conditions are to some extent ous sclerosis and lymphangioleiomyomatosis has led to the intro-
hormonally dependent. However, the metastasising leiomyomas form duction of drugs targeting the growth factor that is normally
distinct tumours – sharply outlined spherical masses that usually inhibited by the hamartin/tuberin protein product of the tuberous
exceed 2 cm in diameter and may rarely be cystic. Histologically, they sclerosis genes referred to above. One such agent is the mammalian
exactly reproduce the appearances of benign myometrial fibroids, con- target of rapamycin (mTOR) inhibitor sirolimus and trials of this
taining smooth muscle that is readily recognisable as such, unlike the drug are currently underway.345,430,430a
immature cells of lymphangio­leiomyomatosis. Leiomyomas are also Metalloproteinases appear to play a role in the pathogenesis of
HMB-45-negative and the patients either have uterine fibroids or have lymphangioleiomyomatosis and because an ancillary action of the
had them removed. Although immature, lymphangioleiomyomatosis tetracycline antibiotic doxycyclin is the inhibition of these enzymes it
cells lack the atypia of a sarcoma, which was the diagnosis in what has been proposed for the treatment of lymphangioleiomyo­
was probably the first report of the condition.415 Lymphangiomatosis matosis.431 Trials to assess the efficacy of doxycycline in lymphangio-
(see p. 632) is distinguished from lymphangioleiomyomatosis by leiomyomatosis are currently underway.430a
being evidently vascular, confined to the major connective tissue Further in the future, the lymphangiogenic vascular endothelial
planes of the lung and lacking the distinctive HMB-45-positive cells. growth factors C and D represent possible pharmacotherapeutic
Emphysema also lacks these cells, as do the metastases of endometrial targets following the recent recognition that they are involved in the
stromal sarcoma,416,417 two further conditions that have been mistaken pathogenesis of lymphangioleiomyomatosis.432
for lymphangioleiomyomatosis. Concern that children born to affected patients may suffer from
tuberous sclerosis appears to be unwarranted and genetic counselling
is not currently considered necessary, although pregnancy itself may
be inadvisable because of reports of the lung disease being exacer-
Treatment
bated during childbearing. An informative patient support group may
Because the disease is largely confined to women in the reproductive be consulted at http://lam.uc.
years attempts have been made to arrest the condition by oophorec-

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6.2  Alveolar filling defects

BOOP inevitably led to confusion with bronchiolitis obliterans affect-

CHAPTER CONTENTS
ing proximal bronchioles and therefore characterised by airflow
Cryptogenic organising pneumonia (idiopathic obstruction. Whilst it is true that the luminal fibrosis of organising
bronchiolitis obliterans organising pneumonia) 308 pneumonia extends proximally into alveolar ducts, respiratory bron-
Acute fibrinous and organising pneumonia 310 chioles and even membranous bronchioles, it remains limited to rela-
tively peripheral air spaces and the functional deficit is restrictive
Desquamative interstitial pneumonia 311
rather than obstructive. An appreciation of the geometry of the airways
Respiratory bronchiolitis and respiratory (see Table 1.2, p. 3) helps in understanding the different functional
bronchiolitis-associated interstitial lung disease 313 and clinical effects of proximal and distal airway obliteration.
Exogenous lipid pneumonia 314 The corticosteroid-sensitivity of COP is probably attributable to its
Endogenous lipid pneumonia (obstructive collagen being of type III (newly formed, flexible and susceptible to
pneumonitis) 315 enzymatic digestion) rather than the more mature type I, and the
Alveolar lipoproteinosis 316 abundance of proteolytic enzymes within the Masson bodies.6 This
corticosteroid-sensitivity probably applies to organising pneumonia
Cholesterol pneumonitis 319
irrespective of the cause of the initial exudate.
Corpora amylacea 320
Alveolar microlithiasis 320
Clinical features
Calcospherites (conchoidal bodies) 321
COP presents a distinct clinicopathological syndrome, recognition
‘Blue bodies’ 321
of which is important because it is responsive to corticosteroid-
Schaumann bodies 321 responsiveness.2–4 Men and women are affected equally and most are
Alveolar ossification 322 in the 40–60-year age group. Persistent cough, shortness of breath and
References 322 malaise are common complaints. The onset is insidious. Chest radio-
graphs show widespread blotchy opacities, which regress in some
places whilst progressing in others and developing anew elsewhere.7
High-resolution computed tomography (HRCT) scans typically show
CRYPTOGENIC ORGANISING PNEUMONIA bilateral consolidation, which has a predominantly subpleural and
peribronchial distribution (Fig. 6.2.1). Reticular changes, localised
(IDIOPATHIC BRONCHIOLITIS OBLITERANS nodules and ground-glass opacification are less common. The changes
ORGANISING PNEUMONIA) wax and wane, unlike those of bronchioloalveolar carcinoma, which
COP may otherwise resemble radilgraphically. Pulmonary function
The first description of this alveolar filling defect should probably be tests generally show a predominantly restrictive ventilatory defect but
attributed to Liebow and Carrington,1 who used the title interstitial some patients have a mixed obstructive and restrictive pattern. The
pneumonia with bronchiolitis obliterans (BIP) despite the predomi- erythrocyte sedimentation rate is elevated but no evidence of infection
nant involvement of air spaces rather than the interstitium. Subsequent can be detected, either by culture or serologically. Bronchoalveolar
workers drew attention to the corticosteroid-sensitivity of the condi- lavage shows a lymphocytosis with a low T-helper/suppressor cell ratio
tion2,3 and the terms cryptogenic organising pneumonia (COP)4 and (see Table A3, p. 760).8,9
bronchiolitis obliterans organising pneumonia (BOOP)5 followed, Some patients are affected each spring and in these there is an
the latter covering both the idiopathic variety and those of known intriguing association with cholestasis.10 Circulating immune com-
causation. The emphasis on bronchiolar involvement in the term plexes have been identified in some patients.11 Another intriguing

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Box 6.2.1  Conditions resulting in organising pneumonia

Suggestive
histological features
Bacterial pneumonia Neutrophilia, organisms
on special stains
Bronchial obstruction, Lipid-laden
chronic bronchiolitis macrophages
Diffuse alveolar More diffuse low-
damage (organising power distribution,
phase) exudative foci
Radiation
Aspiration pneumonia Foreign material
Fume and toxin
exposure
Connective tissue Other manifestations
disease of such disease (e.g.
rheumatoid nodules)
Figure 6.2.1  Cryptogenic organising pneumonia. High-resolution
computed tomography shows patchy bilateral air space consolidation Extrinsic allergic Bronchocentricity,
with a predominantly subpleural distribution. Focal ground-glass shadows alveolitis granulomas
are also seen. Pulmonary Eosinophils
eosinophilia
Drug reactions Eosinophils
Transplantation (bone
observation is that postirradiation organising pneumonia appears to marrow, lung,
‘prime’ the non-irradiated areas of the lungs as these may sub­­­ kidney)
sequently develop the same changes,12–14 a point of difference from Inflammatory bowel
the usual form of radiation pneumonitis which is generally confined disease
to the irradiated area of lung. One woman suffered self-limited attacks Adjacent disease, e.g. Abscess
a few days before each menstrual period.15 Wegener’s Vasculitis, granulomas
The prognosis is usually excellent, particularly with corticosteroid granulomatosis
therapy, but patients may relapse when these are withdrawn. Rare Neoplasms Tumour
patients have unusually severe disease and deteriorate rapidly despite Langerhans cell Langerhans cells
treatment. Autopsy in such cases has shown interstitial fibrosis rather histiocytosis
than the intra-alveolar fibrosis seen on biopsy.16 Cryptogenic

Histopathology4,5,17,17a
Various conditions cause organising pneumonia (Box 6.2.1) but, Organising pneumonia is easily distinguished from the exudative
whatever its aetiology, biopsy shows micropolypoid buds of granu­ phase of diffuse alveolar disease (DAD) by an absence of hyaline
lation tissue (bourgeons conjonctifs or Masson bodies) in the air spaces membranes but the organising phase of DAD may show organising
(Fig. 6.2.2). The buds may extend from one alveolus to the next pneumonia and only be separable by review of the clinical data.
through the pores of Kohn (which were first identified by this process). Features that favour COP over organising DAD include a patchy peri-
Alveoli are mainly affected but the process also involves respiratory bronchiolar distribution and relatively little expansion of the intersti-
bronchioles and the more peripheral membranous bronchioles. tium by oedematous fibroinflammatory tissue. IgG4-related systemic
Occasionally, residual fibrin is seen in or near the connective tissue sclerosing disease, which is dealt with on page 485, may also be con-
buds, which also contain small numbers of lymphocytes, plasma cells, fused with organising pneumonia as intra-alveolar organisation may
neutrophils, macrophages and fibroblasts. The inflammatory cells be part of its spectrum of presentation in the lung. It is characterised
tend to cluster in the centres of the buds. Chronic inflammation and by a heavy infiltrate of IgG4-bearing plasma cells, the recognition of
interstitial fibrosis of the alveolar walls may also be seen but the pre- which is key to the diagnosis, along with obliterative phlebitis
dominant change is that within the air spaces. The alveoli are often and involvement of other organs such as the pancreas. In similar
lined by reactive type II cells. Electron microscopy shows evidence of fashion, organising pneumonia may mask underlying Langerhans cell
acute alveolar epithelial injury.18 histiocytosis, lymphoma and vasculitis,20 so the background lung
should be carefully scrutinised in any case showing organising
pneumonia.
Differential diagnosis Pathologists conducting necropsies on patients dying of broncho­
A striking histological feature of organising pneumonia is its temporal pneumonia will be familiar with the histological pattern of organising
homogeneity, which gives the impression of damage occurring at a pneumonia but, before dismissing it in a biopsy as yet another
single moment. This contrasts with usual interstitial pneumonia example of healing bacterial pneumonia, they should ask themselves
(UIP), where fibroblastic foci lie adjacent to areas of well-established why a condition that is usually diagnosed without such recourse
interstitial fibrosis. However, in time, the intra-alveolar granulation should be so investigated. Consultation with the clinician may lead
tissue of organising pneumonia may be incorporated into the alveolar to a diagnosis of COP and successful treatment with corticosteroids.
wall by an accretive process, resulting in interstitial fibrosis and a Many causes of organising pneumonia are only identifiable clinically.
similarity to UIP, with a correspondingly worse prognosis.16,19 In such Without clinical input, a reasonable pathological conclusion is
cases, HRCT may reveal more typical features elsewhere in the lungs. ‘organising pneumonia, aetiology not apparent’.

309
 Pathology of the Lungs

A B

C D

Figure 6.2.2  Cryptogenic organising pneumonia. (A) Air space consolidation is evident on low-power microscopy. (B) Higher power shows buds of
granulation tissue within alveoli adjacent to a bronchovascular bundle. (C) Partial epithelialisation of the periphery of the granulation tissue buds may
occur. (D) An elastin stain highlights the intra-alveolar rather than interstitial location.

Acute fibrinous and organising pneumonia tion, associations that are also seen with the more typical pattern of
organising pneumonia described above. Other associations have
On occasion organising pneumonia may be associated with promi- included collagen vascular disease, bacterial infection, lymphoma and
nent knots of fibrin, resulting in a histological pattern that has been a variety of environmental and occupational exposures.22 Acute fibri-
termed acute fibrinous and organising pneumonia (Fig. 6.2.3).21,22 The nous and organising pneumonia probably represents a florid variant
clinical features and course of the disease are more those of acute of organising pneumonia rather than a different disease. Imaging
alveolar injury but the hyaline membranes of diffuse alveolar damage shows bilateral basal opacities that are either diffuse or reticulo­
are not evident and there is no eosinophilia. Cases have been described nodular. The prognosis is poor, similar to that seen in acute lung
in association with drug toxicity and following stem cell transplanta- injury of any cause.

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Figure 6.2.4  ’Desquamative’ interstitial pneumonia represents an alveolar

filling defect rather than an interstitial disease.

Figure 6.2.3  Acute fibrinous and organising pneumonia. The alveoli

contain both fibrin and buds of granulation tissue.

DESQUAMATIVE INTERSTITIAL PNEUMONIA

Desquamative interstitial pneumonia (DIP) is characterised by an

excess of alveolar macrophages so marked that the alveoli are practi-
cally filled by these cells. This is accompanied by only a mild degree
of chronic interstitial inflammation so that the alveolar walls are only
slightly thickened, if at all. The adjective ‘interstitial’ therefore puts the
wrong emphasis on what is essentially an alveolar filling defect (Fig.
6.2.4). Furthermore, the term ‘desquamative’ is quite inappropriate. It
was introduced23 in the belief that the free cells were exfoliated (desq-
uamated) alveolar epithelial cells, a misconception that is easy to
understand when only routinely stained sections are examined (Fig.
6.2.5): the true nature of the free cells was shown first by electron
microscopy24,25 and then by immunocytochemistry (Fig. 6.2.6), which
demonstrate that they are macrophages. Nevertheless, although the
term ‘alveolar macrophage pneumonia’ has been suggested, the con-
sensus view is to continue with the more familiar, if histogenetically
incorrect, term of DIP.26

Figure 6.2.5  ’Desquamative’ interstitial pneumonia. The alveoli are filled

Aetiology by mononuclear cells that morphologically resemble the adjacent
The nature of DIP is not well understood but its recognised associa- hyperplastic alveolar type II epithelial cells and it is easy to imagine a
tions suggest that it is a pathological response to a variety of pulmo- desquamative process.
nary insults rather than a specific disease. In adults it mainly affects
cigarette smokers and in these individuals it may be regarded merely other cases (see p. 46). There remains a small group of patients, who
as an excessive macrophage response to inhaled smoke.27 DIP is also despite all clinical investigations have no evidence of any potential
seen in workers exposed to exceptionally dusty environments.25,28,29 causative association and may therefore be regarded as having idio-
Others apparently develop DIP in response to relatively low levels of pathic DIP.36
atmospheric pollution, presumably being hypersensitive to dust.30
Long-term therapy with drugs such as nitrofurantoin may also result
in DIP.31 A minority of patients have connective tissue disorders, Clinical features
although it remains uncertain whether this association is coincidental, Most patients with DIP are middle-aged cigarette smokers who
represents a direct effect or is related to smoking.32–34 A role has also complain of breathlessness and cough of insidious onset. Chest
been proposed for osteopontin, raised levels of which have been radiographs show hazy ‘ground-glass’ opacification of the lower lung
identified in bronchoalveolar lavage from patients with both DIP and fields, sometimes accompanied by reticular markings and cystic
Langerhans cell histiocytosis.35 DIP is also encountered in children, change (Fig. 6.2.7).37–39 Pulmonary function tests show a restrictive
sometimes as a manifestation of surfactant apoprotein B deficiency. pattern with a reduction in diffusing capacity. Hypoxaemia is often
Other children with DIP have had lipid storage diseases and it is pos- evident on blood gas analysis. Bronchoalveolar lavage shows increased
sible that unrecognised metabolic defects may be responsible for numbers of macrophages, eosinophils (mean 18%) and neutrophilis

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 Pathology of the Lungs

Figure 6.2.8  ‘Desquamative’ interstitial pneumonia. The macrophages

that fill the alveoli include multinucleate forms.

Figure 6.2.6  ‘Desquamative’ interstitial pneumonia. Immunostaining for

(A) the macrophage marker CD68 and (B) the epithelial (cytokeratin)
marker MNF116 shows that the cells filling the alveoli are macrophages
rather than desquamated epithelial cells. Figure 6.2.9  ‘Desquamative’ interstitial pneumonia. Lymphoid foci
representing follicular bronchiolitis stand out against the general
consolidation.

(mean 11%).39 Most patients respond well to corticosteroids,26,38,40–42

especially if they quit smoking. They may recover completely, or sta-
bilise, but relapse many years later is recorded,43,44 even after lung
transplantation.45 In a minority of patients the disease progresses
slowly to interstitial fibrosis,37,46 ultimately proving fatal after, on
average, 12 years.40 The outcome is worse in children, especially in
infants and those with familial disease.

Pathological features
The principal histopathological feature is consolidation of the lung
by large numbers of alveolar macrophages, which may be multi­
nucleate (see Figs 6.2.4, 6.2.5 and 6.2.8). This is accompanied by an
interstitial lymphocytic infiltrate and fibrosis, both of which are
usually mild. There is often also follicular bronchiolitis, the scattered
lymphoid follicles contrasting with the diffuse macrophage accumula-
tion (Fig. 6.2.9). The macrophages have abundant eosinophilic cyto-
plasm, which often contains brown granules that stain variably with
both Perls and periodic acid–Schiff reagents (Fig. 6.2.10). Eosinophils
are occasionally evident, but not so many in lung tissue as on lavage.
Figure 6.2.7  ‘Desquamative’ interstitial pneumonia. High-resolution Centriacinar emphysema may be seen as an independent smoking-
computed tomography shows patchy peripheral ground-glass shadowing. related condition.36

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 Diffuse parenchymal disease of the lung Chapter |6|

RESPIRATORY BRONCHIOLITIS AND

RESPIRATORY BRONCHIOLITIS-ASSOCIATED
INTERSTITIAL LUNG DISEASE

The term ‘respiratory bronchiolitis’ (RB) was coined in 1974 to

describe the presence of pigmented macrophages within the respira-
tory bronchioles of healthy young cigarette smokers.52 RB was subse-
quently recognised in patients with evidence of mild respiratory
dysfunction and the term ‘respiratory bronchiolitis-associated intersti-
tial lung disease’ or RBILD was introduced for this clinical syndrome.53
RBILD has been regarded as the clinical correlate of RB, and RB as the
histopathological basis of RBILD, but attention is increasingly
being drawn to centriacinar interstitial fibrosis in cigarette smokers,
thus extending the histopathological basis of RB-ILD.54–56
Patients with RB or RBILD are almost universally heavy cigarette
Figure 6.2.10  ‘Desquamative’ interstitial pneumonia. Endogenous smokers.27,50 Conversely, RB is present in almost all heavy smokers
cytoplasmic pigment granules are strongly stained by the periodic but not all smokers develop RBILD.
acid–Schiff reaction. RBILD is considered in this chapter rather than that preceding
because of its link to RB and hence DIP, both of which affect the air
spaces more than the interstitium. These diseases all largely affect
smokers and are characterised by an accumulation of smokers’ mac-
Differential diagnosis rophages. They also show considerable clinical and radiological
As well as being a response to extrinsic stimuli such as smoke, dust overlap.27,36,54 It may be that DIP is a particularly florid form of RB.57,58
and drugs, DIP, or an appearance very like it, often accompanies other Many cases formerly identified as DIP would now be regarded as
lung diseases, which it may mask.47 For example, the small focal showing RB or RBILD and the three may merely be regarded as dif-
lesions of Langerhans cell histiocytosis are often accompanied by an ferent aspects of ‘smoking-related interstitial lung disease’.34,50,59
excess of alveolar macrophages and may consequently be over-
looked.48 Similarly, alveolar macrophages are often considerably Clinical features
increased near a tumour and may be the only abnormality evident in
a small biopsy: if a neoplasm is suspected clinically but only an excess Patients with RB are often asymptomatic and unaware that there is
of macrophages is found, a further biopsy should be advised rather anything amiss with their lungs whereas those with RBILD generally
than proffering a diagnosis of DIP. In resolving eosinophilic pneu­ complain of cough and mild breathlessness.53,57 Other symptoms
monia eosinophils may be scanty and macrophages numerous so include chest pain, weight loss and, rarely, fever and haemoptysis.
that the appearances simulate DIP. Crepitations are heard on auscultation but clubbing is unusual. Chest
The frequent association of DIP with cigarette smoking is also seen radiographs usually show airway thickening but may be normal. There
in respiratory bronchiolitis-associated interstitial lung disease (RBILD: may also be linear opacities suggestive of interstitial lung disease.
see below), which it closely resembles histologically, the principal dif- HRCT scans show varying degrees of patchy ground-glass opacity and
ferences being the centriacinar concentration of the macrophages and centrilobular nodules (Fig. 6.2.11).60 Lung function tests may be
the mild peribronchiolar fibrosis of the latter condition. The term normal or show a mild restrictive defect. If the patient gives up
‘smoking-related interstitial lung disease’ has been proposed to encom- smoking or receives corticosteroids the changes largely clear: the prog-
pass DIP, RBILD and Langerhans cell histiocytosis,34,49,50 but there are nosis is good.27,57
differences in the spectrum of associated clinical disorders.26
UIP may be associated with considerable numbers of alveolar mac-
Pathology
rophages and therefore resemble DIP but the latter is more uniform
in its distribution and appearance: the patchy subpleural preponder- In both RB and DIP the predominant change is an excess of alveolar
ance of UIP is not seen in DIP. Any fibrosis that develops in DIP is macrophages but in RB the changes are centriacinar, the excess mac-
diffuse and temporally uniform, resembling non-specific interstitial rophages filling the lumina of the respiratory bronchioles and alveoli
pneumonia more than UIP, and possibly representing a further effect surrounding the terminal and respiratory bronchioles rather than
of smoking.36 being diffusely distributed throughout the acinus (Fig. 6.2.11). In both
If multinucleate macrophages are prominent, the giant cell intersti- diseases the macrophages contain an abundance of brown smoke
tial pneumonia of cobalt workers may be considered but the multi- particles. The interstitial component of RBILD consists of a variable
nucleate epithelial cells that characterise this condition are not evident degree of fibrosis around the bronchioles and involving the walls
in DIP. of adjacent alveoli. The fibrosis is described as hyaline, hypocellular
A lipidosis may result in a pattern resembling DIP. Cytoplasmic and resembling amyloid.55 The peripheral pulmonary parenchyma is
vacuolation of the alveolar macrophages favours such a diagnosis, usually normal but rare cases may show patchy subpleural fibrosis.
especially if there is no evidence of airway obstruction, which com- ‘Honeycombing’ is not a feature and if present suggests that the RB is
monly causes the accumulation of foamy macrophages. an incidental finding.55,60
Lastly, DIP may be mimicked by an unusual pattern of carcinoma,
one in which the neoplastic cells are poorly cohesive and fill rather
than destroy the alveoli. Immunostaining for epithelial and macro-
Differential diagnosis
phage markers (cytokeratin and CD67 respectively) readily distin- RB and RBILD are distinguished from DIP by the distribution of the
guishes the two.51 pigmented macrophages, as outlined above, while RBILD also has its

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 Pathology of the Lungs

A B

C D

Figure 6.2.11  Respiratory bronchiolitis-associated interstitial lung disease. (A) High-resolution computed tomography shows patchy ground-glass
attenuation with evidence of air-trapping. (B) Microscopy shows alveolar filling by macrophages and mild focal thickening of the interstitium by chronic
inflammation and fibrosis. Unlike desquamative interstitial pneumonia, the distribution is centriacinar rather than diffuse (compare with Fig. 6.2.4).
(C) Peribronchiolar fibrosis may also be seen. (D) Brown (smoker’s) pigment is evident in the cytoplasm of the macrophages.

interstitial component. The distinction of RB and RBILD from other

patterns of interstitial pneumonia is the same as for DIP but some EXOGENOUS LIPID PNEUMONIA
workers stress the hypocellular nature of the fibrosis.55 RB often
accompanies other smoking-related changes and if seen alone in a Exogenous lipid pneumonia results from the aspiration or inhalation
biopsy from a patient who has been confidently diagnosed as having of oils, which may be animal, vegetable or mineral. A common
another smoking-related disease there has probably been a sampling example is liquid paraffin, which gains access to the lungs via the
error. Thus, RB may accompany and obscure the focal lesions of trachea when it is taken orally as a lubricant for constipation and
Langerhans cell histiocytosis, which is also strongly related to cigarette inadvertently aspirated,62–67 or when it is used as a vehicle for drugs
smoking. Other independent smoking-related changes such as administered by a nasal spray. It is not very irritative and the patient
emphysema may also accompany RB. Inflammation and fibrosis of is often unaware that aspiration is occurring. Aspiration of the ingested
the bronchiolar wall are also described in cigarette smokers61 and may oil occurs during sleep and is especially likely if there is achalasia of
therefore be associated with RB. the cardia or hiatus hernia with reflux.65 Aspiration of petroleum jelly

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 Diffuse parenchymal disease of the lung Chapter |6|

applied to the nose has also led to exogenous lipid pneumonia.68

Examples of animal or vegetable fat being aspirated include milk69 or
fatty dietary supplements such as ghee70 entering the lungs of debili-
tated children with feeding difficulties. The aspiration of vegetable oil
also occurred in the past from the use of menthol in olive oil for the
treatment of tuberculous laryngitis, and occasionally from the use of
iodinated vegetable oils for bronchography.71,72 Unusual causes of
exogenous lipid pneumonia include occupational exposure to oil
mists73 and the smoking of blackfat tobacco,74 while an acute form
may occur after massive aspiration by fire-eaters.75 Clinically, patients
typically present with non-resolving consolidation (Fig. 6.2.12) but
occasionally a localised mass mimicking malignancy may occur.
In the lungs, the oil gives rise to a chronic granulomatous lesion
that radiologically may simulate a carcinoma, and in some such cases
lobectomy has been undertaken unnecessarily.62 The term ‘paraffi-
noma’ is often applied to localised tumour-like lesions caused by the
aspiration of liquid paraffin. In other cases, a widespread ‘pneumonia’
has proved fatal, its true nature only being recognised postmortem
(see Fig. 6.2.12).64
Histologically, droplets of oil are surrounded by macrophages and
foreign-body giant cells. The droplets may form a fine sieve-like
pattern, but adjoining droplets tend to coalesce, with the result that
many alveoli are filled by a single large globule (Fig. 6.2.13A). Since
the oil is dissolved out in histological processing, the alveoli appear
empty and may be mistakenly thought to have contained air rather
than lipid. Attention may then be concentrated on the relatively minor
interstitial changes and the alveolar filling may be overlooked. On
closer examination, however, multinucleated giant cells are evident
stretched around the globules, and this should suggest the true diag-
nosis. If reserve tissue is available, frozen sections may be stained for
fat (Fig. 6.2.13B).
In contrast to the relatively inactive long-chain saturated hydrocar-
bons of mineral derivation, animal oils may cause intense inflamma-
tion and even necrosis. This is caused by injurious free fatty acids,
which may be present in the oil itself, or released by enzymatic action
within the lungs. Most animal and vegetable oils contain unsaturated
lipids, which are osmiophilic, whereas mineral oils such as liquid
paraffin that are fully saturated do not stain with osmic acid.
Halogenated hydrocarbons such as the bronchography medium
lipiodol (iodized poppy seed oil) can be differentially stained with
brilliant cresyl blue.76 In a few cases, infrared spectrophotometry has
been used to identify the nature of the oils.63,65,66
In infants the presence of foamy macrophages in the sputum or
bronchoalveolar lavage is often taken to indicate gastric reflux and
poorly defined respiratory problems are then ascribed to the aspira-
tion of gastric material,77,78 but this cannot go unchallenged as mac-
rophage clearance is one of the ways the lung normally rids itself of
spent surfactant, resulting in lipid-laden foamy macrophages. Figure 6.2.12  Exogenous lipid pneumonia that was only recognised
postmortem. Subsequent enquiries established that, unknown to her
medical attendants, the patient had been ingesting massive amounts of
liquid paraffin to counter constipation.
ENDOGENOUS LIPID PNEUMONIA
(OBSTRUCTIVE PNEUMONITIS)
disrupted, impairing the clearance of lung lipids, as in diffuse fibrosis.
The lung generates considerable amounts of lipid to reduce alveolar In long-standing cases foamy macrophages may distend the intersti-
surface tension. Much of this lipid is recycled by the alveolar epi­ tium rather than the air spaces and the appearances simulate those of
thelium but some is cleared through the airways and, if these are diffuse panbronchiolitis (see p. 124). Endogenous and exogenous
obstructed, for example by a tumour, the spent surfactant accumulates lipid are compared in Table 6.2.1.
in alveolar macrophages. These cells then increase in number and size Chronic interstitial pneumonia generally develops, and if the
and take on the usual appearance of lipophages, developing a volu- obstruction is not relieved, infection is almost inevitable, causing
minous foamy cytoplasm (Fig. 6.2.14). The alveoli become filled with acute pneumonia, which may progress to abscess formation or bron-
these cells and macroscopically the affected area shows yellow con- chiectasis. Occasionally granulomatous inflammation destroys the
solidation, sometimes referred to as golden or obstructive pneumo- walls of airways beyond the obstruction, closely simulating the
nia.79,80 Similar changes develop when the alveolar architecture is appearances of bronchocentric granulomatosis. Sometimes the foamy

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 Pathology of the Lungs

A
A

Figure 6.2.13  Exogenous lipid pneumonia. (A) What might appear at B

first sight to be air spaces represent dissolved globules of liquid paraffin;
multinucleate foreign-body giant cells stretched around the globules
provide a clue to the diagnosis. (B) Oil red O fat stain performed on Figure 6.2.14  Endogenous lipid pneumonia due to bronchial
frozen section showing that the spaces contain lipid rather than air. obstruction. The clearance of lung lipids, chiefly spent surfactant, is
impaired and foamy macrophages fill the alveoli (A). (B) In contrast to
exogenous lipoid pneumonia the cytoplasm shows fine vacuolation.

macrophages disintegrate to release their charge of ingested lipid and

the accumulation of this material may closely simulate the appear- Table 6.2.1  Comparison of exogenous and endogenous lipid
ances of alveolar lipoproteinosis, which is described next, even to the pneumonia
extent of including cholesterol crystals. Endogenous lipid pneumonia
may also develop without airway obstruction in lipidoses such Exogenous Endogenous
Niemann–Pick disease81 and in response to amphiphilic drugs such
as amiodarone (Table 6.2.2). Foamy Intra-alveolar and Intra-alveolar
macrophages interstitial
Giant cells Around droplets Absent (except around
cholesterol crystals)
ALVEOLAR LIPOPROTEINOSIS
Extracellular fat Many and varied in size Absent
droplets
Alveolar lipoproteinosis is a rare condition characterised by finely
granular eosinophilic material filling the air spaces. It was first named, Obstructing Absent Present
and is still generally known as, pulmonary alveolar proteinosis,82,83 lesion
but lipoproteinosis reflects better the chemical composition of the
Lipid Usually mineral (saturated Animal (unsaturated and
alveolar material. The nature of the lipoprotein varies and several
and therefore non-  therefore osmiophilic)
causes are now recognised. Since its initial description in 1958 over
osmiophilic)
400 cases have been reported.83

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 Diffuse parenchymal disease of the lung Chapter |6|

Table 6.2.2  Causes of endogenous lipoid pneumonia

Localised Airway obstruction (usually tumour)

Successful tumour ablation
Bronchocentric Diffuse panbronchiolitis
Diffuse Drug reaction (e.g. amiodarone)
Inborn error of metabolism (e.g. Niemann–Pick)

Aetiology and pathogenesis

Alveolar lipoproteinosis has long been regarded as representing
a failure of the alveolar macrophages to rid the lungs of spent
surfactant84–86 and it is now recognised that this defect generally
has an autoimmune basis. In most cases the condition is attributable
to the development of autoantibodies that neutralise granulocyte–
macrophage colony-stimulating factor (GM-CSF) and so impair
macrophage function.87–91 An alveolar CD4 lymphocytosis is evident Figure 6.2.15  Alveolar lipoproteinosis. High-resolution computed
once the alveoli have been cleared of the lipoproteinaceous tomography shows a ‘crazy paving’ pattern of opacification.
material.92
In other patients the condition is secondary to heavy dust ex­­
posure.93–97 Here it appears to be due to hypersecretion of surfactant
exceeding the capability of the normal clearance mechanism. Evidence
for this derives from animal dusting experiments leading to alveolar The pathogenesis in these patients is poorly understood but the
lipoproteinosis in which it was found that surfactant synthesis trebled lipoprotein may represent autophagosomal residual bodies extruded
whereas macrophage clearance only doubled.98,99 Such experiments from degenerate alveolar cells.128 A similar mechanism may operate
also show that the condition evolves through a stage of endogenous in the rare cases that complicate pulmonary infection129 or lung
lipid pneumonia characterised by the accumulation of large lipid- transplantation.116,130
laden macrophages that eventually break down to release their burden Appearances very similar to those of alveolar lipoproteinosis may
of spent surfactant.100,101 At first the released material is loosely result from bronchial obstruction, as described above under endog-
floccular and weakly staining but it gradually condenses to assume enous lipid pneumonia. They have also been described in association
the characteristic staining properties of alveolar lipoproteinosis with a surfactant-secreting bronchioloalveolar cell carcinoma.131
described below.102 Some patients exhibit both alveolar lipoproteino- One conclusion to be drawn from these varied observations is that
sis and endogenous lipid pneumonia.103 alveolar lipoproteinosis represents a clinicopathological syndrome of
In a further animal model, rats given high doses of amphiphilic multiple causation rather than a single disease.
drugs such as chlorphentermine, iprindole and amiodarone over long
periods developed endogenous lipid pneumonia104–106 and occasion-
ally this progressed to alveolar lipoproteinosis.107 These drugs block
Clinical features
lysosomal sphingomyelinase and phospholipase and the material that Alveolar lipoproteinosis may affect patients of any age, but in one
accumulates in the alveoli of these animals represents the accumu- large cohort the median age at diagnosis was 51 years and men out-
lated substrate of these lipases. The process here is analogous to the numbered women by 2 to 1.91 However, the genetic defects referred
lipid storage disorders, except that the lysosomal deficiency is acquired to above generally manifest themselves in childhood. Most studies
rather than inborn. report an increased incidence of smoking.132,133
Alveolar lipoproteinosis has also been reported in children with The main symptom is slowly increasing dyspnoea.91 Radiographically,
various enzyme defects, notably those that result in deficiency of alveolar lipoproteinosis is often characterised by patches of conso­
surfactant proteins (see p. 46).108–113 It seems likely that in these chil- lidation alternating with normal lung, although in the first case
dren the alveolar lipoproteinosis represents a compensatory hyper­ to be described there were perihilar feathery opacities that suggested
secretion of surfactant. Again there is an initial stage of endogenous oedema.82 However, no cause for oedema was apparent and no
lipid pneumonia, representing macrophage ingestion of the excess evidence of oedema is ever found on auscultation. HRCT scan is
surfactant. Alveolar lipoproteinosis has also been reported in patients characteristic, showing a ‘crazy paving’ pattern of alveolar ‘ground-
with lysinuric protein intolerance, appearing first in either child- glass’ consolidation with interlobular septal thickening (Fig.
hood114–116 or adult life.117 It is uncertain whether the lipoproteinosis 6.2.15).133–135 The diagnosis may be established by alveolar lavage (Fig.
in these patients results from a defect in surfactant synthesis or faulty 6.2.16),132,136–138 while the identification of autoantibodies against
macrophage function. Other children with alveolar lipoproteinosis GM-CSF is diagnostic in those cases in which these antibodies play a
show mutation of the gene responsible for the β-chain of the GM-CSF causative role.139
receptor.118 Genetic defects presumably account for rare familial cases Spontaneous remission occurs in about a third of patients with the
reported in the older literature.119,120 autoimmune form of the disease, a further third stabilise, and the
Other patients with alveolar lipoproteinosis have leukaemia, lym- remainder progress.140 These last patients formerly died of the disease
phoma or other diseases characterised by immunosuppression,121–124 but therapeutic lung lavage136,141–143 has transformed the prognosis.
In these patients surfactant is only weakly represented in the alveolar More recently the administration of GM-CSF by either subcutaneous
material125,126 and there is also interstitial pneumonia or fibrosis.127 injection or aerosol has been introduced as a further treatment

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tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

Figure 6.2.16  Alveolar lipoproteinosis. Lung lavage shows clumps of

acellular proteinaceous debris with very few inflammatory cells.

option.92,144–146 The regulatory relationship between interleukin-10 Figure 6.2.17  Alveolar lipoproteinosis. Therapeutic bronchoalveolar
and GM-CSF suggest that levels of interleukin-10 and anti-GM-CSF lavage recovers an opalescent, white fluid.
titres are indicative of response to GM-CSF therapy.143,147,148
Therapeutic lavage is performed under general anaesthesia, one
lung being washed out at a time with up to 30 litres of saline intro-
duced through a cuffed double-lumen tube that permits respiration for surfactant apoprotein-A.152 The alveolar walls are generally unre-
to continue in the other lung.136,141 The recovered lavage fluid is milky markable and the condition is essentially an alveolar filling defect.
white and with time white flocculent material precipitates out (Fig. However, those cases in which the disease complicates immuno­
6.2.17). Residual saline is rapidly absorbed.149 Lavage may be repeated suppression differ in that surfactant apoprotein is only weakly repre-
if the disease recurs and ultimately this treatment generally proves sented126 and there is also interstitial pneumonia or fibrosis.126–128
effective. Some patients have undergone lung transplantation but At autopsy the lungs are heavy, firm and yellow on the cut surface (Fig.
recurrent alveolar lipoproteinosis is recorded, even following double- 6.2.20).
lung transplantation.150

Pathological features Differential diagnosis

Chemical analysis of material washed from patients’ lungs shows The differential diagnosis of alveolar lipoproteinosis is from
considerable amounts of lipids, including those that normally lower Pneumocystis jirovecii pneumonia and pulmonary oedema, but the
the alveolar surface tension. However, the lavage material is deficient alveolar material is granular rather than foamy or amorphous, and
in such physical properties, perhaps due to lysosomal activity within is associated with cholesterol crystal clefts and foamy macrophages
alveolar macrophages, but its surface activity can be restored by that are not found in either of these conditions. In children the
ethanol.151 possibility of a surfactant protein gene mutation needs to be
Histologically, the alveoli are filled with a finely granular acellular considered.
deposit that is eosinophilic, and generally periodic acid–Schiff-posi-
tive and diastase-resistant (Fig. 6.2.18A, B).82,121 The staining with
periodic acid–Schiff reagents is explained by the presence of large Complications
amounts of surfactant apoprotein, which is heavily glycosylated. The Opportunistic infections represent the major complication of
surfactant apoprotein can also be demonstrated immunohistochemi- alveolar lipoproteinosis. Nocardia and fungi are mainly involved
cally (Fig. 6.2.18C).125,126 Electron microscopy shows that the alveolar but mycobacterial infection may also develop.153–155 It is notable that
deposit consists of innumerable osmiophilic lamellar bodies consist- the growth of these microbes is enhanced in vitro if their culture
ent with denatured surfactant.(Fig. 6.2.19).136 Foamy macrophages medium is enriched with the lipoproteinaceous material obtained at
and cholesterol crystal clefts are often found within the granular mate- lavage.156 Infection is also promoted by abnormalities in surfactant
rial together with eosinophilic globules, the latter representing sur- apoprotein and poor macrophage function impairing host
factant apoprotein-D, in contrast to the granular material which stains defence.84–86

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 Diffuse parenchymal disease of the lung Chapter |6|

Figure 6.2.19  Alveolar lipoproteinosis. Electron microscopy of the

alveolar material recovered in lung washings. The granular material  
is lamellar and osmiophilic. The appearances are those of a complex  
lipid and are consistent with the material representing denatured
surfactant.

CHOLESTEROL PNEUMONITIS

Cholesterol accumulation in the lung is manifest in paraffin sections

as sheaves of acicular crystal clefts in both the alveolar spaces and
interstitium (Fig. 6.2.21). The cholesterol crystals are frequently
attended by foreign-body giant cells and a non-specific chronic inflam-
matory infiltrate. Large numbers of cholesterol crystals may be seen
in obstructive pneumonitis, and also without recognised cause.157
Disruption of the alveolar architecture, as in diffuse fibrosis, impairs
the clearance of lung lipids and leads to the accumulation of sur-
factant, which may be manifest as focal alveolar lipoproteinosis and
cholesterol pneumonitis. Diffuse pulmonary fibrosis is often accom-
panied by type II cell hyperplasia and the metabolic activity of these
C surfactant synthesising cells may also contribute to the accumulation
of cholesterol and other lipids.158
Figure 6.2.18  Alveolar lipoproteinosis. The alveoli are filled by Scanty cholesterol crystal clefts are often a feature of extrinsic aller-
eosinophilic amorphous or finely granular material in which there are the gic alveolitis and are occasionally seen in other granulomatous condi-
acicular clefts of dissolved cholesterol. The alveolar walls are tions, for example, sarcoid. They are also recorded in pulmonary
unremarkable. (A) Haematoxylin and eosin stain. (B) Periodic acid–Schiff hypertension,159,160 and localised collections are found in necrotic foci
stain. (C) Immunoperoxidase stain for surfactant apoprotein.
such as chronic tuberculous lesions and progressive massive fibrosis
of coal-workers.
A review161 of idiopathic cholesterol pneumonitis identified it as a
disease of the elderly, particularly men who were heavy smokers, but
the disease is also encountered in children, sometimes in siblings.
In children it may sometimes coexist with or progress to alveolar
lipoproteinosis (see Figs 6.2.20 and 6.2.21).162 The relationship of
cholesterol pneumonitis to alveolar lipoproteinosis is also demon-

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tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

Figure 6.2.21  Cholesterol pneumonitis. Numerous elongated clefts of

dissolved cholesterol crystals are evident in this lung biopsy of a young
girl who within 4 years had died of alveolar lipoproteinosis (shown in  
Fig. 6.2.20).

Figure 6.2.20  Alveolar lipoproteinosis. At autopsy the lungs are heavy,

firm and yellow on the cut surface.

strated by the development of either condition in patients with errors

in surfactant synthesis and lysinuric protein intolerance.114,115,117
Changes resembling those of cholesterol pneumonitis are found in
alkane lipogranulomatosis but this is a generalised storage disorder
Figure 6.2.22  Corpus amylaceum. Corpora amylacea are sometimes
that affects many other organs as well as the lungs (see p. 492).
found incidentally in the lungs, free in the alveoli. This one has a central
black particle, which has possibly acted as the starting point on which
the body has formed.
CORPORA AMYLACEA

Corpora amylacea identical to those more commonly seen in the

prostate were first described in the lungs by Friedrich in 1856.163 They black spherule is evident, suggesting that a dust particle has provided
are an incidental finding, more common in the elderly, and on occa- a nidus on which alveolar secretions of cellular components may have
sion they may be observed in the sputum.164 They are round, intra- precipitated (see Fig. 6.2.22).164,167 Corpora amylacea are merely
alveolar structures, 50–150 µm in diameter (Fig. 6.2.22), which stain microscopic curiosities that have no clinical importance, unless they
uniformly with both eosin and Congo red. With the latter stain, are mistaken for fungal spores or parasitic ova.
polarisers show both the birefringence and dichroism of amyloid,164
which immunocytochemically is shown to be derived from β2 mac-
roglobulin.165 Polarising filters also show both radial striations and
circumferential lamellae,164 the latter representing periodic precipita- ALVEOLAR MICROLITHIASIS
tion zones (Liesegang rings) that occur spontaneously in colloidal
solutions.166 Electron microscopy164 shows that the bodies consist Alveolar microlithiasis is a rare condition characterised by extensive
largely of sheaves of microfibrils, possibly representing cytokeratin alveolar accumulation of calcified microliths. It was first described in
derived from alveolar epithelial cells. Elongated macrophages occa- 1918168 and received its current designation in 1933.169 Virtually any
sionally adhere to the surface of the bodies. Occasionally a central age group may be affected but the third and fourth decades are most

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 Diffuse parenchymal disease of the lung Chapter |6|

frequently involved.170–173 Both sporadic and familial cases are

reported, the latter reflecting autosomal-recessive inheritance.170,171,174,175
Males outnumber females in the sporadic cases whereas the reverse
is true when the disease is familial. There is a wide geographical
distribution but exceptionally high numbers are reported from Turkey,
Italy and the USA.175–177 The cause appears to be mutation of the type
IIb sodium phosphate co-transporter gene SLC34A2.178,179 This is
involved in phosphate homeostasis in several organs, including the
lung where its gene product, which is expressed by type II alveolar
epithelial cells, controls uptake of the phosphate required for
surfactant synthesis. Loss of function of the gene product results
in calcium chelation and hence microlith formation.
The disease is characterised by a distinctive fine micronodular cal-
cification in the lungs that is heaviest basally or around the hila but
may be so extensive as to produce almost complete radiographic
opacification. Lymph nodes are not enlarged. The condition may be
symptomless and discovered by chance on routine chest radiography.
HRCT shows dense alveolar calcification with a perilobular and bron-
chovascular distribution.180 The disease may stabilise at any time but
more often over a period of many years it progressively restricts lung
movement and impairs gas diffusion until it eventually leads to severe A
dyspnoea and death from respiratory and cardiac failure.171,181,182
Serum levels of surfactant proteins A and D correlate with progression
of the disease, and may provide a useful monitoring tool. No effective
medical treatment has yet been reported except for regression of the
opacification in one patient treated with disodium editronate, an
agent that inhibits the microcrystalline growth of hydroxyapatite.183
Lung transplantation has proved successful in some cases.184,185
Most cases have been diagnosed at necropsy, when the lungs are
rock-hard and extremely heavy, and a band saw is generally needed
to cut them into slices. However, with greater recognition of the dis-
order, diagnosis is now usually made on either transbronchial biopsy
or bronchoalveolar lavage, or, when other family members are affected,
by HRCT alone.177 In decalcified sections, enormous numbers of wavy
concentrically laminate microliths, up to 300 µm in diameter, can be
seen filling the alveoli (Fig. 6.2.23). The alveolar walls surrounding
them may undergo fibrosis. In less advanced areas, only occasional
microliths are scattered among otherwise normal air spaces. Rarely,
the microliths are also present in the alveolar interstitium and bron- B
chial mucosa.186 Sometimes they are identified in the sputum,171,187
where they are to be distinguished from the larger ‘liths’ that derive Figure 6.2.23  Alveolar microlithiasis. (A) High-resolution computed
from a focus of dystrophic calcification eroding a bronchus.188,189 tomography shows patchy alveolar shadowing with dense subpleural and
Analysis shows them to consist of calcium and phosphorus salts in septal opacification. (B) The alveoli are filled by innumerable heavily
the form of carboxyapatite.173,190,191 calcified lamellar bodies of wavy configuration.

CALCOSPHERITES (CONCHOIDAL BODIES) of alveolar macrophages, as in DIP; they probably represent the
extruded residual bodies of lysosomes. They are a histopathological
The term ‘calcospherite’ or ‘conchoidal body’ is applied to certain curio of no clinical importance, unless mistaken for life-threatening
laminated calcified structures found in either the air spaces or the conditions such as alveolar microlithiasis (see above).195
tissues of the lung, where they are respectively known as blue bodies
and Schaumann bodies.
Schaumann bodies
Schaumann bodies are found within connective tissue rather than the
‘Blue bodies’ air spaces but will be dealt with here as they are similar to blue bodies.
Blue bodies are laminated intra-alveolar structures that are usually They are commonly found in granulomas and, like blue bodies, they
found in focal collections (Fig. 6.2.24).192–194 Individually, they probably represent the residuum of lysosomal activity. They may be
measure 15–40 µm in diameter and are hence smaller than microliths found in large numbers in the scars of healed sarcoidosis or berylliosis
or corpora amylacea. The name blue body derives from their weak (see Fig. 6.1.31). They are larger than blue bodies, measuring up to
haematoxyphilia. Calcium carbonate in a mucopolysaccharide matrix 80 µm in diameter, and are more distinctly laminate and calcific.
is the major component but there is also an outer rim of iron. Blue Similar calcospherites are sometimes found within the stroma of
bodies are most frequently found when there is an excessive number papillary tumours, in both the lung and other organs.

321
tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

Figure 6.2.24  Alveolar calcospherites. These structures probably derive Figure 6.2.25  Alveolar ossification. An incidental finding in the lungs of
from alveolar macrophage lysosomal activity, being found in conditions a man dying of unrelated causes.
marked by increased numbers of these cells. Their haematoxyphilia is
responsible for their colloquial name of ‘blue bodies’.

alveoli of otherwise normal appearance (Fig. 6.2.25).196,197 This form

ALVEOLAR OSSIFICATION of ossification is commonest in the elderly and particularly in associa-
tion with prolonged pulmonary congestion or thromboembolism. It
Dystrophic ossification is common in the lung but is interstitial and is therefore likely to represent a form of acquired metaplasia rather
is therefore dealt with elsewhere (see p. 149). This section deals with than a congenital heterotopia. It is generally an incidental finding of
isolated foci of laminated bone that are found on occasion within no clinical consequence.

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 Chapter 7 

Occupational, environmental and

iatrogenic lung disease
7.1  Occupational disease

CHAPTER CONTENTS Paint spraying 355

Mineral oils and petroleum 355
Pneumoconiosis: general features 327 Welding 355
Definition of pneumoconiosis 327 Toxic fumes and gases 355
Dust deposition in the lung 328 Anoxic asphyxia 357
Dust clearance from the lung 328 Occupational asthma 357
The zonal distribution of pneumoconiosis 329 Byssinosis 358
Pulmonary reactions to mineral dust 329 Occupational fevers 358
Identification of the dust 329 References 358
Radiological grading of pneumoconiosis 331
Silicosis 333
Amorphous silica 336
Silicates 337
Inert dusts 337 This chapter deals with the pneumoconioses, occupational asthma,
Mixed-dust pneumoconiosis 337 occupational fevers and the effects o£ toxic fume and gases.
Coal pneumoconiosis 338 Occupational diseases of the lung considered elsewhere include the
effects of atmospheric pressure changes (see p. 368), extrinsic allergic
Pneumoconiosis and rheumatoid disease
alveolitis (see p. 279), carcinoma of the lung (see p. 534) and asbes-
(Caplan’s syndrome) 341
tos-induced pleural disease (see pp. 714–729). Dusty occupations in
Asbestosis 342 general are also associated with an increased risk of chronic obstruc-
Asbestos-induced lung cancer 349 tive pulmonary disease.1,2
Asbestos-induced airway disease 350
Aluminium 351
Rare earth (cerium) pneumoconiosis 351 PNEUMOCONIOSIS: GENERAL FEATURES
Hard-metal disease (cobalt lung) 351
Berylliosis 352 Definition of pneumoconiosis
Polyvinyl chloride pneumoconiosis 354
The term ‘pneumoconiosis’ is an abbreviation (and etymological
Flock worker’s lung 354 corruption) of Zenker’s pneumonokoniosis,3 which derives from
Popcorn worker’s lung 355 pneumon (lung) and konis (dust) and therefore translates as dusty lung;

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00007-0 327
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 Pathology of the Lungs

in practice the term is confined to the effects of mineral dust on the

lungs. Diseases caused by organic dusts are not included among the Impaction
pneumoconioses and, in medicolegal practice at least, the presence of
dust alone is insufficient to indicate pneumoconiosis: for compensa-
tion to be considered, the mineral dust must alter the structure of the
lung and cause disability. The British Industrial Injuries Advisory
Council defined pneumoconiosis as ‘permanent alteration of lung
structure due to the inhalation of mineral dust and the tissue reactions
of the lung to its presence, excluding bronchitis and emphysema’.4
Parkes recommends that cancer and asthma caused by mineral dust
should also be excluded from the definition, an opinion with which
we concur.5

Dust deposition in the lung

To reach the lung, dust particles have to be very small. Particle density
and shape also affect the aerodynamic properties of dust. Host factors
such as airflow characteristics, airway branching patterns and airway Sedimentation
disease also affect dust deposition. Three deposition mechanisms are
recognised (Fig. 7.1.1):
1. Inertial impaction: When air streams change direction or
velocity, the inertia of the entrained particles causes them to
maintain their original direction for a distance that depends
upon their density and the square of their diameter. The same
rules govern a car approaching a bend too fast: the car crashes
into the outside of the bend.
2. Sedimentation (gravitational settlement): Under the influence of
gravity, particles settle with a speed that is proportional to their Gravity
density and the square of their diameter.
3. Diffusion: Very small airborne particles acquire a random
motion as a result of bombardment by the surrounding gas
molecules. Diffusion

Inhaled dust particles are liable to sediment out in the alveoli if

they have a diameter in the range of 1–5 µm, are roughly spherical in
shape, and in density approximate to that of water. Larger or denser
particles impact or precipitate on the walls of the conductive airways
and are rapidly removed by ciliary action. Smaller particles may reach
the alveoli but do not sediment so readily and many are therefore
exhaled. Very small particles are deposited on the walls of alveoli by
diffusion but because they are so small the total amount of dust
deposited in this way is insignificant compared with that deposited
by sedimentation (Fig. 7.1.2). Direct measurement shows that most Figure 7.1.1  Mechanisms of particle deposition in the respiratory tract.
lung dust (96%) has a particle diameter less than 2.5 µm.6
Fibrous dust particles behave differently. Fibres over 100 µm in
length may reach the alveoli if they are very thin and remain aligned
with the air stream. Fibre penetration is inversely related to path
length and the number of bifurcations.7 Tall people have longer largely effected by macrophages, principally via the airways to the
conductive airways and experience more deposition in these sites pharynx but also via lymphatics to the regional lymph nodes. The
than short people who have greater alveolar deposition for the same airway and interstitial routes interconnect at the bronchiolar level11
level of exposure.8 where some dust-laden macrophages leave the interstitium for the air
Slightly more dust is deposited in the right lung than the left, space.12 This interconnection is probably the route utilised by
probably because the right main bronchus is more in line with the circulating macrophages clearing other parts of the body of endog-
trachea, and is broader and shorter than the left, and carries 55% of enous or exogenous particulate matter via the lung.13 Long asbestos
the inhaled air.9,10 fibres present a particular problem to macrophage clearance. Some
minerals, notably chrysotile asbestos, undergo slow physicochemical
dissolution in the lungs.
Dust clearance from the lung
Only a small fraction of the inhaled dust gains access to the inter-
Inhaled dust that settles in the conductive airways is removed within stitium, a necessary step if it is to cause pneumoconiosis. Some free
a day or two by ciliary action. Only dust that reaches the alveoli is dust enters through the bronchus-associated lymphoid tissue11,12 and
liable to cause pneumoconiosis and much of this is also removed, but some is taken up by, or pierces, the alveolar epithelium (Fig. 1.34,
the clearance rate here is much slower: many coalminers continue to p. 21).14–16 Some of this is transported within hours to the hilar lymph
expectorate mine dust years after retirement. Alveolar clearance is nodes.17 So rapid is this translocation that it is thought not to involve

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

100 most, the lesions are more numerous and better developed in the
upper lobes than the bases but the reverse is true of asbestosis. The
T reasons for this are complex but undoubtedly involve the dust
80 deposition:clearance ratio for the effect of the dust will depend upon
both its amount and the duration of its stay in the lungs. There
are well-recognised regional differences in the distribution and clear-
Deposition (%)

60 ance of inhaled material, which in turn are dependent upon man’s

C upright posture, the consequent gravitational forces being maximal
A at the apices.35 When standing at rest, the apices of the lungs are
40 hardly perfused, so that lymph formation and clearance are much
better at the bases.36–38 Similarly, the apices are relatively less well
aerated; alveoli in the lower lobes receive more air than those in the
20 upper lobes.37,39 The greater respiratory excursions at the bases are
thought to promote macrophage mobility there. It is to be expected
therefore that the bases would both receive and clear more dust than
0 the apices, rendering it difficult to predict on theoretical grounds
0 2 4 6 8 10 which parts of the lungs carry the heaviest dust burden. In fact, more
dust of all types is found in the upper lobes, the part most severely
Particle size (microns)
affected by every type of pneumoconiosis except asbestosis.40,41 The
Figure 7.1.2  Percentage dust deposition in the respiratory tract predilection of asbestos to affect the periphery of the lower lobes is
according to particle diameter. The major alveolar impact is that of attributed to the dangerous long asbestos fibres preponderating
particles 1–3 µm diameter. Submicron particles are of negligible mass. T, there.41,42
total dust deposition; C, deposition on the ciliated epithelium; A, alveolar
deposition.
Pulmonary reactions to mineral dust
The main tissue reaction to mineral dust is fibrosis. Silica is highly
fibrogenic and is therefore very likely to cause pneumoconiosis.
phagocytes, although interstitial macrophages are undoubtedly
Carbon is non-fibrogenic and therefore, unless there are
important in continuing the transportation of dust to the nodes.
complications, coal pneumoconiosis causes little disability. Tin too is
Ultrafine dust particles are particularly liable to be transported across
harmless, and stannosis therefore unimportant, although the chest
the alveolar epithelium.11 The integrity of the alveolar epithelium is
radiograph is highly abnormal because tin is very radiopaque.
very important to dust translocation from the air spaces to the inter-
Stannosis is one of several terms that specify pneumoconiosis due to
stitium. Much more dust reaches the interstitium if the epithelium is
a particular mineral, the best known being silicosis, asbestosis and
damaged.18,19
anthracosis. Table 7.1.1 summarises the various pulmonary reactions
It is widely thought that macrophages that have left the interstitium
to mineral dust.
for the alveolar space never return,17,20 but this is probably untrue.21
Heavily laden macrophages accumulate in alveoli bordering the ter-
minal and respiratory bronchioles, eventually filling them completely. Identification of the dust
Erosion of the alveolar epithelium permits re-entry of these macro-
phages into the interstitium,22 very close to foci of bronchial mucosa- The blackness of carbon and red-brown colour of iron give ample
associated lymphoid tissue (MALT), which are found near the terminal evidence, both naked-eye and microscopically, of the type and amount
bronchioles.23 These aggregates guard the mouths of lymphatics, of these dusts when they are present in the lung (Fig. 7.1.3), but other
which commence at this point; alveoli are devoid of lymphatics. Dust- inorganic dusts may be more difficult to identify. However, a flick-out
laden interstitial macrophages accumulate in and around the bron- substage condenser and Polaroid filters to test for refractility and
chial MALT, which Macklin therefore referred to as dust sumps.24 Most birefringence respectively are useful adjuncts that are too often
pneumoconiotic lesions are found in the region of the dust sumps neglected by the histopathologist. Crystalline silica is traditionally
and are therefore focal. Asbestosis is diffuse rather than focal because regarded as being only weakly birefringent, in contrast to silicates
the long asbestos fibres are not readily mobilised and cannot be con- which generally show up brightly with simple crossed Polaroid
centrated in the centriacinar dust sumps. This is also seen on occasion filters.43 However, with modern microscope lamps, if the light source
with platy non-fibrous dusts such as talc, mica, kaolinite and feld- is set at high intensity when using Polaroid filters, both silica and
spar.25–33 Within the dust sumps the dust particles are not static. They silicates are birefringent.44 Mineralogists use polarising microscopy
are constantly being freed and reingested by interstitial macrophages for analysis, but only by studying large polished crystals with con­
and, because these cells are mobile, successively inhaled dusts soon trolled orientation of the light. The small dust particles found in
become intimately mixed.34 Macrophages play an important role in tissue sections are too small to permit analysis by this technique
pneumoconiosis and if the dust is fibrogenic the repeated phagocyto- but it is nevertheless very useful for detecting their presence
sis of indestructible mineral particles results in constant fibroblast (Fig. 7.1.4).
stimulation. Particle shape gives a useful indication of mineral type but
appearances are sometimes deceptive: the plate-like crystals of talc are
seldom observed as such, usually being viewed edge-on, when they
appear to be needle-shaped. Occasionally, stains can be used to
The zonal distribution of pneumoconiosis identify minerals, e.g. a modified Perls’ reaction for inhaled iron, and
Pneumoconiosis affects both lungs but seldom evenly and some Irwin’s aluminon stain for aluminium, but these too have largely been
pneumoconioses show characteristic patterns of lung involvement. In replaced by modern analytical techniques.

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 Pathology of the Lungs

Microincineration combined with dark-field microscopy can also

Table 7.1.1  Pulmonary reactions to mineral dust
be used to demonstrate small particles. Incombustible mineral parti-
cles that cannot be seen with bright-field or polarising microscopy are
Pulmonary reaction Examples
rendered visible by this technique and their position on the slide can
Macrophage accumulation Anthracosis be compared with tissue reactions evident in a serial section that has
with a little reticulin Siderosis not been incinerated. Microincineration has, however, also been
deposition Stannosis largely replaced by modern analytical techniques that will now be
Baritosis considered.
Coal pneumoconiosis (macules) Analytical electron microscopy is very helpful in identifying miner-
Aluminium pneumoconiosis (granular als, whether applied to lung digests or tissue sections.45–48 Scanning
aluminium) electron microscopy permits the examination of thicker sections than
transmission electron microscopy but does not detect very small
Nodular or massive fibrosis Silicosis
particles. However, scanning electron microscopy allows more tissue
Mixed-dust pneumoconiosis
to be examined and avoids the difficulty of cutting mineral particles
Coal pneumoconiosis (nodules)
with an ultramicrotome.
Diffuse fibrosis Asbestosis Mineral particles in a 5-µm thick deparaffinised section can
Hard-metal pneumoconiosis be recognised in a scanning electron microscope set to collect the
Aluminium pneumoconiosis (aluminium back-scattered electrons.46 The instrument can then be focused on
fume and stamped aluminium) points of potential interest and switched to X-ray diffraction, which
Epithelioid and giant cell Chronic berylliosis provides information on crystal structure (Fig. 7.1.5). Alternatively,
granulomas elemental analysis may be undertaken with either energy-dispersive
or wavelength-dispersive X-ray spectroscopy. With energy-dispersive
Alveolar lipoproteinosis ‘Acute’ silicosis, but also seen with X-ray spectroscopy, all elements of atomic number above 11 are
heavy exposure to other dusts (see identified, whilst with wavelength-dispersive X-ray spectroscopy the
p. 317) section can be scanned for one particular element. With the former
Small-airway disease Various dusts (see p. 123) technique different elements are shown graphically as individual

A B

Figure 7.1.3  (A) Coal and (B) haematite miner’s lungs. The respective black and red colours of these lungs give a good indication of their mineral
content. Paper-mounted whole-lung sections. (Courtesy of WGJ Edwards, London, UK.)

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

Figure 7.1.4  Talc pneumoconiosis. Only carbon is evident when the

lesions are viewed with (A) non-polarised light, whereas the abundant
talc particles are readily seen when (B) polarised light is employed.

peaks, the heights of which are proportional to the amounts of Figure 7.1.5  Electron diffraction patterns of gold, used for calibration
the different elements within the particle studied, thereby giving infor- purposes. The ring pattern (A) indicates that the material is polycrystalline
mation on probable molecular formula (Fig. 7.1.6). Thus, different and the spot pattern (B) indicates that it is a single crystal: amorphous
materials give no regular pattern. The spacing of the rings gives
silicates can be distinguished from each other and also from silica,
information on crystalline structure and can be usefully applied to
which registers as pure silicon, oxygen (atomic number 8) not being
distinguish the various crystalline forms of silica (quartz, tridymite,
detected. The fact that the elements of low atomic number that con- cristobalite) for example. (Courtesy of Dr M Wineberg, London, UK.)
stitute organic chemicals are not detected means that any minerals
present (except beryllium, atomic number 4) can be recognised easily
in tissue sections. Only particles can be analysed however: elements
present in only molecular amounts cannot be detected by X-ray
analysis.
The detection of trace amounts of substances such as beryllium by exposing the patient’s lymphocytes to metals and measuring their
requires bulk chemical analysis or techniques that are not widely reaction in vitro.52
available such as atomic absorption spectrometry, neutron activation
analysis and microprobe mass spectrometry.49,50 The last of these
techniques can also provide molecular (as opposed to elemental)
Radiological grading of pneumoconiosis
analysis of organic as well as inorganic particles.51 Another analytical
technique of interest is microscopic infrared spectroscopy which pro- A scheme for grading pneumoconiosis radiologically by comparison
vides data on the compound nature of microscopic particles in tissue with standard radiographs has been adopted by the International
sections (Fig. 7.1.7). Micro-Raman spectroscopy is also useful in this Labour Organisation (ILO) and is widely used.53 Small opacities (up
respect. Some metals cause hypersensitivity, which can be identified to 1 cm diameter) are graded by their profusion, 1, 2 and 3 indicating

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 Pathology of the Lungs

Si
No. of Counts

Al

Mg K
P S Ca Fe B

1.16 Energy keV 6.40

C

Figure 7.1.6  Dust particles in the lung: electron microprobe analysis. (A) The secondary (scanning) electron microscopic image of a deparaffinised
5-µm-thick section of lung showing clumps of macrophages in an alveolar lumen. (B) Back-scattered scanning electron microscopic image showing
three of the macrophages at higher power: several bright particles worthy of further attention are evident. (C) X-ray energy spectrum of one of the
particles showing it to be a silicate. The section had been transferred from a glass to a Perspex slide to avoid background signals, glass being siliceous.
Each element emits a unique energy pattern when bombarded by electrons while the number of counts is in proportion to the amount of the
particular element that is present in the particle. (Courtesy of Professor DA Levison, Dundee, UK.)

increasing numbers, and by their size, increasing through p, q and r

if rounded and s, t and u if irregular. Type p opacities are described
as punctiform and measure up to 1.5 mm in diameter; larger lesions
up to 3 mm in diameter (type q) are described as micronodular or
miliary; and those over 3 mm and up to 1 cm in diameter (type r) are
described as nodular. Irregular opacities cannot be sized so accurately,
s, t and u indicating fine, medium and coarse respectively. Large
opacities (over 1 cm diameter) are graded by their combined size,
increasing through A, an opacity measuring between 1 and 5 cm in
diameter; B, one or more opacities whose combined area does not
exceed the equivalent of one-third of the area of the right lung field
(when they are regrouped in the mind’s eye or measured with a trans-
parent ruler); and C, one or more opacities whose combined area
exceeds one-third of the area of the right lung field (when similarly
regrouped). In coalworkers, small opacities (up to 1 cm diameter)
Figure 7.1.7  Infrared spectra of calcium oxalate. Top, reference standard; correspond to simple coalworker’s pneumoconiosis and large opaci-
centre and bottom, crystals in human tissue sections. (Courtesy of Professor ties (over 1 cm diameter) to complicated coalworker’s pneumoconio-
DA Levison, Dundee, UK.) sis, which is also known as progressive massive fibrosis.

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inhabitants of the Sahara, Libyan and Negev deserts and those living
SILICOSIS43 in windy valleys high in the Himalayan mountains,59–65 whilst in
California the inhalation of dust raised from earth has led to silicate
pneumoconiosis in farm workers,66 horses67 and a variety of zoo
Mineralogy
animals.68
Silicosis is caused by the inhalation of silica (silicon dioxide, SiO2), The silica in rocks such as granite, slate and sandstone is largely in
which is to be distinguished from the silicates, these being more the form of quartz and this is therefore the type of silica encountered
complex compounds in which silicon and oxygen form an anion in most of the industries considered above. Cristobalite and tridymite,
combined with cations such as aluminium and magnesium: talc, which are possibly even more fibrogenic than quartz, are more likely
for example, is a hydrated magnesium silicate with the formula to be encountered in the ceramic, refractory and diatomaceous earth
Mg3Si4O10(OH)2. The element silicon is also to be distinguished from industries where processing involves high temperatures.
the synthetic organic polymer silicone, used in implants.
Crystalline silica is highly fibrogenic whereas amorphous silica and Clinical features
silicates other than asbestos are relatively inert. Silica exists in several
crystalline forms, of which quartz, cristobalite and tridymite are the Many workers with silicosis are asymptomatic. As a general rule,
most important: tridymite is the most fibrogenic and cristobalite more exposure to silica dust extends over many years, often 20 or more,
so than quartz.43,54 before the symptoms of silicosis first appear: by the time the disease
becomes overt clinically, much irreparable damage has been inflicted
on the lungs. The initial symptoms are cough and breathlessness.
Occupations at risk From then onwards, respiratory disability progresses, even if the
patient is no longer exposed to silica dust. Ultimately, there may be
Silicotic lesions have been identified in the lungs of Egyptian
distressing dyspnoea with even the slightest exercise.
mummies, and the injurious effects on the lungs of inhaling mine
Silicosis sometimes develops more rapidly, perhaps within a year or
dust have been recognised for more than 400 years. As long ago as
so of first exposure. Such ‘acute silicosis’ was observed in the scouring
the sixteenth century in Joachimsthal, Bohemia (now Jachymov,
powder industry in the 1930s when these cleansing agents consisted of
Czech Republic), diseases of miners’ lungs were attributed to the dust
ground sandstone mixed with a little soap and washing soda.69,70 The
the miners breathed. Silicosis, tuberculosis and lung cancer are all
additives were considered to have rendered the silica in the sandstone
now known to have been prevalent among the miners in this region,
more dangerous but it is possible that the rapidity of onset of the
the cancer being largely attributable to the high level of radioactivity
disease merely reflected the intensity of the dust cloud to which the
in the mines.
packers were exposed. Confusingly, the term ‘acute silicosis’ has since
Silicosis was recognised in the UK soon after the discovery in 1720
been applied to a further effect of heavy dust exposure in tunnellers,
that the addition of calcined flint to the clay from which china is made
sand blasters and silica flour workers, namely pulmonary alveolar
produced a finer, whiter and tougher ware. The preparation and use
lipoproteinosis (see below),71,72 whilst the terms ‘accelerated silicosis’
of this flint powder were highly dangerous, causing the condition
or ‘cellular phase silicosis’ have been substituted for ‘acute silicosis’ in
known as potter’s rot, one of the first of the many trade names by
referring to the rapid development of early cellular lesions.43,73
which silicosis has since been known. Aluminium oxide (alumina)
The time from first exposure to the development of symptoms (the
now provides a safe, effective substitute for flint in this industry.
latency period) is inversely proportional to the exposure level.
In 1830 it was noted that Sheffield fork grinders who used a dry
However, it is evident that a certain amount of silica can be tolerated
grindstone died early, and amongst other preventive measures it was
in the lungs without fibrosis developing, indicating either a time factor
recommended that the occupation should be confined to criminals:
in the pathogenetic process or a threshold dust load that has to be
fortunately for them, the substitution of carborundum (silicon
reached before fibrosis develops.
carbide) for sandstone was effective enough. However, silicosis still
occurs in some miners, tunnellers, quarrymen, stone dressers and
metal workers. Pathological findings
Silica in one form or another is used in many trades – in the manu- Silica particles that are roughly spherical in shape and of a diameter
facture of glass and pottery, in the moulds used in iron foundries, as in the range of 1–5 µm sediment out in the alveoli and are con­
an abrasive in grinding and sandblasting, and as a furnace lining that centrated within macrophages at Macklin’s dust sumps, as explained
is refractory to high temperatures. Rocks such as granite and sandstone previously (see p. 27). Early lesions, as seen in so-called accelerated
are siliceous and their dusts are encountered in many mining and or cellular phase silicosis, consist of collections of macrophages
quarrying operations. In coal mining in the UK the highest incidence separated by only an occasional wisp of collagen. The early lesions
of the disease was in pits where the thinness of the coal seams required have been likened to granulomas and on occasion have been mistaken
the removal of a large amount of siliceous rock, a process known as for Langerhans cell histiocytosis or a storage disorder, but Langerhans
‘hard heading’. In South Africa, silicosis causes a high mortality among cells are scanty and the histiocytes contain dust particles rather than
the gold miners on the Witwatersrand, where the metallic ore is accumulated lipid or polysaccharide. The macrophages of the early
embedded in quartz. Slate is a metamorphic rock that contains lesion are gradually replaced by fibroblasts and collagen is laid down
both silica and silicates, and slateworkers develop both silicosis and in a characteristic pattern. The mature silicotic nodule is largely
mixed-dust pneumoconiosis.55,56 Nor are rural industries immune acellular and consists of hyaline collagen arranged in a whorled
from the disease, particularly if ventilation is inadequate, as it is in pattern, the whole lesion being well demarcated (Fig. 7.1.8) and
certain African huts where stone implements are used to pound meal sometimes calcified. Small numbers of birefringent crystals are gener-
and the occupants develop mixed-dust pneumoconiosis.57 Silicosis ally evident within the nodules when polarising filters are used, but
and mixed-dust pneumoconiosis have also been reported in dental these mainly represent silicates such as mica and talc, inhaled with
technicians.58 the silica. Silica particles are generally considered to be only weakly
Desert sand is practically pure silica but the particles are generally birefringent,43 but fairly strong birefringence is evident in strong light
too large to reach the lungs. However, silicosis has been reported in (see above).44

333
 Pathology of the Lungs

Figure 7.1.8  A silicotic nodule consisting of hyaline collagen arranged in

a whorled pattern.

The silicotic nodules are situated in the centres of the pulmonary

acini and are more numerous in the upper zones than the bases (Fig.
7.1.9A). They measure up to 5 mm across and are hard and easily
palpable. They are grey if caused by relatively pure silica but black in
coalminers and red in haematite miners.
Silicotic nodules develop first in the hilar lymph nodes and are
generally better developed there than in the lungs.74–76 Indeed, silicotic
nodules are occasionally found in the hilar lymph nodes of persons
who have no occupational history of exposure to silica and whose
lungs are free of such lesions, the silica in the nodes being presumed A
to represent inhaled particles derived from quartz-rich soil.77 Severely
affected lymph nodes often calcify peripherally, giving a characteristic
eggshell-like radiographic pattern. This is sometimes the only radio-
logical abnormality.76 Such enlarged lymph nodes may occasionally
press upon and obstruct adjacent large bronchi78 or result in a
left recurrent laryngeal nerve palsy,79 so simulating malignancy.80
Sometimes the nodules develop within the walls of major bronchi,
occasionally causing a middle-lobe syndrome (see p. 92).81 Silicotic
nodules are also found along the lines of the pleural lymphatics75,82
where they have been likened to drops of candle wax on the visceral
pleura. Very rarely, silica-induced fibrosis is more pronounced in the
pleura than in the lungs.83
Lung tissue between the nodules is often quite normal and not until
the process is very advanced is there any disability (Fig. 7.1.9B). In
severe cases large masses of fibrous tissue are formed, which may
undergo central necrosis and cavitation (Fig. 7.1.10).84 On close
inspection it is evident that these consist of conglomerations of many
silicotic nodules closely packed together. In such severe cases cor
pulmonale develops. Occasionally, silicotic nodules develop in the
abdominal as well as the thoracic lymph nodes, and in the liver,
spleen, peritoneum and bone marrow.85–89
B
In about 10% of cases, the typical pulmonary nodules that pre-
dominantly affect the upper lobes are accompanied by diffuse fibrosis
Figure 7.1.9  Silicosis. (A) The nodules are most numerous in the upper
that is maximal in the lower lobes.27,33,90–92 The latter may show part of the lung where there is a conglomerate silicotic mass at one
‘honeycombing’ and closely resemble idiopathic pulmonary fibrosis. point. Paper-mounted whole-lung section. (B) Microscopy shows silicotic
The association is too common to be explained by chance and the nodules scattered throughout otherwise normal lung tissue.
diffuse fibrosis is therefore regarded as a further manifestation of the
pneumoconiosis, possibly due to an interaction between the dust and
the immunological factors discussed below.
that the hardness of the silica was responsible, but this was
discounted by the observation that silicon carbide (carborundum) is
Pathogenesis harder than silica but is non-fibrogenic. Theories based on the piezo-
The pathogenesis of silicosis has excited much interest and many dif- electric property and on the solubility of silica were successively aban-
ferent theories have been advanced over the years. An early theory held doned although the latter had a long period of popularity. It gained

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support from Kettle’s experiments which showed that fibrosis

developed about chambers placed in an animal’s peritoneal cavity if
the chambers contained silica powder sealed in by a collodion mem-
brane through which solutes such as silicic acid could pass. However,
it was later shown that the pores in a collodion membrane are quite
irregular in size and when the experiments were repeated using cham-
bers guarded by millipore membranes, no fibrosis developed, despite
solutes being able to diffuse out.93 The solubility theory also fails to
take account of the differing fibrogenicity of the various forms of silica
despite them being of similar solubility.54 Furthermore, if the outer,
more soluble layer of the particles is removed by etching, fibrogenicity
is increased although solubility is decreased. In line with this, freshly
fractured crystalline silica is more pathogenic in every respect than its
aged equivalent,94 which may partly explain the severity of silicosis in
trades such as sandblasting. These observations suggest that the fibro-
genicity of silica is connected with its surface configuration.
It is now known that uptake of the silica by macrophages is
necessary for silicosis to develop. If silica and macrophages are
enclosed together in peritoneal millipore chambers, a soluble product
of the macrophages diffuses out and causes fibrosis. This observation
led to the realisation that the fibrogenicity of the various crystalline
forms of silica correlated well with their toxicity to macrophages and
for a time macrophage death was thought to be necessary.95 It is now
considered that before the macrophages are killed by the ingested
silica, they are stimulated to secrete factors that both damage other
con­stituents of the lung and promote fibrosis.96–102 Transforming
growth factor-β is one fibrogenic factor that has been implicated in
the pathogenesis of silicosis.103–105
Toxic damage to macrophages is due to silica particles injuring the
phagolysosomal membranes, so releasing acid hydrolases into the
cytoplasm.95 It is important in the pathogenesis of the disease in­­
directly because when the macrophage crumbles, the silica particles
A are taken up by fresh macrophages and the fibrogenic process contin-
ues. It has been suggested that early involvement of the hilar lymph
nodes in the fibrogenic process promotes the development of the
disease in the lung by delaying dust clearance.74

Immunological aspects of silicosis

Immunological factors have been implicated in the pathogenesis of
silicosis because many patients with silicosis have polyclonal hyper-
gammaglobulinaemia, rheumatoid factor or antinuclear antibodies,
and because there is a well-recognised association between auto­
immune diseases such as systemic sclerosis and rheumatoid disease
and exposure to silica.43,106–109 The relation of immunity to dust expo-
sure appears to be a reciprocal one: on the one hand, the presence of
dust results in rheumatoid lesions in the lungs being more florid (see
Caplan’s syndrome, p. 341), whilst on the other, non-specific immun­
isation of rabbits with horse serum results in experimental silicotic
lesions being larger and more collagenous.110 It is doubtful whether
pneumoconiosis and autoimmune disease play a causative role in
each other but one seems to aggravate the other and may lead to its
earlier development.

B
Tuberculosis complicating silicosis (silicotuberculosis)
Figure 7.1.10  Silicosis. (A) The nodules are larger than in Figure 7.1.9a One of the commonest and most feared complications of silicosis is
and have fused together. Cavitating conglomerate silicosis destroys most chronic respiratory tuberculosis.109 Once this infection has been added
of the upper lobe. Paper-mounted whole-lung section. (B) Microscopy of to the silicosis, the prognosis rapidly worsens. It is thought that in the
conglomerate silicosis.
presence of silica, the tubercle bacilli proliferate more rapidly because
the ingested silica particles damage phagolysosomal membranes and
thereby interfere with the defensive activity of the macrophages. The
synergistic action of silica dust has long been held responsible for the
inordinately high incidence of respiratory tuberculosis in mining

335
 Pathology of the Lungs

communities. Many former South African gold miners now have

acquired immunodeficiency syndrome (AIDS) as well as silicosis and
tuberculosis has consequently reached almost epidemic proportions
amongst these men. Phagocyte damage by ingested dust particles may
also cause some cases of chronic necrotising aspergillosis complicat-
ing pneumoconiosis.111

Silica-induced lung cancer

A series of studies suggesting that there might be a link between silica
inhalation and lung cancer was reviewed by the International Agency A
for Research on Cancer in 1987, leading to the conclusion that
the evidence for carcinogenicity of crystalline silica in experimental
animals was sufficient, while in humans it was limited.112 Subsequent
epidemiological publications were reviewed in 1996, when it was
Si
concluded that the epidemiological evidence linking exposure to silica
to the risk of lung cancer had become somewhat stronger113 but that
in the absence of lung fibrosis remained scanty.113 The pathological
evidence in humans is also weak in that premalignant changes around
silicotic nodules are seldom evident.114 Nevertheless, on this rather
insubstantial evidence, lung cancer in the presence of silicosis (but
not coal or mixed-dust pneumoconiosis) has been accepted as a pre- Ti
scribed industrial disease in the UK since 1992.115 Some subsequent
studies have provided support for this decision.116 In contrast to the
sparse data on classic silicosis, the evidence linking carcinoma of the
lung to the rare diffuse pattern of fibrosis attributed to silica and
mixed dusts is much stronger and appears incontrovertible.33,92

Alveolar lipoproteinosis in response

to heavy dust exposure
A further complication of exposure to silica is the development of B 2 4 6 8 keV
alveolar lipoproteinosis (see p. 317).71,72,117,118 Very heavy experimental
exposure to silica, and indeed other dusts, stimulates hypersecretion Figure 7.1.11  Diatomaceous earth. (A) Scanning electron micrograph
of alveolar surfactant to such an extent that the normal clearance showing the calcified diatoms, ×15 000. (B) Electron microprobe analysis
shows only silicon (Si); the oxygen with which silicon is combined in silica
mechanism is overwhelmed.119–125 Alveolar macrophages are enlarged
(silicon dioxide, SiO2) is of too low an atomic number to register. The
by numerous phagolysosomes distended by lamellar bodies that titanium (Ti) peak derives from the sample holder. (Courtesy of Dr D
represent ingested surfactant. The alveoli are filled by such cells and, Dinsdale, Leicester, UK and Professor B Nemery, Leuven, Belgium.)
having a foamy cytoplasm, they produce the appearances of endog-
enous lipid pneumonia, similar to that more usually encountered as
part of an obstructive pneumonitis distal to a bronchial tumour.
The macrophages gradually disintegrate and the free denatured sur- Amorphous silica
factant slowly becomes compacted, during which time its staining
with both eosin and the periodic acid–Schiff reagents intensifies until Manmade submicron forms of silica, variously known as amorphous,
the appearances are finally those of alveolar lipoproteinosis. This vitreous, colloidal, synthetic or precipitated silica, are widely used in
process prevents the aggregation and concentration of the dust in industry. They consist of pure non-crystalline silicon dioxide. Particle
the usual foci and thereby hinders the development of silicosis. size ranges from 5 to 200 nm but aggregates of the particles measure
Lipoproteinosis and silicosis may be seen in conjunction but, more from 1 to 10 µm. Industrial surveys suggest that inhalation of such
often, different areas of the lung show one or the other. The lipo­ dust is harmless, observations that are in accord with the results of
proteinosis has its own severe impact on lung function, but, unlike animal experiments.54
silicosis, is potentially reversible (by massive alveolar lavage).
Diatomaceous earth (keiselguhr)
An amorphous silica is the principal component of the fossilised
Silica-induced renal disease remains of diatoms that constitute the sedimentary rock, diatomite
Occasional patients exposed to silica develop renal disease.126–129 (Fig. 7.1.11). This is generally obtained by open-cast mining, follow-
Two mechanisms appear to operate. First, translocation of silica ing which the rock is crushed and calcined. The calcined product is
particles from the lungs leads to their deposition in the renal inter­ used in filters, insulation material and as a filler. Being amorphous,
stitium with resultant nephrotoxity. Second, silica stimulates an the silica in diatomite is harmless, but calcining (>1000°C) results in
autoimmune response characterised by the formation of various its conversion to crystalline forms of silica. Diatomaceous earth
antibodies, notably rheumatoid factor and antinuclear antibodies, pneumoconiosis is unusual and its risk appears to be related to the
which leads to the development of immune complex-mediated amount of cristobalite and tridymite (two forms of crystalline silica)
glomerulonephritis.128,129 produced in the calcining process.130

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constituent of coal, which is dealt with separately below, and large

SILICATES43 amounts of pure carbon may be inhaled by workers involved in the
manufacture of carbon black, carbon electrodes and charcoal.141–144
The silicates are complex compounds in which silicon and oxygen Although carbon is regarded as being non-fibrogenic, the very heavy
form an anion combined with cations such as aluminium and mag- lung burdens encountered in industries such as these may lead to the
nesium: talc, for example, is a hydrated magnesium silicate with the complicated form of pneumonconiosis known as progressive massive
formula Mg3Si4O10(OH)2. Silicates include fibrous forms (asbestos fibrosis that is more commonly encountered in coal workers (see
and the zeolites), plate-like forms (talc and mica) and clays (kaolinite p. 340). Heavy pure carbon deposition may also be acquired domesti-
and fuller’s earth). In histological sections, the platy talc and mica cally when wood is burnt in buildings devoid of a chimney, so-called
particles are generally cut tangentially and therefore appear needle- ‘hut lung’,145 a term that is also applied to the domestic acquisition
shaped (see Fig. 7.1.4). They are strongly birefringent whereas the of carbon mixed with silica or silicates, resulting in forms of mixed-
clays are only weakly so. Talc particles in the lung exceeding 5 µm in dust pneumoconiosis.57,64,65
length should arouse suspicion of intravenous drug abuse.131 Anthracofibrosis is a term introduced by Chinese bronchoscopists
Of the fibrous silicates, zeolite is used as a building material in for bronchial stenosis or obliteration associated with carbon pig­
certain communities, notably in central Turkey. Pneumoconiosis is mentation of the mucosa.146 Although the original description in­­
not a problem but zeolites are of medical interest because, like criminated tuberculosis, mixtures of various mineral dusts acquired at
asbestos, they present a mesothelioma risk. Asbestos is dealt with work or domestically are a more likely cause.147–150
separately (see below). Iron dust in the lungs was first described by Zenker in 1867, when
Pneumoconiosis has been described with various non-fibrous sili- he also introduced the terms siderosis and pneumonokoniosis.3
cates, notably in the rubber industry, which uses talc and, less com- Zenker was describing a woman who coloured paper with iron oxide
monly, mica as lubricants. Other occupations posing a risk include powder (‘rouge’), a substance which is still encountered by some
the extraction of kaolinite from china clay (kaolin),27,132,133 and in the workers engaged in polishing silver, glass, stone and cutlery. Siderosis
open-cast and underground mining of fuller’s earth (montmorillo­ is also found in welders, iron foundry fettlers, steel workers, boiler
nite, bentonite and attapulgite clays, which were originally used in scalers and haematite miners and crushers. Iron dust particles are
‘fulling’ (degreasing) wool).134,135 However, all these substances are reddish-brown but in the lung may be masked by carbon151: when
commonly contaminated with silica, asbestos or both, and it has been evident, or revealed by microincineration, they resemble haemo­
questioned whether in pure state they are at all fibrogenic. The siderin and generally give a positive Perls’ reaction, but particularly
modifying effect of inert substances such as iron on that of silica is with haematite, heat (60–80oC) and concentrated (12N) hydrochloric
well known (see mixed-dust pneumoconiosis, below) and it has been acid may be necessary.152
suggested that talc, mica and fuller’s earth act in a similar way in Haematite miners in both the UK (Cumbria) and France (Lorraine)
regard to their more fibrogenic contaminants, the pneumoconioses have an increased risk of bronchial carcinoma, but radon gas rather
attributed to them in reality representing mixed-dust pneumoconiosis than haematite is the suspected carcinogen. Radon is a decay product
or asbestosis. Contrary evidence comes from reports of pulmonary of uranium. Minute amounts are present in all rocks but local
fibrosis in persons heavily exposed to pure talc, mica or kaolin.32 concentrations occur and these are liable to build up in mines if
All these silicates are evident in the tissues as plate-like birefringent ventilation is limited.
crystals which often provoke a foreign-body giant cell reaction (see Silver, as well as iron, is found in the lungs of silver polishers, where
Fig. 7.1.3) and may result in fibrotic nodules. Large focal lesions it stains elastin in alveolar walls and pulmonary vessels grey. Such
resembling the progressive massive fibrosis of coalworkers may be argyrosiderosis is as harmless as siderosis.
produced, and also a diffuse ‘asbestosis-like’ form of pneumoconiosis, Tin miners are subject to silicosis but not stannosis because the
the latter attributed to poor macrophage mobilisation of the plate-like ore, which is found in association with siliceous rocks, contains
particles.27–32,132–138 It would appear therefore that silicates are indeed only low concentrations of the metal. Tin smelters, on the other hand,
fibrogenic if enough is inhaled; they appear to vary in fibrogenicity and factory workers exposed to high concentrations of tin dust or
but in all cases they are less fibrogenic than silica. fume, are liable to inhale large amounts of this inert metal and
develop the striking chest radiograph of stannosis. They remain in
good health however for tin is completely non-fibrogenic. Tin
particles in the lung resemble carbon but are strongly birefringent and
INERT DUSTS remain after microincineration: microprobe analysis provides positive
identification.
Inert dusts are non-fibrogenic and therefore of little clinical con­ Other inert dusts include barium, which also has a high atomic
sequence, although elements of high atomic number can give rise to number and is therefore radiopaque,139 and minerals of low radio­
a striking chest radiograph.139 It should be noted however that inert density such as limestone, marble and cement (all chiefly composed
or lowly fibrogenic materials may be associated with substances of calcium carbonate) and gypsum (hydrated calcium sulphate).
of medical importance, for example, kaolin, bentonite and barytes However, the extraction of barium ore (almost entirely in the form of
(barite) may all be contaminated with silica27,134,140 and talc may be barium sulphate, which is known as barytes in Europe and barite in
contaminated with asbestos. the USA) may entail exposure to silica and silicates. Pure baritosis
The best known of the inhaled inert mineral dusts is carbon while, resembles stannosis and siderosis.
of the remainder, iron is the most widespread. Others include tin and
barium. With all these dusts, particles retained in the lung are gathered
at Macklin’s dust sumps by heavily laden macrophages which are MIXED-DUST PNEUMOCONIOSIS
lightly bound together there by a few reticulin fibres. Collagen is not
formed and the worker suffers no ill-effects. The lungs take on the The term ‘mixed-dust pneumoconiosis’ refers to the changes brought
colour of the dust and in siderosis assume a deep brick-red hue. about by inhaling a mixture of silica and some other less fibrogenic
Carbon deposition is commonly found in the lungs, particularly substance such as iron, carbon, kaolin or mica.33,151,153–155 The pro­
those of city dwellers and tobacco smokers. It is also the principal portion of silica is usually less than 10%. Typical occupations include

337
 Pathology of the Lungs

foundry work and welding and the mining of coal, haematite, slate, coalminers’ lungs, ranging from coal pneumoconiosis through mixed-
shale and china clay. dust pneumoconiosis to silicosis; the findings in any individual
The action of the silica is modified and, although fibrotic nodules depend upon the nature of the coal being mined and the type of work
are formed, they lack the well-demarcated outline and concentric undertaken.
pattern of classic silicosis. The lesions are found in a centriacinar In high-rank British collieries the development of coal pneumo­
position and are stellate in outline with adjacent scar emphysema. coniosis appears to depend on the total mass of dust inhaled, whereas
They are firm and generally measure no more than 5 mm in diameter. in low-rank British collieries the mineral content of the lung dust
They closely resemble the fibrotic nodules of simple coal pneumo­ appears to be more important.159 This may explain apparently con-
coniosis (see below). Confluent lesions also occur on occasions. These trary data drawn from different coalfields – data based on coals of
resemble the progressive massive fibrosis of coalworkers and appear different composition that are not strictly comparable. Some workers
to represent a single large lesion rather than a conglomeration of have stressed the importance of silica in the dust whereas others,
individual nodules, as in advanced silicosis. Abundant dust is gener- particularly in the high-rank coalfields of south Wales, have been
ally evident in lesions of all sizes; this consists of black carbon or unable to detect any association between silica and the level of
brown iron mixed with crystals of varying degrees of birefringence, pneumoconiosis. Both findings may be correct, but only for the
silicates generally being strongly birefringent and silica weakly so. particular group of miners examined in each case.160
Calcification is unusual. Mixed-dust pneumoconiosis carries an
increased risk of pulmonary tuberculosis, but not to the same degree
Pathology
as silicosis. In some cases the stellate nodules are accompanied by
diffuse fibrosis, as in silicosis and again possibly involving inter­ The lesions of coal pneumoconiosis are generally focal and fall into
actions between the dust and immunological factors. Involvement of one or other of two major types, simple and complicated, depending
the bronchi with consequent stenosis (so-called anthracofibrosis) is upon whether the lesions measure up to or over 1 cm; simple corre-
described above. sponds to categories 1–3 of the ILO grading system (see p. 331) and
complicated, which is also known as progressive massive fibrosis, to
ILO categories A–C. More diffuse interstitial fibrosis has been reported
in about 16% of Welsh and West Virginian coalminers, usually in­­
COAL PNEUMOCONIOSIS156 volving those carrying a particularly heavy dust burden; it runs a more
benign course than non-occupational interstitial fibrosis (idiopathic
The term ‘anthracosis’ was initially applied to changes observed in a pulmonary fibrosis).161 Similar findings have been reported from
coalminer’s lung157 but is now often extended to include the common France.162
carbon pigmentation of city dwellers’ lungs, and the term ‘coal pneu- Simple coal pneumoconiosis consists of focal dust pigmentation of
moconiosis’ is more appropriate to a special form of pneumoconiosis the lungs, which may be associated with a little fibrosis and varying
to which coalworkers are subject, particularly those who work under- degrees of emphysema. Its clinical effects are relatively minor. Some
ground. The principal constituent of coal, carbon, is non-fibrogenic, degree of black pigmentation (anthracosis) of the lungs is common
so suspicion has naturally fallen on the ash content of mine dust, in the general urban population, especially in industrial areas, but
some of which derives from the coal, some from adjacent rock strata much denser pigmentation is seen in coalminers, whose lungs at
and some from stone dust laid in the roadways to minimise the risk necropsy are black or slate-grey. Black pigment is evident in the
of coal dust explosions. Coal itself appears to be the responsible agent visceral pleura along the lines of the lymphatics and on the cut surface
because coal-trimmers, working in the docks and not exposed to rock where it outlines the interlobular septa and is concentrated in
dust, also develop the disease.158 Coalminers encountering siliceous Macklin’s centriacinar dust sumps (Fig. 7.1.12). The dust is generally
rock are, of course, also liable to develop silicosis like other under- more plentiful in the upper parts of the lungs and in the hilar lymph
ground workers. nodes, possibly due to poorer perfusion and consequently poorer
lymphatic drainage there (see p. 21).162
Two forms of coal dust foci are recognised, macules and nodules,
Mineralogy the former being soft and impalpable and the latter hard due to sub-
Coal consists largely of elemental carbon, oxygen and hydrogen with stantial amounts of collagen. Both lesions are typically stellate but the
traces of iron ore and clays such kaolinite, muscovite and illite, but more fibrotic the nodules, the more rounded they become, until it is
no silica. The mineral content varies with the type and rank (calorific difficult to distinguish them macroscopically from those of silicosis.
value) of the coal. All coal derives from peat, the youngest type being In these circumstances reliance has to be placed on the whorled
lignite and the oldest anthracite, with bituminous (house) coal in pattern of the collagen that is evident microscopically in silicosis. The
between. As it ages, the oxygen and mineral constituents diminish and stellate nodules are analogous to those seen in mixed-dust pneumo-
the coal hardens. Lignite is soft and said to be of low rank, anthracite coniosis caused by mixtures of silica and inert dusts other than carbon
hard and of high rank, with bituminous coal intermediate. (see above). With polarising filters, small numbers of birefringent
Although high-rank coal is of low mineral content, its dust is more crystals may be seen in both macules and nodules, usually represent-
toxic to macrophages in vitro and is cleared more slowly in vivo. This ing mica or kaolinite derived from rock that bordered the coal.
observation may explain why, in the UK, high-rank coal is associated Macules consist of closely packed dust particles, free or within
with a higher prevalence of coal pneumoconiosis. heavily laden macrophages, so that the lesion appears black through-
The low mineral content of high-rank coal is reflected in the mineral out (Fig. 7.1.13). Appropriate stains show that the dust-laden macro-
content of the lungs of those who hew such coal in the UK, but in the phages and free dust are lightly bound by reticulin. Very little collagen
Ruhr, in Germany, and in Pennsylvania, in the USA, anthracite miners’ is evident. Although striking in their appearance, dust macules are
lungs contain more silica than those who hew bituminous coal, the thought to have little effect on lung function.
silica presumably deriving from other sources. Not surprisingly, the Nodules contain substantial amounts of collagen and are thought
presence of silica is reflected in the tissue reaction to the inhaled dust, to have an adverse, but limited, effect on respiration. They vary from
resulting in a more fibrotic reaction very analogous to mixed-dust a heavily pigmented, stellate lesion, which apart from its collagen
pneumoconiosis. A spectrum of changes is therefore encountered in content resembles the dust macule (Fig. 7.1.14), to one that is less

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

Figure 7.1.12  A coalminer’s lung showing heavy dust deposition in the

centres of the acini (Macklin’s dust sumps). On palpation the dust
deposits felt soft and were consequently described as macules rather
than nodules. Despite the heavy dust deposition, there is minimal
pneumoconiosis. Part of a paper-mounted whole-lung section.

pigmented and more circumscribed. The stellate, heavily pigmented

type of nodule is seen in lungs that have a relatively low ash content Figure 7.1.13  Coal macule. A centriacinar dust deposit of stellate outline
whilst the more rounded and less pigmented nodule is seen in lungs consisting of macrophages heavily laden with coal dust and bound
with relatively high ash loads.163 together by only a little reticulin. Collagen is not a feature.
Radiologically (see p. 321), p-type opacities correspond to macules,
q-type opacities to the stellate nodules that resemble those of mixed-
dust pneumoconiosis and r-type opacities to the rounded nodules that
resemble those of silicosis.53,164 Thus, the radiological changes of
simple coalworker’s pneumoconiosis are due to the dust and the small
amount of collagen present and do not reflect any emphysema that
may also be present. However, pulmonary dust foci are often associ-
ated with emphysema (Fig. 7.1.15) and the severity of the emphysema
appears to correlate with the dust load. The prevalence of chronic
bronchitis and emphysema is high in the coal industry and it has long
been debated whether occupation or cigarette smoking is the major
factor contributing to emphysema in coalminers.165–168 As well
as mineral dust, nitrous fumes from shot-firing form another
occupational hazard of coal mining.
Heppleston made a special study of the emphysema found in coal-
miners, claiming that it differs from centriacinar emphysema, as seen
in smokers in the general population, and attributing it to the dust.169
He introduced the term ‘focal emphysema of coalworkers’ to describe
this special process. Others find it very difficult to identify any con-
vincing difference between the emphysema of coalworkers and that
encountered outside the industry but Heppleston based his claims on
the study of serial sections. By this means he showed that, although
both forms affect respiratory bronchioles, the focal emphysema of
coalworkers affects more proximal orders of these airways and is Figure 7.1.14  Coal nodule. A centriacinar dust nodule of stellate outline
not associated with the bronchiolitis seen with centriacinar emphy- in which coal dust-laden macrophages are mixed with moderate amounts
sema. Furthermore, focal emphysema is a dilatation lesion whereas of collagen.

339
 Pathology of the Lungs

Figure 7.1.15  Coalworker’s pneumoconiosis – simple type, consisting of

coal macules and nodules associated with focal emphysema. Paper- Figure 7.1.16  Coal pneumoconiosis – complicated type. In addition to
mounted whole-lung section. the focal dust deposits there is a large area of progressive massive
fibrosis in the upper lobe. Paper-mounted whole-lung section.

centriacinar emphysema involves destruction of adjacent alveolar

coniosis, also known as progressive massive fibrosis, can have very
walls. By definition, therefore, focal emphysema is not a true emphy-
serious consequences. Particularly when the lesions are large, it is
sema at all (see p. 102). However, it has been shown that mineral dusts
associated with productive cough, breathlessness, significant impair-
cause elastin and collagen breakdown in the rat lung.170 Focal emphy-
ment of lung function and premature death. The major factor account-
sema may progress to the destructive centriacinar form and this has
ing for the development of progressive massive fibrosis appears to be
strengthened claims that mine dust plays a causal role in centriacinar
the sheer bulk of coal dust in the lung, rather than coal rank or the
emphysema.1,171–176 In the UK, these claims have been accepted and
silica content of the mine dust.179 Progressive massive fibrosis has
chronic bronchitis and emphysema in coalminers and metal pro­
occasionally been recorded in dockers loading silica-free coal into the
duction workers have been accepted as prescribed industrial diseases
holds of ships158 and in workers exposed to pure carbon in the
since 1992.177 In Germany too, chronic obstructive pulmonary disease
manufacture of carbon black and carbon electrodes.141–143
is now compensatable as an occupational disease. The conditions
Progressive massive fibrosis is characterised by large (over 1 cm)
for compensation in the UK were initially:
black masses, situated anywhere in the lungs but most common in
• underground coal mining for a minimum of 20 years in the upper lobes. The lesions may be solitary or multiple and very large,
aggregate occupying most of the lobe and even crossing an interlobar fissure to
• forced expiratory volume in 1 second at least 1 litre below that involve an adjacent lobe (Figs 7.1.3B, 7.1.16). They cut fairly easily,
expected or less than 1 litre in total often with the release from a central cavity of black fluid flecked by
• radiological category of at least 1/1. cholesterol crystals. For many years it was believed that the condition
However the last of these criteria has now been dropped. The was the result of synergism between mycobacterial infection and dust
inclusion of a time element and the omission of some estimate of but the failure of the attack rate to decrease as tuberculosis declined
dust load (such as radiological category) have been criticised, with negated this view.180 Today, more emphasis is placed on total dust load
some justification.178 As with lung cancer caused by chromates benefit for the lesions tend to affect lungs that carry an unduly heavy dust
is paid irrespective of smoking habits. burden. If the remainder of the lung shows little evidence of dust
Whereas simple coal pneumoconiosis, particularly the macular accumulation, the possibility of the masses representing Caplan-
variety, has little effect on lung function, complicated coal pneumo- type lesions (see below) should be considered.

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

Microscopically, the lesions consist of dust and connective tissue

intermixed in a random fashion. Central necrosis and cavitation com-
monly occur. The necrosis is thought to be ischaemic.181 It is amor-
phous or finely granular, and eosinophilic apart from abundant dust
particles and cholesterol crystal clefts. The fibrotic component in a
complicated pneumoconiotic lesion is rich in fibronectin, with col-
lagen only more abundant at the periphery.182 Two types of progres-
sive massive fibrosis are recognisable, corresponding to the two types
of nodule described in simple coal pneumoconiosis.163 The first
appears to have arisen by enlargement of a single nodule, whereas the
second is a conglomeration of individual lesions, each of which cor-
responds to the more circumscribed type of nodule seen in simple
coal pneumoconiosis. The ash content of the lungs bearing these two
types of progressive massive fibrosis varies in the same way as with
the two types of simple pneumoconiotic nodules, the enlarged single
lesion being found in lungs with a relatively low ash content, and the
conglomerate lesion in lungs with a relatively high ash content. The
second type resembles the conglomerate nodules of large silicotic
lesions but lacks the characteristic whorled pattern of the latter.
The diffuse interstitial fibrosis found in a minority of coalworkers Figure 7.1.17  Caplan lesions in a coalminer’s lung, which
characteristically shows only light dust deposition. (Courtesy of Dr R Seal,
is associated with heavy dust deposition. It may progress to honey-
formerly of Penarth, UK.)
combing but, as with the focal forms and unlike idiopathic interstitial
fibrosis, it is better developed in the upper zones, the reasons for
which are discussed above (see the zonal distribution of pneumoco-
niosis, p. 329).

Pathogenesis
The pathogenesis of coal pneumoconiosis has much in common with
that of silicosis, and indeed many other pneumoconioses. It involves
the promotion of fibrogenic factor synthesis and release by cells
phagocytosing the inhaled dust. Several such factors have now been
identified, the degree of fibrosis produced varying with the amount
of dust inhaled and the ability of its constituents to promote the
production of the responsible cytokines. These include platelet-
derived growth factor, insulin-like growth factors 1 and 6, transform-
ing growth factor-β and tumour necrosis factor-α.101,183,184 As with
other minerals, the indestructability of the dust perpetuates the
process.
As in silicosis, immunological factors appear to be involved,
for there is an increased prevalence of rheumatoid arthritis185 and
Figure 7.1.18  A Caplan lesion, characterised by successive bands of dust
of circulating autoantibodies186–188 in miners with coal pneumo­
within the centre of a large necrobiotic nodule.
coniosis. Rheumatoid factor has also been demonstrated within the
lung lesions.189 These abnormalities are generally more pronounced
in miners with complicated pneumoconiosis but are also found in
those with the simple variety. It is also possibly pertinent to the Pathologists recognise the lesions as particularly large necrobiotic
immunological basis of coal pneumoconiosis that some of the pul- nodules similar to those seen in rheumatoid patients who are not
monary manifestations of rheumatoid disease are more pronounced exposed to dust (Fig. 7.1.17). However, because of their large size (up
in coalminers. This was first pointed out by Caplan and will be con- to 5 cm diameter) they may be confused with progressive massive
sidered next. fibrosis undergoing central ischaemic necrosis (see above) or silicosis
complicated by caseating tuberculosis. Such errors will be less likely
if the radiological evolution of the lesions is considered for they tend
Pneumoconiosis and rheumatoid disease to cavitate and undergo rapid remission, only to be succeeded by
others. They are also well demarcated radiologically. Pathologically,
(Caplan’s syndrome)
they resemble rheumatoid nodules in showing peripheral palisading
Caplan described distinctive radiographic opacities in the lungs of but differ in their large size and the presence of dust.191 The dust
coalminers with rheumatoid disease,190 and it is now recognised that accumulates in circumferential bands or arcs within the necrotic
similar lesions may develop in rheumatoid patients exposed to sili- centres of the lesion (Fig. 7.1.18), an arrangement that suggests
ceous dusts. The development of such rheumatoid pneumoconiosis periodic episodes of inflammatory activity. Caplan lesions differ from
does not correlate with the extrapulmonary or serological activity of tuberculosis in lacking satellite lesions and tubercle bacilli, and from
the rheumatoid process. Nor is there a strong relation to dust burden: progressive massive fibrosis in showing characteristic bands of dust
Caplan lesions are characteristically seen in chest radiographs that pigmentation (Table 7.1.2) and only light dust deposition in the
show little evidence of simple coal pneumoconiosis. surrounding lung.

341
 Pathology of the Lungs

Table 7.1.2  Histological features of Caplan lesions,

silicotuberculosis and progressive massive fibrosis

Caplan Silicotuberculosis Progressive

lesions massive fibrosis

Palisading + – –
Dust banding + – –
Satellite – + –
tubercles
Necrosis + + +
Cholesterol + ± +
crystals
Calcification + + ±

+ present; ± poorly represented; – absent.

Table 7.1.3  Asbestos production by country, 2000194

Country Tons

Russia 752 000
China 350 000
Canada 320 000
Figure 7.1.19  A sample of Quebec chrysotile showing the fibrous nature
Brazil 209 000 of the ore.
Kazakhstan 179 000
Zimbabwe 152 000
They readily fragment into short particles that are easily ingested by
Others 88 000 macrophages and in the acidic environment of the macrophage
phagolysosome they are particularly unstable. The half-life of
chrysotile in the lungs is estimated to be in the order of only a few
months.195,196 Not surprisingly therefore chrysotile is the least harmful
ASBESTOSIS type of asbestos in respect of all forms of asbestos-induced pleuro­
pulmonary disease.197–199 It may nevertheless cause pulmonary fibrosis
Asbestosis is defined as diffuse interstitial fibrosis of the lung caused if sufficient is inhaled.200,201
by exposure to asbestos dust.192,193 It does not cover asbestos-induced In contrast to chrysotile, amphibole forms of asbestos consist of
carcinoma of the lung or asbestos-induced pleural disease. The de­­ straight rigid fibres that are stable within the lung. They do not frag-
velopment of asbestosis depends on the presence of fairly large dust ment, they are insensitive to chemical attack and their clearance half-
burdens: this is in contrast to mesothelioma and other forms of lives are in the order of decades rather than months.196 The main
asbestos-induced pleural disease, which, although also dose-related, amphibole forms of asbestos of commercial importance are crocido-
occur following the inhalation of far smaller amounts of asbestos dust. lite (blue asbestos) and amosite (brown asbestos). Crocidolite, reput-
edly the most dangerous in regard to all forms of asbestos-related
disease, was formerly mined in Western Australia (Wittenoom) and
Asbestos types and production South Africa (Cape Province and the Transvaal); it was the principal
Asbestos is a generic term for more than 30 naturally occurring fibrous amphibole used in the UK. Amosite, the name of which derives from
silicates, fibre being defined as an elongated particle with a length-to- the acronym for the former Asbestos Mines of South Africa company
breadth (aspect) ratio of at least 3. Asbestos fibres have a high aspect in the Transvaal, was the principal amphibole used in North America.
ratio, generally over 8. Based on their physical configuration they can Amphiboles are no longer imported by the developed countries but
be divided into two major groups, serpentine and amphibole. The much remains in old lagging and presents a considerable dust hazard
physical dimensions and configuration of asbestos fibres are strongly when this is removed. Tremolite, a further amphibole asbestos, con-
linked to their pathogenicity. taminates Quebec chrysotile deposits, Montana vermiculite and many
Chrysotile (white asbestos) is the only important serpentine form. forms of commercial (non-cosmetic) talc and is responsible for much
It accounts for most of the world production of asbestos of all types of the asbestos-related disease in chrysotile miners and millers.202
(Table 7.1.3).194 Being a serpentine mineral, chrysotile consists of Another amphibole asbestos, anthophyllite, was formerly mined in
long, curly fibres that can be carded, spun and woven like cotton (Fig. Finland. It causes pleural plaques (see p. 716) but not lung disease,
7.1.19). The curly chrysotile fibres are carried into the lungs less possibly because its fibres are relatively thick (Fig. 7.1.20).203
readily than the straight amphibole asbestos fibres, and once there Erionite is a zeolite rather than a type of asbestos but is comparable
undergo physicochemical dissolution and are cleared more readily. in form to amphibole asbestos and is also biopersistent. It is found

342
 Occupational, environmental and iatrogenic lung disease Chapter |7|

A B

C D

Figure 7.1.20  Electron micrographs of dispersed samples of asbestos. (A) Chrysotile; (B) crocidolite; (C) amosite; (D) anthophyllite, all ×2800, the bar
representing 10 µm. (Reproduced from Wagner et al. (1980)203 by permission of Professor FD Pooley and the British Medical Bulletin.)

343
 Pathology of the Lungs

dumb-bell appearance. In time, a distinctive segmentation of this

Table 7.1.4  Asbestos consumption by country, 2000194
outer layer develops (Fig. 7.1.21). These coated structures are termed
‘asbestos bodies’. Because other fibres may gain a similar coat, the
Country Tons kg/capita/year
non-specific term ‘ferruginous body’ has been advocated. However,
Russia 447 000 3.4 coated carbon fibres (so-called coal bodies) are easily recognised as
such by their black core.206 In practice, ferruginous bodies with the
China 410 000 0.4 appearance of asbestos bodies almost always prove to have an asbestos
Brazil 182 000 1.3 core.207,208 Long fibres are more likely to be coated than short ones,
which are cleared more quickly: in one study few fibres less than 5 µm
India 125 000 0.2 in length were coated and few fibres over 40 µm in length were
Thailand 121 000 3.0 uncoated.209 Amphiboles form bodies more readily than chrysotile. A
comparison of light and electron microscopic fibre counts found that
Japan 99 000 1.5 0.14% of chrysotile, 5% of crocidolite and 26.5% of amosite formed
Indonesia 55 000 0.3 bodies.210 Nevertheless, sufficient chrysotile fibres are coated to permit
recognition of asbestosis by standard histological criteria (diffuse
South Korea 29 000 1.9 fibrosis and asbestos bodies), even if chrysotile is the only asbestos
Mexico 27 000 0.4 present.211 Despite the biodegradability of chrysotile, asbestos body
numbers do not materially diminish with time.212 Very occasionally
Others 178 000 however a patient with diffuse pulmonary fibrosis and a history of
asbestos exposure has no evident asbestos bodies but analysis shows
a fibre burden within the range found in asbestosis, justifying fibre
analysis in such cases.212a
in parts of central Turkey where it causes both mesothelioma and a There is evidence that alveolar macrophages are involved in the
pattern of interstitial pulmonary fibrosis that is comparable to coating of asbestos fibres to form asbestos bodies and that the bodies
asbestosis.204,205 are less harmful to the macrophages than uncoated fibres.213 Asbestos
bodies give a Prussian blue reaction for iron when stained by Perls’
Asbestos use and exposure method and their yellow-brown colour makes them easily recog­
nisable in unstained films of sputum or in unstained histological
Exposure to asbestos occurs in countries where it is extracted (Table
sections. Sections may be cut 30 µm thick to increase the yield and
7.1.3), which is mostly by the open-cast method, and in those coun-
help identify bodies that lie at an angle to the microtome blade. There
tries that continue to use this mineral (Table 7.1.4). The developed
is a good correlation between the numbers of asbestos bodies seen in
nations have largely ceased to use asbestos but countries keen to
lung sections and those in tissue digests.214,215 The bodies may be
develop their industrial base and less concerned with health issues
found singly or in irregular clumps or stellate clusters. They are un­­
continue to use considerable amounts in a vast range of trades.
evenly distributed but in well-established asbestosis they are easily
Asbestos is used particularly for fireproofing, in heat and sound in­­
found. If they are not evident, asbestos burden may be assessed
sulation and for strengthening plastics and cement. Thus, unless
quantitatively in tissue digests (see below). Their presence in lung
adequate precautions are taken, exposure is experienced by dockers
tissue, sputum or bronchoalveolar lavage fluid merely confirms expo-
unloading asbestos in the close confines of a ship’s hold, by thermal
sure, not the presence of disease. However, the number of asbestos
insulation workers (laggers and strippers) in shipyards, power
bodies in lavage fluid correlates well with lung asbestos burden216,217
stations, train maintenance depots, factories and other large buildings,
and the number in sputum correlates with the duration and intensity
by construction workers such as carpenters cutting asbestos building
of exposure.216–218
panels, and by workers making asbestos products such as fireproof
textiles, brake and clutch linings, and specialised cement.
As well as such direct exposure, exposure may also be: Fibre counts193,208,219–223
• indirect, as experienced by the families of asbestos workers Quantitation is desirable in certain circumstances (Box 7.1.1), in
• paraoccupational, as experienced by those working alongside an which case it is best effected on 2-cm3 blocks of fixed or fresh lung
asbestos worker tissue obtained from three different sites, avoiding tumour and thick-
• neighbourhood, as experienced by those living downwind of an ened pleura. The tissue blocks are digested with caustic soda or bleach,
asbestos works or mine following which the fibres may be collected on a millipore membrane
• ambient, as experienced by those living or working in a building or viewed in suspension in a red blood cell-counting chamber. If
containing asbestos. phase contrast optics are used both coated and uncoated fibres can be
Exposure to asbestos incorporated in the structure of a building carries assessed.219 Alternatively, dark ground illumination can be used to
a negligible health risk if the asbestos material is well maintained to demonstrate uncoated fibres.221 However, electron microscopy is to be
prevent shedding of dust. Stripping asbestos out is more dangerous preferred as it detects far more fibres than are visible by light micros-
than maintaining it in situ, but maintenance is sometimes neglected. copy and can also provide information on fibre type. It is important
The near indestructibility of asbestos accentuates the health problems that the laboratory is well practised in fibre analysis and has estab-
that its ubiquity poses. lished its own control range for the general population as well as
asbestosis as most lungs contain some asbestos.
Ambient fibres are generally shorter than 5 µm and some workers
Asbestos bodies therefore confine their counts to fibres that are at least as long as
Because of their aerodynamic properties, fibres of 100 µm or more in this.224 Justification for this comes from animal experiments demon-
length may reach the finer bronchioles and alveoli. Once impacted, strating that long fibres cause more inflammation, chromosomal
the sharp asbestos fibres become coated with a film of protein that is damage, fibrosis, lung tumours and mesotheliomas than short
rich in iron. The coating is thickest at the ends of the fibres, giving a fibres,225–228 and from studies in humans suggesting that long fibres

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

Figure 7.1.21  Asbestos bodies seen by light microscopy in (A) an unstained 30-µm-thick paraffin section; (B) by scanning electron microscopy in the
digest of an asbestos worker’s lung and (C) by transmission electron microscopy in lung tissue. The asbestos fibres have acquired the iron-protein
coating that characterises an asbestos body. In most places the coating has become segmented, giving rise to bead-like formations, a change
accompanying ageing of the bodies. ((B) Courtesy of Dr B Fox, London, UK and (C) courtesy of Miss A Dewar, Brompton, UK.)

are responsible for asbestosis.229 Other human studies have shown

that, although asbestos load is maximal in the upper lobes, more long
fibres are found at the bases, where fibrosis is most marked.41,230 A
Box 7.1.1  Circumstances in which asbestos fibre counts further reason for limiting attention to the longer fibres is that the
are desirable shorter ones are cleared more easily and their number therefore varies
Quantitation desirable Quantitation unnecessary with the time lapsed since last exposure. For these reasons asbestos
regulations in many countries now limit attention to fibres that are
Mesothelioma if exposure is Mesothelioma if there is a
over 5 µm in length and have a length-to-diameter (aspect) ratio
disputed and asbestos bodies are history of exposure or
not evident asbestos bodies are evident greater than 3: such fibres have become known as regulatory or World
Pulmonary fibrosis (with or without If there is obvious asbestosis Health Organization (WHO) fibres.
carcinoma of the lung) in an Values are best expressed as fibres/g dry lung. By light microscopy,
asbestos worker but asbestos normal values range up to 50 000: over 20 000 is seen with meso­
bodies are not evident theliomas, and over 1 000 000 in asbestosis (Table 7.1.5).216,224,231,232
Carcinoma of the lung in an However, compared with electron microscopy, light microscopy is
asbestos worker if there is no relatively insensitive, showing only 26.5% of the amosite, 5% of the
fibrosis crocidolite and 0.14% of the chrysotile.210 Light microscopic counts
correlate poorly with severity of asbestosis219 and electron microscopy

345
 Pathology of the Lungs

Table 7.1.5  Lung asbestos fibre counts per gram of dried lung Box 7.1.2  Molecular formulae of various forms of
asbestos. When subjected to microprobe analysis, the
Light Electron total counts recorded for each element (see Fig. 7.1.6c)
microscopy microscopy are proportional to the numbers of their atoms in the
Normal city dwellers Up to 50 000 Up to 5 000 000 molecule. Thus, with tremolite the silicon peak would be
four times as high as that for calcium and a little less
Mesothelioma Over 20 000 Over 1 000 000 than twice as high as that for magnesium
Asbestosis (minimal) Over 100 000 Over 10 000 000 Chrysotile Mg3(Si2O5)(OH)4
Asbestosis (established) Over 1 000 000 Over 100 000 000 Crocidolite Na2Fe5(Si8O22)(OH)2
Amosite (Fe,Mg)7(Si8O22)(OH)2
The light microscopic counts include total fibres (coated and uncoated).   Tremolite Ca2Mg5(Si8O22)(OH)2
The electron microscopic counts include only amphibole asbestos. Results  
from different laboratories vary and these figures, derived from several
sources,216,231,232 provide only a general guide. Reliable results depend upon
counts being made regularly and the normal range from that laboratory being
ascertained. Ratios of counts obtained by electron and light microscopy vary
greatly but approximate to 100. Table 7.1.6  Mean percentage lung fibre type by diagnostic
category in a group of British asbestos factory workers
compared to local controls199

Fibre Controls Asbestosis Carcinoma Pleural

type of the mesothelioma
lung

Crocidolite 2.8 60.1 56.7 20.2

Amosite 2.6 17.7 30.4 39.3
Chrysotile 25.9 4.0 6.9 17.0
Other 68.7 18.2 6.0 23.5
(mainly
fly ash)

Non-asbestos fibres commonly found in the lung include mullite,

which derives from fly ash. This may constitute up to 70% of the total
fibre burden (see Table 7.1.6) and is thought to be harmless. There is
no firm evidence that manmade fibres present a health hazard237 but
in certain localities natural non-asbestos mineral fibres, zeolites for
example, are important causes of mesothelioma (see p. 718) and also
Figure 7.1.22  At high magnification chysotile fibres are seen to be
cause interstitial pulmonary fibrosis.204
tubular. Transmission electron micrograph ×51 000. (Courtesy of Miss A
Dewar, Brompton, UK.)
Clinical and radiological features
In contrast to the first half of the twentieth century, much of the
is better in this respect.197–199 By transmission electron microscopy, asbestosis encountered today is asymptomatic, identified radiologi-
values may range up to 5 000 000 in controls, with asbestosis gener- cally or histologically in lungs resected for carcinoma or removed at
ally above 100 000 000 and mesotheliomas found at any level down autopsy. Symptomatic cases are characterised by an insidious onset
to 1 000 000, all these figures representing amphibole fibres/g dried of breathlessness, a dry cough and crackles over the lower lung fields.
lung (see Table 7.1.5).216,231,232 It should be noted that counts from Finger clubbing is a variable feature. Lung function tests show a restric-
different parts of the same lung may vary widely;42,231–235 caution tive respiratory defect. Radiology initially shows small irregular basal
should therefore be exercised in interpreting a count obtained on a opacities that gradually coalesce to become linear, coarsen and
single sample. There is also wide discrepancy between laboratories, eventually progress to a honeycomb pattern of small cysts.
even when analysing the same sample.234 Results obtained in an The principal differential diagnosis, both clinically and pathologi-
individual case therefore have to be evaluated against a standard cally, is from idiopathic pulmonary fibrosis. This is aided by the slow
set of values unique to that laboratory. progression of asbestosis, which often extends over 20 years, as
Electron microscopy also provides valuable information on the type opposed to an average course of 2–3 years from presentation to death
of fibre. Chrysotile differs physically from the amphiboles in two for the idiopathic condition.
respects: its fibres are both curved and hollow (Figs 7.1.20 and 7.1.22). Most cases of asbestosis are diagnosed solely on the occupational
With an electron microscope equipped for microprobe analysis, the history and these clinicoradiological features. Recourse to histology is
various forms of asbestos may also be distinguished from other fibres unusual but biopsy (preferably as a wedge of lung) may be undertaken
and from each other (Box 7.1.2),230,236 an important point as the if the clinical features are atypical. Histology also arises when the
amphibole forms of asbestos are far more dangerous than chrysotile pathologist samples lung parenchyma remote from a resected carci-
(Table 7.1.6).197–199 noma (the universal importance of which cannot be overemphasised).

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Box 7.1.3  Criteria for grading asbestosis193,245,246

Extent
A None
B Less than 25% of the lung substance involved
C 25–50% of the lung affected
D More than 50% of the lung diseased
Severitya
0 No appreciable peribronchiolar fibrosis, or fibrosis
confined to the bronchiolar walls
1b Fibrosis confined to the walls of respiratory bronchioles
and the first tier of adjacent alveoli
2b Extension of fibrosis to involve alveolar ducts and/or
two or more tiers of alveoli adjacent to the
respiratory bronchiole, with sparing of at least some
alveoli between adjacent bronchioles
3 Fibrotic thickening of the walls of all alveoli between
at least two adjacent respiratory bronchioles
4 Honeycomb change
a
An average score is obtained for an individual case by adding the scores for
each slide (0–4), then dividing by the number of slides examined
b
Grade 1 and, to a lesser extent, grade 2 need to be distinguished from
smoking-induced peribronchiolar fibrosis and mixed-dust pneumoconiosis.

bodies. Both components must be present. The fibrosis is pauci­

Figure 7.1.23  Asbestosis. Fine interstitial fibrosis is evident beneath the cellular, lacking any significant degree of inflammation and being
pleura at the base of the lung. Barium sulphate-impregnated specimen.
collagenous rather than fibroblastic.
It is generally considered that asbestosis begins about the respira-
Coroners require autopsy verification of the diagnosis in all suspected tory bronchioles and alveolar ducts where most of the asbestos fibres
cases and this also necessitates hystology. impact.15 Alveolar walls attached to these bronchioles show fine inter-
stitial fibrosis. However, this early lesion has to be interpreted with
caution because it is not specific to asbestos, being found with other
Morbid anatomy inhaled mineral dusts239,240 and even in many cigarette smokers who
When the lungs from a patient with asbestosis are seen at autopsy, have not been so exposed.241 It more likely represents a non-specific
pleural fibrosis is often found, and although this may also be attribut- reaction to a variety of inhaled particles. It may cause mild airflow
able to asbestos exposure it is to be regarded as an independent obstruction but is not associated with the radiographic, clinical or
process and not part of the asbestosis: it is dealt with separately on restrictive changes of classic asbestosis.
page 715. As the disease progresses, the focal changes join up so that the basal
Slicing the lung affected by asbestosis shows a fine subpleural subpleural regions show widespread interstitial fibrosis and eventually
fibrosis, especially of the lower lobes (Fig. 7.1.23). In severe cases the complete destruction of the alveolar architecture. In severe cases there
fibrosis often extends upwards to involve the middle lobe and lingula, may be honeycombing and metaplastic changes in the alveolar and
and sometimes the upper lobes also. Microcystic change associated bronchiolar epithelium. Apart from the presence of asbestos bodies
with the fibrosis develops in advanced cases and in severe disease there the changes resemble those of non-specific interstitial pneumonia, or
may be cysts over 1 cm in diameter. However, these classic changes more rarely usual interstitial pneumonia. Fibroblastic foci may be
are seldom seen in developed countries today. Following decades of found but they are uncommon. There is often an increase in alveolar
dust suppression in asbestos factories, current patients have mild to macrophages but the desquamative interstitial pneumonia that has
moderate asbestosis and are dying of related cancer or of non-pulmo- been reported in association with asbestos242,243 is not to be regarded
nary disease.238 In some of these cases the asbestosis is only detectable as a variant of asbestosis192; concomitant smoking is a more likely
microscopically. Fixation of the lungs through the bronchi and the cause.241 A variety of other non-specific inflammatory processes such
use of Heard’s barium sulphate impregnation technique facilitate as organising pneumonia have been reported in asbestos workers and
demonstration of the fibrosis (see p. 757 and Fig. 7.1.23). The mild if localised some have been suspected of representing malignancy
degree of asbestosis currently encountered is of little functional sig- until biopsied.244
nificance but is often critical in determining whether an associated Several schemes have been proposed for grading the extent and
carcinoma of the lung should be attributed to asbestos exposure (see severity of asbestosis. These are of value in epidemiological studies
below). but should only be applied to cases meeting the histopathological
criteria for a diagnosis of asbestosis. One such scheme is shown in
Box 7.1.3.193,245,246
Histological appearances In well-established asbestosis asbestos bodies are numerous and
The histological diagnosis of asbestosis requires an appropriate easy to find, aggregates of them sometimes forming clumps (Fig.
pattern of interstitial fibrosis associated with the presence of asbestos 7.1.24). In earlier lesions a detailed search may be necessary, in which

347
 Pathology of the Lungs

Figure 7.1.25  Cytoplasmic hyaline in asbestosis. (A) Eosinophilic

inclusions are seen in the cytoplasm of several hyperplastic type II
pneumocytes. Haematoxylin & eosin. (Courtesy of Professor VL Roggli,
Durham, USA.) (B) Electron microscopy shows that the inclusions represent
a tangle of microfilaments. (Courtesy of Professor D Henderson, Adelaide,
B Australia.) (Both images reproduced by permission of the publishers of Archives of
Pathology and Laboratory Medicine.193)
Figure 7.1.24  Asbestosis. Interstitial fibrosis is associated with many
asbestos bodies (A), which are shown in detail in (B).

case the examination of unstained or Perls-stained sections facilitates pulmonary conditions.248–251It is seen as small eosinophilic cyto­
their identification. Minimum criteria for the diagnosis of asbestosis plasmic inclusions within hyperplastic type II alveolar epithelial cells
require the identification of diffuse interstitial fibrosis in well-inflated (Fig. 7.1.25A). Electron microscopy shows that the inclusions consist
lung tissue remote from a lung cancer or other mass lesion and the of a tangle of tonofilaments (Fig. 7.1.25B) and by immunocytochem-
presence of either two or more asbestos bodies in tissue with a section istry a positive reaction is obtained with antibodies to cytokeratin,
area of 1 cm2 or a count of uncoated asbestos fibres that falls in the both these features being typical of Mallory’s hyalin in the liver. The
range recorded for asbestosis by the same laboratory.192,193 There are inclusions also react for ubiquitin, the accumulation of which is indic-
marked variations in the concentration of asbestos fibres between ative of cellular damage, in particular faulty proteinolysis.251
samples from the same lung216,235 and it is therefore recommended
that at least three areas be sampled, the apices of the upper and lower
lobes and the base of the lower lobe.223
Differential diagnosis
The equivalent of Mallory’s alcoholic hyalin of the liver has been The differential diagnosis of asbestosis includes pulmonary fibrosis
described in the lungs in asbestosis,193,247 and subsequently in other due to many other causes, any of which may of course affect an asbes-

348
 Occupational, environmental and iatrogenic lung disease Chapter |7|

tos worker as much as members of the general population. The pro-

Table 7.1.7  Excess mortality from carcinoma of the lung
portion of diffuse pulmonary fibrosis in asbestos workers that is not
attributable to asbestos exposure and cigarette smoking in
attributable to asbestos has been estimated to be as high as 5% and
insulation workers.278 Together, these factors have a
likely to rise as the risk of asbestosis diminishes with better industrial
multiplicative rather than additive effect
hygiene.252
The principal differential diagnosis of asbestosis is from idiopathic
Group Mortality ratio
pulmonary fibrosis. Both diseases affect the bases and periphery of
the lungs predominantly. In the late stages, cystic change is more Non-smoking controls 1
evident in idiopathic pulmonary fibrosis but this criterion is not
totally reliable. Nor is the presence of pleural fibrosis, although it is Non-smoking asbestos workers 5
usually present in asbestosis and is seldom found in idiopathic pul- Cigarette-smoking controls 11
monary fibrosis. Asbestosis seldom progresses or does so very slowly
after exposure ceases253,254 whereas idiopathic pulmonary fibrosis typi- Cigarette-smoking asbestos workers 53
cally proves fatal within 3–4 years from onset. The fibrosis of asbes-
tosis is generally paucicellular: inflammation is not a feature and the
fibroblastic foci that characterise the usual interstitial pneumonia
pattern of fibrosing alveolitis are seldom observed in asbestosis. Asbestos exposure predisposes to two varieties of malignant neo-
Very often the distinction from idiopathic pulmonary fibrosis has plasm, carcinoma of the lung and mesothelioma of the pleura and
to be based on the amount of asbestos in the lung and, if asbestos peritoneum. The risk of malignancy increases with dose but the rela-
bodies are not readily identifiable, this has to depend on fibre counts. tive risk of carcinoma is much smaller than that of mesothelioma. For
Errors are made both by overlooking substantial numbers of asbestos example, with heavy exposure, as in lagging, the risk of mesothelioma
bodies completely and by ascribing undue importance to scanty is increased 1000-fold whereas it is increased only fivefold for lung
bodies. If considering the possibility of minimal asbestosis (to justify cancer. Hence, with light exposure there is a substantial risk of mes-
attributing carcinoma of the lung to asbestos, for example) it should othelioma but only a small risk of lung cancer. Asbestosis requires
be remembered that a little peribronchiolar fibrosis is also character- heavy exposure and in one group of patients with asbestosis, 39%
istic of smokers’ lungs, centriacinar emphysema and early mixed- died of pulmonary carcinoma, 10% of mesothelioma and 19% of
dust pneumoconiosis.239–241,255 As described above, at least two asbestos other respiratory diseases.238 Although there were many earlier reports,
bodies/cm2 in the presence of interstitial fibrosis distant from any lung the link with carcinoma of the lung may be considered to have been
cancer or other mass lesion is required for a diagnosis of firmly established by 1955,275 that between crocidolite asbestos and
asbestosis.192 mesothelioma by 1960,276 and that between amosite asbestos and
mesothelioma by 1972.277 Mesothelioma is considered on page 717.
In regard to carcinoma of the lung, asbestos is not such a potent
Pathogenesis
pulmonary carcinogen as cigarette smoke but together their effects
Although the causes of asbestosis and idiopathic pulmonary fibrosis are multiplicative rather than additive (Table 7.1.7).278,279 However,
are very different, they resemble each other in several ways, suggesting the risk attributable to asbestos is the same regardless of smoking
that similar pathogenetic mechanisms may operate.105,256–258 In both history, being increased fivefold in both smokers and non-smokers.
these diseases there is degeneration of the alveolar epithelium and There is usually a latent period in excess of 20 years between first
capillary endothelium, with patchy loss of the former,256 and exposure to asbestos and the development of lung cancer and the
bronchoalveolar lavage shows an increase in macrophages that might risk increases the greater the cumulative exposure. The increased
perpetuate the damage by releasing lysosomal enzymes, nitric oxide risk involves carcinomas of all the histological types encountered in
and hydroxyl radicals.257,259–261 Both diseases are also characterised by the lung, although adenocarcinoma has been disproportionately
an increased prevalence of circulating non-organ-specific autoanti- overrepresented.245,280–285
bodies.262 Experimentally, asbestos exposure leads to the activation It is uncertain114 whether the increased risk of carcinoma is caused
of a variety of fibrogenic cytokines at sites of lung injury.105,263–268 by the asbestos192,286–291 or the asbestosis.292–299 The latter view envis-
Inhaled asbestos activates a complement-dependent chemoattract- ages the carcinoma arising in the foci of alveolar epithelial hyperplasia
ant for macrophages269 and macrophage stimulation involves the and dysplasia that commonly accompany any interstitial fibrosis
secretion of fibroblast stimulating factors,270–272 asbestos being inter- (see carcinoma complicating idiopathic pulmonary fibrosis, p. 275).
mediate between haematite and silica in regard to macrophage-medi- However, most carcinomas complicating asbestosis arise in the
ated fibrogenicity.273 The epithelial damage could be mediated directly bronchi rather than the alveolar tissue. On the other hand, more
by the needle-like asbestos fibres or indirectly through enhanced arise in the sites worst affected by asbestosis, the lower lobes
phagocyte generation of free radicals (which is much greater with and the periphery of the lung, than in the general population
amphibole asbestos than with either chrysotile or silica).268,274 (Fig. 7.1.26).238,245,281–285
Fibrogenic cytokines released by activated pulmonary phagocytes and The majority view has been that asbestosis is a necessary precursor
regenerating alveolar epithelial cells in asbestosis include tumour of the carcinoma but evidence to the contrary is finding increasing
necrosis factor-α and transforming growth factor-β,268 as in idiopathic support (Table 7.1.8).192 In the UK, industrial compensation was for-
pulmonary fibrosis. merly only awarded to an asbestos worker for carcinoma of the lung
if there was also asbestosis or diffuse pleural fibrosis but new rules
were introduced in 2006. Asbestosis remains a sufficient criterion but
Asbestos-induced lung cancer diffuse pleural thickening is not and asbestosis is no longer a neces-
As a result of better industrial hygiene, asbestosis is less severe today sary criterion: asbestos is deemed to have been responsible if the
than in earlier years when it followed much heavier exposure, with patient worked in asbestos textile manufacture, spraying, lagging or
the consequence that death from respiratory failure and cor pulmo- gas mask manufacture for at least 5 years before 1975 or 10 years after
nale is less common and sufferers are surviving longer. There is there- 1975. The basis for these changes is the premise that heavy asbestos
fore now a greater risk of asbestos-related cancer eventually developing. exposure is sufficient in itself to account for carcinoma of the lung.

349
 Pathology of the Lungs

Table 7.1.8  Requirements for attributing carcinoma of the lung

to asbestos

The traditional view The Helsinki criteria,192 which

that the carcinoma are based upon substantial
complicates asbestosis exposure

1. Asbestosis 1. Asbestosis diagnosed clinically,

and radiologically or histologically
2. A minimum lag time of or
20 years A minimum count of 5000
asbestos bodies per gram dry lung
tissue (/g dry), or an uncoated
asbestos fibre burden of 2 million
amphibole fibres more than 5 µm
in length/g dry, or 5 million
amphibole fibres more than 1 µm
in length/g dry
or
Estimated cumulative exposure to
asbestos of at least 25 fibres/
ml-years
or
An occupational history of 1 year
of heavy exposure to asbestos
(e.g. manufacture of asbestos
products, asbestos spraying) or
5–10 years of moderate exposure
(e.g. construction or ship-building)
and
2. A minimum lag time of 10 years

Box 7.1.4  Compensation standards for asbestos-associ-

ated lung cancer in different countries289

Figure 7.1.26  Asbestosis associated with carcinoma of the lung. The Government standards vary considerably and in the civil courts claims
asbestosis has been highlighted by barium sulphate impregnation and is are often based on lesser evidence. Some examples of government
seen as a grey subpleural band to the right of the picture. Although the standards are:
carcinoma has arisen in the same lobe as the asbestosis it has not UK
obviously arisen in an area affected by asbestosis.
Asbestosis or employment in a specified industry for a specified time
(see text)
USA
The presence of asbestos-related bilateral pleural plaques or
Lung fibre counts in the asbestosis range (see Table 7.1.5) provide
asbestos-related bilateral pleural thickening and occupational
valuable evidence of such exposure. Compensation standards for exposure and a lag time of at least 12 years
asbestos-associated lung cancer in different countries are shown in
Box 7.1.4.192,289 Germany
The presence of asbestosis or pleural plaques or diffuse pleural
thickening or fibre-years of exposure
Asbestos-induced airway disease
Denmark
Although asbestosis causes a restrictive respiratory defect, airflow Only fibre-years of exposure are taken into account
limitation is also seen in this disease. Much of the airflow limitation
is attributable to cigarette smoking but it is also seen in non-smoking Finland
asbestos workers and is worse in those with asbestosis.300 The Exposure, at least 10 years’ latency and asbestos-related pleural or
pathological basis of this appears to be small-airways disease (see parenchymal changes
p. 123).301 It is possibly a non-specific reaction to inhaled dust or ciga- Sweden
rette smoke.302 Because it is not established that this lesion progresses
Asbestosis is not required but smoking is taken into consideration
to interstitial alveolar fibrosis (asbestosis) the term ‘asbestos airways
disease’ is suggested.302 Fibrosis limited to the bronchioles is specifi- Norway
cally excluded from the definition of asbestosis in the latest guidelines Attempts are made to quantify separately the attributability to
(although these retain grade 0 for fibrosis limited to the bronchiolar asbestos, smoking and other factors (e.g. radon)
walls).193 It should also be noted that, although emphysema is con-
sidered to be a destructive rather than fibrotic condition, a little focal

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

fibrosis is generally evident in this common condition255 and does not action of body fluids when such dust is inhaled. In certain circum-
necessarily indicate early asbestosis. stances, however, non-polar lubricants in the form of mineral oils
have been substituted for stearin. This happened in Germany during
the Second World War when munition production was stepped up
but stearin was difficult to obtain,306,307 and in the UK in the 1950s to
ALUMINIUM make the powder darker for purely commercial reasons.308 In vitro,
oil-coated stamped aluminium powder reacts with water to produce
aluminium hydroxide, which affords the underlying metal no protec-
Aluminium has been implicated in the development of respiratory
tion against further attack, so that aluminium hydroxide continues to
disease during the refining of its principal ore, bauxite, to yield various
be formed.309 This substance is a protein denaturant, once used in the
aluminium oxides (aluminas), in the preparation of the metal by
tanning industry, and it is believed that this property underlies the
smelting alumina, in the production of corundum abrasive and in the
very ex­­ceptional cases of severe pulmonary fibrosis that have occurred
production of special aluminium powders used in explosives.
in connection with stamped aluminium powder produced with
mineral oil rather than stearin.309,310 The fibrosis has a very character-
Refining of bauxite istic pattern, affecting the upper lobes and progressing rapidly, the
Bauxite is a mixture of various aluminium oxides, hydroxides and sili- interval from onset of symptoms to death being as short as 2 years.308
cates, iron oxide and titanium dioxide. The oxides of aluminium are There is marked shrinkage of the lungs with gross elevation of the
obtained by differential heating of the ore and the respiratory effects diaphragm and buckling of the trachea (Fig. 7.1.27). The lungs are
of this work appear to be no more than mild airway irritation. It is grey (Fig. 7.1.28) and microscopically, numerous small black jagged
generally accepted that aluminium oxide is inert. particles are seen. These can be shown to contain aluminium with
Irwin’s aluminon stain or by microprobe analysis.311
What appears to be a different pathological effect of aluminium
Aluminium smelting dust on the lungs is the rare development of granulomatous disease
Aluminium is prepared by the electrolytic reduction of its oxide dis- resembling sarcoidosis and berylliosis.312,313 This represents hyper­
solved in sodium aluminium fluoride (cryolite), a process releasing a sensitivity to the metal, amenable to confirmation with a lymphocyte
considerable amount of fluoride-rich effluent. Exposed workers have transformation test similar to that used to diagnosis berylliosis (see
complained of what is termed pot-room asthma. The pathology of below).
this condition is not well described but the pathogenesis is thought
to involve irritation rather than allergy.303
Aluminium welding
Rare cases of desquamative interstitial pneumonia and pulmonary
Abrasive manufacture fibrosis have been reported in aluminium welders.311,314
The abrasive corundum is formed from bauxite mixed with coke and
iron heated in an electric arc furnace, a process in which workers may
be exposed to the fumes of alumina and free silica. In the past some
of these workers developed diffuse pulmonary fibrosis (Shaver’s RARE EARTH (CERIUM) PNEUMOCONIOSIS
disease)369 and, although this was initially attributed to the alumin-
ium, it is now agreed that the free silica was the responsible agent.
Elements with atomic numbers from 57 (lanthanum) to 71 (lutetium)
The exposure to free silica has been reduced and the disease is now
are known as the lanthanides or rare earth metals. They are used in
regarded as historic.
many manufacturing processes, including the production of high-
temperature ceramics and the grinding of optical lenses. Carbon arc
Aluminium powder lamps used in reproduction photography emit appreciable quantities
Aluminium powder holds a paradoxical position in regard to lung of oxidised lanthanides, particularly cerium oxide, and there are
disease. In certain industries it has caused very severe pulmonary reports of pneumoconiosis in exposed individuals.315 The patho­
fibrosis, yet in others it has proved harmless. Indeed, at one time logical changes reported have varied from granulomatous nodules to
Canadian miners breathed aluminium dust before work, in the belief diffuse interstitial fibrosis indistinguishable from the idiopathic
that this would reduce the danger of silica in the mine dust304 and variety except for the presence of rare earth elements (usually cerium)
more recently silicosis has been treated by such means in France.305 It detected by polarising light microscopy and electron microprobe
is questionable whether this practice is effective but it at least appears analysis.315
to cause no harm. The explanation for these contradictory observa-
tions probably lies in differing methods of manufacture of aluminium
powder.
Aluminium metal appears to be an inert substance but this is only HARD-METAL DISEASE (COBALT LUNG)
because it has a high affinity for oxygen and the surface layer of
aluminium oxide so formed is firmly bound to the underlying metal, Hard metal is a tungsten alloy containing small amounts of cobalt,
unlike ferric oxide which permits further rusting of iron. Granular titanium, molybdenum and nickel. It is exceptionally tough and once
aluminium powders, produced in a ball mill or from a jet of molten formed can only be worked with diamond. It is used in the tips of
aluminium, therefore acquire a protective coat of surface oxide and drill bits, on abrasive wheels and discs, and in armaments. Interstitial
are inert. With stamped aluminium powders, however, surface lung disease is liable to arise in its manufacture or in those using hard
oxidation is prevented by lubricants added to aid the separation of metal as an abrasive.316 Experimental work suggests that cobalt is the
these flake-like particles. The usual lubricant (stearin) contains stearic dangerous constituent317 but this element is soluble and, unless
acid and this polar compound combines with the underlying metal, industrial contact has been recent, analysis of lung tissue usually
which is thereby protected from both atmospheric oxidation and the shows tungsten and titanium but no cobalt. The role of cobalt is also

351
 Pathology of the Lungs

A B

Figure 7.1.27  Aluminium pneumoconiosis. (A) A chest radiograph showing opacification of the lung apices. (B) A barium swallow showing severe
buckling of the oesophagus due to fibrous contracture of the lung apices and adjacent mediastinal tissues, as seen in Figure 7.1.B. (Courtesy of the late
Professor RE Lane, Manchester, UK.)

fibrosis. However, an unusual feature is the presence of moderate, or

perhaps only small numbers, of giant cells (Fig. 7.1.29A, B).316,320 Not
only are there multinucleate alveolar macrophages but syncytial cell
forms develop in the alveolar epithelium. Electron microscopy con-
firms that these are multinucleate type II pneumocytes (Fig. 7.1.29C).316
Such epithelial changes are well known in measles pneumonia but
the viral inclusion bodies that characterise this infection are not found
in hard-metal pneumoconiosis. The changes are those initially
described as a particular pattern of idiopathic interstitial pneumonia
termed giant cell interstitial pneumonia or GIP (see p. 264). Elemental
analysis shows that many, but not all, cases of GIP represent hard-
metal disease. The exceptions seldom give a history of cobalt exposure
and must be presumed to represent true idiopathic cases. Conversely,
epithelial giant cells are not always found in hard-metal pneumoco-
niosis and so their presence, although highly characteristic, is neither
totally specific nor totally sensitive.

BERYLLIOSIS

Figure 7.1.28  Aluminium pneumoconiosis. The lungs postmortem show Beryllium is the lightest of metals. It has an atomic weight of 4 and
severe fibrosis of the apex and overlying pleura. (Courtesy of the late Dr G special properties that make it especially useful in many applications.
Manning, Bolton, UK.) It is more rigid than steel, has a high melting point and is an excellent
conductor of heat and elecricity. Unfortunately, the inhalation of
beryllium dust or fume is exceedingly dangerous.321,322 Those who
indicated by the development of similar interstitial lung disease in worked with beryllium compounds before precautionary measures
diamond polishers using high-speed polishing discs made with a were taken suffered a high morbidity and mortality. Sometimes, the
diamond-cobalt surface that lacked tungsten carbide and the other escape of dangerous fumes from the factories was on such a scale that
constituents of hard metal.318,319 people living in nearby houses, downwind from the places in which
Hard-metal lung disease and cobalt lung take two forms, an these materials were being worked, contracted and occasionally died
industrial asthma and interstitial fibrosis. The latter has a diffuse lower from berylliosis (‘neighbourhood cases’).323 Alternatively, contamina-
zonal distribution and the appearances mimic idiopathic pulmonary tion of a beryllium worker’s clothes might lead to berylliosis in a

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

temperatures. The alloys of beryllium are also now widely used,

especially those with copper, on which it confers elasticity and resist-
ance to fatigue. Alloy manufacture and the machining of beryllium
alloys are therefore further activities that entail a risk of berylliosis, as
is the recovery of the metal in the recycling of scrapped electronic and
computer parts. Seemingly innocuous occupations such as dental
laboratory technician are not without risk of chronic berylliosis.329

Pathogenesis
There are good grounds for regarding chronic berylliosis as being an
allergic condition. Many of those affected react strongly to skin tests
with dilute solutions of beryllium salts, although these must be
undertaken with care: occasionally in a highly sensitised person even
so small an exposure may evoke a systemic reaction. The skin reaction
is of the delayed type, occurs in only 5% of exposed individuals, is
not associated with a clear-cut dose–response curve and represents a
granulomatous response. Further evidence for the disease having an
A
allergic basis derives from bronchoalveolar lavage, which demon-
strates an excess of T-helper lymphocytes that proliferate in vitro on
exposure to beryllium salts.330 A positive transformation test given
by these lymphocytes is a more reliable indicator of disease than in
vitro blood lymphocyte transformation testing,52 which is safe but
not wholly reliable and indicates only sensitization, rather than
berylliosis.
Susceptibility to berylliosis varies widely from person to person and
it is notable that chronic pulmonary disease is strongly associated with
the HLA antigen DPβ1 and the Glu69 gene.331,332 The importance of
genetic factors is supported by a report of the disease in identical
twins.333
Chronic berylliosis is thought to be initiated by the metal binding
to tissue proteins and acting as a hapten to initiate a delayed
hypersensitivity response characterised by a proliferation of T-helper
lymphocytes. These sensitised cells in turn secrete a variety of cyto­
kines (e.g. interleukin-2, tumour necrosis factor-α and interferon-γ)
B that recruit and activate macrophages, which mature into epithelioid
cells. The resultant epithelioid cell granulomas destroy the lung tissue
Figure 7.1.29  Giant cell interstitial pneumonia in hard-metal workers. and lead to pulmonary fibrosis.
(A) There is interstitial pneumonia and fibrosis and several alveolar
epithelial cells are multinucleate (arrows). (B) Higher magnification shows
a light lymphocytic infiltrate, numerous alveolar macrophages and several Pathological changes
multinucleate giant cells.
If beryllium enters the subcutaneous tissues through a cut or abrasion,
as often happened in the earlier days of fluorescent lamp manufacture,
a sarcoid-like granuloma soon appears at the site; in time, the
overlying epidermis may break down to form an ulcer.
relative.324 Beryllium compounds may also cause contact dermatitis Even more serious are the lesions produced by the inhalation of
and conjunctivitis.325 Beryllium is also classified as a probable beryllium. Chronic pulmonary berylliosis takes the form of a wide-
pulmonary carcinogen,326 but this is controversial. spread granulomatous pneumonia with a histological picture identi-
Two forms of berylliosis are recognised, acute and chronic. Acute cal to that of sarcoidosis (Fig. 7.1.30A). Both berylliosis and sarcoidosis
berylliosis was first reported in Germany in 1933327 and is now largely affect the upper lobes more than the lower (Fig. 7.1.30B) and in
of historical interest, being only encountered as a result of rare acci- both diseases the granulomas are preferentially distributed along
dental or unexpected exposure. It follows the inhalation of a soluble lymphatics and may involve adjacent blood vessels. In neither condi-
beryllium salt and represents chemical injury, the pathology being tion is there widespread necrosis but in both diseases the granulomas
that of diffuse alveolar damage (see p. 136). Further consideration occasionally display a little central necrosis or hyalinisation. As in
will be confined to chronic berylliosis, which is allergic in nature. sarcoidosis, the hilar lymph nodes may be involved but, unlike
sarcoidosis, not in isolation.
Over a period of many years, the sarcoid-like granulomas
Uses of beryllium and occupations at risk gradually undergo progressive fibrosis, with consequent impairment
Chronic berylliosis was first reported in 1946 in the fluorescent lamp of pulmonary function. In the later stages, when the disease has
industry.328 Beryllium has now been replaced in this application but become chronic, dispersal of beryllium from its site of initial absorp-
it has since proved to be of great value in the nuclear, electronic, tion may lead to generalisation of the disease and to the appearance
computer and aerospace industries and the production of refractory of similar granulomas elsewhere, particularly in the liver, kidneys,
materials and crucibles that are to be subjected to particularly high spleen and skin, but this is unusual.

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 Pathology of the Lungs

and there is a lifelong risk of disease. Progression often entails alter-

nating exacerbations and remissions, long after exposure has ceased.

Analysis
In keeping with the view that berylliosis is a hypersensitivity reaction,
very little beryllium is necessary to cause the disease. Particulate
beryllium is so scanty in the affected tissues and the atomic number
of beryllium so low that electron microprobe analysis is generally
unsuitable for its detection. Furthermore conventional detectors are
protected by a beryllium window. However, the substitution of a
polymeric window has enabled beryllium to be detected by electron
microprobe analysis, presumably in a patient with fairly heavy expo-
sure.334 Ion or laser microprobe mass spectroscopy can also detect very
small amounts of beryllium in tissue sections but these techniques are
A not widely available.

Differential diagnosis
The differential diagnosis of chronic berylliosis is from sarcoidosis, to
which it is identical morphologically.335–337 However, as noted above,
it is unusual for berylliosis to cause significant hilar lymphadenopathy
in the absence of pulmonary disease, which is a common feature
of sarcoidosis. Extrathoracic granulomas, erythema nodosum and
uveitis, which are all common in sarcoidosis, are unusual in
berylliosis. However, one group found that 6% of patients initially
diagnosed as having sarcoidosis actually had chronic berylliosis.338
Similar findings have been reported by others.324,339 Any patient
thought to have sarcoidosis who has worked with or near metals
should be offered a beryllium lymphocyte transformation test. A list
of laboratories performing this test can be found at www.dimensional.
com/~mhj/medical_testing.html.

POLYVINYL CHLORIDE PNEUMOCONIOSIS

Although polyvinyl is not a mineral and the reaction of the lungs to

its presence is therefore not a true pneumoconiosis, it is generally so
termed and is dealt with here for convenience. Workers are exposed
to polyvinyl chloride dust in the milling and bagging of this
plastic and micronodular opacities may be detected in their lungs
radiologically. However, the material is non-fibrogenic and histology
merely shows a foreign-body reaction to the dust particles.340 The
radiological opacities may abate when exposure ceases.341 Nevertheless,
one polyvinyl chloride worker developed systemic sclerosis,342 which
is a recognised complication of silicosis (see p. 335). Polyvinyl
chloride is produced from vinyl chloride monomer, which has a
causal association with angiosarcoma of the liver and probably other
forms of cancer, including carcinoma of the lung (see p. 534).

B
FLOCK WORKER’S LUNG
Figure 7.1.30  Chronic berylliosis. (A) Numerous non-necrotising
epithelioid and giant cell granulomas are seen in the lungs. (B) The upper
and middle lobes and the apex of the lower lobe are contracted by In the late 1990s a characteristic lung disease was identified in workers
extensive fibrosis. Paper mounted whole lung section. at several factories producing plush material by spraying nylon flock
on to an adhesive backing material.343–346 The flock fibres are too large
to be inspired but may be mixed with smaller nylon shards of
respirable size. The workers complained of cough and breathlessness
Clinical features and were found to have a restrictive ventilatory defect with interstitial
Chronic berylliosis is characterised by the gradual onset of cough, markings on radiography. Their symptoms improved on removal
shortness of breath, chest pain, night sweats and fatigue. These symp- from the workplace but relapsed on return to work. Pathologically,
toms may develop within a few weeks of exposure or many years later. there was lymphocytic bronchiolitis and peribronchiolitis with wide-
Once the worker is exposed, the beryllium is retained in the tissues spread lymphoid hyperplasia represented by lymphoid aggregates.

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Granulomas were not identified. The histological appearances suggest

Table 7.1.9  Principal respiratory risks of welding
a severe immunological reaction and raise possibilities such as
rheumatoid disease and Sjögren’s syndrome but consideration of the
Source Derivative Effect
clinical and serological setting and the occupation should permit
recognition of the cause. Metals being Iron Siderosis
welded Zinc Metal fume fever
Beryllium Berylliosis (acute or
chronic)
POPCORN WORKER’S LUNG Chrome, nickel Asthma
Cadmium, Diffuse alveolar damage
The industrial production of popcorn and other foodstuffs appears to manganese Lung cancer
carry a risk of obstructive airway disease.347–350 Biopsy of affected Chrome, nickel,
workers has shown peribronchiolar fibrosis and granulomas and air arsenic
sampling has identified many volatile organic compounds, of which Burning of adjacent Isocyanates Asthma
the flavouring agent diacetyl (2,3-butanedione) is suspected of being surfaces Phosgene Bronchitis, bronchiolitis
responsible for the bronchiolitis. Tetrafluoroethylene Polymer fume fever
Oxides of nitrogen Bronchitis
Electrode insulation Asbestos Mesothelioma
PAINT SPRAYING Protective clothes
Gas used to Carbon dioxide Asphyxia
It is difficult to continue paint spraying (air brushing, aerographics) prevent oxidation
without adequate respiratory protection but in the early 1990s several
small aerographic factories operated in the neighbourhood of Alicante, Combustive gas Carbon monoxide Carbon monoxide
poisoning
southeastern Spain without any concern for the workers’ health. The
workers were required to paint patterns on textiles using a hand-held Ultraviolet light Ozone Bronchitis
spray gun. The atmospheric pollution was intense but complaints of
Various Silica, silicates Silicosis, mixed-dust
respiratory difficulties were met with reassurances and the workers
pneumoconiosis
urged to continue. This they did because of the otherwise poor
economy, often returning to work when disabling breathlessness had
settled down. A change of paint (to Acramin F) may have contributed
because the worst-affected workers were employed at two plants that WELDING
had made this switch. Their illness has been described as the ‘Ardystil
syndrome’ after the name of one of these factories. Some workers were
left with permanent respiratory disability. One required a lung trans- Welder’s pneumoconiosis, first recognised in 1936,364 essentially
plant and 6 others died.351–354 Transbronchial biopsy showed organ­ represents the fairly harmless deposition of iron in the lungs (siderosis
ising pneumonia, which in the fatal cases had progressed to irreversible – see p. 337). However, welders may suffer various ill-effects from the
interstitial fibrosis. A similar outbreak of respiratory disease was sub- inhalation of substances other than iron (Table 7.1.9). Some of these
sequently reported in Algerian textile factories where Acromin F was are para-occupational risks, that is, encountered by welders because
applied by the same technique.355,356 Acromin F is marketed as a paste they work near another process and are inadvertently exposed: thus,
and used as such without ill-effect. Its use in heavy spray form appears shipyard welders may be exposed to asbestos,365 and those in
to be responsible for the ‘Ardystil syndrome’. foundries to silica. Welders may therefore develop a mixed-dust
pneumoconiosis (see p. 337), rather than just siderosis. However, one
analytical investigation identified excess amounts of iron alone in
association with pulmonary fibrosis; the silicon content did not differ
MINERAL OILS AND PETROLEUM from that in controls.366
More directly, welders may be exposed to asbestos insulation that
Workers in engineering workshops may be exposed to the prolonged they themselves use, while welders of special steel alloys run the risk
inhalation of fine sprays or mists of the longer-chain hydrocarbons of metal-induced asthma, metal fume fever, polymer fume fever and
that constitute many mineral oils. This may result in exogenous lipid the consequences of toxic metal fume inhalation,367 all of which are
pneumonia,357 which is described on page 314, or extrinsic allergic described separately in this chapter, as is lung disease in aluminium
alveolitis.358–360 The vapour of shorter-chain hydrocarbons such as welders. Chronic bronchitis has been attributed to the inhalation of
paraffin oil (kerosene: C10–16) and petrol (gasoline: C4–12) and gaseous low concentrations of irritants such as ozone and nitrogen dioxide
hydrocarbons such as propane may act as acute asphyxiants or central by welders but this risk is unproven and the subject of much contro-
nervous system depressants but have negligible pulmonary toxicity. versy. Welders may also inhale carcinogenic hexavalent chromium
However, if they are ingested or aspirated in their liquid form they are compounds in the course of their work and therefore develop lung
acutely toxic to the lungs, producing a chemical pneumonitis with the cancer. The term ‘welder’s lung’ is often applied indiscriminately to
features of diffuse alveolar damage. Ingestion may be accidental or any of these diseases and, as it has no specific meaning, is best avoided.
deliberate (see Fig. 4.19, p. 142) whereas aspiration is generally inad-
vertent, occurring in siphoning accidents, such as those experienced
by fairground operatives who ‘breath or eat fire’ (‘fire-eater’s lung’).361,362 TOXIC FUMES AND GASES
Animal experiments involving the intratracheal injection of kerosene
resulted in acute pulmonary exudates, which cleared except for resid- Dust, fume and gas are some of the terms used to describe different
ual bronchiolitis.363 physical forms of respirable agents. They are defined in Table 7.2.1 on

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 Pathology of the Lungs

page 372. The parts of the respiratory tract at which they exert their were most sensitive.383 In long-term experiments, hyperplastic
maximal effect are influenced by particle size and solubility (see Table bronchiolar Clara and ciliated cells extended peripherally to line
7.2.2 and Fig. 7.2.2, p. 372). alveolar ducts.384 The role of granulocytes is stressed in some experi-
mental studies385 and it is notable that neutrophil migration is promi-
nent when the human lungs are damaged by ozone.386
Toxic metal fume368 Aldehydes such as acetaldehyde, formaldehyde and acrylic
aldehyde (acrolein) are widely used in the plastics and chemical
The finely divided fume of several metals is highly toxic to the lungs industries. The first is a liquid and the others are water-soluble gases.
and capable of producing severe acute and chronic damage to both Pathologists are of course familiar with formaldehyde solution from
the conductive airways and the alveoli, resulting in acute tracheo­ its use as a disinfectant and histological fixative. All these aldehydes
bronchitis and bronchiolitis, diffuse alveolar damage, obliterative are intensely irritant and their acute effects generally prevent pro-
bronchiolitis and pulmonary fibrosis. Important metal fumes in this longed exposure to high concentrations. Chronic effects include skin
respect include aluminium, which is released together with silica sensitivity and asthma, and in rats nasal carcinoma. However, the
fume in bauxite smelting (see Shaver’s disease,369 above), cadmium doses to which these experimental animals were exposed far exceed
from welding or cutting special steels, chromium from cutting its any that are likely to be encountered by humans, in whom there is
alloys or in the manufacture of chromates, cobalt released in the no convincing evidence of aldehyde-induced cancer.387
production and use of its alloys (see hard-metal disease, above), Ammonia gas is extensively used in industry as a raw material,
mercury released in various industries and in the home,370 nickel notably in the manufacture of nitrogenous products such as fertilisers
carbonyl released during the purification of metallic nickel or the and plastics. It is highly soluble and its acute irritative effects are
manufacture of nickel alloys371 and beryllium (see above). mainly felt in the eyes, nose and throat, but high levels affect the
major airways, possibly leading to them being blocked by exudates.
Survival usually brings full recovery but bronchiectasis and
Toxic gases obliterative bronchiolitis have been described.
Many irritant gases cause severe acute and chronic damage to both the Chlorine gas is widely used in the chemical industry. It is trans-
conductive airways and alveoli. The changes are non-specific and ported and stored under pressure in liquid form. Heavy exposure
similar to those wrought by toxic metal fumes (see above) and viruses through its accidental release or use as a war gas has proved fatal
amongst other agents. They consist of acute tracheobronchitis and through its acute toxicity causing exudative airway occlusion and pul-
bronchiolitis, obliterative bronchiolitis, diffuse alveolar damage and monary oedema. Survivors usually recover completely but, as
pulmonary fibrosis. with nitrogen dioxide and ammonia, there is a risk of obliterative
The gases liable to produce such damage include oxides of nitrogen, bronchiolitis.
sulphur dioxide, ozone, phosgene, chlorine, ammonia and various Phosgene (carbonyl chloride, COCl2) is a poisonous, colourless gas
constituents of smoke, notably acrolein. Some of these are also that was responsible for thousands of deaths during World War I,
touched upon in Chapter 7.2 because they are of general as well when it was used in chemical warfare. It is used industrially in the
as occupational importance, although there is no rigid difference preparation of some organic chemical compounds and is formed,
between general and occupational pollution. perhaps inadvertently,388 by the combustion of methylene chloride in
Ozone, sulphur dioxide and nitrogen dioxide are oxidising gases products such as paint strippers. Phosgene causes injury to terminal
that may be found together as industrial atmospheric pollutants. Each bronchioles and alveoli, with resulting oedema and hyaline mem-
is capable of producing diffuse alveolar damage by means of its brane formation. The mechanism of cell damage is uncertain but it
oxidising properties and the release of free active radicals. In addition, may depend on inactivation of intracellular enzymes by the gas. Long-
they cause damage to distal airways, particularly terminal and term problems are rare but chronic bronchitis and emphysema have
respiratory bronchioles, with resulting bronchiolitis. been described in survivors.
Oxides of nitrogen may be encountered with fatal consequences by Mustard gas (bichloroethyl sulphide, C4H8Cl2S) is a further agent
farmhands seeking to free a blockage in a silo when they encounter that has been used in chemical warfare. It is primarily a skin vesicant
pockets of this gas that have accumulated on top of the fermenting but when inhaled it results in widespread epithelial destruction and
silage: the term ‘silo-filler’s disease’ is generally applied to the initial pulmonary oedema. Survivors may be left with irritant-induced
haemorrhagic oedema or the obliterative bronchiolitis that develops asthma (reactive airways dysfunction), chronic bronchitis, tracheo-
in those who survive the initial chemical injury.372–375 Asphyxia due to bronchomalacia, bronchiectasis and bronchiolitis obliterans.389–391
the farmhand encountering pockets of carbon dioxide is a further Thionyl chloride is used in the manufacture of lithium batteries where
hazard within agricultural silos. Other farmhands have suffered from it is liable to result in the release of sulphur dioxide and hydrochloric
the inhalation of toxic gases or bacteria when handling liquid acid fumes. Workers in such factories have developed lung injury
manure.376–379 Welding, which is considered below, may also involve varying from mild, reversible interstitial disease to severe obliterative
exposure to toxic gases such as oxides of nitrogen. bronchiolitis.392
Ozone, the principal oxidant gas of photochemical smog, produces Hydrogen sulphide is the principal chemical hazard of natural gas
pulmonary changes at relatively low levels and may be encountered production. High levels of the gas also buid up in sheds housing large
at higher concentrations in various industries. Potentially dangerous numbers of pigs, the source here being the pig manure. Once inhaled
levels of ozone are produced from atmospheric oxygen by ultraviolet the gas is rapidly absorbed into the blood stream. The effects are
radiation given off in welding while ozone is used in industry to steri- therefore widespread but include the usual respiratory effects of irri-
lise water, bleach paper, flour and oils, and mask the odour of organic tant gases, varying from sneezing to pulmonary oedema and acute
effluents. The damage wrought by ozone is predominantly centri­ respiratory distress, depending upon the exposure. In Alberta 221
acinar in distribution, affecting terminal and respiratory bronchiolar cases were identified over a 5-year period. The overall mortality was
epithelium and proximal alveolar epithelium.380–382 There is loss of 6%; 5% of victims were dead on arrival at hospital. Most required
cilia and necrosis of centriacinar alveolar type I epithelial cells. The admission to hospital but the survivors experienced no long-term
changes are dose-dependent and, in one study, the youngest animals adverse effects.392a

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Table 7.1.10  Work-related respiratory disease in the UK394 Table 7.1.11  Agents that cause occupational asthma and
examples of the occupations involved397
Disease Estimated annual
number of cases Causative agent Occupations involved

Occupational asthma 941 High-molecular-weight agents (patients are

usually atopic)
Non-malignant pleural disease 730
Laboratory animals Laboratory animal handling
Mesothelioma 644
Flour and grain Baking, milling, farming
Pneumoconiosis 341
Enzymes Detergent and drug manufacture,
Inhalation accidents 280
baking
Lung cancer 70
Seafoods Food processing
Infectious disease 59
Gums Carpet and drug manufacture
Extrinsic allergic alveolitis 46
Low-molecular-weight agents (patients are not
Bronchitis 38 necessarily atopic)
Byssinosis 1 Isocyanates Foam and plastic manufacture, spray
Other diagnoses 117 painting, insulation

Total 3207 Anhydrides Plastic and epoxy resin handling

Wood dusts Forestry, carpentry
Soldering fluxes Electronics
Formaldehyde, glutaraldehyde Histopathology, nursing, radiography
ANOXIC ASPHYXIA
Amines Shellac and lacquer handling,
soldering
The danger of asphyxia from the inhalation of gases devoid of oxygen
is fairly widespread in industry.393 It generally arises from the use of Chloramine Cleaning
inert gases, which, being non-toxic, give a false sense of security. Dyes Textiles
Pockets of these gases tend to form in confined spaces. Anoxic death
from the accumulation of methane is well known in mines and has Acrylates Adhesive application
also occurred in slurry pits and sewers. Anoxic asphyxia in diving (and Metals Solderers, refiners
anaesthesia) has resulted from the incorrect connection of gas
cylinders or failure to notice that a mixed gas contains insufficient Drugs Pharmaceutical work
oxygen. Deaths have occurred in welding when argon or carbon
dioxide has been used to shield the weld and prevent oxidation of the
metals at the high temperatures employed. Deaths have also resulted
from inadvertent entry to discharged oil tanks filled with nitrogen to logical agents have been identified.399 In the UK a third are organic, a
reduce the risk of explosions, or from the formation of pockets of third chemical, 6% metallic and the rest miscellaneous. The common-
nitrogen gas applied in liquid form to freeze the contents of damaged est, in descending order, are isocyanates, flour and grain, laboratory
pipes so that they can be repaired without the necessity to drain down. animals, glutaraldehyde, solder or colophony and hardening agents.400
The respiration of a gas devoid of oxygen causes loss of conscious- Atopy appears to predispose to occupational asthma when the
ness within seconds because it not only fails to provide oxygen but allergen is of high molecular weight but not when it is of low molecu-
removes that present in the pulmonary arterial blood. The changes at lar weight. For example, atopic individuals are particularly prone
autopsy are those common to cellular hypoxia. They include cerebral to develop asthma if employed in the manufacture of biological
and serosal petechiae and pulmonary congestion and haemorrhage detergents, whereas atopy does not increase the risk of asthma from
but these features are not specific and are not always present. The sensitisation to toluene di-isocyanate, which is a serious health
cause of death can generally only be surmised from the circumstances problem in the manufacture of polyurethane. Similarly, platinum salts
surrounding the death. are such potent sensitising agents that nearly all those exposed to
them develop asthma. Asthma-provoking metals other than platinum
include chromium, cobalt, nickel and vanadium, all of which are used
in steel alloys, and possibly aluminium (see pot-room asthma, p.
OCCUPATIONAL ASTHMA 357). Other asthma-inducing factors encountered in industry include
grain and flour dust, certain wood dusts, soldering fluxes containing
Occupational asthma is the commonest cause of work-related colophony (pine resin), epoxy resin hardeners such as phthallic anhy-
respiratory disease in many western countries (Table 7.1.10).394–396 The dride, isocyanate-containing foams and paints, formaldehyde and the
reported incidence ranges from 13 per million workers in South Africa excreta of laboratory animals. Contaminated humidifiers may cause
to 174 per million workers in Finland.395,396 It occurs in many indus- occupational asthma as well as humidifier fever and extrinsic allergic
tries (Table 7.1.11)397 and occupational factors can be identified as alveolitis.401 Pathologically, occupational asthma is identical to non-
contributing to asthma in about 15% of adult cases.398 Over 250 aetio- occupational asthma (see p. 109).

357
 Pathology of the Lungs

Byssinosis stances that also lead to the development of a form of extrinsic allergic
alveolitis, and not surprisingly the same name has been extended
Byssinosis is a further form of occupational asthma,402 one en­­ to this latter condition, with inevitable confusion. Both diseases
countered in the cotton industry. The sensitising agent is a component are caused by microbiological contamination of humidifiers or air
of the cotton bract, which is the part of the cotton harvest other than conditioners so that a fine spray of microorganisms is emitted into
the cotton fibre. Bract consists of dried leaf, other plant debris and the office, factory or home. Investigations have generally shown the
soil particles and contains a variety of fungal and bacterial residues, baffle plates of the air conditioner to be covered with a slime of
including lipopolysaccharide endotoxin, but the exact nature of the bacteria, fungi or protozoa (mainly amoeba and ciliates), and extracts
sensitising agent remains unknown.403 The endotoxin is unlikely of this have been used to identify precipitins in the patient’s sera,
to be responsible for byssinosis but may be the cause of so-called as in extrinsic allergic alveolitis. However, unlike extrinsic allergic
mill fever, a self-limiting illness characterised by malaise, fever and alveolitis, humidifier fever resolves within a day and leaves no perma-
leukocytosis that is experienced by many people on first visiting a nent injury. For this reason there is seldom the opportunity to study
cotton mill. the tissue changes, and partly for this reason it remains unclear
Dust levels and the risk of byssinosis are particularly high in the whether the disease is mediated by immune complexes, as in extrinsic
carding rooms where the raw cotton is teased out before it is spun. allergic alveolitis, or by endotoxins derived from the contaminants.
Affected workers are worse when they return to work after the weekend
break, a feature attributed to antibody levels having built up during
this brief respite from the cotton dust. There is no link with atopy and Pulmonary mycotoxicosis
the fluctuating antibodies are precipitins of the immunoglobulin G A febrile illness occurring in precipitin-negative farm-workers after
class. Complement activation by both arms of the complement heavy exposure to fungi in their silos was attributed to inhaled fungal
cascade has been reported.404,405 toxins and named pulmonary mycotoxicosis.409 It is also known as
When the Lancashire economy was largely cotton-based, necropsies precipitin test-negative farmer’s lung and organic dust toxic
on workers suffering from byssinosis generally showed gross syndrome.410 The condition is generally self-limiting and is seldom
emphysema, and this came to be accepted as evidence of byssinosis. biopsied but desquamative interstitial pneumonia and diffuse
However, it is now realised that in this heavily industrialised part of alveolar damage have been reported.411,412
the UK, emphysema is as common in the general population as in
cotton workers and it can no longer be considered a component of
byssinosis. Other findings in byssinosis are more commensurate with Metal fume fever
asthma, namely an increase in bronchial muscle and mucous cells.406 This is a self-limiting acute illness characterised by fever, sweating,
No granulomas or other evidence of extrinsic allergic alveolitis are myalgia, chest pain, headache and nausea, that comes on Monday
found. mornings when occupational exposure is experienced after a week-
end’s respite, as with bysinnosis and humidifier fever; during the week
tolerance develops.368,413 The disease involves the release of cytokines
OCCUPATIONAL FEVERS such as tumour necrosis factor and is presumed to have an allergic
basis.414 The metals involved are chiefly zinc, copper and magnesium,
and, to a lesser extent, aluminium, antimony, iron, manganese and
Fever may be the predominant feature in a variety of occupational nickel. Occupations at risk include any that generate such metal
illnesses and the unifying term ‘inhalation fever’ has been proposed.407 fumes, but particularly welding. It is most commonly associated with
However, the individual occupations are of interest and these con­ welding zinc-coated surfaces. If the symptoms persist, alternative diag-
ditions will therefore be considered separately. Mill fever has been noses, such as acute cadmium poisoning and other specific toxic metal
mentioned above under byssinosis. fume diseases, should be suspected: these are not self-limiting and
may cause severe bronchiolitis or diffuse alveolar damage (see above).
Humidifier fever408
Humidifier fever is an acute illness characterised by malaise, fever,
Polymer fume fever
myalgia, cough, tightness in the chest and breathlessness, all of which This illness resembles metal fume fever except that it occurs without
are worse on Monday mornings if the humidifier responsible is at regard to previous exposure: no tolerance develops and there is there-
work rather than home. The chest complaints, and their aggravation fore no particular susceptibility on Mondays. The polymers concerned
on return to work after the weekend, are features shared with are quite inert, except when heated to produce fume: polytetra­
byssinosis (see above) but the general complaints fit better with extrin- fluorethylene (PTFE, Teflon, Fluon, Halon) is a notable example. As
sic allergic alveolitis (see p. 279). Humidifier fever develops in circum- with other self-limiting diseases, little is known of the tissue changes.

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392a.  Burnett WW, King EG, Grace M, Hall WF. Occupational contribution to the burden Occupational fevers
Hydrogen sulfide poisoning: review of 5 of airway disease. Am J Respir Crit Care 407. Raskandersen A, Pratt DS. Inhalation fever
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Anoxic asphyxia 1994;7:346–71. 408. MRC Symposium. Humidifier fever. Thorax
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394. Ross DJ, Sallie BA, McDonald JC. SWORD Occupational asthma in a factory with a Organic dust toxicity (pulmonary
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Occup Med 1995;45:175–8. 402. Rooke GB. The pathology of byssinosis. 411. Lougheed MD, Roos JO, Waddell WR,
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complement by extracts of cotton mill Pulmonary mycotoxicosis: A
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American Thoracic Society Statement: Thorax 1975;30:612–23.

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7.2  Environmental lung disease

gas. This carcinogen is liable to accumulate in buildings and be in­­

CHAPTER CONTENTS
haled, so subjecting the occupants to an increased risk of lung cancer.
Environmental irradiation 368 The installation of underfloor ventilation is therefore advocated in
Atmospheric pressure changes 368 such areas. This subject is explored more fully on page 533.
Blast injury 368
Chest squeeze 369
Burst lung 369 ATMOSPHERIC PRESSURE CHANGES
Decompression sickness (caisson disease) 369
Mountain sickness 370 The body is vulnerable to both increases and decreases in pressure
Drowning 370 and it is the lungs that often bear the brunt of the damage. Increased
pressure may result in blast injury or crushing of the chest while
Inhaled toxic agents 371 decreased pressure may result in the lungs literally bursting or dis-
Air pollution 371 solved gases being released within the blood (caisson disease), or the
Tobacco smoke 373 vascular alterations that underlie mountain sickness developing.
Burns and smoke inhalation 373 Some of these pressure changes entail a risk of pneumothorax and it
is essential that this is properly investigated postmortem by the chest
Methyl isocyanate, the chemical released
being opened under a water seal. Loud music has been incriminated
at Bhopal 374
as a specific form of air pressure change causing pneumothorax and
Tear gas 375 metereologists have shown that ‘spontaneous’ pneumothoraces tend
Ingested toxic agents 375 to occur in clusters associated with natural drops in atmospheric
Paraquat 375 pressure.1,2
Toxic oil syndrome 375
Sauropus androgynus 376
Recreational drugs 377 Blast injury
Marijuana 377 Explosions may cause injury by the body being violently thrown
Cocaine 377 against a less moveable object, by objects being thrown against the
Heroin 378 body or by the blast wave hitting the body. These mechanisms often
act together but sometimes there is only blast injury, to which the
‘Filler embolism’ 378
lungs are particularly vulnerable. For a time it was considered that the
4-methyl-aminorex 378 damage was direct, the blast wave travelling down the airways to injure
References 379 the lungs. However, at the start of the Second World War, experiments
conducted in the UK showed that the lungs were injured indirectly,
the blast wave being transmitted to them through the chest wall:
pulmonary blast injury is worst on the side of the body towards the
explosion, and can be reduced by protective clothing.3 Underwater
ENVIRONMENTAL IRRADIATION explosions are particularly dangerous because water is incompressible.
There may be severe internal injury but no external evidence of
Environmental irradiation chiefly affects the skin but in some parts of damage other than a trickle of blood from the mouth or nose. This is
the world rocks near the surface release significant amounts of radon because the injury is rate-dependent. Quite small thoracic deform­

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

ation may produce severe pulmonary damage if peak compression is

attained very quickly, typically in less than 5 ms. Conversely, severe
chest wall distortion may produce only minor pulmonary contusion
if this time is extended beyond 20 ms.4
At necropsy, the lungs are contused, with blood evident in the
airways and parenchyma. Depending on the force of the blast, the
haemorrhage may be pinpoint, patchy or confluent. It tends to follow
the lines of the ribs and may be accompanied by pleuropulmonary
lacerations having the same distribution. In this case there will also
be haemothorax, pneumothorax and possibly air embolism. Patchy
pulmonary haemorrhages cuff the blood vessels.5,6 In patients who
survive for a few days, the lungs resemble the liver macroscopically
and histologically show chronic interstitial inflammation and fibrosis
as well as haemorrhage.7 Other injuries are often present and fat
embolism, aspiration pneumonia, fluid overload and infection may
all be added to the effects of the blast wave.

Figure 7.2.1  Sea lion lung. The smallest airways of deep-diving

mammals such as the sea lion are buttressed by cartilage to ensure that
Chest squeeze all air is evacuated from the lungs when the animal is at depth to
prevent the lungs bursting on rapid ascent. In humans there are several
‘Chest squeeze’ is another form of barotrauma caused by high pressure generations of airways that lack cartilage (the bronchioles) and
but here the body is compressed rather than subject to a sudden wave consequently close before exhalation is complete. The trapped gas (the
of pressure as in blast injury. It is experienced by divers who descend residual volume) is normally of no consequence but it poses a danger
very deeply, thereby subjecting their bodies to such high pressure that that the lungs may burst or of decompression sickness if ascent is rapid,
their chest walls are literally crushed, so that their ribs break and their whether in the sea or by air. (Courtesy of Professor D Denison, Brompton, UK.)
lungs are severely compressed. More common mishaps experienced
by divers include drowning and decompression sickness, both of
which are dealt with below, and neurological syndromes such as
nitrogen narcosis, which will not be considered further.8

Decompression sickness (caisson disease)

The same circumstances that lead to burst lung may also cause
Burst lung
decompression sickness, which is also known as caisson disease.9 In
‘Burst lung’ is the most acute form of decompression sickness.9 It is this condition there is a sudden release of nitrogen gas that has gone
experienced by divers and submariners making rapid ascents from into solution in the lipids of adipose tissue and of myelinated nervous
depth and by aviators who ascend too rapidly in unpressurised aero- tissue at the higher pressure: the released nitrogen gains access to the
planes, experience failure of a plane’s pressure system or have to eject blood stream in which it forms bubbles.15 Doppler ultrasound tech-
at high altitudes. Injury to the lung is caused by trapped alveolar gas niques show that this is quite customary when divers ascend from
expanding so rapidly that it exceeds total lung capacity before it can depth,16 but the lungs generally provide an effective filter so that there
escape through the trachea. The lungs literally burst: the alveolar walls are no untoward systemic effects, although there may be sudden chest
rupture and blood mixes directly with alveolar air. The victim experi- pain on deep inspiration (’the chokes’). Gradual decompression
ences chest pain and there may be blood-stained froth at the mouth permits the nitrogen to diffuse across the alveolar membranes and be
or frank haemoptysis. Air may enter the alveolar walls to cause inter- exhaled. If, however, substantial amounts of nitrogen are released
stitial emphysema or air embolism. Asthmatics may be at particular from solution, sufficient pulmonary arteries may be blocked to cause
risk because of regional air-trapping.10. Diving mammals such as pulmonary hypertension, with resultant opening of arteriovenous
porpoises and whales are protected from such dangers of peripheral communications or a patent foraman ovale, so permitting the gas to
air-trapping by cartilage extending far out into the finest conductive enter the systemic circulation. This is often followed by limb pains
airways so that these passages never close, even at the end of full (’the bends’) and perhaps cerebral symptoms (’the staggers’). Fatal
expiration (Fig. 7.2.1).11,12 cases are characterised by gas bubbles within blood vessels through­
Patients requiring positive-pressure artificial respiration are also at out the body and froth in the heart chambers. Delayed effects include
risk of burst lung, but the complications of the resultant interstitial ischaemic necrosis of bones and other tissues.17
emphysema differ from those experienced by divers. In divers, the Deep-diving mammals are protected by the same mechanism that
chest wall is buttressed by the surrounding water and air in the inter- prevents them suffering from burst lung. They exhale before diving
stitium is liable to track towards the hilum of the lungs and enter and during the dive the chest is compressed to the extent that virtually
pulmonary veins, with resultant cerebral and coronary air embolism, all the gas in the lungs passes into the cartilage-buttressed non-
either of which may prove fatal.13 Iatrogenic burst lung, on the other respiratory airways (see Fig. 7.2.1), resulting in very little to be
hand, takes place in patients whose chest wall is not so buttressed, absorbed by the blood. The pulmonary collapse also serves to reduce
and then outward rupture of the interstitial air is more likely, resulting buoyancy. The distribution of the little gas that is absorbed is mini-
in pneumothorax. Extension of the interstitial emphysema to the mised by bradycardia.18 Many viscera experience anaerobic respiration
mediastinum, neck and chest wall is also more likely in such patients, but hypoxia is minimised in the heart and musculature by high levels
resulting in surgical emphysema at these sites. However, there are of haemoglobin and myoglobin. The brain is further protected by the
exceptional cases marked by both cerebral embolism and extensive air supplying arteries drawing on oxygen stored in an unusual sponge-
tracking.14 like cervical organ known as the rete mirabilis.

369
 Pathology of the Lungs

Mountain sickness pulmonale. Livestock taken from lowland plains to high-altitude pas-
tures suffer similarly but the natural stock of the Himalayas and
Mountain sickness is due to reduced atmospheric pressure brought Ethiopian highlands are apparently immune. So too are other species
about more slowly than that responsible for decompression sick- long established at high altitude such as the llama and yak. These
ness.19,20 It may be acute or chronic. species are said to have adapted to their climate, that is, the forces of
natural selection have bred out the pulmonary vasoconstrictive
response to hypoxia. Cattle of European origin and humans acclima-
Acute mountain sickness
tise to high altitude by processes such as increasing their red cell
Acute mountain sickness is likely to be experienced by anyone who mass but generally they are not adapted like native species and
ascends above 3000–4000 m without a period of acclimatisation at suffer hypoxic pulmonary hypertension at altitudes in excess of
intermediate levels. Symptoms are as liable to occur in people born 3000 m. Certain Himalayan highlanders may be an exception
at high altitude who return after a few weeks spent at sea level as in to this in that their small pulmonary arteries are reported not to
those who go to the mountains for the first time: acclimatisation is show the muscularisation that characterises hypoxic pulmonary
obviously short-lived and is therefore necessary whenever an ascent is hypertension.33
to be made. The ill-effects are commonly precipitated by exercise. In In cattle of European origin, the dependent oedema of right-sided
the susceptible, acute mountain sickness commonly appears within 3 cardiac failure caused by hypoxic pulmonary hypertension affects the
days of ascent. breast (brisket) particularly and in the Rocky Mountains of North
The basis of acute mountain sickness is tissue hypoxia. It results in America such cattle are said to have ‘brisket disease’.34 A human
deteriorating intellectual and psychological function, headache, counterpart of this has been described in children of Chinese ancestry
nausea, vomiting, and more rarely pulmonary and cerebral oedema. who have been taken to reside in Tibet and who have developed a
High-altitude pulmonary oedema is characterised by increasing fatal form of subacute infantile mountain sickness.35
dyspnoea, cyanosis and a dry cough, and later the production of A small minority of permanent residents in the Andes develop the
copious, frothy sputum, which sometimes becomes blood-stained.21 changes of chronic mountain sickness to a marked degree and are said
The pulmonary artery pressure is markedly raised but wedge pressures to suffer from Monge’s disease.36 The basis of this is alveolar hypo­
are normal, indicating that the left side of the heart is unaffected and ventilation, which leads to a progressive fall in systemic arterial oxygen
that pulmonary venous constriction is unlikely to be an important saturation and elevation of haemoglobin concentration to an
contributory factor. unusually severe degree. The latter averages about 25 g/dl, which
The pulmonary oedema fluid has a high protein content22 and the exceeds even the 20 g/dl found in healthy high-altitude residents.
condition has been characterised as a non-cardiogenic high-permea- Patients with Monge’s disease are so deeply cyanosed that their
bility oedema associated with excessive pulmonary hypertension.23,24 lips are virtually black. Their pulmonary artery resistance is also mark-
Hypoxia is a well-known cause of pulmonary arteriolar constriction edly raised. The cause of the alveolar hypoventilation is uncertain
but in acute mountain sickness the vascular response appears to be but the only cases of Monge’s disease that have come to necropsy
exaggerated for the pulmonary artery pressure is considerably higher had conditions such as kyphoscoliosis that predispose to alveolar
than is usual for the altitude. An association with certain HLA com- hypoxia.
plexes (HLA-DR6 and HLA-DQ4) suggests that this has a genetic
basis.25 Although arteriolar constriction only tends to protect the pul-
monary capillaries, it could explain the oedema if the process was
patchy – as is the resultant oedema – for patchy arteriolar constriction
would subject the rest of the lung to abnormally high pressures DROWNING
and lead to capillary stress failure in these areas (see pp. 402 and
448).26,27 Measurements of capillary pressure suggest that this is Drowning is defined as suffocation by submersion, and usually occurs
indeed the case.28 Furthermore, vasodilators such as calcium channel in water. It is the commonest cause of accidental death among divers
blocking agents and inhaled nitric oxide gas23,29,30 have been used with but 96% of drowning accidents do not involve deep descents. Falling
success to counter acute mountain sickness, supporting the idea that into quite shallow water is a particularly common cause of drowning
hypoxic vasoconstriction plays a central role. in young children. In adults, men outnumber women by 4 to 1. More
Autopsy shows the lungs to be heavy and firm. The cut surface die in fresh water than the sea, not because it is more hazardous to
weeps oedema fluid, which is often blood-stained, but a striking the lungs than sea water, but because unguarded inland waters and
feature is the patchy distribution of the changes. Areas of swimming pools are visited more frequently. Alcohol consumption
haemorrhagic oedema alternate with others that contain clear oedema contributes to many deaths by drowning.
fluid and others that are normal apart from overinflation. Pulmonary Drowning is not simply a matter of being unable to keep one’s head
arterial thrombi are commonly found. Microscopy confirms the pres- above water. This may be merely a secondary event. For example, the
ence of haemorrhagic oedema and may show neutrophils and hyaline entry dive may result in underwater head injury, or the exertion of
membranes in the alveoli. The alveolar capillaries are congested and swimming may precipitate a heart attack. Furthermore, the struggling
may contain thrombi. There may also be an increase in mast cells and swimmer going down for the third time (’drowning not waving’) is
rarely pulmonary infarction. The right ventricle is commonly dilated the exception: most drowning is characterised by the swimmer failing
whereas the left ventricle is normal. Highlanders generally show right to surface or quietly dropping beneath the surface without anyone
ventricular hypertrophy and increased muscle in their pulmonary noticing.
arteriesm, changes that are not apparent in lowlanders.31,32 Swimming underwater can be extremely hazardous if it is pre­
ceded by hyperventilation, a danger that needs to be more widely
appreciated. Hyperventilation results in undue loss of carbon dioxide
Chronic mountain sickness so that instead of hypercapnia forcing the swimmer to surface to
Prolonged residence at high altitude leads to hypoxic pulmonary breathe, progress under water may be continued until hypoxia causes
hypertension (see p. 424), an increase in red cell mass and cor sudden loss of consciousness.

370
 Occupational, environmental and iatrogenic lung disease Chapter |7|

Panic contributes to many swimming accidents and is often • ’dry drowning’

precipitated by the inadvertent aspiration of just a little water. Most • true drowning
people are naturally buoyant, but only slightly so. With the lungs fully • hypothermia
expanded the average adult has a positive buoyancy of about 2.5 kg, • circulatory failure after rescue.
which is sufficient to keep the head out of the water if the rest of the True drowning is indicated by froth in the airways and heavy water-
body is submerged. If an arm (weight about 3 kg) is raised to wave filled lungs. Both fresh and salt water contain numerous microscopic
for help, the head will go down. If the swimmer shouts, exhalation algae known as diatoms and those representative of the water in
reduces buoyancy to neutral at normal end-expiration and to negative which the drowning occurred are found in the lungs. Unless
at residual volume. Buoyancy cannot be regained when the head is death occurred before submersion, diatoms are also found in other
submerged and unless able to swim to the surface, the person will viscera because these tiny life forms easily enter the circulation.
continue to sink. Thus, the presence of diatoms in digests of organs such as the kidneys,
Autopsy generally shows that the lungs are full of water, but some liver, brain and bone marrow suggests that death was due to
victims die of ‘dry drowning’ due to laryngospasm. Events may also drowning. Because they have a siliceous capsule, diatoms are resistant
be modified by the temperature of the water. Sudden immersion in to putrefaction as well as digestion and can be identified in the
cold water may result in tachycardia, hypertension and hyperventila- body long after death. However, a positive test is not always accepted
tion, making it difficult for the victim to keep the airways free of water. as proof of drowning and a negative test does not exclude
It may also result in sudden death due to ventricular fibrillation. Even drowning.
a good swimmer loses consciousness within an hour of immersion in
very cold water. Drowning is then inevitable unless a correctly fitted
life jacket is worn, in which case there is a danger of death from
hypothermia. However, as in open heart surgery, cold prolongs the
INHALED TOXIC AGENTS
interval before there is irreversible brain damage.
If the person is rescued, water in the lungs is quickly absorbed, even
if it is saline, and therefore hyperosmolar:aspirated sea water is quickly The various physical forms in which respirable environmental agents
equilibrated by pure water joining it from the blood but the alveolar may be encountered are defined in Table 7.2.1. Some effects of
epithelial barrier remains impermeable to protein and once osmotic inhalant lung injury are recognised as distinct disease entities and are
equilibrium is reached, all is quickly reabsorbed.37–39 Fresh water is dealt with elsewhere: for example, the pneumoconioses on page 327,
absorbed even more quickly. It is unnecessary to tip the patient to extrinsic allergic alveolitis on page 279, chronic bronchitis on page 98
hasten this process. Any water recovered in this way comes from the and lung cancer on page 532. Other respirable agents, such as lead
stomach and time that should be devoted to mouth-to-mouth fume and carbon monoxide gas, exert their harmful effects elsewhere
breathing and cardiac massage is lost. These resuscitative efforts may in the body and will not be considered further. This section is con-
need to be prolonged as fresh water in particular inactivates alveolar cerned with toxic substances that may be inhaled by the general
surfactant, leading to alveolar collapse which persists until the sur- public. Those that are more likely to be encountered in the workplace
factant is replenished. Very few victims who are resuscitated on site or in war zones are considered on page 355.
fail to survive, and very few who cannot be resuscitated on site recover The lungs have a rather stereotyped pattern of response to inhaled
later. toxins, displaying degenerative changes and inflammation of varying
Interchange of fluid between the blood and air spaces may cause degree, the former sometimes amounting to necrosis. In general, the
major fluctuations in plasma volume with consequent changes in site of maximal absorption or injury is related to solubility (for gases
ionic concentrations and haemolysis. Hypervolaemia may cause cir- and vapours) and particle size (for aerosols such as dusts, fog, fumes,
culatory problems but hyperkalaemia consequent upon the haemo­ mists, smog and smoke): the less water-soluble and the smaller the
lysis is not thought to be as important as was formerly believed: particle size, the further down the respiratory tract the agent will pen-
ventricular fibrillation following submersion is more likely to be a etrate (Fig. 7.2.2 and Table 7.2.2).40–42 Thus, ammonia produces
complication of hypothermia than of electrolyte imbalance. intense congestion of the upper respiratory passages and laryngeal
Circulatory collapse may ensue shortly after rescue. This is due to oedema whereas phosgene has little effect on these sites but causes
loss of the circulatory support provided by the pressure the water pulmonary oedema.40
exerts on the body, which results in a considerable increase in cardiac
output while the body is immersed. On leaving the water the loss of
this support results in a tendency to venous pooling. Although this is Air pollution43–47
countered by baroreceptor responses, these are reduced by prolonged The toxic (as opposed to allergenic) air pollutants thought to pose the
immersion in cold water. Circulatory collapse is believed to be the greatest threat to the lungs comprise smoke particles, sulphur dioxide,
cause of death in many persons who perish within minutes of rescue. oxides of nitrogen, various aldehydes and ozone. Smoke and sulphur
To counter this effect, patients should be lifted out of the water in the dioxide derive particularly from the combustion of fossil fuels in
prone position. domestic fires and power stations, nitrogen dioxide is an important
It can be seen that, in fatal cases, the pathologist is faced with several car exhaust and domestic gas appliance pollutant and ozone is the
possibilities. Thus, death may have been due to: principal photochemical product of smog. Aldehydes such as
• natural causes before the body entered the water formaldehyde and acrylic aldehyde (acrolein) also contribute to
• unnatural causes before entry, the body merely being disposed general air pollution because they are released in the combustion of
of in the water diesel oil and petrol. Collectively, these pollutants have been incrimi-
• natural causes in the water nated in the exacerbation (rather than causation) of asthma. They also
• injuries received in the water from impact with rocks, a boat or predispose to respiratory infection and result in airway inflammation
a ship’s propeller, or in tropical waters from predators such as a and hypersecretion.48,49 Their effect on children is of particular concern
crocodile or a shark (any of which may also be incurred after because development of the lungs is known to continue well into
death, as may disfigurement by fish and rats) childhood and damage to the lungs before their growth is complete

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 Pathology of the Lungs

Table 7.2.1  Definitions of respirable agents by physical form Table 7.2.2  Relation of solubility of an inhaled gas to its major
site of absorption or toxicity41
Gas A formless compressible fluid in which all molecules of
the agent move freely at room temperature (25°C) and
Gas Henry’s Major site of absorption
standard pressure (760 mmHg) to fill the space
constant or toxicity
available
at 37°C
Vapour Gaseous state of an agent which is normally liquid or
solid at room temperature and standard pressure Ammonia 0.0011 Upper respiratory tract

Aerosol Dispersion of solid or liquid particles of microscopic size Sulphur dioxide 0.05 Upper respiratory tract and trachea
in a gaseous medium. The following are all examples:
Formaldehyde 0.56 Upper respiratory tract and trachea
Dust Dispersion of solid particles. Those of respirable size are
Ozone 6.4 Tracheobronchial
not readily seen with the naked eye unless they are
bathed in bright light Nitrogen dioxide 8.8 Tracheobronchial and pulmonary
Fog Dispersion of liquid particles generated by condensation Oxygen 42 Pulmonary
from the vapour state
Nitrogen 77 Pulmonary
Fume Dispersion of solid particles generated by condensation
from the vapour state Henry’s constant: moles/l(air)/moles/l(water).

Mist Dispersion of liquid particles generated by condensation

or mechanical means (e.g. nebulisation). The droplets
are generally larger than those of a fog and may be
visible individually to the naked eye

Smog Mixture of smoke and fog, the former being the result of
industrial pollution, the latter of natural climatic factors is likely to be irreparable. At the other extreme of life episodes of
severe air pollution are known to hasten the deaths of many patients
Smoke Dispersion of small particles (usually less than 0.1 µm
with chronic airway disease. Particularly high concentrations of the
diameter) resulting from incomplete combustion of
organic substances agents responsible for air pollution may be encountered in industry
and their effects are therefore also considered in Chapter 7.1, on
occupational diseases of the lung. Many of the polycyclic hydrocar-
bons found in polluted air are carcinogenic (see p. 532) and it is
therefore not surprising that urban air pollution has been found to
be associated with excess mortality from lung cancer.50
Domestic air pollution is rife in many of the poorer parts of the
world due to the burning of biomass (wood, dried cow dung, bagasse,
straw) in unventilated living rooms for heating and cooking. The
women are particularly at risk of developing chronic bronchitis while
their children have an increased incidence of acute respiratory
infections.51,52,52a
Volcanic ash (tephra) irritates the eyes, skin and respiratory tract
Ammonia and in some eruptions may contain much free silica (e.g. Montserrat
Sulphur dioxide in 1995 and Mount St Helens, Washington state, USA in 1980) or be
Formaldehyde associated with the release of radon gas (e.g. the Azores in 1957).53
The destruction of the World Trade Center in 2001 caused massive air
pollution of New York city that had lasting respiratory effects on sur-
vivors, rescue workers and local residents.54–56 At the time of the dis-
aster there was much smoke from combustion of aeroplane fuel and
Ozone
flammable materials in the building while the collapse of the twin
towers released dust from cement and dry-wall partitions that was
Nitrogen dioxide
highly alkaline.57–59 This caused considerable irritation of the eyes and
the conductive airways. A year later many victims were still suffering
from bronchial hyperreactivity and poor ventilatory function, in a
so-called reactive airways dysfunction syndrome54,55 and there was
Oxygen
Phosgene
continuing spirometric decline 5 years later.60 The respirable portion
Nickel carbonyl of the dust formed only a small fraction of the whole but given
the level of exposure its future effects cannot be discounted, particu-
larly as it contained substances such as asbestos. Unusual effects
attributed to the disaster include acute eosinophilic pneumonia and
Figure 7.2.2  The site of maximum uptake of an inhaled gas is
dependent upon its solubility. Thus, ammonia, sulphur dioxide and
granulomatous pneumonitis.61,62
formaldehyde, which are highly soluble, have their major impact on the Allergenic air pollutants are dealt with in detail in the sections on
upper respiratory tract and trachea whereas oxygen, phosgene (COCl2) asthma (see p. 109) and extrinsic allergic alveolitis (see p. 279).
and nickel carbonyl (Ni(CO)4), which are less soluble, are taken up in the Allergenic air pollution is generally occupational or domestic but
alveoli, where their toxicity is mainly experienced. periodic widespread air pollution was responsible for the epidemics

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

Quite advanced interstitial fibrosis has been reported in smokers

Box 7.2.1  Diseases related to smoking with no clinical evidence of interstitial lung disease.69b Early changes
detectable in smokers include chronic bronchiolitis, fibrosis of the
Respiratory diseases caused by smoking bronchiolar wall and mild peribronchiolar interstitial fibrosis.70,71
Carcinoma Even earlier changes are detectable at the molecular level: as many as
Chronic obstructive lung disease 152 smoking-responsive genes that are significantly up-regulated or
down-regulated have been identified in normal cigarette smokers.72
Chronic bronchitis
There is marked individual variation, which may explain why many
‘Small-airways disease’ lifelong heavy smokers experience no respiratory problems.
Emphysema Histological evidence that a patient smokes is provided by
Respiratory bronchiolitis an increase in the number of alveolar macrophages and a character-
Desquamative interstitial pneumonia istic brown discoloration of cytoplasm due to the phagocytosis
of tar and other particulate matter derived from tobacco smoke
Respiratory diseases that are commoner or worse (Fig. 7.2.3).
in smokers Cigarette smokers are at greater risk of lung disease than cigar and
Adult respiratory distress syndrome pipe smokers, probably because they inhale more deeply. They do this
because cigarette smoke is more acid than cigar and pipe smoke and
Respiratory infections
its nicotine content is therefore absorbed more easily through the
Common cold lungs than the buccal mucosa. Smokers obviously put their own
Influenza health at greatest risk but the lesser hazards of passive smoking are
Varicella pneumonia now well recognized (see p. 532). Passive smoking involves both the
Bacterial pneumonia smoke exhaled by others and that coming from smouldering tobacco
Tuberculosis between puffs, the latter being known as sidestream smoke. The
harmful effects of maternal smoking on the unborn child also come
Pneumothorax
in this category. They include increased airway responsiveness and
Cryptogenic fibrosing alveolitis reduced lung function during the neonatal period and an increased
Langerhans cell histiocytosis risk of sudden infant death syndrome. Reduced numbers of alveolar
Asbestosis attachments to the bronchioles have been demonstrated in such
Goodpasture’s disease infants.73 Smoking is also associated with disease of other organs (e.g.
carcinoma of the oesophagus and bladder) but these are outwith the
Respiratory diseases that are less common or less remit of this text.
severe in smokers Tobacco smoking by waterpipe (shisha, hubble-bubble) is
Extrinsic allergic alveolitis enjoying a rise in popularity, both in its heartland, the Middle East,
Sarcoidosis and western countries, and wherever it is practised it is widely
perceived as being less dangerous than smoking cigarettes.74 This is
probably a mis­conception. What evidence there is suggests that water-
pipe tobacco smoking is just as harmful as cigarette smoking, if not
more so.75

of asthma seen in Barcelona in the 1980s, which were eventually

traced to ships discharging cargoes of soya flour (see p. 114). Burns and smoke inhalation
The lungs may be injured in burned patients in many ways (Box
7.2.2)76,77 but an important consideration when a body is recovered
Tobacco smoke
from a fire is whether death was due to the fire or took place before-
Smoking-related diseases figure large throughout this book and in this hand, the latter raising the possibility of foul play. A vital reaction to
section they are merely summarised collectively. Of the greatest the skin burns and the presence of soot in the lower airways provide
importance, both in the number of patients they affect and in their evidence that death occurred in the fire but an absence of soot from
clinical effects on the individual, are the various forms of chronic the airways may be due to death occurring rapidly, from asphyxia or
obstructive lung disease and lung cancer, but there are many other poisoning by gases released in the conflagration. Soot is cleared
respiratory diseases associated with smoking, and a few that are less rapidly and if the patient survives a few days an absence of soot from
common in smokers (Box 7.2.1).63 Not surprisingly, these diseases the airways is to be expected.76
are often encountered in combination and sometimes one may Lung injury may result directly from heat and smoke inhalation or
obscure another. For example, a cigarette smoker may have emphy- indirectly from the release of mediators associated with blast injury
sema in the upper lobes and idiopathic pulmonary fibrosis in the or shock. Although air temperature in a fire may reach very high
lower lobes.64,65 Alternatively, Langerhans cell histiocytosis and de­­ temperatures thermal injury seldom extends beyond the carina but
squamative interstitial pneumonia may affect the same parts of the more extensive injury from heat alone was seen in men exposed to
lungs, in which case the focal lesions of the former may be masked steam escaping from a fractured boiler pipe.78 Those dying immedi-
by the latter condition.63 ately showed coagulative necrosis of the respiratory mucosa down to
The term ‘smoking-related interstitial lung disease’ has been the level of the alveolar ducts and alveolar congestion and oedema,
introduced to cover a spectrum of interstitial diseases related to while those surviving a little longer exhibited diffuse alveolar damage.
smoking63,66,67 as well as being used in a more restricted sense to The diffuse alveolar damage probably represented a manifestation of
describe a combination of air space enlargement and interstitial shock from their extensive cutaneous scalding whereas the mucosal
fibrosis predominantly affecting the lower lobes.68,69,69a necrosis is directly attributable to heat. Diffuse alveolar damage is

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 Pathology of the Lungs

Box 7.2.2  Possible pulmonary insults in burned patients,

arranged in approximate sequential order
Blast injury
Asphyxia
Poisoning by combustion products (e.g. carbon monoxide, cyanide)
Direct thermal injury (largely limited to the trachea)
Irritant smoke, fume and gas (e.g. oxides of nitrogen, ammonia,
acrolein, sulphur dioxide)
Hypovolaemic shock secondary to skin loss
Septicaemic shock from:
A Infected skin burns
Infected central lines
Secondary viral and bacterial pneumonia
Fluid overload
Tracheostomy complications, including tracheobronchitis, pneumonia
and barotrauma
Oxygen toxicity
Absorption of toxic topical disinfectants
Thromboembolism
Uraemia

usually part of systemic multiorgan failure in these patients, and is the

leading cause of death in burns.79
The ubiquity of plastics today means that smoke contains
numerous irritants, including isocyanates, aldehydes and fluorinated
organic chemicals. Irritant smoke products have two principal effects.
Firstly, they cause an immediate painful stimulation of the eyes and
B respiratory tract which at low concentrations may prevent escape and
at high concentrations may cause laryngeal spasm and death. Secondly,
they cause bronchopulmonary injury some hours after exposure.
Burned patients dying within 4–12 days often show tracheobronchial
necrosis and diffuse alveolar damage with prominent hyaline mem-
branes.76,77,80 Secondary herpesvirus infection is often present.81,82
The respiratory changes caused by heat and smoke are non-specific
and careful consideration of the many causes of lung injury in
burned patients listed in Box 7.2.2 and of the clinical circumstances
and management is generally required. Often it will be concluded
that the cause of the lung injury is multifactorial. Long-term
consequences of smoke inhalation include bronchiectasis and oblit-
erative bronchiolitis.83

Methyl isocyanate, the chemical

released at Bhopal
The Bhopal catastrophe of 1984 was caused by the accidental release
of 30 tons of methyl isocyanate gas (CH3–N=C=O) from a pesticide
plant.84 Over 200 000 people were exposed, of whom 2500 died,
mostly within hours of exposure, and 60 000 were seriously injured.
C
The victims complained of intense ocular and respiratory irritation.
Some survivors were left with persistent respiratory impairment,
Figure 7.2.3  Macrophages of a heavy cigarette smoker. (A) Numerous
brown macrophages fill the alveoli. Electron microscopy shows that the
which was thought to be due to obliterative bronchiolitis.85,86
lysosomal dense bodies are increased in number and contain lipidic ‘tar Methyl isocyanate is an extremely potent respiratory irritant,
bodies’ (B) or the needle-shaped crystals of kaolinite (C). (Transmission destroying the epithelium throughout the conducting airways, with
electron micrographs, courtesy of Miss A Dewar, Brompton, UK.) comparatively less parenchymal injury. In survivors, epithelial re­­
generation, often involving squamous metaplasia, quickly com-
mences, but not before endobronchial granulation tissue projections
have developed, resulting in obliterative bronchiolitis.

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

Tear gas + +
Tear gases are chemical irritants delivered as an aerosol for the purpose CH3N NCH3 Paraquat
of riot control. They react with mucocutaneous sensory nerve
receptors causing intense irritation of the eyes, mucous membranes
and skin. The respiratory effects are mainly concentrated on the upper
NH3(CH2)4NH2 Putrescine
tract so that there is violent sneezing, severe rhinorrhoea and cough
but there may also be tracheobronchitis and rarely pulmonary NH3(CH2)4NH(CH2)3NH2 Spermidine
oedema.87 Patients with pre-existent asthma or chronic obstructive
pulmonary disease are most severely affected while others may be left NH3(CH2)3NH(CH2)4NH(CH2)3NH2 Spermine
with reactive airways dysfunction.
Figure 7.2.4  Formulae of paraquat and the endogenous oligoamines
putrescine, spermine and spermidine showing the molecular similarities.
The name paraquat derives from the chemical’s para-methyl groups and
INGESTED TOXIC AGENTS its quaternary nitrogen atoms.

Toxins reaching the lungs via the blood stream may be drugs, food
contaminants, metabolites produced elsewhere in the body, or victims of accidental paraquat poisoning die from progressive pulmo-
chemicals ingested intentionally or accidentally, either in the home nary fibrosis between 10 and 14 days after ingestion. In those who
or the workplace. survive longer, a honeycomb pattern of pulmonary fibrosis may be
The lungs are selectively damaged by certain blood-borne toxins for apparent.91
a variety of reasons. For example, the herbicide paraquat is preferen- Paraquat is a powerful oxidant and owes its toxicity to the
tially taken up by the lungs because of its molecular homology with production of active oxygen radicals. The lungs are particularly sus-
certain endogenous substances. As detailed below, the type I alveolar ceptible because paraquat is concentrated there by an active uptake
epithelial cells are the cells that bear the brunt of the damage in mechanism in the alveolar epithelium. The inadvertent uptake of
paraquat poisoning. On the other hand, the alveolar capillary endo­ paraquat probably stems from a similarity between the molecular
thelium has its own selective uptake mechanisms (see Metabolic func- arrangement of its quaternary nitrogen atoms and the amine groups
tions of the pulmonary endothelium, p. 23) which may be responsible of endogenous oligoamines such as putrescine, spermidine and sper-
for it being selectively damaged by other chemicals. mine, which are concerned in alveolar epithelial cell division and
The bronchiolar Clara cells are selectively injured by some ingested differentiation (Fig. 7.2.4).92 This results in paraquat levels being 6–10
chemicals because they are equipped to deal with inhaled xenobiotics, times higher in the lung than in the plasma. Once taken up by the
but occasionally this activity results in metabolites that are extremely lung, paraquat is not metabolised but participates in redox cycling so
toxic. An example of this from veterinary medicine is provided by the that superoxide radicals are constantly produced. Epithelial injury is
furan-derivative 4-ipomeanol, which is found in mouldy sweet proportional to the concentration of paraquat, while it is lessened by
potatoes and results in acute pulmonary oedema in cattle fed such a hypoxia and antioxidants such as superoxide dismutase, and potenti-
diet. When this chemical is injected into mice, the bronchioles are ated by increased concentrations of oxygen.93–96 The high concentra-
denuded of Clara cells whereas the intervening ciliated cells are com- tion of oxygen in the alveoli is a further reason why the lungs are
pletely unaffected. The selective damage to the bronchiolar Clara cells particularly vulnerable to paraquat.
appears to stem from the oxidative efficiency of their P-450 cyto- Knowledge of the toxic effects of paraquat comes from observations
chromes,88 which is much higher than those of the liver. Chemicals on autopsy series89,97,98 and from experimental studies that have
having a similarly selective effect on bronchiolar Clara cells include enabled the sequence of pulmonary changes to be observed.99–102 In
3-methylfuran, carbon tetrachloride, naphthalene and 1,1-dichlo- accordance with paraquat being taken up by the alveolar epithelium,
roethylene, the last of which is a volatile compound that is widely electron microscopy shows that these cells suffer more profound
used in the plastics industry. Procarcinogens may be activated in the damage than the endothelium.99 Type I epithelial cells swell and
airways by similar mechanisms. undergo necrosis (Fig. 7.2.5),103 whilst type II cells, although remain-
ing capable of proliferation, show ultrastructural evidence of damage
with derangement of cell organelles.99,100 Histological changes in the
Paraquat lungs follow the pattern of diffuse alveolar damage, with a character-
Paraquat is a dipyridylium compound that is widely used in istic feature of the early exudative phase being intense vascular
agriculture as a herbicide. It kills all green plants but is inactivated on congestion and alveolar haemorrhage.89,97,104 Hyaline membranes are
contact with the soil. It is applied as a spray and if the manufacturer’s most clearly seen by about 5 days (Fig. 7.2.6) and epithelial prolifera-
instructions are followed there is no danger to health. Most fatal cases tion and fibrosis are conspicuous by about 14 days.
of paraquat poisoning, both accidental and suicidal, have been due The pattern of pulmonary fibrosis in paraquat poisoning has been
to ingestion of the 20% aqueous solution Gramoxone. The less con- disputed. Some authors have stressed its interstitial position, whereas
centrated granular form Weedol is unlikely to be ingested accidentally others have clearly demonstrated that it is intra-alveolar.98,102,104–107
but may be taken suicidally.89 Paraquat is not absorbed by the intact However, as described on page 148, it generally assumes an oblitera-
skin but repeated or prolonged application damages the epidermis so tive pattern of intra-alveolar fibrosis in which the lumina of several
that absorption into the blood stream with consequent systemic adjacent alveoli are totally effaced, rendering them completely airless
effects is possible, but rare.90 (see Fig. 4.24, p. 148).
Although paraquat has toxic effects on the liver, kidneys and
myocardium, these are transient and attention has centred on the
Toxic oil syndrome
pulmonary changes, which are usually fatal. Following suicidal inges-
tion of large amounts of paraquat, death from multiorgan failure and A new multisystem disease appeared abruptly in the environs of
pulmonary haemorrhage occurs within a few days, whereas most Madrid in 1981.108–110 Over 20 000 people were affected and about 1

375
 Pathology of the Lungs

in 60 died. The disease was initially thought to be Mycoplasma

pneumonia but was soon found to be associated with the use of
adulterated oil sold illicitly by door-to-door salesmen. Although it was
sold for culinary purposes the oil had been produced for industrial
use in steel manufacture. It consisted of rapeseed and olive oil mixed
with liquified animal fat, aniline and other organic chemicals. It has
not been possible to identify the exact chemical responsible for the
disease or to reproduce the changes in other species but the later
induction of similar pathological changes by another substance
contaminated with an aniline derivative is possibly relevant (see
111
l-tryptophan-induced eosinophilia–myalgia syndrome, p. 389).
Some clinical and pathological features of the disease suggest that
immune mechanisms may also be involved.
The initial clinical features included fever, respiratory distress,
cough, haemoptysis, skin eruptions and marked eosinophilia.
A
Radiographs suggested pulmonary oedema and sometimes showed
pleural effusion. About 5% of patients died at this stage but most
recovered quickly. However, within a few weeks many were readmitted
to hospital with nausea, vomiting, diarrhoea and abdominal pain.
About a quarter then proceeded to develop weakness, myalgia, weight
loss, scleroderma-like skin signs and pulmonary hypertension.112,113
Many of these patients died after a long, wasting illness or are perma-
nently disabled with neurological and hepatic disorders.
In the early phase the lungs showed the most severe changes, which
consisted of a combination of diffuse alveolar damage, eosinophilic
infiltrates and arterial luminal narrowing by endothelial swelling
and vacuolation, intimal foam cell infiltration and a non-necrotising
vasculitis.109,112,114 There was also capillary thrombosis, which later
extended into arteries and veins, culminating in fibrosing obliteration
of these blood vessels. In some patients dying of haemoptysis, dilated
thin-walled blood vessels were identified in the mucosa of major
B blood-filled airways. Late features in the lungs included plexogenic
arteriopathy (see p. 420), possibly secondary to changes in the liver.
Figure 7.2.5  Paraquat poisoning. After initial swelling of the cytoplasm Similar inflammatory and vascular changes were seen in many
(A) the type I alveolar epithelial cells proceed to complete necrosis (B), other tissues. Notable extrapulmonary features included fasciitis,
exposing the basement membrane (arrow) they share with the alveolar vasculitis, neuronal degeneration, perineuritis, hepatic injury and
capillary endothelium to alveolar air. Flecks of fibrin are seen in the tissue eosinophilia.
alveolus. Intact endothelium and part of an erythrocyte are seen beneath
the denuded basement membrane. (Reproduced by permission of the editors
of the Journal of Pathology99 and Progress in Respiratory Research.103) Sauropus androgynus
Sauropus androgynus is a vegetable that is widely cultivated for the table
in many south-eastern Asian countries. It is apparently harmless when
cooked but recently there has been a vogue in Taiwan for consuming
large amounts of its unprocessed juice, blended with that of guavas
or pineapple, because of its supposed efficacy as a slimming aid and
in blood pressure control. Coincident with this fad there has been an
upsurge in patients with symptoms of obstructive lung disease. Within
a 4-month period more than 60 such patients were seen at one hos-
pital.115–117 They had four features in common: recent consumption of
uncooked S. androgynus juice, fixed ventilatory obstruction, radiologi-
cal evidence of bilateral bronchiectasis and an absence of any previous
chronic respiratory disease. Four patients agreed to undergo open-lung
biopsy. This showed chronic bronchiolitis or obliterative bronchiolitis
of constrictive pattern. The lymphocytes were mainly T cells but
immunofluorescent and electron microscopy showed no evidence of
an immune process. Four patients underwent single-lung transplanta-
tion. The excised lungs showed sclerotic obliteration of bronchial
arteries in the walls of bronchi 4–5 mm in diameter with segmental
necrosis of bronchi 2–4 mm in diameter. The changes were consid-
Figure 7.2.6  Suicidal paraquat poisoning. The ingestion of large ered to fit best with segmental ischaemic necrosis of bronchi at the
amounts of the chemical has led to death from pulmonary haemorrhage watershed zone of the bronchial and pulmonary vasculature.118 Further
and diffuse alveolar damage within 3 days. Note the hyaline membrane patients have required lung transplantation but public education of
formation and early interstitial fibrosis. (Courtesy of Dr D Melcher, Brighton, the dangers of this herbal medicine now appears to have been
UK.) successful.119

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

RECREATIONAL DRUGS

Alcohol and nicotine outstrip all other recreational drugs in popular-

ity and their effects are of course well known. Those of tobacco
smoking are summarised above and dealt with in detail in the chap-
ters on obstructive lung disease (Chapter 3) and carcinoma of the
lung (Chapter 12.1). Less well known is the lung disease that results
from smoking Blackfat tobacco, a practice popular with Guyanese
Indians. Blackfat is the trade name of a type of tobacco that is
flavoured with mineral oil, some of which vaporises and is inhaled
when the tobacco is smoked, to cause exogenous lipid pneumonia
(see p. 314 [Ch8]).120 In recent years the smoking of two other sub-
stances, marijuana and cocaine, has gained in popularity. It would not
be surprising if the long-term effects of smoking these substances were
similar to those of cigarette smoking but as yet it is too early to judge.
However, the short-term effects are similar to those of tobacco smoking
and this bodes badly for their ultimate effects.

Marijuana
Marijuana consists of the dried leaves of the cannabis plant, also
known as hemp, as opposed to hashish, which is the plant’s resin,
and a further extract known as ‘weed oil’. All these substances are
smoked because they contain cannabis alkaloids which have psycho-
active effects. However, this habit also exposes the lungs to many
of the same respiratory irritants that are found in tobacco smoke.
Initial exposure to marijuana smoke often results in coughing while
habitual smokers produce black sputum. Bronchial biopsy shows
inflammation and squamous metaplasia and bronchoalveolar lavage
demonstrates increased numbers of cells, which are predominantly Figure 7.2.7  Bilateral pneumothoraces in a 23-year-old man who died
suddenly while smoking marijuana. The collapsed lungs (arrows) have
macrophages but also include neutrophils.121–125 These changes are
retracted towards the mediastinum. (Courtesy of Dr JF Tomashefski Junior,
virtually identical to the short-term effects of tobacco smoke and are
Cleveland, USA.131)
therefore likely to be similarly followed by the development of chronic
obstructive lung disease and lung cancer. Indeed, the dangers of
smoking marijuana are probably greater than those of smoking
tobacco as compared with tobacco smoking it is associated with a
fivefold greater increase in blood carboxyhaemoglobin and a threefold being known as ‘snorting’. However, a heat-stable free-base form that
increase in the amount of tar inhaled.126 It is estimated that three can be smoked is easily prepared from the hydrochloride with baking
cannabis cigarettes result in the same degree of bronchial damage as powder and a solvent such as ether. This process results in a crystalline
20 tobacco cigarettes.127 There is also evidence that the effects of deposit that is known as ‘rock’ because of its appearance or ‘crack’
smoking marijuana and tobacco are additive.128 because of the crackling sound it emits when heated. When smoked,
Not surprisingly therefore, epidemiological studies report a dose- the cocaine is readily absorbed and an intense surge of euphoria is
related impairment of large-airway function in marijuana smokers.129 experienced within 8 seconds. The intravenous route takes twice as
There are also several reports attributing pneumothorax to marijuana long and ‘snorting’ several minutes. The hard addict therefore prefers
smoking (Fig. 7.2.7).130,131 The pneumothorax may be spontaneous or to smoke ‘crack’.
develop during the deep, sustained inspiratory effort involved in A variety of pulmonary complications of smoking free-base cocaine
smoking marijuana (or cocaine), which may be enhanced by a partner has been reported.128,135–144 Acute effects include cough, shortness
applying positive ventilatory pressure by mouth-to-mouth contact. of breath, chest pain and haemoptysis. Asthma may be aggravated,
Thoracoscopy in such cases has shown predominantly apical, irregular black sputum is produced, and pneumothorax and interstitial
bullous emphysema, while lung biopsy has demonstrated widespread emphysema have resulted from Valsalva manoeuvres undertaken in
alveolar filling by heavily pigmented macrophages.131,132 Evidence is the belief that they promote even more rapid absorption. Biopsy has
also beginning to accumulate that long-term cannabis use increases shown pulmonary congestion and oedema, organising pneumonia,
the risk of lung cancer.133 Smoking cannabis in the form of weed oil haemorrhage, haemosiderosis, diffuse alveolar damage and interstitial
is also reported to result in exogenous lipid pneumonia.134 pneumonia or fibrosis. Less common effects include eosinophilic
pneumonia, extrapulmonary eosinophilic angiitis, medial thickening
of pulmonary arteries and the barotrauma described above (see
Cocaine
Fig. 7.2.7). Severe burning of the airways has also been seen due
Cocaine hydrochloride is a fine white powder derived from the leaves to ‘crack’ being smoked before all the ether used in its preparation
of the plant Erythroxolon coca by a complex chemical process. It is has evaporated.
heat-labile and therefore cannot be smoked. Users inject it intra­ ’Snorting’ unheated cocaine has its own complications: substances
venously or inhale it unheated through the nose, the latter practice such as cellulose or talc with which the drug is ‘cut’ (mixed as a

377
 Pathology of the Lungs

diluent) are liable to provoke a foreign-body giant cell reaction in the and Table 7.2.3) and elemental composition, as studied by X-ray
lungs (Fig. 7.2.8).145 However, particles of foreign material larger than spectroscopy (see p. 330).
those in the usual respirable range (allowing for the fibrous shape of
substances such as cellulose) should suggest intravenous use (see
‘Filler embolism’, below).
4-methyl-aminorex
This ‘designer’ drug, taken for its central stimulant activity (street
names ‘ice’ or ‘U-4-E-uh’, pronounced euphoria), is related to the
Heroin
appetite suppressor aminorex, discussed on page 424, and has simi-
Heroin is usually injected, but it may be smoked, when, as with larly been associated with pulmonary hypertension.154
marijuana, it is liable to lead to a very pronounced macrophage
response. Intravenous heroin abuse sometimes causes the sudden
onset of a potentially fatal high-permeability pulmonary oedema (Fig.
7.2.9). Intravenous abuse of heroin and other drugs is also liable to
cause ‘filler embolism’, which will now be considered.

‘Filler embolism’
‘Filler embolism’ is the result of illicit drug usage in which compounds
designed for oral use are injected intravenously to heighten their
effects. Oral preparations consist largely of fillers such as talc or starch
and this insoluble particulate matter accumulates in the pulmonary
capillaries. It provokes a foreign-body giant cell reaction, thrombosis
and fibrosis and may cause pulmonary hypertension (Fig. 7.2.10 and
see Fig. 8.1.13, p. 412).146–153 The various materials may be distin-
guished by their morphology, staining characteristics (see Fig. 7.2.10

Figure 7.2.9  Frothy oedema fluid protrudes from the nostrils of a person
Figure 7.2.8  A foreign-body granulomatous response in the lungs to who died while injecting heroin intravenously. Similar froth filled the
cellulose filler inhaled by a cocaine sniffer. Section viewed by partially whole respiratory tract. (Courtesy of Dr JF Tomashefski Junior, Cleveland,
polarised light microscopy. USA.131)

Table 7.2.3  Tablet filler materials

Filler Shape Size Polarisation Histochemistry

Starch Round 8–12 µm Maltese cross d-PAS

Talc Platy but seen edge-on as needles 5–15 µm Strong None
Cellulose Fibrous 25–200 µm Strong PAS, Congo red
Crosprovidone Globular or coral-like 100 µm Negative Mucicarmine, Congo red
Magnesium stearate Irregular 5–10 µm Positive None
Silica Irregular 10–20 µm Positive None

d-PAS, diastase-controlled periodic acid–Schiff.

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

A B

C D

Figure 7.2.10  Tablet filler materials in the lungs. (a) Intravascular and perivascular deposits of the tablet dispersant crospovidone eliciting a foreign-
body giant cell reaction. (b) A crosprovidone granuloma stained with mucicarmine. (c) A starch granuloma stained with periodic acid–Schiff reagents.
(d) The Maltese cross birefringence of starch viewed by polarized light. (Courtesy of Dr JF Tomashefski Junior, Cleveland, USA.131)

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123. Gong H, Fligiel S, Tashkin DP, et al.
Tracheobronchial changes in habitual,

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7.3  Iatrogenic lung disease

CHAPTER CONTENTS
ADVERSE DRUG REACTIONS
Adverse drug reactions 383
Reduced respiratory drive 384 It is estimated that 5% of all hospital admissions are due to effects
Drug-induced bronchospasm 384 of therapeutic drugs, that 10–18% of inpatients experience a drug
reaction and that 3% of deaths in hospital may be related to drug
Oblitereative bronchiolitis 385
therapy.1–4 The lungs are often involved in these adverse reactions.
Cytotoxic effects of drugs 385
Phospholipidosis 387
Mechanisms of adverse drug reactions5
Alveolar proteinosis 388
The mechanism of an adverse drug reaction may be based on:
Eosinophilic pneumonia 388
Churg–Strauss syndrome 389
• overdosage: toxicity linked to excess dose, or impaired excretion,
or both
Eosinophilia–myalgia syndrome 389 • side-effect: undesirable pharmacological effect at recommended
Granulomatous alveolitis 389 dose
Aspiration lesions 389 • interaction with other drugs
Pulmonary hypertension 390 and in susceptible individuals only:
Pulmonary embolism 390 • intolerance (representing a low threshold to the normal action
Diffuse pulmonary haemorrhage 390 of the drug)
• idiosyncrasy (an abnormal reaction based on a genetically
Opportunistic infection 391
determined metabolic or enzymic deficiency)
Metastatic calcification 391 • allergy in the form of any of the four main hypersensitivity
Carcinoma of the lung 391 reactions:
Pleural disease 391 1. immediate IgE-mediated hypersensitivity
Radiation injury 391 2. IgG- or IgM-mediated cytotoxicity
3. IgG- or IgM-mediated immune complex disease
Respirator lung and oxygen toxicity 391 4. T-cell-mediated cellular hypersensitivity
Blood transfusion 392 • pseudoallergic reaction: A reaction with the same clinical
Cardiopulmonary bypass 392 manifestations as an allergic reaction (e.g. as a result of
Complications of cardiac injury 393 histamine release) but lacking immunological specificity.
Complications of radiofrequency ablation 393
Complications of central vascular cannulation 393 Classification of adverse drug reactions
Complications of tracheal manipulations 393 One classification of adverse drug reactions is that based upon the
Complications of bronchoscopy 393 type of drug (Box 7.3.1).6 This is not adopted here but in passing it
is worth noting that pharmacists are generally very helpful in supply-
Complications of thoracic drainage tubes 394
ing details of adverse reactions to specific drugs. Alternatively,
Pneumonectomy 394 information on the long list of potentially pneumotoxic drugs may
References 394 be obtained at http://www.pneumotox.com. A useful scheme for

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Box 7.3.1  Principal therapeutic agents known to cause Table 7.3.1  Pathological patterns of drug-induced lung disease
pulmonary disease6
Pathological pattern Prototypic drug(s)
Chemotherapeutic Analgesics
drugs Diamorphine (heroin) Cytotoxicity Chemotherapy
Azathioprine Ethchlorvynol Diffuse alveolar damage
Bleomycin Methadone Interstitial fibrosis (NSIP, UIP, mixed)
Busulphan Naloxone Organising pneumonia
Chlorambucil Propoxyphene Phospholipidosis Amiodarone
Cyclophosphamide Salicylates
Etoposide Alveolar proteinosis Chemotherapy
Cardiovascular drugs
Ifosfamide Eosinophilic pneumonia Nitrofurantoin
Amiodarone
Melphalan
Angiotensin-converting enzyme
Mitomycin Eosinophilia–myalgia syndrome l-tryptophan
inhibitors
Nitrosoureas
Anticoagulants Granulomatous alveolitis Methotrexate
Procarbazine
β-antagonists
Vinblastine Aspiration lesions Liquid paraffin
Cytosine arabinoside Fibrinolytic agents
Methotrexate Pulmonary vascular disease
Protamine
Hypertension Aminorex
Antibiotics Tocainide
Thromboembolism Oestrogen
Amphotericin B Inhalants Haemorrhage Anticoagulants
Nitrofurantoin Aspirated mineral oil
Sulphasalazine Opportunistic infection Immunosuppressive agents
Oxygen
Sulphonamides Metastatic calcification Vitamin D
Intravenous agents
Pentamidine
Ethanolamine oleate (sodium morrhuate) Carcinoma of the lung Arsenicals
Anti-inflammatory Iodised oil (lymphangiography)
drugs Fat emulsion Pleural disease Practolol
Acetylsalicylic acid
Miscellaneous NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia.
(aspirin)
Gold Bromocriptine
Methotrexate Dantrolene
Non-steroidal anti- Hydrochlorothiazide
inflammatory agents Methysergide Reduced respiratory drive
Penicillamine Oral contraceptives
Tocolytic agents Central depression of respiration occurs as a side-effect of
Immunosuppressive Tricyclics barbiturates, morphine and its derivatives, and even mild sedatives,
drugs l-Tryptophan and may be particularly troublesome in patients suffering from
Ciclosporin X-irradiation chronic obstructive lung disease. Ventilation in such patients may be
Interleukin-2 largely dependent on hypoxic respiratory drive and treatment with
Particularly common agents are italicized.
oxygen may therefore also have an adverse effect on respiration by
lowering the degree of hypoxia and so diminishing the stimulation of
the respiratory centre. Peripheral impairment of the respiratory drive
may be brought about by aminosides and other antibiotics, while
corticosteroids may result in a myopathy affecting the respiratory
assessing whether a particular clinical manifestation represents an
muscles. Other iatrogenic hazards affecting the peripheral nerves con-
adverse drug reaction considers previous experience with the drug,
trolling respiration include nerve root disease complicating immuni-
alternative aetiological agents, the timing of events, drug levels, and
sation and surgical damage to the spinal and phrenic nerves.
the effect of withdrawing the drug and rechallenge with the drug.7 It
is worth bearing in mind that:
• One drug may cause several patterns of disease. Drug-induced bronchospasm
• One pattern of disease may be produced by a variety of Asthmatic patients are particularly susceptible to exacerbations of
drugs. their disease by drugs (Box 7.3.2). This effect may occur either
• A drug reaction may develop long after the drug has been as a predictable pharmacological side-effect of the drug or as an
withdrawn. idiosyncratic response. Examples of the former include β-adrenergicic
• A drug reaction may develop suddenly even though the dose of antagonists and cholinergic agents while examples of the latter include
the drug has not been altered. sensitivity to the colouring agent tartrazine, for which reason many
• Drug effects may be augmented by factors such as age, previous manufacturers have eliminated tartrazine from their red, orange and
radiotherapy and elevated oxygen levels. yellow tablets. Allergic bronchoconstriction also forms part of gener-
• Drug reactions may be localised. alised anaphylactic reactions induced by vaccines and antisera and
• Many drugs cross the placenta to affect the fetus. occurs as a localised response to penicillin, iodine-containing contrast
An alternative classification of adverse drug reactions, which is more media, iron dextran and other medicaments. Bronchospasm may also
appropriate to pathology practice and which will be followed here, is be initiated by the non-specific irritant effect of inhaling nebulised
one based on the pattern of disease. Some pathological patterns of drugs if they are prepared as a hypotonic solution, a side-effect that
drug-induced lung disease are shown in Table 7.3.1. is prevented by using isotonic solutions.

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

Pulmonary toxicity due to busulphan was first described in 1961,20

Box 7.3.2  Drugs known to cause or aggravate and has been the subject of several subsequent studies.21–24 It remains
bronchoconstriction the mainstay of treatment for chronic myeloid leukaemia. Like other
alkylating agents, it acts by cross-linking DNA strands. Clinical
Non-specific estimates of the incidence of pulmonary toxicity vary around 4% but
Hypotonic nebulised preparations subclinical damage is thought to be much more common. Although
not strictly dose-dependent, toxicity is rarely seen with a total
Pharmacological
cumulative dose of less than 500 mg. Synergy with radiation and
β-sympathetic antagonists other cytotoxic drugs occurs.25 Similar effects have been reported
Cholinergic agents, e.g. pilocarpine for most cytotoxic agents, particularly bleomycin.26 Pulmonary toxic-
Idiosyncratic ity is seen less commonly with other alkylating agents, such as cyclo­
phosphamide and melphalan.27–30
Penicillin
Iodine-containing contrast media Bleomycin is a cytotoxic antibiotic derived from Streptomyces species.
Iron dextran It is widely used in the treatment of neoplasms such as lymphomas
Tartrazine and germ cell tumours, and is thought to produce its therapeutic and
toxic effects by altering the normal balance between oxidants (active
Prostaglandin potentiation oxygen radicals) and antioxidant systems.26 Bleomycin produces
Aspirin and other non-steroidal anti-inflammatory agents superoxide radicals when incubated with oxygen and iron in vitro.
Oxygen enhances its effects,31 a fact well known to anaesthetists who
Occupational allergy
accordingly take care to limit concentrations of inspired oxygen to
Penicillin 30% in patients on bleomycin who are undergoing surgery.32–34
Cephalosporin Radiotherapy and cytotoxic agents such as bleomycin are also
synergistic. Bleomycin is preferentially concentrated in the lungs and
pulmonary fibrosis can be produced in animals when it is adminis-
tered intravenously, intraperitoneally or by intratracheal instillation.
Aspirin-induced asthma has been recognised for many years and Electron microscopy shows that the early changes consist of swelling
more recently several of the newer anti-inflammatory drugs have been and vesiculation of endothelial cells, interstitial oedema and type I
found to exacerbate asthma in certain sensitive individuals. The basis epithelial cell necrosis.35,36 The reported incidence of bleomycin
for this is uncertain but the likelihood of an individual anti- toxicity varies from 2 to 40% depending on the type of patient being
inflammatory drug provoking an asthmatic response is related to its treated and on dosage. In general, toxic effects increase with age and
potency as an inhibitor of prostaglandin cyclooxygenase pathway, cumulative dose: above a total dose of about 500 units they rise
resulting in the production of leukotrienes.8–10 significantly.
As well as asthma being exacerbated by drugs, the disease has been The acute morphological changes attributable to drugs include
caused by occupational exposure in the pharmaceutical industry to pulmonary oedema and diffuse alveolar damage. Acute pulmonary
certain drugs which can be inhaled during manufacture, notably oedema is seen in heroin addicts who die while injecting themselves
penicillin, cephalosporin, methyldopa, cimetidine and piperazine. intravenously but it is also seen in patients administered a variety of
drugs therapeutically, for example hydrochlorothiazide, salicylate,
Obliterative bronchiolitis opiates, vinorelbine,and desferrioxamine. The oedema is of the high
permeability type (see p. 402), rich in protein, and is occasionally
Obliterative bronchiolitis of the constrictive type has been reported haemorrhagic or accompanied by the hyaline membranes of diffuse
with penicillamine11,12 and gold13,14 but in many cases it is possibly alveolar damage.
the underlying condition rather than the drug that is res­ponsible (see Diffuse alveolar damage has alveolar epithelial necrosis as its basis
p. 123). This is often rheumatoid disease, which is sometimes (Figs 7.3.1 and 7.3.2). However, the continuing action of many cyto-
complicated by bronchiolitis obliterans whether the patient is under toxic drugs affects the regeneration process so that atypical type II
treatment or not.15 epithelial cells develop, a characteristic feature that was first described
Organising pneumonia extending into peripheral bronchioles with busulphan and subsequently with bleomycin.21,37 These two
(see p. 120) may be seen with a variety of drugs but results in a drugs differ chemically but both act (by different mechanisms) on
restrictive rather than obstructive lung defect and is to be regarded DNA. The atypical cells have abundant deeply eosinophilic or
as a cytotoxic effect of the drug acting primarily at the alveolar amphophilic cytoplasm and large nuclei, which may be multiple but
level (see below). are usually single. The nuclei measure up to 12 µm and are densely
Raw Sancropus androgyns taken as a slimming aid causes severe stained throughout or contain either large homogeneous deeply eosi-
obliterative bronchiolitis (see p. 376). nophilic inclusions or clear vacuoles (Fig. 7.3.3). Electron microscopy
distinguishes the inclusions from nucleoli and shows them to consist
of tubular aggregates derived from the internal nuclear membrane.37
Cytotoxic effects of drugs
Airway epithelium shows similar nuclear changes and often undergoes
The cytotoxic effects of drugs may be acute or chronic, leading to squamous metaplasia. The presence of such cells in sputum specimens
changes as varied as pulmonary oedema, diffuse alveolar damage, submitted for cytology can lead to a misdiagnosis of malignancy.
pulmonary haemorrhage and haemosiderosis, organising pneu­ Fibrosis may follow diffuse alveolar damage or develop insidiously,
monia, interstitial pneumonitis and interstitial fibrosis.16,17 Some of perhaps many years after drug therapy ceased (Fig. 7.3.4).38 It may be
the most severe acute effects are seen with the chemotherapeutic both interstitial and intra-alveolar. The interstitial component is often
agents used in malignant disease18 but they are also recorded with accompanied by a non-specific chronic inflammatory infiltrate. The
drugs that are not traditionally thought to be cytotoxic, e.g. desferri- proportions of inflammation, which is potentially reversible, and
oxamine administered as a prolonged intravenous infusion in acute fibrosis, which when collagenous is irreversible, obviously bear on
iron poisoning.19 the prognosis. However, most case reports antedate the recent

385
 Pathology of the Lungs

Figure 7.3.3  Busulphan toxicity. The alveoli are lined by regenerating

epithelial cells and the central cell has a very prominent nucleus.

Figure 7.3.1  Drug toxicity. A cancer patient administered a cocktail of

cytotoxic drugs developed acute respiratory distress and biopsy showed
loss of the type I alveolar epithelial cells when examined by electron
microscopy. The alveolar basement membrane is bare on its alveolar
aspect (above). Capillary endothelial cells show cytoplasmic swelling.
(Courtesy of Miss A Dewar, Brompton, UK.)

Figure 7.3.4  Fatal pulmonary fibrosis resulting from busulphan therapy,

which had been administered for 2 years several years previously.

classification of interstitial pneumonia described in Chapter 6 and it

is uncertain how their pathological appearances would now be clas-
sified. The majority lack the classic features of usual interstitial pneu-
monia and fibrotic non-specific interstitial pneumonia. Many show
Figure 7.3.2  Amiodarone toxicity resulting in diffuse alveolar damage overlapping patterns of intersitital pneumonia and this alone should
characterised by hyaline membrane formation. arouse suspicion that a drug may have been responsible. However,

386
 Occupational, environmental and iatrogenic lung disease Chapter |7|

Some cytotoxic drugs result in pulmonary changes by more than

one mechanism: for example, methotrexate may produce hyper­
sensitivity reactions with granuloma formation41–44 or pulmonary
eosinophilia45 as well as diffuse alveolar damage. Pulmonary toxicity
is also occasionally seen in patients undergoing treatment with gold
salts for rheumatoid disease: in addition to diffuse alveolar damage,
there may be eosinophilia and dermatitis in these cases, again indicat-
ing possible hypersensitivity.46 Nitrofurantoin is another example of
a drug resulting in a variety of patterns of alveolar injury: diffuse
alveolar damage, desquamative interstitial pneumonia, giant cell
interstitial pneumonia, organising pneumonia and eosinophilic
pneumonia have all been recorded in association with this drug.47–49
It should also be noted that in patients with neoplastic disease,
clinical features suggestive of a pulmonary drug reaction may be due
to factors other than drugs. In leukaemic patients, for example, these
include direct infiltration of the lungs by leukaemic cells, opportunist
A
infection and, if bone marrow transplantation has been undertaken,
the effects of irradiation and possibly graft-versus-host disease.

Phospholipidosis
Phospholipidosis is encountered with drugs such as the antidysrhyth-
mic agent amiodarone,50 which block lysosomal enzymes involved in
the breakdown of complex lipids. This leads to their accumulation
throughout the body but the effect is most marked in tissues that take
up the drug and contain cells rich in lysosomes. The lung fulfils both
these requirements through its rich complement of alveolar macro-
phages. These cells accumulate the enzyme substrate (phospholipid)
in their cytoplasm with the result that large foam cells fill the alveoli
(Fig. 7.3.6). The appearances are those of endogenous lipid pneu­
monia, similar to that seen in obstructive pneumonitis. However, with
amiodarone cytoplasmic vacuolation is also seen in epithelial and
interstitial cells. The phospholipid inclusions contained within the
vacuoles are particularly well seen in unstained frozen sections viewed
by polarised light.51 Identical changes to those induced by amiodarone
were seen in the lungs of rats exposed to very high levels of the
antidepressant drug iprindole52 and the anorectic drug chlor­
B phentermine.53 These three compounds, iprindole, chlorphentermine
and amiodarone, all belong to the amphiphilic group of drugs
Figure 7.3.5  Nitrofurantoin toxicity. The lung shows patchy subpleural which block lysosomal phospholipase and sphingomyelinase.
fibrosis (A) with fibroblastic foci (B). These are the classic features of Although their pharmacological actions are very different, a molecular
usual interstitial pneumonia but lung function improved after withdrawal homology is apparent (Fig. 7.3.7).
of the drug. It is likely that all patients receiving substantial amounts of
amiodarone develop phospholipidosis throughout the body, but this
is generally well tolerated. Only a minority experience respiratory
impairment and in these there is also evidence of pulmonary in­­
flammation and fibrosis, which is possibly mediated immunologi-
there are drugs that undoubtedly cause a usual interstitial pneumonia cally.54 These patients generally have a restrictive lung deficit, the onset
pattern, for example the chemotherapeutic agents and nitrofurantoin of which may be acute or chronic. Bronchoalveolar lavage shows
(Fig. 7.3.5), while others, for example the statins, are recorded as foamy macrophages but these cells indicate exposure to the drug
having induced a non-specific interstitial pneumonia pattern.39 A drug rather than drug toxicity; nor are they specific to amiodarone, being
history is therefore imperative when assessing any patient with diffuse observed on occasion with other drugs. Lymphocytes of suppressor
parenchymal lung disease. type may also be detected on lavage.54 Histologically, amiodarone
Organising pneumonia similar to the cryptogenic condition toxicity is diagnosed on a combination of phospholipidosis and inter-
described on page 308, and probably similarly reversible with ster- stitial pneumonia and fibrosis. Occasionally the hyaline membranes
oids, has been encountered with a variety of drugs, including amio- of diffuse alveolar damage are superimposed on the interstitial
darone, sulphasalazine and pencillamine.40 Penicillamine has also changes (see Fig. 7.3.2).55–57 In some patients the fibrosis is intra-
been incriminated in the development of both diffuse alveolitis and alveolar rather than interstitial and the appearances are those of
bronchiolitis obliterans, but both these changes could well be due to organising pneumonia.58 The process may be localised and mimic a
the underlying rheumatoid disease for which the pencillamine is neoplasm radiologically.59,60
administered.15 In busulphan lung there may be an organising intra- Amiodarone toxicity is probably dose-dependent but there is
alveolar fibrinous exudate,21 which at its most extreme results in irre- considerable individual variation in the amount required,61,62 which
versible effacement of the alveolar architecture by sheets of loose appears to be under genetic control.63 Amiodarone toxicity is un­­
connective tissue (see p. 148). common in patients taking daily doses of 200 mg or less whereas the

387
 Pathology of the Lungs

I
C2H5
CO O (CH2)2 N+ H
C2H5
I
(CH2)3CH3
O Amiodarone

CH3
N (CH2)3 N+ H Iprindole
A CH3

CH3
Cl CH2 C N+H3 Chlorphentermine
CH3

Figure 7.3.7  Formulae of several amphiphilic drugs, all of which block

lysosomal phospholipases and cause endogenous lipid pneumonia. The
pharmacological actions of these drugs differ but a molecular homology
is evident.

prevalence of the disease exceeds 50% in patients treated with doses

of 1200 mg/day. Duration is also important: it may require 2–3 years
for a patient on 200 mg/day to develop symptoms but only 10 months
for one on 400 mg/day. The drug has a long half-life and may take
weeks to clear the body completely. Previous pulmonary injury renders
the lung unduly sensitive to amiodarone. Acute toxicity has been
encountered in patients on moderate doses who have experienced
recent or even concomitant pulmonary procedures such as intubation,
lobectomy or ventilation with high concentrations of oxygen.64

Alveolar proteinosis
With continued experimental administration of the drug iprindole
mentioned above, the phospholipidosis it produced gradually evolved
B into alveolar proteinosis (more properly called lipoproteinosis; see
p. 316),65 but this has not been reported as a drug effect in humans.
Figure 7.3.6  Phospholipidosis due to prolonged amiodarone Alveolar proteinosis has however been recognised in a number of
administration. Amiodarone blocks lysosomal phospholipases, leading to patients receiving chemotherapy for conditions such as leukaemia.
the accumulation of phospholipids in many organs. In the lung this is The mechanism here is probably based on the cytotoxic action of the
manifest as endogenous lipid pneumonia. (A) By light microscopy the drug and the material filling the alveoli may represent the detritus of
alveoli are filled with foamy macrophages. (B) Electron micrograph
degenerate alveolar cells rather than excess pulmonary surfactant, as
showing an alveolar macrophage (top) packed with osmiophilic lamellar
in the primary auto-immune form of alveolar proteinosis.
bodies. The macrophage covers several type II pneumocytes that, in
addition to their normal surfactant inclusions (arrows), contain large
lamellated drug-induced inclusions (asterisks), which are also seen in Eosinophilic pneumonia
capillary endothelial cells. C, capillary. (Reproduced with permission from
Costa-Jussa et al. (1984).50) Eosinophilic pneumonia, the pathology of which is described on
page 461, may be caused by several drugs, including nitrofurantoin,
para-aminosalicylic acid, sulphasalazine, phenylbutazone, gold
compounds, aspirin and penicillin (see Box 9.3, p. 460).66,67 It may
also follow radiation to the chest.68 The tissue eosinophilia is generally
accompanied by a rise in the number of eosinophils in the blood. The

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

clinical picture varies from transient asymptomatic opacities on a

chest radiograph to a life-threatening illness with severe respiratory
distress and hypoxaemia, so-called acute eosinophilic pneumonia
(see p. 462). The reaction is often associated with a florid rash.
Withdrawal of the drug may be all that is required to effect resolution
but corticosteroids are usually given as they produce a marked
improvement.

Churg–Strauss syndrome
This syndrome of necrotising granulomatosis, vasculitis and eosino­
philia in asthmatic patients, which is described more fully on page
465, has been reported when leukotriene receptor antagonists have
been used to treat asthma. However, it is likely that the syndrome has
been merely unmasked by the antileukotriene permitting a reduction
A
in corticosteroid dose rather than representing a direct effect of the
antileukotriene.69,70 Mesalazine has also been implicated in inducing
a vasculitis during treatment for inflammatory bowel disease.71

Eosinophilia–myalgia syndrome
The eosinophilia–myalgia syndrome was identified in the USA in
1989 and quickly identified as being due to the ingestion of l-
tryptophan from one particular Japanese supplier. Withdrawal of this
substance led to the virtual elimination of the disease, but not before
2000 patients had been affected, 1 in 60 fatally.72–76 Cases were
subsequently described in Europe where there were further fatalities.
l-tryptophan is an essential amino acid that is freely available
to the public: its purchase does not require a medical prescription. It
has been promoted as a dietary supplement and as an agent against
insomnia and premenstrual tension. Women in the reproductive years
preponderated in the patients affected by the resultant eosinophilia–
myalgia. The clinicopathological features of the syndrome are similar B
to those of the Spanish toxic oil syndrome (see p. 375) and differ
more in degree than type. The discovery of an aniline-derived con- Figure 7.3.8  l-tryptophan toxicity. (A) There is a diffuse interstitial
taminant in the tryptophan-induced condition is a further link con- infiltrate of lymphocytes with smaller numbers of eosinophils. (B) The
necting these two syndromes.77 An immune basis is suggested by the same infiltrate involves pulmonary blood vessels. (Courtesy of Dr TV Colby,
Scottsdale, USA.)
identification of T lymphocytes activated against fibroblasts in the
eosinophilia–myalgia syndrome.78
The illness is a multisystem disorder and besides blood eosinophilia
and myalgia there may be arthralgia, fever, rash and involvement of acinar or lymphangitic concentration of these conditions is usually
the lungs, liver and central nervous system. As in the toxic oil lacking. However, unless an infective agent can be demonstrated the
syndrome, there is fasciitis, wasting and muscle pain associated with diagnosis generally requires consideration of the clinical and environ-
blood and tissue eosinophilia. The lungs are affected in 60% of cases. mental details, including any drug regimen.
Pulmonary symptoms have included cough, dyspnoea and chest pain.
Radiographs have shown diffuse bilateral infiltrates and pulmonary
hypertension has been documented in a few cases.79 Aspiration lesions
Histology of the lungs shows an oedematous myxoid intimal thick- Exogenous lipid pneumonia may result from the unintentional
ening affecting small pulmonary blood vessels and a diffuse inter­ aspiration of various fat-based medicaments such as liquid paraffin,
stitial lymphocytic and eosinophilic infiltrate.72,73,75,76,80 These cells oily nose drops and petroleum jelly or of fat-rich dietary supplements
may also be seen within the walls of the thickened blood vessels (Fig. in the form of ghee.91–97 The consumption of liquid paraffin as an
7.3.8).72,76 Massive ingestion of l-tryptophan has resulted in the aperient is common in some countries and may be taking place
appearances of an organising pneumonia.81 without the knowledge of the patient’s medical practitioner.
Regurgitation and aspiration of ingested oil are especially likely to
happen during sleep in the presence of a hiatus hernia or when the
Granulomatous alveolitis
oesophagus fails to empty completely into the stomach because of
As an adverse drug reaction, granulomatous alveolitis is best exem­ achalasia of the cardia. The aspiration of vegetable oil occurred in the
plified by the extrinsic allergic alveolitis of pituitary snuff-takers, but past from the use of menthol in olive oil for the treatment of tuber-
it is also encountered on rare occasions with cytotoxic and other culous laryngitis, and occasionally from the use of iodinated vegetable
drugs, including methotrexate, bacille Calmette–Guérin (BCG) immu- oils for bronchography.98–101 More recently exogenous lipid pneumo-
nisation, interferons, ciprofloxacin, antiviral therapy and tumour nia has developed from the constant sucking of lollipops formulated
necrosis factor antagonists.42–44,48,82–90 The histological appearances for the administration of the analgesic fentanyl but also containing a
may suggest extrinsic allergic alveolitis or sarcoidosis but the centri- stearate component.102 The treatment of epistaxis by nasal packing

389
 Pathology of the Lungs

with paraffin gauze has also led to exogenous lipid pneumonia. The
pathology of exogenous lipid pneumonia is described on page 314.
Other medicines may also be aspirated unwittingly, for example a
ferrous sulphate tablet may cause brown iron staining and necrosis of
the bronchus at the point of impact, progressing to bronchial steno-
sis.103–105 Distal infection is then likely, as with any foreign body.
Barium sulphate aspiration may complicate gastrointestinal radiogra-
phy.106 Large amounts may impair ventilation but being inert there is
no permanent injury to the lungs, although the striking changes are
evident on the chest radiograph.

Pulmonary hypertension
An outbreak of pulmonary hypertension affecting many Swiss,
Austrian and German patients in the period 1966–68 was probably
due to the anorectic drug aminorex,107 which was accordingly with- A
drawn with regression in the number of new cases. The pathology in
these patients was identical to that of primary pulmonary hyper­
tension (see p. 420) and it proved impossible to reproduce the condi-
tion in laboratory animals but the epidemiological evidence that
aminorex was to blame is very strong. Fenfluramine and phentermine,
further anorectic drugs that are chemically similar to aminorex, have
also been associated with such plexogenic pulmonary hyperten-
sion,108–112 and with fibroproliferative plaque on the tricuspid valve
and pulmonary arteries.113
Pulmonary hypertension due to pulmonary veno-occlusive disease
has sometimes complicated the use of cytotoxic chemotherapeutic
agents114 or followed bone marrow transplantation.115
Non-steroidal anti-inflammatory agents such as indomethacin and
diclofenac cross the placenta and, if given in late pregnancy, may cause
premature closure of the ductus arteriosus, resulting in severe neonatal
pulmonary hypertension.116,117
Pulmonary hypertension is a well-recognised association of human B
immunodeficiency virus (HIV) infection but until recently has been
unexplained. Now, however, evidence is emerging that the highly Figure 7.3.9  Agglutination of emulsified fat administered intravenously.
active antiretroviral therapy administered to HIV-positive patients (A) With haematoxylin and eosin staining, seemingly empty vacuoles
might be responsible for the pulmonary hypertension.118 appear to occupy the alveolar capillaries. (B) The agglutinated fat has not
been dissolved in processing and can be demonstrated by Sudan black.
(Courtesy of Dr G Hulman, Nottinghamshire, UK.)
Pulmonary embolism
The older high-oestrogen contraceptive drugs carried a slight risk of
thromboembolism but this is not seen with the newer preparations.
administering calcium and other mineral supplements through the
Pulmonary thromboembolism has also occurred with a drug-induced
same venous line as the fat. Once agglutinated, the fat is less soluble
lupus syndrome associated with anticardiolipin antibodies. Chemo­
and may be demonstrated in paraffin sections. Sudan black is espe-
therapeutic drugs such as mitomycin may cause widespread small-
cially useful for this purpose (Fig. 7.3.9). Microvascular crystal embo-
vessel thrombosis resulting in the haemolytic–uraemic (thrombotic
lism is a further risk of parenteral nutrition, the crystals representing
microangiopathic) syndrome. There is prominent involvement of
various calcium salts that may precipitate in the circulation.126
pulmonary vessels and patients often suffer from respiratory as well
Transient diffusion abnormalities attributed to oil embolism are
as renal insufficiency, and pulmonary hypertension. The syndrome
very common in patients undergoing lymphangiography but serious
can develop during treatment or up to several months after the drug
respiratory impairment is limited to those patients with pre-existing
has been withdrawn. Pulmonary thromboembolism is also recorded
lung disease or in whom substantial amounts of contrast medium are
as a complication of immunoglobulin infusion.119
injected rapidly.127–130
Non-traumatic fat embolism has resulted from the agglutination or
Other emboli of an iatrogenic nature described in pulmonary
‘creaming’ of fat emulsions administered intravenously as a source of
arteries include the broken-off ends of intravenous catheters and
calories to debilitated patients.120–125 The agglutinated liposomes
cannulas, particles from dialysis tubing,131 prosthetic implants of
occlude fine blood vessels throughout the body, causing effects
substances such as Teflon and silicone88,132–135 and various materials
such as priapism, osteonecrosis and pancreatitis. They may be
injected to occlude abnormal blood vessels.136,137
demonstrated in the pulmonary capillaries but the lungs have consid-
erable vascular reserve and it is uncertain what effect the vascular
occlusion has on pulmonary function. Agglutination of these fat
Diffuse pulmonary haemorrhage
emulsions is particularly common in severely ill patients and this has
been attributed to the elevated blood levels of acute-phase proteins, Diffuse pulmonary haemorrhage may result from interference with
especially C-reactive protein, that are found in the very ill. The agglu- the clotting mechanism by anticoagulants138 or from widespread
tination is also induced by calcium and may be brought about by pulmonary capillaritis, the latter reported in leukaemic patients

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

treated with retinoic acid.139 Pulmonary haemorrhage has also been is irradiated, as in the treatment of widespread pulmonary metastases
reported as an idiosyncratic reaction to lymphangiography media140 or as part of whole-body irradiation prior to marrow transplantation
and as a complication of immunoglobulin infusion,141 while the for the treatment of leukaemia. Radiation pneumonitis, usually local-
development of anti-basement membrane antibodies resulting in ised, is estimated to affect about 8% of patients.149
Goodpasture’s syndrome has been attributed to penicillamine.141a Therapeutic irradiation is given as divided doses over several weeks
in order to minimise damage to adjacent tissue. The effects of such
fractionated treatment are cumulative. In the lungs an early exudative
Opportunistic infection phase soon passes and progressive damage becomes apparent only
Infection is a common pulmonary hazard in any patient receiving after months or even years.150,151 The changes are generally confined
corticosteroids, chemotherapy or any other immunosuppressant drug. to the area of lung that is irradiated but are widespread when the
Viral, bacterial, fungal and protozoal infections, often in combination, whole body is irradiated prior to bone marrow transplantation or
may all develop in the lungs of such patients and tissue reactions may there is accidental whole-body irradiation. However, localised irradia-
be atypical. Pneumocystis jiroveci, for example, may elicit a granuloma- tion of the lung has been followed by abnormalities in non-irradiated
tous reaction or cause diffuse alveolar damage rather than the usual areas. These include bilateral alveolar exudates,152 migratory organis-
foamy alveolar exudate (see p. 226). ing pneumonia affecting both lungs153,154 and fulminant bilateral
interstitial pneumonia.155 The likelihood of lung injury is increased
by the simultaneous use of cytotoxic drugs and oxygen therapy.156
Metastatic calcification Furthermore, chemotherapy following irradiation may result in exac-
erbation of the injury in areas previously irradiated, a phenomenon
Metastatic calcification, described on page 489, may result from any termed ‘recall pneumonitis’.157,158 In the long term, irradiation also
drug causing hypercalcaemia, e.g. high doses of vitamin D, calcium results in an increased incidence of lung carcinoma. This was seen in
and inorganic phosphate or excessive alkali intake in the treatment of patients given therapeutic irradiation to the spine for ankylosing
peptic ulceration. spondylitis159 and is still encountered on occasion following
irra­diation for breast cancer.160 The pathogenesis of radiation injury
is described on page 146.
Carcinoma of the lung
Radiation damage to the lung is traditionally separated into fulmi-
Carcinoma of the lung may be promoted by drugs. Arsenicals cause nant acute injury coming on within days, subacute pneumonitis devel-
squamous metaplasia of the bronchi and occasionally squamous oping within several weeks (typically 2–3 months) and interstitial
carcinoma, while peripheral scar cancers, usually adenocarcinomas, fibrosis slowly evolving from the subacute stage or making itself
have developed in lungs showing fibrosis due to drugs such as apparent years later. The migratory organising pneumonia referred to
busulphan. above is an unusual further effect, as is chronic eosinophilic pneu­
monia.68 In the pleura, radiation causes fibrinous effusions and
adhesions. Pleural effusion and pulmonary oedema may be
Pleural disease augmented by the long-term effects of radiation on the heart.
Drugs may result in a variety of pleural diseases.142 Common examples Fulminant acute injury is an unusual and unexpected effect of thera-
include effusions, chronic inflammation and fibrosis. These are peutic radiation but one that is likely to come to the attention of the
usually encountered in isolation but may be associated with chronic pathologist as an autopsy is often requested. The clinical features are
interstitial pneumonia or fibrosis. Sometimes there is also serological those of acute lung injury and the pathological changes are those of
evidence of systemic lupus erythematosus: many drugs, including diffuse alveolar damage. The cause is likely to be accidental overdos-
hydantoin, practolol, procainamide, hydralazine and sulphonamides, age, augmentation of the radiation damage by accompanying oxygen
are associated with the development of a syndrome resembling therapy or treatment with cytotoxic drugs. Occasionally however these
systemic lupus erythematosus that includes pleural disease. Whether factors can be excluded, in which case the damage has to be ascribed
the drugs are directly responsible for the syndrome or merely promote to ‘hypersensitivity’.
the development of latent natural disease is uncertain. Subacute radiation pneumonitis is encountered more commonly.
Ergotamine derivatives such as methysergide and bromocriptine are After an interval of about 2–3 months the patient complains of
notable for the production of pleural fibrosis, which is sometimes shortness of breath and a non-productive cough. The chest radiograph
associated with mediastinal and retroperitoneal fibrosis large amounts shows hazy opacification proceeding to more dense consolidation.
or prolonged treatment are generally required to produce this Lung biopsy shows alveolar and interstitial oedema, possibly with
effect.143–145 In patients given practolol, pleural thickening has become residual hyaline membranes, proliferation of atypical alveolar epi­
evident several years after the drug was discontinued. This shows the thelial cells and interstitial fibroblasts and organising thrombosis.
need for a careful drug history in any patient with unexplained pleural Later, as the process advances, there is widespread fibrosis comparable
fibrosis. to that illustrated in Figure 4.24 on page 148 and ultimately dense
scarring (Fig. 7.3.10).
Tracheal and aortic injury may complicate radiation treatment of
tracheal lesions, sometimes resulting in an aortotracheal fistula.161
RADIATION INJURY

Reports of radiation-induced lung damage began to appear soon after

ionising radiation became widely used in the treatment of malignant RESPIRATOR LUNG AND OXYGEN TOXICITY
disease.146–148 Despite refinements in radiotherapy techniques it is
often impossible to avoid irradiating small areas of lung when treating Patients requiring mechanical ventilation are liable to suffer lung
cancer of the lung, breast, spine, thymus and oesophagus. Parts of the injury in a number of ways. In addition to effects of barotrauma such
lungs are also included in ‘mantle’ irradiation of mediastinal lymph as pneumothorax and surgical emphysema, they often develop diffuse
nodes affected by lymphoma. Occasionally, the whole of both lungs alveolar damage. The high oxygen tension that is often combined with

391
 Pathology of the Lungs

major undertaking that poses its own hazards; it is therefore gen­

erally reserved for patients who remain hypoxaemic despite other
measures.179 Intravenous blood oxygenators are employed to mini-
mise the supplementation of inspired oxygen and partial liquid ven-
tilation utilising perfluorocarbon has also been used.180 Experimentally,
disruption of CD40 binding to reduce the release of proinflammatory
cytokines has shown promising results in blunting oxygen-induced
lung injury.181
None of the morphological changes attributable to oxygen toxicity
is specific.174 The earliest ultrastructural change in experimental oxygen
poisoning is swelling of endothelial cells, the cytoplasm of which
becomes grossly oedematous and vacuolated. Swelling and fragmen-
tation of type I epithelial cells follow and these cells become separated
from their basement membrane, which is then coated by thin strands
of protein.178 This coating is replaced by proliferating type II cells
by the 12th day. With recovery in room air the lungs practically
return to normal.182 The full clinical picture of oxygen poisoning is
the acute respiratory distress syndrome and the corresponding patho-
logical changes are those of diffuse alveolar damage,174 as described
on page 136.

BLOOD TRANSFUSION

Patients with hypovolaemic shock or undergoing major surgery

Figure 7.3.10  Radiation damage. A dense scar is seen in an area of the often require massive blood transfusions and this provides another
lung that had been irradiated previously. possible cause of pulmonary damage. Although hypervolaemia is the
commonest cause of pulmonary oedema after blood transfusion,
transfusion-related acute lung injury is more often fatal. Platelet and
white cell aggregates are known to develop in stored blood, but a
relationship between the number of microaggregates transfused and
mechanical ventilation is a major factor162–164 but mechanical forces
the degree of respiratory impairment has not been convincingly dem-
other than the high pressures responsible for barotrauma can also
onstrated. Leukocyte antibodies are a more likely cause of lung injury
contribute to this form of lung injury, notably by resulting in excessive
in these patients. Such antibodies are often found in multiparous
end-expiratory stretch and repeated collapse/recruitment of the alveo-
female donors as a result of sensitisation by fetal white cells during
lar walls.165,166 Low tidal volume ventilation is therefore a fundamental
pregnancy. Alternatively, the recipient may have developed them
part of the management of diffuse alveolar damage.
during pregnancy or as a result of previous blood transfusions. The
Although oxygen is necessary to life, it is cytotoxic in high con­
implicated antibodies are thought to initiate alveolar capillary
centrations. Severe hyperoxia damages DNA, inhibits cellular pro­
damage within hours of transfusion by stimulating granulocyte
liferation and ultimately kills cells. Its toxicity is thought to be due to
aggregation.183,184 Electron microscopy has shown capillary endo­
the intracellular production of active oxygen radicals, some of which
thelial damage with activated granulocytes in contact with alveolar
derive from activated neutrophils attracted to the site of injury.167–170
basement membranes.185
Under normal conditions most of the oxygen is reduced to water by
cytochrome oxidase, and any active radicals produced are eliminated
by superoxide dismutase, catalase and other antioxidants. However,
these defence mechanisms may prove inadequate when active radicals
are produced in excess.171 CARDIOPULMONARY BYPASS
Problems are likely to arise in clinical practice when lung disease
necessitates the concentration of oxygen in the inspired air being Cardiopulmonary bypass entails oxygenation and circulation of the
raised in order to maintain normal blood levels of oxygen and prevent blood by extracorporeal devices, so permitting major heart surgery. In
cerebral hypoxia.172–174 A ‘safe’ level for oxygen administration is not the early days of such surgery it was not unusual for patients to
firmly established and, because of species differences in susceptibility develop fatal respiratory insufficiency in the postoperative period. This
to oxygen, caution is needed in extrapolating from animal studies. led to the term ‘postperfusion lung’. Electron microscopic studies
However, animal experiments have shown that previous damage showed alveolar damage with degranulation of neutrophils in pulmo-
to the lungs renders them unduly sensitive to oxygen175,176 and con- nary capillaries.186,187 The syndrome is now less common but infants
versely that prior exposure to high levels of oxygen confers some remain susceptible.188
resistance to subsequent oxygen exposure.177 Clinical studies suggest The most likely explanation is that the synthetic materials with
that less than 50% oxygen (at atmospheric pressure) can be tolerated which blood comes into contact during the bypass procedure are able
for long periods without ill effect. Little, if any, serious lung damage to activate complement. This is mediated by Hageman factor (factor
results from administration of 100% oxygen for up to 48 hours but XII) and the alternative pathway. Aggregation of neutrophils leads to
concentrations between 50% and 100% carry a risk of damage if this their sequestration in the lungs and damage results from their release
period is exceeded.171,178 Extracorporeal oxygenation of the blood of lysosomal enzymes and active radicals.188–190 The process is delayed
circumvents the problem but if it is to be prolonged it becomes a by hypothermia.189

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 Occupational, environmental and iatrogenic lung disease Chapter |7|

COMPLICATIONS OF CARDIAC INJURY

A postcardiac injury syndrome develops after a variety of myocardial

or pericardial injuries: it has been described after cardiac surgery (post-
pericardiotomy syndrome), myocardial infarction (Dressler’s syn-
drome), blunt trauma to the chest, percutaneous puncture of the heart
and implantation of a pacemaker.191 There is a delay of anything
between a few days and a few months between the cardiac injury and
the onset of symptoms, which comprise chest pain, breathlessness,
dyspnoea and fever. Examination usually reveals haemorrhagic pleural
or pericardial effusions and pulmonary infiltrates. The syndrome
usually resolves spontaneously and few pathological studies have
therefore been conducted. However, the changes of diffuse alveolar
damage have been reported, principally hyaline membrane formation
and type II pneumocyte hyperplasia.192 The pathogenesis is obscure.
Antibodies reacting with myocardial antigens often develop after
cardiac surgery but there is no relationship between these and the
development of the syndrome.192–194 Figure 7.3.11  Tracheal stenosis following prolonged intubation. The
tracheal wall shows fibrosis while the tracheal cartilage is dysplastic and
shows osseous metaplasia, appearances similar to those seen in relapsing
polychondritis (compare with Fig. 3.4, p. 95).
COMPLICATIONS OF RADIOFREQUENCY
ABLATION
may also lead to interstitial emphysema, pneumothorax and surgical
This minimally invasive technique is used to destroy lesions as emphysema.
varied as pulmonary metastases and the connection between the Asphyxia may follow an endotracheal tube becoming blocked by
left atrium and ectopic foci in the muscular sleeves that surround secretions or through it being badly positioned. Secretions need to be
the terminations of the pulmonary veins (see p. 76). The former may constantly removed yet repeated suctioning to achieve this has led to
be complicated by pneumothorax and the latter by pulmonary vein cardiac dysrrythmia and even cardiac arrest.202
stenosis.195,196 If the balloon on the endotracheal tube is too near the
tracheostomy it may act as a fulcrum, causing the tip of the tube to
press into the tracheal wall. Pressure necrosis and perforation
COMPLICATIONS OF CENTRAL may follow, leading to mediastinitis, tracheo-oesophageal fistula or
erosion of a large blood vessel. These are also complications of tra-
VASCULAR CANNULATION cheobronchial laser therapy.
Pressure from the balloon may lead to a tracheal diverticulum and
Central venous cannulation (synonym: catheterisation) is widely used after the tube is withdrawn the trachea may become narrowed at either
in treating seriously ill patients and may give rise to serious complica- the site of the incision or further down where the balloon on the
tions. The commonest early complications related to the respiratory tracheal tube causes pressure. Small, shallow ulcers generally heal
tract are caused by local trauma: they include pneumothorax, sub­ quickly but deeper ulcers cause necrosis of the tracheal cartilage, and
cutaneous emphysema, haemothorax and air embolism. Infection healing is then often accompanied by fibrous stenosis (Fig. 7.3.11) or
occurs later, causing endocarditis, septic emboli and lung abscesses.197 web formation. This results in wheezing and dyspnoea but not before
Thrombosis is another common late complication: one autopsy study the trachea has narrowed to 30% of its original size, which may take
of patients with central venous lines showed that 15% had major months. Earlier narrowing may be caused by oedema or a fibrinous
pulmonary emboli and 65% had microscopic emboli in their pseudomembrane.203,204 Sometimes the stenosis takes the form of a
pulmonary arteries.198 Pulmonary artery cannulation, for example large mass of granulation tissue at the tracheostomy site, a so-called
with a Swan–Ganz catheter, may result in pulmonary infarction or granuloma ball. In children especially, intubation may lead to tracheo­
any of the traumatic complications of central venous catheterisation malacia so that after the tube is removed the airway collapses.205
mentioned above. Necrotising sialometaplasia is a further complication of prolonged
intubation.206 The incidence of such posttracheostomy complications
can be minimised by careful placement of the stoma and tube, avoid-
COMPLICATIONS OF TRACHEAL ance of large apertures and high cuff pressures, elimination of heavy
connecting equipment and meticulous care of the tracheostomy.
MANIPULATIONS199,200 Nasogastric feeding tubes may of course lead to aspiration lesions
in the lungs and even fatal asphyxia if they are inadvertently allowed
Tracheotomy entails a small immediate risk of haemorrhage from to enter the trachea rather than the oesophagus.
damaged subthyroidal arteries, while an endotracheal tube pre­
disposes to infection, as with all foreign bodies. Infection is also
promoted by the filtering action of the upper respiratory air passages
being bypassed. The latter factor also necessitates humidification of COMPLICATIONS OF BRONCHOSCOPY
the inspired air and on occasion the humidifier or ventilator has
become contaminated so that an aerosol of bacteria is introduced Bronchoscopy is generally a safe, almost routine procedure. A review
directly into the lower respiratory tract.201 High-pressure ventilation of 23 862 patients who underwent bronchoscopy identified severe

393
 Pathology of the Lungs

complications in 152 (0.637%), of whom three died.207 The fatal cases pneumonectomy and may compromise the function of the other
comprised a 78-year-old with coronary heart disease who developed lung.
cardiac arrest and two patients who had had tracheal transplantation Pathologists conducting autopsies long after the operation may find
for oesophageal cancer and required bronchoscopic laser treatment complete fibrous obliteration of the postpneumonectomy space,
but died of airway obstruction. coupled with mediastinal shift and elevation of the hemidiaphragm,
but often there is persistent brown fluid, which may be clear, cloudy
or occasionally purulent.210 The remaining lung is generally enlarged,
with its volume greater than predicted. Animal studies have shown
COMPLICATIONS OF THORACIC that if one lung is excised early in life the enlargement is partly due
DRAINAGE TUBES to enhanced growth but later it represents only dilatation of existing
air spaces. Hepatocyte growth factor is thought to be involved in the
The pleural cavity is intubated in the treatment of pneumothorax and proliferation of residual lung cells following pneumonectomy.211
pleural effusions the tube being placed anteriorly to drain air and Pulmonary complications include those typically seen after other
posteriorly to drain fluid. Complications include laceration of an thoracic procedures, such as haemorrhage and infection, and those
intercostal artery or vein, the lung, the diaphragm and the heart. unique to the postpneumonectomy state, namely anastomotic
dehiscence and postpneumonectomy pulmonary oedema. The latter
presents as the acute respiratory distress syndrome and represents the
early stages of diffuse alveolar damage. It follows severe shift of the
PNEUMONECTOMY208 heart and mediastinum, which is commoner in children and young
adults, in whom the tissues are more compliant.212–215 The condition
Pneumonectomy has been practised since the 1930s, since when the complicates up to 4% of lung resections216,217 and is commoner fol-
mortality associated with this operation has dropped from over 50% lowing excision of the right lung when severe herniation of the left
to near zero in the best hospitals. Risk factors include underlying lung lung into the postpneumonectomy space stretches the trachea and left
disease, other medical conditions and more extensive procedures such main bronchus and the latter is compressed between the left pulmo-
as pleuropneumonectomy and pneumonectomy combined with chest nary artery in front and the arch of the aorta behind. In the long term
wall resection. the compression can result in bronchomalacia and postobstructive
The anatomical changes that take place soon after pneumonectomy bronchiectasis. If postpneumonectomy oedema develops the immedi-
have been extensively studied by radiologists who describe the ate postoperative mortality is high – 50% following pneumonectomy,
air-filled postpneumonectomy space gradually filling with fluid and 42% following lobectomy and 22% following sublobar resections.217,218
contracting as the mediastinum shifts and the ipsilateral dome of the The pathogenesis is probably multifactorial but apart from factors
diaphragm rises.209 Much of the space is filled by fluid within 2 weeks such as fluid overload and high inspired oxygen concentrations there
but complete opacification may take up to 6 months. Rapid filling in is probably an element of alveolar wall injury, induced by oxidant
the immediate postoperative period suggests haemorrhage or chylo­ generation secondary to lung stretching and general surgical
thorax. However, fluid accumulation is normally rapid after pleuro­ trauma.219,220

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 Chapter 8 

Vascular disease
8.1 Congestion and oedema; thrombosis, embolism and infarction; aneurysms

CHAPTER CONTENTS
PULMONARY CONGESTION AND OEDEMA
Pulmonary congestion and oedema 401
Pulmonary oedema 401 Congestion of the lungs may be active or passive, the former
Pulmonary thrombosis and thromboembolism 404 accompanying inflammation and the latter the result of an increase
in pressure in the pulmonary veins, typically due to failure of the left
Thromboembolism 404
ventricle or mitral stenosis. The active variety includes the congestive
Pulmonary infarction 408 atelectasis that results from circulatory shock (see p. 143).
Partial and complete infarction 408 At necropsy the pulmonary vessels are engorged, the lungs are heavy
Pulmonary venous infarction 410 and blood can be expressed from the cut surface. Histologically the
capillaries are distended. Pulmonary congestion is often associated
Non-thrombotic pulmonary emboli 410
with pulmonary oedema and haemosiderosis.
Fat embolism 410
Amniotic fluid embolism 410
Trophoblastic embolism 410
Pulmonary oedema
Decidual embolism 410 Pathogenesis
Tumour embolism 411 In accordance with Starling’s law, water moves between the vascular
Other tissue embolism 411 and interstitial compartments of the lung in response to net hydro­
Foreign-body embolism 411 static and osmotic forces acting across the vessel wall, modulated by
the permeability of this membrane. The capillaries constitute the main
Air embolism 412
site of microvascular fluid exchange, but small arteries and veins are
Pulmonary aneurysms 413 also involved. Water movement chiefly takes place through the
Pulmonary varix 414 endothelial cell junctions; beyond these the endothelial basement
References 414 membrane offers no barrier to fluid transport.1 Within the inter­
stitium, water again flows along a hydrostatic gradient, in this case to
the corners of the alveoli, and thence to the connective tissue sur­
rounding the arteries and bronchioles at the centres of the acini and
This section deals with several important pulmonary vascular diseases the veins in the interlobular septa.2,3 These are the sites where lym­
but some others are dealt with elsewhere – congenital anomalies of phatics commence.3,4 There is considerable reserve in the clearance
pulmonary vessels in Chapter 2, shock in Chapter 4 and vascular capacity of the pulmonary lymphatics, which may increase their load
tumours of the lung in Chapter 12.3. 10-fold when pulmonary oedema threatens,5 but above this, spillover

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00008-2 401
 Pathology of the Lungs

into the alveoli is inevitable. Before this the lungs sound dry on
auscultation but the patient may nevertheless be breathless because
the increased interstitial pressure triggers juxtacapillary nociceptors,
which are represented by fine nerve terminals in the alveolar
interstitium.6,7
In circumstances that involve only pressure changes, the oedema
fluid is generally similar to normal interstitial fluid but in other cir­
cumstances the permeability of the vessels is increased and blood cells
and high-molecular-weight plasma proteins, such as fibrinogen,
escape into the tissues. Two main types of pulmonary oedema
are therefore described, haemodynamic and cytotoxic (or irritant),
characterised by the escape of low- and high-molecular-weight
blood substances respectively. Electron microscopy shows that in
haemodynamic oedema there is widening of the interstitial spaces
in the alveolar walls by fluid, with separation of the collagen and
elastin fibres, but that this is confined to the thick side of the
air–blood barrier. In contrast, in cytotoxic oedema fluid also
accumulates in the thin part of the air–blood barrier so that the
endothelial cells are detached from their basement membranes and
are often stretched over large subendothelial blebs of fluid (Fig.
8.1.1),8 changes that do not occur in uncomplicated haemodynamic
pulmonary oedema.9
The separation of haemodynamic and cytotoxic oedema is not
absolute: large haemodynamic forces alone can result in the escape of
high-molecular-weight blood proteins.10,11 Electron microscopy shows
that when the alveolar capillary pressure is raised above 40 mmHg in
anaesthetised rabbits, breaks develop in both the endothelium of the
alveolar capillaries and the alveolar epithelium.12-16 Such stress failure
results in high-permeability pulmonary oedema, and even frank alve­
olar haemorrhage. This explains why the oedema fluid of mitral steno­
sis is often tinged with blood, and why haemosiderosis is seen in other
diseases characterised by raised pulmonary venous pressure, such as
veno-occlusive disease (see p. 427) and lymphangioleiomyomatosis
(see p. 293).
Stress failure of the alveoli also explains the occasional sudden
demise of a thoroughbred racehorse from a ‘burst blood vessel’.17
These animals have been bred to such an extent that their cardio­
vascular systems develop very high pulmonary vascular pressures on
exercise. Alveolar haemorrhage is common in these horses, although
it is seldom apparent to their attendants. Similar exercise-induced
pulmonary haemorrhage has also been described in racing grey­
hounds and it is possible that the lungs of top athletes may also
develop stress failure on occasion.15,18,19 Stress failure is also seen when
there is overinflation of the lung, such as that which occurs when there Figure 8.1.1  Cytotoxic oedema. Fluid has accumulated on the thin side
is a sudden drop in atmospheric pressure (see ‘burst lung’, p. 369) or of the air–blood barrier, raising the alveolar capillary endothelium off its
basement membrane and producing two subendothelial blebs (B) which
when alveolar gas pressures are raised unduly by mechanical
stretch right across the capillary. Arrows mark the points at which the
respiratory assistance devices in intensive care units. endothelium is lifted off its basement membrane. Transmission electron
Specific causes of pulmonary oedema include: micrograph of the lung of a rat that had been subjected to very high
doses of the antidepressant drug iprindole. (Courtesy of Dr GS
• Pulmonary venous hypertension. This is the common factor by Balasubramaniam, Melbourne, Australia.)
which conditions such as left ventricular failure, mitral stenosis
and pulmonary veno-occlusive disease contribute to
haemodynamic pulmonary oedema. A rise in pressure at the
venous end of the pulmonary capillaries causes increased • Intravenous fluid overload. Intravenous fluid overload may lead to
amounts of fluid to leave these vessels, with fluid that cannot be pulmonary oedema by causing both left ventricular overload
reabsorbed by the capillaries or drained by lymphatics and dilution of the plasma proteins.
accumulating as oedema. In left ventricular failure the • Re-expansion of the lungs. Rapid drainage of a pleural effusion or
accumulation of fluid is compounded by sodium retention, the removal of a large pleural tumour occasionally alters
which is an important consequence of ‘forward heart failure’ pulmonary haemodynamics to such an extent that pulmonary
through its effects on adrenocortical perfusion and aldosterone oedema results.20 The oedema fluid is rich in protein, suggesting
secretion. that vascular permeability is increased and that there is stress
• Hypoproteinaemia. This is a potential cause of haemodynamic failure of the alveolar walls.
pulmonary oedema, and underlies that occasionally observed in • Airway obstruction. Suggested mechanisms involved in the
cirrhosis. pulmonary oedema that occasionally accompanies airway

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 Vascular disease Chapter |8|

obstruction include negative intrathoracic pressure causing • Heroin overdosage. This is a well-recognised cause of pulmonary
transiently low interstitial pressure in the lungs, impaired left oedema. Its pathogenesis is not well understood but high
ventricular function and hypoxic postcapillary vasoconstriction.21 protein levels in the oedema fluid suggest increased pulmonary
Low protein levels in the oedema fluid favour a hydrostatic capillary permeability.42 Adrenergic hyperactivity similar to that
mechanism.22 envisaged in neurogenic injury may be involved.
• Inhalation of irritant gases. The accidental inhalation of gases • Prostacyclin therapy. Prostacyclin has been used to dilate the
such as ammonia, sulphur dioxide, chlorine, ozone and the pulmonary arteries in patients with pulmonary hypertension but
oxides of nitrogen may cause widespread cytotoxic injury to the its continuous intravenous administration has been complicated
pulmonary capillaries as well as the alveolar epithelium, by pulmonary oedema when the hypertension has been due to
resulting in high-permeability pulmonary oedema.23 postcapillary obstruction, as in pulmonary veno-occlusive
• Oxygen. Oxygen in high concentration, necessarily administered disease and pulmonary capillary haemangiomatosis.43
in some cases of severe lung injury, may further damage the
lung and lead to cytotoxic pulmonary oedema.24–26
• Acute pulmonary infection. Oedema is a common feature of most Pathological findings
pulmonary infections. It is attributable to the direct or indirect At necropsy, an oedematous lung may weigh as much as 1 kg, nearly
effects on the capillary endothelium and alveolar epithelium of three times its normal weight. It feels firm and fails to collapse when
toxins produced by the infective agent. the thorax is opened, so that the pleural surface remains smooth.
• Chemotherapy. Treatment with drugs such as busulphan is Pleural effusion is often also present. Frothy fluid fills the airways
occasionally complicated by pulmonary oedema because of and watery fluid escapes from the exposed cut surface. The fibrin-
their cytotoxicity to alveolar endothelial and epithelial cells. containing fluid of ‘toxic’ oedema does not run from the cut surface
• Shock lung. This condition is characterised by severe cytotoxic as freely as the watery fluid of haemodynamic oedema due to its high
pulmonary oedema. The endothelial damage is attributable to fibrin content. The appearances may simulate haemorrhage if red cells
several factors, notably nitric oxide, which is released in large have escaped in large numbers into the fluid. Interstitial oedema is
amounts by activated macrophages, and oxygen and hydroxyl seen to distend the loose connective tissue of the interlobular septa
neutrophils sequestered in the pulmonary capillaries. The and that around the airways and arteries. The subpleural lymphatics
detailed pathology of shock lung is described on page 142. may be visibly distended and often the hilar lymph nodes are consid­
• Renal failure. Several mechanisms contribute to the development erably enlarged, soft and moist.
of pulmonary oedema in renal failure. They include fluid Microscopically, the interlobular septa and the periarterial connec­
retention, hypertensive cardiac failure and hypoproteinaemia. tive tissue sheaths are swollen and lymphatics within them are dilated
The fluid is rich in protein, suggesting that cytotoxic factors or (see Fig. 2.8). Alveolar oedema is seen as a homogeneous, eosinophilic
stress failure may also operate.27,28 proteinaceous material filling the air spaces (Fig. 8.1.2). Entrapped air
• High altitude. The pulmonary oedema of acute mountain bubbles are represented by rounded spaces within the proteinaceous
sickness (see p. 370) has a complex pathogenesis but the contents of the alveoli. Only scanty threads of fibrin are generally
possibility that haemodynamic factors are involved is suggested found, but in severe cases, especially of the toxic variety, much fibrin
by the undue susceptibility to the condition of persons with is present in the fluid. The lungs are then particularly firm and have
aplasia or hypoplasia of one pulmonary artery.29,30 The lung been described as showing ‘congestive consolidation’. There may
lavage fluid is rich in protein31 and electron microscopy shows also be many red blood cells in the air spaces. Iron-containing
subendothelial blebs characteristic of cytotoxic injury (see Fig. macrophages may be found in chronic cases.43a
8.1.1) or even disruption of the alveolar walls,32 indicating that Organisation of the fibrinous material may occur, leading to
there is haemodynamic stress failure.12,33 The oedema can be fibrosis in the alveoli.44 This takes the form of intra-alveolar plugs of
prevented or treated successfully with vasodilators such as oedematous granulation tissue known as bourgeons conjonctifs or
calcium channel blocking agents taken orally34,35 or inhaled Masson bodies.45 Similar bodies develop in the bronchioles and
nitric oxide,36 suggesting that hypoxic vasoconstriction plays an the appearances closely mimic those found in healing bacterial pneu­
important pathogenetic role. Hypoxia is a powerful stimulus to monia and in cryptogenic organising pneumonia. The connective
pulmonary vasoconstriction but it mainly affects precapillary tissue plugs may be incorporated into the alveolar walls, causing
vessels and would therefore seem to protect the capillary bed. interstitial fibrosis by an accretive process.46,47 Interstitial fibrosis may
This apparent anomaly may be explained by the patchy nature also arise as a direct consequence of interstitial oedema, so-called
of the oedema. If the hypoxic vasoconstriction affected some gefässlose (vessel-less) organisation.48 The combination of haemo­
pulmonary arteries more than others some capillaries would be siderosis and fibrosis spawned the term ‘brown induration of the
protected and the remainder subjected to abnormally high lungs’ for the changes that develop in long-standing mitral stenosis
pressures: patchy vasoconstriction would lead to patchy stress (Fig. 8.1.3).49
failure. Hypoxic venous constriction may also be involved37 The vascular changes resulting from pulmonary venous hyper­
(relevant to which is evidence that flow through the valve-less tension are described in Chapter 8.2.
pulmonary veins is controlled by sphincters38).
• Cerebral injury. Neurogenic pulmonary oedema is a well-
recognised feature of cerebral damage, especially that caused by
Radiological findings44,50,51
trauma or subarachnoid haemorrhage. Its pathogenesis appears Interstitial oedema is recognisable in radiographs of the chest by a
to involve massive adrenergic release mediated by the combination of hilar enlargement, caused by peribronchial and
hypothalamus.39–41 This results in widespread vasoconstriction periarterial cuffing, and peripheral linear opacities resulting from
with marked systemic hypertension. Fluid then shifts from the oedema of the interlobular septa. There is a greater concentration of
systemic circulation to the relatively more compliant pulmonary perivascular and peribronchial connective tissue at the hila and
circulation, with a resultant outpouring of fluid into the lung. consequently the hilar opacities are enlarged, more dense and less
Stress failure is invoked to explain the high-permeability nature well defined. Septal thickening is visualised radiologically as a series
of the oedema fluid.12 of non-branching, horizontal lines, 1–3 cm long, extending to the

403
 Pathology of the Lungs

PULMONARY THROMBOSIS AND

THROMBOEMBOLISM

Pulmonary thrombosis, as distinct from thromboembolism, is seldom

symptomatic in the absence of other pulmonary vascular disease. It is
most commonly encountered as a complication of pulmonary hyper­
tension of any cause, and then confounds the histological distinction
of thromboembolic pulmonary hypertension from that due to other
causes, in particular the primary variety. It is necessary therefore to
search for the specific histological features of the other varieties of
pulmonary hypertension (which are dealt with in the next chapter)
whenever pulmonary thrombosis is recognised. Although atheroma
is a feature of pulmonary hypertension (see Fig. 8.2.17),52 it is
generally confined to the large elastic pulmonary arteries and seldom
attains the advanced, ulcerated degree that predisposes to aortic
thrombosis. Thrombosis complicating pulmonary hypertension prob­
ably commences in the smaller muscular pulmonary arteries, which
narrow in this condition.
As well as complicating pulmonary hypertension, pulmonary
thrombosis and infarction also develop in systemic lupus erythema­
tosus,53 sickle cell disease,54–58 spherocytosis,59 thalassaemia,60,61
paroxysmal nocturnal haemoglobinuria,62 the antiphospholipid anti­
body syndrome,53,63 the hypereosinophilic syndrome,64,65 rare varieties
Figure 8.1.2  Pulmonary oedema. Eosinophilic proteinaceous fluid fills of pulmonary vasculitis that affect the large elastic arteries,66,67 diffuse
many alveoli. alveolar damage and unusual varieties of vascular infection.68
Pulmonary thrombosis is also predisposed to by low blood flow, as
in congenital anomalies such as pulmonary stenosis and in pulmo­
pleura at the lung bases. They are popularly known as Kerley nary aneurysms.
B lines.
Alveolar oedema exaggerates the hilar prominence of the inter­ Thromboembolism
stitial oedema that precedes it to produce a ‘bat’s wing’ or ‘butterfly’
shadow. This picture was first described in cases of uraemia but is now Aetiology
known to occur with other causes of pulmonary oedema. The opaci­ Pulmonary thromboembolism is rare in the third world but common
fication is particularly marked in severe oedema, such as occurs in in developed countries.69 Economic development in Hong Kong has
shock, when there may be a total ‘white-out’ of the lung fields been accompanied by an increasing incidence of the disease70,71 and
except for patent bronchi which are seen as if forming a ‘negative in the USA the incidence of pulmonary thromboembolism among
bronchogram’. non-whites is much the same as in whites.72
In addition to the features of oedema, the chest radiograph often In western countries, thrombotic pulmonary emboli, often unsus­
shows enlargement of the heart and widening of vessels to upper pected in life, are commonly encountered at necropsy, especially in
zones of the lungs. The latter may be a direct effect of raised venous elderly and obese people who have been confined to bed with con­
pressure on vessels that are normally at lower than alveolar pressure gestive cardiac failure, and in adults of any age who have undergone
and therefore collapsed, or it may be a consequence of the vascular major surgery, suffer from cancer or have been the victims of major
remodelling seen at the lung bases in pulmonary venous hyperten­ trauma.73–79 They develop in people who sleep in chairs that hinder
sion, which is described on page 427. venous return from the legs (e.g. deck chairs) and especially in air-
travellers who are immobile for a long time. Nearly half prove fatal.80
Pulmonary embolism is also prone to occur after childbirth.
Contributing factors are listed in Box 8.1.1.81–83 They operate in three
Clinical features ways, as described by Virchow in his well-known triad:
Breathlessness is an early feature of pulmonary oedema, encountered
• by promoting blood stasis
when the process is still interstitial because of stimulation of the
• by damaging vascular endothelium
juxtacapillary nociceptors.6,7 With the onset of alveolar oedema crepi­
• by activatiing coagulation factors.
tations are heard on auscultation and in severe cases watery sputum
is produced, sometimes tinged by blood, and the patient is cyanosed Thrombosis after operations and childbirth is promoted by the
and hypoxaemic. It is often essential to maintain cerebral oxygenation increased numbers of platelets that accompany any form of trauma.
by augmenting the concentration of inspired oxygen despite the It often occurs in tributaries of the main veins of the legs and thighs,
deleterious effect this may have on an already injured lung. Patients where the vascular stasis that follows immobilisation is known to be
in left ventricular failure are prone to attacks of severe breathlessness most pronounced. Puerperal thromboembolism is more frequent in
when recumbent, typically at night. This is aptly termed paroxysmal women whose lactation has been suppressed by the administration of
nocturnal dyspnoea but is often still referred to by the older term oestrogens than among those who breast-feed and in line with this it
‘cardiac asthma’. The distinction from bronchial asthma (see p. 109) is known that the older high-oestrogen contraceptive pill carried a
may be blurred by oedematous swelling of the bronchial wall causing small risk of promoting thromboembolism by affecting the clotting
the patient to wheeze. factors VII and X and platelet aggregation. This risk is believed to be

404
 Vascular disease Chapter |8|

Figure 8.1.3  ‘Brown induration’ representing a combination of haemosiderosis and interstitial fibrosis due to chronic pulmonary congestion and
oedema in patients with long-standing left-sided cardiac failure. (A) Paper-mounted whole-lung section showing brown discoloration. (Courtesy of WG
Edwards, London, UK.) (B) Haematoxylin and eosin section showing septal fibrosis and increased numbers of brown alveolar macrophages. (C) An elastin
van Geison stain shows intimal sclerosis of the pulmonary veins within the fibrosed interlobular septa. (D) A Perls stain shows marked haemosiderosis.

405
 Pathology of the Lungs

Box 8.1.1  Risk factors for venous thromboembolism83 Table 8.1.1  Deaths from pulmonary embolism per million
population by age and sex in England and Wales
Major risk factors
Age (years)
Surgery
• Major abdominal/pelvic surgery All ages <45 45–54 55–64 65–74 75–84 >84
• Hip/knee replacement
• Postoperative intensive care Men 20 0 54 16 67 210 461
Obstetrics Women 33 1 4 12 61 218 497
• Late pregnancy
• Caesarean section
• Puerperium
Lower-limb problems Table 8.1.2  Deaths from pulmonary embolism by seasona
• Fracture
• Varicose veins Season Deaths (n)
Malignancy January to March 2898
• Abdominal/pelvic
• Advanced/metastatic April to June 2651

Reduced mobility July to September 2646

• Hospitalisation October to December 2893
• Institutional care
a
11088 cases assembled from 23 reports from the northern hemisphere.90
Miscellaneous
• Previous venous thromboembolism
Minor risk factors
Cardiovascular Table 8.1.3  Incidence of pulmonary embolism according to the
site of leg vein thrombosis93
• Congenital heart disease
• Congestive cardiac failure
• Hypertension Pulmonary embolism Incidence
• Superficial venous thrombosis
Calf vein thrombosis 0/21 patients
• Indwelling central vein catheter
Calf and thigh vein thrombosis 8/15 patients
Oestrogens
• Oral contraceptive Pulmonary embolism detected by lung perfusion and ventilation scans.
• Hormone replacement therapy Leg vein thrombosis detected by venography, impedance plethysmography and
radiofibrinogen scanning.
Miscellaneous
• Chronic obstructive pulmonary disease
• Neurological disability
• Occult malignancy
of antithrombin III, factor V (Leiden), protein C and protein S. Usually
• Thrombotic disorders
• Long-distance sedentary travel
these need to interact with acquired risk factors before thrombosis
• Obesity occurs, being otherwise uncommonly associated with idiopathic
• Othera thromboembolism. For example, factor V (Leiden) defect in isolation
increases the risk of thromboembolism 3–5-fold but in conjunction
a
Inflammatory bowel disease, nephrotic syndrome, chronic dialysis, with oestrogen therapy 35-fold.83 Further conditions characterised by
myeloproliferative disorders, paroxysmal nocturnal haemoglobinuria, Behçet’s hypercoaguability include the antiphospholipid syndrome and
disease.
microalbuminuria.63,86
Despite the dangers of childbirth and oral contraception, the stand­
ardised mortality rate from thromboembolism is roughly the same
for men and women; the increased risk of major trauma in young
male adults balances the risks special to women. However, the crude
almost non-existent with the present low-oestrogen contraceptive death rate from thromboembolism is much greater in women than in
pills. 84 men87 because of the marked effect of advancing age on the incidence
Hypercoaguability is fairly prevalent in the general population and of thromboembolism and the greater number of elderly women in
presumably augments the other factors contributing to thrombosis the population (Table 8.1.1). There is also a minor seasonal variation
listed in Box 8.1.1. It can be recognised in 25% of patients with in the incidence of pulmonary thromboembolism, the risk being
venous thromboembolism and in an even higher number of patients greater in the colder months (Table 8.1.2).88–92
whose thrombosis is otherwise unexplained. High levels of factors VIII It is when calf vein thrombi propagate proximally to reach the main
and XI are fairly common in the general population (each has a veins of the thigh that they are most likely to break off and reach the
prevalence of about 10%) but abnormalities in the levels of many lungs as emboli (Table 8.1.3).93 Proximal propagation is encountered
other clotting factors are also recognised.85 They include deficiencies in approximately 20% of patients with calf vein thrombosis and

406
 Vascular disease Chapter |8|

Total Incidence
630,000

Died within 1 hr Survived over 1 hr

67,000 (11%) 563,000 (89%)

Not initially diagnosed Diagnosed and treated

400,000 (71%) 163,000 (29%)

Died Survived Died Survived

120,000 (30%) 280,000 (70%) 13,000 (8%) 150,000 (92%)

Figure 8.1.4  Annual incidence and survival in pulmonary thromboembolism in the USA. (Reproduced from Dalen & Alpert (1975)74 with permission.)

approximately 50% of those with proximal leg vein thrombosis Distribution of the emboli
develop pulmonary embolism.94 Residual deep-vein thrombosis can
When clots are introduced into a rabbit’s systemic vein, both the size
be demonstrated in most patients who have recently suffered pulmo­
of the clots and the anatomy of the pulmonary arterial tree affect their
nary embolism.95 The danger of leg vein thrombosis and embolism is
subsequent distribution in the lungs.100 Whilst large emboli lodge in
lessened by the use of prophylactic massage and exercise. Treatment
any of the main arteries, those of medium size are carried dispropor­
is mainly based on anticoagulation but may involve venous ligation
tionately often into the vessels of the posterior basal segments. In
proximal to the thrombus and thromboembolectomy. Leg vein
humans, pulmonary infarcts are commoner in the posterior basal
thrombosis is nearly always bilateral and this should be kept in mind
segments of the lower lobes96 and solitary metastatic tumours are
when ligation is being considered. Approximately 11% of patients
more frequently basal than apical. The explanation lies in the anatomy
with pulmonary thromboembolism die within 1 hour and only 29%
of the pulmonary arteries: they have a large axial trunk that gives off
of the remainder are correctly diagnosed and treated appropriately,
its branches at an angle and terminates in the posterior basal segment.
which is unfortunate as there are 10 times as many deaths in the
undiagnosed and untreated majority (Fig. 8.1.4).74
The periprostatic venous plexus is another source of pulmonary Pathological findings
emboli, particularly multiple small emboli. Thrombosis here is pro­
The sudden impaction of a large embolus in the pulmonary trunk
moted by local inflammation as well as by sluggish venous flow as in
brings the circulation virtually to a halt. The small volume of blood
heart failure. Less often, thrombotic emboli originate in the veins of
that can percolate past the thrombotic mass is quite insufficient to fill
the arms or in the chambers on the right side of the heart. Other
the left side of the heart and maintain normal systemic arterial pres­
sources include intravenous cannulae and endocarditis affecting the
sure and an adequate circulation through the cerebral and coronary
valves on the right side of the heart. In one study 86% of thrombotic
arteries. In such cases, the embolus is found at necropsy to be coiled
emboli reached the lungs via the inferior vena cava, 3% came via the
on itself, straddling the bifurcation of the pulmonary trunk (Fig.
superior vena cava, 3% originated in the heart and in 8% of cases the
8.1.5). The chambers of the right side of the heart and the venae cavae
thrombosis was widespread.96
are distended, the left atrium and ventricle contracted, and the lungs
pale. The coiling distinguishes embolic thrombi from thrombi that
have formed in the pulmonary arteries. When the embolus is removed
Clinical features from its site of impaction and is uncoiled it is seen to be of a diameter
Sometimes the embolus is a massive one, and its lodgement in the that corresponds to the calibre of the vessels in which it formed. Its
pulmonary trunk or main pulmonary artery is immediately fatal surface is marked in correspondence with the venous valves: the
because it obstructs the pulmonary circulation. In only 28% of such broken ends of the thrombotic cast of the tributary veins can also be
cases is a diagnosis of pulmonary thromboembolism made before recognised and it may be possible to match these with the thrombus
death.96 More frequently the embolus is small and without significant remaining in the veins.
effect. Alternatively, the embolus may result in pulmonary infarction, Both thrombi formed in situ and thrombotic emboli are firm but
which is indicated clinically by an attack of localised pleural pain, friable, and show striae of Zahn, which are evident to the naked eye
dyspnoea and haemoptysis. Often there is more than one embolic and indicative of their development during life (Fig. 8.1.6): these
episode. Multiple microemboli as a cause of pulmonary hypertension features distinguish them from clots, which are formed postmortem.
is considered on page 426. Clots are shiny, soft and elastic: when pulled carefully from the vessels
The high prevalence of unsuspected pulmonary thromboembolism they show a characteristic ‘horse’s tail’ appearance, their end being a
evident at autopsy has been demonstrated in life with perfusion scans, cast of blood from the smaller branches of the pulmonary artery. Clots
emphasising that once a diagnosis of peripheral venous thrombosis may show a transition from red to yellow, due to postmortem sedi­
has been established, anticoagulant therapy should be instituted mentation of the cellular constituents of the stagnant blood, leaving
without delay.97 Thromboendartectomy is being increasingly a paler zone of serum in the eventual coagulum: this demarcation
undertaken.98,99 lacks the alternate white and red layers formed respectively of platelets

407
 Pathology of the Lungs

Figure 8.1.5  Massive pulmonary thromboembolism. Coiled thrombus

occludes the pulmonary trunk and the main pulmonary arteries. (Courtesy
of Dr GA Russell, Tunbridge Wells, UK.)

B
and fibrin-enmeshed blood cells that characterise the striae of Zahn
in a thrombus. Figure 8.1.6  Thrombotic emboli showing the striae of Zahn. The striae
Fresh thrombus may fragment and disperse into smaller pulmonary represent successive layers of platelets and fibrin-enmeshed blood cells,
arteries, of which there is a great reserve, but within a few days indicating that the material was formed in life and therefore represents
thrombotic emboli undergo organisation and become firmly adherent thrombus rather than clot. (A) Thrombus showing the striae is seen in
pulmonary arteries on the cut surface of the lung (arrow). Note that the
to the vessel wall.98,99 In 4–6 weeks they are converted into fibrous
postmortem clot to the right lacks the striae. (B) Thrombus removed from
tissue, often with recanalisation. Some emboli seem to disappear and
the lung again shows the striae (centre).
it is presumed that they are destroyed by fibrinolysin. Thin fibrous
bands stretching across the lumen of major pulmonary arteries are
sometimes the only evidence of previous thromboembolism
(Fig. 8.1.7A).101 More often, the lumen of smaller arteries is divided of a pulmonary artery. The explanation for this is the dual blood
up into multiple channels by the usual process of recanalisation supply to the lung and the lung’s independence of the blood stream
(Fig. 8.1.7B).102 for oxygen. True infarction is therefore rare and to produce even a
partial infarct some factor other than failure of the pulmonary arterial
supply is required. This factor is frequently a cardiac condition com­
promising the bronchial arterial supply. Although bronchial arteries
PULMONARY INFARCTION normally supply little blood to peripheral lung tissue, they are capable
of supplying more should the pulmonary artery supply fail. A common
Like other infarcts, those in the lungs are generally wedge-shaped. An clinical setting for pulmonary infarction is the patient confined to bed
occluded pulmonary artery is found at the apex of the infarct; the base with heart failure. This promotes thromboembolism and at the same
of the infarct is on the pleura. Often the edge of a lobe is involved, in time compromises the bronchial arterial supply. Pulmonary infarction
which case the lesion is diamond-shaped rather than wedge-shaped is very rare in the absence of passive pulmonary venous congestion.
(Fig. 8.1.8). Any part of the lung may be affected but infarction is Partial infarcts are initially characterised by oedema but within
commonest at the bases, for the reasons explained above. Pulmonary 48 hours capillaries rupture and the resultant lesions are intensely
infarcts are commonly multiple. haemorrhagic, swollen, firm and dark red (see Fig. 8.1.8). The edge is
sharply demarcated. Acute inflammation develops where infarcts
border healthy lung and fibrin is found on the pleural surface of the
Partial and complete infarction
involved area. Microscopically, the alveoli are filled with blood. Their
Completely infarcted tissue is beyond recovery and healing is only walls are intact however and the basic architecture of the tissue is
possible by repair (rather than by resolution), culminating in a fibrous unaltered. Complete and rapid resolution is frequently observed
scar. This is the situation in only a minority of pulmonary infarcts: radiologically and if the patient then dies, perhaps of a further
most resolve completely, indicating that the lung tissue is not damaged massive embolism, no abnormality other than haemosiderin-laden
irretrievably. The infarction is only partial. Frequently the lung escapes macrophages can be detected in the recently infarcted area. Less often,
even this state of partial devitalisation, despite complete obstruction necrosis is found, signifying true infarction. Healing is then by organi­

408
 Vascular disease Chapter |8|

Figure 8.1.8  Recent infarct of lung. The dark area is infarcted lung in
which the air spaces have become filled with blood. Just above the lesion
B can be seen the supplying pulmonary artery occluded by thrombus.
(Reproduced by permission of the Curator of the Gordon Museum, Guy’s Hospital,
Figure 8.1.7  (A) Thin fibrous bands stretching across the lumen of London, UK; courtesy of Miss P Turnbull, Charing Cross Hospital and Medical
pulmonary arteries may be the only remains of organised thrombotic School, London.)
emboli. (B) The bands are seen as intraluminal fibrous strands on
microscopy.

sation, which is marked by slow paling and shrinkage, until eventually impression of Wegener’s while palisading of the reparative cells may
only a barely detectable scar remains. As with most scars in organs suggest a rheumatoid nodule. In these circumstances the diagnosis of
that are subject to constant movement, such as the lung and the heart, infarction is often no more than tentative, based partly upon negative
they are rich in elastin.103 If the lesion is excised before it has been features, such as an absence of extrapulmonary and serological
fully organised, the central necrosis is seen to be bordered by granula­ evidence of Wegener’s granulomatosis and rheumatoid disease and no
tion tissue rich in foam cells and haemosiderin-laden macrophages. evidence of infection being found.
However, if these features are not well developed conditions such as If the embolus is infected, as may happen with abdominal sepsis,
Wegener’s granulomatosis, rheumatoid nodule and chronic infection infected venous cannulae or bacterial endocarditis affecting the valves
enter the differential diagnosis, especially if the classic wedge shape on the right side of the heart, septic infarction is likely. Suppuration
of an infarction is not well represented.104 Basophilic karyorrhexis and soon causes this to resemble any other lung abscess. A few initially
chronic inflammation involving both the granulation tissue and the sterile lung infarcts become abscesses by colonisation of the de­­
wall of the artery in which the embolus impacted may further the vitalised tissue by airborne bacteria.

409
 Pathology of the Lungs

Pulmonary venous infarction matter. However, the kidney is the best organ in which to identify
systemic fat embolism microscopically because it filters the blood and
In contrast to the infarcts caused by pulmonary artery occlusion, pul­ the fat accumulates in the glomeruli.
monary venous infarction is very rare. This is attributable to the rich Some patients with fat embolism develop severe respiratory failure.
network of venous collateral vessels that drain the lung. Most of the This is seldom due to extensive occlusion of the pulmonary circula­
few reported cases have been due to sclerosing mediastinitis. Other tion. More often it is caused by traumatic shock, which has its own
recorded causes include left atrial myxoma, left atrial thrombosis profound effects on the lungs (see p. 142). Alternatively, it is suggested
complicating mitral stenosis, venous thrombosis following pulmo­ that the lungs are damaged by irritant fatty acids released by lysis of
nary resection and carcinoma of the lung.105,106 The infarcts are similar the fat.112–114
to those caused by arterial occlusion. Chronic venous obstruction, as Microembolism of agglutinated fat emulsions110,115,116 or of crystals
seen in pulmonary veno-occlusive disease (see p. 427) may result in derived from infusions during the course of total parenteral nutri­
interstitial fibrosis. These areas of scarring are rich in haemosiderin tion117 is described on page 390.
and possibly represent healed venous infarcts.

Amniotic fluid embolism

NON-THROMBOTIC PULMONARY EMBOLI Occasionally, during childbirth, amniotic fluid with its content of
particulate debris, mostly epidermal squames and meconium, is
Pulmonary embolism may result from various kinds of material forced by strong uterine contractions into the maternal circulation
forming in, or gaining access to, the systemic veins. Apart from through small incomplete lower uterine tears, resulting in fatal micro­
thrombi, these include fat droplets, various types of tissue, clumps of embolism of the mother’s small pulmonary arteries.118 The emboli
tumour cells, gas bubbles and a variety of foreign substances. In some may be quite sparse, suggesting that death is due to anaphylactic shock
parts of the world parasitic emboli are important: these include the rather than pulmonary vascular occlusion, a possibility that is sup­
eggs of schistosomes (p. 254) and the adult form of the canine heart ported in some cases by the amniotic fluid embolism being accom­
worm Dirofilaria immitis (p. 258).107 In contrast to thrombotic emboli, panied by disseminated intravascular coagulation (see p. 144), mast
the effects of non-thrombotic emboli are not purely mechanical but cell degranulation and complement activation.119 Recognition of the
are also linked to the nature of the embolus. meconium mucus and epidermal squames is facilitated by the applica­
tion of a mucous stain such as alcian blue and immuno­histochemistry
using antibodies against cytokeratin (coupled with an endothelial
Fat embolism marker such as CD34 to distinguish the squames from degenerate
exfoliated endothelial cells).
Fat embolism is usually the result of bone or soft-tissue trauma, but
other causes such as liposuction or bone marrow infarction complicat­
ing haemoglobinopathy are occasionally responsible (Box 8.1.2).107–111 Trophoblastic embolism
Under any of these circumstances, fat or oil globules enter the systemic
veins and reach the lungs. Small fat globules can almost always be Trophoblastic tissue may be found in the lungs in a large proportion
demonstrated in pulmonary capillaries after any fracture if frozen of women who die during pregnancy or the puerperium.120 It is par­
sections are stained appropriately and only a small proportion of ticularly common in women suffering from eclampsia and in those
patients develop symptoms referable to the embolism. undergoing uterine surgery for hydatidiform moles and as a side-effect
The classic fat embolism syndrome consists of hypoxaemia, cerebral of chemotherapy for choriocarcinoma.121 Trophoblastic embolism is
disturbance, tachycardia and a petechial rash that is typically maximal recognisable as isolated multinucleated syncytiotrophoblastic cells
over the front of the chest. The hypoxaemia is attributed to the emboli within pulmonary blood vessels (Fig. 8.1.9) and can be confirmed as
blocking pulmonary capillaries and causing pulmonary arteriovenous such by the immunocytochemical demonstration of human chorionic
anastomoses to open so that venous blood bypasses the lungs. gonadotrophin. Chorionic villi are not observed in the pulmonary
The extrapulmonary symptoms are attributed to emboli that have vessels in normal pregnancies but are common in molar pregnan­
similarly bypassed the pulmonary capillaries to occlude small sys­ cies.122 It is believed that uterine contractions dislodge the tropho­
temic arteries. The presence or absence of lesions is determined by the blastic tissue and enable it to enter the blood stream. The trophoblastic
extent of vascular anastomoses in the organ concerned and the relative emboli cause no structural changes in the lung and appear to
susceptibility of the tissue to oxygen lack. For these reasons the brain be immunologically inert, in spite of their fetal origin. They do not
is particularly affected, showing petechial haemorrhages in the white predispose to thrombosis and usually undergo early lysis120 but rare
fatal cases of massive trophoblastic embolism are recorded in which
over 80% of the pulmonary vessels are occluded.123 In exceptional
cases of benign hydatidiform mole, it has been noted radiologically
Box 8.1.2  Causes of fat embolism107 that masses within the lungs may persist for up to a year, but regress
and totally disappear thereafter124; they presumably represent tropho­
Bone fracture blastic emboli that have gained a temporary foothold in the lungs.
Soft-tissue trauma
Liposuction
Bone marrow infarction complicating haemoglobinopathy Decidual embolism
Bone marrow harvest
Viral hepatitis affecting a fatty liver Small foci of decidua are occasionally observed in the lungs in preg­
Pancreatitis nancy. Such foci located immediately beneath the pleura125 may repre­
Intravenous injection of various oils by accident or intent sent focal metaplasia of the overlying serosa but deep in the lung an
Periurethral injection to treat stress incontinence embolic aetiology is generally assumed, although the decidual tissue
Breast augmentation is usually extravascular. The nature of this tissue is discussed further
under the subject of pleuropulmonary endometriosis (see p. 495).

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 Vascular disease Chapter |8|

Figure 8.1.10  Bone marrow embolism incurred as a terminal event

during unsuccessful attempts at cardiac massage in which ribs were
fractured.

Figure 8.1.9  Trophoblast embolism. The trophoblast is recognisable as a

clump of multinucleated syncytiotrophoblastic cells within a pulmonary
artery.

Tumour embolism
Tumour emboli are common in the lungs. A few survive to form
metastatic deposits but most die very soon after arriving in the lungs:
the embolus then becomes enclosed by platelets and finally undergoes
organisation.126 Vascular occlusion by tumour emboli is sometimes
so widespread that it leads to right-sided heart failure127–133 whilst
massive tumour emboli have sometimes proved fatal134–136 or neces­
sitated emergency embolectomy.137 In other patients they have caused
flitting radiographic opacities, which presumably represent infarcts.138
Occlusion of the pulmonary arteries may be due to tumour alone or
the tumour may promote thrombosis, organisation of which results
in fibrocellular intimal thickening, so-called carcinomatous throm­
botic microangiopathy or vascular intimal carcinomatosis (see p.
682).139–142 Embolic sarcoma is distinguished from the primary
sarcoma of the pulmonary arteries described on page 638 by the
presence of an extrapulmonary source. Figure 8.1.11  Bile embolism in a patient who died suddenly from
rupture of a hepatic hydatid cyst. Partial organisation of the bile indicates
that bile leakage had been occurring for some time before death.
Other tissue embolism Haematoxylin and eosin. (Courtesy of Dr T Jelihovsky, Sydney, Australia.)

Bone marrow is frequently seen plugging small pulmonary arteries

postmortem when ribs have been broken during unsuccessful attempts the injury to the vessels is extensive.148 Widespread pulmonary fibrosis
at cardiac resuscitation or following trauma to other bones (Fig. may also develop, occasionally mimicking pneumoconiotic pro­
8.1.10). Other traumatic emboli may consist of brain tissue,143,144 liver gressive massive fibrosis.156 Starch particles can be identified by their
tissue,145,145a bile (Fig. 8.1.11),146 bone fragments (Fig. 8.1.12) or very characteristic Maltese cross appearance on polarising microscopy, and
rarely atheromatous cholesterol crystals.147 Haemorrhage has been talc by its platy form on polarising microscopy and by elemental
ascribed to the last of these but none of the others is of clinical con­ electron microprobe analysis.156 Cellulose fibres can be distinguish
sequence; they merely represent incidental necropsy findings. from platy crystals such as talc by their reaction with periodic acid–
Schiff, silver methenamine and Congo red stains.153,157 Crosprovidone
is seen as basophilic, coral-like particles, the nature of which can be
Foreign-body embolism
confirmed by infrared spectroscopy.158 Any of these particles may leave
Some drug addicts break up preparations of drugs intended for oral the blood vessels and be found in the interstitial tissues and even air
use and inject an aqueous suspension intravenously. Substances used spaces. Talc particles in the lung exceeding 5 µm in length should
as fillers in the manufacture of tablets include starch, cellulose, talc arouse suspicion of intravenous drug abuse,159 but cellulose fibres up
and crosprovidone (poly[N-vinyl-2-pyrrolidone]). When injected to 120 µm in length may reach the lungs and cause granulomatosis
intravenously, these lodge in pulmonary vessels and induce thrombo­ in addicts who inhale their illicit drugs.157,160
sis and a local foreign-body granulomatous reaction (Fig. 8.1.13 and Other embolic foreign bodies described in pulmonary arteries
see Fig. 7.2.10, p. 379).148–155 Pulmonary hypertension may result if include airgun pellets,161 shrapnel, whole bullets,162 masonry and

411
 Pathology of the Lungs

Figure 8.1.14  Embolised vegetable matter is present within a pulmonary

artery in a patient who died of a ruptured oesophagus. (Courtesy of Dr CA
Seldenrijk, Nieuwegein, The Netherlands.)

Figure 8.1.12  Bone embolism. A fragment of bone is lodged in a

pulmonary artery after failed resuscitation.

Figure 8.1.15  Therapeutic embolisation with foam introduced by

percutaneous cannulation of the bronchial arteries in an unsuccessful
attempt to stem haemorrhage into an aspergilloma cavity.

Figure 8.1.13  Drug addict’s lung viewed with partially polarised light
showing a granulomatous response to numerous birefringent plate-like infarction of neoplasms. It involves the cannulation of bronchial
talc crystals. Although reaching the lungs by the pulmonary arteries, the arteries via a femoral artery and the aorta. Bronchial arteries are
crystals work their way through the vessel walls and eventually become chosen because aspergillomas and tumours derive their blood supply
widely distributed in the lungs. from these systemic vessels, as is the case with most pulmonary
disease. If the procedure fails to stem the haemorrhage and surgery is
resorted to, or the patient dies, the pathologist may be asked to
stone fragments, food particles (Fig. 8.1.14), the broken-off ends of confirm that the bronchial arteries do contain the injected material.
intravenous catheters and cannulas, plastic particles from dialysis This is usually a synthetic foam and is easily recognised as such (Fig.
tubing and other intravascular devices,163,163a therapeutic injections or 8.1.15), but Verhoeff–van Gieson staining is recommended as a
prosthetic implants of substances such as Teflon, hyaluronic acid and means of facilitating its recognition.178
silicone,164a,168a lymphangiography contrast medium,169–172 various
materials injected to occlude abnormal blood vessels or deprive a
Air embolism
tumour of its blood supply,173,174 and mercury, this last generally
introduced into the circulation with suicidal intent.175 Patients with Venous air embolism may occur whenever a vein above the level of
psychiatric problems have also injected themselves with various the heart is opened and exposed to the atmosphere, for example
other substances, such as olive oil, resulting in pulmonary during operations on the head and neck or pelvic operations in which
lipogranulomatosis.176 the patient is put in the Trendelenburg position. Air may also enter
Bronchial, as opposed to pulmonary, artery embolisation is some­ veins during peritoneal insufflation at laparoscopy or be inadvertently
times carried out therapeutically in an attempt to stem intractable injected under pressure during urgent transfusions. A central venous
haemorrhage from lesions that are difficult to resect, such as an pressure line carries a high risk of air embolism. Air embolism also
aspergilloma.177 The same technique is used on occasion to induce occurs during high pressure mechanical ventilation or due to dramatic

412
 Vascular disease Chapter |8|

Box 8.1.3  Causes of pulmonary artery aneurysms182

Congenital
with arteriovenous communication
Isolated
As part of hereditary haemorrhagic telangiectasia
without arteriovenous communication
Vasculitic
Infective
Syphilitic
Tuberculous
‘Mycotic’ (from septic emboli)
Non-infective
Behçet’s syndrome
Hughes–Stovin syndrome
Tuberous sclerosis185
Hypertensive
Figure 8.1.16  Idiopathic aneurysm of the pulmonary artery. The patient
died of respiratory failure secondary to scoliosis, which was also Traumatic
idiopathic. Idiopathic183,184

changes in atmospheric pressure (see p. 368) or there is severe chest

trauma.
Following venous air embolism, the fine bubbles into which the air
is churned during its passage through the heart are carried into the
pulmonary arteries. The cause of death is generally acute heart failure
and the embolism is recognised by a frothy mixture of air and blood
filling the chambers of the right side of the heart and pulmonary
trunk. The volume of air needed to produce fatal air embolism in this
way may be 100–200 ml or more. More rarely, air embolism results
in pulmonary oedema.181
Systemic air embolism occurs most frequently during open-heart
surgery but may also develop after chest trauma or as a sequel to
venous air embolism in patients with an arteriovenous shunt (para­
doxical air embolism). It is also recorded in aeroplane passengers with
cystic lung disease.179,180 A few millilitres of air introduced into the
systemic arteries may prove fatal through obstruction of small vessels
in the brain stem. A

PULMONARY ANEURYSMS

An aneurysm is defined as a localised vascular dilatation but the term

is usually confined to arterial dilatations. Localised venous dilatations
are generally termed varices. Both are rare in the pulmonary
circulation. Either may be saccular or fusiform.
Historically, most pulmonary aneurysms have been syphilitic or
tuberculous but these causes are now very rare. Today, various other
causes are recognised but sometimes no cause can be identified (Fig.
8.1.16 and Box 8.1.3).182–185 The basic fault in all aneurysms is a
localised defect in the arterial media. Most are dealt with elsewhere:
arteriovenous on p. 76, infective on p. 437, Behçet’s syndrome and
Hughes–Stovin syndromes on pp. 447 and 479 and hypertensive on
p. 431. Traumatic aneurysms may be true or false, the latter represent­
ing a haematoma alongside and communicating with the parent
artery through a complete defect in the vessel wall but walled off
externally by a fibrous capsule. B
Dissecting aneurysms have also been reported in pulmonary arter­
ies, usually complicating pulmonary hypertension.186,187 They may Figure 8.1.17  Dissection of a systemic artery supplying a pulmonary
also be encountered in a systemic vessel supplying an extralobar sequestration. (A) Haematoxylin and eosin stain; (B) elastin van Gieson
sequestration (Fig. 8.1.17). stain.

413
 Pathology of the Lungs

Figure 8.1.18  Pulmonary varix. (A) A circumscribed blood-filled cyst is present within the lower lobe. (B) Microscopy shows a thin fibrous wall, which
contains variable amounts of disordered elastin fibres (c).

Pulmonary varix
a congenital anomaly or to develop postnatally because of a
A pulmonary varix is a localised dilatation of a pulmonary vein (Fig. con­genital defect in the vein wall. A substantial number of
8.1.18).188 Apart from rare examples that bleed, sometimes with fatal pulmonary varices, perhaps half, are secondary to mitral valve regur­
results, the condition is discovered incidentally at autopsy or by gitation.190 Rarely, they are found in association with end-stage liver
radiography.189 In many cases the varix is assumed to represent disease.189

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embolotherapy of cerebral arteriovenous

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8.2  Pulmonary hypertension

In diffuse fibrosis the pulmonary pathology is dominated by the

CHAPTER CONTENTS
parenchymal disease, but with the other causes the vascular changes
Plexogenic pulmonary arteriopathy 420 preponderate. These fall into distinct categories that largely
Congenital heart disease 422 correspond to the cause of the hypertension, the principal ones being
plexogenic, hypoxic, thromboembolic and venous, as indicated in
Primary pulmonary hypertension 423
Table 8.2.1 and Figure 8.2.1. Thus, to a large extent, the pathological
Hepatic disease 424 changes indicate the cause of the hypertension, as well as its presence
Ingested agents 424 and severity.4,5 This classification serves pathologists well but is appar­
Human immunodeficiency virus infection 424 ently of less benefit to clinicians and a multispecialty international
group has therefore devised an alternative classification, which is
Hypoxic pulmonary hypertension 424
shown in Box 8.2.1.6,7 This concentrates on clinical parameters rather
Pulmonary hypertension in diffuse parenchymal than histological features and thus facilitates categorisation of the
lung disease 425 many patients who are not studied histologically. However, it may be
Embolic pulmonary hypertension 426 noted that in this classification diseases that show the same histologi­
Venous pulmonary hypertension 427 cal pattern of vasculopathy (e.g. left-sided heart disease and compres­
Mitral stenosis 427 sion of large veins) appear in different categories, whilst others that
are profoundly different histologically are grouped together (e.g.
Pulmonary veno-occlusive disease (pulmonary
plexogenic arteriopathy and pulmonary veno-occlusive disease).8
occlusive venopathy) 427
We therefore adhere to the scheme depicted in Table 8.2.1 and
Pulmonary capillary haemangiomatosis (pulmonary Figure 8.2.1. Whichever classification is preferred, certain histological
microvasculopathy) 429 features are shared by all categories and these will be described first.
Pulmonary hypertension in connective tissue disease 429 An elastin stain is invaluable in appreciating the vascular changes.
Effects of pulmonary hypertension 431 The earliest vascular changes are not specific and are present
Cor pulmonale 431 irrespective of the cause. In mild pulmonary hypertension histological
diagnosis will be entirely dependent on the recognition of these early
Treatment of pulmonary hypertension 432
changes. They consist of medial hypertrophy, which is followed by
References 432 subendothelial intimal fibrosis (Fig. 8.2.2). Isolated intimal fibrosis is
not indicative of pulmonary hypertension as it is merely a common
age change encountered irrespective of the pressure in the lesser
circulation. Medial thickening is not an age change but is due to
Normally the pressure in the pulmonary artery seldom exceeds prolonged contraction of its smooth muscle and represents a form of
30/15 mmHg but in a variety of cardiopulmonary diseases this figure work hypertrophy, probably stimulated by mediators released by the
can increase up to fourfold. Pulmonary hypertension is defined as a endothelium, notably endothelin, which counters the action of the
mean pulmonary artery pressure greater than or equal to 25 mmHg endothelium-derived vasodilatory agent nitric oxide.9
at rest.1 The causes operate at the precapillary, capillary or post­ Medial thickening is conveniently quantitated by tracing the inter­
capillary level, as listed in Table 8.2.1. Pre- and postcapillary forms of nal and external elastic laminae on a digitising tablet and using a
pulmonary hypertension are distinguished haemodynamically by computer to express the media as a proportion of the whole vessel in
capillary wedge pressures of ≤15 or >15 mmHg respectively.2,3 terms of either its diameter or area. The vessel is often collapsed and

419
 Pathology of the Lungs

Table 8.2.1  Causes of pulmonary hypertension and their

principal pathological features

Cause Pathology

Precapillary: constrictive Plexogenic arteriopathy

Unknown (primary pulmonary
hypertension)
Hyperkinetic congenital heart disease
Chronic liver disease with portosystemic
venous shunting
Human immunodeficiency virus  
infection
Appetite-suppressing drugs (aminorex,
fenfluramine)
Hereditary haemorrhagic telangiectasia
Connective tissue disease

Precapillary: hypoxic Peripheral extension of

medial muscle and
Prolonged residence at high altitude
the development of
Chronic obstructive lung disease
longitudinal muscle
Sleep apnoea obesity syndrome
within the intima
Figure 8.2.1  Patterns of vasculopathy in pulmonary hypertension. (1)
Precapillary: embolic Plexogenic arteriopathy characterised by medial hypertrophy, concentric
Thromboembolic Recanalisation intimal fibrosis, necrotising arteritis and a variety of dilatation lesions. (2)
Parasitic (schistosomal) Thromboembolic vasculopathy, characterised by eccentric intimal
Tumour emboli thickening and duplication of the lumen by intimal bands. (3) Venous
hypertension characterised by medial hypertrophy and either eccentric or
Capillary concentric thickening of the arterial media coupled with intimal sclerosis
of the postcapillary vessels. (4) Hypoxic vasculopathy, characterised by
Widespread pulmonary fibrosis mild medial hypertrophy and the development of longitudinal bundles of
Capillary haemangiomatosis smooth muscle in the intima. (Reproduced from Wagenvoort (1973)4 by
Diffuse smooth-muscle proliferation permission of the editor of Chest.)

Postcapillary
Venous muscular
Left-sided heart disease hypertrophy and
Veno-occlusive disease luminal obliteration
fibrinoid arteriopathy (Fig. 8.2.3) and the development of character­
istic dilatation lesions, some of which are plexiform.12–15
The cellular component of the concentric intimal fibrosis is made
up of fibroblasts, myofibroblasts and smooth-muscle cells, largely
the elastic laminae consequently wrinkled but the computer can be derived from the media but with contributions from the endothelium
programmed to express the diameter of the vessel as if it had been and circulating stem cells.16–19 Concentric intimal fibrosis is also
fixed in the filled state and the elastic laminae were smooth.10 Normal encountered in some connective tissue disease, particularly systemic
values are best obtained by the same operator but the medial thickness sclerosis (see p. 430).
of a normal muscular pulmonary artery has been given as 3–5% of The necrotising arteriopathy is very similar morphologically to the
its external diameter (compared with 15–20% in systemic arteries).11 autoimmune arteritides dealt with in the next chapter but is to be
regarded as a consequence of severe medial contraction rather than
an immune process. It is seldom seen in isolation, nearly always being
accompanied by the dilatation lesions that develop from it.
PLEXOGENIC PULMONARY ARTERIOPATHY Dilatation lesions are thin-walled vascular structures that come off
a greatly thickened muscular artery. Beyond their point of origin the
The word ‘plexogenic’ indicates a potential to develop plexiform parent artery is usually obliterated by intimal fibrosis (Fig. 8.2.4).20
lesions rather than their presence and was chosen to identify the They are thought to represent ‘blow-out lesions’ at points of necrotis­
disease as a whole, including the early stages described above because ing arteritis in the wall of the parent vessel.14,20 It is therefore justifiable
the plexiform lesions occur only in the final stages of the disease.12 It to condense into one the last three grades of the traditional Heath
is notable that plexiform lesions are not encountered in chronic and Edwards grading system (Table 8.2.2),14,21,22 which was devised
pulmonary venous hypertension, chronic hypoxic pulmonary hyper­ specifically for patients with hyperkinetic pulmonary hypertension
tension or pulmonary hypertension due to chronic thrombo­ secondary to congenital heart disease but can be equally applied to
embolic disease. They are limited to forms of pulmonary hypertension plexogenic arteriopathy of whatever cause.
characterised by intense vasoconstriction, which are those listed Dilatation lesions involve the supernumerary arteries where these
under Precapillary: constrictive in Table 8.2.1. vessels leave the axial arteries (see Fig. 8.2.4).20,23 Supernumerary
In plexogenic arteriopathy the medial hypertrophy described above arteries differ from axial arteries in that they do not accompany
is followed in sequence by concentric intimal fibrosis, necrotising bronchioles or branch at a narrow angle: they leave the axial vessel at

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 Vascular disease Chapter |8|

Box 8.2.1  Revised clinical classification of pulmonary

hypertension (Venice 2003)6,7
1. Pulmonary arterial hypertension (PAH)
1.1. Idiopathic (IPAH)
1.2. Familial (FPAH)
1.3. Associated with (APAH):
1.3.1. Collagen vascular disease
1.3.2. Congenital systemic-to-pulmonary shunts
1.3.3. Portal hypertension
1.3.4. Human immunodeficiency virus (HIV) infection
1.3.5. Drugs and toxins
1.3.6. Other (thyroid disorders, glycogen storage disease,
Gaucher disease, hereditary telangiectasia,
haemoglobinopathies, myeloproliferative disorders,
splenectomy) A
1.4. Associated with significant venous or capillary involvement
1.4.1. Pulmonary veno-occlusive disease (PVOD)
1.4.2. Pulmonary capillary haemangiomatosis (PCH)
1.5. Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension with left heart disease
2.1. Left-sided atrial or ventricular heart disease
2.2. Left-sided valvular heart disease
3. Pulmonary hypertension associated with lung diseases and/or
hypoxaemia
3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
3.3. Sleep-disordered breathing
3.4. Alveolar hypoventilation disorders
3.5. Chronic exposure to high altitude
3.6. Developmental abnormalities
4. Pulmonary hypertension due to chronic thrombotic and/or embolic
disease
4.1. Thromboembolic obstruction of proximal pulmonary arteries
4.2. Thromboembolic obstruction of distal pulmonary arteries
4.3. Non-thrombotic pulmonary embolism (tumour, parasites,
foreign material)
5. Miscellaneous B
Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of
pulmonary vessels (adenopathy, tumour, fibrosing mediastinitis) Figure 8.2.3  (A) Necrotising arteritis in a patient with severe pulmonary
hypertension secondary to a ventricular septal defect. (B) In another
patient with pulmonary hypertension an early dilatation lesion has
developed consequent upon the arterial wall being weakened by focal
necrosis.

an obtuse angle and feed alveolar capillaries soon after their origin.24
Thus they rapidly narrow and there is considerable reduction in
pressure over a short distance. When the arterial pressure is raised
there is significant physical stress on these arteries and it is likely that
this is involved in the development of the necrotising arteritis and the
subsequent dilatation lesions.
Dilatation lesions are described as being simple, plexiform or
angiomatoid. Simple dilatation lesions are saccular aneurysms,
whereas plexiform lesions represent such aneurysms filled by connec­
tive tissue that is rich in myofibroblasts and is intersected by a complex
of fine endothelium-lined spaces (Fig. 8.2.5).16,25 It is reported that
the endothelial cell proliferation is monoclonal in primary but not in
Figure 8.2.2  Pulmonary hypertension. There is marked medial
secondary pulmonary hypertension.26,27 Plexiform lesions often lead
hypertrophy and cellular intimal thickening. Pulmonary arteries normally to wide thin-walled vessels which in turn feed into capillaries (Fig.
have an extremely thin media and the thickening here represents marked 8.2.6).20 They occasionally reach a diameter of l mm. The multiple
hypertrophy. Its proximity to an airway indicates that this blood vessel is fine channels probably represent organised and recanalised thrombi
an artery rather than a vein. within an otherwise simple dilatation lesion. The narrow channels of

421
 Pathology of the Lungs

Figure 8.2.4  A computer-aided reconstruction of the distal pulmonary

Figure 8.2.5  A plexiform lesion. The media of this pulmonary artery is
arteries in plexogenic pulmonary hypertension. Plexiform lesions (white)
deficient on one side and here the lumen communicates with a plexus of
occur in supernumerary arteries just proximal to a point where the larger
fine channels. On the other side of the artery the media is greatly
axial arteries are obliterated by intimal proliferation (green). Only a few
hypertrophied.
patent vessels remain (arrows). (Reproduced from Yaginuma et al. (1990)20 by
permission of the editor of Thorax.)

Table 8.2.2  Heath & Edwards21 grading system of hypertensive

pulmonary vascular disease. This system was designed for use
in connection with congenital heart disease. It is applicable to
other causes of plexogenic pulmonary arteriopathy but not to
other causes of pulmonary hypertension. Because dilatation
lesions are now thought to be due to fibrinoid necrosis,14
grades 4–6 could well be condensed into one. The critical area
regarding reversibility lies in the region of grades 2 and 3 and
there is a case for dividing these according to the degree of
luminal narrowing22

Grade Histological criteria

1 Medial hypertrophy
2 Grade 1 plus cellular intimal thickening Figure 8.2.6  A plexiform lesion. The point of origin from the adjacent
artery is not evident but surrounding the plexiform lesion is a collection
3 Grade 1 plus fibrous intimal thickening
of wide thin-walled vessels.
4 Grades 2 or 3 plus dilatation lesions
5 Grade 4 plus haemosiderosis
Siderophages, cholesterol granulomas and focal fibrosis represent
6 Grade 5 plus necrotising arteritis secondary changes consequent upon pulmonary haemorrhage, which
may complicate severe or longstanding cases of plexogenic pulmonary
hypertension.15 Pulmonary arterial thrombosis, identical in appear­
ance to thrombotic embolism, is generally a further secondary
a plexiform lesion are probably responsible for the microangio­ change15 but in primary pulmonary hypertension it may be an inher­
pathic haemolytic anaemia that occasionally complicates plexogenic ent component of the pathogenetic process, as discussed below.30
pulmonary arteriopathy.28 The angiomatoid lesion consists of several
thin-walled cavernous spaces linking a muscular pulmonary artery to
its capillary bed and resembling a haemangioma (Fig. 8.2.7). They
Congenital heart disease
were once thought to represent congenital malformations but are now Congenital cardiovascular anomalies characterised by left-to-right
recognised to be acquired. shunting, such as patent ductus arteriosus and septal defects, result in
Plexiform lesions need to be distinguished from organised recanal­ a hyperkinetic form of pulmonary hypertension in which the blood
ised thrombus with florid endothelial cell proliferation. The essential enters the pulmonary arteries in greater volume or at a higher pressure
difference is that plexiform lesions lie alongside the parent artery than usual. In cases of atrial septal defect, blood passes from the left
whereas organised thrombus is within. Elastin stains are helpful in to the right atrium, and so adds to the quantity of blood entering the
that pulmonary arteries containing recanalised thrombus usually have pulmonary artery. This can usually be accommodated because of the
intact internal and external elastic laminae whereas these structures marked distensibility of the pulmonary vasculature and hypertension
are destroyed at the site of plexiform lesions.29 seldom develops before middle age. However, when there is a ven­

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Figure 8.2.7  An angiomatoid lesion. A convoluted, wide, thin-walled

vessel simulating a haemangioma leads directly off a hypertrophied
pulmonary artery; the narrow sinusoids of a plexiform lesion are not
apparent in this type of dilatation lesion.

tricular septal defect or patent ductus arteriosus, the increase in the

volume of the blood in the pulmonary circulation is accompanied by
a substantial increase in pressure. The changes in the walls of the
pulmonary arteries are consequently more severe and develop early
in life. There is severe constriction of small muscular arteries, which
undergo medial hypertrophy and raise the pulmonary resistance
through their hypertonicity. At this stage they are still capable of
relaxation and there is enough circulatory reserve to meet the needs B
of exercise, but when severe hypertension persists the lumen of the
small muscular arteries becomes further narrowed by thickening of Figure 8.2.8  Aorta (left) and pulmonary trunk (right) in congenital
the intima. Initially this is due to concentric laminar cellular prolifera­ pulmonary hypertension secondary to a ventricular septal defect (A), and
tion but later intimal fibrosis supervenes. The vessels are then less in acquired pulmonary hypertension secondary to bronchopulmonary
capable of adaptive dilatation, the hypertension becomes irreversible disease that developed in adult life (B). The fragmented elastin pattern of
and the patient enters a perpetual state of high pulmonary resistance the normal adult pulmonary trunk is maintained in acquired pulmonary
hypertension but in patients in whom the pulmonary hypertension has
and low circulatory reserve. Further vascular changes are those
been present from birth the fetal pattern (which is identical to that in the
described above under plexogenic arteriopathy. There may also be
aorta) is maintained. Elastin van Gieson stain.
secondary pulmonary artery thrombosis, organisation of which leads
to eccentric plaques of intimal fibrosis. The practical point is that the
underlying congenital anomalies should be corrected before the
pulmonary arteries are permanently narrowed by intimal fibrosis. In conditions leading to low pulmonary flow rates or diminished
Lung biopsy can be useful in assessing the reversibility of hyper­ pulmonary artery pulse pressure, such as congenital pulmonary steno­
kinetic pulmonary hypertension,31–33 but carries a risk of severe haem­ sis, perhaps as part of Fallot’s tetrad, the pulmonary arteries show
orrhage and most cases are now assessed by cardiac catheterisation. changes the reverse of those described above, namely medial atrophy,
Histological features that are compatible with a successful corrective so that they are extremely thin-walled. A media is sometimes not
operation include medial hypertrophy, cellular concentric intimal apparent. The low blood flow and the almost invariably raised
thickening of moderate degree and eccentric intimal fibrosis conse­ haematocrit promote thrombosis and evidence of this in the form
quent upon thrombosis. Conversely, severe intimal fibrosis, fibrinoid of eccentric intimal plaques or subdivision of the lumen is often
necrosis and dilatation lesions suggest that the pulmonary hyper­ apparent. However, this is seldom so extensive that it causes
tension will progress despite corrective surgery. However, potential pulmonary hypertension, but corrective procedures entailing shunts
reversibility probably differs from safe operability. Medial hyper­ may lead to plexogenic arteriopathy.
trophy is potentially reversible but may be associated with fatal
pulmonary hypertensive crises at operation.34
Primary pulmonary hypertension
The major pulmonary arteries are elastic vessels and at birth the
pattern of their elastic laminae closely resembles that of the aorta. The microscopic features of primary pulmonary hypertension are
However, within the first few months of life there is fragmentation of those of plexogenic pulmonary arteriopathy, as described above. They
the elastic fibres and an irreversible ‘adult pattern’ is reached by about are indistinguishable from those seen in plexogenic pulmonary hyper­
the age of 6 months. This ‘adult pattern’ is maintained even if tension due to any of the other causes listed in Table 8.2.1. A diagnosis
pulmonary hypertension develops in later life, whereas in congenital of primary pulmonary hypertension can therefore only be made when
pulmonary hypertension the ‘aortic pattern’ found at birth persists all other possible causes of plexogenic pulmonary arteriopathy have
(Fig. 8.2.8). been excluded by full clinical and radiological examination, cardiac

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catheterisation and, if necessary, open-lung biopsy. Despite this, the in one series pulmonary venous intimal thickening was identified in
term ‘primary pulmonary hypertension’ has been used by clinicians 65% of cirrhotic patients.65
when the condition remains unexplained after investigations that fall
short of histological assessment. Pathological examination in 156
such cases showed that 70% were plexogenic, 20% were thrombotic Ingested agents
and 6% showed venous obliteration.13 Similar heterogeneity has been A notable increase in the incidence of ‘primary’ pulmonary hyperten­
reported in other series.35 Although plexogenic, thromboembolic and sion occurred in Switzerland, Austria and Germany during the period
veno-occlusive pulmonary hypertension cannot be distinguished 1966–68 when the anorectic drug aminorex was marketed.66 It was
without histological assessment, their histological distinction is often not possible to reproduce the disease experimentally but the epide­
blurred by plexogenic arteriopathy being complicated by thrombo­ miological evidence that aminorex fumarate was responsible for the
sis,30 by the changes of veno-occlusive disease extending proximally pulmonary hypertension is strong. The drug had been on sale only in
to involve arteries and by venous abnormalities being identified in these three countries and the increase in the frequency of pulmonary
plexogenic arteriopathy.15 Some workers therefore regard primary hypertension closely followed the rise in its sale, while following its
plexogenic arteriopathy, thrombotic pulmonary vascular disease and withdrawal there was a corresponding fall in the number of cases of
veno-occlusion as facets of one condition and term this primary pulmonary hypertension. Another anorectic drug, fenfluramine, has
pulmonary hypertension, on the basis that the cause is unknown also been linked to the development of pulmonary hypertension.67–70
whatever the predominant histological pattern.35–37 Thus, the term Plexiform lesions have been described with both these drugs.71
‘primary pulmonary hypertension’ is currently used in three different Pulmonary hypertension formed part of the Spanish toxic oil
ways, of which we prefer the first: episode and the L-tryptophan-induced eosinophilia–myalgia syn­
1. for primary plexogenic pulmonary hypertension drome. The changes wrought by these ‘dietary’ supplements include a
2. for pulmonary hypertension that cannot be explained despite pulmonary vasculitis and differ from those of plexogenic arteriopathy.
full clinical investigation (but falling short of histological They are described on pages 375 and 389.
assessment) Pyrollizidine alkaloids derived from various species of Senecio
3. for pulmonary hypertension due to intrinsic pulmonary vascular (ragworts and groundsels) cause intense vasoconstrictive pulmonary
disease regardless of whether histology shows this to be hypertension in laboratory animals but there is no evidence that
thrombotic, plexogenic or veno-occlusive. ingestion of these plants causes pulmonary hypertension in humans.
Primary plexogenic pulmonary hypertension can occur at any age Nevertheless, observations such as these support the histopathological
but most commonly affects young adults, with women outnumbering evidence that primary plexogenic pulmonary hypertension is vaso­
men by about 2 to 1.13,38 A family history is evident in approximately contrictive in nature due to an as yet unidentified neural or
6% of patients38 but the identification first of the responsible gene on humoral agent.
chromosome 2 (2q32-34),39,40 and then its expression in seemingly
sporadic cases of primary pulmonary hypertension,41,42 suggests that
Human immunodeficiency virus
the true prevalence of familial cases is considerably higher. The gene
concerned encodes for bone morphogenetic receptor protein-II (HIV) infection
(BMPR2), which controls the action of transforming growth factor-β An association of pulmonary hypertension with HIV infection is well
on the vessel wall.43–46 It is therefore relevant that the genes for established but until recently has been unexplained.72–75 The virus
hereditary haemorrhagic teleangiectasia (Osler–Weber–Rendu disease cannot be identified in the pulmonary vessels but tubuloreticular
– see pp. 76 and 481), of which plexogenic pulmonary hypertension structures suggestive of cytokine accumulation have been identified
is a rare feature, also control the vascular transforming growth factor-β there by electron microscopy in HIV-positive individuals.76 Evidence
pathway.47,48 Mutation of the BMPR2 gene is found in 70% of patients now emerging suggests that it is the highly active antiretroviral drugs
with familial pulmonary hypertension and up to 10% of patients with administered to HIV-infected patients that are responsible for the
sporadic primary pulmonary hypertension.49 vascular injury rather than the virus itself.77
Endothelial factors such as angiotensin-converting enzyme, The incidence of pulmonary hypertension in HIV-positive patients
endothelin and (deficiency of) nitric oxide are further likely is 1 in 200, the male-to-female ratio is 1.6 : 1 and the age range is
mediators.50–52 Female sex hormones may also play a role.53 A reported 3–56 years, with a mean of 32 years.78 The arteriopathy is generally
increase in airway neuroendocrine cells54–56 and the detection of plexogenic but thrombotic or veno-occlusive changes are described
Chlamydia pneumoniae in the hypertrophied pulmonary arteries of a in 15% of cases.78 Suggestions that Kaposi sarcoma herpesvirus is
patient dying of pulmonary hypertension57 are of uncertain signifi­ similarly associated with pulmonary hypertension have not been
cance. Raynaud’s phenomenon is found in 10% and a positive anti­ substantiated.79
nuclear antibody test in about 30% of patients with primary pulmonary
hypertension.38 There is also a high prevalence of autoimmune thyroid
disease.58 Pulmonary hypertension associated with more pronounced
connective tissue disease is considered below. HYPOXIC PULMONARY HYPERTENSION

The pulmonary circulation differs from the systemic circulation in that

Hepatic disease
it reacts to hypoxia by vasoconstriction rather than vasodilatation.
The prevalence of plexogenic pulmonary hypertension in cirrhosis is Hypoxia, whether due to high altitude or a ventilatory lung defect,
in the order of 0.7%59 and the fact that it takes this form of arterio­ causes the muscular pulmonary arteries to constrict and, although the
pathy60,61 suggests that it is vasoconstrictive, perhaps the result of consequent pulmonary hypertension may be life-threatening, the
metabolites that are normally inactivated in the liver. Paradoxically, intense spasm that leads to necrotising arteriopathy and dilatation
some patients with cirrhosis of the liver develop pulmonary arterial lesions of plexogenic arteriopathy is not a feature. The mechanism by
dilatation and arteriovenous communications in the lungs62–64 while which hypoxia leads to pulmonary artery constriction is unclear but

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Figure 8.2.9  Normal precapillary blood vessels of the lungs. As

pulmonary arteries narrow, the muscle of the media thins progressively
and in vessels between 100 and 30 µm in diameter it is represented only
Figure 8.2.10  Hypoxic pulmonary hypertension. Intralobular arteries
by a spiral so that in cross-section arteries of this size are only
smaller than 30 µm diameter with a well-developed medial coat
muscularised for part of their circumference. Below 30 µm diameter,
indicative of pulmonary hypertension are especially found with hypoxia.
precapillary vessels have no muscle at all in their walls, which consist only
Elastin van Gieson stain.
of fibroelastic tissue.

it operates at the local level, affecting only those vessels in the immedi­
ate vicinity of airways with low oxygen tensions.80,81 It is likely that it
involves changes in the levels of vasoactive factors synthesised and
released by the arterial endothelium, in particular nitric oxide, which
has vasodilatory properties, and endothelin, which is a vasoconstrictor
(see p. 24).50,51,82–84 The arteries involved are principally small precapil­
lary vessels80,81 but small pulmonary veins are also affected.85 However,
the earliest morphological response to hypoxia is found in the carotid
bodies, which undergo hyperplasia before any structural changes are
detectable in the lungs.86
Ventilatory disorders causing pulmonary hypertension include
chronic obstructive pulmonary disease (see p. 102), bronchiectasis
(see p. 119) and extrapulmonary causes of poor ventilation such as
kyphoscoliosis and obesity. In emphysema, there is no correlation
between the extent of capillary loss and right ventricular weight87,88:
vaso­constriction is held to be responsible, as in other forms of hypoxic
pulmonary hypertension. It is also possible that cigarette smoke com­ Figure 8.2.11  Hypoxic pulmonary hypertension. The arterial media is
ponents may augment the hypoxia by acting directly on the artery hypertrophied and longitudinal bundles of smooth muscle have
wall.89 In bronchiectasis, both hypoxia and left-to-right shunts conse­ developed in the intima.
quent upon bronchopulmonary arterial anastomoses contribute to
the pulmonary hypertension.
Morphological changes characteristic of hypoxic pulmonary hyper­ hypoxic forms. The arterial changes found in hypoxic pulmonary
tension include mild medial hypertrophy affecting the smallest pre­ hypertension are reversible, but irreversible airway disease or pro­
capillary vessels. Below 100 µm diameter, the medial muscle normally longed residence at high altitude may result in death in right-sided
spirals out and none at all is normally seen in vessels below about 30 heart failure that is directly attributable to the hypoxic pulmonary
µm in diameter: between 100 and 30 µm diameter, muscle is normally hypertension.
limited to one side of the vessel (Fig. 8.2.9). Fully muscularised vessels
below 100 µm diameter and partially muscularised vessels below 30
µm diameter therefore indicate medial hypertrophy (Fig. 8.2.10).
PULMONARY HYPERTENSION IN DIFFUSE
A further feature is the occasional development of longitudinal
bundles of smooth muscle in the intima of small pulmonary arteries PARENCHYMAL LUNG DISEASE
(Fig. 8.2.11).90–93 It is suggested that the development of longitudinal
smooth muscle in the intima is caused by repeated stretching of the Pulmonary hypertension develops when there is widespread
small pulmonary vessels as a consequence of wide respiratory excur­ pulmonary destruction, whatever the cause, but particularly pulmo­
sions: in some experimental models, stretching of vessels results in nary fibrosis. Thus, it is seen in advanced idiopathic pulmonary fibro­
such laying-down of longitudinal muscle,94 but this is not confirmed sis, sarcoidosis, pneumoconiosis and Langerhans cell histiocytosis. In
by others, who regard the process as a component of normal repair.95 the fibrotic parts of the lung, occlusive intimal fibroelastosis akin to
Longitudinal smooth muscle is found in pulmonary arteries in other endarteritis obliterans is evident at a relatively early stage. With
forms of pulmonary hypertension,15,96 but not so noticeably as in the advancing disease there is widespread loss of capillaries and in less

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 Pathology of the Lungs

Figure 8.2.13  Thromboembolic pulmonary hypertension. The artery has

a double lumen separated by a collagenous band that represents
organised thrombus. Elastin van Gieson stain.

Figure 8.2.12  Pulmonary hypertension associated with diffuse smooth-

muscle proliferation of the lungs. (Courtesy of Dr M Goddard, Papworth, UK.)

Changes such as these are generally taken to indicate thrombo­

embolism103 but could equally represent primary pulmonary throm­
bosis. Indeed, there are those who believe that thromboembolism is
severely affected parts small precapillary vessels are fully muscular­ seldom the cause of pulmonary hypertension; evidence adduced in
ised. In sarcoidosis the granulomas may involve the media and even favour of this includes the observation that it is very difficult to induce
the intima of pulmonary blood vessels (see Fig. 6.1.33, p. 287). pulmonary hypertension experimentally by repeated embolisation of
Rare examples have been reported of middle-aged men with severe thrombi.104 This is in line with the third use of the term ‘primary
pulmonary hypertension and diffuse smooth-muscle cell proliferation pulmonary hypertension’ described above, namely it being applied
of the lungs (Fig. 8.2.12).97,98 The smooth-muscle cell proliferation irrespective of whether the changes are predominantly plexogenic,
involves bronchioles, alveoli and small pulmonary arteries and veins; thrombotic or veno-occlusive.35–37 Contrary evidence derives from
the vascular involvement accounts for the severe pulmonary hyper­ studies showing that the demographic features of patients with
tension, which results in cor pulmonale. The changes differ from multiple small-vessel occlusion are similar to those with proximal
those of pulmonary lymphangioleiomyomatosis (see p. 293) but are artery disease and that they lack genetic features found in idiopathic
nevertheless also considered to be hamartomatous.98 pulmonary hypertension.105 Pulmonary hypertension developed
within 2 years of a first objectively confirmed episode of pulmonary
embolism in 2 of 135 Italian patients, an incidence of 1.5%.106
Pulmonary thrombosis occasionally causes pulmonary hyperten­
EMBOLIC PULMONARY HYPERTENSION sion in conditions such as sickle cell disease,107–110 paroxysmal
nocturnal haematuria111 and the Klippel–Trenaunay syndrome.112–115
Pulmonary hypertension may result from progressive diminution of Splenectomy also appears to be a risk factor.116 The morphological
the pulmonary vascular bed by multiple emboli. Thrombotic emboli changes are then identical to those of multiple small thromboemboli
may be very numerous but small and clinically silent. In these circum­ but with plexiform lesions also described in some patients.108,109
stances lung biopsy may show occlusion of small pulmonary arteries Secondary thrombosis is common in all forms of pulmonary hyper­
by thrombi in various stages of organisation. Totally organised emboli tension and may make it difficult to distinguish thromboembolic
appear as eccentric fibrotic intimal plaques or show the multiple new pulmonary hypertension from other types complicated by throm­
lumina that indicate recanalisation (Fig. 8.2.13).99 Occasionally the bosis. If thromboembolic or thrombotic pulmonary hypertension
organisation of the thrombus takes the form of multiple fine channels can be recognised early enough, some mitigation of their progress can
and the appearances mimic those of a plexiform lesion. However, the be achieved with anticoagulant drugs.
latter develops in a thrombosed dilatation lesion and is situated On rare occasions, emboli from malignant tumours obstruct the
alongside the parent artery whereas organisation of thrombotic pulmonary circulation and cause pulmonary hypertension,117–120 or
emboli is confined to the obliterated arterial lumen. The elastic excite a fibrocellular intimal proliferation that occludes small pulmo­
laminae are intact in recanalised arteries but destroyed at the site of nary arteries121 while in some countries severe schistosomiasis is an
a plexiform lesion.29 We do not support the view that thrombo­ important cause of embolic pulmonary hypertension. Schistosomal
embolic pulmonary hypertension is characterised by plexiform eggs block the lumen of the small pulmonary arteries, damage the
lesions, as proposed by some workers.100 As well as recanalisation by wall to cause thrombosis and work their way through into the sur­
conventional thin-walled vessels, channels having a thick muscle coat rounding tissues where they excite a severe foreign-body inflammatory
and believed to be bronchial arteries are described within the fibrosed reaction. Proximal to the obstruction, changes indicative of severe
intima of affected pulmonary arteries (so-called vessel-within-vessel pulmonary hypertension are found, including angiomatoid and pos­
or double-media lesion).101,102 However, although many pulmonary sibly plexiform lesions.60 The intravenous injection of drugs formu­
arteries may be occluded, the lesions are focal and beyond them distal lated for oral use is another embolic cause of pulmonary hypertension
branches appear quite normal, yet are non-functioning. (see pp. 378 and 411).

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Figure 8.2.15  Pulmonary venous hypertension. In a case of mitral

stenosis, a postmortem arteriogram shows marked pruning of the finer
vessels in the lower lobe, the lobar difference being due to the venous
hypertension being added to the hydrostatic forces entailed in our
upright posture.

our upright posture.123 In very severe cases there may be necrotising

B arteriopathy but this is unusual and plexiform lesions are not a feature
of such passive pulmonary hypertension. The distinctive feature of
Figure 8.2.14  Pulmonary venous hypertension. (A) In a patient with passive pulmonary hypertension is the venous hypertrophy and scle­
cardiomyopathy, small blood vessels show medial hypertrophy while in rosis. However, in mitral stenosis the arterial changes do not merely
the same patient (B) pulmonary veins show intimal fibrosis. (B) Elastin van
reflect transmission of the raised left atrial pressure across the pulmo­
Gieson stain.
nary capillary bed: pulmonary artery pressure rises disproportionately
to the left atrial pressure, indicating that there is arterial constric­
tion.124 Pulmonary venous hypertension is also characterised by pul­
monary oedema,125,126 interstitial fibrosis127 and haemosiderosis which
together characterise the condition long known as ‘brown induration
VENOUS PULMONARY HYPERTENSION of the lungs’ (see Fig. 8.1.3, p. 405).

An increase of pressure in the pulmonary veins may result from mitral Pulmonary veno-occlusive disease
stenosis, prolonged left ventricular failure, fibrosing mediastinitis, or
rarely, pulmonary veno-occlusive disease.122 (pulmonary occlusive venopathy)128–135
Pulmonary veno-occlusive disease is a rare disorder of unknown
aetiology that is seldom diagnosed in life, and then usually by lung
Mitral stenosis
biopsy. However, the presence of Kerley B lines in the absence of any
In mitral stenosis, the medial muscle of the pulmonary veins is evidence of left atrial enlargement provides a valuable clue to the
hypertrophied, especially in the lower lobes, and there is a similar diagnosis in life.130 As in true primary pulmonary hypertension, chil­
hypertrophy of the media on the arterial side of the capillaries (Fig. dren and young adults are mainly affected but, unlike primary pul­
8.2.14A).123 In both arteries and veins there is also intimal sclerosis monary hypertension, there is no female predominance: in children
(Fig. 8.2.14B) and again the changes are worse in the lower lobes (Fig. no predilection for either sex has been observed but in adults men are
8.2.15). This is due to the added hydrostatic forces which result from affected twice as often as women.131 Familial cases are described.136,137

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 Pathology of the Lungs

Box 8.2.2  Causes of pulmonary veno-occlusive disease

Idiopathic – the great majority of cases
Chemotherapy138,139
Radiotherapy140
Bone marrow transplantationa,141
Renal transplantation142
Human immunodeficiency virus infectionb,143,144
Felty’s syndrome145
Systemic sclerosisc,128,146
Antiphospholipid syndrome147
Sickle cell disease108,109
a
Generally preceded by whole-body radiation.
b
Also associated with plexogenic arteriopathy.
c
More often associated with arteriopathy.

Figure 8.2.16  Pulmonary veno-occlusive disease. Two blood vessels are

greatly narrowed by intimal fibrosis. The larger has distinct internal and
external elastic laminae, as seen in pulmonary arteries, but the position
of these blood vessels within an interlobular septum indicates that they
are ‘arterialised’ pulmonary veins.
Aetiology
Pulmonary veno-occlusive disease is to be distinguished from pulmo­
nary vein stenosis, which represents congenital atresia of the extrapul­
monary veins (see p. 76). In pulmonary veno-occlusive disease the
intra- or extrapulmonary veins are narrowed or obliterated by fibrous
thickening of the intima. This is presumed to be post­thrombotic but
thrombosis is seldom seen. The cause of the fibrosis is unknown,
except in a few cases. where factors such as chemotherapy, radio­
therapy, bone marrow transplantation, renal transplantation, HIV
infection, Felty’s syndrome, systemic sclerosis, sickle cell disease
and the antiphospholipid syndrome have been incriminated (Box
8.2.2). There is no recognised connection with the bush teas that
cause hepatic veno-occlusive disease, despite the observation that
related pyrollizidine alkaloids cause an arterioconstrictive form of
pulmonary hypertension in experimental animals.60 Very rarely,
immune complexes are identified in the pulmonary vessels,148 or there
is a granulomatous pulmonary phlebitis149,150 or the disease is seen in
the setting of a generalised venulopathy.151 An onset characterised by
fever may suggest a viral aetiology but could equally reflect pulmonary
infarction attributable to the disease. However, in a case believed to Figure 8.2.17  Pulmonary veno-occlusive disease. At necropsy the lungs
have been contracted in utero, the baby also had myocarditis and the show alternating areas of intense congestion and pallor, the latter due to
mother was thought to have had a viral infection when pregnant.152 interstitial fibrosis consequent upon severe interstitial oedema.

Pathology
The condition is characterised by obliterative sclerosis of pulmonary Sometimes it is the small intralobular veins that are diseased, either
veins, either between the lungs and the heart or within the lungs alone or in conjunction with larger veins.155 These are difficult to
themselves and therefore evident on lung biopsy. The venous recognise without elastin stains but there are often clues that they are
obliteration causes venous hypertension, which in turn results in occluded. Firstly there may be focal areas of intense capillary conges­
venous medial hypertrophy. This may be so extreme that the veins tion within the affected lobules (Fig. 8.2.18),128 a change that is practi­
resemble arteries in structure, with internal and external elastic cally pathognomonic of venular obstruction. Secondly, there may be
laminae, but the true nature of the affected vessel can still be recog­ so-called endogenous pneumoconiosis. This oddly termed process
nised from its anatomical location in an interlobular septum, con­ may be found whenever there is pulmonary haemosiderosis but is
trasting with the centriacinar position of the arteries alongside the especially common in veno-occlusive disease. The haemosiderosis not
airways (Fig. 8.2.16).The venous obstruction also results in marked only takes the form of iron-laden alveolar macrophages but encrusts
pulmonary congestion and haemosisderosis. It also leads to the devel­ the capillary basement membranes and venular elastic laminae, often
opment of leashes of fine anastomotic vessels both around and within with calcium being deposited there as well as iron. The heavily min­
the occluded veins,153 simulating the appearances of pulmonary capil­ eralised laminae are unduly rigid and break up to attract foreign-body
lary haemangiomatosis, if this is indeed a separate condition (see giant cells (see Figs 8.3.23 and 8.3.24, p. 450). Not realising the
below). The venous obstruction also results in prolonged severe inter­ significance of this unusual change, earlier workers referred to it as
stitial oedema, which in turn causes interstitial fibrosis (Fig. 8.2.17).154 ‘endogenous pneumoconiosis’.156 More recently it has been termed
Attention to the veins will help the pathologist avoid the error of mineralising pulmonary elastosis.157 It is not confined to veno-
diagnosing idiopathic pulmonary fibrosis in such cases. occlusive disease but is very suggestive of this condition. It is also seen

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 Vascular disease Chapter |8|

dioxycycline, an angiogenesis inhibitor.172 In another patient,

pulmonary capillary haemangiomatosis was associated with multiple
pulmonary vascular malformations that formed part of hereditary
haemorrhagic telangiectasia.173

Pathology
At autopsy the lungs appear firm and haemorrhagic. They may be
affected diffusely or there may be well-circumscribed nodules, with
the most severely affected areas found in the periphery of the lower
lobes.174 The characteristic histological finding is alveolar wall thicken­
ing by a proliferation of small, thin-walled, capillary-sized vessels (Fig.
8.2.19A–C), although in one case the vessels were much larger, meas­
uring up to 180 µm in diameter.175 The proliferating vessels also infil­
trate the walls of larger blood vessels, particularly veins, and there is
marked involvement of the interlobular septa. The veins are often
obliterated whereas arteries are usually less severely involved. In the
most severely affected areas nodules of new capillaries replace the lung
parenchyma. The distribution of the proliferating capillaries is particu­
larly well demonstrated by CD34 immunostaining (Fig. 8.2.19D).155
Figure 8.2.18  Pulmonary veno-occlusive disease affecting small Where the pulmonary architecture is better preserved, alveolar walls,
interlobular vessels and leading to focal areas of intense capillary which at low magnification appear congested, can be seen on close
engorgement. Venous occlusion is also evident (centre). examination to consist of a double layer of capillaries.161 The process
may extend to involve the pleura. It may also invade the walls of
bronchi to form intraluminal tufts of capillaries (Fig. 8.2.19C).
less frequently with other causes of pulmonary haemosiderosis, such Haemorrhage and congestion lead to haemosiderosis, with
as capillary haemangiomatosis (see below).155 accumulation of haemosiderin-laden macrophages. Secondary
Muscular pulmonary arteries show medial hypertrophy, and throm­ hypertensive changes in the arteries include medial hypertrophy and
bosis may cause eccentric intimal thickening similar to that seen in intimal fibrosis.
thromboembolic pulmonary hypertension or on rare occasions may
be the presenting feature.158 It is debatable whether the arterial changes
are entirely secondary, as implied by the name veno-occlusive disease, Aetiology and differential diagnosis
or represent a primary component of a wider process, in which case In the first reported case, the endothelial cells of the proliferating
the name vaso-occlusive disease would be more appropriate.133 vessels were atypical and the authors regarded the process as being
Widespread small-vessel occlusion justifying the term vaso-occlusive neoplastic.159 However, atypia has not been seen in other examples
disease is seen in the pulmonary hypertension associated with sickle and the disease remains confined to the lungs and pleura. Its age
cell disease (see p. 483) and the antiphospholipid syndrome,147 where distribution (14–71 years) renders hamartomatous growth unlikely
the occlusion is due respectively to sludging of deformed red cells and but its development in three siblings suggests that it might have a
platelets. genetic basis, possibly involving the release of as yet unidentified
angiogenic factors.162 Rarely, the condition appears to complicate
severe passive pulmonary congestion.176
Pulmonary capillary haemangiomatosis The distinction between pulmonary capillary haemangiomatosis
(pulmonary microvasculopathy) and pulmonary veno-occlusive disease is a fine one, if it exists at all.
Pulmonary capillary haemangiomatosis is a very rare condition that The histological similarities are close and described differences are
represents one of the more unusual patterns of pulmonary debatable.155 The distinction is said to depend on the presence of
hypertension.159–168 Its supposed neoplastic nature is questionable and infiltrating capillaries in the lung parenchyma and larger vessels, in
it possibly represents an unusual manifestation of pulmonary veno- contrast to fibroelastic obliteration of veins in veno-occlusive disease,
occlusive disease.155,161 The term ‘pulmonary microvasculopathy’ is but this may merely represent the establishment of more florid
suitably non-committal aetiologically.135 anastomoses bypassing occluded veins. Angiogenesis is a feature
of pulmonary veno-occlusive disease153 and pulmonary capillary
haemangiomatosis may represent an exaggerated degree of such
Clinical features angiogenesis. Figure 8.2.20 outlines a proposed relationship
Most patients are young adults (age range 14–71 years, mean 35 years) between the two conditions.155
who present with dyspnoea and are found to be in cardiac failure. Capillary haemangiomatosis should not be confused with the
They may also complain of haemoptysis. Chest radiographs and com­ separate condition of diffuse pulmonary haemangiomatosis, which is
puted tomography usually show pulmonary infiltrates or nodules, or a form of vascular malformation and is described on page 632.
pleural effusion. Radiological and hemodynamic findings are similar
to those found in pulmonary veno-occlusive disease but differ from
those identified with other causes of pulmonary hypertension.169 The
PULMONARY HYPERTENSION IN
patient usually dies of right-sided heart failure within a few years;
median survival from the first clinical manifestation is 3 years. The CONNECTIVE TISSUE DISEASE
diagnosis is rarely established before death,163 although focal lesions
have been identified incidentally.170,171 However, one patient diag­ Pulmonary disease of very varied type may develop in several
nosed on biopsy went into complete remission when treated with connective tissue disorders (see Table 10.1, p. 472).74,145,146,177–189

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tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

A B

Figure 8.2.19  Pulmonary capillary haemangiomatosis. (A) An area of alveolar wall thickening is seen. (B) At high power, the thickening is seen to be
due to an irregular proliferation of alveolar capillaries. (C) In a separate case, the proliferating capillaries infiltrate the bronchiolar epithelium.  
(D) Immunostaining for CD34 highlights the capillary proliferation.

Pulmonary hypertension is one of the less common of these and which resembles the many skins of an onion, or by the deposition of
when present may be secondary to another pulmonary manifestation acellular collagenous material, often resulting in gross reduction or
of the connective tissue disorder, particularly interstitial fibrosis. obliteration of the lumen (Fig. 8.2.21). Although described in several
Pulmonary hypertension secondary to parenchymal lung disease is connective tissue disorders, this pattern of disease is particularly seen
considered above and this section deals only with the pulmonary in systemic sclerosis, in which condition such changes are well
hypertension that develops in patients with connective tissue disor­ described in systemic arteries.177 The form of systemic sclerosis most
ders who do not have parenchymal lung disease. likely to be associated with pulmonary hypertension is that known as
Although the changes in any one connective disease are often said the CREST syndrome (calcinosis, Raynaud’s phenomenon,
to be distinctive, on comparing them they obviously have much in oesophageal dysfunction, sclerodactyly and telangiectasia). In some
common, not only with each other but also with those of primary patients with pulmonary hypertension complicating systemic
pulmonary hypertension, at least in the early stages of that disease. sclerosis histology shows the changes of pulmonary veno-occlusive
However, an important difference from primary pulmonary hyper­ disease, as described above (see also p. 476).189
tension is a relative rarity of plexiform or angiomatoid lesions in the Another change described in pulmonary hypertension associated
connective tissue diseases. with connective tissue disease is vasculitis.190 It is likely that this rep­
The characteristic changes in pulmonary hypertension associated resents a true vasculitis, probably of an immune nature, rather than
with connective tissue diseases are to be found mainly in small intra­ the necrotising arteritis of plexogenic arteriopathy, but this is dis­
lobular pulmonary arteries and chiefly affect the intima, although puted.178 A further association is veno-occlusion.190 This is particularly
such media as extends into these small vessels is often hypertrophied. seen in patients with the antiphospholipid syndrome, which may be
The intima is thickened by a concentric spindle cell proliferation, idiopathic but is often associated with systemic lupus erythematosus

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tahir99-VRG & vip.persianss.ir
 Vascular disease Chapter |8|

Secondary Figure 8.2.20  Proposed relationship of pulmonary

Primary insult capillary haemangiomatosis to pulmonary veno-occlusive
changes
(thrombosis, phlebitis, ?other) disease. It is envisaged that in both conditions
postcapillary obstruction leads to the excessive growth of
new capillaries representing an attempt to bypass the
Venous obstruction. The primary insult is probably multifactorial
Venous occlusion Veno-occlusive infarction
(concentric, eccentric, recanalisation) disease and may be repetitive and of variable chronicity.155

Perivenular
scars
Capillary congestion
(endothelial damage, ?stretch, Interstitial fibrosis
?ischemia, leads to angiogenesis)
Hemosiderosis
Endogenous
Excess capillary proliferation pneumoconiosis
Capillary
within alveolar walls, vessels, haemangiomatosis
airway epithelium Secondary
arterial changes

Other causes of post-capillary obstruction

? Primary disease

or other connective tissue disorder.147 In these patients lung biopsy

shows platelet thrombi occluding small arteries and veins. The
occlusion of small intralobular veins leads to secondary changes
such as the patchy capillary congestion and haemosiderosis described
above under pulmonary veno-occlusive disease.

EFFECTS OF PULMONARY HYPERTENSION

In long-standing pulmonary hypertension the larger pulmonary

arteries may be dilated, and atheromatous plaques may be found in
them at necropsy (Fig. 8.2.22).191 Secondary thrombosis may super­
vene, occasionally resulting in pulmonary infarction. The dilatation
may assume aneurysmal proportions and rupture is recorded, often
A in association with mucoid medial degeneration (cystic medial ‘necro­
sis’) and even dissection.192–194 Some of the breathlessness associated
with pulmonary hypertension may be due to aneurysmal dilatation
of a major pulmonary artery pressing on the adjacent bronchus.
Cholesterol granulomas have been described in the lungs of patients
with pulmonary hypertension of varied aetiology,195 but this is a rare
finding.

Cor pulmonale
Irrespective of its pathogenesis, long-standing pulmonary hyper­
tension leads to right heart strain and hypertrophy of the right ventri­
cle (Fig. 8.2.23). For poorly understood reasons, the left ventricle also
undergoes hypertrophy but not so markedly as the right.196,197
Ultimately the hypertrophied right ventricle fails and passive venous
congestion develops in the systemic circulation. If the pulmonary
hypertension is caused by disease within the lung, the term ‘cor pul­
B monale’ may be used to denote the consequent right heart strain. Cor
pulmonale is defined as ‘hypertrophy of the right ventricle resulting
from diseases affecting the function or structure of the lung, except
Figure 8.2.21  Pulmonary arteries in two patients with the CREST variant
of systemic sclerosis and severe pulmonary hypertension (see text for when the pulmonary alterations are the result of diseases that prima­
details). In one (A) the pulmonary arteries show marked ‘onion-skinning’ rily affect the left side of the heart or of congenital heart disease’.198
(circumferential intimal cell proliferation) while in the other (B) hyaline Hypertrophy of the right ventricle can only be assessed accurately
intimal fibrosis reduces the lumen to a thin slit. from its weight; thickness of the ventricular muscle is affected by dila­

431
tahir99-VRG & vip.persianss.ir
 Pathology of the Lungs

Figure 8.2.23  Cor pulmonale in a patient dying of pulmonary veno-

occlusive disease. The dilated right ventricle is hypertrophied to such an
extent that its thickness equals that of the left.

Figure 8.2.22  Atheroma of large pulmonary arteries, a change that is TREATMENT OF PULMONARY
virtually confined to patients with pulmonary hypertension.
HYPERTENSION

tation of the heart and is a poor index of hypertrophy.197 To weigh the Apart from the appropriate treatment of any recognisable cause of
ventricles separately, the heart should be divided at the atrioventricu­ pulmonary hypertension, such as surgery for congenital heart disease,
lar ring and the right ventricle trimmed away from the septum and dietary modification, HIV treatment and anticoagulation, therapy is
left ventricle.199 Normal values are right ventricle 65 g and left ventricle aimed at arterial dilatation for which an array of drugs has recently
plus septum 185 g. Right ventricular hypertrophy is indicated by a been developed. These include calcium channel blockers, prostacyclin
right ventricular weight over 80 g or a ratio of the weights of the left (iloprost), endothelin receptor antagonists (bosentan, sitaxsentan,
ventricle plus septum to right ventricle of less than 2 : 1. This ratio ambrisentan) and phosphodiesterase inhibitors (sildenafil). Lung and
normally lies between 2.3 : 1 and 3.3 : 1. heart/lung transplantation present is a further options.

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Clin Pathol 2000;113:655–62.

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 Chapter 8 

8.3  Vasculitis and granulomatosis; haemorrhage and haemosiderosis

classification they largely come in the small vessel category (Box

CHAPTER CONTENTS
8.3.1),1 and are frequently combined with granulomatosis. Forms of
Pulmonary vasculitis and granulomatosis 437 vasculitis and granulomatosis dealt with elsewhere include broncho­
Infective and embolic vasculitis 437 centric granulomatosis on page 464, allergic granulomatosis (Churg–
Strauss syndrome) on page 465, lymphomatoid granulomatosis on
Wegener’s granulomatosis 438
page 664 and hypertensive arteritis on page 420. Most of the diseases
Limited forms of Wegener’s granulomatosis 442 considered here have an immune basis and are treated by immuno­
Conditions linking Wegener’s granulomatosis with suppressive therapy. However, they share many morphological fea­
sarcoidosis and other disorders 443 tures with the infective granulomas and it is very important that an
Necrotising sarcoid angiitis and granulomatosis 443 infective aetiology is excluded before treatment is commenced. To
Sarcoidosis combined with disseminated visceral emphasise the importance of this, infective vasculitis will be consid­
giant cell angiitis 444 ered first.
Pulmonary involvement in other forms of systemic
vasculitis 444
INFECTIVE AND EMBOLIC VASCULITIS
Polyarteritis nodosa 444
Microscopic polyangiitis 445 Infective vasculitis may be due to bacterial, fungal or parasitic infec­
Hypersensitivity vasculitis 445 tion of the vessel wall. Haematogenous Pseudomonas pneumonia is a
Vasculitis in the connective tissue diseases 445 good example as it is typically characterised by heavy bacterial colo­
Giant cell arteritis 445 nisation of the arterial wall, which results in vasculitis, thrombosis
and infarction (see Fig. 5.2.13, p. 187). Such arterial involvement is
Behçet’s disease 447
also seen on occasion in pulmonary tuberculosis, with inflammatory
Pulmonary haemorrhage and haemosiderosiss 448 weakening of the vessel wall resulting in aneurysm formation
Goodpasture’s syndrome (anti-basement membrane (Rasmussen aneurysms).2 Aneurysms caused by infected emboli
disease) 449 (so-called mycotic aneurysms – a term used regardless of whether the
Antineutrophil cytoplasmic antibody-associated infection is fungal or bacterial) are best known on the cerebral arteries
pulmonary haemorrhage 451 but are occasionally encountered in the pulmonary circulation, the
Immune complex-mediated pulmonary cause usually being infective endocarditis of the valves of the right
haemorrhage 451 side of the heart secondary to congenital disease or intravenous drug
abuse (see Fig. 5.4.25B,C, p. 235).3
Idiopathic pulmonary haemosiderosis 451
Drug addicts also develop granulomatous pulmonary arteritis
References 452 because they inject substances intended for oral use. Many tablets
include fillers such as talc, starch and cellulose, which impact on small
pulmonary arteries causing foreign-body granulomas within and
PULMONARY VASCULITIS around the vessel (see Fig. 7.2.10, p. 379), with subsequent thrombo­
sis.4–7 A similar form of granulomatous arteritis is provoked by schisto­
AND GRANULOMATOSIS some ova lodging in small pulmonary vessels but here, in addition to
foreign-body giant cells, there may also be a necrotising arteritis,
This section deals with certain vasculitides in which the lungs are the which is presumed to represent an immune response to the ova (see
sole or major site of involvement. In the Chapel Hill consensus p. 254).8

437
 Pathology of the Lungs

Aetiology
WEGENER’S GRANULOMATOSIS
The recognition of circulating antineutrophil cytoplasmic antibodies
(ANCA) in Wegener’s disease and related conditions provides consid­
A triad combining necrotising granulomatous inflammation and vas­ erable evidence that these diseases have an autoimmune basis.15–17
culitis of the upper and lower airways with glomerulonephritis was ANCA titres correlate with disease activity and in vitro it has been
initially described by Klinger,9 and only later by Wegener,10,11 but it shown that ANCA cause cytokine-primed neutrophils to degranulate,
was the eponymous term Wegener’s granulomatosis that was popular­ releasing lysosomal enzymes and toxic oxygen radicals. This
ised by Godman and Churg.12 These workers redefined the triad as mechanism probably underlies the ‘pathergic’ process envisaged by
comprising: (1) granulomatosis of the upper and lower respiratory Fienberg, which is characterised in its early stages by granulomas
tracts; (2) generalised vasculitis; and (3) glomerulonephritis, thus centred on small collections of neutrophils.18,19 ANCA binding causes
recognising that the vasculitis has a wide distribution. So too does the primed neutrophils to adhere to endothelial surfaces, with neutrophil
granulomatosis but it is the respiratory tract that is most frequently degranulation at this site accounting for the vasculitis.17,20
affected (Table 8.3.1).13 The glomerulonephritis was the major factor The cause of ANCA production is not fully understood but there is
in the once high mortality of the disease but since cyclophosphamide increasing evidence incriminating cross-reactivity with certain bacte­
became widely used in the 1960s the 5-year survival rate has improved rial antigens. Staphylococcus aureus can often be recovered from the
from less than 10% to over 80%.14 Limited forms of the disease, largely nose of patients with Wegener’s granulomatosis, and by broncho­
confined to the lungs, are dealt with below (p. 442). alveolar lavage when there is recrudesence of the disease,21,22 while
more recently the Gram-negative bacilli Escherichia coli, Klebsiella pneu-
moniae and Proteus mirabilis have attracted attention. These bacteria
Box 8.3.1  The Chapel Hill consensus classification of attach to host epithelia by adhesion molecules located at the tips of
systemic vasculitis1 their fimbriae and cross-reactivity has been demonstrated between
one of these molecules and a constituent of the neutrophil granule.
Large vessels Immunisation of laboratory rats with the fimbrial antigen resulted
Giant cell arteritis Typically involves the temporal in the production of neutrophil autoantibodies and the development
arteries in patients older than 50. of crescentic glomerulonephritis and a haemorrhagic pulmonary
May involve the aorta. Pulmonary vasculitis.23,24
involvement rare As well as Wegener’s granulomatosis, ANCAs are associated with the
Takayasu’s arteritis Typically involves the aorta in Churg–Strauss syndrome (see p. 465) and microscopic polyangiitis
patients younger than 50. May (see p. 445). Immune deposits are not readily identifiable in any of
involve the major pulmonary these conditions and they are therefore termed pauci-immune.
arteries
Medium-sized vessels Clinical features25
Polyarteritis nodosa Pulmonary involvement rare Wegener’s granulomatosis is a rare disease with a prevalence of about
Kawasaki disease Children. Pulmonary involvement not 3 per 100 000.26 It affects men more than women and occurs at all
described ages. It generally presents with systemic features such as fever, weight
Small vessels loss, anaemia and arthralgia, combined with respiratory complaints
Wegener’s granulomatosis Typically involves the respiratory tract such as nasal discharge and crusting, otitis media, cough, haemoptysis
Churg–Strauss syndrome Typically involves the respiratory tract and chest pain. Rarer forms of presentation include acute pulmonary
Microscopic polyangiitis Typically involves the respiratory tract haemorrhage,27–29 glomerulonephritis14,30 and thromboembolism.31
Henoch–Schönlein purpura Respiratory involvement unusual Saddle-nose deformity of the nose may occur and nasal destruction
Essential cryoglobulinaemic Respiratory involvement unusual may be so great as to suggest lethal midline granuloma. Almost all
vasculitis patients have involvement of the lungs or upper respiratory tract but
Cutaneous leukocytoclastic Limited to the skin virtually any organ may be affected. A classic triad of pulmonary,
angiitis upper respiratory tract and renal disease is described but is not always
evident: it was encountered in only 56% of patients in one series.32

Table 8.3.1  Frequency of organ involvement in Wegener’s granulomatosis, microscopic polyangiitis and Churg–Strauss syndrome13

Wegener’s granulomatosis (%) Microscopic polyangiitis (%) Churg–Strauss syndrome (%)

Lung 90 50 70
Upper respiratory tract 90 35 50
Kidney 80 90 45
Musculoskeletal 60 60 50
Skin 40 40 60
Neurological 50 30 70
Gastrointestinal 50 50 50

438
 Vascular disease Chapter |8|

Radiological examination shows multiple lung masses resembling high, about 95% in the classic form of the disease and about 65% in
metastases or, if cavitating, abscesses. Eosinophilia is not a feature of the limited form. The rare false positives are encountered with diseases
the disease and if present should alert one to the possibility of Churg– of the lung such as tuberculosis, lymphoma, human immunodefi­
Strauss granulomatosis (see p. 465). Fibroptic and aspiration biopsies ciency virus (HIV) infection, various connective tissue disorders and
are of limited use in the diagnosis of Wegener’s granulomatosis but thromboembolism.39 The sensitivity varies with disease activity and
the identification of any one of the characteristic pathological features this provides a useful means of monitoring treatment.33,36,40
may suggest the diagnosis, provided that other processes such as
infection have been ruled out. Serological tests, which are dealt with
Pathological features of the lung lesions41–43
next, may also be helpful, but in many cases a surgical biopsy is
required to establish the diagnosis. At necropsy, multiple irregular but well-circumscribed masses of
various size are seen in the lungs. They consist of grey indurated tissue
surrounding a soft, friable, grey or haemorrhagic necrotic centre,
Antineutrophil cytoplasmic antibodies which may cavitate (Fig. 8.3.2). There is often a fibrinous pleurisy or
The recognition of circulating ANCA in Wegener’s disease and related effusion. The large airways may be ulcerated, thickened by nodules of
conditions represents a major advance in diagnosis.15,16,20,33–35 There granulation tissue, or stenotic.44,45
are at least two such antibodies, both of which are of IgG type. Under Microscopically, the nodules show irregular areas of necrosis sur­
indirect immunofluorescent microscopy, one antibody gives centrally rounded by inflammatory granulation tissue (Fig. 8.3.3). The outlines
accentuated granular staining in the cytoplasm of neutrophils: the of necrotic vessels or other structures may be evident centrally and
antigen here is a 29-kDa serine proteinase 3 and the antibody is
known as cytoplasmic, c- or PR3-ANCA. The second antibody is
recognised by perinuclear staining. It is directed principally against
myeloperoxidase and is known as perinuclear, p- or MPO-ANCA
(Fig. 8.3.1). However, atypical immunofluorescent patterns are some­
times encountered and more specific, solid-phase enzyme-linked
immunoabsorbent assays (ELISAs) are preferred.36 More recently a
third ANCA has been identified, one that reacts with lysosomal mem­
brane protein-2, which is contained in the same neutrophil granules
that harbour MPO and PR3.23
There is considerable overlap in the histological features associated
with c- and p-ANCAs,34,37 but Wegener’s granulomatosis shows a
strong association with c-ANCA, the Churg–Strauss syndrome with
p-ANCA and microscopic polyangiitis with either c- or p-ANCA (Table
8.3.2).38 The specificity of c-ANCA for Wegener’s granulomatosis is

A B

Figure 8.3.1  Antineutrophil cytoplasmic antibodies (ANCA)

demonstrated by fluorescent microscopy following the application of the
patient’s serum to test smears. (A) Cytoplasmic antibodies (c-ANCA);   Figure 8.3.2  Wegener’s granulomatosis. Numerous pale, cavitating
(B) perinuclear antibodies (p-ANCA). (Courtesy of Dr G Valesini, Rome, Italy.) masses replace the lung tissue, which elsewhere is haemorrhagic.

Table 8.3.2  Frequency of antineutrophil cytoplasmic antibody (ANCA) types in pauci-immune vasculitis38

ANCA type Wegener’s granulomatosis Microscopic polyangiitis Churg–Strauss syndrome

Cytoplasmic (PR-3) 75% 40% 10%

Perinuclear (MPO) 20% 50% 60%

439
 Pathology of the Lungs

Figure 8.3.4  Wegener’s granulomatosis. Neutrophilic microabscesses

bordered by a granulomatous reaction probably represent an early stage
in the development of the larger irregular areas of necrotising
granulomatosis.

Figure 8.3.3  Wegener’s granulomatosis. (A) A central area of necrosis is

bordered by granulation tissue that is infiltrated by numerous
lymphocytes and plasma cells and an occasional multinucleate giant cell.
(B) The necrotic debris is often notably haematoxyphilic due to A
neutrophilic debris.

there is often extensive karyorrhexis resulting in the accumulation of

fine haematoxyphilic nuclear dust (see Fig 8.3.3). The inflammatory
infiltrate of the surrounding granulation tissue includes lymphocytes,
which are predominantly T cells,46 plasma cells, neutrophils and
macrophages, the last often arranged in a palisade about the necrosis.
Variable numbers of multinucleate foreign-body or Langhans giant
cells may be seen, scattered individually or forming loose clusters, but
seldom forming cohesive tuberculoid granulomas. Neutrophilic
microabscesses form a further pattern of tissue necrosis and probably
represent an early change (Fig. 8.3.4).18,19 Eosinophils are seldom
conspicuous, except in a rare eosinophilic variant of Wegener’s granu­
lomatosis47 in which there is intense tissue eosinophilia within the
inflammatory granulomatosis but not the eosinophilic pneumonia or
the blood eosinophilia and asthma of the Churg–Strauss syndrome.
The granulomatosis is fairly characteristic but the possibility of infec­ B
tion should always be kept in mind and stains for mycobacteria and
fungi undertaken. Figure 8.3.5  Wegener’s granulomatosis. (A) A pulmonary artery is
The necrotizing granulomatosis is accompanied by focal vasculitis involved by necrotising vasculitis. (B) Deficiencies in the external elastic
that involves medium-sized or small arteries or veins, or capillaries lamina of this pulmonary artery indicate that it has been previously
(Fig. 8.3.5). Its primary nature is best appreciated in areas not involved affected by necrotising vasculitis. Elastin van Gieson stain.

440
 Vascular disease Chapter |8|

Figure 8.3.7  Wegener’s granulomatosis. The vasculitis is sometimes

manifest as a capillaritis, which is evident as a neutrophilic infiltrate of
A the alveolar walls.

(Fig. 8.3.8). Previous haemorrhagic episodes are characterised by

haemosiderosis.
Immunofluorescence microscopy for immunoglobulins and
complement is either negative or very weakly positive, giving rise to
the term ‘pauci-immune’.
The vasculitis causes thrombosis and wedge-shaped areas of
haemorrhagic infarction but it is unlikely that the extensive necrosis
is ischaemic as small foci are seen in the earliest form of the disease19
and larger necrotising lesions are seen away from foci of vasculitis.48
The lung between the lesions may show non-specific changes,
including organising pneumonia, bronchiolitis, obstructive lipid
pneumonia, haemorrhage and haemosiderosis, any of which may
mask the characteristic lesions.42,49 Also, the classic histological
features may be considerably diminished if the biopsy is taken after
the instigation of treatment.50 Often, the pathologist is confronted
with very small biopsy specimens from which the vasculitic lesions,
formerly thought essential to the diagnosis, may be absent. However,
B foci of necrosis bordered by inflammatory granulation tissue
with palisaded histiocytes at the interface are by themselves
Figure 8.3.6  Bronchocentric injury in Wegener’s granulomatosis. (A) A strongly suggestive – some would say diagnostic – of Wegener’s
focus of necrosis is centred on a bronchiole. However, the necrosis is granulomatosis.19,51
notably haematoxyphilic, raising the possibility of Wegener’s
granulomatosis. (B) An elastin stain shows destruction of a vessel wall
adjacent to the necrotic area but more significant vasculitis was evident
elsewhere in the lung well away from the granulomatosis. Positive Extrapulmonary lesions
cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) provided The same combination of necrotising granulomatous inflammation
further support for the diagnosis of Wegener’s granulomatosis. (Courtesy and vasculitis is seen in the upper respiratory tract52–54 and skin55,56
of Dr D Rassl, Papworth, UK.)
but biopsies may not show the full spectrum of changes. It is claimed
that cutaneous biopsies characterised by leukocytoclastic vasculitis
indicate a worse prognosis than those showing granulomatous inflam­
mation.56 The vascular lesions may be indistinguishable from those
in the granulomatosis. Involved arteries and veins show transmural of classic polyarteritis nodosa. Such lesions may be present in the
infiltration by neutrophils, lymphocytes, plasma cells and giant cells kidneys as well as the focal and segmental necrotising glomerulo­
in varying proportions, and there is often fibrinoid necrosis. The nephritis that forms part of the classic triad of lesions. The glomer­
vasculitis is sometimes granulomatous. Elastin stains are useful for ulonephritis is characterised by fibrinoid necrosis of capillary
demonstrating the partial loss of elastic laminae indicative of a previ­ loops and epithelial crescent formation (Fig. 8.3.9).57
ous necrotising vasculitis (see Fig. 8.3.5). The process is usually focal,
involving only a segment of the vessel wall. Occasionally, the necrosis
is strikingly bronchocentric (Fig. 8.3.6),44 but vasculitis can also be
identified. Capillaritis is manifest as a heavy neutrophil infiltrate of
Differential diagnosis (Table 8.3.3)
the alveolar septa (Fig. 8.3.7).29 It may be leukocytoclastic and often Granulomatous fungal and mycobacterial infection must always be
leads to alveolar haemorrhage, which may obscure the inflammation considered in the differential diagnosis of Wegener’s granulomatosis.

441
 Pathology of the Lungs

Figure 8.3.9  Wegener’s granulomatosis. Kidney showing the classic focal

necrotising glomerulonephritis (right) and also necrotising arteritis (left).

A
Wegener’s granulomatosis that is predominantly broncho­
centric44,45,58 has to be distinguished from bronchocentric granuloma­
tosis (see p. 464), which is characterised by necrotising granulomatous
inflammation centred on airways but lacks the vasculitis of Wegener’s
disease.
Wegener’s granulomatosis that is centred on the pulmonary
capillaries has to be distinguished from microscopic polyangiitis
(see p. 445), a condition that lacks the distinctive necrotising
granulomatosis and is characterised by either p- or c-ANCA.
Other entities that enter the differential diagnosis of Wegener’s
granulomatosis include lymphomatoid granulomatosis (see p. 664),
which is distinguished by the presence of atypical lymphoid cells
of B-cell phenotype within the infiltrate and a relative absence of
destructive vasculitis, and rheumatoid nodules (see p. 473), which
also lack a vasculitic component and show even more prominent
palisading.

Figure 8.3.8  Wegener’s granulomatosis resulting in diffuse pulmonary Limited forms of Wegener’s granulomatosis
haemorrhage. (A) Gross appearances; (B) microscopy. Wegener’s granulomatosis does not always show the widespread
distribution described above. Limited forms of the disease have
been described.18,59,60 These lack the upper respiratory and glomerular
components but show the typical pulmonary lesions, which are
Well-formed granulomas favour infection (or sarcoidosis) but the sometimes solitary.61 Alternatively, there may be only capillaritis
histopathological appearances can be very similar and special stains, with diffuse pulmonary haemorrhage.62,63 One biopsy series of
culture, serology or even molecular techniques may be necessary to Wegener’s granulomatosis comprised 48 cases of classic disease and
identify infection. However, Wegener’s granulomatosis entails a risk 19 of the limited form.42
of opportunistic infection and both processes may be present. Tests Limited Wegener’s granulomatosis affects women more than men
for ANCA are helpful as these are negative in patients with infection and has a much better prognosis than the classic disease.60 About 30%
(apart from very occasional patients with tuberculosis) or of patients with limited Wegener’s granulomatosis lack ANCA. As with
sarcoidosis. the classic form of the disease, granulomatous infection figures promi­
Churg–Strauss granulomatosis shares some histopathological nently in the differential diagnosis. At one hospital, the application
features with Wegener’s granulomatosis but there is also marked tissue of simple stains for mycobacteria and fungi to 86 archival cases that
eosinophilia. The p-ANCA test is positive and c-ANCA negative, and had been filed as ‘solitary necrotising granulomas’ of the lung revealed
there is usually asthma and blood eosinophilia. The pattern of organ an infectious aetiology in 75, presumably representing patients who
involvement also differs (see Table 8.3.3). had not received the appropriate treatment.64

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Table 8.3.3  The differential diagnosis of pulmonary vasculitis and granulomatosis

Vessels ANCA Necrotising Parenchymal Sarcoid Palisaded Blood Asthma Atypical

involved type vasculitis necrosis granulomas granulomas eosinophilia cells

Polyarteritis Small to – + – (except – – – – –

nodosa medium infarction)
systemic
arteries

Microscopic Capillaries c=p + – – – – – –

polyangiitis

Wegener’s Small arteries, c>p + + – + – – –

granulomatois veins and
capillaries

Necrotising Small arteries – + + + – – – –

sarcoid and veins
granulomatosis

Churg–Stauss Small arteries p>c + + – + + + –

syndrome and veins

Lymphomatoid Small arteries – – (infiltration) + – – – – +

granulomatosis and veins

Bronchocentric None – – + ± + + + –
granulomatosis

Sarcoidosis Veins and small – – – + – – – –

arteries

Infective Any involved in – ± + + + – – –

granuloma the
inflammation

Rheumatoid Any near the – – + – + – – –

nodule granuloma

ANCA, antineutrophil cytoplasmic antibody.

Necrotising sarcoid angiitis

CONDITIONS LINKING WEGENER’S
and granulomatosis
GRANULOMATOSIS WITH SARCOIDOSIS AND
OTHER DISORDERS Necrotising sarcoid angiitis and granulomatosis combines the vascu­
litis and necrotising granulomatosis of Wegener’s granulomatosis
with numerous non-necrotising sarcoid granulomas.71 Women are
affected more than men and the age range is wide, with a mean of
Vascular involvement is common in sarcoidosis (se p. 286 and Fig. about 35 years.72–77 Some patients are asymptomatic but most have
6.1.33) but is usually no more than an incidental histological finding non-specific respiratory symptoms accompanied by malaise.77
rather than a component of a systemic vasculitic syndrome. However, Chest radiographs usually show multiple nodules or masses meas­
the two conditions that are about to be described indicate that there uring up to several centimetres in diameter, most numerous in the
is a spectrum of conditions between sarcoidosis and Wegener’s granu­ lower zones. Occasionally the lesions are unilateral or even single.72,78
lomatosis. In their classic forms sarcoidosis and Wegener’s granulo­ Diffuse infiltrates are also reported.77 Cavitation is rare.
matosis are very different but these intermediate conditions Evidence of extrapulmonary involvement is uncommon but hilar
demonstrate that there can be considerable overlap. Other unusual lymph node enlargement was a feature of more than half the patients
combinations are pulmonary vascular lesions in the so-called non- in one series73 and granulomas may be found in these nodes. Ocular
infectious granulomatous angiitis with a predilection for the nervous and central nervous system involvement has also been reported73,77,79–81
system65 and temporal arteritis associated with Wegener’s granuloma­ and in some patients the disease has been associated with dacro­
tosis.66,67 There are also occasional reports of Wegener’s granul­ adenitis and ulcerative colitis82 or cutaneous involvement.83 Gener­
omatosis being associated with alpha-1 antitrypsin deficiency and ally however, the disease is confined to the lungs and the prognosis
bullous emphysema, both perhaps adversely affecting proteinase/ is good, with resolution occurring either spontaneously or following
antiproteinase balance in the lung.68–70 corticosteroid therapy.76

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 Pathology of the Lungs

Figure 8.3.10  Necrotising sarcoid granulomatosis. The lung contains Figure 8.3.12  Necrotising sarcoid granulomatosis. A pulmonary artery
numerous non-necrotising epithelioid and giant cell granulomas and a shows a granulomatous vasculitis.
necrotising arteritis is also evident.

because well-formed non-necrotising sarcoid granulomas are rarely

a feature of Wegener’s. Differentiation from infection may be more
difficult and requires negative special stains and culture. Whether the
condition is to be distinguished from sarcoid is a moot point that is
considered next.

Aetiology
It has been suggested that necrotising sarcoid granulomatosis merely
represents a variant of sarcoidosis in which mass lesions form,
so-called nodular sarcoidosis.73,84 This is supported by reports of raised
levels of serum angiotensin-converting enzyme and selective migra­
tion of T-helper lymphocytes to the lung,85 and by the development
of the disease in one of a family with a strong history of sarcoidosis.86
Furthermore, a granulomatous vasculitis is frequently seen in sar­
coidosis.87 However, the broad areas of necrosis seen in necrotising
sarcoid granulomatosis are not a feature of classic sarcoidosis. In one
case onset coincided with Chlamydia pneumoniae infection.88
Figure 8.3.11  Necrotising sarcoid granulomatosis. This low-power view
shows non-necrotising sarcoid-like granulomas (right) in conjunction with
a large area of necrosis (left). Sarcoidosis combined with disseminated
visceral giant cell angiitis
Pathological features In contrast to necrotising sarcoid angiitis and granulomatosis, which,
The lesions form irregular areas of induration, which microscopically with the rare exceptions noted above, is confined to the lungs,
consist of confluent aggregates of epithelioid and giant cell granulo­ occasional patients combine the features of sarcoidosis with those
mas with surrounding fibrosis and chronic inflammation (Fig. 8.3.10). of disseminated visceral giant cell angiitis.89–92 Such patients have
The granulomas are identical to those seen in sarcoidosis and, as in disseminated necrotising granulomatosis, glomerulonephritis and
sarcoidosis, they tend to follow lymphatic pathways in the broncho­ systemic angiitis (the full spectrum of classic Wegener’s granulomato­
vascular bundles, the interlobular septa and the pleura, and may show sis) combined with typical sarcoid granulomas.
a small central area of necrosis. However, there are also larger areas of
coagulative necrosis (Fig. 8.3.11). Regression of the inflammation may
leave the necrotic areas surrounded only by hyaline connective tissue.
Various patterns of vasculitis may be seen, all involving both arteries
PULMONARY INVOLVEMENT IN OTHER
or veins, and destroying the vessel wall to a varying extent. The vessels FORMS OF SYSTEMIC VASCULITIS
may show discrete granulomas, a more diffuse proliferation of giant
cells and epithelioid macrophages, or merely lymphocyte and plasma Polyarteritis nodosa
cell infiltration (Figs 8.3.11 and 8.3.12). There may also be bronchial
involvement, as in Wegener’s granulomatosis. When polyarteritis nodosa was first described in the nineteenth
century it was stressed that it was a disease of the systemic
circulation and that pulmonary involvement was unusual.93 This has
Differential diagnosis subsequently been borne out94 but when a national survey of ‘biopsy-
The differential diagnosis is chiefly from Wegener’s granulomatosis proven’ cases was conducted in 1957, roughly half were classified as
and infection. The distinction from Wegener’s is usually not difficult being of ‘respiratory type’.95 However, the clinical details of these cases

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Figure 8.3.13  Polyarteritis nodosa affecting pulmonary arteries, an Figure 8.3.14  Microscopic polyangiitis represented by focal interstitial
unusual feature of this disease. neutrophil accumulation.

include features such as nasal granulomatosis or eosinophilia and it Hypersensitivity vasculitis

is evident that they represent Wegener’s granulomatosis or Churg–
Strauss granulomatosis rather than polyarteritis nodosa. This demon­ The term ‘hypersensitivity vasculitis’ covers a variety of clinical
strates that the same vasculitis is seen in these three conditions. The conditions that are characterised pathologically by leukocytoclastic
term ‘polyangiitis overlap syndrome’ has accordingly been applied to small-vessel disease. They include clinical syndromes such as Henoch–
any systemic vasculitis that shows features of two or more of the well- Schönlein purpura107,108 and essential mixed cryoglobulinaemia.109
defined vasculitic syndromes: polyarteritis nodosa, Churg–Strauss These conditions typically involve sites such as the skin or the bowel
syndrome, Wegener’s granulomatosis, temporal arteritis, Takayasu’s and pulmonary manifestations are unusual.96,110 They are thought to
arteritis and Henoch–Schönlein purpura.96,97 be due to deposition of immune complexes in vessel walls. The
On the occasions when polyarteritis nodosa does affect the lungs it antigen may be exogenous, such as a drug or infective agent, or
is generally limited to the bronchial vessels but it occasionally involves endogenous, as in some connective tissue diseases. Haemoptysis is
the pulmonary circulation in the absence of features such as granulo­ the principal complaint in all the hypersensitivity vasculitides that
matosis or eosinophilia or the presence of ANCAs that place it in one involve the lungs and the pathology is assumed to be a capillaritis, as
of the other categories of vasculitis (i.e. Wegener’s and Churg–Strauss described above. The hypocomplementaemic urticarial vasculitis
granulomatosis), resulting in necrotising inflammation of medium- syndrome is sometimes associated with progressive airflow obstruc­
sized muscular pulmonary arteries (Fig. 8.3.13).98–99a So-called tion due to emphysema, possibly related to the release of proteolytic
microscopic polyarteritis nodosa affects capillaries, arterioles and enzymes from the disrupted leukocytes (Fig. 8.3.15).111
venules and is accordingly better known as microscopic polyangiitis,
under which title it is dealt with next.
Vasculitis in the connective tissue diseases
Capillaritis has been identified in some patients with systemic lupus
Microscopic polyangiitis erythematosus complicated by alveolar haemorrhage112–117 (see p.
Microscopic polyangiitis affects only the smallest blood vessels – 477), and necrotising pulmonary vasculitis in rare rheumatoid
arterioles, capillaries and venules – as opposed to the medium- patients (Figs 8.3.16 and 8.3.17)118–120 seen as either an autoimmune
sized arteries affected in polyarteritis nodosa. Most patients have phenomenon or a component of plexogenic pulmonary hyperten­
glomerulonephritis and ANCA, which may be of either cytoplasmic sion.121 Vasculitis is rare in the other connective diseases but is recorded
or perinuclear type (see Table 8.3.2). About 50% of patients have as an apparently isolated phenomenon in a patient with anti-Jo-1
pulmonary involvement and in about a third the upper respiratory antibodies, which are usually associated with myositis.35
tract is involved (see Table 8.3.1). Pulmonary involvement is generally
characterised by lung haemorrhage; the granulomatosis of Wegener’s
Giant cell arteritis
disease is not a feature. Microscopic polyangiitis is the commonest
cause of combined pulmonary and renal haemorrhagic failure (the Giant cell arteritis of the lung principally occurs in three clinical
pulmonary–renal syndrome). In the lungs it is manifest as a haemor­ settings: Takayasu’s disease,122–124 temporal arteritis125,126 and
rhagic capillaritis characterised by neutrophil infiltration of the disseminated visceral giant cell arteritis.127,128 These conditions differ
alveolar walls, sometimes with diffuse alveolar damage (Fig. in the distribution of the lesions, the size of the arteries involved and
8.3.14).13,38,62,63,63,100–104 Cases in which the changes are limited to the the type of patient they affect rather than the pathological changes
lungs have been referred to as isolated pauci-immune pulmonary within the affected vessels.
capillaritis.105 One group reported on 17 patients with all the features Takayasu’s disease is a giant cell arteritis that typically affects the
of idiopathic pulmonary fibrosis but who also had ANCA, of whom arch of the aorta and its branches, leading to so-called pulseless
seven developed microscopic polyangiitis.106 Microscopic polyangiitis disease. It occurs predominantly in young women and is commonest
is touched upon again under diffuse pulmonary haemorrhage (see in Japan whereas temporal arteritis typically affects elderly men and
below). the racial distribution is wide. Only 10% of patients with temporal

445
 Pathology of the Lungs

B
B
Figure 8.3.16  (A, B) Vasculitis in systemic lupus erythematosus. The lung
Figure 8.3.15  Hypocomplementaemic urticarial vasculitis syndrome shows both follicular bronchiolitis and small-vessel vasculitis. Mixed
associated with emphysema. (A) At low power, the main feature is patterns of lung disease are often seen in connective tissue disorders.  
panacinar emphysema. (B) At high power, capillaritis and focal small- (B) Elastin van Gieson stain.
vessel vasculitis are evident.

arteritis have extracranial involvement and pulmonary involvement is

very rare, whereas evidence of pulmonary artery involvement is
present in up to 70% of patients with Takayasu’s disease.122,123
Disseminated visceral giant cell arteritis is very rare and involvement
of the pulmonary arteries is usually overshadowed by disease of
systemic arteries such as those supplying the myocardium. The age
range is wide (infancy to old age) and the arteries affected are small
muscular vessels whereas Takayasu’s disease and temporal arteritis
typically involve the large elastic arteries (Table 8.3.4).
Takayasu’s disease is characterised by chronic giant cell inflamma­
tion of the affected arteries resulting in elastic tissue defects, eccentric
intimal fibrosis or complete occlusion and recanalisation (Fig.
8.3.18).129–131 Some of the stenosis is caused by cicatricial contracture,
as indicated by the greatly reduced external diameter of the affected
arteries.131 Angiomatoid lesions (see p. 421) are also described, evi­ Figure 8.3.17  Pulmonary arteritis as a manifestation of rheumatoid
dence that Takayasu’s disease may cause pulmonary hypertension.131 disease.

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Table 8.3.4  Giant cell arteritis involving the lungs

Takayasu’s Temporal Disseminated

disease arteritis visceral giant
cell arteritis

Age Below 50 Over 50 years Any age

years
Symptoms Pulmonary Pulmonary Sudden death,
infarction infarction, e.g. from
headache, myocardial
polymyalgia infarction
rheumatica
Extrapulmonary Aorta and its Temporal Coronary, renal,
distribution major artery hepatic,
branches pancreatic,
gastric and
mesenteric
arteries
Pulmonary Large elastic Large elastic Small muscular
distribution arteries arteries arteries

Figure 8.3.19  Behçet’s disease. Three aneurysms are seen arising from
segmental branches of the lobar pulmonary artery. Rupture of one of
these resulted in fatal haemorrhage. (Courtesy of Dr B J Addis, formerly of
Brompton, UK.)

Figure 8.3.18  Takayasu’s disease. This involvement of a medium-sized

pulmonary artery represents peripheral extension of disease that
principally affected a lobar artery and led to infarction of that lobe. Giant
cells are very prominent amongst the inflammatory infiltrate. (Courtesy of Behçet’s disease
Dr Sj Sc Wagenaar, Utrecht, Netherlands.) Behçet’s disease, which is also considered on page 479, is a form of
systemic vasculitis associated with immune complex deposition.140–142
It is particularly common in Japan and eastern Mediterranean coun­
tries and predominantly affects young men of HLA-B51 phenotype;
This is partly attributable to pulmonary artery obstruction and partly the average age is 36 years and the male:female ratio 11.143 The diag­
to recanalisation by bronchial arteries establishing bronchopulmo­ nostic criteria are oral ulceration and any two of genital ulceration,
nary shunts.131 More often, pulmonary Takayasu’s disease is asympto­ typical eye lesions (most commonly uveitis), pustular skin lesions and
matic or mimics thromboembolic disease, sometimes resulting in a positive pathergy test, this last consisting of a sterile pustule that
infarction of a whole lung or lung lobe.132–135 develops 24–48 hours after a needle prick to the skin.144
Very rarely, giant cell arteritis is limited to the lesser circulation and Pulmonary lesions are rare and usually take the form of a
categorisation then depends solely upon the age and sex of the necrotising vasculitis involving arteries, veins and capillaries of all
patient, which is imprecise. Because pulmonary involvement is much sizes.145,146 The lesions may be single or multiple. Small vessels usually
commoner in Takayasu’s disease than in temporal arteritis and because show a leukocytoclastic vasculitis associated with deposition of IgA
the pulmonary vessels affected are large elastic arteries it would be and complement, while larger vessels generally show a transmural,
reasonable to regard isolated pulmonary disease as a manifestation of predominantly mononuclear, inflammatory infiltrate. Adventitial
the Takayasu’s disease, but if the patient were an elderly man this fibrosis may result in prominent perivascular cuffing while inflamma­
would be a counterargument. Few such patients have been tory destruction of the media leads to aneurysm formation (Fig.
reported.132,133,135–139 Of five available for review by one author, three 8.3.19).146–148 Computed tomography shows aneurysms, irregularities
were women aged 25, 34 and 42 years, and two were men aged 33 or sharp cut-offs of the pulmonary arteries.143,149 Repeated haemopty­
and 66 years: only one was Japanese.135 sis is common and may be fatal.150,151

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 Pathology of the Lungs

Pulmonary artery aneurysms are also a feature of the so-called

Hughes–Stovin syndrome, which probably represents a variant of Box 8.3.2  Causes of pulmonary haemorrhage and
Behçet’s disease.146,149 It affects young males, in whom the aneurysms haemosiderosis
develop in association with recurrent episodes of peripheral venous
thrombosis and a pyrexial illness. Blood cultures are negative and, Localised
although the oral and genital ulcers of Behçet’s disease are lacking, Tuberculosis, carcinoma, infarction, Wegener’s granulomatosis
pustular skin lesions may be present.152–154 Occasionally, the bronchial
Diffuse
arteries may be affected.155
Generalised bleeding disorders
Capillary hypertension
Mitral stenosis, atrial myxoma, mediastinal fibrosis
PULMONARY HAEMORRHAGE
Pulmonary veno-occlusive disease
AND HAEMOSIDEROSIS Pulmonary lymphangioleiomyomatosis
Stress failure
This section will concentrate on diseases that result in widespread
alveolar haemorrhage. However, it should be remembered that Chemical injury
haemorrhage from localised lesions such as neoplasms and tuber­ Silicone implants
culosis may be disseminated widely through the lower respiratory Lymphography
tract by aspiration.
Asphyxia
Autoimmune vascular disease
Aetiology (Box 8.3.2) ANCA-associated capillaritis
Widespread leakage of blood into alveolar spaces may be caused by a Microscopic polyangiitis
bleeding diathesis, increased capillary pressure or capillary damage. Wegener’s granulomatosis (capillaritis variety)
Increased pulmonary capillary pressure generally reflects
pulmonary venous hypertension or occlusion of pulmonary veins, the Antibasement membrane disease
principal causes of which are mitral stenosis, left atrial myxoma, (Goodpasture’s syndrome)
mediastinal fibrosis, pulmonary veno-occlusive disease (see p. 427), Immune complex-mediated vasculitis
lymphangioleiomyomatosis (see p. 293) and capillary haemangio­ Systemic lupus erythematosus
matosis (see p. 429). Arterial constriction tends to protect the pulmo­ Rheumatoid disease
nary capillary bed from pressure surges but if patchy the capillaries in Behçet’s disease
those areas of the lung in which there is little upstream constriction Henoch–Schönlein purpura
are subjected to inordinately high pressures and may suffer stress Coeliac disease
failure. This is probably the mechanism underlying the haemorrhagic Dermatitis herpetiformis
oedema seen in acute mountain sickness (see pp. 379 and 402).
Haemolytic anaemia
Similar stress failure with resultant haemorrhage in highly trained
Cow’s milk hypersensitivity
racehorses and occasional athletes is touched upon on page 402
[ch 8.1]. Trimellitic anhydride-induced
Diffuse capillary damage may be due to extraneous chemicals but Naphthylene-1,5-diisocyanate-induced
is mainly autoimmune, representing small-vessel vasculitis.13,62,63,100–105 Penicillamine-induced
Immune mechanisms fall into three categories: anti-basement mem­ Idiopathic pulmonary haemosiderosis
brane disease (Goodpasture’s disease), immune complex-mediated
injury and conditions characterised by ANCA (pauci-immune vascu­ ANCA, antineutrophil cytoplasmic antibody.
litis). In all these categories the pulmonary haemorrhage may be
combined with haematuria caused by glomerulonephritis. In one
series of 40 cases in which lung haemorrhage was associated with
glomerulonephritis 7 had anti-basement membrane disease, 22 had
systemic vasculitis and 11 had neither basement membrane antibodies renal syndrome.157 Chest radiographs show widespread, ill-defined,
nor systemic vasculitis.156 Anti-basement membrane disease, immune transient opacities. Carbon monoxide transfer may appear to be
complex-mediated disease and pauci-immune vasculitis are consid­ increased but the gas is being taken up by blood sequestered in the
ered separately below but together with idiopathic pulmonary haemo­ air spaces rather than transferred to the circulation. Serological tests
siderosis they share many clinical and pathological features and these for ANCA, rheumatoid factor and antinuclear factor may give clues to
aspects will be dealt with collectively. However, differences between the aetiology and help diagnostically.62,63 Further diagnostic support
these categories may be apparent on immunofluorescent or electron is provided by the identification of haemosiderin-laden macrophages
microscopy (Table 8.3.5) and it may therefore be worth ensuring that in sputum or lavage material,158,159 but it should be noted that stains
some biopsy material is appropriately preserved if diffuse pulmonary for iron may be positive in healthy smokers, foundry workers and
haemorrhage is suspected clinically or on frozen section. patients with conditions as diverse as idiopathic pulmonary
fibro­sis, chronic bronchitis and carcinoma of the lung.160 However,
haemosiderin-laden macrophages are not a normal feature of the lung
Clinical features in infancy and if at autopsy the cause of an infant’s death is not readily
The clinical features of diffuse pulmonary haemorrhage vary from identified haemosiderin-laden macrophages should alert the
massive life-threatening haemoptysis to recurrent or continuous slow pathologist to the possibility of an asphyxial death from overlying or
leakage leading to tiredness from iron-deficiency anaemia. There is smothering rather than the case being an example of the sudden
often concomitant haematuria and renal failure, forming a pulmonary– infant death syndrome.161,162

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 Vascular disease Chapter |8|

Table 8.3.5  Immunohistochemical and ultrastructural

abnormalities in the lung in various immune disorders and
idiopathic pulmonary haemosiderosis

Immunofluorescent Electron-dense
pattern deposits

Immune complex- Granular Present

mediated disease
Goodpasture’s Diffuse Absent
(anti-basement
membrane) disease
Neutrophil Little or none Absent
cytoplasmic (pauci-immune)
antibody-mediated A
disease
Idiopathic pulmonary None Absent
haemorrhage

Pathological features
Whatever the aetiology, biopsy shows a combination of alveolar
haemorrhage and haemosiderosis (Fig. 8.3.20). The cause of the
haemorrhage is often not evident histologically but there may be
intense neutrophil infiltration of the alveolar walls representing capil­
laritis and rare cases show diffuse alveolar damage (see p. 136).29,163
The haemosiderin is largely contained within alveolar macrophages,
which generally congregate in the centres of the acini. It is a brown,
coarsely granular pigment that gives a strongly positive Prussian blue
reaction with Perl’s stain (Figs 8.3.20B and 8.3.21), in contrast to B
smoker’s pigment, which is finely dispersed and gives a weaker
Prussian blue reaction. Haemosiderin takes 2–3 days to develop after Figure 8.3.20  (A) Pulmonary haemorrhage and (B) haemosiderosis. In
haemorrhage has occurred. It has been identified in tracheal macro­ biopsy material haemorrhage is of uncertain significance as it could be
phages 50 hours after acute pulmonary haemorrhage and in cultured operative but haemosiderosis provides firm evidence of previous
macrophages 72 hours after the uptake of red blood cells.164 A similar bleeding.
time course is reported in rats whose airways were injected with
blood.165,166
In severe haemosiderosis there is also encrustation of the elastic
laminae of small blood vessels and alveolar walls (Figs 8.3.21 and
8.3.22). Calcium is often added to the iron (Fig. 8.3.23), as in the
Gamna–Gandy nodules that develop in haemorrhagic splenic infarcts.
The mineralised elastic fibres tend to fragment and attract giant cells
of foreign-body type, a process that has been quaintly termed ‘endog­
enous pneumoconiosis’ (Fig. 8.3.24).168,169 Mild interstitial fibrosis
and type II alveolar epithelial cell proliferation may also be seen.

Goodpasture’s syndrome
(anti-basement membrane disease)
The term ‘Goodpasture’s syndrome’ was first applied to the association
of pulmonary haemorrhage and glomerulonephritis in 1958,170 nearly
40 years after Goodpasture’s original report, which was written in the
wake of the 1918–19 influenza pandemic with the primary object of
discussing the aetiology of influenza.171 The eponym is now reserved
for those cases in which antibodies to glomerular or alveolar base­
ment membrane can be demonstrated, and is often replaced by the
term ‘anti-basement membrane disease’. It is not clear what initiates Figure 8.3.21  Pulmonary haemosiderosis giving a strongly positive
the disease but it has been suggested that damage to basement mem­ Prussian blue reaction. The haemosiderin is largely contained within
brane by external agents, such as viruses or chemicals, alters its anti­ alveolar macrophages but also impregnates elastin in the walls of small
genicity.172 Some patients have both anti-basement membrane and pulmonary blood vessels. Perl’s stain.

449
 Pathology of the Lungs

Figure 8.3.24  Pulmonary haemosiderosis. The heavily mineralised elastin

fibres tend to fragment and attract foreign-body giant cells, giving an
appearance that has been likened to pneumoconiosis, although here the
minerals are endogenous.

Figure 8.3.22  Electron microscopy shows that haemosiderin is

preferentially deposited in the basement membrane and interstitial elastin
tissue of the alveolar walls, sparing the collagen. Electron micrograph ×
34 000. (Reproduced from Corrin et al. (1987)167 by permission of the editor of with the major histocompatibity antigens HLA-DR2 and HLA-DQ
the Journal of Pathology.)
have been reported.176 Almost invariably, respiratory symptoms
precede evidence of renal disease, sometimes by weeks or months.177
Most patients have episodes of haemoptysis, although some develop
anaemia, radiographic abnormalities and hypoxaemia without
haemoptysis. Proteinuria, haematuria and renal failure indicate
glomerular disease, which takes the form of a focal segmental
glomerulonephritis with crescent formation. Immunofluorescent
microscopy of biopsy material was initially used to demonstrate the
antibodies but serological assays are now preferred, despite them not
being completely sensitive.178 Therapy involves immunosuppression
and removal of antibodies by plasma exchange.103,179
Immunofluoresence microscopy shows that antibodies are depos­
ited along basement membranes in both glomeruli and alveolar walls
(Fig. 8.3.25 and Table 8.3.5).180 In 90% of cases they can also be
demonstrated in the serum181 and the disease can be passively trans­
ferred to animals.182 The severity of the disease is proportional to the
antibody titre. Cross-reactivity between pulmonary and renal base­
ment membranes has been demonstrated.183 The antiglomerular base­
ment membrane antibodies consist of a mixture of IgG subtypes184
that react with a non-collagenous domain of the alpha3 chain of type
Figure 8.3.23  Pulmonary haemosiderosis. Calcium is often added to the IV collagen.185,186 The alpha3 chain is restricted to sites such as the
haemosiderin deposits and being basophilic is evident without special glomerular and alveolar basement membranes, in contrast to the
stains. ubiquitous alpha1 and alpha2 type IV chains. Antibody is deposited
in a linear fashion along glomerular basement membranes, outlining
the capillary loops, and similar linear fluorescence is seen in alveolar
ANCA and here it is possible that the former arise because of immune walls. In about two-thirds of cases immunoglobulin deposition is
complex-mediated damage to the basement membrane.173 accompanied by complement deposition with a similar pattern.187
Most patients with Goodpasture’s syndrome are male. The mean Electron microscopy (see Table 8.3.5) shows fragmentation of the
age is about 20 years but the age range is wide and the disease has basement membranes but not the dense deposits evident in immune
been reported in children.174,175 Family clustering and associations complex-mediated disease.188,189

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 Vascular disease Chapter |8|

such as systemic lupus erythematosus,113–117,193 Henoch–Schönlein

purpura,107,108 Behçet’s disease,145,194,195 rheumatoid disease,119 cystic
fibrosis196 and some instances of isolated pulmonary haemorrhage.105
Immune complex disease also appears to underlie occasional cases of
pulmonary haemorrhage associated with penicillamine therapy197 or
exposure to epoxy resin paint powder containing the curing agent
mellitic anhydride.198,199 Diffuse pulmonary haemorrhage is also
described in patients undergoing lymphangiography,200,201 receiving
silicone implants202,203 or smoking cocaine204 but the pathogenesis in
these cases is not well understood.
The haemorrhage is usually due to pulmonary capillaritis, which
may develop in isolation, together with larger pulmonary vessel
disease or as part of a systemic vasculitis. Capillaritis may be difficult
to recognise but periodic acid–silver methenamine staining helps in
the identification of basement membrane abnormalities.104 In well-
A established disease, neutrophils, nuclear debris, fibrin thrombi, fibri­
noid necrosis, disruption of alveolar walls and fibrin lining alveoli
may be seen.29,115,116
The association of immune complex-mediated glomerulonephritis
and diffuse pulmonary haemorrhage is indistinguishable clinically
from Goodpasture’s syndrome. However, in contrast to Goodpasture’s
disease and idiopathic haemosiderosis, granular deposits of IgG may
be demonstrated along alveolar walls205 and electron-dense deposits
in the capillary basement membrane (see Table 8.3.5).205 Sometimes
there is evidence of immune complex deposition in the kidney but
not in the lung,206–208 or immunostaining may be negative in both
organs207 despite the presence of circulating complexes209 or
vasculitis.94

Idiopathic pulmonary haemosiderosis

Pulmonary haemorrhage and haemosiderosis may occur without
B evidence of vasculitis, immune complex deposition, antiglomerular
basement membrane antibodies or associated renal disease. If the
Figure 8.3.25  Goodpasture’s syndrome. Immunofluorescent microscopy other causes of pulmonary haemorrhage listed in Box 8.3.2 can be
showing linear deposition of immunoglobulin in the glomerular (A) and excluded the condition falls into the category of idiopathic pulmonary
alveolar (B) basement membranes. (Courtesy of Dr A Paiva-Correia, formerly of haemosiderosis.210,211
Oporto, Portugal.)

Epidemiology and clinical features

Idiopathic pulmonary haemosiderosis is predominantly a disease of
Antineutrophil cytoplasmic antibody- children and young adults, usually occurring in the first three decades
associated pulmonary haemorrhage of life. The sex incidence is equal in children whereas in adults there
is 2 : 1 male predominance.212 Familial cases have been described.213–215
ANCAs are associated with pulmonary haemorrhage in conditions
The disease tends to be more severe in children: they develop severe
such as microscopic polyangiitis (including cases limited to the lungs,
iron deficiency and have episodes of massive pulmonary haemor­
known as isolated pauci-immune pulmonary capillaritis, see p.
rhage, which may prove fatal. A more prolonged course is seen in
445),38,62,63,100–105,105 Wegener’s granulomatosis (see p. 438),27–29,100,190,191
adults and overt haemorrhage is not an invariable feature in this age
Churg–Strauss syndrome (see p. 465)192 and systemic vasculitis.115 In
group.158 Treatment with steroids and azathioprine is empirical and,
all these conditions immunofluoresence microscopy shows only a
because of the varying course of the disease, difficult to assess,216 but
weak or negative (‘pauci-immune’) reaction and electron microscopy
immunosuppressive treatment has been successful in several cases.217,218
fails to demonstrate electron-dense deposits (see Table 8.3.5). Wegener’s
granulomatosis and the Churg–Strauss syndrome usually show necro­
tising granulomatosis and inflammation of medium-sized vessels Aetiology
but microscopic polyangiitis is limited to the smallest blood vessels The cause of the disease is unknown but exposure to as yet unrecog­
and in the lung haemorrhage is the predominant lesion. Microscopic nised inhaled agents may play a role. Certain associations suggest that
polyangiitis is the commonest cause of the pulmonary–renal the disease has an immunological basis: these include coeliac disease,
syndrome. or at least a flattened jejunal mucosa,219–223 dermatitis herpetiformis,
autoimmune haemolytic anaemia,224 thyrotoxicosis225 and sensitivity
Immune complex-mediated to cow’s milk, this last being seen in young children who have a
positive skin test and serum precipitins to cows’ milk, and who
pulmonary haemorrhage
improve when cows’ milk is removed from the diet.226,227 An elevated
Immune complex deposition is the probable pathogenetic mecha­ serum IgA has also been noted in children with idiopathic
nism of diffuse pulmonary haemorrhage associated with conditions pulmonary haemosiderosis.228

451
 Pathology of the Lungs

Pathological features Immunostaining of the lung shows no evidence of immunoglobu­

lin or complement deposition (see Table 8.3.5). Various ultra­
Bronchoalveolar lavage is the method of choice to confirm the alveo­
structural features have been described but no consistent pattern has
lar bleeding, especially if this is occult.229 The lavage fluid shows free
emerged and it is uncertain whether the changes represent a primary
red blood cells and phagocytosed erythrocytes within macrophages if
manifestation of the disease or are secondary to the haemorrhage.167,231
there has been recent bleeding, and numerous haemosiderin-laden
The abnormalities described include focal defects in the vascular
macrophages if the bleeding is old. Transbronchial biopsy can also
endothelium and its basement membrane, and are more severe in
show haemosiderosis but only open-lung biopsy can exclude other
children than adults. The capillary basement membrane may show
causes of diffuse alveolar haemorrhage.
focal thickening, splitting with the accumulation of fibrillar material
The microscopic features are not specific, consisting merely of
and duplication.167 Non-specific abnormalities include damage to
centriacinar collections of haemosiderin-laden macrophages, as
type I epithelial cells and regeneration of type II epithelial cells.
described above. Interstitial fibrosis is sometimes regarded as being
more characteristic of idiopathic pulmonary haemosiderosis than of
other diseases which cause alveolar haemorrhage230 but this is more
likely to reflect the long duration of the disease than a specific process.

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haemosiderosis and coeliac disease. Eur 226. Stafford HA, Polmar SHJ, Boat TF.
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et al. Co-occurrence pulmonary Pediatr Res 1977;11:898–903.

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 Chapter 9 

Pulmonary eosinophilia

communities in which these parasites are prevalent (Box 9.2). In some

CHAPTER CONTENTS
parts of the world filariasis is the cause: this is tropical pulmonary
Simple pulmonary eosinophilia 460 eosinophilia, which can be readily diagnosed from the patient’s
Chronic eosinophilic pneumonia 461 history of residence in the tropics, by the presence of extraordinarily
high levels of both serum IgE and antifilarial antibodies, and by
Acute eosinophilic pneumonia 462
the dramatic therapeutic response to filaricides.3–5 Pulmonary eosino­
Bronchocentric granulomatosis 464 philia is also caused by a number of drugs, notably nitrofurantoin
Allergic angiitis and granulomatosis but occasionally sulphonamides and aspirin, amongst others (Box
(Churg–Strauss syndrome) 465 9.3). Pulmonary eosinophilia may also be a manifestation of
Hypereosinophilic syndrome 467 rheumatoid disaease.6
References 468 In other patients the cause of the pulmonary eosinophilia is not
recognised: such cases are categorised as suffering from cryptogenic
pulmonary eosinophilia.7 A majority of these patients are atopic,
giving a history of rhinitis or asthma.8 There is a high level of activated
Pulmonary eosinophilia is a clinical term used to describe the associa­ helper T lymphocytes in their bronchoalveolar lavage fluid.9 They also
tion of radiographic lung opacities and blood eosinophilia.1 Synonyms show a transient increase in circulating immune complexes.10 The
include ‘pulmonary infiltrates with eosinophilia’ and ‘PIE syndrome’.2 Churg–Strauss syndrome of allergic angiitis and granulomatosis may
Some lung diseases that are characterised by an eosinophilic lung be regarded as a subset of cryptogenic pulmonary eosinophilia but
infiltrate are not associated with blood eosinophilia and are therefore the hypereosinophilic syndrome is quite distinct from all these
dealt with elsewhere – eosinophilic granuloma (now termed reactive forms of eosinophilia and probably represents a leuko­
Langerhans cell histiocytosis) on page 288 and reactive eosinophilic proliferative disorder.
pleurisy on page 711. Other eosinophilic infiltrates are associated with
blood eosinophilia but not with radiographic opacities, e.g. asthma.
Pathogenesis
The eosinophilia–myalgia syndrome seen with the ingestion of certain
tryptophan preparations may well have been considered in this The eosinophil leukocyte is central to the pathogenesis of all the
chapter but is dealt with under drug reactions (see p. 389). diseases in this chapter. Eosinophil leukocytes are produced in the
Pulmonary eosinophilia may be classified clinically, aetiologically bone marrow under the control of cytokines secreted by type 2 helper
or pathologically. Here the emphasis will be on pathology, but first lymphocytes, notably interleukin-5. Once released into the blood they
the aetiology and pathogenesis will be outlined. normally remain there for 12–18 hours, maintaining a count of 50–
250/µl. An absolute count is more meaningful than the percentage in
a differential white blood cell count. They enter the tissues under the
Aetiology influence of chemotactic agents known as eotaxins,11 of which three
Aetiologically, pulmonary eosinophilia may be classified as cryp­ are now recognised. These agents are small proteins produced by a
togenic or of known cause, the latter including allergy to fungi, variety of cells, which in the lung include bronchial epithelial cells,
parasites or drugs (Box 9.1). smooth-muscle cells and fibroblasts, acting under the influence of
Allergic aspergillosis is a common cause of pulmonary eosinophilia interleukins derived from type 2 helper lymphocytes and mast cells
in the UK whereas infestation by metazoan parasites is commoner in (see Fig. 3.30, p. 115).11–13

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00009-4 459
 Pathology of the Lungs

Box 9.1  Aetiology of pulmonary eosinophilia Box 9.3  Drugs causing eosinophilic lung disease
Allergic bronchopulmonary mycosis (usually aspergillosis) Ampicillin Methotrexate
Parasitic infestation – see Box 9.2 Beclamethasone dipropionate Methylphenidate (Ritalin)
Drug sensitivity – see Box 9.3 (inhaled) Minocycline
Cryptogenic Bleomycin Naproxen
Carbamazepine Nickel
Chlorpromazine Nitrofurantoin
Clofibrate Para-aminosalicylic acid
Cocaine (inhaled) Penicillin
Box 9.2  Parasites causing eosinophilic lung disease Cromolyn (inhaled) Pentamidine (inhaled)
Ancylostoma sp. Desipramine Phenytoin
Ascaris sp. Diclofenac Pyrimethamine
Brugia malayi Febarbamate Rapeseed oil
Clonorchis sinesis Fenbufen Sulfadimethoxine
Dirofilaria immitis Glafenine Sulfadoxine
Echinococcus sp. GM-CSF Sulfasalazine
Opisthorchiasis sp. Ibuprofen Sulindac
Paragonimus westermani Interleukin-2 Tamoxifen
Schistosoma sp. Interleukin-3 Tetracycline
Strongyloides stercoralis Iodinated contrast dye Tolazamide
Toxocara sp. L-tryptophan Tolfenamic acid
Trichinella spiralis Mephenesin carbamate Vaginal sulphonamide cream
Trichomonas tenax
Leukotriene antagonists are not included as it is suspected that their association
Wuchereria bancrofti with Churg–Strauss syndrome represents an unmasking of this condition when
these drugs are substituted for corticosteroids.73 GM-CSF, granulocyte–
macrophage colony-stimulating factor.

Tissue eosinophilia does not necessarily correlate with blood

eosinophilia even though the two usually go together: blood counts
may dip as eosinophils flood the lung and then rise as the infiltrate reacting substance of anaphylaxis. Eosinophils also phagocytose
resolves due to a lag in bone marrow response. Sputum and broncho­ immune complexes and mast cell granules, and tend to dampen
alveolar lavage counts reflect lung tissue eosinophilia better than reaginic hypersensitivity reactions. However, they also secrete
blood counts but, like neutrophils, eosinophils appear to be washed substances such as reactive oxygen radicals, major basic protein and
out of the lung more easily than macrophages so that raised lavage eosinophil cationic protein which, whilst helping to eliminate para­
counts are encountered in diseases such as idiopathic pulmonary sites, are also toxic to host cells (Fig. 9.1).14–17 These eosinophil prod­
fibrosis that are seldom characterised by any appreciable degree of ucts are thought to be responsible for much of the tissue damage in
tissue eosinophilia. Bronchoalveolar lavage eosinophils are usually the eosinophilic disorders about to be described. Activation of the
expressed as a percentage of total cells recovered from the lungs, the cells involved in cryptogenic eosinophilic pneumonia is suggested by
normal being less than 3%. Eosinophils in sputum are generally the demonstration that they express intercellular adhesion molecules,
expressed only in broad qualitative terms (e.g. ‘small, moderate or probably under the influence of the activated T lymphocytes referred
large numbers’). When there is eosinophilic pneumonia, eosinophils to above.18 Electron microscopy shows that released eosinophil
are the predominant cell in both sputum and bronchoalveolar lavage granules are closely associated with degenerate and necrotic alveolar
fluid. They are represented at levels greatly in excess of those found tissue.19
in diseases such as idiopathic pulmonary fibrosis. Corticosteroids act on eosinophils in a variety of ways.20 They cause
Biopsy is the only way to establish tissue eosinophilia with certainty rapid eosinophil sequestration in peripheral blood vessels and inhibit
but in practice a tissue diagnosis is often inferred from the clinical their production in the bone marrow. They also reduce eosinophil
features coupled with sputum, blood and bronchoalveolar lavage survival by blocking lymphokines that inhibit eosinophil apoptosis.
findings. If a tissue diagnosis is deemed essential a transbronchial Eosinophil adherence and chemotaxis are also diminished by corti­
biopsy will generally suffice because most of the conditions causing costeroids. In view of these many actions it is not surprising that
pulmonary eosinophilia affect sufficiently large areas of the lung to corticosteroids are effective in treating many diseases characterised by
be targeted successfully by the bronchoscopist. However, some forms eosinophilia.
of tissue eosinophilia are characterised by an associated vasculitis
and it is unlikely that a transbronchial biopsy will identify this.
Vasculitis is more likely to be revealed by thoracoscopic biopsy.
Alternatively, it may be identified in more accessible tissue, such as SIMPLE PULMONARY EOSINOPHILIA
skin or muscle.
Once in the tissues, eosinophils secrete a number of products, some The Swiss physician Löffler described two conditions that were
of which counter the action of substances secreted by mast cells. characterised by blood eosinophilia. One is the hypereosinophilic
Histaminase and aryl sulphatase, for example, respectively destroy syndrome, which is dealt with below. The other is one that later came
histamine and the leukotriene complex formerly known as slow- to be known as simple pulmonary eosinophilia.21 Rarely a patient may

460
 Pulmonary eosinophilia Chapter |9|

Figure 9.2  Fatal cryptogenic eosinophilic pneumonia. Confluent areas of

consolidation represent alveoli filled with eosinophils.

Clinical features
The onset is insidious, with gradually worsening cough, dyspnoea,
fever and weight loss. There is blood and sputum eosinophilia.
However, blood and tissue eosinophil levels are not always elevated
Figure 9.1  Electron micrograph of an eosinophil. A bilobed nucleus is contemporaneously, the raised blood counts often having abated
surrounded by granules, many of which have a bar-shaped electron- whilst eosinophils are still evident in the lung tissue. Bronchoalveolar
dense core. The granule core consists of a basic protein whilst the
lavage cell counts correlate better with the tissue findings, eosinophils
surrounding matrix contains cationic protein, both of which are highly
being the predominant cell in lavage fluid from an involved segment.13
toxic.14 (Courtesy of Miss A Dewar, Brompton, UK.)
The chest radiograph is distinctive, showing bilateral opacification
that is peripheral and apical.27 It has been likened to the plume of a
volcano or the photographic negative of the perihilar shadowing of
display features of both conditions.22 The term ‘Löffler’s syndrome’ is pulmonary oedema. This is mirrored by subpleural consolidation on
confusingly applied to both and therefore best avoided. high-resolution computed tomography.
Simple pulmonary eosinophilia is characterised by migratory
pulmonary opacities accompanied by blood eosinophilia and minimal Pathology
or no pulmonary symptoms. Ascariasis was prevalent in Switzerland In the occasional case that comes to autopsy the lungs are found to
in Löffler’s day and was probably the cause of the eosinophilia in his be heavy and firm with irregular areas of pale consolidation (Fig. 9.2).
cases. Drug reactions are a more important cause today but many cases Microscopically, eosinophils fill the alveoli and infiltrate the inter­
are unexplained. Löffler emphasised the benign transient nature of stitium (Fig. 9.3).8,23,28 The alveoli also contain a variable number of
the condition. Corticosteroids are highly effective but are rarely macrophages, some of which may be multinucleate (Fig. 9.4). The
required because the condition is usually self-limiting. However, an macrophages may outnumber the eosinophils to mimic the appear­
underlying cause such as parasitic infestation should always be ances of desquamative interstitial pneumonia (Fig. 9.5). Focal
considered. The lung is seldom biopsied but it may be presumed collections of eosinophils may undergo necrosis to form so-called
to show changes similar to those seen in chronic eosinophilic eosinophil abscesses, which are sometimes attended by foreign-body-
pneumonia. type giant cells engulfing eosinophilic debris (Fig. 9.6).8 Sparse
sarcoid-like granulomas are occasionally seen, and in rare cases are
unduly prominent.29 The eosinophil infiltrate may involve small
CHRONIC EOSINOPHILIC PNEUMONIA blood vessels but necrotising vasculitis is not encountered: its presence
would suggest Churg–Strauss allergic granulomatosis, which is dealt
with below. Knowledge of treatment is important as eosinophils
Chronic eosinophilic pneumonia is a serious condition which gener­
diminish with corticosteroid administration. Healing, whether occur­
ally requires treatment with corticosteroids.8,20,23–26 These usually
ring spontaneously or in response to such treatment, usually results
prove efficacious but may have to be continued for many months, or
in complete resolution but may be by repair, this resulting in alveolar
even indefinitely, to prevent relapse. The disease is occasionally
fibrosis that is indistinguishable from any other organising
life-threatening. The peak incidence is in the fifth decade and
pneumonia.10,30
females preponderate 2 : 1. There is often a history of atopic illnesses
such as rhinitis or asthma and the condition is regarded as having an
allergic basis. Any of the aetiological agents outlined above may be Differential diagnosis
responsible, drugs, fungi or parasites, or the cause may not be The location of the eosinophils in air spaces as well as in the intersti­
identified. tium helps to distinguish eosinophilic pneumonia from eosinophilic

461
 Pathology of the Lungs

Figure 9.3  Eosinophilic pneumonia. The alveoli contain many eosinophil

polymorphonuclear leukocytes.
Figure 9.4  Eosinophilic pneumonia in which the alveoli are filled by both
eosinophils and macrophages. (Courtesy of Dr T Jelihovsky, Sydney, Australia.)

granuloma (Langerhans cell histiocytosis), as do the presence of eosi­

nophils in the blood, sputum and bronchoalveolar lavage fluid and a
lack of Langerhans cells aggregation. Pneumothorax may provoke a
reactive eosinophilic infiltrate but this is limited to the alveoli imme­
diately beneath the pleura.
Aetiology
Most cases reported to date have been cryptogenic but a few appear
ACUTE EOSINOPHILIC PNEUMONIA to have represented drug reactions or have been associated with
smoking.35,36 In the latter case, disease onset has generally been within
1 month of the patient starting to smoke, restarting or substantially
Clinical features
increasing the number of cigarettes smoked.37
The term ‘acute eosinophilic pneumonia’ was introduced in 1989 for
a condition characterised by the sudden onset of a febrile illness
accompanied by myalagia, pleuritic pain and hypoxaemia.31,32 Patients
may be of any age and either sex.33 Chest radiographs show extensive Pathology
bilateral opacification and effusions.27 Blood eosinophil counts are Acute eosinophilic pneumonia shows the features of diffuse alveolar
often normal but many eosinophils are found on bronchoalveolar damage in its exudative or organising phases, coupled with a heavy
lavage and pleural aspirates. A history of asthma is unusual but there interstitial infiltrate and a lesser alveolar exudate of eosinophils.38 In
may be one of allergic rhinitis.34 Apart from the lavage and aspirate its exudative phase diffuse alveolar damage is characterised by hyaline
findings, the clinical features suggest severe infection or the acute membranes and in its organising phase by interstitial fibroblast
respiratory distress syndrome. The condition is life-threatening but proliferation, prominent alveolar epithelial regeneration and organis­
responds well to corticosteroids. ing alveolar exudates (Fig. 9.7).

462
 Pulmonary eosinophilia Chapter |9|

Figure 9.5  Eosinophilic pneumonia. There is moderate eosinophil

exudation but these cells are outnumbered by alveolar macrophages.

Figure 9.7  Acute eosinophilic pneumonia. (A) The alveolar walls are
expanded by oedema and a mixed inflammatory cell infiltrate, which
includes eosinophils. The alveolar epithelium shows focal desquamation
and there is prominent type II pneumocyte hyperplasia. (B) An
eosinophilic microabscess (left centre) is highlighted in (C).

Figure 9.6  An eosinophilic ‘abscess’ consisting of agglutinated necrotic

eosinophils attended by a giant cell granulomatous reaction.

463
 Pathology of the Lungs

Differential diagnosis
Acute eosinophilic pneumonia is more likely to be mistaken for
diffuse alveolar damage than chronic eosinophilic pneumonia:
therefore, whenever diffuse alveolar damage is being considered it is
advisable to search for eosinophils, which may be focal in acute
eosinophilic pneumonia. Chronic eosinophilic pneumonia lacks the
features of diffuse alveolar damage seen in the acute condition and
usually shows more eosinophils, which are often mixed with alveolar
macrophages. The Churg–Strauss syndrome, which is described
below, is also characterised by vasculitis, necrotising granulomatosis
and asthma, features which are not seen in acute eosinophilic
pneumonia.

BRONCHOCENTRIC GRANULOMATOSIS

Bronchocentric granulomatosis was first described in 1973 as a Figure 9.8  Bronchocentric granulomatosis as a manifestation of allergic
necrotising granulomatous inflammation of the airway walls and bronchopulmonary aspergillosis. The lesion was thought to be neoplastic
until it was resected and dilated airways impacted with mucopurulent
surrounding lung tissue.39 It may be associated with asthma but this
debris were identified.
is not always the case.40,41

Clinical features and prognosis

In one series of 23 patients, the mean age was 22 years in the 10
asthmatic patients, and 50 years in the 13 non-asthmatics. The sex
distribution was almost equal in both groups.40 Asthmatics with bron­
chocentric granulomatosis complain of increased wheezing, cough,
fever and occasionally haemoptysis. Blood eosinophilia and positive
sputum culture for Aspergillus are commonly seen.40 The non-asthmatic
patients are a more heterogeneous group. They may be asymptomatic
or present with an acute febrile illness and cough. Blood eosinophilia
is uncommon in this group. Chest radiographic abnormalities are
similar in the two groups and include solitary or multiple infiltrates
or tumour-like masses and areas of atelectasis, usually involving the
upper lobes.27,40,42 Apart from fever and blood eosinophilia the
condition is confined to the lungs. The prognosis is good. Cortico­
steroids generally result in rapid clinical and radiological resolution.
Some patients recover without treatment.

Aetiology and pathological findings

Bronchocentric granulomatosis usually represents a type of allergic
bronchopulmonary aspergillosis that affects more distal airways than
mucoid impaction.43–45 Medium or small bronchi, or even
bronchioles, are affected rather than large central airways.39,40,46,47 The
condition is characterised by a necrotising granulomatous inflamma­
tion (Figs 9.8 and 9.9). This destroys much of the airway wall and
results in necrotic debris occluding the lumen (see Fig. 5.4.18 on
p. 231 and Figs 9.8 and 9.9). The inflammation usually includes many
eosinophils, together with lymphocytes, plasma cells and prominent
epithelioid cells, which often border the necrotic debris in a palisade
pattern. That the process is bronchocentric may sometimes be
recognisable only from its location alongside unaffected pulmonary
arteries or by tracing its distribution in step sections. Often, just a
remnant of respiratory epithelium indicates that the disease is centred
on the airways. Sparse hyphae are generally to be found within
mucous plugs occluding larger airways. Rarely, bronchocentric granu­
lomatosis may complicate an aspergilloma.48
Figure 9.9  Bronchocentric granulomatosis. Several areas of necrotising
In other cases no allergen is ever identified: these cases differ from granulomatous inflammation are seen. They are situated alongside
those caused by aspergillus in that there is no blood eosinophilia arteries, which are themselves largely spared, and an occasional remnant
or history of asthma and eosinophils are sparse in the affected of respiratory epithelium confirms that they are centred on airways. In
tissues, where plasma cells are predominate.46 In other patients the absence of recognisable bronchial remnants the bronchocentricity of
bronchocentric granulomatosis is associated with other pathogens, the lesion has to be inferred from its location next to a pulmonary artery.

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 Pulmonary eosinophilia Chapter |9|

such as Echinococcus, mycobacteria, Blastomyces, Histoplasma or

Mucor.49–52 Tuberculosis, histoplasmosis, blastomycosis and Box 9.4  Criteria for the diagnosis of Churg–Strauss
coccidioidomycosis may all show a histological process indistinguish­ syndrome of which at least four must be fulfilled76
able from bronchocentric granulomatosis and many cases of broncho­ Asthma
centric granulomatosis in non-asthmatic patients may represent
Eosinophils forming over 10% of the white cell differential count
unrecognized infections.50 Atopy does not appear to be important in
Mononeuropathy or polyneuropathy
these cases but sometimes the patient is immunosuppressed.51
Broncho­centric granulomatosis has also been reported in association Non-fixed pulmonary infiltrates
with rheumatoid arthritis,53–55 ankylosing spondylitis,56 glomerulo­ Paranasal sinus abnormalities
nephritis57 and red cell aplasia.58 It is also described beyond an ob­­ Tissue eosinophils on biopsy
structing bronchial carcinoma, the mechanism here being sustained
non-allergic inflammation.59,60 A bronchocentric form of Wegener’s
granulomatosis is distinguished from bronchocentric granulomatosis
by its characteristic necrotising vasculitis.61

ALLERGIC ANGIITIS AND GRANULOMATOSIS

(CHURG–STRAUSS SYNDROME)

Allergic angiitis and granulomatosis is a clinicopathological syndrome,

consisting of asthma, eosinophilia, vasculitis and necrotising gran­
ulomas, that was first described in 1951 by Churg and Strauss.62
Since then, several additional series have appeared.63–65 The cause
is unknown but the predominant clinical features implicate the
respiratory tract as the portal of entry of an as yet unidentified
antigen. The condition shares with Wegener’s granulomatosis and
microscopic polyangiitis an association with antineutrophil cyto­
plasmic antibodies (ANCAs), for which there is increasing evidence
that cross-reactivity with certain bacterial antigens is responsible (see
p. 438). There are rare reports of allergic angiitis and granulomatosis
Figure 9.10  Allergic angiitis and granulomatosis (Churg–Strauss
developing in patients with allergic bronchopulmonary mycoses66,67 or syndrome). Multiple confluent yellow nodules are seen while several
diffuse panbronchiolitis.68 airways show mucous plugging indicative of the underlying asthma.

Clinical features
The majority of patients are atopic. They initially suffer from allergic asthma or drug sensitivity) carried a sensitivity of 95% and a
rhinitis and then asthma. They next develop pulmonary infiltrates specificity of 99.2%.76
accompanied by blood eosinophilia (often exceeding 5 × 109/l) and
finally enter a vasculitic phase.63,65 Serum IgE levels may be increased
during the vasculitic phase.65 Many patients have systemic symptoms,
Pathology
such as fever and weight loss. Non-cavitating pulmonary infiltrates Three histological features accompany the asthma and blood eosino­
that may be diffuse and transient or massive and nodular, are gener­ philia: tissue eosinophilia, vasculitis and necrotising granulomatosis.
ally found.27 There may be eosinophilic pleural effusions. Myocardial These features are not necessarily seen together and in practice the
or pericardial lesions are evident in about 50% of patients. Most diagnosis is usually made on clinical grounds with histological
deaths are associated with complications of cardiac involvement.65 verification of perhaps just one of them. The likelihood of all three
Many patients also have involvement of the skin, gastrointestinal tract, features being identified increases with the size and number of the
joints, muscles, nervous system or lower urinary tract63; thymic and biopsies and is greatest in autopsy material.
laryngeal lesions have also been described.69,70 Renal disease is usually At autopsy or in an adequate biopsy soft yellow nodules may be
mild and renal failure is rare. Antimyeloperoxidase antibodies seen on the cut surface of the lung (Fig. 9.10). These represent foci of
(p-ANCA) are found in the majority of cases.71,72 Unlike Wegener’s eosinophilic pneumonia within which irregular areas of necrosis
granulomatosis, cytotoxic therapy is rarely indicated and cortico­ containing the debris of dead eosinophils and Charcot–Leyden
steroids usually provide effective treatment. The substitution of crystals are often seen.
leukotriene antagonists for corticosteroids in the treatment of Granulomas may be numerous but more usually are infrequent
asthma appears to be unmasking previously unsuspected cases and may not be readily identifiable in biopsy material. Early
of Churg–Strauss syndrome73,74; the syndrome has also been recog­ granulomas consist of small irregular clusters of giant cells and
nised in asthmatic patients who have had their corticosteroid dosage histiocytes, usually with a small central focus of densely eosinophilic
reduced or who have been transferred from systemic to inhaled necrosis. Epithelioid cells are not a feature and the granulomas
corticosteroids.75 lack the cohesion and lymphocytic rim typical of those seen in
The American College of Rheumatology has established six criteria, sarcoidosis. In larger granulomas the central necrotic area is
of which four must be fulfilled for a diagnosis of Churg–Strauss surrounded by radially arranged palisading histiocytes and multi­
syndrome (Box 9.4). This yields a sensitivity of 85% and a specificity nucleate cells (Fig. 9.11).
of 99.7%. Alternatively, three particular criteria (asthma, blood The vasculitis, which involves arteries, veins and even capillaries,77
eosinophilia greater than 10% and a history of allergy other than may be eosinophilic, neutrophilic or granulomatous78 but usually

465
 Pathology of the Lungs

Figure 9.11  Allergic angiitis and granulomatosis (Churg–Strauss

A
syndrome). A necrotising granuloma and prominent eosinophil infiltration
are seen in the pericardium.

takes the form of focal necrosis of vessel walls associated with

perivascular and transmural infiltration by eosinophils (Fig. 9.12).
Capillary involvement may cause alveolar haemorrhage.79 If the
vasculitis is neutrophilic the appearances are similar to those of poly­
arteritis nodosa80 and the diagnosis of allergic granulomatosis
has to depend upon extravascular features. Affected vessels may be
obliterated by fibrous tissue. Electron-dense deposits,77 IgE63 and IgM65
have all been reported in the vascular basement membrane.
Other changes in the lungs include those of asthma, as described
on page 109 (Figs 9.10 and 9.13). Extrapulmonary lesions show vas­
culitis and necrotising granulomatosis with prominent tissue eosi­
nophilia, as in the lungs (Fig. 9.14).

Differential diagnosis
B
The relationship of the Churg–Strauss syndrome to other forms of
vasculitis, hypereosinophilia and granulomatosis has been the subject
of much debate.65,81–83 Strictly speaking, the eponym should be
reserved for cases in which all the criteria are present: asthma, eosi­
nophilia, vasculitis and necrotising granulomatosis, but Churg and
Strauss62 considered the combination of marked tissue eosinophilia
and granulomatosis to be pathognomonic. All their patients were
asthmatic. Patients with the histological features of the Churg–Strauss
syndrome but lacking a history of asthma and blood eosinophilia
have been variously regarded as suffering from an eosinophilic variant
of Wegener’s granulomatosis83 or atypical forms of the Churg–Strauss
syndrome.69,84 At various stages in the course of the Churg–Strauss
syndrome patients may fulfil the criteria for the hypereosinophilic
syndrome (see below) or simple pulmonary eosinophilia, as described
above.
The differences between Churg–Strauss syndrome and Wegener’s
granulomatosis are both clinical and pathological. Asthma and blood
eosinophilia are not features of Wegener’s granulomatosis whilst the
destructive upper respiratory tract lesions of this condition are not
present in the Churg–Strauss syndrome. The pulmonary lesions
are generally less extensively necrotic in the Churg–Strauss syndrome C
than in Wegener’s granulomatosis. Tissue eosinophilia is found in an
eosino­philic variant of Wegener’s granulomatosis83 but is usually Figure 9.12  Allergic angiitis and granulomatosis (Churg–Strauss
syndrome). The vasculitis predominantly involves medium-sized and small
limited to the chronic inflammatory granulation tissue that surrounds
pulmonary arteries (A and B), but may also involve pulmonary capillaries
areas of necrosis rather than flooding air spaces as in the eosinophilic (C).
pneumonia of the Churg–Strauss syndrome. The pathological changes

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 Pulmonary eosinophilia Chapter |9|

Table 9.1  Systemic involvement in hypereosinophilic

syndrome89

Cardiovascular 58%
Cutaneous 56%
Neurological 54%
Pulmonary 49%
Splenic 43%
Hepatic 30%
Ocular 23%
Gastrointestinal 23%

described above. This one represents a rare and often fatal systemic
disease of uncertain aetiology that is regarded by many as representing
Figure 9.13  Allergic angiitis and granulomatosis (Churg–Strauss a leukoproliferative disorder.86 The disease is marked by sustained
syndrome). On the left there is an area of geographic necrosis, within overproduction of eosinophils (blood eosinophils in excess of 1.5 ×
which foci of vasculitis can be seen while on the right there is a bronchus 109/l for longer than 6 months) and widespread organ damage.87 It
plugged by mucus, reflecting the patient’s underlying asthma. affects adults in the third and fourth decades and men outnumber
women by 7 to 1.88 Many organs are involved (Table 9.1), those with
cardiac or central nervous system involvement having a particularly
poor prognosis.89 Vascular involvement is generally described as being
thrombotic or haemorrhagic rather than vasculitic.

Aetiology
The proposed leukoproliferative basis of the hypereosinophilic
syndrome is supported by the identification of monoclonal cell
populations. Conventional cytogenetic analysis is often normal but a
cryptic interstitial deletion of chromosome 4 resulting in the forma­
tion of an FIP1L1-PDGFRA fusion gene has led to the recognition that
many patients who would previously have been regarded as having
the hypereosinophilic syndrome actually have chronic eosinophilic
leukaemia.90,91 In other patients with hypereosinophilia there is a
clonal proliferation of type 2 helper lymphocytes (Th2, CD4 cells).86,92
Th2 cells produce cytokines implicated in eosinophil proliferation
and activation, notably interleukin-5. The consequent eosinophil acti­
vation results in the release of cytotoxic factors such as major basic
Figure 9.14  Allergic angiitis and granulomatosis (Churg–Strauss protein and eosinophil cationic protein that are probably responsible
syndrome). A muscle biopsy shows necrotising vasculitis and eosinophilia. for much of the tissue damage encountered in the syndrome. In rare
cases, lymphoma or leukaemia cells overproduce interleukin-5, and
consequently hypereosinophilia.
in the kidney may be similar in the two diseases but they are rarely
progressive in the Churg–Strauss syndrome and cause only mild
Clinical features
impairment of function. Lastly, the p-ANCA test tends to be positive
in the Churg–Strauss syndrome and c-ANCA negative, the reverse of The clinical picture is generally dominated by cardiovascular or
what is found in Wegener’s granulomatosis. The Churg–Strauss neurological features. Vascular disease is characterised by an early
syndrome, Wegener’s granulomatosis and microscopic polyangiitis thrombotic phase followed by fibrosis and cardiac involvement by
are compared in Table 8.3.1 (see p. 441). dysrhythmia, valvular incompetence, and ultimately heart failure.
Neurological disease is characterised by intellectual impairment, a
variety of localising signs and peripheral neuropathy. The commonest
respiratory symptom is a non-productive cough: asthma is rare. Pleural
effusions are common but are generally transudates attributable to
HYPEREOSINOPHILIC SYNDROME cardiac failure; they rarely contain eosinophils. Interstitial pulmonary
infiltrates are detected in about a quarter of cases and these may
The term ‘hypereosinophilic syndrome’ was introduced in 1968 for progress to the adult respiratory distress syndrome.93 Computed
what had previously been known as Löffler’s syndrome, one of two tomography findings include small pulmonary nodules with or
conditions named after the Swiss physician who first described without a halo of ground-glass attenuation and focal areas of ground-
them.22,85 The other is simple pulmonary eosinophilia, which is glass attenuation which are mainly peripheral.27,94 Many patients with

467
 Pathology of the Lungs

pulmonary involvement respond to corticosteroids but cytotoxic cells, often with small foci of necrosis. There may be many Charcot–
drugs have been deemed necessary in severe cases.93 Leyden crystals, as with any heavy eosinophil infiltrate. Thus, in the
lungs the pathological features of the hypereosinophilic syndrome are
identical to those of eosinophilic pneumonia (see above). Secondary
Pathology
changes include widespread thrombosis and infarction.
Pulmonary involvement is characterised by a heavy infiltrate of
mature eosinophils and consolidation of the air spaces by the same

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Br J Dis Chest 1987;81:197–201. 70. Al-Ammar AY, Yasin SS, Al-Muhsen SZ, et al. Medicine 1975;54:1–27.
55. Hellems SO, Kanner RE, Renzetti AD. A laryngeal presentation of Churg–Strauss 88. Spry CJF, Davies J, Tai PC, et al. Clinical
Bronchocentric granulomatosis associated syndrome in childhood. Ann Saudi Med features of fifteen patients with the
with rheumatoid arthritis. Chest 2009;29:142–5. hypereosinophilic syndrome. Q J Med
1983;5:831–2. 71. Gaskin G, Ryan JJ, Rees AJ, et al. Anti- 1983;205:1–22.
56. Rohatgi PK, Turrisi BC. Bronchocentric myeloperoxidase antibodies in vasculitis: 89. Weller PF, Bubley GJ. The idiopathic
granulomatosis and ankylosing spondylitis. relationship to ANCA and clinical hypereosinophilic syndrome. Blood
Thorax 1984;39:317–8. diagnosis. APMIS 1990;98:33. 1994;83:2759–79.
57. Warren J, Pitchenik AE, Saldana MJ. 72. Tervaert JWC, Elema JD, Kallenberg CGM. 90. Cools J, DeAngelo DJ, Gotlib J, et al. A
Bronchocentric granulomatosis with Clinical and histopathological association tyrosine kinase created by fusion of the
glomerulonephritis. Chest 1985;125:751–6. of 29kD-ANCA and MPO-ANCA. APMIS PDGFRA and FIP1L1 genes as a therapeutic
58. Martinez-Lopez MA, Pena JM, Quiralte J, 1990;98:35. target of imatinib in idiopathic
et al. Bronchocentric granulomatosis 73. Wechsler ME, Finn D, Gunawardena D, hypereosinophilic syndrome. N Engl J Med
associated with pure red cell aplasia and et al. Churg–Strauss syndrome in patients 2003;348:1201–14.
lymphadenopathy. Thorax 1992;47: receiving montelukast as treatment for 91. Bain BJ. Relationship between idiopathic
131–3. asthma. Chest 2000;117:708–13. hypereosinophilic syndrome, eosinophilic

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leukemia, and systemic mastocytosis. Am J hypereosinophilic syndrome. N Engl J Med 94. Kang EY, Shim JJ, Kim JS, et al. Pulmonary
Hematol 2004;77:82–5. 1994;330:535–8. involvement of idiopathic hypereosinophilic
92. Cogan E, Schandené L, Crusiaux A, et al. 93. Winn RE, Kollef MH, Meyer JI. Pulmonary syndrome: CT findings in five patients.
Brief report: clonal proliferation of type 2 involvement in the hypereosinophilic J Comput Assist Tomogr 1997;21:
helper T-cells in a man with the syndrome. Chest 1994;105:656–60. 612–5.

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 Chapter 10 

Pulmonary manifestations of systemic disease

CHAPTER CONTENTS Blood disorders 483

Anaemia 483
Connective tissue diseases 472
Hypercoaguability 483
Rheumatoid disease 473
Sickle cell disease 483
Rheumatic fever 475
Thalassaemia 483
Systemic sclerosis 476
Myeloproliferative disease 483
Systemic lupus erythematosus 477
Chronic granulomatous disease 484
Polymyositis and dermatomyositis 477
Sea-blue histiocytosis 485
Mixed connective tissue disease 478
Mastocytosis 485
Ankylosing spondylitis 478
IgG4-related systemic sclerosing disease 485
Sicca syndrome and Sjögren’s syndrome 478
Splenectomy 485
Relapsing polychondritis 478
Alimentary tract disorders 486
Behçet’s syndrome and Hughes–Stovin syndrome 479
Disorders of the upper alimentary tract 486
Cutis laxa 480
Coeliac disease 486
Ehlers–Danlos syndrome 480
Inflammatory bowel disease 486
Pseudoxanthoma elasticum 480
Whipple’s disease 487
Marfan’s syndrome 480
Pneumatosis coli 487
Hypertrophic pulmonary osteoarthropathy 480
Hepatic disease 487
Vascular disease 480
Pancreatic disease 487
Anomalies of the great vessels compressing the
trachea 481 Neuromuscular disease 488
Hereditary haemorrhagic telangiectasia ‘Neurogenic’ pulmonary oedema 488
(Osler–Weber–Rendu disease) 481 Tuberous sclerosis 488
Klippel–Trenaunay syndrome 482 Neurofibromatosis 488
Idiopathic arterial calcification of infancy 482 Metabolic and endocrine disorders 489
Blue rubber bleb disease 482 Obesity 489
Yellow-nail syndrome 482 Antiphospholipid syndrome 489
Aortic fistula 482 Hypercalcaemia and metastatic calcification 489
Renal disease 482 Systemic amyloidosis 489
Renal failure 482 Storage disorders 491
Autosomal-dominant polycystic kidney disease 483 Erdheim–Chester disease 492
Familial Fanconi syndrome (renal tubular acidosis) 483 Rosai–Dorfman disease 492

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00010-0 471
 Pathology of the Lungs

Acromegaly 494 systemic connective tissue disorders. Drug reactions are usually sys-
Thyroid disease 494 temic, but are dealt with separately on pages 383–391.
Diabetes mellitus 494
Hypovitaminosis A 494
Skin disease 494
CONNECTIVE TISSUE DISEASES
Cutaneous manifestations of malignant lung
disease 494 The connective tissue diseases form a heterogeneous group of
immunologically mediated disorders that share certain characteristics,
Skin disease associated with non-malignant
notably inflammation of synovial and serosal membranes, connective
lung disease 494
tissue and blood vessels in various tissues. The lung is often involved
Gynaecological and obstetric conditions 495 in this group of diseases, probably because of its abundant connective
Meigs’ syndrome 495 tissue and vasculature. Pulmonary associations of connective tissue
Pregnancy 495 diseases include abnormalities of airways, alveoli, pulmonary blood
Thoracic endometriosis 495 vessels, pleura and chest wall, any of which may precede, accompany
or follow the onset of the systemic disease (Table 10.1). Many of
References 496
the pulmonary associations of connective tissue diseases also occur
in isolation, although often accompanied by serological markers.
A prime example is interstitial pulmonary fibrosis but it is
notable that, in contrast to the idiopathic form of the disease, the
Some systemic diseases particularly affect the lungs but are dealt with histological pattern is more often that of non-specific interstitial
exclusively in other chapters: examples of these include sarcoidosis pneumonia (NSIP) than usual interstitial pneumonia (UIP).1–5 Also,
(p. 283), vasculitis and granulomatosis (p. 437) and Langerhans cell its progression is often slower and its prognosis correspondingly
histiocytosis (p. 288). Other diseases often affect the lungs in isolation better.6–8 The few patients with connective tissue diseases who show
and are described in full elsewhere but as they also form part of sys- a UIP pattern have fewer fibroblastic foci and a correspondingly better
temic illnesses they also have to be referred to here: examples of these prognosis than patients with idiopathic interstitial pneumonia
include interstitial pneumonia, which is associated with many of the and UIP.9,10

Table 10.1  Respiratory associations of acquired connective tissue disorders

Airways Alveoli Pulmonary Pleura Diaphragm and chest wall

vessels

Rheumatoid arthritis Bronchitis Pneumonia Hypertension Pleurisy

(see also Box 10.1) Bronchiectasis Interstitial pneumonia (NSIP Vasculitis Empyema
Follicular bronchiolitis or, rarely, UIP or LIP)
Constrictive Rheumatoid nodules
bronchiolitis
Systemic lupus Interstitial pneumonia (DAD Hypertension Pleurisy ’Shrinking lungs’ with high
erythematosus or rarely NSIP, UIP or OP) Thrombosis diaphragms
Vasculitis
Haemorrhage
Systemic sclerosis Interstitial pneumonia (NSIP or Haemorrhage ‘Hidebound’ chest
rarely UIP, OP, DAD or LIP)
Aspiration pneumonia
Sjögren’s syndrome ’Sicca’ features Interstitial pneumonia (NSIP or Pleurisy
LIP, rarely UIP, OP or DAD)
Lymphoma
Dermatomyositis and Aspiration pneumonia Myositis
polymyositis Interstitial pneumonia (NSIP or
OP, rarely UIP, DAD)
Ankylosing spondylitis Upper-lobe fibrosis Costovertebral restriction
Behçet’s syndrome Stenosis Arteritis
Ulceration Aneurysms
Relapsing polychondritis Stenosis
Rheumatic fever DAD Vasculitis Pleurisy
Diaphragmatic paralysis

NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia; LIP, lymphoid interstitial pneumonia; OP, organising pneumonia; DAD, diffuse alveolar  
damage.

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 Pulmonary manifestations of systemic disease Chapter | 10 |

The histological features of connective tissue diseases need to be

separated from the effects of therapy, including drug reactions and Box 10.1  Respiratory abnormalities in rheumatoid disease
opportunistic infections, as well as any coexistent disease processes Cricoarytenoid arthritis
not directly associated with the connective tissue disease. This may
Pleurisy
be difficult as, in most cases, the histological patterns found in the
Empyema
lung are rarely specific for a particular connective tissue disease.
Detailed clinicopathological correlation is therefore essential.7 Necrobiotic nodules
A further association of lung disease and various connective tissue Non-specific interstitial pneumonia
disorders is seen with the pneumoconioses, particularly silicosis. Usual interstitial pneumonia
There is a well-recognised association between silicosis and disorders Organising pneumonia
such as systemic sclerosis and rheumatoid disease.11–13 It is doubtful Lymphocytic interstitial pneumonia
whether the relationship is causal but the one seems to aggravate the Diffuse alveolar damage
other and may lead to its earlier development. For example, the Apical fibrosis
presence of dust results in rheumatoid lesions in the lungs being Bronchitis
particularly florid (see pp. 335 and 341 [Caplan’s syndrome]). Bronchiectasis
Bronchocentric granulomatosis
Rheumatoid disease Follicular bronchiolitis
It was the association of pulmonary fibrosis with rheumatoid arthritis Constrictive bronchiolitis
that first drew attention to the fact that this disease is not confined to Diffuse panbronchiolitis
the joints, and led to the use of the term ‘rheumatoid disease’ (rather Pulmonary hypertension
than arthritis) to indicate the generalised nature of the disorder.14 It Pulmonary vasculitis
is now recognised that rheumatoid disease has many pleuro­ Pulmonary drug toxicity
pulmonary manifestations (see Table 10.1 and Box 10.1), some of Carcinoma of the lung
which are dealt with in the appropriate chapters.
Lymphoma of the lung
Although rheumatoid disease is commoner in women, pulmonary
Pulmonary involvement in systemic amyloidosis
complications are more frequent in men, possibly reflecting the
prevalence of smoking, which may increase pulmonary vascular
permeability and aggravate the inflammatory process in the lung. As
with many connective tissue disorders, the pulmonary manifestations The nodules in the lungs may be recurrent or appear first in one
of rheumatoid disease may precede other clinical or serological evi- lung and then the other. They may be solitary or multiple and may
dence of the disease, although in most cases there are other features, enlarge, remain static or shrink to an insignificant scar. Resolution
such as arthritis, subcutaneous nodules, digital vasculitis and positive is usually by absorption but occasionally a nodule cavitates and
serology. discharges its necrotic contents through an airway. Erosion of both
an airway and the pleura establishes a bronchopleural fistula,
Pleurisy15–18 and perhaps pyopneumothorax.21,22 Direct involvement of the pleura
Pleural effusion is the commonest respiratory manifestation of by rheumatoid nodules is considered on page 714.
rheumatoid disease. The effusion is often small and asymptomatic Patients with rheumatoid nodules may present with haemoptysis,
but it may be large and bilateral and cause pleuritic pain, fever and or chest pain if there is pleural involvement, or they may have no
breathlessness. It is an exudate rather than a transudate (see p. 709). symptoms. The radiographic findings may be suspected of represent­
Most rheumatoid pleural effusions resolve spontaneously. Biopsy ing malignant disease. Rheumatoid nodules have a tendency to
usually shows non-specific chronic inflammation of the pleura but develop in the subpleural regions of the upper and mid zones.24 They
multiple rheumatoid nodules or a linear granulomatous process are round and typically measure up to 3 cm across but larger nodules
showing prominent palisading of histiocytes may replace the mesothe- are sometimes found, particularly when synergistic factors such as
lium, in which case epithelioid histiocytes recognisable in the mine dust are also present (see Caplan’s syndrome, p. 341).27 As else-
pleural aspirate may permit a cytological diagnosis (see Fig. 13.7, where, the nodules have a necrotic centre of finely granular eosi-
p. 714).15,19 nophilic debris surrounded by a capsule of chronic inflammatory
granulation tissue (Fig. 10.1A). The boundary between dead and viable
Empyema tissue is marked by a characteristic palisade of radially oriented mac­
rophages (Fig. 10.1B). The inflammatory cells include a small number
Patients with rheumatoid disease are prone to infections20 and
of giant cells as well as plentiful lymphocytes and plasma cells. Fungal
occasionally a pleural effusion in a rheumatoid patient is found
colonisation is a rare complication of rheumatoid nodules.28
to be purulent. Occasionally there is pyopneumothorax,21,22 probably
The differential diagnosis is principally from infection and Wegener’s
due to rupture into the pleural cavity of a pleural or subpleural
granulomatosis (see Table 8.3.3, p. 443). The satellite granulomas
rheumatoid nodule.
seen in tuberculosis are not a feature of rheumatoid nodules, and
special stains for mycobacteria and fungi give negative results.
Rheumatoid nodules However, staining for these organisms should always be undertaken
Nodules identical to those found in the subcutis of patients with if there is any doubt about the diagnosis. Less common infective
rheumatoid disease occasionally develop in the substance of the lung granulomas that enter the differential diagnosis include syphilis and
or the trachea.23–26 They may be the only manifestation of rheumatoid dirofilariasis, the former requiring serological investigation and the
disease, developing before there is any arthritis or seroconversion.23 latter step sections to identify fragments of the worm (see pp. 216 and
Thus, they may herald generalised disease. As they may develop in any 258 respectively). In Wegener’s granulomatosis there is also vasculitis
part of the body, the occasional involvement of the major airways whereas blood vessels near rheumatoid nodules show intimal fibrosis
should occasion no surprise.25 and a cuff of lymphocytes, but not a true vasculitis.

473
 Pathology of the Lungs

A B

Figure 10.1  A pulmonary rheumatoid nodule. (A) The nodule consists of a necrotic centre surrounded by a thick fibrous capsule and an intervening
inflammatory zone. (B) As in the subcutaneous nodules of rheumatoid disease, a palisade of radially oriented macrophages borders the central
necrosis.

Interstitial pneumonia Bronchial disease

Clinically overt pulmonary parenchymal disease in the form of inter- Bronchitis and bronchiectasis are commoner in patients with
stitial pneumonia is reported in approximately 5% of patients with rheumatoid arthritis than in matched controls38,39 and occasional
rheumatoid arthritis but the figure rises to 19% when patients without rheumatoid patients develop bronchocentric granulomatosis.40 High
respiratory symptoms are studied by high-resolution computed resolution computed tomography (HRCT) has permitted the recogni-
tomography (HRCT).29 All seven patterns of interstitial pneumonia tion of airway disease in a high proportion of patients with rheuma-
described in the consensus classification (see p. 264) have been toid arthritis.41
described, with UIP, NSIP and organising pneumonia being especially
frequent, and often seen in association with follicular bronchio­
Follicular bronchiolitis
litis.5,8,10,30–34 The available data on prognosis are contradictory: some
groups have reported that the prognosis of these patterns in rheuma- Rheumatoid disease is characterised by widespread lymphoid hyper-
toid disease corresponds to that seen in their idiopathic counterparts plasia. This is best seen in lymph nodes but the bronchopulmonary
while others claim that it is better when they are associated with lymphoid tissue is also involved in this process, resulting in the devel-
connective tissue disease.8–10,31,34 opment of lymphoid follicles alongside the bronchioles, a process
termed follicular bronchiolitis (Fig. 10.2).42,43 Patients complain of
breathlessness with cough, fever or recurrent pneumonia. They have
Apical fibrosis bilateral reticulonodular radiographic opacities and lung function
Occasional patients with rheumatoid disease develop cavitating tests show an obstructive, restrictive or combined defect. When follicu-
upper-lobe fibrosis similar to that described in ankylosing spondylitis lar bronchiolitis accompanies an interstitial pneumonia it suggests
(see below).35–37 that the latter is part of a systemic connective tissue disorder.10

474
 Pulmonary manifestations of systemic disease Chapter | 10 |

may have an infective basis. However, the obliterative process has

the constrictive pattern seen when there is constant attrition of the
respiratory epithelium rather than the proliferative intraluminal form
of the disease seen after brief viral or chemical injury (see p. 121). It
is notable that a case of obliterative bronchiolitis attributed to the
domestic inhalation of a common cleansing agent concerned a patient
with rheumatoid disease and that the airway obliteration was of
the constrictive variety,50 suggesting that the process was the result
of continuing injury rather than an isolated episode of fume
inhalation.

Diffuse panbronchiolitis
This disease, which is described on page 124, is also recorded in
association with rheumatoid arthritis.51,52

Pulmonary hypertension
Figure 10.2  Follicular bronchiolitis as a manifestation of rheumatoid
disease. Several lymphoid follicles are seen, particularly bordering the Pulmonary hypertension is occasionally reported in rheumatoid
central bronchiole. disease. The vascular changes are described as showing advanced
fibroelastic intimal proliferation that obliterates the lumen of small
arteries, either in isolation53,54 or in combination with pulmonary
arteritis.55 The dilatation lesions of plexogenic arteriopathy are not
observed.53–55

Pulmonary vasculitis
Digital vasculitis is a common manifestation of rheumatoid disease
and identical changes are occasionally encountered in the pulmonary
vasculature (see Fig. 8.3.17, p. 446).55–57 It is likely that this represents
a true vasculitis, probably of an immune nature, rather than the
necrotising arteritis of plexogenic arteriopathy, although this is
disputed.55

Pulmonary drug toxicity

Adverse pulmonary effects may be caused by drugs used in the
treatment of rheumatoid disease. For example, aspirin and other non-
steroidal anti-inflammatory drugs may cause asthma and eosinophilic
pneumonia while gold and penicillamine may exert a cytotoxic
Figure 10.3  Constrictive obliterative bronchiolitis in a patient with effect resulting in diffuse alveolar damage and pulmonary fibrosis.
rheumatoid disease. The mucosa of the bronchiole seen to the left is Similarly, methotrexate may result in varying patterns of interstitial
thickened by granulation tissue so that the airway lumen is reduced to a
pneumonia.58
pinpoint.

Pulmonary eosinophilia
Constrictive bronchiolitis obliterans As well as representing a reaction to the drugs used to treat
rheumatoid disease, eosinophilic pneumonia may be a manifestation
Rare patients with rheumatoid disease and other connective tissue
of the rheumatoid process itself.59
disorders develop a bronchiolar disorder that is of considerably
greater clinical consequence than follicular bronchiolitis, one that is
characterised by a severe ventilatory disturbance that often proves Pulmonary malignancy
fatal. This is the constrictive form of obliterative bronchiolitis (Fig.
10.3).44–46 The primary lesion appears to involve continuing auto­ Both carcinoma and lymphoma occasionally arise at the edge of a
immune damage to the respiratory epithelium. This is replaced by rheumatoid nodule.60–62
granulation tissue, which is laid down in a circumferential pattern and
gradually narrows and finally obliterates the airway lumen. It has been Rheumatic fever
suggested that the process is a consequence of penicillamine47,48 or
gold49 antirheumatoid therapy rather than a direct result of the Rheumatic fever is now rare in developed countries but remains
connective tissue disease but as rheumatoid patients who have not common in many parts of the world. It involves serosal surfaces and
received these drugs have also developed constrictive obliterative often results in pleurisy, which is generally manifest as a sterile
bronchiolitis this appears unlikely. Furthermore, constrictive oblitera- exudative effusion. Less commonly, there is a fibrinous alveolar
tive bronchiolitis has not been reported in patients treated with peni- exudate, organisation of which results in Masson bodies, hyaline
cillamine for disorders such as Wilson’s disease and primary biliary membrane formation, chronic interstitial pneumonia or a focal necro-
cirrhosis. Alternatively, it has been suggested that the bronchiolitis tising process involving alveoli and pulmonary blood vessels.63–66

475
 Pathology of the Lungs

A
C

Figure 10.4  Pulmonary fibrosis as a manifestation of systemic sclerosis. (A) The fibrosis is seen as a subpleural band of pallor, chiefly affecting the base
and posterior of the lung. (B) Microscopy shows non-specific interstitial pneumonia. (C) Malignant change may complicate the fibrosis. Here there is
both non-specific interstitial pneumonia and adenocarcinoma.

Systemic sclerosis Interstitial pneumonia

Interstitial pneumonia is the commonest pulmonary manifestation of
Systemic sclerosis (also known as scleroderma) is a multisystem systemic sclerosis (Fig. 10.4), the prevalence at autopsy being approxi-
disease that is subclassified according to the degree of skin involve- mately 70%.76,77 However, many of these cases have subclinical
ment as diffuse or limited cutaneous. The former is associated with a involvement78 and the prognosis is better than in idiopathic inter­
greater degree of visceral disease and carries a worse prognosis. The stitial pneumonia.7,79–81 NSIP is the commonest pattern, accounting
limited cutaneous form is more often associated with the CREST for 55–77% of cases.2–4,8,82 The second commonest pattern is UIP but
syndrome (calcinosis cutis, Raynaud’s phenomenon, oesophageal dys- the adverse prognosis associated with this pattern in idiopathic disease
function, sclerodactyly and telangiectasia) and has a better prognosis, is not so marked.3,4,10,82 This may be related to differences in neu-
although it is the form that is more often associated with pulmonary trophil numbers and degranulation in the lung.83 Other histological
hypertension.67 Parenchymal pulmonary involvement in systemic patterns seen in systemic sclerosis include desquamative interstitial
sclerosis may take the form of interstitial pneumonia3,7,68 or diffuse pneumonia and respiratory bronchiolitis although, it is likely that
alveolar haemorrhage,69,70 whilst oesophageal involvement may result these patterns are related to smoking more than systemic sclerosis.72,84
in aspiration pneumonia and centriacinar fibrosis.71 Constrictive Organising pneumonia has been reported in occasional patients,85 as
bronchiolitis is also reported72,73 and there is an increased risk of has diffuse alveolar damage.33,70,86 Sarcoid granulomas have also been
lung cancer, particularly adenocarcinoma, which is often of lepidic noted but whether they relate to systemic sclerosis or are incidental is
(bronchioloalveolar) pattern.74,75 unknown.3,87

476
 Pulmonary manifestations of systemic disease Chapter | 10 |

Pulmonary hypertension ‘shrinking lungs’ is often applied to these cases but this is misleading
as the fault lies in the respiratory muscles, which show myopathic
In some patients with systemic sclerosis the lung parenchyma is unre-
changes, rather than in the lungs.108 Dyspnoea has been attributed to
markable but there are marked vascular changes. These patients
the tight skin about the chest but the cutaneous changes rarely affect
have severe pulmonary hypertension and are mainly those with the
respiratory function.
CREST variant of systemic sclerosis (see above).67 Pathologically
there is generally myxoid thickening of the wall of small pulmonary
arteries, usually involving intimal fibroblasts arranged circumferen- Pulmonary vascular disease
tially in an ‘onion skin’ pattern (see Fig. 8.2.21, p. 431); the appear- Pulmonary vascular disease in SLE may be secondary to systemic
ances are similar to those described in the kidney in systemic venous thrombosis (pulmonary thromboembolism), or widespread
sclerosis.88,89 There is also adventitial fibrosis90 but plexiform lesions thrombosis may affect the pulmonary as well as the systemic circula-
are not seen.88,91 In other patients with the CREST variant of systemic tion while diffuse alveolar haemorrhage and haemosiderosis are well-
sclerosis pulmonary hypertension is caused by veno-occlusive recognised complications of SLE.100,109–113 Pulmonary thrombosis,
disease.91–93 infarction and haemorrhage have been linked to the presence of
Pulmonary hypertension is also recorded in the POEMS syn- circulating phospholipid antibody (also known as cardiolipin or
drome,94,95 a rare variant of plasma cell dyscrasia with multisystem lupus anticoagulant) in the antiphospholipid syndrome (see p.
features. The name POEMS is an acronym for its principal features, 489).114 Thrombosis may underlie the pulmonary hypertension that
polyneuropathy, organomegaly, endocrinopathy, M protein and skin has been reported in association with SLE,114–119 or the pathogenesis
changes that resemble scleroderma. It is noteworthy that in the of the hypertension may involve vasospasm, which is suggested by the
POEMS syndrome there is overproduction of the endothelial cell- frequent association of Raynaud’s phenomenon with pulmonary
specific mitogen and potent angiogenic peptide vascular endothelial hypertension in SLE.115 As in systemic sclerosis, the dilatation lesions
growth factor,95 which has also been reported in the plexiform lesions of plexogenic arteriopathy are seldom observed.116,117,119 Pulmonary
of other patients with pulmonary hypertension.96 Other pulmonary veno-occlusive disease, probably due to organisation of widespread
manifestations of the POEMS syndrome include restrictive lung venular thrombosis, has also been described in SLE.120
disease, respiratory muscle weakness, diminished diffusing capacity Other patients with SLE have pulmonary vasculitis or capillaritis
and pleural effusions.97 with evidence of immune complex deposition.99,121–125 The capil­
laritis may be complicated by diffuse alveolar haemorrhage109–112 or
haemosiderosis.113 Tubuloreticular endothelial cell inclusions, once
Systemic lupus erythematosus thought to be specific for SLE but later identified in AIDS and other
Systemic lupus erythematosus (SLE) is a chronic multisystem disorder conditions, are probably non-specific indicators of cell damage, pos-
associated with antinuclear autoantibodies and immune complex sibly mediated by interferon.126
deposition. Women of child-bearing age are most commonly affected,
the female-to-male ratio being approximately eight. Particularly Malignant change
common manifestations include arthropathy, skin lesions, renal
disease and serositis. There are also several pleuropulmonary mani- Rare examples of pulmonary lymphoma are recorded in SLE.127,128
festations,98 in addition to which reactions to drugs such as methotrex-
ate and cyclophosphamide used to treat SLE may affect the lungs.
Respiratory disease is commoner in SLE than in any other connective Polymyositis and dermatomyositis
tissue disease but the prognosis is more dependent upon renal than
pleuropulmonary involvement. These inflammatory disorders of skin and skeletal muscle affect
women more frequently than men and have a peak onset in the sixth
decade. The most common pleuropulmonary complication of these
Pleural disease diseases is aspiration pneumonia due to a depressed cough reflex and
Pleuritis, seen either as a dry fibrinous exudate or an exudative weakness of pharyngeal and intercostal muscles and the diaphragm,
effusion, is the commonest respiratory manifestation of SLE. The which may result in ventilatory failure.129
effusion contains neutrophils, lymphocytes, lupus erythematosus cells
and antinuclear factor in high titre, and shows positive nuclear
Interstitial pneumonia
immunofluorescence.
Patients with myositis may develop interstitial pneumonia, the inci-
dence of this complication being less than 10% in patients with poly-
Parenchymal disease myositis130 but in the region of 41–67% in dermatomyositis.129,131,132
Although parenchymal disease is less common than pleural involve- Patients with polymyositis and antibodies against histidyl-tRNA
ment, it is more serious. Acute lupus pneumonitis is characterised by synthetase (Jo-1) also have a high incidence of interstitial lung
diffuse alveolar damage or, less commonly, by pulmonary haemor- disease.133–136 The commonest histological pattern is NSIP (see p.
rhage or cryptogenic organising pneumonia.99–102 Infection, which is 276), which is often mixed with a component of organising
common because of the use of immunosuppressive drugs, needs to pneumonia.1,134,137,138 Other patterns of interstitial lung disease that
be excluded in such acute cases.103 In survivors, healing may be by have been associated with myositis include DAD, UIP and, rarely,
resolution but more commonly leaves the lungs permanently scarred. alveolar proteinosis.137,137a
Chronic pulmonary injury is rarer in SLE than in rheumatoid disease
and systemic sclerosis104 but both UIP and NSIP have been reported,99
and, more rarely, organising pneumonia,101,102 amyloidosis106 and lym- Pulmonary vascular disease
phoid interstitial pneumonia (LIP).107 Renal involvement may lead to Pulmonary vasculitis has also been reported in patients with
uraemic pulmonary oedema. Some patients with SLE are severely polymyositis and the anti-Jo-1 syndrome.134,136,139 Antibodies against
breathless and radiologically appear to have small lungs; the term endothelial cells may underlie the capillaritis and resultant

477
 Pathology of the Lungs

pulmonary haemorrhage that have been described in a few patients

with dermatomyositis.139,140

Pulmonary malignancy
Dermatomyositis is often a complication of malignant disease and
so may be secondary to bronchopulmonary carcinoma. Pulmonary
lymphoma has also been described in association with
dermatomyositis.141

Mixed connective tissue disease

Mixed connective tissue disease is characterised by overlapping
features of other connective tissue disorders, notably SLE, systemic
sclerosis and polymyositis, in association with high titres of an anti-
nuclear antibody that gives a speckled pattern of immunofluores-
cence.142 The frequency of pulmonary involvement has ranged from
25 to 85%, the commonest form being interstitial pneumonia, fol-
lowed by pleuritis, pulmonary hypertension, vasculitis and diffuse
alveolar damage.33,143–147 Pulmonary hypertension is especially seen
when features of systemic sclerosis are prominent but the pathological
features are those of plexogenic arteriopathy rather than the myxoid
intimal thickening seen in systemic sclerosis.148

Ankylosing spondylitis
Ankylosing spondylitis typically affects the spine of young men with Figure 10.5  Gross apical fibrosis in a patient with ankylosing spondylitis.
an HLA-B27 haplotype. Pulmonary associations include apical
fibrosis. This develops in 1–2% of patients with ankylosing spondyli-
tis, typically many years after the onset of the joint disease.149,150
Whereas the spinal lesions typically appear early in adult life, it is not destruction of the glands is of unknown cause. In both sicca and the
until the fifth decade or so that pulmonary disease develops, often full Sjögren’s syndrome, the glands show a heavy lymphoid infiltrate
being discovered incidentally on chest radiographs. Initially, the with destruction of the secretory acini (Fig. 10.6).157 Further extensions
changes may be unilateral but they have often become bilateral if of the sicca syndrome are encapsulated in the term TASS syndrome
cough or dyspnoea first draws attention to pulmonary involvement. As (thyroiditis, Addison’s disease, Sjögren’s and sarcoidosis).158 The asso-
the disease progresses, cystic changes develop and the appearances ciation with rheumatoid disease, thyroiditis and Addison’s disease
resemble those of tuberculosis, but mycobacteria do not appear to play suggests an autoimmune aetiology. The immunoparesis associated
a causal role. However, like all cavities in the lungs, those of ankylosing with human immunodeficiency virus infection is also reported in the
spondylitis are liable to secondary saprophytic infection by Aspergillus sicca syndrome.159
species or colonisation by opportunistic mycobacteria.151
At necropsy, there is bilateral apical fibrosis (Fig. 10.5), which may Parenchymal disease
be associated with bronchiectasis and bulla formation. Secondary
infection may be found but generally microscopy shows only fibrosis Parenchymal disease occurs in both primary and secondary Sjögren’s
and lymphocytic infiltration. The process is not granulomatous and disease but is more common in the latter, where it often reflects the
the aetiology is unknown. The changes cannot be attributed to the pulmonary manifestations of the associated connective tissue disease.
irradiation that was formerly used to treat ankylosing spondylitis as Parenchymal disease includes amyloidosis and the formation of
this was confined to the spine and the pulmonary changes may bullae (Fig. 10.7).160–164 Interstitial pneumonia of NSIP pattern is
develop without such therapy. Occasionally, identical changes are the commonest manifestation of primary Sjögren’s disease.165
found in association with rheumatoid disease35 or with psoriatic Pulmonary hypertension, LIP, UIP and organising pneumonia are
spondylitis.152 also reported.165–172

Sicca syndrome and Sjögren’s syndrome Pulmonary lymphoma

Primary pulmonary lymphoma has been reported in Sjögren’s
Bronchial disease syndrome, usually marginal zone non-Hodgkin’s lymphomas
The sicca syndrome of dry eyes and dry mouth, due respectively to of the mucosa-associated lymphoid tissue.173–175
keratoconjunctivitis sicca and xerostomia, may be combined with one
of the connective tissue disorders, usually rheumatoid disease, to form
Sjögren’s syndrome. The dryness of the eyes and mouth is due to
Relapsing polychondritis
inflammatory destruction of the lacrimal and salivary glands. The Relapsing polychondritis is a rare systemic disorder affecting
same process may extend into the lower respiratory tract to destroy connective tissues with a high content of glycosaminoglycans, notably
the tracheobronchial glands and lead to dryness of the trachea and cartilage, the aorta, the sclera and cornea.176–180 It is associated
bronchi.153–156 Airway clearance is impaired and bronchitis, with rheumatoid arthritis in about 20% of cases. Autoantibodies to
bronchiectasis, bronchiolitis and pneumonia may develop. The cartilage and type III collagen are sometimes found181 and there

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 Pulmonary manifestations of systemic disease Chapter | 10 |

Figure 10.6  Sjögren’s syndrome. The bronchial glands show an intense

lymphoid infiltrate.

may be vasculitis, glomerulonephritis, rheumatoid disease, Sjögren’s

syndrome, SLE or other autoimmune disease.180,182,183
Constitutional symptoms are common while involvement of the
pinnae and nasal cartilage leads to crumpled ears and a saddle-nose
deformity.178,179 Involvement of the lower respiratory tract is
uncommon, especially in isolation, but may result in life-threatening
tracheobronchial narrowing (see p. 95).184–186
Histologically, there is erosion of the edges of the affected cartilages
by a dense lymphocytic, plasma cell and giant cell infiltrate (see Fig.
3.4, p. 95). Immunoglobulins and complement components have
been demonstrated at the chondrofibrous junction.187 Resolution of
the inflammation, which may be spontaneous, may leave a deformed
cartilage showing fibrosis and metachromasia of its ground
substance.186 B

Figure 10.7  Sjögren’s syndrome. (A) The lung shows amyloidosis,

Behçet’s syndrome and lymphoid hyperplasia and air space destruction. (B) High-resolution
Hughes–Stovin syndrome computed tomography scan showing cystic destruction and peripheral
nodules, the latter probably reflecting the focal amyloid deposition.
Behçet’s syndrome combines recurrent orogenital ulceration with a
variety of systemic disorders. A family history is sometimes obtained
and the disease is associated with HLA-B51, suggesting that it has a result in widespread pulmonary thrombosis.189 Other respiratory
genetic basis. Pulmonary involvement occurs in up to 8% of cases, manifestations include pulmonary embolism, pleurisy, pulmonary
most commonly as multiple pulmonary artery aneurysms due to a fibrosis, bronchial ulceration and stenosis, and chyloptysis.188,190–197
necrotising arteritis (see Fig. 8.3.19, p. 447).188 Arteries of any size may The Hughes–Stovin syndrome of haemoptysis due to pulmonary
be affected. Leakage or rupture of the aneurysms causes pulmonary artery aneurysms probably represents a limited form of Behçet’s
haemorrhage, which may be fatal. Alternatively, the arteritis may syndrome.198–200

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 Pathology of the Lungs

and cutis laxa have both been associated with Mounier–Kuhn’s and
Klippel–Trenaunay syndromes (see pp. 163 and 482).

Pseudoxanthoma elasticum
Pseudoxanthoma elasticum is a further generalised connective tissue
disorder that has its principal manifestations in the skin but may
involve the lung. As in other tissues the pulmonary elastic tissue is
damaged and the site of dystrophic calcification.206

Marfan’s syndrome
Marfan’s syndrome is a further hereditary disorder of connective tis­
sue. It is an autosomal disorder caused by mutation of the gene encod-
A ing fibrillin-1, which is a major component of the microfibrillar part
of elastin.207 Dysregulation of transforming growth factor-β (TGF-β)
signalling due to mutations in the TGF-β genes has also been im­­
plicated in certain patients with Marfan’s syndrome.208 Patients with
Marfan’s syndrome are of a tall, thin build and have arachnodactyly,
a high arched palate, pectus excavatum, scoliosis, flat feet, dislocation
of the lens, aortic incompetence, dissection of the aorta and mitral
valve prolapse. Pulmonary complications of the connective tissue
fragility include recurrent pneumothoraces and emphysema.209–211

Hypertrophic pulmonary osteoarthropathy

Hypertrophic pulmonary osteoarthropathy is characterised by digital
clubbing associated with arthropathy and periostitis that mainly
affects the distal long bones in a symmetrical manner and causes
painful swelling of the ankles, wrists, knees and elbows. Scans show
abundant periosteal new bone. The condition is mainly associated
B with primary carcinoma of the lung, of which it may be the presenting
feature. The tumour is usually peripheral and may be of any cell type
but is rarely small cell. The numerous other associations include
Figure 10.8  Ehlers–Danlos syndrome. (A) Fibrous scars, shown red in this
van Gieson stain, are probably the result of spontaneous tearing of the bronchopulmonary carcinoid, carcinoma of the oesophagus, thymus
lung. (B) Fibrous pseudotumours may represent a development of the and thyroid, thoracic lymphoma, localised fibrous tumour of the
same process. pleura, leiomyoma of the oesophagus, pleuropulmonary sepsis, cystic
fibrosis, sarcoidosis, cyanotic congenital heart disease, thyrotoxicosis
and inflammatory bowel disease. The aetiology is obscure. Vagal stim-
ulation, hormonal and immune mechanisms have all been suggested
while the digital clubbing has been attributed to the release of growth
Cutis laxa factors following the impaction of platelet aggregates in distal blood
vessels.
Cutis laxa is a rare hereditary disease of connective tissue in which the
skin lacks its normal elasticity and hangs in folds like the dewlaps of
a bloodhound. It may be associated with dissection of the aorta and
pulmonary emphysema.201 VASCULAR DISEASE

Cardiovascular disease often leads to cardiac hypertrophy and if this

Ehlers–Danlos syndrome
is severe it may affect the lungs. For example, the enlarged heart may
Ehlers–Danlos syndrome is another hereditary defect of connective come to occupy a significant proportion of the thoracic space, restrict-
tissue, one caused by mutation of the gene that encodes the chains ing lung volume, or an enlarged left atrium may compress the
of type III procollagen. There are 10 recognised subtypes, with oesophagus, causing swallowing difficulties and so promoting aspira-
corresponding clinical heterogeneity. The syndrome is generally tion pneumonia. In infancy the bronchi are narrow and still quite
characterised by soft, hyperextensible skin and hyperextensibility of pliable and are therefore liable to be compressed at certain points if
the joints. Visceral abnormalities include fragility of blood vessels the pulmonary arteries are distended, as in acyanotic congenital
with consequent haemorrhage, hernias, visceral rupture, mitral valve cardiac disease, resulting in absorption collapse (Fig. 10.9).212
prolapse and premature rupture of the membranes in pregnancy. Congenital heart disease may have profound effects upon the pulmo-
Respiratory complications include tracheobronchomegaly, pulmonary nary circulation, as may failure of the left ventricle and mitral stenosis;
laceration with subsequent haemorrhage, cystic change, fibrous pseu- these conditions are considered in Chapters 2 and 8.1 respectively.
dotumours that frequently show osseous metaplasia (Fig. 10.8), pneu- Pulmonary hypertension secondary to disorders of the heart and
mothoraces and haemothorax.202–205 Occasionally some of these systemic vasculature is dealt with in Chapter 8.2 and vasculitis in
respiratory features are seen in isolation. Ehlers–Danlos syndrome Chapter 8.3.

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 Pulmonary manifestations of systemic disease Chapter | 10 |

4
A

IB LB 1 2 Figure 10.10  Left pulmonary artery sling syndrome. In comparison with

the normal arrangement shown on the left, the left pulmonary artery
3 passes to the right and then backwards over the origin of the right main
bronchus before crossing to the left side behind the trachea just above
its bifurcation and in front of the oesophagus. The arrow indicates the
course of the left pulmonary artery. (Reproduced from Brewis RAL, Corrin B,
Geddes DM et al. (eds) Respiratory Medicine, 2nd edn. London: Saunders, 1995,
LUB with permission.)

RMB
Figure 10.9  The major airways and thoracic arteries viewed from in front arteriosus connecting the anomalous right subclavian artery to
with the latter in dotted outline demonstrating the sites where the
the right pulmonary artery to the right
bronchi and arteries are in particularly close proximity and the narrow,
3. a right-sided aortic arch with an anomalous left subclavian
pliable bronchi of infants are liable to be compressed if the pulmonary
arteries are distended. 1. The superior aspect of the left bronchus (LB) is artery. This is the mirror image of the above and here the
compressed where it is crossed by a distended left pulmonary artery. 2. vascular ring is formed by the heart in front, the aortic arch to
The posterior aspect of the left upper-lobe bronchus (LUB) is compressed the right, an anomalous left subclavian artery behind and a
as the left pulmonary artery hooks around it. 3. The lateral side of the ductus (or ligamentum) arteriosus connecting the left subclavian
junction of the intermediate (IB) and right middle-lobe (RMB) bronchi is artery to the left pulmonary artery to the left (Fig. 10.11).214
compressed by the right lower-lobe artery. 4. A distended left pulmonary
It will be noted that in two of these conditions there is a right-sided
artery pushes the aorta (A) medially and upwards against the left lateral
aspect of the trachea (T) to accentuate the normal indentation of the aortic arch. This can be identified radiologically and in a child thought
trachea by the aorta. (Reproduced from Stanger et al. (1969)212 by permission of to have corticosteroid-resistant asthma is a valuable indication that
the editor of Pediatrics.) the true cause of the child’s wheezing is a vascular ring compressing
the trachea.215

Hereditary haemorrhagic telangiectasia

Anomalies of the great vessels compressing (Osler–Weber–Rendu disease)
the trachea
Hereditary haemorrhagic telangiectasia is an autosomal-dominant
Four vascular anomalies are liable to compress the trachea. These condition characterised by multiple telangiectases in the skin and
are the left pulmonary artery sling syndrome and three varieties of mucous membranes, often resulting in distressing and sometimes
vascular ring. life-threatening haemorrhage.216–218 Epistaxis and gastrointestinal
haemorrhage are common manifestations while there may be
haemoptysis, haematuria and iron-deficiency anaemia. Viscera such
The left pulmonary artery sling syndrome
as the lungs, liver and brain may also be involved. The telangiectases
In this syndrome,213 the left pulmonary artery crosses to the right in connect arteries and veins, bypassing the normal resistance vessels so
front of the trachea, curls around it above the origin of the right main that they are subject to arterial pressure.219 They act as arteriovenous
bronchus and runs to the left between the trachea and the oesophagus fistulae and increase cardiac output. About 15% of patients have large
(Fig. 10.10). The lower trachea is liable to be compressed, causing pulmonary arteriovenous fistulae (see p. 76).220 These permit para-
stridor or wheeze. doxical embolisation with the danger of infarction and abscesses in
sites such as the brain.
Vascular rings Genetic mutations have been identified at three loci involving cell
surface receptors for TGF-β. Two, which are located at 9q33-34 and
Certain congenital anomalies of the great vessels result in a ring of 3p22 and respectively encode for endogline and ALK1, are found in
arteries surrounding and possibly compressing the trachea. Three families in whom pulmonary arteriovenous fistulae are common.221–
conditions are liable to do this: 223
The third mutation, which is less common, has been mapped to
1. a double aortic arch in which the ring is formed by the heart to the long arm of chromosome 12.224 This mutation is associated with
the front, the twin arches to either side and the common primary (plexogenic) pulmonary hypertension rather than pulmonary
descending aorta behind arteriovenous fistulae.224–226 Thus, two mechanisms underlie the
2. an anomalous right subclavian artery. Here the ring consists of development of pulmonary hypertension in hereditary haemorrhagic
the heart to the front, the aortic arch to the left, an anomalous telangiectasia: there may be either high-output left-sided cardiac
right subclavian artery behind and a ductus (or ligamentum) failure or primary pulmonary vasoconstriction.227

481
 Pathology of the Lungs

Box 10.2  Renal disease associated with pulmonary

haemorrhage
RS
ALS
With anti-GBM antibody
RCC Goodpasture’s syndrome
LCC
AA
Without anti-GBM antibody
Without systemic disease
LD
Glomerulonephritis
Penicillamine-associated disease
With connective tissue disorders
Systemic lupus erythematosus
Systemic sclerosis
Rheumatoid disease
PT Mixed connective tissue disease
With systemic vasculitis
Wegener’s granulomatosis
DA Polyangiitis overlap syndrome
Henoch–Schönlein purpura
Behçet’s disease

GBM, glomerular basement membrane.

Figure 10.11  Right-sided aortic arch with anomalous left subclavian

artery. In this condition a vascular ring is formed by the heart in front,
the aortic arch (AA) to the right, an anomalous left subclavian artery
(ALS) behind and a left ductus arteriosus (LD) connecting the left Yellow-nail syndrome
subclavian artery to the left pulmonary artery to the left. Arrows indicate This syndrome is characterised by lymphatic hypoplasia,
aortic flow; DA, descending aorta; PT, pulmonary trunk; RCC, right
lymphoedema, chylous effusions and yellow discoloration of the
common carotid artery; LCC, left common carotid artery; RS, right
subclavian artery. (Reproduced from Stewart et al. (1966)214 with permission
nails. It is described more fully on page 709.
from the American Journal of Roentgenology.)

Aortic fistula
Fistulas between the aorta and the tracheobronchial tree may com­
plicate previous thoracic vascular surgery, aortic aneurysm, bacterial
aortitis or radiation therapy. They often present as recurrent episodes
of haemoptysis but the initial event may be a catastrophic flooding
Klippel–Trenaunay syndrome of the airways.234
This is a congenital disorder characterised by a triad of cutaneous
vascular lesions, venous abnormalities of the extremities and soft-
tissue or bony hypertrophy. Venous thromboembolism is a common
complication, sometimes leading to pulmonary hypertension and RENAL DISEASE
right heart failure.228–231 Occasionally, there are also pulmonary
angiomas. A combination of haematuria and pulmonary haemorrhage (or
haemosiderosis) is seen in a variety of pulmonary–renal syndromes
(Box 10.2).
Idiopathic arterial calcification of infancy Microalbuminuria is a risk marker for thromboembolism, probably
In this condition there is calcification of the arterial internal elastic because it reflects generalised endothelial dysfunction.235
laminae, generally involving systemic vessels but also pulmonary
arteries on occasion.232 Affected babies usually die in infancy and the
diagnosis is often made at autopsy. Medium-sized arteries are rigid
Renal failure
and as well as showing calcification of the internal elastic lamina they The commonest respiratory conditions encountered in renal failure
are often obliterated by secondary thrombosis and fibrosis. are infection and pulmonary oedema. The latter is often described
as ‘uraemic lung’ but is indistinguishable from pulmonary oedema
of other cause, described in full on page 401. Several mechanisms
Blue rubber bleb disease may contribute to the development of pulmonary oedema in renal
Blue rubber bleb disease is characterised by cavernous haemangiomas failure. They include fluid retention; hypertensive left ventricular
involving the skin and gastrointestinal tract. Rarely the lesions extend failure secondary to chronic glomerulonephritis, chronic pyelo­
into the trachea and bronchi where they are seen as discrete bluish nephritis and polycystic renal disease; and hypoproteinaemia, which
mucosal nodules.233 is a prominent feature of the nephrotic syndrome.236 Cytotoxic factors

482
 Pulmonary manifestations of systemic disease Chapter | 10 |

may also operate.237 Pleural effusion may develop for the same inuria.260 The thrombosis and subsequent organisation may be
reasons. widespread and lead to pulmonary hypertension of the pattern seen
Renal failure may be complicated by secondary hyperparathyroidism, in thrombo­embolic disease (see p. 404).260
leading to absorption of bone and a secondary rise in serum calcium
levels. This may be followed by metastatic calcification, in which the
lungs are amongst the most commonly affected organs (see below). Sickle cell disease
Pulmonary hypertension is also reported in chronic renal failure, affect- Sickle cell disease is a serious haemolytic disorder caused by
ing 29% of such patients in one study; its etiology is poorly understood homozygosity for haemoglobin S. The sickle cell trait is its milder
but it appears to be unrelated to secondary hyperparathyroidism or heterozygous counterpart in which there is both haemoglobin S and
pulmonary vascular calcification.238 A. The gene is found in Africa and Mediterranean countries. Whenever
The treatment of renal failure introduces further respiratory hazards. oxygen tension drops, haemoglobin S is liable to alter its molecular
The immunosuppression involved in renal transplantation is shape and deform the red blood cell, causing haemolysis and throm-
associated with azathioprine-associated interstitial pneumonitis, bosis. Infarction is widespread and may involve the lungs. Two major
opportunistic infection and posttransplantation lymphoproliferative clinical forms of pulmonary involvement are recognised: an acute
disease, while dialysis has its own detrimental effects on lung func- chest syndrome and sickle cell chronic lung disease. Acute chest syn-
tion. Peritoneal dialysis entails a reduction in diaphragmatic excur- drome is characterised by fever, chest pain and the appearance of new
sions so that a low vital capacity and hypoxaemia are regularly seen radiographic opacities. It represents an acute pulmonary vaso-occlusive
with this form of dialysis. Haemodialysis may be accompanied by crisis leading to acute right ventricular failure and sometimes death.
hypoxaemia, probably because the filters employed activate comple- Histologically, this may mimic veno-occlusive disease by causing
ment and lead to the sequestration of neutrophils in the pulmonary patchy congestion through capillary sludging of the abnormal red
capillaries, as in shock (see Figs 4.20 and 4.21, p. 144). blood cells (Fig. 10.12). Exchange transfusion has been shown to be
effective.261 Chronic lung disease on the other hand is manifest as
Autosomal-dominant polycystic radiographic infiltrates, impaired pulmonary function and, in its most
severe form, pulmonary hypertension.262–264 The pulmonary hyper­
kidney disease tension is due to pulmonary thrombosis (Fig. 10.13).250–255 In severe
The association of bronchiectasis with this renal disorder is described cases there is plexogenic arteriopathy.265,266 Veins as well as arteries
on page 65. thrombose and, when the venous thrombus organises, the appear-
ances are similar to those seen in veno-occlusive disease. Rarely, pneu-
mococcal septicaemia is also seen in sickle cell disease, possibly
Familial Fanconi syndrome because of the splenic infarction that occurs in this condition. Fatal
(renal tubular acidosis) bone marrow embolism is a further occasional complication of sickle
cell disease.259,267
An unexplained association of bilateral diffuse pleural fibrosis has
been described in two siblings with renal tubular acidosis.239
Thalassaemia
Thalassaemia is another serious haemoglobinopathy, in this case
BLOOD DISORDERS caused by persistence of fetal haemoglobin because of a genetic inabil-
ity to form adult haemoglobin A. Again there is haemolysis coupled
Attention here will be concentrated on the respiratory associations of with hypercoaguability of the blood, leading to thrombosis and in­­
diseases that are essentially haematological, although it may be noted farction. Pulmonary hypertension may develop but is not as common
that any lung disease liable to impair oxygenation of the blood as in sickle cell disease.258 Haemosiderin deposition is a prominent
may give rise to secondary polycythaemia while the paraneoplastic pulmonary change and may lead to interstitial fibrosis.258,259,268,269
syndromes associated with lung tumours include conditions such Hypoxaemia is often noted in thalassaemia; this is possibly due to
as red cell aplasia.240 Lymphoproliferative disease is dealt with in arteriovenous anastomoses in the form of ‘spider naevi’ that have been
Chapter 12.4. demonstrated in the periphery of the lung by postmortem injection
techniques in thalassaemia patients that also have cirrhosis, which is
a further complication of this disease.258 Such anastomoses are
Anaemia recorded in the lungs of other patients with liver disease (see below).
Anaemia from any cause is liable to give rise to breathlessness because Mixed sickle cell thalassaemia has led to fatal bone marrow
of impaired oxygen transport, even when cardiorespiratory function embolism.259
is normal. More specific is an association of autoimmune haemolytic
anaemia with idiopathic pulmonary fibrosis.241
Myeloproliferative disease
Myeloproliferative disease may extend from the bone marrow to the
Hypercoaguability
lung, generally involving the pulmonary interstitium. Pulmonary
Hypercoaguability of the blood gives rise to pulmonary thrombo­ involvement in myelofibrosis is seen as interstitial fibrosis
embolism, pulmonary thrombosis and pulmonary infarction, condi- accompanied by foci of extramedullary haemopoiesis.270–272 In rare
tions that are accordingly seen in association with polycythaemia,242 cases there is also air space and vascular involvement leading to
thrombocythaemia,242 myelomatosis, macroglobulinaemia,243 cryo­ pulmonary haemorrhage and pulmonary hypertension.242,273 Thus, in
globulinaemia,244 cryofibrinogenaemia,245 the antiphospholipid syn- diseases such as polycythaemia and thrombocythaemia, pulmonary
drome (see p. 489),246–249 the hypereosinophilic syndrome (see p. hypertension may be the result of either thromboembolism or
467) and haemoglobinopathies such as sickle cell disease,250–255 sphe- plugging of pulmonary blood vessels by haemopoietic cells.242
rocytosis,256 thalassaemia258,259 and paroxysmal nocturnal haemoglob- Leukaemic processes also infiltrate the interstitial compartment of the

483
 Pathology of the Lungs

Figure 10.13  Sickle cell disease. A pulmonary artery shows

recanalisation, following thrombosis.

Figure 10.14  Chronic granulomatous disease. A collection of neutrophils

B is surrounded by epithelioid and giant cells and beyond that chronic
inflammatory granulation tissue. Eosinophils are prominent throughout.
Figure 10.12  Sickle cell disease. (A) In a patient who died of an acute (Courtesy of Dr K Dhaene, Ghent, Belgium.)
vaso-occlusive crisis the lungs show differential congestion similar to that
seen in veno-occlusive disease but here due to sludging of the abnormal
red blood cells (B) rather than postcapillary obstruction.

lung, but generally as a terminal event274: before the lungs are directly and Aspergillus species being particularly implicated.277,278 It is due
involved they are liable to be the seat of opportunistic infection. to a genetic disorder that impairs the production of oxygen metabo-
Alveolar lipóproteinosis is also described (see p. 316). Pulmonary lites by neutrophils, eosinophils and macrophages. Over 400 gene
fibrosis is recorded in occasional patients with human T-cell lympho- defects are recognised, involving both mutations and inactivating
tropic virus type I-associated myelopathy275 and leukaemia.276 The recombinations. They are all recessive and may be either X-linked or
pulmonary effects of treating leukaemia with cytotoxic drugs and by autosomal.
bone marrow transplantation are discussed on page 668. Phagocytic cells lack nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase and ingested microbes are therefore not killed fol-
lowing phagocytosis. Abscesses develop throughout the body in the
Chronic granulomatous disease first year of life, and the lung is only one of many organs affected.
Chronic granulomatous disease is characterised by opportunistic Within the lung, the granulomatosis may affect the lung parenchyma
infections, both bacterial and fungal, with Staphyloccus aureus, Nocardia or be centred on the airways.279,280 Often a balance is arrived at whereby

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 Pulmonary manifestations of systemic disease Chapter | 10 |

viable microbes survive within granulomas composed of lymphocytes

and yellow-brown, foamy macrophages centred on collections of
neutrophils and eosinophils (Fig. 10.14).

Sea-blue histiocytosis
Sea-blue histiocytosis takes its name from the appearance of
macrophages laden with cytoplasmic granules of this colour in
Giemsa-stained preparations. In haematoxylin and eosin-stained sec-
tions the macrophages have an abundant pale, granular cytoplasm.
Such cells are seen in Niemann–Pick disease (see below) and occa-
sionally within the pulmonary interstitium and air spaces in a variety
of acquired haematological disorders, including myelofibrosis.281

Mastocytosis
A
Mastocytosis is a rare disease of uncertain aetiology, characterised by
infiltration and proliferation of mast cells in the skin (urticaria pig-
mentosa), bone marrow, gastrointestinal tract and lymph nodes.
Pulmonary mast cell infiltration is particularly rare.282

IgG4-related systemic sclerosing disease

The term ‘IgG4-related systemic sclerosing disease’ has been applied
to lymphoproliferative lesions found in various sites throughout the
body in association with high serum levels of IgG4.283–285c The lesions
contain abundant IgG4-positive cells, generally accompanying
exuberant fibrous tissue, which progresses to dense hyalinosis.
Idiopathic retroperitoneal fibrosis and sclerosing pancreatitis are
archetypal examples. The lungs have been involved in some cases of
multisystem disease286,287 and in a few instances pulmonary pseudo-
tumours (plasma cell granulomas) have represented the sole evidence
of hyper-IgG4 disease.288,289 Such patients have ranged from 42 to 78
years in age and shown an equal sex distribution. Several were asymp-
tomatic at presentation. Imaging varies from ill-defined infiltrative
lesions to nodular or multifocal opacities. Histology shows varying B
degrees of fibrosis with intense infiltration by lymphocytes, plasma
cells, scattered neutrophils and occasional aggregates of eosinophils
(Fig. 10.15A). Obliterative venulitis and obliterative arteritis
(mimicking lymphomatoid granulomatosis) are common and there
is sometimes a stenosing peribronchiolar infiltrate (see Fig. 10.15B,
C). Immunohistochemistry shows polyclonality and many IgG4-
positive plasma cells, identification of which distinguishes the condi-
tion from its principal mimics, lymphatoid granulomatosis and NSIP.
Most patients have been treated surgically but it is becoming apparent
that the condition responds well to systemic corticosteroids.288,290 The
cases that have been classified as plasma cell granuloma or inflamma-
tory pseudotumour need to be distinguished from inflammatory
myofibroblastic tumour, a further condition to which these terms have
been applied but which is now considered to be neoplastic (see
p. 620). The distinction may be difficult as inflammatory myofibrob-
lastic tumours also contain IgG4-positive plasma cells, as do condi-
tions such as Rosai–Dorfman disease.291 The precise relationship of
the IgG4-related sclerosing disease to various lung disorders requires
further elucidation.
C

Splenectomy Figure 10.15  IgG4 disease. (A) Lung biopsy showing bronchiolocentric
and subpleural consolidation. (B) The infiltrate narrows the airway lumen.
Splenectomy results in lowered immunity, particularly to (C) The infiltrate mainly consists of plasma cells, many of which stain for
pneumococcal infection. Many patients who have lost their spleen IgG4.
have died of pneumococcal pneumonia or septicaemia and all who
have undergone this operation should be offered pneumococcal
immunisation. Splenectomy also appears to be a risk factor for chronic
thromboembolic pulmonary hypertension.292

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 Pathology of the Lungs

Box 10.3  Disorders of the upper alimentary tract Table 10.2  Respiratory associations of inflammatory bowel
associated with aspiration syndromes disease

Dental sepsis Ulcerative Crohn’s

Neuromuscular disease colitis disease
Congenital oesophageal atresia
Congenital tracheo-oesophageal fistula Bronchitis304–310,331,332 + +
Pharyngeal diverticulum Granulomatous bronchitis/ – +
Aplasia of the oesophagus bronchiolitis308,323
Oesophageal stricture Bronchiectasis304,310–312,324,331,332 + +
Hiatus hernia with gastro-oesophageal reflux
Bronchial stenosis 306
+ +
Bronchiolitis 314
+ +
Organising pneumonia 315
+ +
Interstitial pneumonia 314,316–318
+ +
ALIMENTARY TRACT DISORDERS
Pulmonary eosinophilia (drug-related) 325
+ +

Disorders of the upper alimentary tract Pyogenic nodules 309

+ –

A variety of upper alimentary tract disorders may be associated with Necrotising granulomata327 + +
pulmonary disease, chiefly the consequence of aspiration of ingested Amyloidosis319 – +
material or of alimentary tract secretions (Box 10.3). The patient may
be unaware of such aspiration. Otherwise asymptomatic gastro- Apical fibrosis320 + –
oesophageal reflux has been associated with several respiratory disor- Thromboembolism + +
ders.293 Complications of aspiration include chronic cough, asthma,
recurrent infections, aspiration pneumonia, abscess, empyema, bron- Hypoproteinaemic oedema 321
– +
chiectasis, exogenous lipid pneumonia, Mendelson’s syndrome (see Pleurisy + +
p. 145) and chronic interstitial pneumonia and fibrosis.
Antineutrophil cytoplasmic antibody 322
+ –

Coeliac disease
In coeliac disease there is villous atrophy in the small intestine because
Inflammatory bowel disease
of allergy to dietary gluten. Some patients with coeliac disease
experience respiratory problems and it is likely that these are also Pulmonary abnormalities are being increasingly recognised in
based on hypersensitivity. Of particular interest are allergy to avian association with inflammatory bowel disease, both ulcerative colitis
protein and pulmonary haemosiderosis. and Crohn’s disease, but particularly the former.303 A wide variety of
When it was discovered that some patients with coeliac disease and pulmonary associations has now been described (Table 10.2).304–327
respiratory symptoms had serum antibodies against avian antigens,294 Furthermore, it is possible that some patients have subclinical lung
it was naturally assumed that they also had bird fancier’s lung, involvement as bronchoalveolar lavage has shown lymphocytosis in
a form of extrinsic allergic alveolitis (see p. 279). However, further Crohn’s disease patients who are free of pulmonary symptoms.328,329
investigations showed that the antigen concerned was a globulin and Similarly, lung function studies have shown that about 20% of patients
that this was not found in bird droppings, unlike the avian albumin with active bowel disease have a reduced diffusing capacity.330 In a
responsible for bird fancier’s lung.295 The source of the allergen is minority of cases the lung disease precedes that in the bowel.309 Lung
believed to be egg yolk and the allergy probably stems from the inges- disease has also developed many years after the colon has been totally
tion of hens’ eggs rather than the inhalation of bird droppings. removed.
Attempts to establish a link between coeliac disease and other forms The commonest respiratory association of inflammatory bowel
of extrinsic allergic alveolitis such as farmer’s lung296 have proved disease is inflammation of the airways.304-311,331,332 There is a productive
inconclusive. The relationship of the antibodies against avian globulin cough yet the patient is usually a non-smoker.331 Biopsy shows either
to the patients’ respiratory disease is unclear. Increased lung perme- severe non-specific chronic inflammation332 or non-necrotising
ability and reduced gas transfer suggest that there is an alveolitis, but tuberculoid granulomas (Fig. 10.16).308,325,326,333 The appearances have
most histological investigations have been limited to transbronchial been likened to those in the bowel and it is possible that the gut and
biopsies. These are reported to show peribronchiolar fibrosis and the lung are both affected because they share common antigens.
chronic inflammation.297 Radiology has identified bronchiectasis in Progression of the bronchitis to bronchiectasis304,310,311,324,331,332 and tra-
one coeliac patient.298 cheobronchial stenosis306 has been reported, and occasionally the
The second area of interest in coeliac disease is pulmonary airway disease causes acute respiratory failure.334 When inflammatory
haemosiderosis. bowel disease was sought in patients with large-airways disease the
Some patients diagnosed as having idiopathic pulmonary prevalence was found to be four times higher than expected.335
haemosiderosis are found to be suffering from malabsorption associ- Many of these associations listed in Table 10.2 have been reported
ated with jejunal villous atrophy, and some of them improve on in patients under treatment with salazine-type drugs but, except
removing gluten from the diet.299–302 The association appears to be for pulmonary eosinophilia, they are all recorded in patients who
more than coincidental but its basis is unclear. were not under treatment. However, drug effects need to be excluded

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 Pulmonary manifestations of systemic disease Chapter | 10 |

nary hypertension, possibly due to T. whippelii colonizing the

pulmonary arteries.348,351
Lung biopsy shows nodular collections of foam cells surround­
ing the centriacinar bronchioles and arteries and thickening the inter-
lobular septa and pleura. As in the intestine, the foam cells stain
strongly with diastase-controlled periodic acid–Schiff reagents and
electron microscopy shows that they contain numerous bacilli.346

Pneumatosis coli
In this condition there are numerous gas-filled cysts beneath the
mucosa of the colon. It has been associated with emphysema and was
once thought to be due to interstitial emphysema tracking through
the mediastinal and retroperitoneal tissues. However, it is now
A considered that the gas is produced locally by intestinal bacteria and
that the association with emphysema is not a causal one.

Hepatic disease
Pulmonary vascular disease
A number of abnormalities of the pulmonary blood vessels may be
found in association with cirrhosis.352 It is suspected that vasoactive
substances that are normally metabolised in the liver and thereby
prevented from reaching the lungs do so through the portosystemic
anastomoses that develop in cirrhosis. Pulmonary hypertension of the
plexogenic variety (see p. 424) is a particularly serious but rare
complication of cirrhosis associated with portal hypertension.353–357
Hypoxaemia is a commoner finding, often referred to as the hepato­
pulmonary syndrome.358 Although pulmonary arteriovenous anasto-
moses (’spider naevi’) have been demonstrated in such patients,258,359–361
B they are uncommon and a more likely explanation of the syndrome
is that the normal vasoconstrictive response of the lungs to hypoxia
Figure 10.16  Necrotising granulomatous lung disease associated with is inhibited, with consequent ventilation/perfusion mismatching (see
(A) ulcerative colitis and (B) Crohn’s disease. p. 22).362–364

Ascites and pleural effusion

before attributing pulmonary symptoms to the inflammatory bowel
disease. Ascites is common in cirrhosis because of portal hypertension and
hypoproteinaemia and, if the effusion is large, lung volumes are
reduced, resulting in breathlessness. In many patients this is
Whipple’s disease aggravated by a concomitant right-sided pleural effusion, which is
attributable to the pressure difference between the pleural and
Whipple’s disease338 is a rare disorder that was for long considered to
peritoneal cavities drawing fluid into the thorax through
be a storage disorder of uncertain aetiology but is now known to
diaphragmatic defects.
represent infection by the bacilliform bacterium Tropheryma
whippelii.339–341 Patients usually give a long history of polyarthritis and
insidious weight loss due to malabsorption, which later results in
anaemia and diarrhoea.342 Diagnosis is usually by jejunal biopsy, Primary biliary cirrhosis
which shows heavy mucosal infiltration by macrophages distended by The pathological basis of this liver disease is a granulomatous
diastase-resistant periodic acid–Schiff-positive material. Electron destruction of intrahepatic bile ducts and it is therefore noteworthy
microscopy shows that the macrophages contain large numbers that there are reports of pulmonary or multiorgan granulomas similar
of bacilli, which may be identified as T. whippelii by immuno­ to those of sarcoidosis in association with the condition.366–368 Other
histochemistry.341,343 Few inflammatory cells are seen. It is postulated biopsy studies have demonstrated a non-granulomatous lymphocytic
that a cytopathic effect of T. whippelii to plasma cells contributes to infiltrate of either the alveoli369,370 or the airways.371 Sjögren’s syn-
the bacilli evading the local immune response.341,344,345 The condition drome, the pulmonary manifestations of which are described earlier
usually responds to antibiotic treatment.346–348 in this chapter, has also been reported in association with primary
The changes may extend to lymph nodes and other viscera, includ- biliary cirrhosis.372 Interstitial pneumonia is largely confined to those
ing the lungs.346–350 Respiratory symptoms such as breathlessness, patients with primary biliary cirrhosis who also have another autoim-
cough and pleuritic pain may precede the diarrhoea, and, rarely, mune disease, such as systemic sclerosis.370,373 It is possible that many
pulmonary disease may be detected in the absence of intestinal patients with primary biliary cirrhosis have subclinical lung disease as
features.347 Radiographs show pleural thickening and effusion and they have been shown to have a pulmonary lymphocytosis by bron-
patchy pulmonary opacification. Some patients suffer from pulmo- choalveolar lavage.374

487
 Pathology of the Lungs

Hepatitis myomatosis (see p. 293) is clinically evident in only 2.3% of these

patients386 but accounts for 10% of deaths.387 However, radiological
The incidence of hepatitis C virus infection appears to be raised in
scans show clinically silent lung cysts suggestive of lymphangioleio-
idiopathic pulmonary fibrosis, leading to speculation that the
myomatosis in 34–39%.388,389 In an another form of tuberous sclero-
association is causal, although not necessarily direct.375 Autoimmune
sis, which is attributable to mutation of a gene known as TSC2 located
factors are prominent in several forms of hepatitis and some patients
on the short arm of chromosome 16p13.3, more severe lymphangio-
with chronic active hepatitis and non-organ-specific autoantibodies
leiomyomatosis develops and is responsible for most deaths. This
also develop interstitial pneumonia.241,376 Bronchiectasis,377 LIP378 and
form of tuberous sclerosis is not hereditary and is often termed the
pulmonary haemorrhage379 have also been reported in association
sporadic form of pulmonary lymphangioleiomyomatosis. Neither the
with autoimmune hepatitis on occasion.
TSC1 nor the TSC2 gene is carried on a sex chromosome and, indeed,
tuberous sclerosis typically affects both sexes but, with very few excep-
α1-Antitrypsin deficiency tions, whenever there is lymphangioleiomyomatosis the patient is
female, and sexually mature. This is attributed to the lesional cells
This genetic disorder may cause panacinar emphysema (see p. 103) or bearing receptors responsive to normal levels of oestrogen and pro-
cirrhosis. The coexistence of the two conditions in affected patients is gesterone. The protein products of the TSC1 and TSC2 genes are
recorded, but is rare.380 respectively known as hamartin and tuberin. They dimerise to form a
coiled complex that plays a pivotal role in the phosphoinositide sig-
Liver abscess nalling pathway, functioning as an inhibitor of cell growth, prolifera-
tion and differentiation. It is not surprising therefore that mutation
Pyogenic or amoebic abscesses in the liver are prone to spread through of either gene results in increased cell growth.390 Pulmonary lym-
the diaphragm to cause right-sided pleurisy, pneumonia, lung abscess phangioleiomyomatosis is described in full on p. 293.
or hepatobronchial fistula. An even rarer pulmonary manifestation of tuberous sclerosis is the
multifocal micronodular type II pneumocyte hyperplasia described on
page 701. This lesion may be seen alone or in association with
Pancreatic disease pulmonary lymphangioleiomyomatosis but has not been described
The inflammation involved in acute pancreatitis may spread through in patients who do not have the classic (TSC1) form of tuberous
the diaphragm to cause left-sided, or rarely bilateral, pleurisy. Acute sclerosis. Aneurysms of systemic arteries are a rare feature of tuberous
pancreatitis of severe degree causes shock and the clinical and patho- sclerosis and occasionally affect a pulmonary artery.391
logical features of this condition may develop (respectively, adult Angiomyolipomas of the kidney, retroperitoneum and liver are a
respiratory distress syndrome and diffuse alveolar damage).381,382 The further feature of tuberous sclerosis and are found in about half the
pancreas and the lungs may both be involved in IgG4 systemic scleros- women with lymphangioleiomyomatosis.392 A few examples have
ing disease, described above.291 been reported in the lungs (see p. 630), one in a patient with tuberous
sclerosis but not lymphangioleiomyomatosis.393 Renal angiomyo­
lipomas are commoner in women and those associated with tuberous
sclerosis often have progesterone receptors, suggesting that hormonal
NEUROMUSCULAR DISEASE factors are important in their pathogenesis, as in lymphangioleio­
myomatosis.394 The benign clear cell tumour of the lung described on
Neuromuscular diseases secondary to non-metastatic broncho­ page 625 may also develop in patients with tuberous sclerosis.395 The
pulmonary neoplasia (the paraneoplastic neuromuscular syndromes) constituent cells of lymphangioleiomyomatosis, angiomyolipoma
are considered on page 544 and this section will be limited to the and benign clear cell tumour of the lung share an unusual mixed
pulmonary manifestations of neuromuscular disease. Neuromuscular phenotype in that they express both smooth-muscle and melanocyte
disease of varying aetiology may promote pulmonary infection by markers. It is suggested that they derive from certain ‘perivascular
impairing the cough reflex and weakening respiration. Also, there is a epithelioid cells’ and their resultant lesions have therefore been col-
danger of aspiration if swallowing is affected. lectively termed PEComas.396,397

‘Neurogenic’ pulmonary oedema Neurofibromatosis

‘Neurogenic’ pulmonary oedema is a well-recognised feature of Neurofibromatosis is a common disorder of dysregulated tissue
cerebral damage, especially that due to trauma and subarachnoid growth secondary to mutations of the tumour suppressor gene NF1.
haemorrhage. Its pathogenesis is thought to involve widespread One of its many manifestations is pulmonary hypertension, which
adrenergic vasoconstriction resulting in marked systemic hyper­­ has a plexogenic pattern, indicating prolonged vasoconstriction (see
tension.383–385 Fluid then shifts from the systemic circulation to the p. 420).398 Neurofibromatosis is occasionally associated with intersti-
relatively more compliant pulmonary circulation, with a resultant tial lung disease described as pulmonary fibrosis indistinguishable
outpouring of fluid into the lung. pathologically from the variety (idiopathic pulmonary fibrosis).399–403
However, these reports antedate current concepts of disease patterns
in interstitial pneumonia and, although they describe fibrocystic
Tuberous sclerosis
disease, the appearances are not those of UIP. A review of 156 patients
Tuberous sclerosis is a genetic disorder characterised by hamartomas with neurofibromatosis found little evidence to support an association
in multiple tissues. The classic form of the disease is a dominant with parenchymal lung disease and the authors suggested that previ-
hereditary condition caused by mutation of a gene known as TSC1, ous reports may have, in part, represented the effects of smoking.404
which is situated on the long arm of chromosome 9q34. The brain, The thoracic neurofibromas of von Recklinghausen’s disease and their
skin and kidney are chiefly affected. Pulmonary lymphangioleio­ obstructive complications are dealt with on page 640.

488
 Pulmonary manifestations of systemic disease Chapter | 10 |

frequently found in this condition.410–412 Activation of vitamin D nor-

METABOLIC AND ENDOCRINE DISORDERS mally takes place in the kidneys and renal failure may be complicated
by secondary hyperparathyroidism, again leading to hypercalcaemia
and metastatic calcification. Metastatic calcification involving viscera
Obesity takes the form of whitlockite ((CaMg)3(PO4)2), whereas in the soft
Obesity restricts ventilation by the fat splinting the chest wall and tissues it is deposited as hydroxyapatite ((Ca10(PO4)6(OH)2).
buttressing the underside of the diaphragm. This increases the work The lungs, kidneys and stomach are particularly likely to be involved
of breathing and contributes to the common symptom of breath­ in metastatic calcification. Virchow suggested that this was because all
lessness, which may be present at rest but is accentuated by the effort these organs excrete acid and are therefore slightly alkaline.413 In line
of moving an overweight body. In the supine position gas exchange with this is the observation that metastatic calcification may be
is compromised in the lower lobes, resulting in relative hypoxaemia localised to lung tissue beyond an obstructed pulmonary artery, the
in the inferior pulmonary veins.405 Not surprisingly therefore, poor increased ventilation–perfusion ratio there raising the pH.414 Basement
lung function is found in the metabolic syndrome, a complex disorder membranes and elastic fibres are favoured sites of calcium deposition
in which obesity is combined with elevated triglycerides, hyperten- and the walls of blood vessels and alveoli are therefore particularly
sion, hyperglycaemia and insulin resistance.405a,b affected by metastatic calcification.413,415–417 In severe cases every alveo-
A few grossly obese patients have a severely disturbed sleep pattern lar wall is delicately impregnated. The calcium is recognisable in
due to repeated episodes of nocturnal apnoea, attributable to neck fat routine sections due to its affinity for haematoxylin (Fig. 10.17), but
compressing the pharyngeal airway. The resultant daytime som­ if only a little is present the diagnosis may be confirmed with von
nolence is well illustrated by the fat messenger boy Joe described by Kossa’s stain. Not surprisingly, the permeability of the alveolar walls
Charles Dickens in his Pickwick Papers, hence the term ‘pickwickian may be increased; some patients with severe pulmonary involvement
syndrome’ (see p. 93). Further respiratory diseases linked to obesity have died of massive pulmonary oedema.418 Organisation of such
include chronic obstructive pulmonary disease, asthma, thromboem- protein-rich oedema fluid may explain the alveolar fibrosis that some-
bolism and aspiration pneumonia.406,407 times accompanies metastatic calcification. In rare cases the calcifica-
A retrospective autopsy study of 76 obese patients showed a greater tion is confined to the airway mucosa.419
occurrence of diabetes mellitus, systemic hypertension, pulmonary
oedema, haemorrhage and pulmonary hypertensive changes than a
control group. Cardiomegaly with biventricular hypertrophy was
Systemic amyloidosis
found in all obese patients and 72% showed evidence of pulmonary Amyloidosis of the lower respiratory tract may develop as part of
venous hypertension, in 50%. Eight had thrombosed or recanalised generalised amyloidosis or in isolation. The isolated form is dealt with
pulmonary blood vessels but none showed vascular necrosis or plexi- on page 696 and this section deals only with involvement of the lungs
form lesions. The authors attributed the pulmonary venous hyperten- in systemic amyloidosis. Pathological evidence of pulmonary
sion to hypoxia and left ventricular dysfunction.408 involvement is common in all forms of systemic amyloidosis, includ-
ing the rare familial and senile (cardiac) forms420–426a and the α2-
Antiphospholipid syndrome microglobulin-derived amyloidosis that sometimes complicates
long-term haemo­dialysis.423,427 Despite this multiplicity of amyloid
The antiphospholipid syndrome, first described in 1983,114,408a is a types evident pathologically, most patients with respiratory symptoms
systemic autoimmune disorder characterised by venous, arterial and attributable to systemic amyloidosis have primary or myeloma-
capillary thrombosis and raised titres of antiphospholipid antibodies. associated disease. The amyloid is therefore of the light-chain (AL)
It usually occurs in isolation but may be associated with other autoim- type. This is also true of amyloidosis confined to the lungs. The dis-
mune diseases, especially systemic lupus erythematosus (SLE). Up to tinction of localised from systemic amyloidosis is clinically important.
a third of patients with SLE develop secondary antiphospholipid syn- The two forms are distinguished by their organ distribution, as
drome. Young women are mainly affected, the mean age at diagnosis revealed by cardiac echocardiography and serum amyloid protein
being 34 (standard deviation 13) years and the male : female ratio scintigraphy, screening for plasma cell dyscrasias and biopsy.
being 1 : 3.5 for primary disease and 1 : 7 when the syndrome is sec- In primary systemic amyloidosis there is usually a fine diffuse
ondary to SLE. interstitial deposition. Multifocal nodules may develop but the mass
The clinical features of the antiphospholipid syndrome are lesions of localised amyloid are not seen. Microscopy shows a
diverse as the disease may affect any system. The pulmonary effects widespread delicate thickening of the alveolar and vascular walls by
include venous thromboembolism, pulmonary hypertension, micro- an eosinophilic, amorphous deposit (Fig. 10.18). Larger pulmonary
vascular thrombosis (possibly resulting in veno-occlusive disease) and vessels are also involved, in similar fashion to systemic vessels.
alveolar haemorrhage.120,246–249,408b Extrapulmonary features include Electron microscopy shows that the amyloid is preferentially
recurrent fetal loss, pre-eclampsia, transient ischaemic attacks, stroke, deposited in the alveolar epithelial and endothelial basement mem-
non-bacterial thrombotic endocarditis, myocardial infarction, renal branes.425 On occasion there may be prominent pleural involve-
infarction and microangiopathy. Treatment depends mainly upon
anticoagulation.

Hypercalcaemia and metastatic calcification Box 10.4  The causes of hypercalcaemia

The causes of hypercalcaemia include hyperparathyroidism, skeletal Hyperparathyroidism

metastases, tumours secreting a parathormone-like peptide, sar­ Skeletal metastases
coidosis and hypervitaminosis D (Box 10.4). In sarcoidosis the epi- Neoplastic parathormone-like activity
thelioid cells of the granulomas participate in a number of metabolic Sarcoidosis
activities, including the final hydroxylation and hence activation of Hypervitaminosis D
vitamin D,409 thereby accounting for the hypercalcaemia that is so

489
 Pathology of the Lungs

Figure 10.17  Metastatic calcification in a patient with hypercalcaemia.

Heavy deposition of calcium salts renders the alveolar walls basophilic.

ment.428 The alveolar wall thickening is liable to be mistaken for

interstitial fibrosis but the inflammatory component that usually
accompanies such scarring is not a feature and a Congo red stain
should quickly lead to the correct diagnosis. The potassium
permanganate/Congo red reaction conforms to the amyloid being of
the AL type (derived from immunoglobulin)421 and this is supported
by immuno­histochemistry.429,430 If what appears to be amyloid fails to
stain as such, it might represent pulmonary involvement in light-chain
deposition disease, which is considered on page 698.431 Multifocal
nodules of amyloid may stimulate the foreign-body giant cell reaction
that is more characteristic of localised bronchopulmonary amyloido-
sis (see p. 696).
The severity of the pulmonary involvement generally parallels that
in the heart but to a lesser degree.421 It is often an incidental postmor-
tem finding in patients known to have amyloid elsewhere but it may
impair gas transfer and only be discovered when lung biopsy is under-
taken to investigate the cause of abnormal blood gases or, rarely, dys-
pnoea. Pulmonary blood vessels are particularly involved and rarely
this may be so severe as to cause pulmonary hypertension.432,433
B
In secondary (AA-type) amyloidosis, pulmonary involvement is
generally limited to blood vessels and bronchial glands: alveolar walls
Figure 10.18  Systemic amyloidosis. (A) The alveolar walls are slightly
are not affected and there is seldom any clinical evidence of lung
thickened by a diffuse interstitial deposition of amyloid. (B) The media of
disease.420 a pulmonary artery shows deposition of amyloid.

490
 Pulmonary manifestations of systemic disease Chapter | 10 |

Figure 10.19  Fabry’s disease as an example of a lipidosis. Electron

microscopy shows numerous large osmiophilic lamellar inclusions.
Figure 10.20  Gaucher’s disease. The alveoli are filled by macrophages
which have a swollen eosinophilic cytoplasm.
Storage disorders
The storage disorders comprise a wide variety of rare congenital foamy and the features are those of endogenous lipid pneumonia. The
defects. They often involve specific lysosomal enzymes, in which case process also involves ciliated cells but spares the alveolar lining cells
they are generally manifest by the accumulation of the enzyme’s sub- (Fig. 10.21).
strate and deficiency of its reaction product. They are best known by
the chemical character of the substrate and are often grouped under
Ceroidosis and the Hermansky–Pudlak syndrome
terms such as lipidoses, mucopolysaccharidoses and glycogenoses.
The excess substrate is stored in the reticuloendothelial system and The storage disorders seldom affect the lungs in isolation but very
hepatosplenomegaly is a common feature of many storage diseases. occasionally conspicuous pulmonary lipidosis is associated with
The lungs contain many cells of the histiocyte series and pulmonary insignificant systemic involvement. This is seen particularly in patients
involvement is therefore commonly found postmortem. It is seldom with malignant cachexia who develop ceroidosis.447,448 In these cases
troublesome in life but may cause significant morbidity, for example the swollen macrophages contain much brown ceroid pigment. The
in adults with Niemann–Pick disease type B, in which case whole-lung histological appearances simulate those of haemosiderosis but stains
lavage may be successful.434 In the lungs there is an increase in both for iron and ceroid readily distinguish these two conditions.
alveolar and interstitial macrophages, the cytoplasm of which is In contrast to isolated pulmonary involvement, the Hermansky–
swollen due to the accumulation of the indigestible lysosomal sub- Pudlak syndrome is characterised by generalised ceroid storage, which
strate, which in the lipidoses is generally evident on electron micros- is associated with albinism and platelet dysfunction resulting in a
copy as membrane-bound inclusions of osmiophilic, lamellar material bleeding diathesis.449,450 This familial condition, largely confined to
(Fig. 10.19). In the mucopolysaccharidoses the macrophage cyto- Dutch and Puerto Rican patients, is of interest to pulmonologists
plasm is weakly haematoxyphil, and in cystine storage disease free because it is sometimes associated with chronic interstitial pneumo-
crystals can be identified if an alcoholic fixative and polarisers are nitis and fibrosis with honeycombing (Fig. 10.22). The changes are
used. widespread and lack the basal and subpleural predilection seen in
idiopathic pulmonary fibrosis. The fibrosis is maximal around respira-
tory bronchioles and is accompanied by florid foamy swelling of type
Gaucher’s disease II pneumocytes.450–457 The ceroid accumulation is thought to reflect
This lipidosis is characterised by an accumulation of lipid peroxidation, with oxygen radical release during this process
glucosylceramide.435–439 The alveolar macrophage cytoplasm may be being responsible for the pulmonary fibrosis. Identification of the
foamy or finely granular and eosinophilic and the appearances may ceroid from its autofluorescent properties in urinary sediment or
mimic those of desquamative interstitial pneumonia (Fig. buccal scrapings aids the diagnosis.
10.20).434,440,441
Morquio’s disease
Fabry’s disease Morquio’s disease represents a further storage disorder that is
In this lipidosis periodic acid–Schiff-positive laminated inclusion occasionally responsible for respiratory disability. It is due to a defi-
bodies of β-galactoside are found in endothelial cells, alveolar epithe- ciency of galactosamine-6-sulphatase, which leads to a build-up of
lial cells and bronchial muscle,443 sometimes narrowing the airways.444 keratin sulphate. Deposits of this substance may obstruct the upper
Their ultrastructural features are illustrated in Figure 10.19. airways or impair movement of the chest wall.458

Niemann–Pick’s disease Xanthogranulomatosis

This lipidosis is characterised by an accumulation of sphingomyelin This condition is characterised by focal collections of foamy macro-
and cholesterol lipidosis.434,441,442,445,446 The macrophage cytoplasm is phages rich in cholesterol and other lipids. Such deposits are found

491
 Pathology of the Lungs

formula C29H60 or C31H64. Histologically the deposits resemble cho-

lesterol granulomas as they take the form of acicular crystals being
engulfed by macrophages and foreign-body giant cells (Fig. 10.23).

Erdheim–Chester disease
Erdheim–Chester disease is a rare form of generalised histiocytosis
that is chiefly characterised by fibrosis and foam cell infiltration of the
bone marrow resulting in osteosclerosis, particularly of the long bones
of the legs.461–463 Clonality has been reported.464
The sexes are affected equally and the mean age at presentation is
in the sixth decade. Pulmonary involvement is characterised by
dyspnoea of insidious onset or, rarely, acute respiratory failure.
Pulmonary function tests show restricted lung volumes. Imaging
shows diffuse thickening of the interlobular septa and pleurae with
centriacinar nodules.
Microscopically, a fibrosing infiltrate of foamy CD68-positive
reticular cells thickens the interlobular septa, pleura and broncho­
A
vascular bundles but spares the alveolar tissue (Fig. 10.24).465–469
Grouping of the cells may simulate granulomatous disease.466
Diabetes insipidus and pulmonary fibrosis are features that
Erdheim–Chester disease shares with Langerhans cell histio­
cytosis,463,470,471 and occasionally the two diseases are associated.465
However, in Erdheim–Chester disease the infiltrate fails to react for
the Langerhans cell marker CD1a. The osteosclerotic lesions of
Erdheim–Chester disease also differ from the osteolysis seen in
Langerhans cell histiocytosis. Pulmonary involvement generally
augers a poor prognosis,467,468 although one case showed a response
to immunosuppressive therapy.472

Rosai–Dorfman disease
Rosai–Dorfman disease, which is also known as sinus histiocytosis
with massive lymphadenopathy, represents a rare idiopathic, non-
neoplastic proliferation of histiocytes that typically affects children
and young adults.473 It is primarily a disease of lymph nodes,
particularly those in the neck, but extranodal sites are involved in
about a third of cases and the lungs are affected in about 2% of these.
B Pulmonary involvement is thus particularly rare but solitary or mul-
tiple masses may affect the airways or lungs, or there may be diffuse
Figure 10.21  Niemann–Pick disease. (A) The alveoli are filled by pulmonary or pleural infiltration.473–477a The basic fault appears to be
macrophages which have a swollen foamy cytoplasm and some of the hypersecretion of macrophage colony-stimulating factor leading to
macrophages show Touton-type giant cell formation. The appearances monocyte chemotaxis and differentiation, but the underlying cause is
are those of a florid endogenous lipid pneumonia. (B) Bronchiolar unknown.
epithelial cells also have a foamy cytoplasm, in contrast to the type II
Histologically, lymph node sinuses are distended by large numbers
alveolar lining cells seen in (A), which do not.
of histiocytes while pulmonary involvement is characterised by
replacement or infiltration of the tissues by these cells. The histiocytes
in the lung in diabetes mellitus and generalised xanthomatosis.459 have oval nuclei with dispersed chromatin and one or more nucleoli,
Cholesterol pneumonitis is considered further on page 319. and abundant palely staining eosinophilic cytoplasm which reacts for
S-100, CD31 and CD68, but not CD1a. Plasma cells and lymphocytes
are also seen, with the latter often invading the histiocytes by a process
Alkane lipogranulomatosis known as emperipolesis. The plasma cells may react strongly for
Certain indigestible waxes found in the skin of apples and other IgG4.477a The differential diagnosis includes Langerhans cell histiocy-
foodstuffs are absorbed unaltered. The amounts are usually trivial and tosis, Erdheim–Chester disease, Hodgkin’s lymphoma, Gaucher’s
of no importance but persons consuming inordinate amounts of such disease, IgG4 systemic sclerosing disease and mycobacterial infection.
foodstuffs are liable to have these alkane waxes deposited in their Negative staining for CD1a helps to exclude Langerhans cell histiocy-
tissues. One French farmer, for example, was estimated to have con- tosis, while the eosinophils seen in that condition are not a feature of
sumed 5 tons of apples. He was found to have lipogranulomatous Rosai–Dorfman disease, nor is the characteristic osteosclerosis of long
nodules throughout his lungs while being investigated for angina, and bones that is seen in Erdheim–Chester disease, and none of these
after he died of coronary disease similar deposits were identified in other diseases shows the lymphocyte emperipolesis that is character-
many other organs, including the liver, spleen, adrenal glands and istic of Rosai–Dorfman disease.
lymph nodes.460 Mass spectrometry showed the lipid to consist of Cases in which the disease is limited to the lymph nodes usually
straight-line saturated aliphatic hydrocarbons (n-alkanes) with the resolve spontaneously but systemic disease carries a worse prognosis

492
 Pulmonary manifestations of systemic disease Chapter | 10 |

A B

Figure 10.22  Hermansky–Pudlak syndrome. (A) There is widespread interstitial fibrosis and inflammation resembling non-specific interstitial
pneumonia. (B) Higher magnification shows marked vacuolation of the type II pneumocytes (top left) with the interstitial accumulation of pale
histiocytes, occasionally containing golden brown pigment.

Figure 10.23  Alkane lipogranulomatosis. The granulomas consist of Figure 10.24  Erdheim–Chester disease. (A) There is prominent fibrous
macrophages and foreign-body giant cells surrounding alkane crystals, thickening of the interlobular septa. (Courtesy of Dr M Kambouchner, Paris,
which are acicular and resemble those of cholesterol. (Courtesy of Dr France.) (B) At high power, histiocytes and eosinophils are seen. (Courtesy
Duboucher, Paris, France.)
of Dr T Ashcroft, Newcastle-upon-Tyne, UK.)
493
 Pathology of the Lungs

and may prove fatal despite surgery or radiotherapy. Chemotherapy is are several skin conditions that, although not malignant themselves,
ineffective. are sometimes associated with systemic cancer, including broncho­
pulmonary carcinoma. They include the cutaneous consequences
of thrombophlebitis migrans (one of Trousseau’s signs), dermato­
Acromegaly myositis, acanthosis nigricans, arsenical keratoses and several non-
The lungs share in the general visceromegaly seen in acromegaly. metastatic endocrinopathies that elicit changes in the skin, for
Being a disease of adult life, they are affected after development is example, ectopic adrenocorticotrophic hormone secretion and
complete and for this reason the lung enlargement represents an acromegaly.497,498 Lastly, nicotine staining of the fingers should alert
increase in alveolar size rather than number. Acromegalic enlargement the physician to the increased danger of cancer and other lung diseases
of the tongue and laryngeal tissues may cause upper-airway caused by smoking.
obstruction, and pulmonary venous hypertension may stem from
acromegalic cardiomyopathy.
Skin disease associated with
Thyroid disease non-malignant lung disease
A retrosternal goitre may compress the trachea, thyrotoxicosis may Psoriasis may be associated with spondylitis, including that of the
result in pulmonary hypertension secondary to high-output cardiac ankylosing variety, which is sometimes associated with apical lung
failure478 and myxoedema may be associated with pericardial and fibrosis.152 Pemphigoid of the sclerosing variety, also known as benign
pleural transudates479 related to the perivascular deposits of amor- mucous membrane pemphigoid, rarely extends below the larynx but
phous, eosinophilic material that have been described in this disease.480 has caused fatal tracheobronchial obstruction.499 Necrotising tracheo-
bronchitis has also complicated paraneoplastic pemphigus,500 and
Diabetes mellitus pustules similar to those seen in the skin in acute febrile neutrophilic
dermatosis (Sweet’s syndrome) have been described in the bronchial
Lung function is impaired in diabetes mellitus because of autonomic mucosa and lung in patients with this disease.501–503 Pulmonary
neuropathy and pulmonary microangiopathy. The former is probably manifestations of pyoderma gangrenosa are rare but multiple nodules
responsible for diminished ventilatory responses to hypoxaemia and showing aseptic necrosis are recorded,504 similar to those occasionally
hypercapnia, and the latter for a mild reduction in diffusing capacity seen in the lungs in inflammatory bowel disease (see above).309
and pulmonary capillary blood volume.481,482 Changes within the Cutis laxa and Ehlers–Danlos syndrome sometimes involve the lungs,
lungs develop independently of those attributable to diabetes in other as described on page 482. Other diseases manifest in both the skin
organs. and lungs, which are also described elsewhere, include tuberous sclerosis
No dramatic morphological changes are evident in the lungs in (p. 488), various vasculitides (p. 437), systemic sclerosis (p. 476), rheu-
diabetes but microangiopathy similar to that observed elsewhere in matoid disease (p. 473), Langerhans cell histiocytosis (p. 288), sarcoidosis
the body has been reported – principally thickening of the alveolar (p. 283) and the Birt–Hogg–Dubé syndrome, which is described
capillary and epithelial basement membranes.483–487 Micronodular next. Erythema multiforme may be a manifestation of sarcoidosis or
fibrosis of alveolar walls is a rarely reported phenomenon.488 changing immunity to tuberculosis and a variety of infections may
Occasional perivascular xanthogranulomatous deposits have also be common to the skin and lungs. Lastly, drug reactions developing
been identified.459 during the treatment of many lung diseases may be first evident in
Similar basement membrane and connective tissue alterations have the skin.
been described in laboratory animals rendered diabetic with alloxan
or streptozotocin,489–493 together with impairment of lung growth in
young animals491: insulin treatment prevented all these changes.
Birt–Hogg–Dubé syndrome
Diabetes mellitus predisposes to infection and confers an increased
risk of bronchitis, bronchiectasis, pneumonia, pulmonary tuber­ This rare familial condition is characterised by multiple benign skin
culosis and fungal lung disease. tumours, a variety of renal tumours and pulmonary cysts.505 The
mutant gene is an autosomal dominant that has been mapped
to 17p12q11.2 and the normal gene product, which is possibly a
Hypovitaminosis A tumour suppressor, has been named folliculin after the cutaneous
Vitamin A is essential to the integrity of the respiratory mucosa. fibrofolliculomas that characterise the syndrome.506 The pulmonary
Deficiency leads to squamous metaplasia.494 This has led to proposals cysts generally measure no more than a few millimetres in diameter
that hypovitaminosis A is a cofactor promoting the development of but they are thin-walled and liable to rupture into the pleural cavity,
lung cancer. Extensive trials of vitamin A and carotene supplemen­ resulting in pneumothorax, often in adult life. This appears to be
tation have consequently been conducted, but these have failed to the only clinical effect of the lung cysts of any consequence and
show that these dietary measures have any effect on the incidence of indeed may be the only manifestation of the mutation as this
lung cancer.495,496 abnormality has now been identified in patients with familial
pneumothorax who do not have the skin lesions and renal tumours
of the complete syndrome,507–509 in which case the non-apical location
of the cysts may suggest the diagnosis.510 Histology shows that the
SKIN DISEASE cysts are closely associated with the peripheral interlobular
septa, often at a septopleural junction. They are lined by cuboidal
Cutaneous manifestations of malignant epithelium resting on delicate connective tissue, devoid of muscle
(Fig. 10.25).510,511 Significant mortality attaches to the syndrome,
lung disease chiefly due to the development of renal cell carcinoma and for
Apart from skin metastases and infections of the skin secondary to this reason annual abdominal computed tomography scans are
impaired host defence consequent upon disseminated cancer, there recommended.

494
 Pulmonary manifestations of systemic disease Chapter | 10 |

Figure 10.25  Birt–Hogg–Dubé syndrome. Microscopy shows a small cyst

that is intimately involved with an interlobular septum, although
immunocytochemistry shows that it is lined by epithelial cells and
represents an expanded air space. (Cytokeratin immunostain courtesy of Dr K
Hiroshima, Chiba, Japan.)

GYNAECOLOGICAL AND
OBSTETRIC CONDITIONS

Meigs’ syndrome
Meigs’ syndrome consists of a pleural effusion associated with ascites
and a pelvic neoplasm, removal of which results in resolution of both
effusions.512,513 The ascitic fluid is thought to spread to the pleural
space through small apertures in the diaphragm. The effusion is right-
sided in 70% of cases, bilateral in 20% and left-sided in 10%. The Figure 10.26  Pleural endometriosis comprising both endometrial glands
pelvic tumour is usually an ovarian fibroma but ovarian cysts and and endometrial stroma. (Courtesy of Dr M Neyra, Lyons, France.)
uterine fibroids have also been responsible.514

Pregnancy to transdiaphragmatic spread of pelvic endometriosis, whereas embo-

lism is the probable explanation of the parenchymal lesions. The
Increased levels of progesterone result in an increased respiratory drive clinical effects of pleural and pulmonary endometriosis also differ,
from the early weeks of pregnancy while in the third trimester the except that either may first be identified coincidentally as an asymp-
mechanical effects of the enlarging uterus may cause breathlessness. tomatic tumour.
Successful deliveries have been achieved despite severe lung disease Pleural endometriosis is usually characterised by catamenial pneu-
but pulmonary hypertension may deteriorate during pregnancy. mothorax,519–521 and occasionally by catamenial haemothorax,522 both
Accelerated lung transplant rejection is also recorded during preg- of which are almost always limited to the right side. Serosal metaplasia
nancy.515 Complications of pregnancy that may have an adverse affect is a possible explanation but many cases have pelvic endometriosis,
on the lungs include uterine haemorrhage and infection, either of congenital diaphragmatic perforations and multiple endometriotic
which may result in ‘shock lung’, and eclampsia, which is sometimes implants on both the visceral and the parietal pleura and in these,
associated with pulmonary oedema.516,517 The incidence of throm- transdiaphragmatic spread of pelvic endometriosis seems likely. The
boembolism is also increased in pregnancy. Embolism of amniotic almost universal limitation of the disease to the right side is attributed
fluid, trophoblast and decidua is considered on page 410. to diaphragmatic fenestrations preponderating on that side.523
Pneumothorax secondary to pneumoperitoneum, and haemothorax
secondary to haemoperitoneum are also largely limited to the right,
Thoracic endometriosis
as is the pleural effusion of Meigs’ syndrome (see above).523 Many
Thoracic endometriosis generally affects the pleura and subpleural small diaphragmatic fenestrae must go unnoticed but a complicating
lung tissue but occasionally the process appears to be entirely intra­ factor is that some diaphragmatic perforations may be secondary to
pulmonary.518 The mechanisms underlying pleural and pulmonary endometriotic implants.523
endometriosis differ but proffered explanations are not entirely satis- Intrapulmonary endometriosis is even rarer than the pleural
factory. Pleural deposits may represent serosal metaplasia or be due variety.524–526 It is typically characterised by catamenial haemoptysis,

495
 Pathology of the Lungs

affects either or both lungs and is seldom associated with pelvic well circumscribed or infiltrative, nodular, cystic or nodulocystic.
endometriosis.526 On the other hand, there is a strong association with Rarely the disease may be predominantly endobronchial.530,531 The
gynaecological surgery,526 suggesting that blood-borne endometrial heterotopic tissue consists of both stroma and glands and reproduces
seeding of the lung following uterine instrumentation or parturition the appearances of normal endometrium in every way (Fig. 10.26).
is responsible. This is supported by animal experiments in which Decidual change takes place in pregnancy532,533 and cyclic haemor-
intravenously injected endometrial tissue migrated from pulmonary rhagic disruption, with consequent haemosiderosis, may obscure the
blood vessels into the lung substance where it remained viable and nature of the tissue, in which case immunocytochemistry may be used
underwent cyclic change.527 to demonstrate oestrogen and progesterone receptors and in the
Whatever its pathogenesis, thoracic endometriosis is similar in its stromal component CD10.534 The ectopic tissue also responds to
age distribution (23–45 years) and pathological appearance to that steroid derivatives that suppress gonadotrophin release526 and this has
encountered more commonly elsewhere. CT findings include irregular proved successful therapeutically.518,535 Others prefer local surgical
opacities, nodular lesions, cystic change and bulla formation.528,529 resection to avoid the side-effects of hormonal therapy.536 Pleural
Magnetic resonance imaging is also useful as it highlights changes abrasion is reported to be superior to hormonal treatment in the
related to bleeding.530 Grossly, lesions may be single or multifocal, management of pneumothorax.535

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507
 Chapter 11 

Lung transplantation
Revised by Margaret Burke and Alexandra Rice

use of live donors, easing of donor selection criteria and ex vivo

CHAPTER CONTENTS
techniques to recondition lungs of marginal viability.2,3About 2% of
Types of lung transplant 509 lung transplants are repeat operations, performed because of graft
Recipient selection 510 failure. Patients receiving lung transplants have ranged from infants
to the elderly, with the peak age being about 50 years. The principal
Donor matching 510
conditions treated by lung transplantation in adults have been
Immunosuppression 511 chronic obstructive pulmonary disease/emphysema (36%), idiopathic
Recipient monitoring 511 pulmonary fibrosis (21%), cystic fibrosis (16%), α1-antitrypsin defi-
Role of the histopathologist 511 ciency (7%) and primary pulmonary hypertension (4%). The remain-
der include sarcoidosis, lymphangioleiomyomatosis, connective tissue
Complications 511
disease and, rarely, lung cancer.4 The commonest indication for
Perioperative allograft injury 512 lung transplantation in adolescents is cystic fibrosis and in children
Complications involving the airway anastomosis 512 congenital heart disease.5
Complications involving the vascular anastomosis 512
Rejection 514
Infection 520 TYPES OF LUNG TRANSPLANT
Aspiration 521
Neoplasia 521 Combined heart and lung transplantation, which was first performed
Posttransplantation lymphoproliferative disorders 521 in 1981, was followed by single-lung transplantation, then double-
lung transplantation, and lastly sequential bilateral lung transplant­
Graft-versus-host disease 522
ation. The combined operation requires total cardiopulmonary bypass
Recurrent disease in the allograft 523 and if successful carries a risk of accelerated coronary atheroma and
Drug injury 523 problems resulting from cardiac denervation. However, it is relatively
Future prospects 523 simple technically, maintains coronary–tracheobronchial arterial
anastomoses that help the tracheal anastomosis to heal, and is par-
References 524
ticularly suitable when both heart and lungs are damaged, as in pul-
monary hypertension. In cystic fibrosis, it is necessary to replace both
lungs to avoid the risk of spillover infection. Double-lung transplant­
Human lung transplantation was first performed in 1963 but few ation is a complex procedure but was initially used in emphysema
patients survived and the operation was largely abandoned until the because it was feared that with single-lung transplantation the native
advent of ciclosporin and the development of combined heart and diseased lung would be preferentially ventilated. This proved not to
lung transplantation nearly 20 years later. Today over 30 000 lung be the case and single-lung transplantation is now widely used for
transplants have been performed and the procedure is firmly estab- both severe emphysema and pulmonary fibrosis. It is the commonest
lished amongst the therapeutic options available for patients with procedure, the simplest to perform, is associated with the fewest
severe lung disease.1 Donor shortage is the main factor limiting its postoperative complications, requires the least amount of donor
application and this drives the search for new strategies to increase tissue and enables the greatest number of recipients to benefit from a
the number of lungs available for transplantation. These include the single donor.6

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00011-2 509
 Pathology of the Lungs

100
α-1 antitrypsin (N=2,085) CF (N=3,746) COPD (N=8,812)
IPF (N=4,695)) Pulmonary hypertension Sarcoidosis (N=597)
(N=1,065)

75
Survival (%)

50

50% survival
α-1 antitrypsin: 6.1 years
25 CF: 7.0 years
COPD: 5.1 years
IPF: 4.3 years
Pulmonary hypertension: 5.6 years
Sarcoidosis: 5.3 years
0
0 1 2 3 4 5 6 7 8 9 10 11 12

Years
Figure 11.1  Adult lung transplantation: actuarial survival by diagnosis.4 CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; IPF, idiopathic
pulmonary fibrosis; PH, pulmonary hypertension.

Except for bronchial artery revascularisation, which is undertaken because of the immunosuppression and therefore militates against
in only a few centres, no attempt is made to reanastomose the severed successful transplantation. An aspergilloma is a contraindication to
tracheal or bronchial blood vessels and nerves in any of these any form of lung transplantation as its attempted removal inevitably
operations, or the lymphatics, which are also severed if the heart leads to seeding of the pleural cavity and mediastinum. Previous
is not included. Loss of these structures promotes postoperative thoracic surgery may make it difficult to operate and the possibility
haemorrhage, breakdown of the tracheal or bronchial anastomosis, a of a future lung transplant should therefore be borne in mind when
reduction in the cough reflex and pulmonary oedema. A further considering the best treatment for conditions such as pneumothorax.
aspect of lung transplantation is that some lymphatic tissue is inevi- Left ventricular function should be normal or near normal, although
tably included in the allograft, entailing a risk of graft-versus-host treatable coronary artery disease is not an absolute contraindication.
disease. This is greatest when the whole mediastinum is transferred, Ventilator support prior to transplantation is a significant risk factor.7
as in combined heart and lung transplantation, but in practice it is Pulmonary neoplasia is generally regarded as a contraindication
a rare complication. because of its early dissemination but bronchioloalveolar carcinoma
The mortality associated with lung transplantation is constantly (now termed adenocarcinoma-in-situ) is often limited to the lungs
diminishing as techniques and immunosuppression improve. In 2009 and double-lung transplantation has been employed to treat this form
the International Society of Heart–Lung Transplantation reported sur- of lung cancer.8 Contraindications of less importance include age over
vival rates of 79%, 52% and 29% at 1, 5 and 10 years respectively for 65 years and body mass index over 30.
lung transplantation and 64%, 41% and 26% at the same periods for In the USA, priority is given to those patients with rapidly pro­
combined heart–lung transplantation (Fig. 11.1).4 In the first postop- gressive conditions such as idiopathic pulmonary fibrosis and who are
erative month mortality is chiefly due to sepsis, haemorrhage and in most need of a lung transplant. This is achieved with a numerical
poor lung preservation. After the first month the principal causes scoring system that takes into account the probability and duration
of death are infection and rejection in the form of obliterative of survival without a transplant as compared to that following trans-
bronchiolitis. plantation. The system, which was introduced in 2005, has resulted
in increased numbers of patients with idiopathic pulmonary fibrosis
receiving transplants and a decrease in both waiting-list mortality and
waiting-list time.9,10 However, a high score predicts increased morbid-
RECIPIENT SELECTION ity and mortality following transplantation, reflecting the poor clinical
condition of many of the patients transplanted.11,12 Such a system has
Lung transplantation is an operation of last resort. There are insuf­ yet to be widely adopted: in the UK organs are currently allocated on
ficient donors and patients are unlikely to be considered unless other the basis of proximity and time on the waiting list.
measures have failed and their short-term prognosis is otherwise poor.
The presence of uncontrolled systemic disease precludes consideration
and good renal and hepatic function is essential, particularly in view
of immunosuppressant drug toxicity. This is particularly important in DONOR MATCHING
α1-antitrypsin deficiency and cystic fibrosis, both of which may affect
the liver directly. Any infection that cannot be eliminated, either The selection and management of donors and preservation of the
before or by the operation, is likely to disseminate postoperatively harvested lung are crucial to reducing the impact of brainstem death

510
 Lung transplantation Chapter | 11 |

on the lung and minimising reimplantation injury. Brainstem death

leads to adrenergic systemic hypertension, which results in fluid Box 11.1  The role of the histopathologist in lung
shifting to the lesser circulation and neurogenic pulmonary oedema. transplantation
Such injury is part of a generalised release of cytokines and other Diagnosis of the underlying disease before transplantation
inflammatory mediators that damage many organs, including the
Examination of the explanted lung to verify the diagnosis and identify
lungs, where it may compound the other causes of injury, so that only
any other diseases
about 20% of donated cadaver lungs can be used.13
Examination of any unused donor tissue
Current donor selection criteria include age less than 65 years, ABO
Biopsy assessment of posttransplant complications
compatability, a clear chest X-ray, no airway mucosal inflammation at
bronchoscopy and no history of lung contusion, severe chest trauma, Postmortem examination
previous cardiopulmonary surgery or aspiration.14 Donor sero­ As well as contributing to the outcome of the transplantation, the
positivity for cytomegalovirus is dangerous in a seronegative recipi- histopathologist is well placed to undertake collaborative research.
ent.7 Persistent hepatitis B and C antigenaemia and human
immunodeficiency virus infection are further contraindications.
However mild asthma and smoking do not adversely affect outcome.15 endomyocardial biopsies provide an unreliable guide to pulmonary
Physiotherapy, bronchial toilet, prophylactic antibiotics as required rejection.
and monitoring of blood gases and pulmonary wedge pressure are all
important in managing a potential donor. Harvested lungs are best
stored inflated, cooled and flushed through the pulmonary artery with
Euro-Collins solution. Ischaemia is tolerated for up to 8 hours.14 ROLE OF THE HISTOPATHOLOGIST
Donor–recipient matching includes an approximate similarity in
chest size, although volume reduction surgery may circumvent this if Histopathology plays a major role in assessing the postoperative com-
there is a significant mismatch. One lobe of an adult’s lung may be plications of transplantation, but can contribute more than this to the
used to replace a whole lung of a child.16 Tissue transplanted into a management of transplant recipients, both before and after the opera-
child grows at a normal rate.17 tion (Box 11.1).19,20 An accurate preoperative diagnosis is important
Potential recipients are screened for donor-specific lymphocytoxic because histopathological reassessment of the potential recipient may
antibodies against a panel of HLA-A, -B and -DR antigens.17a The result affect the choice of transplantation procedure and identify conditions
is considered positive if the recipient’s serum reacts to more than 10% treatable by other means or that need to be eradicated before trans-
of the HLA antigens in the panel, in which case donor-specific T- and plantation is undertaken. It may also predict the presence of systemic
B-lymphocytotoxic antibody cross-matching is required. A positive disease and the likelihood of the original disease recurring in the
result here contraindicates transplantation from that donor as it is allograft, or detect malignant disease, which apart from bronchiolo­
associated with accelerated graft rejection.18 alveolar carcinoma (now adenocarcinoma-in-situ) is an absolute con-
traindication to transplantation. Explanted lungs should also be
examined, and without delay, in case they show unsuspected diseases
such as tuberculosis, sarcoidosis or malignancy that may be active
IMMUNOSUPPRESSION elsewhere in the recipient.21 A major discrepancy between the pre-
transplant diagnosis and that apparent on examining the explant has
The recipient’s immunity is suppressed with a combination of been reported in up to 10% of cases.22 Similarly, if only one donor
ciclosporin, azathiaprine and prednisolone with backup provided by lung is used, the other should be examined as this may identify unsus-
immunosuppressive drugs such as tacrolimus, mycophenolate mofetil, pected infection or other disease that is likely also to be present in the
everolimus and sirolimus. All these drugs have side-effects, notably graft. Thus, histopathologists should not be concerned solely in
renal, hepatic and bone marrow toxicity and an increased risk of assessing complications, but this is undoubtedly their major role and
neoplasia. Antithymocyte globulin is now seldom used and cyclo- the rest of this chapter will be largely confined to this aspect of
phosphamide and plasmaphoresis are reserved for use in antibody- transplantation.
mediated rejection. Low-dose Septrin is administered prophylactically
against Pneumocystis infection.
COMPLICATIONS

To assess complications, at least five pieces of alveolated lung should

RECIPIENT MONITORING be examined at a minimum of three levels each, using connective
tissue and fungal stains in addition to haematoxylin and eosin.
Frequent monitoring of the lung transplant recipient is essential in Because sequential sampling is common, the possibility of observed
the first 6 months after transplantation when the risk of the main abnormalities being due to previous biopsies always has to be con­
complications, acute rejection and infection, is greatest. Recipients sidered. It is also important to remember that some patterns of lung
undergo frequent clinical review and bronchoscopy is undertaken in injury are non-specific. For example, diffuse alveolar damage may
response to symptoms, radiographic changes, unexplained fever or a reflect severe reperfusion injury, infection or acute rejection. It may
sudden deterioration in lung function. Both bronchoalveolar lavage require special stains for infective agents and a consideration of the
and transbronchial biopsy are generally performed. Lavage is particu- timing of events to distinguish these causes. There may be both
larly useful for detecting infection while transbronchial lung biopsy, rejection and infection and as their histological features overlap the
despite a false-negative rate of about 20%, is the mainstay in the biopsy findings should always be interpreted in the light of the clinical
diagnosis of allograft rejection. Some centres schedule their biopsies and radiological features, previous biopsy findings and results of
whereas others only biopsy as symptoms dictate. Rejection of the current microbiological and serological investigations. The principal
heart in combined heart and lung transplant recipients is rare and complications are listed in Box 11.2 and will now be considered.

511
 Pathology of the Lungs

Box 11.2  Complications of lung transplantation

• Postoperative
– Haemorrhage and other surgical complications
– Reimplantation syndrome
– Diffuse alveolar damage
• Early and late airway complications
– Anastomotic dehiscence, granulation tissue overgrowth
– Bronchial stenosis, chondromalacia, ectasia
• Rejection
• Infection
• Neoplasia
• Posttransplantation lymphoproliferative disorders
• Graft-versus-host disease
• Recurrence of the underlying disease
• Drug effects

Perioperative allograft injury

Even if the operation goes well and there are no surgical complica-
tions, the early postoperative period is often marked by a temporary
period of dyspnoea. Chest radiographs at this time often show hilar
opacification and if biopsy is undertaken this generally shows pulmo-
nary oedema accompanied by a mild neutrophil exudate (Fig. 11.2).23
These changes, termed reimplantation injury, are variously attributed
to deterioration of the graft, surgical trauma, ischaemia, severance of
the pulmonary lymphatics and the release of free radicals and
chemokines from neutrophils interacting with the graft endothelium
damaged by ischaemia.24 They usually appear within 48 hours and
peak at day 4, slowly settling as lymphatics regenerate and lung
drainage is re-established.
More severe changes include those of diffuse alveolar damage, to
which the term ‘primary graft failure’ has been applied.25 This may
represent a reimplantation response, rejection or infection or occur
for no obvious cause. The risk factors include those relating to the
donor (advanced age, smoking history, prolonged ventilation and B
duration of ischaemia), the recipient (transplantation for pulmonary
hypertension and pulmonary fibrosis) and the operation (cardio­ Figure 11.2  Reimplantation injury presenting as (A) hazy shadowing of
pulmonary bypass and excessive use of blood products).26 Primary left donor lung 3 days after single-lung transplantation for emphysema;
graft failure may progress to parenchymal fibrosis. It is associated with (B) biopsy shows focal interstitial oedema, subacute inflammation,
reduced survival at 1 year.27 pneumocyte hyperplasia and aggregates of alveolar macrophages.
Airway infection promoted by slow recovery of mucociliary
clearance may also complicate the early postoperative period,28,29 is fortunately now rare. More common is the development of ex­­
while alveolar proteinosis and an unusual neutrophil-rich pattern of uberant granulation tissue. This may seriously narrow the airway and
mixed interstitial pneumonitis have also been described.30,31 require endoscopic removal or cryotherapy.35 Late airway com­
plications include stenosis and bronchomalacia (Figs 11.3 and 11.4),
requiring the insertion of stents.36
Complications involving the
airway anastomosis
Complications involving the
Apart from the combined heart–lung procedure, lung transplantation
vascular anastomosis
inevitably involves severance of the tracheobronchial blood supply so
that the donor airway receives only retrograde pulmonary arterial Postoperative obstruction of the pulmonary artery anastomosis is rare
blood until new bronchial arterial anastomoses develop. It is not but kinking may occur when the vessels are long. This usually
surprising therefore that poor healing at the airway anastomosis has develops in the first week. It may be diagnosed by ventilation/
been a serious complication, although bronchial artery revascularisa- perfusion scan or arteriography. Venous obstruction may also develop
tion, performed at a few centres at the time of transplantation, have early after transplantation, especially when size mismatch leads to
rendered it less common.32,33 The anastomosis is also subject to torsion of a small donor lung on its vascular pedicle. The result may
infection until the surface epithelium heals and mucociliary clearance be thrombosis of one or more of the pulmonary veins with infarction
recovers.29 Denervation contributes to the risk of infection by elimi- of the corresponding lobe (Fig. 11.5).37–39 Systemic embolisation
nating the cough reflex and promoting aspiration.34 Dehiscence of the may also occur if the thrombus extends into the left atrium and frag-
airway anastomosis is a devastating early complication, but one that ments. Diagnosis is by transoesophageal echocardiography.38,40 Early

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Figure 11.3  Tracheal stenosis following double-lung transplantation.

Figure 11.4  Bronchomalacia. There is erosion of the limiting plate of the
bronchial cartilage.

A B

Figure 11.5  (A) Thrombosis of pulmonary vein to left lower lobe following torsion of the vascular pedicle resulting in (B) infarction of the entire
lower lobe.

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 Pathology of the Lungs

recognition of this potentially catastrophic complication is essential along vessel walls and in alveolar spaces, and by a strongly positive
if early surgical intervention with salvage of the graft (and patient) is IgG-mediated lymphocytotoxic reaction to donor T and/or B
to be achieved. lymphocytes.46,47

Rejection Acute allograft rejection

The mechanisms underlying lung allograft rejection are not fully Acute rejection is characterised clinically by dyspnoea, fever,
understood but the process is probably initiated by T-cell recognition hypoxaemia and pleuropulmonary opacification (Fig. 11.7). It is most
of histocompatibility antigens on the surface of donor cells.41 The frequent in the first postoperative year, typically developing within
brunt of the rejection damage is on the blood vessels and airways, a few months of the operation but sometimes within a few weeks
presumably reflecting the increased expression of histocompatibility or several years later.
antigens by the pulmonary vascular endothelium and airway epithe- Acute and chronic rejection are classified and graded according to
lium that has been shown to follow transplantation.41 Incompatibility internationally agreed histological criteria (Box 11.3).48 Acute rejection
is followed by the activation and sequestration of platelets, neutrophils may be centred on the blood vessels or the airways but predominantly
and macrophages within the pulmonary capillaries, the release of affects the former and the surrounding lung parenchyma. The vascular
reactive oxygen species and inflammatory cytokines, and increased changes (class A) are treated separately from those involving the
expression of endothelin and inducible nitric oxide synthase.42–44 airways (class B) because the latter may also reflect chronic infection,
The rejection process probably involves both antibody and cell- ischaemia, aspiration or chronic rejection.28,34,49,50
mediated immune mechanisms but the extent to which these each Histologically, the vascular changes are characterised by an infiltrate
contribute varies: hyperacute rejection is generally regarded as being of variable intensity comprising small lymphocytes, plasma cells, his-
antibody-mediated whereas acute and chronic rejection are thought to tiocytes and occasional neutrophils surrounding small blood vessels
be predominantly cell-mediated. and infiltrating the adjacent alveolar interstitium. They are graded as
minimal (grade A1) if they can hardly be discerned without high
magnification and mild (grade A2) if they are just evident at low
Hyperacute allograft rejection magnification and consist of an infiltrate that includes large activated
Hyperacute rejection occurs within 48 hours of transplantation and lymphocytes with pyroninophilic cytoplasm and angulated nuclei.
is caused by the reaction of preformed antibodies to donor endo­ Neutrophils and eosinophils are also seen and there is infiltration
thelial cells. It is characterised by marked congestion and oedema, of the vascular intima (lymphocytic intimitis or endothelialitis).
resulting in the production of copious frothy blood-stained fluid Endothelial cells show hyperplasia. Moderate acute rejection (grade
from the bronchial orifice of the allograft. Risk factors include A3) is characterised by extension of the infiltrate into the alveolar
multiple blood transfusions, pregnancy, surgery and previous trans- interstitium, while in severe (grade A4) acute rejection, which is
plantation, any of which necessitates donor-specific pretransplant usually fatal, the infiltrate is widespread and accompanied by haemor-
T- and B-lymphocytotoxic antibody cross-matching (see above). rhagic oedema, increased numbers of alveolar macrophages, fibrinous
Microscopy shows marked pulmonary congestion and oedema, exudates, hyaline membranes and destructive changes typical of
alveolar haemorrhage, vascular thrombosis, neutrophil infiltration,
endothelial and epithelial damage, and ultimately diffuse alveolar
damage (Fig. 11.6). The diagnosis is confirmed by the detection by
immunofluorescence of C4d complement split product (as a marker
of complement activation) and IgG deposition on endothelium,

Figure 11.6  Hyperacute rejection. Neutrophils engorge the blood vessels

and have passed into the alveolar interstitium and lumen. The patient
died during the operation. Panel-reactive antibodies were positive and a Figure 11.7  Chest radiograph in acute rejection showing opacification of
donor-specific lymphocytotoxic cross-match was strongly positive for T the lower zone of the right lung, which was transplanted because of
and B lymphocytes. emphysema.

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Box 11.3  Revised working formulation for the classification and grading of pulmonary allograft rejection48
A Acute rejection C Chronic airway rejection – bronchiolitis obliterans
Grade 0  None 0  Absent
1  Minimal 1  Present
2  Mild D Chronic vascular rejection – accelerated graft vascular sclerosis
3  Moderate
4  Severe
B Airway inflammation – lymphocytic bronchitis/bronchiolitis
Grade 0  None
1R  Low-grade
2R  High-grade
BX  Ungradable (sampling problems, infection, tangential
sectioning)

A and B may coexist, as may C and D

A B

C D

Figure 11.8  Acute parenchymal rejection. (A) Grade A1 (minimal) changes are not discernible at low magnification but high power shows a sparse
perivascular lymphoid infiltrate. (B) Grade A2 (mild) shows a more marked infiltrate but this is still restricted to the vessels and the alveolar septa are
spared. (C) Grade A3 (moderate) acute rejection showing spread of the infiltrate into surrounding alveolar septa. (D) Grade A4 (severe) acute rejection
is characterised by diffuse alveolar damage and a dense perivascular lymphoid infiltrate.

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 Pathology of the Lungs

A B

C D

Figure 11.9  Immunohistology of acute lung allograft rejection. The perivascular infiltrate stained by haematoxylin and eosin in (A) expresses the
T-cell marker CD3 (B) and the proliferation marker Kiel-67 (C) while class II HLA-DR antigens are strongly expressed by alveolar epithelium and
macrophages (D).

diffuse alveolar damage (Fig. 11.8). Grade A3 and A4 rejection may nosed and graded in the absence of infection.48 The opportunistic
also be associated with organising pneumonia.49,51–53 With successful infections may be viral, particularly herpes simplex and cytomegalo-
suppression of the rejection, follow-up biopsies show a reduction in virus, the distinctive inclusions of which may be modified by prior
the infiltrate (termed resolving rejection/lower grade) and a change in antiviral treatment and therefore difficult to identify (Fig. 11.10).59
its makeup to a mixture of small lymphocytes and haemosiderin- However, the infiltrates of a viral infection are generally more exten-
laden macrophages (termed resolved rejection or grade A0).54 sive and the pattern is predominantly that of an interstitial pneumo-
Immunohistochemistry shows that the majority of the lymphoid nitis with secondary involvement of vessels.59 Perivascular lymphoid
cells are CD8-suppressor lymphocytes (Fig. 11.9).55 They are often infiltrates may also be seen in Pneumocystis jirovecii pneumonia.60 and
pyroninophilic and may express the lymphocyte activation antigen in other fungal and bacterial infections, necessitating special stains,
CD30 and the proliferation antigen Ki-67. B lymphocytes are usually and in difficult cases immunocytochemistry and in situ hybridisa-
sparse; larger numbers may reflect rejection based on humoral rather tion.61,62 Eosinophilic pneumonia is an uncommon manifestation of
than cellular mechanisms and therefore predict a poor response to the graft rejection and, before accepting it as such, infection by organisms
usual cell-based immunosuppressive regimes.56 However, their pres- such as Aspergillus should be excluded.63,64 A predominantly neu-
ence should also prompt consideration of other entities such as trophilic infiltrate, necrosis and granuloma formation all favour infec-
eosinophilic pneumonia, fungal infection and lymphoproliferative tion rather than rejection.
disease.57,58 The vascular endothelium and alveolar epithelium both Acute rejection should also be distinguished from the ischaemia–
show upregulation of class II HLA (HLA-DR) antigens.41 reperfusion injury described above and from the lymphoproliferative
Although perivascular lymphoid cell infiltration is the hallmark of disorders described below.58 Ischaemia–reperfusion injury lacks
acute rejection, similar infiltrates may be seen in patients with infec- the perivascular and interstitial infiltration of rejection while a
tions and other conditions for which augmented immunosuppression polymorphous, perivascular infiltrate of B and T lymphocytes with a
is inappropriate. For this reason acute rejection should only be diag- predominance of the latter favours rejection rather than lympho­

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A
Figure 11.10  Fragmented cytomegalovirus inclusions after treatment
with ganciclovir.

proliferative disease, which is characterised by a monomorphous

infiltrate of large B lymphocytes.57 Mass lesions also favour
lymphoproliferative disease or infection rather than rejection.
Recurrence in the allograft of diseases such as sarcoidosis and
Langerhans cell histiocytosis may also be misinterpreted as acute
rejection if their characteristic features are not well represented.
Airway inflammation in the form of lymphocytic bronchiolitis is
the other major pattern of acute rejection. Evidence that it represents
rejection includes its progression to chronic rejection (bronchiolitis
obliterans) and frequent response to augmented immunosuppres-
sion.65 It may accompany or succeed the perivascular infiltrates
described above or be seen alone, but it most frequently follows the
vascular changes.28,50 Airway inflammation may be graded in the same
way as the perivascular infiltration but in practice the small size
of the biopsies generally precludes the precision required for this. B
The changes range from sparse airway cuffing by small lymphoid
cells (grade B1R) to diffuse infiltration of the lamina propria and
Figure 11.11  Acute airway rejection (lymphocytic bronchiolitis). (A)
epithelium by medium and large lymphoid cells and epithelial Grade B1 acute rejection is characterised by occasional small lymphocytes
apoptosis (grade B2R) (Fig. 11.11). In severe cases the lymphoid infiltrating the bronchiolar epithelium and lamina propria. (B) Grade B3
infiltrate is particularly dense and there is ulceration and fibrino­ acute airway rejection shows extensive infiltration and obliteration of
purulent exudation. The importance of large-airway inflammation bronchiolar epithelium by lymphocytes.
in rejection is unclear as it is more often secondary to infection.
Grading of airway inflammation is therefore currently restricted to the
bronchioles. The histological features are those of constrictive bronchiolitis oblit-
The differential diagnosis of airway inflammation includes the erans. Typically there is concentric or eccentric hyaline fibrous thicken-
presence of bronchus-associated lymphoid tissue of donor origin, ing of the bronchiolar submucosa, encroaching on the airway lumen
low-grade infection and the consequences of aspiration. Bronchus- and eventually resulting in total occlusion (Fig. 11.13).68–71 The
associated lymphoid tissue is distinguished by it comprising aggre- changes may be subtle, in which case an elastin stain can be invaluable
gates of B lymphocytes, sometimes with admixed anthracotic in identifying the fibrosed bronchioles. Residual bronchiolar epithe-
macrophages, in contrast to the T-cell-rich infiltrates of rejection. lium may show squamous metaplasia and there is usually disruption
Prominent neutrophil or eosinophil infiltration is suggestive of infec- of the muscle coat. The process may be active (i.e. associated with
tion or aspiration. However, it is important to note that airway or lymphocytic bronchiolitis) or inactive (consisting of dense fibrous
parenchymal infection, notably by cytomegalovirus, may accompany scarring with minimal or no inflammation), although this is of no
rejection.66 prognostic significance and does not predict response to treatment.
The infiltrating cells are T lymphocytes.72 The process is patchy and
therefore not always evident in small biopsies,73,74 but its presence may
Chronic allograft rejection be suggested by obstructive features such as the accumulation of
Chronic rejection of the transplanted lung is marked by progressive foamy macrophages in distal air spaces. In the current classification
breathlessness, cough, which is often productive, fever and a decline constrictive bronchiolitis is simply recorded as being present (C1) or
in lung function.67 The changes, which can be monitored by absent (C0).
spirometry and imaging (Fig. 11.12), are centred on the bronchioles The recognition of bronchiolitis obliterans is the key discriminator
(class C) and blood vessels (class D). between acute and chronic rejection. The adjacent lung may also show

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 Pathology of the Lungs

A A

Figure 11.13  The histological spectrum of chronic airway rejection

B (bronchiolitis obliterans). (A) Partial occlusion of a bronchiole by
plaque-like submucosal fibrous tissue with sparse chronic inflammation.
Figure 11.12  Computed tomography scan appearances in bronchiolitis (B) An incomplete ring of smooth muscle provides the only evidence that
obliterans syndrome. (A) The inspiratory image shows mild generalised this focal pulmonary scar represents an obliterated bronchiole.
hyperinflation with bronchial dilatation and wall thickening while (B) the
expiratory image shows irregular dark areas of focal air-trapping.
of de novo anti-HLA antibodies following transplantation is also asso-
ciated with an increased incidence of bronchiolitis obliterans, suggest-
evidence of concomitant acute rejection (Fig. 11.14). Most patients ing that humoral rejection may play a role.84,85 Gastro-oesophageal
with bronchiolitis obliterans also have bronchiectasis (Fig. 11.15), reflux and chronic airway infection may also contribute to the devel-
which probably results from a combination of factors, including opment of obliterative bronchiolitis.86–88 Other causes include cytome-
rejection, infection and denervation. Concomitant acute airway galovirus infection,28,59,77,89,90 community-acquired viral infection91,92
inflammation suggests postobstructive infection. and ischaemia.93 Finally, it has been suggested that some early cases,
Unfortunately, sampling error renders the diagnosis of bronchiolitis characterised by acute inflammation on biopsy and lavage (in the
obliterans unreliable on small biopsies and its identification generally absence of infection), respond well to azithromycin therapy (so-called
depends upon recognition of a bronchiolitis obliterans syndrome. neutrophilic reversible allograft dysfunction).94–96
This is defined as ‘graft deterioration due to progressive airways disease The pathogenesis of the obliterative fibrosis has yet to be fully elu-
for which there is no other cause’.75,76 The principal role of trans­ cidated, but it is intriguing that some of the cells that participate in
bronchial lung biopsy is therefore to exclude treatable causes of the fibrosis are derived from circulating fibroblast precursors of
deterioration in lung function. recipient bone marrow origin.97 There is also evidence suggesting
Bronchiolitis obliterans is seldom seen within 6 months of the a role for epithelial–mesenchymal transition in the sclerosing
operation and, while its incidence diminishes after 1–2 years, it affects process.98,99
50% of recipients by 5 years.73 Risk factors include earlier rejection Chronic rejection may also involve the pulmonary vasculature,
episodes and histocompatibility mismatch,57,70,77,78 supporting the resulting in fibrointimal sclerosis of arteries and veins analogous to
view that it represents a late manifestation of rejection50,79 with an that occurring in the coronary arteries of heart and heart–lung allo-
immunological pathogenesis analogous to that occurring in rheuma- grafts (Fig. 11.16).100–103 This uncommon complication may be active
toid and graft-versus-host disease (see p. 121).80–83 The development or inactive and may be seen in association with obliterative bronchi-

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Figure 11.14  Concomitant acute and chronic rejection. Acute rejection is

evidenced by a perivascular lymphoid infiltrate while a bronchiole totally
obstructed by fibrous tissue is indicative of chronic rejection.

Figure 11.16  Chronic vascular rejection. (a) Active chronic rejection

affecting a muscular artery. (b) A pulmonary artery showing severe
intimal fibrosis, the appearances of inactive alveolar infection.

Figure 11.15  Radiological and macroscopic appearances of chronic the features of antibody-mediated rejection being treated successfully
airway rejection complicated by bronchiectasis. (Courtesy of Dr H Tazelaar, with plasmapheresis and intravenous immunoglobulin.105–111 While it
Rochester, Minnesota, USA.) has been suggested that capillaritis may represent antibody-mediated
rejection,109,112,113 there is currently no consensus on what histological
features define the condition in the lung.114 Furthermore C4d deposi-
olitis, which would then dominate the clinical picture. Sclerosis of
tion may be seen in lungs with primary graft failure and infection,115,116
small vessels may also represent chronic rejection but is generally
limiting its use as a marker of rejection remains to be elucidated.
disregarded as it may also follow ischaemia, acute rejection, non-
Recent work has revealed complex interactions between components
rejection-related pulmonary inflammation and non-specific donor-
of the complement system, platelets and endothelial cells as well as
related factors.
evidence suggesting an influence of complement on T and B lym-
phocyte function.104a,114 Endothelial activation appears to play a central
Antibody-mediated rejection role in the development of antibody-mediated rejection and further
Hyperacute rejection is the archetypal form of antibody-mediated work may provide more specific and sensitive markers of this serious
rejection, in which preformed antibodies cross-react with graft anti- complication of lung transplantation humoral rejection.
gens resulting in fulminant rejection. However, it is known from renal
and cardiac transplantation that a less acute form of antibody- Upper-lobe fibrosis
mediated rejection, may occur. The criteria for diagnosing this include Progressive upper-lobe fibrosis has occasionally been described after
the presence of de novo donor-specific antibodies, clinical allograft lung transplantation. Imaging shows interlobular septal thickening
dysfunction, histological features of antibody-mediated rejection and and ground-glass change, progressing to traction bronchiectasis
the deposition of complement protein C4d, a stable biproduct of and honeycombing. Biopsy shows non-specific inflammation and
complement C4d activation, on capillary endothelium.104,104a The role fibrosis.117 Further research is required to determine whether this
of antibody-mediated rejection in lung allograft rejection is far from provisional clinicopathological entity is related to rejection or other
clear but there are reports of lung transplant patients with many of factors.

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 Pathology of the Lungs

Figure 11.17  Cytomegalovirus antigenaemia. Positive

immunohistochemical staining of peripheral blood leukocytes for
cytomegalovirus pp65 antigen.

Infection
Infection is a major hazard for the immunosuppressed recipient of
a lung allograft.118 It is often multiple and may affect the native
lung and other organs as well as the allograft. Its recognition in the
lungs largely depends upon the microbiological examination of
bronchoalveolar lavage fluid but the addition of transbronchial lung
biopsy increases the detection rate.119 Problems in biopsy inter­
pretation include distinguishing rejection from infection, which is
compounded by the atypical host response of the immunosuppressed
patient. Distinguishing colonisation, subclinical infection and
clinically significant disease may also be difficult. The pathology of B
pulmonary infection is described in Chapter 5 but the special
circumstances associated with transplantation warrant further Figure 11.18  Early cytomegalovirus pneumonitis. (A) Focal acute
comment on some infective agents here. interstitial pneumonitis with several possible cytomegaloviral inclusions,
(B) confirmed by immunohistochemistry.

Viruses
Cytomegalovirus infection of a seronegative recipient, transmitted by
blood transfusion or the graft, increases the incidence of rejection,
probably by promoting the expression of the major histocompatibil­
ity antigens in the alveolar epithelium.41,120,121 The recognition of
clinically significant disease (as opposed to mere carriage of the
virus) is based upon identification of blood cytomegalovirus pp65
antigen,122,123 biopsy evidence of interstitial pneumonitis and bronchi-
olitis124 (Fig. 11.17) and the detection of the virus. The latter often
requires immunohistochemistry or molecular techniques such as the
polymerase chain reaction because in the early stages of infection
typical viral inclusions are often sparse (Fig. 11.18). Only in the later
stages are there numerous intranuclear and cytoplasmic inclusions
(Fig. 11.19). Other patterns of cytomegalovirus disease include poorly
formed granulomas, diffuse alveolar damage and mass lesions simu-
lating a tumour.125 Viral prophylaxis may result in fragmented inclu-
sions and an acute neutrophilic pneumonitis (see Fig. 11.10).
Infection by herpes simplex virus is infrequent in lung allograft
recipients but may cause necrotising tracheobronchitis and pneumo-
nia in these patients.126 Similarly, infection by influenza and respira-
tory syncytial viruses may cause significant morbidity and contribute Figure 11.19  Severe cytomegalovirus pneumonitis in a cytomegalovirus-
to the development of bronchiolitis obliterans.92,127 Other viral negative recipient of a cytomegalovirus-positive lung.

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Toxoplasmosis
Infection of the lung allograft by Toxoplasma gondii is rare, having been
largely eliminated in seronegative solid-organ transplant recipients
given a positive organ by prophylaxis with pyrimethamine. It usually
occurs as part of systemic infection following graft mismatch.138
Identification of the organism in biopsy material may be difficult
as the cysts of T. gondii are sparse and extracellular tachyzoites
may be mistaken for haematoxyphil debris (see Fig. 5.5.1, p. 252).
The diagnosis may be confirmed by immunohistochemistry or
by the polymerase chain reaction applied to tissue, body fluids or
peripheral blood.139

Aspiration
Gastro-oesophageal reflux and aspiration are fairly common follow-
ing lung transplantation and are being increasingly recognised as risk
factors for the development of obliterative bronchiolitis through
repeated episodes of epithelial injury.86,140–142 The histological features
are generally those of non-specific active chronic inflammation,
Figure 11.20  Fatal chickenpox pneumonitis. Foci of necrosis are although a foreign-body giant cell reaction to aspirated material
surrounded by extensive alveolar haemorrhage.
occasionally allows a definitive diagnosis (see Fig. 5.2.16, p. 190).
Bronchoalveolar lavage studies suggest that it is the aspiration of bile
salts rather than gastric acid that is related to the subsequent develop-
infections of note in transplant patients include pulmonary and ment of obliterative bronchiolitis.88
systemic infection by varicella-zoster (Fig. 11.20).
Community-acquired respiratory viruses such as rhinovirus, Neoplasia
enterovirus, coronavirus, respiratory syncytial virus, parainfluenza
virus, influenza A and B and adenovirus infect up to 57% of lung After rejection, neoplasia is the most significant factor limiting long-
trans­plant recipients. The severity varies from mild upper respiratory term survival in solid-organ transplantation.7,143 It ranges in incidence
tract disease to severe pneumonia complicated by bacterial or fungal from 6% to 11%.144,145 The tumours may arise de novo or be in­­
superinfection. Some studies have linked such infection with the onset advertently introduced within the allograft. They are often particularly
of acute and chronic rejection. Features on biopsy are often of a non- aggressive. Predisposing factors in addition to immunosuppression
specific interstitial pneumonitis. Occasionally, a specific viral cyto- include ultraviolet irradiation and activation of oncogenic viruses
pathic effect may be seen on biopsy, such as with adenovirus (see p. such as Epstein–Barr virus, papillomavirus and herpesvirus. Molecular
161), but usually viral culture is required to identify the organism. techniques have shown that those tumours apparently arising de
Molecular techniques applied to lavage material greatly enhance the novo may be of donor rather than recipient origin.146
sensitivity and specificity of viral diagnosis. The most frequently encountered de novo tumours include the
posttransplantation lymphoproliferative disorders dealt with see and
cutaneous tumours, notably squamous carcinoma, preceded by pre-
Bacteria malignant skin lesions, which are often multiple. The carcinomas
Opportunistic mycobacteria originating in either the donor or recipi- frequently metastasise and may contain papillomavirus.143,147
ent infect lung allograft recipients on rare occasions, or merely colo- Intraepithelial neoplasia and squamous carcinomas of the uterine
nise the graft without causing disease.128–130 Other bacterial infections cervix, vulva and perineum, also associated with human papillomavi-
of these patients include nocardiosis and Legionella pneumonia. rus infection, may occur. Other tumours reputed to occur with greater
frequency than in the general population include carcinomas of the
kidney,148 hepatobiliary tract and lung,118,149 the last of these often
Fungi presenting at an advanced stage and being of donor origin.146
Pneumocystis jirovecii pneumonia is rare in lung transplantation Cytological specimens of the bronchi often show epithelial atypia but
because of chemoprophylaxis; the reported incidence is less than this is more often reactive than malignant.150
1%.20 It mostly follows the immunosuppression being increased Other tumours seen more commonly in lung transplant recipients
because of acute rejection.131 The histological patterns include a pre- than the general population include Kaposi’s sarcoma151 and low-
dominantly lymphoplasmacytic interstitial pneumonitis with scanty grade leiomyosarcoma.152,153 Between 3% and 7% of single-lung trans-
exudate, and a granulomatous pneumonitis. The fungal cysts are plant recipients develop bronchogenic carcinoma within their native
sparse and the classic foamy alveolar exudate is rarely encountered. lung. This may reflect the large number of transplants performed for
The perivascular component of the lymphoplasmacytic pattern resem- smoking-related diseases such as emphysema and idiopathic pulmo-
bles that of acute rejection, hence the mandatory use of silver staining nary fibrosis.154 The role of immunosuppression in the development
techniques for all transbronchial lung allograft biopsies and the of these tumours is unclear but it is notable that they behave
routine screening of all bronchoalveolar lavage specimens using aggressively.
immunocytochemistry or the polymerase chain reaction.132
Other fungi that infect lung allograft patients include Candida and Posttransplantation lymphoproliferative
Aspergillus. These agents may merely colonise the airways133 or cause
ulcerative tracheobronchitis, dehiscence of the anastomosis, broncho-
disorders
centric granulomatosis, cavitating pneumonia, mediastinitis and A spectrum of lymphoproliferative disorders may complicate
multiple haematogenous abscesses.134–137 transplantation of many organs, including the lungs.155–158

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Immunosuppression would appear to underlie this escape from

normal control as similar disease is seen in other conditions charac- Box 11.4  World Health Organization classification of
terised by profound immunosuppression – the acquired im­­ posttransplantation lymphoproliferative disorders
munodeficiency syndrome (AIDS), for example. Epstein–Barr virus is (PTLD)173
suspected of playing a part in the causation of these lesions, having
been identified in many of them by immunostaining and the applica- 1.  Early lesions
tion of molecular probes.159–161 The incidence of lymphoproliferative Reactive plasmacytic hyperplasia
disease is higher in recipients who are sero-negative for Epstein–Barr Infectious mononucleosis-like lesion
virus before the operation,162 suggesting that the viral infection is
primary rather than representing reinfection or reactivation of latent 2.  PTLD – polymorphic
disease.159 The virus is detectable more often with early than late Polyclonal (rare)
disease. A notable feature is that the lesions are potentially reversible Monoclonal
once immunosuppression is reduced.157,163
3.  PTLD – monomorphic (classify according to
Posttransplantation lymphoproliferative disorders have been
lymphoma they resemble)
described in association with virtually all currently used immuno­
suppressive agents and are thought to result from uncontrolled pro- B-cell neoplasms
liferation of Epstein–Barr virus-immortalised B cells due to loss of Diffuse large B-cell lymphoma
cytotoxic T-cell control.160,164 As with most solid-organ transplants, the Burkitt lymphoma
lymphoproliferation usually involves cells of recipient origin, in con- Plasma cell myeloma
trast to bone marrow transplantation where the lymphoproliferative Plasmacytoma-like lesion
disorders generally involve cells of donor origin.165–170 Nevertheless Other
they often first present in the allograft itself.
Risk factors include the type of transplant, young age, multiple T-cell neoplasms
rejection episodes, multiagent immunosuppression, anti-T-cell Peripheral T-cell lymphoma, not otherwise categorised
therapy and pretransplant Epstein–Barr virus sero-negativity.162,166 The Hepatosplenic T-cell lymphoma
interval between lung transplantation and the development of the Other
lymphoproliferative process is generally short (median time 7
months), as is the median time to death (5 months).161
4.  Classic Hodgkin lymphoma-type PTLD
The incidence of posttransplantation lymphoproliferative disorders
ranges from about 1% with bone marrow and kidney transplants to
nearly 10% with lung and heart–lung and 17% with intestine.167 This granulomatosis. Early lesions may be rich in mature plasma cells or
is thought to reflect the relatively higher levels of immunosuppression show changes suggestive of infectious mononucleosis. Polymorphous
required for lung and intestinal transplantation. infiltrates often include plasmacytoid cells (Fig. 11.21). Monomor­
Posttransplantation lymphoproliferative disease may involve the phous infiltrates may consist of transformed blasts, centroblast-like,
lung in isolation or as part of disseminated disease.158,159,161 The lungs centrocyte-like cells or immunoblasts showing a high proliferation
may also be involved by posttransplantation lymphoproliferative index (Fig. 11.22). Single-cell necrosis is common. Histiocytes and
disease in recipients of other solid-organ transplants.171,172 The disease T lymphocytes often cuff the lesion and infiltrate the bronchiolar
may be asymptomatic or cause cough, fever and malaise. Radiographs epithelium while the uninvolved lung may show patchy organising
may show diffuse infiltrates or single or multiple nodules. High serum pneumonia. Immunoglobulin clonality is variable. Early lesions
levels of Epstein–Barr virus DNA predict the development of post- tend to be polyclonal. Monomorphous lesions are usually mono-
transplant lymphoproliferative disease. Tissue should be examined for clonal while polymorphous lesions may be either polyclonal or
Epstein–Barr virus by immunocytochemistry or in situ hybridisation, monoclonal.167,174
cell phenotype and immunoglobulin clonality, and the lesion A reduction of immunosuppression and treatment with antiviral
clas­sified according to the scheme advocated by the World Health agents usually leads to rapid resolution159 but relapse is frequent and
Organization (Box 11.4).173 Clinical suspicion of posttransplantation may require radiation treatment or chemotherapy. Newer, less toxic
lymphoproliferative disease should be conveyed to the pathologist so treatments such as cytotoxic T-lymphocyte infusions, interferon-α and
that some tissue can be snap-frozen for appropriate molecular studies. antibodies to B cells (anti-CD20; Rituximab) are now available.175–177
Synchronous and metachronous lesions should all be investigated
as variations in clonality and morphology occur both within an
Graft-versus-host disease
individual lesion and between simultaneous or subsequent lesions.
Difficulties encountered in diagnosis, especially on core biopsies, The transplanted lung or heart–lung block contains a significant
stem from the small size of the sample, crush artefact and extensive amount of lymphoid tissue and on rare occasions a rash, colitis, pan-
necrosis caused by angioinvasion. The differential diagnosis includes cytopenia and liver dysfunction may suggest that graft-versus-host
infections such as cytomegalovirus and Pneumocystis, inflammation disease has developed.178–181 The identification of donor lymphocytes
caused by previous biopsies, the presence of bronchus-associated lym- in the blood and bronchoalveolar lavage fluid of such patients sup-
phoid tissue and, in the transplanted lung, acute allograft rejection ports this possibility. Graft-versus-host disease tends to develop in the
and, rarely, graft-versus-host disease. early postoperative period. It may be severe but is fortunately rare and
The chief pulmonary manifestations of posttransplantation lympho­ usually responds to increased immunosuppression. The graft-versus-
proliferative disease are lymphoid hyperplasia, lymphoid interstitial host disease of bone marrow transplantation may cause constrictive
pneumonia and the full spectrum of lymphomas,159,173 all of which obliterative bronchiolitis that is indistinguishable from that seen in
are described in Chapter 12.4. They predominantly involve B lym- lung rejection81,82,182,183 but of course in lung transplantation the donor
phocytes whereas T lymphocytes predominate in the infiltrates that lung is spared this complication.
characterise rejection.158 High-grade lymphomas often show angioin- Biopsy diagnosis is generally dependent upon the histological
vasion and extensive necrosis, thereby resembling lymphomatoid appearances in the skin rather than the lung. The diagnosis may be

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 Lung transplantation Chapter | 11 |

notable that whereas asthma appears to be cured by lung trans­

plantation, it may also be transferred by transplanting the lungs of
asthmatic donors to non-atopic patients.186 Sarcoidosis has recurred
in the graft in up to 60% of cases187–189 but is seldom of clinical sig-
nificance.189 Other diseases that have recurred in the graft include
emphysema in an α1-antitrypsin-deficient recipient,190 the giant cell
interstitial pneumonia of hard-metal workers,191 desquamative inter-
stitial pneumonia,192,193 panbronchiolitis,194 alveolar proteinosis,195
Langerhans cell histiocytosis196–198 and lymphangioleiomyomatosis.199
–201
This last disease is almost entirely confined to women and it is
notable that the donors of some lungs affected by recurrent disease
were men; the recurrent smooth-muscle proliferation is of recipient
origin,202,203 as are the immune cells that contribute to recurrent sar-
coidosis.204 Recurrent bronchioloalveolar cell carcinoma has been
shown to have originated in the recipient and the recurrence to have
taken place despite both lungs having been replaced and there being
no evidence of extrapulmonary involvement.205 Idiopathic pulmonary
A fibrosis and emphysema are examples of diseases that have not yet
been reported to recur in transplanted lungs.

Drug injury
Some of the immunosuppressive drugs used to maintain a transplant
may harm other organs. For example, ciclosporin may cause renal
damage and rhabdomyolysis while azathioprine may damage the liver
and bone marrow. Several patterns of lung disease have been described
in the recipients of lung and other organ transplants following
treatment with sirolimus: these include lymphocytic interstitial
pneumonia, organising pneumonia, diffuse alveolar haemorrhage
and pulmonary haemorrhage.206–208 Sirolimus is also contraindicated
postoperatively as it may cause dehiscence of the bronchial anasto-
mosis. Amiodarone may be used to treat atrial fibrillation, which is a
common postoperative complication, and rare cases of amiodarone
lung have been reported in transplant recipients.

B FUTURE PROSPECTS
Figure 11.21  Pulmonary posttransplantation lymphoproliferative disorder
With increasing numbers of patients awaiting lung transplantation
(polymorphous, lymphoplasmacytoid). (A) Plasma cells, plasmacytoid cells
and medium-sized lymphocytes surround an alveolar duct. (B) CD79a- and a limited donor pool, the pressure on transplant centres is
positivity shows that the infiltrate is of B-cell origin. immense. Advances in the medical treatment of those pulmonary
conditions for which patients are often transplanted (such as cystic
fibrosis, pulmonary hypertension and fibrosing lung disease) will
reduce demand on transplant services but new strategies are required.
confirmed by demonstrating donor and recipient chimerism on Those being explored include attempts to improve the condition
HLA typing of peripheral blood lymphocytes and bronchoalveolar of borderline lungs, the use of mechanical assist devices, xenotrans-
lavage fluid. plantation and the construction of new lungs by bioengineering.
So far the only strategy to enter the clinical arena is reconditioning
ex vivo, whereby the condition of borderline donor lungs is improved
Recurrent disease in the allograft
by mechanical ventilation and perfusion in a specially designed
The systemic effects of underlying diseases such as cystic fibrosis may circuit.209–211 Stem cell therapy may also prove of benefit in recondi-
have a significant impact on recovery but only recurrence in the allo- tioning borderline lungs.
graft will be considered here. While mechanical assist devices have a well-established role in end-
The aetiology of many diseases treated by lung transplantation is stage heart failure, the use of such devices to support patients awaiting
imperfectly understood but our knowledge of them has been broad- lung transplantation is limited. Extracorporeal membrane oxygena-
ened by their behaviour following transplantation. Some of these tion has been used successfully as a short-term bridge to transplanta-
diseases are prone to recur in the new lungs whereas others are not. tion in some patients, but the development of a portable artificial lung
Of particular interest is the finding that lungs transplanted into for longer support outside hospital is still awaited. Pulmonary
patients with cystic fibrosis do not appear to develop the basic defect xenotransplantation is an area of active research, with several groups
of membrane transport that underlies this disease.184,185 It is also exploring the use of porcine lungs.

523
 Pathology of the Lungs

A B

C D

Figure 11.22  Pulmonary posttransplantation lymphoproliferative disorder (monomorphous, large B-cell lymphoma). (A) Large pleomorphic lymphoid
cells, some with immunoblastic features, show angiocentricity. (B) Some of the lymphoid cells infiltrating the vessel wall show immunoblastic features.
(C) CD20-positivity shows that the infiltrate is of B-cell origin. (D) In situ hybridisation for Epstein–Barr virus-encoded RNA shows strong nuclear
positivity. (D courtesy of Dr JA Thomas, London, UK.)

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bronchoalveolar lavage fluid. Am J histocompatibility class II expression in macrophage activation in experimental
Transplant 2004;4:1323–30. transplanted lung. Molecular, legionellosis. J Immunol
106. Ionescu DN, Girnita AL, Zeevi A, et al. immunocytochemical, and histopathologic 1991;147:337–45.
C4d deposition in lung allografts is investigations. Transplantation 135. Kramer MR, Denning DW, Marshall SE, et
associated with circulating anti-HLA 1996;61:418–27. al. Ulcerative tracheobronchitis after lung
alloantibody. Transpl Immunol 121. You XM, Steinmuller C, Wagner TO, et al. transplantation – a new form of invasive
2005;15:63–8. Enhancement of cytomegalovirus infection aspergillosis. Am Rev Respir Dis
107. Girnita AL, McCurry KR, Zeevi A. Increased and acute rejection after allogeneic lung 1991;144:552–6.
lung allograft failure in patients with transplantation in the rat: virus-induced 136. Egan JJ, Yonan N, Carroll KB, et al. Allergic
HLA-specific antibody. Clin Transpl expression of major histocompatibility bronchopulmonary aspergillosis in lung
2007;231–9. complex class II antigens. J Heart Lung allograft recipients. Eur Respir J
108. Girnita AL, McCurry KR, Yousem SA, et al. Transplant 1996;15:1108–19. 1996;9:169–71.
Antibody-mediated rejection in lung 122. Egan JJ, Barber L, Lomax J, et al. Detection 137. Mehrad B, Paciocco G, Martinez FJ, et al.
transplantation: case reports. Clin Transpl of human cytomegalovirus antigenaemia: a Spectrum of Aspergillus infection in lung
2006;508–10. rapid diagnostic technique for predicting

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 Pathology of the Lungs

transplant recipients – Case series and occurring after lung transplantation. Chest study of the relation to Epstein–Barr virus.
review of the literature. Chest 1997;112:283–4. Transplantation 2000;69:897–904.
2001;119:169–75. 153. Somers CR, Tesoriero AA, Hartland E, et al. 167. Nalesnik MA, Jaffe R, Starzl TE, et al. The
138. Wreghitt TG, Hakim M, Gray JJ, et al. Multiple leiomyosarcomas of both donor pathology of posttransplant
Toxoplasmosis in heart and heart and lung and recipient origin arising in a heart–lung lymphoproliferative disorders occurring in
transplant recipients. J Clin Pathol transplant patient. Am J Surg Pathol the setting of cyclosporine A-prednisone
1989;42:194–9. 1998;22:1423–8. immunosuppression. Am J Pathol
139. Holliman R, Johnson J, Savva D, et al. 154. Mathew J, Kratzke RA. Lung cancer and 1988;133:173–92.
Diagnosis of toxoplasma infection in lung transplantation: a review. J Thorac 168. Weissmann DJ, Ferry JA, Harris NL, et al.
cardiac transplant recipients using the Oncol 2009;4:753–60. Posttransplantation lymphoproliferative
polymerase chain reaction. J Clin Pathol 155. Swerdlow SH. Post-transplant disorders in solid organ recipients are
1992;45:931–2. lymphoproliferative disorders: a predominantly aggressive tumors of host
140. Vos R, Blondeau K, Vanaudenaerde BM, morphologic, phenotypic and genotypic origin. Am J Clin Pathol 1995;103:748–55.
et al. Airway colonization and gastric spectrum of disease. Histopathology 169. Chadburn A, Suciufoca N, Cesarman E,
aspiration after lung transplantation: do 1992;20:373–85. et al. Post-transplantation
birds of a feather flock together? J Heart 156. Craig FE, Gulley ML, Banks PM. lymphoproliferative disorders arising in
Lung Transplant 2008;27:843–9. Posttransplantation lymphoproliferative solid organ transplant recipients are
141. Robertson AG, Griffin SM, Murphy DM, disorders. Am J Clin Pathol usually of recipient origin. Am J Pathol
et al. Targeting allograft injury and 1993;99:265–76. 1995;147:1862–70.
inflammation in the management of 157. Swerdlow SH. Post-transplant 170. Spiro IJ, Yandell DW, Li C, et al. Brief
post-lung transplant bronchiolitis lymphoproliferative disorders: a working report: lymphoma of donor origin
obliterans syndrome. Am J Transplant classification. Current Diagnostic occurring in the porta hepatis of a
2009;9:1272–8. Pathology 1997;4:28–35. transplanted liver. N Engl J Med
142. Hadjiliadis D, Duane DR, Steele MP, et al. 158. Reams D, McAdams HP, Howell DN, et al. 1993;329:27–9.
Gastroesophageal reflux disease in lung Posttransplant lymphoproliferative 171. Ohori NP, Whisnant RE, Nalesnik MA, et
transplant recipients. Clin Transplant disorder – Incidence, presentation, and al. Primary pleural effusion posttransplant
2003;17:363–8. response to treatment in lung transplant lymphoproliferative disorder: Distinction
143. Penn I. Occurrence of cancers in recipients. Chest 2003;124:1242–9. from secondary involvement and effusion
immunosuppressed organ transplant 159. Yousem SA, Randhawa P, Locker J, et al. lymphoma. Diagn Cytopathol
recipients. Clin Transpl 1998;147–58. Posttransplant lymphoproliferative 2001;25:50–3.
144. Mihalov ML, Gattuso P, Abraham K, et al. disorders in heart–lung transplant 172. Halkos ME, Miller JI, Mann KP, et al.
Incidence of post-transplant malignancy recipients: primary presentation in the Thoracic presentations of posttransplant
among 674 solid-organ-transplant allograft. Hum Pathol 1989;20:361–9. lymphoproliferative disorders. Chest
recipients at a single center. Clin 160. Delecluse HJ, Kremmer E, Rouault JP, et al. 2004;126:2013–20.
Transplant 1996;10:248–55. The expression of Epstein–Barr virus latent 173. Swerdlow SH, Campo E, Harris N, et al.
145. Rinaldi M, Pellegrini C, D’Armini AM, proteins is related to the pathological WHO Classification of Tumours of
et al. Neoplastic disease after heart features of post-transplant Haemopoietic and Lymphoid Tissues. 4th
transplantation: single center experience. lymphoproliferative disorders. Am J Pathol ed. Lyons, France: IARC Press; 2008.
Eur J Cardiothorac Surg 2001;19:696–701. 1995;146:1113–20. 174. Knowles DM, Cesarman E, Chadburn A, et
146. DeSoyza AG, Dark JH, Parums DV, et al. 161. Ramalingam P, Rybicki L, Smith MD, et al. al. Correlative morphologic and molecular
Donor-acquired small cell lung cancer Posttransplant lymphoproliferative genetic analysis demonstrates three distinct
following pulmonary transplantation. disorders in lung transplant patients: The categories of posttransplantation
Chest 2001;120:1030–1. Cleveland Clinic experience. Modern lymphoproliferative disorders. Blood
147. Harwood CA, Surentheran T, McGregor Pathol 2002;15:647–56. 1995;85:552–65.
JM, et al. Human papillomavirus infection 162. Aris RM, Maia DM, Neuringer IP, et al. 175. Swinnen LJ. Organ transplant-related
and non-melanoma skin cancer in Post-transplantation lymphoproliferative lymphoma. Curr Treat Options Oncol
immunosuppressed and disorder in the Epstein–Barr virus-naive 2001;2:301–8.
immunocompetent individuals. J Med lung transplant recipient. Amer J Respir 176. Milpied N, Vasseur B, Parquet N, et al.
Virol 2000;61:289–97. Crit Care Med 1996;154:1712–7. Humanized anti-CD20 monoclonal
148. Torbenson M, Wang J, Nichols L, et al. 163. Starzl TE, Nalesnik MA, Porter KA, et al. antibody (Rituximab) in post transplant
Renal cortical neoplasms in long term Reversibility of lymphomas and B-lymphoproliferative disorder: a
survivors of solid organ transplantation. lymphoproliferative lesions developing retrospective analysis on 32 patients. Ann
Transplantation 2000;69:864–8. under cyclosporin-steroid therapy. Lancet Oncol 2000;11:113–6.
149. Anyanwu AC, Townsend ER, Banner NR, 1984;1:583–7. 177. Knoop C, Kentos A, Remmelink M, et al.
et al. Primary lung carcinoma after heart 164. Thomas JA, Crawford DH, Burke M. Post-transplant lymphoproliferative
or lung transplantation: management and Clinicopathologic implications of disorders after lung transplantation:
outcome. J Thorac Cardiovasc Surg Epstein–Barr virus related B cell first-line treatment with rituximab may
2002;124:1190–7. lymphoma in immunocompromised induce complete remission. Clin
150. Ohori NP. Epithelial cell atypia in patients. J Clin Pathol 1995;48:287–90. Transplant 2006;20:179–87.
bronchoalveolar lavage specimens from 165. Peterson MR, Emery SC, Yung GL, et al. 178. Chau EM, Lee J, Yew WW, et al.
lung transplant recipients. Amer J Clin Epstein–Barr virus-associated Mediastinal irradiation for graft-versus-
Pathol 1999;112:204–10. posttransplantation lymphoproliferative host disease in a heart–lung transplant
151. Sleiman C, Mal H, Roue C, et al. Bronchial disorder following lung transplantation is recipient. J Heart Lung Transplant
Kaposi’s sarcoma after single lung more commonly of host origin. Arch 1997;16:974–9.
transplantation. Eur Respir J Pathol Lab Med 2006;130:176–80. 179. Smith DM, Agura ED, Ausloos K, et al.
1997;10:1181–3. 166. Swerdlow AJ, Higgins CD, Hunt BJ, et al. Graft-vs-host disease as a complication of
152. Flint A, Lynch JP, Martinez FJ, et al. Risk of lymphoid neoplasia after lung transplantation. J Heart Lung
Pulmonary smooth muscle proliferation cardiothoracic transplantation. a cohort Transplant 2006;25:1175–7.

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180. Assi MA, Pulido JS, Peters SG, et al. transplant recipient. Am J Respir Crit Care 202. Carsillo T, Astrinidis A, Henske EP.
Graft-vs.-host disease in lung and other Med 2004;170:811–4. Mutations in the tuberous sclerosis
solid organ transplant recipients. Clin 191. Frost AE, Keller CA, Brown RW, et al. Giant complex gene TSC2 are a cause of sporadic
Transplant 2007;21:1–6. cell interstitial pneumonitis – disease pulmonary lymphangioleiomyomatosis.
181. Worel N, Bojic A, Binder M, et al. recurrence in the transplanted lung. Am Proc Natl Acad Sci U S A
Catastrophic graft-versus-host disease after Rev Respir Dis 1993;148:1401–4. 2000;97:6085–90.
lung transplantation proven by PCR-based 192. King MB, Jessurun J, Hertz MI. Recurrence 203. Bittmann I, Rolf B, Amann G, et al.
chimerism analysis. Transpl Int of desquamative interstitial pneumonia Recurrence of lymphangioleiomyomatosis
2008;21:1098–101. after lung transplantation. Amer J Respir after single lung transplantation: New
182. Roca J, Granena A, Rodriguez-Roisin R, Crit Care Med 1997;156:2003–5. insights into pathogenesis. Hum Pathol
et al. Fatal airway disease in an adult with 193. Verleden GM, Sels F, VanRaemdonck D, 2003;34:95–8.
chronic graft-versus-host disease. Thorax et al. Possible recurrence of desquamative 204. Milman N, Andersen CB, Burton CM, et al.
1982;37:77–8. interstitial pneumonitis in a single lung Recurrent sarcoid granulomas in a
183. Ralph DD, Springmeyer SC, Sullivan KM, transplant recipient. Eur Resp J transplanted lung derive from recipient
et al. Rapidly progressive air-flow 1998;11:971–4. immune cells. Eur Respir J
obstruction in marrow transplant 194. Baz MA, Kussin PS, Vantrigt P, et al. 2005;26:549–52.
recipients. Possible association between Recurrence of diffuse panbronchiolitis after 205. Garver RI, Zorn GL, Wu X, et al.
obliterative bronchiolitis and chronic lung transplantation. Am J Respir Crit Care Recurrence of bronchioloalveolar
graft-versus-host disease. Am Rev Respir Med 1995;151:895–8. carcinoma in transplanted lungs. N Engl J
Dis 1984;129:641–4. 195. Parker LA, Novotny DB. Recurrent alveolar Med 1999;340:1071–4.
184. Alton EWFW, Khagani A, Taylor RFH, et al. proteinosis following double lung 206. Pham PT, Pham PC, Danovitch GM, et al.
Effect of heart–lung transplantation on transplantation. Chest 1997;111:1457–8. Sirolimus-associated pulmonary toxicity.
airway potential difference in patients with 196. Etienne B, Bertocchi M, Gamondes JP, et Transplantation 2004;77:1215–20.
and without cystic fibrosis. Eur Respir J al. Relapsing pulmonary Langerhans cell 207. Garrean S, Massad MG, Tshibaka M, et al.
1991;4:5–9. histiocytosis after lung transplantation. Sirolimus-associated interstitial
185. Tsang VT, Alton EWFW, Hodson ME, et al. Amer J Respir Crit Care Med pneumonitis in solid organ transplant
In vitro bioelectric properties of bronchial 1998;157:288–91. recipients. Clinical Transplantation
epithelium from transplanted lungs in 197. Habib SB, Congleton J, Carr D, et al. 2005;19:698–703.
recipients with cystic fibrosis. Thorax Recipient Langerhans cell histiocytosis 208. Hamour IM, Mittal TK, Bell AD, et al.
1993;48:1006–11. recurring following bilateral lung Reversible sirolimus-associated
186. Corris PA, Dark JH. Aetiology of asthma transplantation. Thorax 1998;53:323–5. pneumonitis after heart transplantation.
– lessons from lung transplantation. 198. Gabbay E, Dark JH, Ashcroft T, et al. J Heart Lung Transplant 2006;25:241–4.
Lancet 1993;341:1369–71. Recurrence of Langerhans’ cell
187. Kazerooni EA, Jackson C, Cascade PN. granulomatosis following lung Future prospects
Sarcoidosis: recurrence of primary disease transplantation. Thorax 1998;53:326–7. 209. Steen S, Ingemansson R, Eriksson L, et al.
in transplanted lungs. Radiology 199. Nine JS, Yousem SA, Paradis IL, et al. First human transplantation of a
1994;192:461–4. Lymphangioleiomyomatosis recurrence nonacceptable donor lung after
188. Martinez FJ, Orens JB, Deeb M, et al. after lung transplantation. J Heart Lung reconditioning ex vivo. Ann Thorac Surg
Recurrence of sarcoidosis following Transplant 1994;13:714–9. 2007;83:2191–4.
bilateral allogeneic lung transplantation. 200. O’Brien JD, Lium JH, Parosa JF et al. 210. Ingemansson R, Eyjolfsson A, Mared L,
Chest 1994;106:1597–9. Lymphangiomyomatosis recurrence in the et al. Clinical transplantation of initially
189. Walker S, Mikhail G, Banner N, et al. allograft after single-lung transplantation. rejected donor lungs after reconditioning
Medium term results of lung Am J Respir Crit Care Med ex vivo. Ann Thorac Surg 2009;87:255–60.
transplantation for end stage pulmonary 1995;151:2033–6. 211. Pego-Fernandes PM, de Medeiros IL,
sarcoidosis. Thorax 1998;53:281–4. 201. Bittmann I, Dose TB, Muller C, et al. Mariani AW, et al. Ex vivo lung perfusion:
190. Mal H, Guignabert C, Thabut G, et al. Lymphangioleiomyomatosis: Recurrence initial Brazilian experience. J Bras Pneumol
Recurrence of pulmonary emphysema in after single lung transplantation. Hum 2009;35:1107–11.
an α1 proteinase inhibitor-deficient lung Pathol 1997;28:1420–3.

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 Chapter 12 

Tumours
12.1  Carcinoma of the lung

CHAPTER CONTENTS Large cell carcinoma 561

Adenosquamous carcinoma 564
Incidence and mortality 531 Sarcomatoid carcinoma 566
Aetiology 532 Prognostic factors 570
Smoking 532 Staging: the role of the pathologist 570
Environmental carcinogens 533 Histological type and grade 573
Ionising radiation 533 Other prognostic factors 573
Asbestos 533 Developments in treatment 574
Other industrial chemicals 534 References 575
Diet 534
Pulmonary fibrosis 534
Viruses 535
INCIDENCE AND MORTALITY
Heredity 535
Malformations 535
The last 100 years have seen the incidence of lung cancer transformed
Pathogenesis 535 from it being an almost unknown disease to it far outstripping all
Premalignant changes evident morphologically 535 other forms of cancer as a cause of death in many western countries.
Genetic factors in the development of lung cancer 539 The death rate from lung cancer exceeds 60 per 100 000 in Great
Screening for lung cancer 541 Britain and is close to this in many developed countries. In British
men, it is responsible for about 35% of cancer deaths, and about 8%
Site of origin and spread 542 of all deaths, whilst in women it now rivals breast cancer as the major
Clinical effects 542 cause of cancer mortality. In many developed countries the incidence
An asymptomatic solitary pulmonary nodule in men has levelled off and in some it has started to decline, but in
(‘coin lesion’) 542 women it is still rising,1 the lag being almost totally due to women
Local effects 542 taking to smoking later than men. The male-to-female ratio was nearly
equal in England and Wales at the end of the nineteenth century but
Intrathoracic spread 543
climbed to 6 by 1951.2 Now it is again verging on equality as deaths
Extrathoracic spread 544 in men decline slightly and deaths in women rise at a rate comparable
Paraneoplastic manifestations 544 to that seen in men in the first half of the twentieth century.
Diagnostic procedures for obtaining tumour material 546 Furthermore, for a given level of smoking women are at higher risk of
Histological typing 547 developing lung cancer than men.3–5 A higher level of aromatic DNA
adducts (indicating DNA damage) is reported in the lungs of female
Squamous cell carcinoma 549
smokers.6
Adenocarcinoma 553 Many developing countries have a relatively low incidence of lung
Small cell carcinoma 559 cancer but are beginning to see the rises already experienced elsewhere

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00012-4 531
 Pathology of the Lungs

Wales Smoking
Scotland
The evidence linking cigarette smoking and lung cancer was first estab-
England
lished in the early 1950s when the smoking habits of large groups of
Denmark patients with lung cancer were compared with those of matched con-
Czech republic trols. These provided clear evidence that the majority of patients with
Estonia carcinoma of the lung were heavy cigarette smokers and that the
Poland
incidence of the disease in non-smokers was low.13–15 Later prospective
studies, in which the incidence of lung cancer was determined over a
Slovakia
long period of time in large groups of people with different smoking
Slovenia habits, were even more conclusive. One of the best known of these
Europe studies was carried out in the UK on a group of 40 000 doctors. In
Spain 1951, each completed a questionnaire asking for details of their
Finland smoking habits. By 1964 there was ample evidence of a clear link
between cigarette smoking and deaths from lung cancer.16,17 Similar
Iceland
studies were carried out in the USA with identical conclusions.18,19
Italy These studies established that the risk of lung cancer is increased in
Switzerland smokers compared with non-smokers by a factor of 10. Pipe smokers
Netherlands and cigar smokers have a significantly lower incidence than cigarette
Austria smokers, probably due to them not inhaling their smoke to the same
degree.20 The risk increases with the number of cigarettes smoked and
France
is proportional to the length of time a person has smoked, being
USA greatest in those who commenced at an early age.18 The term ‘pack
years’ is often used to quantify this combination of risk factors, ‘1 pack
0 5 10 15 20 25 30 35 40 45 50
year’ equating to 20 cigarettes per day for 1 year or 40 per day for 6
1-year 5-years months. In those who stop smoking, the risk begins to decline
immediately but it takes about 15 years for the risk in ex-
Figure 12.1.1  National 1-year and 5-year survival rates (%) from lung smokers to approach that of non-smokers.16 The incidence of lung
cancer in men. Rates in women are slightly better but broadly similar.10,11
cancer is increased in those with other smoking-related diseases,
such as chronic bronchitis.21
The risk of lung cancer is reduced by switching to filter tip and
as the inhabitants take to smoking in increasing numbers. There are low-tar cigarettes,22 and from cigarettes to cigars or pipes.23 However,
also substantial racial differences in susceptibility to the carcinogenic it is suggested that the switch to low-tar cigarettes has led smokers to
effect of cigarette smoke. For example, at any level of smoking black inhale more deeply and thereby contributed to the increased inci-
Americans have a risk of lung cancer 1.8 times greater than that of dence of peripheral tumours.24 There is no clear evidence that French
their white compatriots.3 It is likely that in the twenty-first century cigarettes, which contain air-cured tobacco, are any safer than those
there will be a significant shift in the geographical distribution of lung made of flue-cured tobacco, but the resultant smoke is more alkaline
cancer. and the contained nicotine can be absorbed from the mouth.
Lung cancer is largely a disease of later life. In patients younger than Consequently, fewer French than British cigarette smokers admit to
40 years of age there is a lower male-to-female ratio and a higher inhaling their smoke and this may contribute to the observed lower
proportion of adenocarcinoma but as in the elderly cigarette smoking incidence of lung cancer in France than the UK, but there are
is the most important cause.7 The tumour is very rare in children but other differences between the two countries: dietary differences are
occasional cases are encountered.8 mentioned below.
Lung cancer carries a very poor prognosis. Surgical survival figures Passive smoking, which is exposure to the cigarette smoke exhaled
may reach 46% (and nearly 60% for T1N0M0 tumours)9 but they are by others and the smoke emitted by their smouldering cigarettes
based on a highly selected group of patients. Spread of the tumour (referred to as mainstream and sidestream smoke respectively), carries
often results in it being inoperable at presentation while many patients a small risk of lung cancer.25,26 Compared with a non-smoker, the
with lung cancer also have coexistent chronic obstructive lung disease increased risk of lung cancer is generally quoted as a percentage for a
that renders them unfit for surgery. Overall 5-year survival rates vary passive smoker but so-many-fold for an active smoker, the respective
from 6% to 14%, the variation being mainly attributable to national figures being in the order of 25% and 13-fold (which equate to 1.25-
differences in access to specialist care (Fig. 12.1.1).10–12 Note also has fold versus 13-fold). A comparison of nicotine metabolite levels sug-
to be taken of the significant number of patients who suffer recurrence gests that passive smoking entails an exposure equivalent of up to 1
more than five years after apparent eradication of their tumour; 11% cigarette a day. It is estimated that passive smoking accounts for one
in one study.12a extra death from lung cancer or heart disease for every 10 000.
Numerous carcinogens have been identified in cigarette smoke. The
more important ones are listed in Box 12.1.1. Many of them are
thought to act by binding to DNA. Of particular note are the polycyclic
AETIOLOGY hydrocarbons found in the neutral fraction of the particulate phase
and the nitrosamines of the basic fraction. The former has been linked
There is convincing evidence that cigarette smoking is by far the most to squamous cell carcinoma and the latter to adenocarcinoma.27
important cause of lung cancer. This is based mainly on sound epi­ There appears to be genetic susceptibility to the carcinogenic effects
demiological studies, supplemented by pathological findings. Other of these chemicals, which is possibly based on differences in the
factors have been identified but these are considerably less important amounts of activating enzymes in the lung, many of which are P450
than cigarette smoking. cytochromes.28

532
 Tumours Chapter | 12 |

Saxony from the Czech Republic. For four centuries ore from these
Box 12.1.1  Major carcinogens of tobacco smoke mountains has proved a rich source of many metals – silver, copper,
lead, cobalt, bismuth, iron and, recently, uranium. For much of this
Particulate phase time, miners in Schneeberg on the Saxony side and Joachimstal on
Neutral fraction Benzpyrene the Czech side suffered from a fatal respiratory disease – Bergkrankheit
Dibenzanthracene – that was recognised as lung cancer in the late nineteenth century. It
Benzofluoranthenes is estimated that as many as 50% of the miners died from this cause;
Basic fraction Nitrosamines the average time from starting work in the mines to the development
Residual fraction Nickel of a tumour was about 17 years. The overall risk of developing lung
Cadmium cancer was about 30 times that of the general population and repeated
Polonium-210 widowhood was commonplace. The lung cancer is attributable to the
Vapour phase miners being exposed to very high levels of ionising radiation in the
Nickel carbonyl form of radon gas that is emitted from the rock face and when inhaled
Hydrazine subjects the respiratory epithelium to α-irradiation.
Vinyl chloride Similar increases in lung cancer incidence were seen in North
Nitrogen oxides American miners exposed to radon and its daughter products41,42 and
Nitrosodiethylamine such exposure probably accounts for the increased incidence seen in
English haematite miners.43 The increase involves both squamous cell
carcinoma and small cell carcinoma, but particularly the latter.44,45
Cigarette smoking is an important cofactor . The increased risk is 67
times greater in heavy smokers exposed to heavy doses of irradiation
Direct evidence of the effects of cigarette smoke on bronchial than in non-smokers with comparable radiation exposure, indicating
epithelium is provided by pathological studies, which demonstrate a multiplicative effect, as seen with asbestos.46,47
a close association between metaplasia and atypia and the number Radon levels may also reach dangerous levels within the home; the
of cigarettes smoked.29,30 Long-term animal experiments have been degree of danger depends on the character of the underlying rock.48,49
difficult to institute but have provided further supportive evidence of It is difficult to prevent radon seeping into buildings and easier to
the link between tobacco smoke and lung cancer.31,32 instal solid floors over a radon sump that can be exhausted to the
Cigarette smoking predisposes to pulmonary carcinoma of all the exterior. Many countries have policies to control indoor radon, usually
major histological types, but the link is strongest with squamous cell focusing on buildings where radon levels exceed a certain level,
and small cell carcinoma, which generally arise in central airways, and although there is evidence that in some countries it would be cost-
weakest with adenocarcinoma, which is commoner in the periphery effective if basic preventive measures were required for all new
of the lung.33,34 homes.50
There is also an increased incidence of lung carcinoma in patients
Environmental carcinogens given therapeutic irradiation, for example to the spine for ankylosing
spondylitis51 and to the breast for mammary carcinoma.52,53
As with constituents of cigarette smoke, many inhaled chemicals are Survi­vors of the Hiroshima and Nagasaki nuclear bombings were
not hazardous as such but are transformed to reactive intermediates also at increased risk of lung cancer.54,55
within the lungs by enzymes such as N-acetyl transferase, glutathione-
S-transferase and members of the P450 family. After allowing for
differences in smoking habits it is found that the risk of lung cancer
Asbestos
is higher in urban areas than in rural areas, suggesting a role for An association between exposure to asbestos and carcinoma of the
general atmospheric pollution.35,36 Major atmospheric pollutants lung was first demonstrated conclusively in 1955.56 As with meso­
include polycyclic hydrocarbons from the combustion of fossil fuels. thelioma, the association is stronger with amphibole asbestos than
Domestic coal fires were formerly the prime source of polycyclic chrysotile, but with all forms of asbestos much higher levels of expo-
hydrocarbons in the UK and it was estimated that in the 1950s air sure are required to produce carcinoma than mesothelioma. All
pollution accounted for about 10% of lung cancer in men.37 Since that histolo­gical types are involved but the proportion of adenocarcinoma
time coal fires have been eliminated in most major conurbations and is increased.57–59 Cigarette smoking is an important cofactor. In a study
concentrations of benzpyrene have fallen dramatically. The main of 17 800 asbestos workers the risk in smokers was 14 times that in
source in the UK, as in many countries, is now motor vehicle exhaust non-smokers.60 Table 7.1.7 (p. 349) provides further data on this,
and particular attention is being paid to diesel smoke. Some epi­ showing that the lung cancer risk for workers heavily exposed to
demiological studies have identified an increased risk of lung cancer asbestos is 5 times that of unexposed persons whatever their smoking
in occupational groups having heavy exposure to diesel exhaust, status, while the risk for smokers is 11 times that of non-smokers
notably one that examined American maintenance workers exposed whether they are exposed to asbestos or not. As a consequence, the
to fumes from diesel locomotives.38 A review by an international lung cancer incidence among smokers exposed to asbestos is 53 times
agency concluded that there was evidence that diesel engine exhaust higher than that among unexposed non-smokers – a multiplicative
was carcinogenic in experimental animals and that there was limited rather than additive effect.61 The risk diminishes in those who cease
support for this in humans.39 There appears to be only a weak link smoking. A practical preventive point arising from this is that most of
between urban nitrogen oxide and sulphur dioxide pollution and lung the excess risk can be abolished by eliminating or decreasing exposure
cancer.40 to either asbestos or cigarette smoke. Also, it suggests that asbestos
acts as a promoting agent rather than a primary carcinogen. The vexed
question of whether asbestos causes lung cancer in the absence of
Ionising radiation asbestosis is considered on page 349. Asbestos fibre burdens are gene­
One of the earliest examples of occupational lung cancer is provided rally low in lungs resected because of cancer, indicating that asbestos
by the miners of the Erzgebirge (‘ore mountains’), which separate is not a major cause of lung cancer in the general population.62,63

533
 Pathology of the Lungs

Exposure to the alkylating agent chloromethyl methyl ether, which

Box 12.1.2  Occupational agents associated with lung is used as a cross-linking agent in ion exchange resins and as an
cancer, categorised by the criteria of the International intermediate in the production of organic chemicals, carries an in­­
Agency for Research on Cancer64 creased risk of lung cancer, particularly if there is contamination with
bis(chloromethyl) ether.76 Small-cell carcinoma is particularly
Known carcinogens (group 1) increased.77
Arsenic Epidemiological studies have also incriminated silica exposure as a
Asbestos risk factor for lung cancer, and as with asbestos there is uncertainty as
Bis(chloromethyl)ether to whether the risk is due to high silica levels alone or to the fibrotic
Chromium, hexavalent process.78 Claims for compensation are therefore more likely to
succeed if silicosis as well as carcinoma can be demonstrated.
Nickel and nickel compounds
Polycyclic aromatic compounds
Radon Diet
Vinyl chloride
Many of the differences in disease incidence seen between
Probable carcinogens (group 2A) Mediterranean and northern European countries have been ascribed
Acrylonitrile to diet, especially the differing intake of antioxidants. Dietary differ-
Beryllium ences are probably important in regard to cardiovascular disease but
Cadmium may also affect cancer incidence. Many cigarette smokers have there-
Formaldehyde fore gleefully increased their consumption of red wine on evidence
that is to date at best equivocal.79
Possible carcinogens (group 2B) Vitamin A deficiency leads to squamous metaplasia of mucosal
Acetaldehyde surfaces, dryness of the skin, eyes and mouth, and to an increased
Manmade fibres susceptibility to cancer.80 Cigarette smoke augments the metaplastic
Silica action of vitamin A deficiency in rats,81 whilst in humans low vitamin
Welding fumes A intake leads to an increased incidence of lung cancer in smokers.82
Folate is another dietary component that protects against squamous
metaplasia.83 Diets high in carotenoid-rich fruits and vegetables are
associated with a reduced risk of lung cancer, as are high serum levels
of vitamin E and beta-carotene, but long-term dietary supplement­
Other industrial chemicals ation with these substances either had no effect or resulted in a
slightly higher incidence of lung cancer in male smokers.84–86
Apart from asbestos and ionising radiation, six other agents encoun-
tered in industry are accepted pulmonary carcinogens: arsenic, chlo-
romethyl ethers, chromium, nickel, polyaromatic hydrocarbons and Pulmonary fibrosis
vinyl chloride. Many others, including cadmium, formaldehyde and
dioxin, are suspected of having a similar effect (Box 12.1.2).64 Cigarette Idiopathic pulmonary fibrosis is associated with a 14-fold increased
smoking is often an additional factor.65 incidence of lung cancer,87–89 similar to that noted above in asbesto-
Workers in the coal gas industry exposed to polyaromatic hydro­ sis.60 In both these diseases, the tumours are of all histological types
carbons have a lung cancer risk twice that of the general population,66 and they arise more frequently in the periphery of the lower lobes
and lung cancer has also been associated with a range of metal- where the fibrosis is most marked.90,91 Although the original
refining and smelting processes: nickel, chromium, arsenic and publications suggested that adenocarcinoma was the most common
cadmium have all been incriminated.67,68 In the 1930s a higher inci- histological type, it is now believed that the cell-type distribution is
dence was reported amongst workers at the Clydach nickel refinery in similar to that in the general population.58 Sarcoidosis has been
south Wales. Changes in the process later resulted in a reduction of reported to convey an increased risk of lung cancer in some studies92,93
the risk but the hazard remains in several other nickel refineries.69 but not in others.94
Exposure to both nickel and cadmium was related to lung cancer in In contrast to these forms of diffuse pulmonary fibrosis, the role of
workers in a battery plant.70 Poorly soluble hexavalent chromium pig- localised scars in the development of lung cancer is now questioned.
ments cause lung cancer but very soluble chromium compounds are Many adenocarcinomas show pronounced pleural puckering due to
comparatively safe.71,72 central scarring (see Fig. 12.1.23, p. 554) and have often been assumed
Arsenic and its compounds are associated with skin and lung to represent ‘scar cancers’, meaning that the scar preceded and predis-
carcinomas, an increased incidence being found in people adminis- posed to the cancer. However, it is often impossible to tell whether
tered arsenic therapeutically, in vineyard workers involved in spraying the tumour developed in a pre-existing scar, and can therefore be
arsenical insecticides, and in copper smelters exposed to arsenic.73 designated a true scar cancer, or whether the central scar is secondary
Arsenic may also be responsible for an increased risk of lung cancer to the tumour.95 Nevertheless, there is considerable evidence, both
identified in antimony workers.74 It is also anticipated that the next radiological and pathological, supporting the view that the scar is the
decade will witness widespread arsenic-induced cancer in Bengal and product of the tumour rather than the reverse. Relevant radiological
Bangladesh following the provision of water free of bacterial contami- observations96 include the following:
nation by extraction from shallow aquifers. Up to 10 million shallow • a scar is not usually evident in previous radiographs
tube wells have been dug and it is estimated that 1 million of these • as peripheral tumours develop they may shrink in size despite
are heavily contaminated with naturally occurring arsenic released by involving a greater proportion of the affected lobe
anaereobic metal-reducing bacteria.75 At least 100 000 cases of arsenic- • initially soft opacities often become more opaque centrally
induced skin growths have been identified and it seems inevitable that • adjacent airways and blood vessels increasingly converge on the
cancer of the skin and respiratory tract will follow. tumour.

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Pathological observations97–101 supporting the view that central scars Malformations

are usually a product of the tumour rather than the reverse include
the following: The cystic type 1 congenital pulmonary airway malformation is often
accompanied by focal mucous cell hyperplasia that occasionally
• the size of the scar generally matches that of the tumour
undergoes malignant transformation, usually to a mucinous
• similar scars develop in extrapulmonary metastases
adenocarcinoma of predominantly lepidic pattern (see p. 59),
• similar scars are found in the pulmonary metastases of other
but the common hamartoma (see p. 626) is not a precursor of bron-
adenocarcinomas
chopulmonary carcinoma.119–121
• psammoma bodies derived from the carcinoma may be found
deep within the central scar
• the scars often show a predominance of myofibroblasts and type
III collagen PATHOGENESIS
• elastin stains often show that the central scar is formed on an
area of collapse consequent upon airway or arterial obstruction
by the tumour. Premalignant changes
Irrespective of whether the scar or the tumour comes first, central evident morphologically
scarring in a pulmonary adenocaricoma is an adverse prognostic indi- Carcinoma of the lung largely arises from the epithelial cells lining
cator, being associated with increased vascular and pleural invasion the air spaces. The few carcinomas that develop in the bronchial
and lymph node metastasis.97,102 glands are dealt with in the next chapter. The next chapter also con­
siders diffuse neuroendocrine hyperplasia as a precursor of tumourlets
Viruses and carcinoids (but not of small cell carcinoma). Attention here is
confined to the precursors of squamous cell carcinoma and adenocar-
Viral oncogenes participate in carcinogenesis by the RNA of the viral cinoma. No precursor of small cell carcinoma has been identified.
genome being transcribed into the DNA genome of the host by the Four main cell types make up the surface epithelium of the bronchi
enzyme reverse transcriptase. The DNA sequences transcribed by viral – basal, mucous, neuroendocrine and ciliated – and only the last of
oncogenes are virtually identical to sequences in the cellular DNA of these appear to be end cells. The others are all capable of division and
most animal species and presumably have the same potential for thus have malignant potential. Clara cells and type II pneumocytes
affecting malignant growth as cellular oncogenes. Viruses have been are the respective stem cells of the bronchioles and the alveoli and are
suggested in the past as being related to the development of some found in some adenocarcinomas of the lung.
lung cancers, and the application of molecular probes has given some
impetus to such investigations. Papillomavirus of types 6 and 11 is
commonly found in tracheobronchial papillomatosis and in Squamous metaplasia and dysplasia
the rare papillary squamous carcinomas that complicate papilloma- The regenerative capability of bronchial epithelial cells has been
tosis103 while type 18 has been identified in a small proportion of the extensively studied. Hyperplasia of the surviving basal cells is an early
more common non-papillary squamous cell carcinomas of the regenerative event that is followed by the development of a stratified
bronchus.104 Particularly notable is an exceptionally high rate of squamous epithelium.122 Further differentiation into mucous cells
human papillomavirus 16- and 18-positive lung cancers in non- and thence ciliated cells follows but mucous differentiation is depend-
smoking Taiwanese women.105 Epstein–Barr virus has been shown to ent upon the availability of vitamin A.81,123 The application of carcino-
be associated with bronchopulmonary as well as nasopharyngeal gens such as benz-pyrene, asbestos or nitrosamines results in the
lymphoe­pitheliomas but with only occasional lung tumours of proliferation of bronchial neuroendocrine cells, which may undergo
the more common histological types.106,107 There is an increased squamous metaplasia.124–126 It is clear therefore that basal, mucous,
incidence of lung cancer in acquired immunodeficiency syndrome neuroendocrine and metaplastic squamous cells are closely related
(AIDS) but this is not thought to be directly attributable to the human and readily transform one to another. This marked metaplastic poten-
immunodeficiency virus.108 tial of the bronchial epithelium provides no support for facile
suppositions regarding the histogenesis of particular types of
lung carcinoma from particular precursor cells.
Heredity The sequence of hyperplasia–metaplasia–dysplasia–carcinoma-in-
The great majority of smokers reaching old age do not die of lung situ–invasive carcinoma (Fig. 12.1.2) is well documented in human
cancer, suggesting that individuals differ greatly in the way they airways127–129 and a grading system, which details the histological
metabolise xenobiotic substances.109 These differences are presumably features evident in the surface epithelium, has been introduced (Table
inborn. Genetic differences could influence the risk of cancer in 12.1.1).130 Changes are also found in the mucosal blood vessels.
several ways.110 They could affect the enzymatic elimination or activa- Several groups have described hyperplastic capillary loops in close
tion of carcinogens,111,112 or the expression of oncogenes or tumour apposition to dysplastic epithelium, giving rise to the term ‘angiogenic
suppressor genes (see below). Epidemiological studies have shown an squamous dysplasia’.131 The vascular changes can be detected by
excess of lung cancer in close relatives, identifying an approximately fluorescence bronchoscopy, suggesting that it may be possible to
twofold-increased risk of lung cancer in those with a family history of eradicate the lesions before they become invasive.132
the disease.113–115 Various genes conferring increased susceptibility to Uranium miners in the USA provided cytopathologists with the
lung cancer have now been identified.116,117 Those located on chromo- opportunity of studying the gradual evolution of bronchial
somes 6 and 15 are particularly notable, chromosome 15 being the carcinoma. Periodic sputum examination showed squamous metapla-
site of the nicotinic acetylcholine receptor gene cluster. The sia followed by gradually increasing cellular atypia in those miners
susceptibility these genes confer appears to be unrelated to smoking who later developed invasive carcinoma of either squamous or small
status or propensity to smoke tobacco.118 The role of genetic factors cell type. Atypical cells could be identified in the sputum for many
in the development of lung cancer is dealt with more extensively years prior to the development of invasive tumours: on average, dys-
below, under pathogenesis. plastic changes lasted 8 years and carcinoma-in-situ a further 4 years

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 Pathology of the Lungs

cally normal, including foci of carcinoma-in-situ and occasional

microinvasive cancers distant from the main tumour.
Foci of hyperplasia, metaplasia and dysplasia are also frequently
seen adjacent to invasive tumours in surgical specimens,134 and similar
changes have been described in experimental dogs exposed to cigarette
smoke.31 Full-thickness squamous metaplasia is not necessary before
atypical features are seen in the proliferating basal cells; dysplasia may
be present beneath an intact surface layer of columnar cells.29 The
transition from normal bronchial epithelium to squamous epithelium
is usually abrupt. Atypical epithelium may extend deeply into
bronchial glands replacing duct and acinar lining cells, resulting in
appearances that mimic microinvasive carcinoma, but the
basement membrane as yet remains intact.
The risk of squamous metaplasia and dysplasia progressing to inva-
A sion has been assessed by following patients with these lesions by
periodic bronchoscopy. One study extending for up to 7 years put the
risk at 4% for squamous metaplasia, 9% for low-grade dysplasia and
32% for high-grade dysplasia.135 Another extending over a similar
period found that low-grade dysplasia did not progress at all but
that the risk of progression in severe dysplasia/carcinoma-in-situ
was 17%.136
In view of the extent of these premalignant changes, it is not surpris-
ing that there is a high incidence of double or second primary lung
cancers.137,137a Even triple primary tumours are described.138 Using
standard criteria of a double primary growth, namely involvement of
different lobes, or different histological types, or a time interval over
3 years,139 it has been shown that 4% of lung cancer patients have
more than one lung tumour at presentation and that a further 6%
develop a second primary lung growth later.137,137a The patients most
at risk of developing lung cancer are therefore those who have had
one in the past. These patients might therefore be worth following up
particularly frequently.
B
Patients with squamous dysplasia or carcinoma-in-situ may be
asymptomatic or present with cough and haemoptysis. However, it is
often difficult to know how much their cough is due to the dysplastic
change rather than other smoking-related diseases such as chronic
bronchitis. The epithelial changes are focal, usually developing at the
bifurcations of segmental bronchi and subsequently extending proxi-
mally and distally. They are sometimes evident as a grey plaque but
are not always visible to the bronchoscopist, particularly when routine
white light is used. Autofluorescence bronchoscopy is more sensi-
tive.140 Treatment is problematical because the lesions are frequently
multiple. Patients are therefore often followed up by serial bronchos-
copy until early invasion is apparent when the lesion may be treated
by local ablation or surgical resection.141

Atypical adenomatous hyperplasia and

adenocarcinoma-in-situ
C The hyperplasia–dysplasia–neoplasia sequence is again encountered
in the periphery of the lung, where it is important in the development
Figure 12.1.2  Smokers’ bronchi showing (A) basal cell hyperplasia (left) of non-mucinous adenocarcinomas,142,143 particularly when there is
and squamous metaplasia (right), (B) squamous dysplasia and   diffuse pulmonary fibrosis.87–89 More recently it has been recognised
(C) carcinoma in situ (right). that focal alveolar hyperplasia in the absence of fibrosis is an impor-
tant precursor of pulmonary adenocarcinoma, evolving through a
stage of adenocarcinoma-in-situ to invasive adenocarcinoma. The
before there was invasion (Table 12.1.2).127 Isolated foci of in situ hyperplasia phase is generally known as atypical adenomatous
squamous cell carcinoma amenable to limited surgical procedures hyperplasia,144–147 although in the past it has also been termed
are occa­sionally identified133 but at presentation invasion has bronchioloalveolar cell adenoma.148,149 Adenocarcinoma-in-situ is a
generally supervened. new term that replaces the older one of bronchioloalveolar cell
Further evidence of dysplasia preceding carcinoma came from a carcinoma.150
large autopsy study in which the whole bronchial tree was examined Remarkably, foci of atypical adenomatous hyperplasia are quite
in a series of patients dying of lung cancer.29 This showed widespread commonly found when sought in lungs resected for cancer, yet they
premalignant changes involving mucosa that appeared macroscopi- have evidently lain undiscovered by generations of pathologists

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Table 12.1.1  Morphology of squamous dysplasia and carcinoma-in-situ130

Abnormality Thickness Cell size Maturation/orientation Nuclei

Mild dysplasia Mildly increased Mildly increased Continuous progression of maturation Mild variation of N/C ratio
Mild anisocytosis and Basilar zone expanded with cellular Finely granular chromatin
pleomorphism crowding in lower third Minimal angulation
Distinct intermediate (prickle cell) Nucleoli inconspicuous or absent
zone present Nuclei vertically oriented in lower third
Superficial flattening of epithelial cells Mitoses absent or very rare
Moderate Moderately Mildly increased Partial progression of maturation Moderate variation of N/C ratio
dysplasia increased Moderate anisocytosis Basilar zone expanded with cellular Finely granular chromatin
and pleomorphism crowding in lower two-thirds Nuclear angulations, grooves, lobulations
Intermediate zone confined to upper Nucleoli inconspicuous or absent
third of epithelium Nuclei vertically oriented in lower
Superficial flattening of epithelial cells two-thirds
Mitotic figures present in lower third
Severe Markedly Markedly increased Little progression of maturation from N/C ratio often high and variable
dysplasia increased May show marked base to luminal surface Chromatin coarse and uneven
anisocytosis and Basilar zone expanded with cellular Nuclear angulations and folding prominent
pleomorphism crowding well into upper third Nucleoli frequently present and
Intermediate zone greatly attenuated conspicuous
Superficial flattening of epithelial cells Nuclei vertically oriented in lower
two-thirds
Mitotic figures present in lower two-thirds
Carcinoma-in- May or may May be markedly No progression of maturation from N/C ratio often high and variable
situ not be increased base to luminal surface Chromatin coarse and uneven
increased May show marked Basilar zone expanded with cellular Nuclear angulations and folding prominent
anisocytosis and crowding throughout epithelium No consistent orientation of nuclei in
pleomorphism Intermediate zone absent relation to epithelial surface
Surface flattening only of most Mitotic figures present through full
superficial cells thickness

N/C, nuclear to cytoplasmic.

adenomatous hyperplasia most often accompanies is a non-mucinous

Table 12.1.2  Evolution of invasive squamous cell carcinoma in
adenocarcinoma, but it is sometimes a large cell or squamous cell
American uranium miners followed by periodic sputum
carcinoma.157 Multiple foci of atypical adenomatous hyperplasia may
examination127
be found, particularly in association with multiple adenocarcinomas.
Molecular studies show that individual lesions differ in their genetic
Average age at Average duration
make-up, establishing that they are independent of each other and of
onset (range) (years)
any accompanying carcinoma and do not represent micrometastases
Mild atypia 48 years (38–59) 2.89 of the latter.158
Atypical adenomatous hyperplasia is a focal lesion, generally less
Moderate atypia 51 years (34–67) 3.23 than 5 mm in diameter, in which the alveoli are lined by cuboidal to
Marked atypia 55 years (38–70) 2.23 low columnar cells (Fig. 12.1.3), which have the ultrastructural fea-
tures of type II pneumocytes and Clara cells. Ciliated and mucous cells
Carcinoma-in-situ 57 years (37–70) 4.04 are not a feature.130,159 The interstitium may show some fibrosis but
Invasive carcinoma 61 years this is generally mild. Atypical adenomatous hyperplasia is distin-
guished from adenocarcinoma-in-situ by its size (generally less than
5 mm whereas most carcinomas exceed 10 mm), gaps between the
epithelial cells as opposed to a continuous cell line and the cells being
cuboidal rather than columnar (Table 12.1.3). They have dense
dealing with such specimens. Admittedly, they are generally small and chromatin, prominent nucleoli and sparse cytoplasm. Mitoses are
easily overlooked. Their identification is facilitated by immersion in rarely evident but varying degrees of atypia are observed146,160 and the
Bouin’s solution.151 They represent foci of hyperplastic type II alveolar fami­liar hyperplasia–dysplasia–neoplasia sequence is easily envis-
epithelial cells or bronchiolar Clara cells. Autopsy studies of cases free aged. Morphometry,161,162 argyrophilic nucleolar organiser counts,163
of lung cancer have identified focal adenomatous hyperplasia in DNA status,162,163 loss of heterozygosity164 and the identification of a
3–6%,152,153 while in lungs resected for cancer atypical adenomatous range of oncogenes within the atypical lesions145,161,165–170 provide
hyperplasia has been reported in up to 50% of cases, with the highest further support for this form of hyperplasia being premalignant. The
figures coming from Japan.148,151,154–157 The tumour that atypical demonstration of monoclonality suggests that it is neoplastic144,171 and

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 Pathology of the Lungs

Table 12.1.3  Atypical adenomatous hyperplasia, peribronchiolar metaplasia (lambertosis, see p. 121) and adenocarcinoma-in-situ
(formerly non-mucinous bronchioloalveolar cell carcinoma)

Atypical adenomatous Peribronchiolar metaplasia Adenocarcinoma-in-situ

hyperplasia (lambertosis)

Size <5 mm <5 mm >10 mm

Cell shape Cuboidal Columnar Columnar or cuboidal
Intercellular gaps Present Absent Absent
Fibrosis Mild Moderate Mild
Cilia Absent Present Absent
Nuclear atypia Present Absent Present

Figure 12.1.4  Adenocarcinoma-in-situ, formerly bronchioloalveolar

carcinoma. The tumour cells grow along the alveolar walls without
disrupting them in a so-called lepidic (scale-like) fashion. There is no
evidence of invasive activity.

its non-invasive nature. The lesional cells grow along the alveolar walls
without destroying them (Fig. 12.1.4), a pattern of growth known as
lepidic, meaning scale-like (as in the scales of a fish). Two forms of
bronchioloalveolar carcinoma have traditionally been described,
mucinous and non-mucinous, but it is now recognised that the
mucinous variety almost always shows some invasive activity.
Adenocarcinoma-in-situ is therefore almost always non-mucinous
while the great majority of tumours formerly classified as mucinous
bronchioloalveolar carcinoma are now termed mucinous adenocarci-
Figure 12.1.3  A focus of atypical adenomatous hyperplasia identified in noma of predominantly lepidic pattern. The latter is accordingly
a random section of lung excised because of carcinoma. described later on page 554. Only non-mucinous adenocarcinoma-in-
situ will be described here.
Non-mucinous adenocarcinom-in-situ predominates in smokers
and is usually evident radiologically as a ground-glass opacity. It con-
it is now widely regarded as being the precursor of most peripheral sists of Clara cells or type II pneumocytes, often in combination (Fig.
adenocarcinomas. Nevertheless, the presence of multiple foci of atypi- 12.1.5).172,173 The Clara cells have a narrow base and a bulbous apex,
cal adenomatous hyperplasia does not appear to be related to patient resulting in a characteristic ‘hobnail’ pattern. On occasion it can be
survival.149,155 Patients without cancer who are found to harbour this difficult to distinguish the tumour from reactive hyperplasia but a tall
lesion should be kept under surveillance: further intervention is not columnar cell shape, cellular crowding, cytological atypia and papil-
warranted. lary infolding all favour malignancy. The presence of cilia does not
As mentioned above, adenocarcinoma-in-situ is a new term that exclude malignancy,174 but renders it unlikely. Immunocytochemistry
replaces bronchioloalveolar carcinoma.156 Its new name reflects better and molecular studies emphasise the differences between non-

538
 Tumours Chapter | 12 |

Normal epithelium
9p and 3p losses

Hyperplasia
17p loss

Mild dysplasia
Telomerase activation

Moderate dysplasia
p53 mutation VEGF overexpression

Severe dysplasia
p16 inactivation, cl2 overexpression

In situ carcinoma
Cylins D1 and E overexpression
A

Invasive carcinoma
Figure 12.1.6  Bronchial carcinogenesis is a multistep process
characterised by the gradual accumulation of genetic and molecular
abnormalities. (Redrawn from a diagram provided by Prof S Lantuejoul, Grenoble,
France.)

single cells also favour invasion.184 The presence of intraluminal

macrophages implies continuity between the malignant cells and sur-
rounding alveolar spaces, favouring non-invasive growth. Conversely,
basement membrane stains, such as those recognising type IV colla-
gen, facilitate the identification of invasion.182,185,186 They also demon-
strate that the epithelial basement membrane is usually destroyed
when there is central fibrosis.187 Not surprisingly, therefore, it has
B
been shown that prominent central scarring as opposed to simple
collapse is an adverse prognostic feature in small peripheral lung
Figure 12.1.5  Adenocarcinoma-in-situ. (A) In this field the tumour cells cancers.97,102,181,188 The terms Noguchi types A–C have come into use:
are cuboidal and largely comprise type II pneumocytes whereas hobnail
type A is an in-situ adenocarcinoma that shows no collapse, type B an
or peg-shaped Clara cells predominate in (B).
in-situ adenocarcinoma that shows collapse and type C an acinar
adenocarcinoma in which invasion is detected within a central scar.
It is envisaged that these represent successive stages in the evolution
mucinous adenocarcinoma-in-situ and mucinous adenocarcinoma
of a peripheral adenocarcinoma.
of predominantly lepidic pattern.175 Non-mucinous adenocarcinoma-
The multifocal micronodular hyperplasia of type II pneumocytes
in-situ expresses the pulmonary marker thyroid transcription
reported in tuberous sclerosis (see p. 701) is not recognised as being
factor (TTF-1) but fails to stain with the colonic marker cytokeratin
premalignant.
20 whereas the reverse is found with mucinous adenocarcinoma
An infectious disease of sheep known as jaagsiekte, droning sickness
of predominantly lepidic pattern.176–179 Also, non-mucinous
or pulmonary adenomatosis closely resembles human adenocarcinoma-
adenocarcinoma-in-situ often displays mutation of the epidermal
in-situ189 but the two are considered to be separate diseases. A report
growth factor receptor (EGFR) gene whereas mucinous adeno­
of a protein immunologically related to the jaagsiekte sheep retrovirus
carcinoma of predominantly lepidic pattern shows K-ras but not
in some human lung carcinomas190 has not been supported by
EGFR when a mutation is present.180
subsequent molecular investigations.191
Invasive activity excludes a diagnosis of adenocarcinoma-in-situ but
it can be difficult to recognise early invasion, particularly when there
is alveolar collapse. The distinction is important because patients with Genetic factors in the development
adenocarcinoma-in-situ show 100% 5-year survival whereas invasion
of lung cancer
implies metastatic potential.181 Microinvasion, defined as invasion no
greater than 5 mm, carries a prognosis intermediate between that of That the morphological changes described above are truly pre­
adenocarcinoma-in-situ and adenocarcinoma containing invasive malignant is supported by the demonstration that they show genetic
areas greater than 5 mm across.182,183 Collapse is recognised by the abnormalities similar to those found in adjacent invasive cancer.192,193
lining cells being similar to those in non-collapsed areas and the They reflect a multistep accumulation of genetic abnormalities, the
spaces being regularly distributed, whereas with invasive tumour number of which gradually increases as dysplasia progresses (Fig.
the acini vary in size and their lining cells are irregular. Solid nests or 12.1.6).128,194–196 The earliest molecular changes may be detected

539
 Pathology of the Lungs

proliferation. Gastrin-releasing peptide (human bombesin) is one

Box 12.1.3  Growth factors involved in pulmonary of the best-known autocrine factors and is particularly involved
carcinogenesis in the remarkably rapid growth of small cell carcinomas.214 The
Epidermal growth factor
gastrin-releasing peptide receptor gene appears to be activated by
cigarette smoke and, being located on the X chromosome, is more
Transforming growth factor
strongly expressed in women than men,215 possibly contributing to
Vascular endothelium growth factor
the greater female susceptibility to tobacco-induced lung cancer
Gastrin-releasing peptide noted above.4
Transferrin Other oncogenes important in pulmonary carcinogenesis include
Insulin-like growth factor members of the ras and myc gene families, especially K-ras and c-myc.
Endothelin Activating point mutations of ras genes result in an aberrant p21
membrane-associated protein that continuously transduces an
inappropriate growth signal. K-ras is mutated in 30% of pulmonary
adenocarcinomas,216 and particularly in smokers with mucinous ad­­
enocarcinomas.180,212,217 It is recorded in the precursor lesion atypical
before any abnormality is evident at the microscopic level. Mutations alveolar hyperplasia that is described above. K-ras mutation is there-
involving a single gene are generally insufficient to cause cancer. fore a good candidate for the early detection of lung cancer as it
Successive mutations affecting 10–20 different genes are required should be detectable in bronchioloalveolar cells shed in sputum or
before malignant change is eventually established.197 Molecular tech- recovered by lavage. K-ras and EGFR mutations are mutually exclusive,
niques therefore enable the identification of premalignant change in the former being involved mainly in smokers’ tumours and the latter
tissues that may be normal histologically.198–202 Some of the earliest mainly in non-smokers’ adenocarcinomas.210 Furthermore, K-ras
genetic changes involve loci on chromosomes 3p and 9p.203,204 mutation is possibly responsible for resistance to cisplatin and the TK
Inactivation of the p17 gene is also an early event, whereas mutations inhibitors referred to above. In adenocarcinoma, a pathway involving
involving the K-ras and p53 genes occur late in the sequence of genetic K-ras appears to be predominant in western smokers whereas the
alterations.196,205 These genetic changes promote malignant transfor- EGFR pathway appears to be more important in East Asian female
mation in a variety of ways, including enhanced cell growth by means non-smokers.210,211
of oncogene activation, inactivation of tumour suppressor genes, inhi- Myc oncogenes encode for cell cycle-specific nuclear phospho­
bition of apoptosis, altered DNA repair leading to cellular immortali- proteins and thereby control cell growth and differentiation. Their
zation and the promotion of angiogenesis.196 Important growth amplification accounts for myc protein accumulation in 20% of small
factors that have been implicated in lung cancer are listed in Box cell carcinomas and 10% of non-small cell carcinomas. Myc gene
12.1.3. They are obviously important to the prognosis of lung cancer amplification is found particularly in patients with recurrent
and are touched upon again under that heading on page 573. tumour.218–220 Conversely, myc genes are seldom amplified in carcino-
mas from patients who have not undergone treatment and thus
appear to be associated with tumour progression rather than initia-
Oncogene activation tion. Some drug regimens result in myc amplification more than
Oncogenes include those identified in viruses (v-onc genes), the others.
possible role of which in pulmonary carcinogenesis is touched upon Fusion genes have long been recognised as being important in
above, and the cellular oncogenes (c-onc genes), which control normal certain haematological malignancies and sarcomas but have not been
cell growth and differentiation and have the potential to influence thought to play a major role in epithelial tumours. Recently however
tumour behaviour. In contrast to tumour suppressor genes, which are the fusion gene EML4-ALK has been identified in non-small cell lung
dealt with next, oncogenes are generally dominant and mutation of cancer as an alternative promoter of TK activity, thus opening up the
only one allele is therefore sufficient to promote undue cell growth. possibility of further TK inhibitors being developed.221 The EML4-ALK
The activity of growth factors is largely dependent on oncogenes gene has been found in about 5–10% of lung cancers, mainly adeno-
because these involve receptors on the cell surface concerned in signal carcinomas in younger non-smokers.222–224 BRAF gene mutations are
transduction. also seen in a minority of non-small cell lung cancers, again mainly
Some of the oncogenes involved in lung cancer belong to the epi- adenocarcinomas.225,226 The Akt/mammalian (mTOR) pathway is fre-
dermal growth factor receptor family, EGFR1 (HER1), EGFR2 (HER2/ quently activated in human cancers and plays an important role in
neu, c-erbB2), HER3 and HER4. They act as transmembrane tyrosine small cell lung cancer biology.227
kinase (TK) receptors, so promoting TKs, enzymes that regulate the Further genes involved in malignant change include the human
activity of other proteins and which have been implicated in the homologue of the Drosophila neurogenic gene hASH1, which pro-
development of many cancers. They are most commonly situated on motes the growth of small cell carcinoma, large cell neuroendocrine
chromosomes 19 and 21 and their presence predicts TK inhibitor carcinoma and some atypical carcinoids,228 and members of the
response.206 They are targeted by the small-molecule TK inhibitors, Forkhead box (Fox) family, dysregulation of which has been demon-
such as gefitinib and erlotinib, and by monoclonal antibodies such as strated in squamous cell carcinomas of the lung, particularly those of
cetuximab and trastuzumab (Herceptin, which counters HER2).206–210 a more malignant nature.229
EGFR genes are especially overexpressed in papillary adenocarcino-
mas, particularly those arising in East Asian female non-smokers.210–212
Other EGFR mutations are associated with drug resistance. EGFR
Tumour suppressor genes
mutations occur early in tumour development with increased copy In contrast to oncogenes, tumour suppressor genes are generally
number being a late event.213 recessive and mutation of both alleles is therefore required for their
A structural homology between certain growth factor receptors and inactivation. The first mutation results in heterozygosity, which has
oncogenes probably underlies the autocrine activity evinced by certain little effect because the mutant gene is recessive, whereas mutation
tumours, in which the tumour secretes substances that induce self- of the other allele involves complete loss of the gene. The second

540
 Tumours Chapter | 12 |

mutation can be detected following suitable amplification, for

Table 12.1.4  Molecular markers associated with lung cancer
example by the polymerase chain reaction, as a single band on gel
electrophoresis, a change that is often termed ‘loss of heterozygosity’.
Gene mutation Chromosome Type of
Tumour suppressor genes (antioncogenes) are believed to play an
important role in the pathogenesis of lung cancer because deletions involved mutation
or mutations of certain chromosomes are frequently found, notably Proto-oncogene activation
chromosomes 3p, 13q and 17p.230–232 13q is the site of the retinoblas-
toma gene, 17p the p53 gene and 3p the FHIT (fragile histidine triad)   K-ras, Ha-ras, N-ras 12p Point mutation
antioncogene. 3p deletion is particularly common in small cell carci-   EGFR-2 (Her-2/neu, 17q Translocation
noma and 13q and 17p deletion in non-small cell carcinoma.233–235 c-erb-B2)  Ki-ras, Ha-ras,
FHIT deletion is one of the earliest mutations and p53 deletion N-ras
one of the last in the bronchial cancer gene sequence but loss of the
  c-myc, L-myc, N-myc  8 Translocation
FHIT antioncogene is relatively late in the atypical adenomatous
c-erb-B2 (Her-2/neu)
hyperplasia–adenocarcinoma-in-situ–invasive peripheral adenocarci-
(epidermal growth factor
noma sequence.168 Mutation of the EGFR is also increasingly found in
receptor gene)
the development of peripheral invasive adenocarcinomas from atypi-
cal adenomatous hyperplasia.169,236 Mutation of p53 is the commonest   bcl-2  c-myc, L-myc, N-myc 14–18 Translocation
genetic alteration in human cancer and occurs in over half of lung
cancers; p53 is normally responsible for apoptosis and abnormalities Tumour suppressor gene inactivation
of this gene are thought to permit unchecked cell proliferation. The   FHIT (fragile histidine triad 3p Deletion
normal p53 protein product is generally undetectable due to a short gene)
half-life but mutations frequently extend this so that the protein
  Retinoblastoma gene 13q Point mutation
accumulates and can be detected imunocytochemically. Accumulation
of p53 protein product has been associated with an adverse prognosis   p53 17p Deletion
in lung cancer and may provide a marker for early diagnosis of pre-
malignant states.237 Telomerase activation
The retinoblastoma gene (Rb) is the main effector of G1 arrest,
which is mediated by p53 and utilised in the repair of DNA damage.
Rb protein expression is lost in 80% of small cell lung cancer and in
15% of non-small cell lung cancer, but is not found in preinvasive
lesions.238 Inactivation of Rb is often due to methylation of p16 or
overexpression of cyclin D1.
Bax and bcl-2 (B-cell lymphoma-2) are further genes involved in
apoptosis, which is promoted by the former and blocked by the latter.
Screening for lung cancer
The bcl-2 gene is overexpressed in preinvasive lesions, a variable
number of non-small cell carcinomas of the lung,239–241 most small Lung cancer fulfils many of the criteria necessary for a successful
cell carcinomas and a variety of other lung tumours showing neuro­ screening programme. The condition is common, the population at
endocrine differentiation, thereby permitting unchecked cell risk is well known and premalignant changes can be detected cheaply
division.242,243 A high bcl-2:bax ratio generally accompanies mutation (by sputum cytology). Unfortunately the premalignant changes
of the p53 tumour suppressor gene.243 cannot be easily eradicated: there is no bronchopulmonary equivalent
of a uterine cone biopsy. Nor does screening for early invasive growths
by a combination of sputum cytology and radiography appear to
Cellular immortalisation reduce mortality.255–257 The relative failure of surgery, radical radio-
therapy and preventive screening programmes is partly explained by
Telomerase is an enzyme that adds nucleotide repeats to the ends
backward extrapolations of observed tumour size doubling times,
(telomeres) of chromosomes to compensate for the nucleotide losses
which suggest that malignant change takes place years before a tumour
that occur with each round of DNA replication.244–247 Normal somatic
is first detectable clinically (Table 12.1.5).258 Nevertheless, sparked by
cells show no telomerase activity and stop dividing when their telo­
the advances in molecular pathology described above and refinements
meres are sufficiently shortened. Telomerase can be detected in most
in high-resolution computed tomography, there has been a renewal
lung cancers and is frequently found in bronchial epithelium showing
of interest in early detection.255 For example, it appears that p53
premalignant change. The indefinite proliferation of cancer cells
immunohistochemistry may assist in the identification of pre­
probably owes much to their telomerase activity.
neoplastic lesions,192 the detection of p16INK4a inactivation in sputum
may identify smokers at increased risk of developing lung cancer,259,260
and low-dose computed tomography (CT) screening trials are
Vascular endothelium growth factor and other
proving more sensitive in detecting small peripheral tumours.261–266
autocrine factors Wedge resection rather than lobectomy is undertaken for these small
Angiogenesis is an important process in the dissemination of invasive asymptomatic lesions, with good results, particularly for those
growths and the autocrine production of vascular endothelium growth showing ground-glass opacification, which is characteristic of
factor by such lung tumours is therefore important in pulmonary adenocarcinoma-in-situ and minimally invasive adenocarcinoma of
carcinogenesis.248,249 Other autocrine factors secreted by certain lung lepidic pattern.267–270 Nevertheless, evidence-based reviews do not
tumours include epidermal growth factor (the genetic control of support general CT screening,256,257 possibly because it identifies many
which is considered above), gastrin-releasing peptide, transferrin, unimportant abnormalities and leads to unnecessary surgery (see
insulin-like growth factor and endothelin (Table 12.1.4).214,250–254 asymptomatic solitary pulmonary nodule, below).

541
 Pathology of the Lungs

Table 12.1.5  Natural history of lung cancer258

Cell type Volume Years from

doubling malignant change to
time the tumour reaching
(days)
1 cm 10 cm
(diagnosis) (death)

Squamous cell carcinoma 88 8.4 9.6

Adenocarcinoma 161 15.4 17.6
Large cell carcinoma 86 8.2 9.4
Small cell carcinoma 29 2.8 3.2

SITE OF ORIGIN AND SPREAD

As might be expected from the relative size of the two lungs, slightly
more carcinomas arise on the right than the left. There is also a slight
preponderance in the upper lobes. Historically, most carcinomas arose
in large central bronchi (Fig. 12.1.7) but increasing numbers now
develop in the periphery of the lung so that whereas the ratio of
central to peripheral tumours was formerly 2 : 1, it now approaches
equality.271–274 This change has been accompanied by one involving
the histological types of bronchopulmonary carcinoma, particularly
squamous cell carcinoma (see Fig. 12.1.18, p. 550).
Within the conductive airways, carcinoma arises particularly at
bifurcations where inhaled particles tend to impinge and mucociliary
clearance is delayed (Fig. 12.1.8 and see Fig. 1.18, p. 13)275–277 It is Figure 12.1.7  Carcinoma involving the right main and intermediate
probably because the trachea lacks side branches that primary bronchi. Note the slight roughening of the bronchial mucosa and the
carcinoma of the trachea is rare.278 The few tumours that arise in the invasion of adjacent hilar lymph nodes. (Courtesy of Dr GA Russell, Tunbridge
trachea are generally of salivary gland type or carcinoids.279 Wells, UK.)
Dissemination of the tumour is chiefly along lymphatic routes, at
least initially. Blood spread usually follows. Metastases in hilar and
mediastinal lymph nodes, and perhaps beyond, have often developed
by the time symptoms first cause the patient to seek attention. on the supposition that the lesion is malignant until proved other-
Retrograde spread within the lung may lead to widespread lymphatic wise. However, improvements in imaging have led to the realisation
permeation, resulting in so-called lymphangitis carcinomatosa, which that small asymptomatic nodules are very common. Up to 51% of
is described in Chapter 12.6, as are other routes of tumour spread smokers older than 49 years have pulmonary nodules and the great
within the lung. Further tumour growth and dissemination give rise majority of these prove to be benign (99% of those no greater than
to a variety of clinical effects, which will now be described. 4 mm diameter). It is therefore now recommended that nodules
measuring 8 mm or less should be merely kept under surveillance.280
In nodules larger than 8 mm, central calcification and a slow growth
rate suggest that the lesion is benign whereas fine linear strands
CLINICAL EFFECTS radiating from the edge of the nodule, cavitation and air broncho-
grams favour the converse, but these features are not wholly reliable.281
Most lung cancers are diagnosed because the patient presents with Not infrequently all investigations short of thoracotomy fail to provide
symptoms: less than 15% are discovered by chance, usually during the a diagnosis and the lesion is biopsied or resected. While it may well
course of radiological investigations performed for other purposes, prove to be fungal in the USA, an echinococcal cyst in the Orient, and
such as routine preoperative assessment, the investigation of chest tuberculosis worldwide, a malignant tumour is often the cause (71%
injuries, the detection of metastases of other tumours or life in a New Zealand series).282 Metastases account for about 20% of such
insurance. malignancies but this figure rises to nearly 50% in patients with an
extrapulmonary cancer.283

An asymptomatic solitary pulmonary Local effects

nodule (‘coin lesion’) Central tumours are prone to obstruct the larger airways (Fig. 12.1.9),
The traditional management of an asymptomatic patient found to leading to pulmonary collapse, infection and ‘endogenous lipid pneu-
have a solitary, well-circumscribed pulmonary opacity has been based monia’ (see p. 315). This results in cough, dyspnoea, pain and fever.

542
 Tumours Chapter | 12 |

Figure 12.1.8  Mucociliary clearance is impaired at bronchial branching

points, as shown in this drawing of a rat’s airways following the
experimental insufflation of carbon, shown here in dark red. (Reproduced Figure 12.1.10  Carcinoma of the bronchus with extensive pulmonary
from Iravani and van As (1972)275 with permission of the editor of Journal of and pleural extension. (Courtesy of W Edwards, Gordon Museum, Guy’s
Pathology.) Hospital, London, UK.)

Haemoptysis caused by ulceration of the tumour is another common

symptom but is not usually severe. However, many peripheral tumours
reach a substantial size and metastasise before causing any symptoms
at all. Cavitation is often evident radiologically, particularly with
squamous cell carcinomas, whilst the radiographic features of
mucinous adenocarcinoma of predominantly lepidic pattern often
simulate those of pneumonic consolidation. Patients being treated for
pneumonia should therefore be observed until there is complete
roentgenographic resolution. Any pneumonia that does not resolve
within 4 weeks should be evaluated further to exclude carcinoma.
The expectoration of large amounts of watery or mucoid sputum
(bronchorrhoea) is occasionally encountered in patients harbouring
adenocarcinoma-in-situ or mucinous adenocarcinomas of pre­
dominantly lepidic pattern.

Intrathoracic spread
Direct spread may cause pleural or chest wall pain whilst either pleural
involvement or poststenotic bronchopneumonia may cause pleural
effusion, which if neoplastic is characteristically haemorrhagic
(Fig. 12.1.10).
Apical tumours are prone to invade the ribs, the brachial plexus and
the cervical part of the sympathetic system (Fig. 12.1.11), causing pain
in the shoulder and the ulnar side of the arm, atrophy of the hand
muscles, Horner’s syndrome (ptosis, constricted pupil, enophthalmos
and decreased ipsilateral facial sweating), bone destruction and an
Figure 12.1.9  Squamous cell carcinoma arising in a central bronchus.
apical radiographic opacity. This syndrome was first described by Hare
The tumour has grown in a largely endobronchial manner within the in 1838,284 but is generally named after Pancoast who described it
intermediate and right lower-lobe bronchi, obstructing the lumen and afresh a century later285; the term ‘superior sulcus syndrome’ is also
causing distal bronchiectasis in the lower lobe and obstructive pneumonia used.285,286 Most tumours that cause Pancoast’s syndrome are squa-
in the middle lobe. mous cell carcinomas.

543
 Pathology of the Lungs

Figure 12.1.11  Pancoast tumour. A tumour in the apex of the left lung
has invaded the ribs, the cervical sympathetic chain and the brachial
plexus.

Hoarseness due to involvement of the left recurrent laryngeal nerve

as it loops around the aorta is another characteristic neurolo­gical
complication of bronchopulmonary carcinoma. Diaphragmatic
paralysis may be caused by involvement of the phrenic nerves,
particularly on the right where the phrenic nerve passes close to the
hilum of the lung.
Superior vena caval obstruction may be caused by compression and
infiltration of the vein by either the primary tumour or metastases in
superior mediastinal lymph nodes (Fig. 12.1.12). Small cell carci-
noma is particularly likely to present in this way, with massive medi-
astinal nodes and a small or even undetectable primary tumour. Hilar
lymph node metastases may also cause bronchial narrowing and its
sequelae. Any lung tumour that extends into the pericardium or
A
oesophagus (Fig. 12.1.13) is likely to cause cardiac tamponade or
dysphagia respectively, but invasion of the heart itself is unusual.

Extrathoracic spread
Many patients with carcinoma of the lung eventually develop cervical
or abdominal lymph node involvement whilst about a third present
with distant metastases, which may obviously lead to a wide variety
of symptoms. These include general features such as loss of appetite,
fatigue and loss of weight, and local effects that depend on the site
involved. Blood-borne metastases of lung carcinoma occur most often
in the liver, adrenal glands, brain, skeleton and kidneys; in many
countries the commonest cerebral tumour of adults is metastatic
carcinoma of the lung. The pattern of metastases varies with the
histological type (Table 12.1.6).287

Paraneoplastic manifestations B
Paraneoplastic syndromes are non-metastatic disorders of distant
organs. They develop in 10–20% of cases of lung cancer. Some of the Figure 12.1.12  Superior vena caval compression by mediastinal tumour.
better-established paraneoplastic syndromes are listed in Box 12.1.4. (A) Cross-section of the mediastinum viewed from above at the level of
Neuromuscular paraneoplastic syndromes include the carcin­ the aortic arch showing compression of the superior vena cava by
metastatic small cell carcinoma. The compressed vein is situated to the
omatous neuromyopathies, a term that covers a variety of encephalo­
right of the ascending aorta and in front of the carbon-pigmented
pathies, myelopathies, peripheral neuropathies and myopathies.288,289 pretracheal lymph node. (B) In life the patient had shown distension of
Polymyositis and dermatomyositis come within the myopathies and veins over the front of the chest.
up to 30% of patients with these diseases have an underlying neo-
plasm.290 Carcinomatous neuropathy and the myasthenia gravis-like
Eaton–Lambert syndrome are particularly associated with small cell

544
 Tumours Chapter | 12 |

lung cancer.291 The Eaton–Lambert myasthenic syndrome is a disorder

of acetylcholine production at neuromuscular junctions in which
an autoantibody directed against determinants on the tumour cell
membrane cross-reacts with components of the nerve terminal.292
Autoantibodies directed against a neuronal or muscle cell antigen
underlie many carcinomatous neuromyopathies.293 These syndromes
are not related to the size or duration of the tumour and may develop
months before the tumour becomes apparent.
Inappropriate or ectopic hormone secretion is responsible for
another important group of paraneoplastic syndromes. It is most
often associated with small cell carcinoma. Common examples
include the secretion of adrenocorticotrophic hormone and anti­
diuretic hormone by the tumour.294 Antidiuretic hormone is raised in
the serum of 30–40% of patients with small cell carcinoma but the
clinical syndrome of severe hyponatraemia, hypo-osmolality of the
A serum and continued urinary sodium excretion is recognised in
only 5–10%.295 Excess antidiuretic hormone is sometimes found with
non-neoplastic lung disease but here it is pituitary in origin rather
than ectopic.
Severe clinical symptoms due to adrenocorticotrophic hormone
production are seen in 3–7% of patients with small cell carcinoma.
The classic features of Cushing’s syndrome (Fig. 12.1.14) are unusual
but glucose intolerance and hypokalaemic alkalosis are often severe
and hyperpigmentation is usually pronounced.296
Less common is the production of atrial natriuretic peptide and
vasopressin297 or the kinins responsible for the carcinoid syndrome.298
Rare peptide syndromes include hypoglycaemia, hyperpigmentation
and hypercalcaemia. Cancer-associated hypercalcaemia is usually
due to bone metastases but occasionally occurs without metastatic
disease, when it is generally mediated by parathyroid-related protein
which increases both bone resorption and renal tubular re­­
absorp­tion of calcium: serum parathyroid hormone levels are charac-
teristically low or unmeasurable in these cases. The lung tumour most
commonly associated with such hypercalcaemia is squamous cell
carcinoma.299 Gynaecomastia and testicular atrophy are occasionally
encountered, again with squamous cell carcinoma. Adenocarcinoma
B of the lung is occasionally responsible for elevated serum levels of
amylase.300 Elevated levels of human chorionic gonadotrophin,
Figure 12.1.13  (A) Anterior and (B) posterior views of a squamous cell α-fetoprotein and other trophoblast markers are sometimes associated
carcinoma of the left main bronchus that metastasised to subcarinal with a variety of non-small cell carcinomas of the lung,301 but notably
lymph nodes and thence invaded the oesophagus which has been ones resembling hepatocellular carcinoma (‘hepatoid carcinoma of
opened from behind to show the tumour. the lung’).302

Table 12.1.6  Metastatic patterns of lung cancer at autopsy (%) in patients dying of lung cancer287

Squamous cell Adenocarcinoma Large cell Small cell

Hilar/mediastinal nodes 77 80 84 96
Pleura 34 60 67 34
Chest wall 20 20 20 13
Limited to thorax 46 18 14 4
Liver 25 41 48 74
Adrenals 23 50 59 55
Bone 20 36 30 37
Abdominal nodes 10 23 30 29
Central nervous system Not stated 37 25 29

545
 Pathology of the Lungs

Box 12.1.4  Paraneoplastic syndromes associated with

lung cancer

Neuromuscular
Polymyositis
Myasthenic syndrome
Sensory motor neuropathy
Encephalopathy
Myelopathy
Cerebellar degeneration
Psychosis
Dementia
Endocrine
Cushing’s syndrome
Inappropriate ADH secretion
Hypercalcaemia
Carcinoid syndrome
Gynaecomastia
Hyperglycaemia
Hypoglycaemia
Galactorrhoea
Growth hormone excess
Secretion of TSH
Calcitonin secretion
Cardiovascular
Superficial thrombophlebitis (Trousseau’s syndrome)
Thrombosis
Marantic endocarditis
Musculoskeletal and cutaneous
Hypertrophic osteoarthropathy
Figure 12.1.14  Cushingoid obesity and facial hirsutism due to
Clubbing inappropriate production of adrenocorticotrophic hormone in a patient
Dermatomyositis with small cell carcinoma of the bronchus.
Acanthosis nigricans
Pruritus
Urticaria
Common haematological abnormalities include the anaemia of
Erythema multiforme
chronic disease and thrombocytosis. As with many other cancers,
Hyperpigmentation
there may be activation of the coagulation cascade resulting in venous
Haematological thrombosis and thromboembolism or disseminated intravascular
Haemolytic anaemia coagulation.303 Cardiovascular syndromes also include non-bacterial
Red cell aplasia
thrombotic (marantic) endocarditis, the vegetations of which
may embolise and cause transient ischaemia. Less commonly,
Polycythaemia
carcinoma of the lung releases haemopoietic growth or chemotactic
Thrombocytopenic purpura
factors, resulting in either blood or local tissue eosinophilia304 or
Thrombocytosis neutrophilia.305–307
Dysproteinaemia Other associated disorders include finger clubbing and pulmonary
Eosinophilia hypertrophic osteoarthropathy (Fig. 12.1.15), acanthosis nigricans
Leukoerythroblastic reaction including thrombocytopenia and scleroderma, while lung tumour antigens may result in immune
Others complex glomerulonephritis and vasculitis.308–311

Nephrotic syndrome
Hyperuricaemia
Amyloidosis DIAGNOSTIC PROCEDURES FOR OBTAINING
Secretion of alkaline phosphatae TUMOUR MATERIAL
Secretion of immunoglobulin A
The main methods of obtaining material for the pathological diag­
ADH, antidiuretic hormone; TSH, thyroid-stimulating hormone.
nosis of lung cancer are sputum collection, bronchoscopy and trans­
thoracic needle aspiration, supplemented as required by tissue

546
 Tumours Chapter | 12 |

periosteal
new bone

Figure 12.1.16  Squamous metaplasia seen over an infiltrating small cell

A B carcinoma. Superficial sampling could lead to erroneous cell typing.

Figure 12.1.15  (A) Finger clubbing and (B) hypertrophic pulmonary

osteoarthropathy affecting the tibia and fibula in a patient with
squamous cell carcinoma of the lung. Arrows indicate periosteal new
widely used when specimens are small; large cell carcinoma is only
bone formation. (Courtesy of Professor M Hodson and Dr I Kerr, Brompton, UK.)
diagnosed when the tumour can be widely sampled and differentia-
tion excluded.325–328 With the limited treatment options available in
the twentieth century this categorisation was quite adequate but the
advent of drugs based on molecular features is now placing greater
obtained at thoracotomy, or on biopsies or aspirates of distant metas- demands upon the pathologist, as discussed in subsequent sections.
tases. Thoracotomy is now generally video-assisted. Mediastinal sam- The degree of differentiation varies greatly from one part of a tumour
pling is important in cancer staging as well as diagnosis but the to another and adequate grading of lung tumours is never possible on
traditional techniques of mediastinoscopy and mediastinotomy are biopsy specimens. Surface abnormalities may not reflect the cell type
now giving way to ultrasound-guided transtracheal, transbronchial of an underlying tumour and caution is needed if the biopsy is unduly
and transoesophageal needle aspiration.311a–c superficial. For instance, small cell carcinoma may be covered by
If necessary, sputum production can be induced by the inhalation atypical metaplastic epithelium or even squamous carcinoma-in-situ
of a saline spray. When cancer is present, the detection rate after four and if the invasive tumour is not sampled an erroneous report may
good specimens of sputum, obtained on waking and after cleaning be issued (Fig. 12.1.16).329
the mouth, is about 85%.312 Poor-quality specimens result in this Transcutaneous fine-needle aspiration is useful for peripheral
figure being considerably lower. A freshly fixed smear stained with growths. It requires fluoroscopic control and the radiologist greatly
Papanicolaou’s stain, haematoxylin and eosin or other stain of choice appreciates the attendance of a laboratory worker in the radiology
may be examined, or sputum may be collected for several days in a suite to attend to the rapid fixation of material for cytology and on-
container of alcohol, and the specimen then smeared or blocked for the-spot verification that the specimen is adequate. However, with the
the preparation of paraffin sections. Alternatively, the sputum may introduction of spring-loaded wide-bore (18-gauge) needles, excellent
first be homogenised.313 Cytological typing of lung tumours is possi­ specimens sufficient for histology are now obtained, negating the need
ble in most cases314 and is often superior to histological typing.315 for laboratory personnel in the radiology department (see p. 753).
Cytological specimens may also be obtained at bronchoscopy, by
washing, brushing or increasingly by transbronchial fine-needle
aspiration316–318 The combination of cytology and biopsy has been
shown to be cost-effective.319 Brushing many branches increases the HISTOLOGICAL TYPING
detection rate and can identify the site of an occult carcinoma.320
When the tumour is located peripherally and cannot be visualised The histological typing of lung cancer has long been subject to debate.
by bronchoscopy, selective bronchial lavage can be useful.321 As noted This is partly due to the heterogeneity many lung tumours display.330
above, transbronchial needle aspiration of enlarged mediastinal Many are of mixed cell type331–335 or their cell type changes on
lymph nodes is now often performed under ultrasound guidance. treatment,336 thus supporting Willis’s unitary view that all pulmonary
It has the advantage of combining diagnosis and staging in a single carcinomas arise from a common stem cell that has the potential
procedure.311a–c,318,322,323 to differentiate along various pathways.337 On the other hand, the
The flexible fibreoptic bronchoscope has greatly facilitated different tumour types clearly differ in their clinical behaviour and
bronchopulmonary biopsy. The specimens are small but many can be response to treatment, so histological typing is of considerable clinical
taken. It is reported that four biopsies are sufficient to ensure the importance. Unfortunately, the small size of fibreoptic bronchoscopic
diagnosis of central tumours but that six may be required if the biopsy specimens imposes considerable problems in the accurate
tumour is peripheral.324 Typing is relatively easy if the tumour is well typing of lung tumours.
differentiated but it can be difficult to type poorly differentiated The classification adopted here is based upon that advocated by the
tumours in these small specimens. For this reason the term ‘undif- World Health Organization (WHO) (Table 12.1.7).130 This was last
ferentiated non-small cell carcinoma – not otherweise specified’ is revised in 2004, since when weaknesses in the subtyping of adeno­

547
 Pathology of the Lungs

Table 12.1.7  The 2004 World Health Organization histological classification of malignant
epithelial tumours of lung130

Squamous cell carcinoma

Variants: Papillary
Clear cell
Small cell
Basaloid
Small cell carcinoma
Variant: Combined

Adenocarcinoma
Mixed adenocarcinoma
Acinar adenocarcinoma
Papillary adenocarcinoma
Bronchioloalveolar carcinoma
Solid adenocarcinoma with mucus formation
Variants: Fetal adenocarcinoma
Mucinous (‘colloid’) carcinoma
Mucinous cystadenocarcinoma
Signet ring adenocarcinoma
Clear cell adenocarcinoma

Large cell carcinoma

Variants: Large cell neuroendocrine carcinoma
Basaloid carcinoma
Lymphoepithelioma-like carcinoma
Clear cell carcinoma
Large cell carcinoma with rhabdoid phenotype
Adenosquamous carcinoma
Sarcomatoid carcinoma
Pleomorphic carcinoma
Spindle cell carcinoma
Giant cell carcinoma
Carcinosarcoma
Pulmonary blastoma
Carcinoid tumour
Typical carcinoid
Atypical carcinoid
Salivary gland tumours
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Epithelial-myoepithelial carcinoma

The adenocarcinoma section has undergone modification – see Box 12.1.5, p. 556.

carcinoma have become apparent and modifications in this area have in relation to the anti-TK drugs, but these supplement rather than
been suggested. One of these has been referred to above, namely the supplant histology. Surgical pathology remains important and is both
transference of bronchioloalveolar cell carcinoma from the frankly cheaper and faster than molecular characterisation. At the moment
malignant to the premalignant category and its rebirth there as therefore the likely clinical response to the new drugs is often inferred
adenocarcinoma-in-situ. Other modifications will be considered in from the histology. This is not wholly reliable but efforts are under
the adenocarcinoma section. way to refine the histological characteristics by applying panels of
The WHO classification depends solely upon light microscopy and antibodies capable of dividing non-small cell carcinomas into various
consequently has the advantage that it can be used by histopatholo- clusters in which one parti­cular histological pattern generally
gists everywhere. However, electron microscopy (Table 12.1.8) and predominates.345
immunohistochemistry can undoubtedly sharpen the histological The relative frequency of the various histological types varies accord-
diagnosis on occasion and with the introduction of new drugs based ing to the type of material examined (Table 12.1.9)57,273,287,312,346–353
upon molecular changes information on these is being increasingly and thus depends upon the site and metastatic potential of the
demanded.330,338–344 Molecular studies are increasingly being required tumour. Surgical series include more peripheral tumours than bron-

548
 Tumours Chapter | 12 |

Table 12.1.8  Histological typing of 75 lung cancers before and Table 12.1.9  Frequency (%) of histological subtypes of lung
after the application of electron microscopy330 carcinoma by source of specimen57,273,287,312,346–353

Histological type by Histological type by light and Biopsy/cytology Surgery Autopsy

light microscopy electron microscopy
Squamous cell 46 59 36
Squamous cell
Small cell 16 3 21
carcinoma (n = 37)
Adenocarcinoma 22 28 26
Pure squamous cell 9
Large cell 16 10 17
Squamous cell and adenocarcinoma 6
Squamous cell and small cell 11
carcinoma
Squamous cell and adeno- and small 11
cell carcinoma stronger with centrally situated tumours such as squamous and small
cell carcinomas than with tumours such as large cell and adenocarci-
Adenocarcinoma  
(n = 26) nomas that are commoner in the periphery of the lung but this is
changing with changes in cigarette manufacture.273,363,364 Asbestos is
Pure adenocarcinoma 7 particularly associated with adenocarcinoma57–59,365 whilst irradiation
Adeno- and squamous cell 5 and chloromethyl ether are both particularly associated with small cell
carcinoma carcinoma.77 It has also been claimed that polyaromatic hydro­
carbons, arsenic, chromates and nickel are all associated with squam­
Adeno- and small cell carcinoma 8 ous cell carcinoma but this is not well substantiated.77
Adeno- and squamous cell and 6 In considering trends in the proportions of the various histological
small cell carcinoma types, it should be borne in mind that the criteria for histological
classification of lung carcinomas have changed.366 Thus, the 1981
Small cell carcinoma   revision of the WHO classification is possibly relevant to some reports
(n = 3) that adenocarcinoma is on the increase, because the revision recom-
Pure small cell carcinoma 2 mended that solid tumours showing mucin secretion should be
categorised as adenocarcinoma, rather than large cell carcinoma, as
Small cell and squamous and 1 previously. However, quite apart from this, there appears to be a
adenocarcinoma genuine increase in the proportion of adenocarcinomas273,355–357,367–369
Large cell carcinoma   This is seen in both men and women but is more marked among
(n = 9) women.356 It presumably reflects the increased popularity of low-tar
and filter-tipped cigarettes364 and the increasing proportion of female
Pure large cell carcinoma 0
smokers. This change in the proportions of the various histological
Adenocarcinoma 7 types appears to be accompanied by a change in their distribution
within the lung so that the historical predominace of adeno­
Squamous cell carcinoma 2
carcinomas in the periphery and squamous cell carcinomas in the
central region is now less distinct.274

choscopic studies whilst those tumours that disseminate early are

more numerous in autopsy series. Figures derived from large surveys SQUAMOUS CELL CARCINOMA
provide the most reliable information but even these vary with time
as smoking patterns change. There are also geographical differences. Squamous cell carcinoma has classically been regarded as a tumour
Squamous cell carcinoma has been the commonest type in many of the central bronchi but there has been a reduction in the number
countries but adenocarcinoma is increasing in frequency and is of central tumours and peripheral examples are now just as common
now the commonest in many American and Japanese series.354–357 (Fig. 12.1.18).24 The cut surface is often granular or friable and large
Figures also vary according to the detail put into the pathological tumours frequently cavitate because of central necrosis (Fig. 12.1.19).
examination. If mucous stains are neglected many poorly differenti- Hilar lymph nodes are often directly invaded. Metastasis occurs
ated adenocarcinomas will be classified as undifferentiated large cell later than with the other histological types of bronchopulmonary
car­cinoma, whilst if electron microscopy is used the undifferentiated carcinoma.
category is eliminated altogether and adenosquamous carcinoma
becomes the commonest (Fig. 12.1.17).358,359 There may also be con-
siderable interobserver variability: one group of pathologists reached
agreement on 72% of small cell carcinomas, 56% of adeno­ Histological appearances
carcinomas, 48% of squamous cell carcinomas and only 5% of Squamous cell carcinomas form irregular nests and strands of tumour
large-cell carcinomas.360 However, less interobserver variation is cells separated by varying amounts of fibrous stroma. The tumour cells
reported in other studies.325,361,362 have large irregular nuclei, clumped chromatin and nucleoli of varying
Many pulmonary carcinogens are associated with particular histo- size. Stratification is often evident but by itself this is considered
logical types of lung cancer. The association with smoking has been inadequate evidence of squamous differentiation as it is also seen in

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 Pathology of the Lungs

occasional poorly differentiated adenocarcinomas. Categorisation

of a pulmonary carcinoma as squamous cell requires evidence of
either keratinisation or intercellular bridging.130 Well-differentiated
squamous cell carcinomas show prominent keratinisation throughout
Sq whereas poorly differentiated tumours require careful scrutiny to
SC LC identify keratinisation or intercellular bridging. Grading is of prognos-
tic value but this is best confined to resection specimens as there is
often considerable variation within a tumour: small biopsies are inad-
equate for tumour grading.
Ad Keratinisation may involve single tumour cells but is easier to
recognise when it forms concentrically laminated squamous ‘pearls’
(Fig. 12.1.20). Individually keratinised cells are rounded and have
slightly refractile eosinophilic cytoplasm. Their nuclei may be pyknotic
Sq
or show karyolysis, but all these features are seen in any apoptotic
tumour cell. To be confident that cytoplasmic eosinophilia represents
keratinisation it is necessary to concentrate on cells with viable nuclei.
Intercellular bridging is another marker of squamous differentiation.
SC The bridges (or ‘prickles’) represent desmosomal cell junctions that
LC are evident at the light microscopic level only because artefactual cell
shrinkage results in the junctions being stretched across intercellular
Ad
spaces, where they are seen as regularly spaced thin cytoplasmic
threads (Fig. 12.1.21).
Figure 12.1.17  Types of lung carcinoma: frequency assessed by light Central necrosis is often evident within groups of squamous
microscopy (top) and electron microscopy (bottom). Sq, squamous cell carcinoma cells, often sharply demarcated from the viable tumour
carcinoma; Ad, adenocarcinoma; SC, small cell carcinoma; LC, large cell cells. Squamous debris may elicit a foreign-body giant cell reaction.
carcinoma. Adenosquamous carcinoma is represented by the overlapping Alternatively, the necrotic debris may be absorbed, leaving a space that
Sq and Ad circles. For the electron microscopist adenosquamous could be misinterpreted as evidence of glandular differentiation. At
carcinoma is the commonest pattern, large cell carcinoma is very rare,
the growing edge of the tumour alveoli may be destroyed or invaded.370
small cell carcinoma is less distinct and rare tumours showing tripartite
differentiation are recognised.
Some squamous cell carcinomas show oncocytic change, due to large

80

69 69 Central
70 65
Peripheral

60
Number of cases (per 3yr period)

50

45 38
40
34
39
30 25
32
28
20
21

10 12

0
0 93-95 96-98 99-01 02-04 05-07 08-09
Years 1993-2009
Figure 12.1.18  Central versus peripheral location of bronchopulmonary squamous cell carcinomas resected at the Royal Brompton Hospital 1993–
2009. There has been a marked reduction in the number of central tumours over this period.

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 Tumours Chapter | 12 |

Figure 12.1.20  Well-differentiated squamous cell carcinoma of the

bronchus showing stratification and two keratin ‘pearls’.

Figure 12.1.19  Two carcinomas of the lung, both squamous cell in type
and both showing central cavitation. They are in different lobes, thereby
fulfilling one of the criteria for double primary tumours.

A B

Figure 12.1.21  (A) Well-differentiated squamous cell carcinoma showing well-developed ‘prickles’ connecting the tumour cells and representing
desmosomes highlighted by artefactual cell shrinkage. (B) Electron micrograph of the desmosomes, without shrinkage artefact. (B courtesy of Professor W
Mooi, Amsterdam, Netherlands.)

numbers of mitochondria within the cytoplasm. Osteocartilaginous in which case they are better classified as carcinoma-in-situ with
stromal metaplasia is a further rare feature.371 Rarely, squamous carci- papillary architecture or even solitary squamous papilloma with
nomas of the lung have a distinctly adenoid structure and correspond dysplasia.374 Most of these tumours are T1N0 and have a 5-year sur-
to those more frequently encountered in the skin, where they are vival of over 60%.375 Examples of the papillary variant developing in
termed adenoacanthoma or adenoid or pseudovascular (pseudo­ the periphery of the lung may show an alveolar filling pattern.24
angiosarcomatous) squamous cell carcinoma.372 Pilomatricoma-like In the clear cell variant (Fig. 12.1.22B) small foci of clear cell change
differentiation is particularly rare.373 are seen in what is otherwise evidently a squamous cell carcinoma.
The WHO classification recognises four variants of squamous cell Such foci are commonly seen but seldom predominate.376 Pure clear
carcinoma – papillary, clear cell, small cell and basaloid.130 The papil- cell carcinomas are classified as a variant of large cell carcinoma and
lary variant (Fig. 12.1.22A) is well differentiated and most examples are described under that heading below. Focal clear cell change in a
are endobronchial. Often there is no evidence of stromal invasion, squamous cell carcinoma is of no prognostic significance.

551
 Pathology of the Lungs

A B

C D

Figure 12.1.22  Variants of squamous cell carcinoma. (A) The papillary variant. Papillae clothed by well-differentiated squamous cell carcinoma protrude
into the bronchial lumen. (B) In the clear cell variant the tumour cell cytoplasm appears empty. (C) The small cell variant. Although the tumour cells are
small (bottom) they lack the characteristic nuclear features of a small cell carcinoma and keratinisation is present in the upper half of the field. (D) The
basaloid variant. Groups of tumour cells show peripheral palisading while the individual tumour cells are cuboidal or fusiform, and have scanty
cytoplasm and hyperchromatic nuclei devoid of prominent nucleoli. Squamoid elements were present elsewhere in tumour.

The small cell variant (Fig. 12.1.22C) is a poorly differentiated (basaloid carcinomas) are classified as a variant of large cell carci-
squamous cell carcinoma in which the cells are small but retain the noma. The basaloid variant of squamous cell carcinoma shows an
nuclear characteristics of a non-small cell carcinoma and show focal even closer resemblance to certain tumours of the upper aerodigestive
squamous differentiation. Thus, it is composed of cells that bear a tract that have been termed basaloid squamous cell carcinoma, and
resemblance to small cell carcinoma in that they are small, but their indeed this name has been applied on occasion to this bronchial
nuclei are vesicular and contain evident nucleoli, lacking the ‘salt and tumour.378 Some studies have shown that the basaloid variant of
pepper’ chromatin pattern of small cell carcinoma. It is to be distin- squamous cell carcinoma carries a worse prognosis than other poorly
guished from the combined variant of small cell carcinoma described differentiated squamous cell carcinomas in stage I and II disease,379–381
below.377 The prognosis is that of a poorly differentiated squamous whilst others have failed to confirm this.382
cell carcinoma.
The basaloid variant (Fig. 12.1.22D) of squamous cell carcinoma is
characterised by foci resembling basal cell carcinoma of the skin in
Immunohistochemistry
that there is peripheral palisading and the tumour cells are small and Squamous cell carcinomas of the lung stain strongly for low-molecular-
have hyperchromatic nuclei. Tumours with such features throughout weight cytokeratins, and in the better-differentiated tumours high-

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 Tumours Chapter | 12 |

Table 12.1.10  Immunophenotypic characterisation of carcinoma ADENOCARCINOMA

of the lung

Cell type Usual immunophenotype In many parts of the world adenocarcinoma of the lung shows an
increase in its incidence that cannot be ascribed solely to changes in
Squamous cell carcinoma (including CK5+ve, CK7−ve > +ve, histological typing.273,354,355,357,368 This may be connected with the
the basaloid variants of both TTF-1−ve, CD56−ve increasing number of women who smoke, for women appear to have
squamous cell carcinoma and a propensity to develop carcinoma of this particular histological
large cell carcinoma) pattern,367 but the major factor is probably the increasing popularity
Most adenocarcinomas and large CK5−ve, CK7+ve, TTF-1+ve,a
of filter-tipped cigarettes, the carcinogens of which are thought to
cell carcinomas (including CD56−ve penetrate more deeply into the lungs. However, although most
sarcomatoid carcinoma) patients with pulmonary adenocarcinoma are elderly cigarette
smokers, there is a higher proportion of adenocarcinoma in non-
Small cell carcinoma and large cell CK5−ve, CK7+ve, TTF-1+ve, smokers393 and the young.394
neuroendocrine carcinoma CD56+ve Most adenocarcinomas of the lung arise in the periphery of the
lung, in what has been called the terminal respiratory unit. This com-
CK, cytokeratin; TTF-1, thyroid transcription factor-1.
a
prises a terminal bronchiole and the respiratory bronchioles, alveolar
Mucinous tumours give variable results with TTF-1 (see text).
ducts and alveoli derived therefrom. In a Japanese study less than 3%
of adenocarcinomas arose in large central bronchi,395 whereas this
figure was over 13% in a British series.396 It has been suggested that a
simple division into central and peripheral would be better than
histological subtyping, firstly because of histological heterogeneity
molecular-weight cytokeratins and carcinoembryonic antigen are also and secondly because location has prognostic relevance, the central
found.383 There may also be focal staining for epithelial membrane growths having the worse outlook.396 Molecular studies demonstrating
antigen. Many squamous cell carcinomas stain for a variety of tropho­ different mutations support the classification of pulmonary adeno­
blast markers301,384–386 and high sensitivity and specificity are carcinoma into bronchial and peripheral subtypes.158,397
reported for desmoglein-3.387 Negative reactions are usually obtained Central adenocarcinomas often show polypoid endobronchial
for TTF-1 and the neuroendocrine marker CD56 (Table 12.1.10). The growth whereas peripheral adenocarcinomas often show central scar-
p63 gene, a member of the p53 family, may be demonstrated by ring with indrawing of the overlying pleura (Fig. 12.1.23). Central
immunohistochemistry in squamous cell carcinomas of many organs, cavitation is not as common as with squamous cell carcinomas.
including those arising in the lungs, and p63 is proving useful in Occasionally peripheral adenocarcinomas spread out over the pleura,
assigning poorly differentiated non-small carcinomas to the squa- thereby mimicking mesothelioma (so-called pseudomesotheliom­
mous cell category when treatment with the TK inhibitor gefitinib is atous carcinoma of the lung398). The bronchioloalveolar pattern of
being considered, a squamous phenotype being a contraindication to adenocarcinoma has its own distinctive gross appearances and is
this drug.388,389 dealt with separately, under its new name adenocarcinoma-in-situ
(see p. 536).

Electron microscopy
Histological appearances
Electron microscopy generally shows a wealth of tonofibrils, many of
which converge on desmosomes and extend into the intercellular The WHO classification of lung tumours (see Table 12.1.7) recognises
bridges (see Fig. 12.1.21). The cytoplasm otherwise contains relatively five subtypes of adenocarcinoma (acinar, papillary, bronchiolo­
few organelles. Keratinisation is marked by increased numbers of alveolar, solid with mucin production and mixed) together with
tonofibrils, sometimes in a perinuclear arrangement. Thickening of several rarer variants (fetal, colloid, mucinous cystadenocarcinoma,
the cell membrane by the deposition of small granules on its inner signet ring and clear cell).130 It was last updated in 2004, since when
surface390 appears to render the membrane impermeable and is others have proposed the addition of several further growth patterns
followed by cytoplasmic shrinkage, pyknosis of the nucleus and – papillary with a prominent morular component,399 micropapil-
ultimately cell death. lary,400 secretory endometrioid-like,401 adenocarcinoma with massive
lymphocyte infiltration,402 basaloid.403 and those showing enteric
differentiation.404–406 These proposals, together with reservations
concerning the value of recognising a mixed subtype, have led the
Differential diagnosis International Association for the Study of Lung Cancer (IASLC),
There is seldom any difficulty in recognising squamous cell carcinoma American Thoracic Society (ATS) and European Respiratory Society
but both histopathologists and cytopathologists need to beware of (ERS) to recommend modifications to the WHO classification in
misinterpreting regenerative atypical squamous metaplasia. Quite several respects (Box 12.1.5). The mixed subtype combines any of the
alarming, but reversible, changes may be seen bordering a necrotising other patterns, frequently exhibiting a lepidic, papillary or tubulopap-
process in the lung, such as a tuberculous cavity, an infarct or Wegener’s illary architecture at its periphery and an acinar or solid pattern cen-
granulomatosis, or in the bronchus if a recent biopsy site is again trally (Fig. 12.1.24A). It makes up about 90% of cases and this
sampled.122 Irradiation, cytotoxic therapy or even previous instrumen- predominance is one of the weaknesses of the WHO classification,
tation may also give rise to false-positive cytology results. Prolonged leading to recommendations for abandoning it and classifying adeno-
tracheal intubation may cause necrosis with extension of regenerative carcinoma of the lung according to the predominant pattern (Box
metaplasia into the submucosal glands, a process known as necro­ 12.1.5).150 Such classification has been shown to correlate with both
tising sialometaplasia (see pp. 97 and 696), which also needs to be prognosis and the presence of mutations of genes such as EGFR and
distinguished from invasive carcinoma.391,392 K-ras.211 IASLC/ATS/ERS also recommend: (1) recognition of a mini-

553
 Pathology of the Lungs

cell carcinomas and large cell carcinomas as a result of central necrosis

and absorption. Remnants of entrapped alveoli may also be mistaken
for glandular differentiation.408
The term ‘lepidic pattern’ (scale-like) is recommended for those
areas where tumour cells grow along the alveolar walls without
destroying them (see Figs 12.1.4A and 12.1.24A). It supplants the
term ‘bronchioloalveolar pattern’ and is applied to non-invasive areas
of a tumour that elsewhere shows evidence of invasive growth (as
opposed to adenocarcinoma-in-situ, which shows non-invasive
growth throughout).
In the papillary pattern (Fig. 12.1.24C), the tumour cells are again
cuboidal or columnar and may again contain mucin but here they
generally cover complex secondary and tertiary papillary structures
with fibrovascular cores.409
In the micropapillary pattern (Fig. 12.1.24D) the minature papillae
A lack stromal cores and free cell clusters lie within the alveoli, often
filling these spaces.400,410–414 This pattern is associated with early lymph
node metastasis and hence a relatively poor prognosis.
The solid pattern (Fig. 12.1.24E, F) is represented by sheets of
polygonal cells devoid of intercellular bridges but containing large
vesicular nuclei, prominent nucleoli and moderately abundant cyto-
plasm in which droplets of mucin may be demonstrated by appropri-
ate methods. A little mucin may be present in squamous cell carcinoma,
carcinoid or small cell lung carcinoma and only when a tumour that
would otherwise be classified as a large cell carcinoma contains sub-
stantial numbers of mucin-positive cells (at least 5 per 2 high-power
fields) is it categorised as an adenocarcinoma of solid pattern.
The fetal pattern of adenocarcinoma takes its name from a fanciful
resemblance to fetal lung in the pseudoglandular stage of development
(see Fig. 2.3, p. 41). However, it also resembles normal endometrium.
Both these likenesses are spurious but have led to the introduction of
two alternative names, pulmonary endodermal tumour resembling
fetal lung and pulmonary adenocarcinoma with endometrioid
B features.415–417,421 The term ‘fetal pattern’ is used in both the WHO and
IASLC classifications, where it is described as a variant of adenocarci-
Figure 12.1.23  (A, B) A peripheral adenocarcinoma of the lung showing noma. Low- and high-grade types are distinguished, dependent on the
a central pigmented scar and indrawing of the overlying pleura. degree of pleomorphism.418 The age range is wide but high-grade
tumours tend to affect the elderly and low-grade ones the middle-
aged.418 Tumours of this pattern are generally parenchymal growths
but endobronchial examples have been described.419,420 Histologically,
they are characterised by complex glandular structures lined by
mally invasive category of adnocarcinoma; (2) recognition of acinar, columnar cells with glycogen-rich clear cytoplasm separated by sparse
papillary, micropapillary, lepidic and solid predominance as the fibromyxoid stroma (Fig. 12.1.25). In places the epithelial cells
major patterns of adenocarcinoma; (3) separate grouping of muci- form solid squamoid collections that have been termed morulae.
nous carcinomas; and (4) changes to the less common variants of Immunocytochemistry shows focal neuroendocrine differentiation in
adenocarcinoma, including the elimination of clear cell and signet the morulae.419 Also in the morulae, the nuclei are often clear, the
ring cell carcinomas as distinct types of lung tumour. Of the five major chromatin forming a thin peripheral rim due to the central accumula-
patterns, lepidic predominance appears to signify a lesser degree of tion of biotin.421,422 Biotin is an essential cofactor for several enzymes
malignancy than acinar and papillary, which are in turn less malignant but is normally found in the cytoplasm rather than the nucleus.
than micropapillary and solid. However, biotin is stored in the nuclei of endometrial epithelial cells
Minimally invasive adenocarcinoma usually measures 2 cm or less in pregnancy and in endometrioid ovarian carcinoma, supporting this
and is of predominantly non-mucinous lepidic pattern. It shows less tumour’s alternative name of pulmonary endometrioid adenocarci-
than 5 mm of invasion at any one point. If multiple areas of micro- noma. Morular cells that express neuroendocrine markers and have
invasive areas are found, the largest invasive area should be measured, optically clear, biotin-rich nuclei also show accumulation of ß-cat-
i.e. the size of invasion is not the summation of all such foci. The enin, a component of cell junctions that also acts as a transcriptional
justification for recognising this pattern of adenocarcinoma is that, activator of the ß-catenin gene, a feature that well-differentiated fetal
although invasive, its prognosis is the same as or close to that of adenocarcinoma shares with pulmonary blastoma as well as endo­
adenocarcinoma-in-situ.183,407 metrioid adenocarcinoma of the female genital tract.423,424 Unlike
The acinar pattern of adenocarcinoma is characterised by a prolif- metastatic endometrioid adenocarcinoma of the female genital tract,
eration of glandular structures in the form of acini and tubules (Fig. fetal adenocarcinoma of the lung is usually positive for cytokeratin 7
12.1.24A, B). The lining tumour cells are typically cuboidal or colum- and TTF-1.
nar with moderately abundant cytoplasm that may contain mucin. Mucinous adenocarcinomas display a wide variety of patterns. In
The tubules of an acinar adenocarcinoma have to be distinguished addition to the predominantly acinar, papillary, lepidic and solid
from the pseudoglandular structures that may develop in squamous patterns described above, they may be of signet ring cell, colloid or

554
 A B

C D

E F

Figure 12.1.24  Principal patterns of adenocarcinoma. (A) Mixed acinar (left) and lepidic (right). (B) Acinar. (C) Papillary. (D) Micropapillary, in which
clusters of tumour cells form small papillary structures that lack stromal cores. (E, F) Solid with mucus formation. (F, di-periodic acid–Schiff stain.)

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 Pathology of the Lungs

Box 12.1.5  Changes to the World Health Organization

histological classification of pulmonary adenocarcinoma
proposed by the International Association for the Study
of Lung Cancer (IASLC)150 in conjunction with the
American Thoracic Society (ATS) and European
Respiratory Society (ERS)
1. Preinvasive
a. Atypical adenomatous hyperplasia
b. Adenocarcinoma-in-situ (formerly bronchioloalveolar cell
carcinoma)a
2. Minimally invasive (a lepidic predominant carcinoma with ≤5 mm
invasion)
3. Invasive
a. Lepidic predominantb
b. Acinar predominantb
c. Papillary predominantb
d. Micropapillary predominantb
e. Solid predominantb
Variant: Mucinous adenocarcinoma (includes most tumours formerly
classified as mucinous bronchioloalvolar carcinoma)a
Variant: Mucinous cystadenocarcinoma
Variant: Colloid carcinoma
Variant: Fetal
Variant: Enteric
a
The great majority of adenocarcinomas-in-situ are non-mucinous. Mucinous
adenocarcinomas that are entirely non-invasive are exceptionally rare. Most
tumours formerly classified as mucinous bronchioloalveolar carcinoma show
some invasion and are included in the mucinous adenocarcinoma variant of
invasive adenocarcinoma. This variant may be subclassified according to the
predominant pattern (lepidic, acinar, papillary, micropapillary and solid) in the
same way as the non-mucinous adenocarcinomas. Most mucinous
bronchioloalveolar carcinomas are now termed mucinous adenocarcinoma
showing lepidic predominance.
b
Most adenocarcinomas are of mixed pattern, hence categorisation according to
the predominant pattern. It is recommended that the pathologist should list all
the patterns present and roughly estimate the proportion of the tumour formed Figure 12.1.25  Well-differentiated adenocarcinoma resembling fetal
of each using 5% increments, e.g. lepidic 45%, acinar 35%, papillary 20%,
lung. Note the clear cytoplasm, which is due to glycogen accumulation.
ensuring that the proportions total 100%.
Note: Signet ring cell and clear cell are no longer recognised as distinct  
subtypes as their characteristic features may be seen in many of the other
patterns.

than multifocal origin. A sparsity of intercellular junctions that would

minimise cellular cohesion and promote such aerial metastasis has
been noted on electron microscopy.427 Molecular studies show that
the multifocal lesions are monoclonal and thus support them being
cystic pattern and sometimes resemble adenocarcinomas of the metastatic.428 A lepidic growth pattern is also seen on occasion in the
bowel.404–406 Except for the mucinous cystadenocarcinoma they carry pulmonary metastases of adenocarcinomas arising in other sites,
a worse prognosis than their non-mucinous counterparts, regardless especially the pancreas, stomach, colon, breast and ovary.429,430 The
of histological pattern.425,426 distinction of primary and metastatic adenocarcinomas is considered
The predominantly lepidic pattern of mucinous adenocarcinoma in Chapter 12.6 (see p. 688).
encompasses the former bronchioloalveolar carcinoma of mucinous A ‘signet ring cell’ pattern is not included in the new IASLC classi-
type as well as mucinous adenocarcinomas of mixed pattern in which fication of adenocarcinoma but still requires a description. It displays
lepidic growth predominates. The tumour cells are relatively mono- more mucin than the solid variety but the tumour cells are similarly
morphic, show little atypia and produce large amounts of mucin, arranged in poorly differentiated sheets. In contrast to the small drop-
which may lead to bronchorrhoea. The tumour is often multifocal or lets of mucin seen in the solid variety, a large vacuole of mucin dis-
affects the lung diffusely. The lung structure is maintained and, when tends the cell and indents the nucleus so much that it forms a crescent
a whole lobe is involved, the appearances may simulate those of lobar at the edge of the cell (Fig. 12.1.27). The appearances are similar to
pneumonia, particularly the mucinous variety produced by Klebsiella those seen in tumours of the same name in the stomach and elsewhere
species (Fig. 12.1.26). Deposits of similar tumour may involve the but there is no evidence of a primary tumour in these sites and reac-
other lung but even when the disease is bilateral the mediastinal tions compatible with a pulmonary origin are obtained. For example,
lymph nodes are frequently free of growth. This has led to speculation TTF-1 and cytokeratin 7 are positive and cytokeratin 20 is negative.431–436
that the multicentricity represents aerogenous dissemination rather Carcinoma of the lung in which a signet ring cell configuration forms

556
 Tumours Chapter | 12 |

Figure 12.1.26  Mucinous adenocarcinoma of lepidic pattern. (A) The

lung is consolidated throughout; the gross appearances mimic those of
lobar pneumonia. (Courtesy of Dr JW Seo, Seoul, Korea.) (B) The consolidation
is due to mucus filling the alveoli. (C) Mucous cells line the alveolar walls
without destroying them.

Figure 12.1.27  Signet ring cell carcinoma. A primary pulmonary

C adenocarcinoma of signet ring cell morphology, mimicking metastatic
gastric carcinoma.

557
 Pathology of the Lungs

epithelioid mesotheliomas, and 20, which is found more frequently

in intestinal carcinomas (see Table 12.1.10). They also generally stain
for carcinoembryonic antigen, BerEP4, AUA1, epithelial membrane
antigen and vimentin. TTF-1446 is a relatively sensitive and specific
marker of pulmonary adenocarcinomas but variable results are
reported with mucinous lung tumours.439 Mucinous adenocarcinoma
of predominantly lepidic pattern generally fails to react with TTF-1
but gives positive results for intestinal markers such as CDX2, CK20
and MUC-2. Mucinous adenocarcinomas described as being com-
posed of goblet rather than signet ring cells may display a similar
intestinal pattern or react for both intestinal and lung markers. It is
suggested that such tumours arise in bronchial rather than bron­
chiolar cells.436,439 The neuroendocrine markers chromogranin and
neuron-specific enolase can be demonstrated in some pulmonary
adenocarcinomas but CD56 is generally negative. Trophoblastic
markers can often be demonstrated, as in other non-small cell
carcinomas of the lung.301,386

Electron microscopy
Figure 12.1.28  Colloid carcinoma. Small groups of tumour cells lie free The heterogeneity of adenocarcinoma of the lung noted above is again
within their abundant mucous secretion. evident when these tumours are examined by electron micro­
scopy.426,447 Some reflect the embryological derivation of the lower
respiratory tract from the primitive foregut by showing the micro­
at least 50% of the tumour is reported to have a particularly poor villous core rootlets and glycocalyceal bodies that are better known in
prognosis.435 Others report a poor prognosis if signet ring cells merely intestinal carcinomas,404,448,449 whilst many are composed of cells rich
exceed 5%.437 An association with the EML4-ALK fusion gene has been in cytoplasmic organelles that indicate active mucin synthesis and
reported.224 storage. The mucin granules vary in size and electron density and tend
The ‘colloid’ pattern of mucinous adenocarcinoma is similar to the to coalesce into large vacuoles. Sometimes the secretory product is
tumour of the same name in the gastrointestinal tract.438 It affects amylase rather than mucin and the cytoplasm contains large zymogen-
the middle-aged or elderly of either sex. The mucoid nature of the like granules.300 Occasionally, neuroendocrine granules are seen, indi-
tumour is evident upon macroscopic examination of the cut surface. cating dual differentiation.300 Many adenocarcinomas are composed
Microscopically, tumour cells with large vesicular nuclei, prominent of cells resembling type II pneumocytes450 or Clara cells173 while in
nucleoli and moderately abundant cytoplasm float free within copious some adenocarcinomas, type II pneumocytes may be seen alongside
amounts of mucin that fill and often distend alveoli. Growth along mucous or Clara cells, and occasionally overlying a basal layer of
the alveolar walls is often deficient (Fig. 12.1.28). Colloid carcinoma myoepithelial cells.451 Various types of nuclear inclusion are described,
lacks the capsule of a mucinous cystadenocarcinoma and the pools of the commonest being granular and staining for surfactant apo­
tumour cell-bearing mucin frequently spill over into neighbouring air protein,452 while others consist of tubular structures derived from the
spaces that are not themselves lined by neoplastic cells. Variable nuclear envelope.453
reactions are reported for cytokeratins 7 and 20.439
Mucinous cystadenocarcinoma is particularly rare. It occurs in
Molecular features
patients who are middle-aged or elderly and of either sex, shows a
wide range of behaviour and is often of only borderline malignancy.440–442 Specific oncogene mutations have been identified in approximately
Some examples have shown no evidence of malignancy whatsoever 60% of pulmonary adenocarcinomas, the commonest involving EGFR
and have been termed cystadenoma.443,444 Some have seeded out on and K-ras. Others include BRAF, PIK3CA, ERBB2 and EML4-ALK.454
to the pleura in a manner reminiscent of pseudomyxoma peritonei EGFR and K-ras are mutually exclusive, indicating that they represent
produced by comparable tumours of the appendix or ovary.445 separate carcinogenic pathways.210 EGFR mutation is reported in up to
Cytological atypia and microglandular solid areas may suggest malig- 50% of adenocarcinomas in Asian cohorts and 10–15% outside Asia,
nancy but there is seldom any evidence of invasive activity. Most can particularly in those tumours with a prominent lepidic or papillary
be excised in their entireity and do not recur. The tumour is typically pattern, and of non-mucinous type.180 Such tumours are most likely
peripheral, well demarcated, cystic and either unilocular or multi­ to respond to TK inhibitors and are found particularly in Far Eastern
locular. It is filled with mucus and microscopically is lined by stratified women who have never smoked.455 There is no strong association
mucous cells, which are sometimes thrown into folds. Its capsule between K-ras mutation and any histological subtype211 but an associa-
distinguishes it from colloid carcinoma. tion between the EML4-ALK fusion gene and signet ring morphology
Adenocarcinoma of enteric pattern reproduces in the lung morpho- has been reported.224.
logical features indistinguishable from those of the common pattern
of colorectal carcinoma.404 Some report that its immunohistological
Differential diagnosis
characteristics are also those of colorectal cancer405 whereas others
find that they differ.406 The pulmonary metastases of adenocarcinomas of other organs are
sometimes histologically indistinguishable from primary lung adeno-
carcinomas, so that in practice the diagnosis of primary adenocarci-
Immunohistochemistry noma of the lung should not be made before the patient has been
Adenocarcinomas of the lung express a wide range of cytokeratins, but screened for a primary tumour elsewhere and immunocytochemical
not 5 and 6, which are characteristic of squamous cell carcinomas and markers have been sought, notably TTF-1 as a marker of primary lung

558
 Tumours Chapter | 12 |

Figure 12.1.30  Small cell carcinoma. Nuclear moulding is clearly evident

in this sputum sample.

Histological subtypes
In the 1981 WHO classification,463 small cell carcinoma was divided
into oat cell, intermediate cell and combined subtypes but this did
not prove to be of prognostic significance.464–466 The differences
between the oat cell and the intermediate cell types are imprecise and
probably artefactual. Classic oat cell carcinoma is most often observed
in traumatised biopsies or poorly preserved autopsy material, whereas
in well-preserved surgical material the intermediate cell type is seen
almost exclusively. Accordingly, a recommendation that the terms oat
cell and intermediate cell be abandoned467 has been adopted in the
Figure 12.1.29  Small cell carcinoma that recurred after chemotherapy, current WHO classification, only the combined variant being retained
extended widely within the thorax and metastasised widely. (see Table 12.1.7).130 The combined subtype, which is reported to
comprise between 3 and 28% of the total, is characterised by the
presence of squamous cell carcinoma, adenocarcinoma or large cell
carcinoma in addition to small cell carcinoma, combinations that are
adenocarcinoma, and markers that are available for an increasing
generally easy to recognise.468,469
range of other adenocarcinomas, e.g. thyroid and prostate. It is par-
ticularly important that the metastases of adenocarcinomas that are
amenable to hormonal manipulation or chemotherapy are identified. Histological appearances
The distinction of primary and secondary adenocarcinomas is consid- Small cell carcinomas consist of closely packed small or medium-sized
ered in detail on page 688. round or elongated cells, arranged in nests or strands or scattered
singly within a scanty stroma.470,471 The edge of the tumour is ill
defined and lacks a capsule. Extensive necrosis is commonly seen.
Mitoses are numerous and the nuclei of adjacent tumour cells char-
SMALL CELL CARCINOMA acteristically press on one another, a feature termed nuclear moulding,
which is especially prominent in cytological specimens (Fig.
Small cell carcinoma generally arises in major airways (Fig. 12.1.29), 12.1.30).472 Rosettes of radially arranged tumour cells may be formed
grows rapidly, metastasises early and initially at least is sensitive to and genuine lumina may also be present, sometimes containing a
platinum-based chemotherapy. Untreated patients survive on average little mucin.
less than 3 months. With treatment, the patient usually dies with Classic oat cells, which, as explained above, are probably artefactual,
widely disseminated disease within 1–2 years: long-term disease-free have dense pyknotic nuclei and very sparse cytoplasm. Well-preserved
survival is seen in only a minority of patients treated with chemo- tumour cells are slightly larger, have a discernible but still small
therapy.456 Until recently oncologists have staged the tumour only as amount of cytoplasm and a nucleus with a finely divided chromatin
being ‘limited’ or ‘extensive’, believing that it has always disseminated pattern (Fig. 12.1.31). Nucleoli are inconspicuous in paraffin sections
by the time it is clinically manifest. However, surgery has been suc- but may be quite striking in plastic sections. These nuclear character-
cessful in early cases457–460and, although these cases are highly selected, istics are more important than cell size in separating small cell
it is now recommended that small cell carcinoma be staged in the carcinoma from large cell carcinoma.472–474 Some small cell carcino-
same way as other lung tumours.150,461,462 Although small cell carcino- mas show scattered tumour cells with hyperchromatic giant nuclei.469
mas are generally central tumours, rare cases present as a peripheral This phenomenon can also be seen in other lung tumour types, and
nodule and it is these that have the best chances of successful surgical is especially common in tumours that have responded well to radio-
eradication. therapy or chemotherapy.475 A partial change to non-small cell

559
 Pathology of the Lungs

Figure 12.1.32  DNA deposition in vessel walls (Azzopardi effect) is seen

in highly cellular necrotic tumours such as this small cell carcinoma.

Table 12.1.11  Comparison of small cell carcinoma and large cell

carcinoma, other than on cell size

Small cell Large cell

carcinoma carcinoma

Cell shape Fusiform Polygonal

Nuclear/cytoplasmic ratio High Low
Chromatin Fine Coarse
Nucleoli Indistinct Prominent
DNA staining of vessels Frequent Rare

Figure 12.1.31  Small cell carcinoma. The tumour cells have little
cytoplasm and finely dispersed nuclear chromatin. Nucleoli are not readily
evident.
Differential diagnosis
histology during the course of the disease is encountered in about a Small cell carcinoma is liable to be mistaken for large cell carcinoma
fifth of patients.476 if attention is concentrated on cell size and the presence of discernible
Haematoxyphil, Feulgen-positive nucleoprotein derived from amounts of cytoplasm but these two tumours are generally separable
degenerate tumour cells may be deposited in the walls of stromal on their nuclear characteristics: the finely divided, evenly dispersed
blood vessels (so-called Azzopardi470 effect – Fig. 12.1.32) but this chromatin of a small cell carcinoma contrasts greatly with the clumped
feature is also found in other cellular tumours, such as lymphoma, chromatin and prominent nucleolus set in an otherwise vesicular
seminoma and even other types of lung carcinoma. In biopsy nucleus of a large cell carcinoma (Table 12.1.11). Lymphocytes, either
specimens, the tumour cells are often crushed so that long strands and reactive or neoplastic, may also be mistaken for small cell carcinoma,
masses of haematoxyphil material are seen. This finding should especially if the tissue is traumatised: however, the carcinoma cells
prompt a careful search for viable, non-traumatised tumour cells. By are larger than reactive lymphocytes and may be distinguished from
itself it does not justify a diagnosis of small cell lung carcinoma lymphoma cells by immunocytochemistry, using antibodies against
because other tumours, such as lymphomas, and also inflammatory leukocytes (CD45) and cytokeratin. Some squamous cell and adeno-
infiltrates, may show the same crush artifact. carcinomas are composed of small tumour cells but these lack the
In bronchial biopsies, the tumour cells are often seen beneath an nuclear features of small cell carcinoma and show no immunohisto-
intact surface epithelium that shows atypical squamous metaplasia chemical or ultrastructural evidence of neuroendocrine differentia-
(see Fig. 12.1.16), which is possibly due to the secretion of growth tion. Wider sampling generally reveals their true nature. If adequate,
factors by the tumour.329 Superficial sampling limited to this surface non-traumatised tissue is provided, small cell carcinomas are rela-
change may lead to erroneous histological classification and hence the tively easily distinguished from other histological types,477 but
wrong treatment: it is essential that invasive tumour be examined. On problematical cases are certainly not rare,478,478a particularly in small
the other hand, there may be infiltration of the overlying epithelium bronchial biopsies.325 This is one of the areas where immuno­
by small groups of tumour cells, similar to that seen in Paget’s disease histochemistry, electron microscopy479 and image analysis480 may
of the nipple. prove to be important.

560
 Tumours Chapter | 12 |

promise between specificity and sensitivity492–496 and the first three of

these fortunately retain their immunoreactivity when there is crush
artefact.495 Chromogranin A is a fairly specific protein component of
endocrine granules but is usually difficult to detect because small cell
lung carcinomas are only sparsely granulated. In situ hybridisation
may be useful here for it demonstrates high levels of chromogranin A
mRNA in these tumours.497 CD56 detects the neural cell adhesion
molecule and is very sensitive but lacks specificity.498,499 The enzyme
neuron-specific enolase and the neural protein PGP 9.5 are not
granule-associated, and are positive in many small cell carcinomas,
but are of low specificity. Leu-7, a surface antigen present on human
natural killer cells and neuroendocrine cells,500 is also of low specifi-
city. In contrast to these neuroendocrine markers, CD44 is reported
to be expressed only by non-small cell carcinomas.501 Despite their
distinct morphological appearances the minor components of
combined small cell carcinomas generally express the same neuro­
endocrine markers as the more abundant small cell component.502

Cytogenetics and molecular pathology

Small cell carcinoma shows a high incidence of chromosomal dele-
Figure 12.1.33  Small cell carcinoma. Electron microscopy demonstrates
tions. Several chromosomes are involved but 3p, 13q and 17p are
the presence of dense-core neuroendocrine granules. (Courtesy of Professor
affected particularly frequently, respectively resulting in loss of the
W Mooi, Amsterdam, Netherlands.)
tumour suppressor genes FHIT, Rb and p53.230–232,238,243,503 Conversely,
the myc oncogene is overexpressed in many small cell carcinomas, but
particularly in those that have recurred after treatment.218,219

Electron microscopy
Ultrastructurally, small cell lung carcinomas usually show neuro­
endocrine differentiation, the hallmark of which is the presence of LARGE CELL CARCINOMA
small cytoplasmic granules.481,482 These granules are round and have
a central homogeneously electron-dense core that is separated from Large cell carcinomas of the lung are aggressive tumours504 distin-
an outer membrane by a thin electron-lucent halo (Fig. 12.1.33). They guished by an absence of differentiation when examined by light
measure 50–200 nm and are often concentrated near the cell microscopy. The tumour cells are arranged in monotonous fields and
membrane. The granules may be difficult to find, there being far fewer individually are distinguished from small cell carcinoma by a variety
than in carcinoid tumours. They have to be distinguished from of cytological features, of which size is one of the least and nuclear
bristle-coated vesicles, small lysosomes and small exocrine granules. detail one of the most important (see Table 12.1.11): they generally
Bristle-coated vesicles have a fuzzy surrounding membrane whilst have a moderate amount of cytoplasm, chromatin that is clumped
lysosomes and exocrine granules lack the halo separating the central at the periphery of the nucleus and a prominent nucleolus
core from the outer membrane. Exocrine granules are also usually (Fig. 12.1.34).472–474
more pleomorphic, and are concentrated near intercellular lumina Immunocytochemistry shows that these tumours often express both
lined by microvilli. cytokeratin and vimentin. Electron microscopy usually reveals evi-
A minority of carcinomas of apparent small cell morphology show dence of squamous or glandular differentiation, or rarely, neuroendo-
undoubted ultrastructural evidence of squamous or mucous cell crine features, or even a combination of the these (see Fig. 12.1.18
differentiation, alone or in combination with neuroendocrine and Table 12.1.7).359,505 Thus, large cell carcinoma is not a distinct
features.377,479,483–485 Of 46 small cell carcinomas examined by electron entity, but rather a collection of very poorly differentiated epithelial
microscopy, 22 proved to be neuroendocrine, 6 were squamous cell, tumours. The subtyping of large cell carcinoma by these special tech-
2 were mucous and 16 were not categorised.486 However, these niques338,339 was of no clinical significance when the only therapeutic
ultrastructural variations do not appear to be reflected in clinical options were chemotherapy (for small cell carcinoma) and surgery
behaviour or response to chemotherapy.487 Conversely, a variety of (for the other types). A diagnosis of ‘non-small cell carcinoma – not
non-small cell carcinomas are sometimes found to contain dense-core otherwise specified’ then sufficed. Indeed, this was advocated to avoid
granules on electron microscopy.488 having to amend a biopsy diagnosis of large cell carcinoma when the
resection specimen showed squamous or glandular differentia-
tion.325,327 In the present era this is no longer adequate. New drugs
Immunocytochemistry
aimed at correcting specific mutations require more specific charac-
In line with their epithelial nature, a range of cytokeratins may be terisation and ideally this is provided by molecular techniques.
demonstrated in small cell lung carcinoma,489 generally with a However, there is some correlation between histological type and
paranuclear dot-like distribution due to the formation of filament oncogene mutation and it may therefore be worth stretching the
whorls.490 Similarly, most small cell carcinomas express TTF-1 (see usual histological parameters. For example, stratification is accepted
Table 12.1.10).491 Immunohistochemistry has been widely used in as evidence of squamous differentiation in carcinoma of the cervix
attempts to distinguish small cell and non-small cell lung carcinoma uteri, oesophagus and skin, but so far not the lung. In the same vein,
but, to date, no completely satisfactory marker of neuroendocrine the histological typing of an undifferentiated non-small carcinoma
differentiation is available. At present, chromogranin A, synapto- could be sharpened by the application of supplementary histological
physin, CD56 and N-cadherin probably represent the best com­ techniques. Thus, it is suggested that an undifferentiated non-small

561
 Pathology of the Lungs

Figure 12.1.35  Clear cell variant of large cell carcinoma. The tumour is
composed solely of undifferentiated large tumour cells with clear
cytoplasm.

carcinoma’ is now restricted to tumours that give negative mucous

stains. They show no evidence of squamous or glandular differentia-
tion on light microscopy but either may be detected by electron micro-
scopy.508 Focal clear cell change is sometimes seen in squamous cell
carcinomas and adenocarcinomas but this is considered insufficient
to justify a diagnosis of clear cell carcinoma. The nuclei may show
little atypicality, in which case the distinction from benign clear cell
tumour of the lung (see p. 625) may be difficult. However, the thin-
walled sinusoidal blood vessels of a benign clear cell tumour are not
evident in clear cell carcinoma. Metastatic renal carcinoma is perhaps
Figure 12.1.34  Large cell carcinoma. The tumour is undifferentiated and a more likely alternative, one that would be supported by the presence
consists of cells with appreciable amounts of cytoplasm and nuclei that of sudanophilic fat within the cytoplasm of tumour cells; however, fat
show coarse chromatin clumping and prominent nucleoli. stains are not possible if the material has all been embedded in
paraffin, and in these circumstances recourse to renal imaging is
probably the best option.510 If mucin stains are positive, metastatic
renal carcinoma, primary clear cell carcinoma and benign clear cell
cell carcinoma that stains for mucin and TTF-1 but not for CK5/6, tumour can all be excluded.
34BE12 and p63 is probably of adenocarcinoma lineage whereas the Some large cell carcinomas display neuroendocrine features and are
reverse pattern favours squamous cell carcinoma.506,507 Molecular char- appropriately termed ‘large cell neuroendocrine carcinoma’. Their
acterisation is the ideal but even then histology is important, in par- diagnosis is based on recognition of both neuroendocrine morphol-
ticular to ensure that the results of molecular analysis reflect viable ogy and the immunohistochemical demonstration of at least one
tumour and not areas of necrosis, stromal tissue, tumour capsule or specific neuroendocrine marker. As in any large cell carcinoma, the
reactive tissue. Often, the initial biopsy will not be large enough cells have moderate amounts of cytoplasm and nuclei that show
to permit these ancillary techniques and further sampling may be peripheral clumping of chromatin and a prominent nucleolus, fea-
necessary.328 Examples of the new drugs that require better tumour tures that distinguish all large cell carcinomas from small cell carci-
characterisation include pemetrexed, which is not effective in noma.511 There is much mitotic activity and extensive necrosis.
squamous cell carcinoma,507a bevacizumab, which is liable to cause However, it is soon noticed that the tumour has an organoid pattern
life-threatening hemorrhage in squamous cell carcinoma342 and the with its cells arranged in cords or well-demarcated groups showing
EGFR-directed TK inhibitors erlotinib and gefitinib, which work best rosette formation or peripheral palisading (Fig. 12.1.36). Some
in adenocarcinomas.342,344 of these features are also seen in carcinoid tumours and the relation-
Five variants of large cell carcinoma are recognised: clear cell, neuro­ ship to carcinoid is strengthened by shared immunocytochemical,
endocrine, basaloid, lymphoepithelioma-like and rhabdoid. In the ultrastructural and molecular features of neuroendocrine differentia-
clear cell variant most of the tumour cells have a pale, watery cyto- tion, such as the presence of chromogranin, synaptophysin or CD56,
plasm, usually due to the presence of glycogen (Fig. 12.1.35).376,508 or their gene expression, and scanty dense-core granules evident on
Early series509 included those that owed their clear cytoplasm to mucus electron microscopy.254,493,512–514 Despite this commonality, there are
but today such tumours would be classified as adenocarcinomas, major differences between carcinoids and the high-grade neuroendo-
despite their lack of glandular differentiation. The term ‘clear cell crine carcinomas, both small cell and large cell, which are summarised

562
 Tumours Chapter | 12 |

Table 12.1.12  Comparison of neuroendocrine large cell

carcinoma and atypical carcinoid

Neuroendocrine Atypical
large cell carcinoid
carcinoma

Histological pattern Large well- Small cell groups

circumscribed cell usually in a
groups with trabecular or
peripheral palisading mosaic pattern
Cell size Large Medium
Mitoses 10 or more/10 More than 2/10 and
high-power fields up to 10/10
A high-power fields
Nuclear/cytoplasmic Low Moderate
ratio
Chromatin Coarse Fine
Nucleoli Prominent Indistinct
Necrosis Large areas Usually confined to
the centres of the
cell groups
Atypia Prominent Moderate
Neuroendocrine Necessary (positive) Optional (positive)
stains

B mitotic activity than this: the average number of mitoses per 10 high-
power fields is in the order of 75. Large ‘geographic’ areas of necrosis
characterise large cell neuroendocrine carcinoma whereas in atypical
Figure 12.1.36  Large cell neuroendocrine carcinoma. (A) There is
peripheral palisading reminiscent of a carcinoid tumour but the tumour carcinoid necrosis is generally confined to the centres of individual
also exhibits much more extensive necrosis than is seen in an atypical cell groups. Small cell carcinoma also enters into the differential diag-
carcinoid. (B) Immunoperoxidase staining for chromogranin is positive. nosis of large cell neuroendocrine carcinoma;478a here reliance has to
be placed upon the different nuclear characteristics, the fine granular-
ity of the small cell carcinoma’s chromatin differing from the clumped
chromatin and prominent nucleoli of neuroendocrine large cell
in Table 12.2.1 on page 599. Genetic differences between small cell carcinoma.
and large cell neuroendocrine carcinoma exist515,516 but many charac- In general, large cell neuroendocrine carcinomas are tumours of
teristics are shared: both neuroendocrine carcinomas show an inverted middle-aged or elderly cigarette smokers that arise in central bronchi.
Bcl-2/Bax ratio, p53 mutation, deletions on chromosomes 3p and 17p Despite the morphological evidence of neuroendocrine differentia-
and Rb inactivation.238,243,503 tion, ectopic hormone secretion is not a feature. The clinical sig­
Occasionally, a conventional squamous cell carcinoma, adenocar- nificance of large cell neuroendocrine carcinoma and non-small cell
cinoma or large cell carcinoma is encountered that is found to express carcinoma with neuroendocrine differentiation has yet to be fully
neuroendocrine markers by immunohistochemistry. Such tumours evaluated but recognition of these tumours is of potential therapeutic
are termed non-small cell carcinoma with neuroendocrine fea- significance for their undoubted neuroendocrine nature links them to
tures.130,517 Neuroendocrine differentiation can be demonstrated by classic small cell carcinoma and it would be important if their metas-
electron microscopy or immunohistochemistry in 10–15% of non- tases were similarly sensitive to chemotherapy. Unfortunately, reports
small cell carcinomas of the lung despite an absence of morphological regarding their chemosensitivity are contradictory.488,512,521–527 Some
neuroendocrine features.513,517–520 advise that these tumours behave like small cell carcinoma528 and
The differential diagnosis of large cell neuroendocrine carcinoma respond to the platinum-based regimens used for small cell
includes atypical carcinoid tumour (Table 12.1.12) but the organoid carcinoma,527others that they are more aggressive than ordinary large
pattern of that tumour is not so well developed in large cell neuro­ cell carcinomas,514,520,529–531 and yet others that neuroendocrine expres-
endocrine carcinoma and the degree of atypia, mitotic activity and sion in large cell carcinoma is of no prognostic significance,532–537 or
necrosis all far exceeds those seen in an atypical carcinoid. A criterion even that it confers longer survival.526,538 The presence of neuroendo-
recommended for distinguishing atypical carcinoid from large cell crine markers in pulmonary adenocarcinoma is reported to be associ-
neuroendocrine carcinoma is mitotic number, atypical carcinoid ated with increased sensitivity to chemotherapy,519,521,524,525,534 and to
having fewer than 10 mitoses per 10 high-power fields and large cell be an independent favourable prognostic factor in chemotherapy-
carcinoma 10 or more (if 1 high-power field = an area of 0.2 mm2).512 treated non-small cell lung carcinoma,526 leading to suggestions that
Most large cell neuroendocrine carcinomas show considerably more this treatment may be considered for those non-small cell carcinomas

563
 Pathology of the Lungs

not the low-molecular-weight cytokeratins (4, 10 and 11) that are

more typical of cornifying squamous epithelium, nor the TTF-1
expressed by most adenocarcinomas and small cell carcinomas of the
lung.541 Like other non-small cell carcinomas, a small proportion
(<10%) of tumour cells may express neuroendocrine markers. The
34βE12 monoclonal antibody against cytokeratins 1, 5, 10 and 14 is
positive in basaloid (and squamous cell) carcinoma but not in neu-
roendocrine tumours of any category. Basaloid carcinoma is liable to
be confused with small cell carcinoma, large cell neuroendocrine
carcinoma and poorly differentiated squamous cell carcinoma, but
none of these has the full constellation of features listed above.
‘Lymphoepithelial carcinoma’ is a term usually applied to a type of
nasopharyngeal carcinoma that shows prominent lymphoid infiltra-
tion but tumours of this pattern have also been described in a number
of other sites, including the lung, where they are regarded as a variant
of large cell carcinoma.106,544–548 As with the nasopharyngeal tumours,
pulmonary lymphoepithelial carcinoma mainly affects Asians, in
whom it is associated with the Epstein–Barr virus (Fig. 12.1.38). Most
of the few lymphoepithelial carcinomas of the lung reported in non-
Asian patients do not contain Epstein–Barr virus,549,550 suggesting that
the presence of this agent may be an epiphenomenon. However,
Epstein–Barr virus was not found in any other form of lung cancer in
a Hong Kong laboratory reporting pulmonary lymphoepithelial car-
cinomas associated with this virus.545 Pulmonary lymphoepithelial
carcinoma is also associated with the bcl-2 oncogene, chemosensi­
tivity and a better survival rate than other large cell carcinomas of
Figure 12.1.37  Basaloid carcinoma. The tumour shows an exophytic the lung.546,547,551
endobrobronchial pattern of growth. Pulmonary lymphoepithelial carcinoma affects adults of all ages
and the sexes are affected equally. There is no strong association with
cigarette smoking.546 The tumour usually forms a solitary, discrete,
subpleural nodule that is amenable to surgery. Major bronchi are not
that express neuroendocrine features and are inoperable.520,532 Other usually affected but the tumour may replace the lining of small
reports discount neuroendocrine differentiation detected only by bronchi. It generally has a soft fleshy appearance on its cut surface.
immunostaining as being of no prognostic importance.539 However, Microscopy shows sheets of large cells with vesicular nuclei and prom-
as yet there have been no large-scale, prospective, controlled trials of inent nucleoli, mixed with numerous lymphocytes and plasma cells,
small cell chemotherapy for this subgroup of large cell carcinomas or and, occasionally, granulomas (see Fig. 12.1.38). Thymoma of mixed
for other non-small cell carcinomas showing neuroendocrine cellularity may be suggested but lymphoepithelial carcinoma contains
differentiation. Furthermore, the clinical importance of neuroendo- CD4- or CD8-positive lymphocytes and the less mature lymphocytes
crine differentiation may diminish if a current trend towards treating of CD1a phenotype encountered in thymoma are not identified. The
all inoperable lung carcinomas with aggressive chemotherapy lymphoid infiltrate may be so prominent as to suggest lymphoma,
continues. from which it is distinguished by the immunocytochemical demon-
Basaloid carcinoma24,379,380,382,540–543 is a relatively rare variant of stration of cytokeratin.
large cell carcinoma, forming only about 3% of all non-small cell Rhabdoid carcinoma is a further rare variant of large cell carcinoma
carcinomas of the lung. Patients with this tumour do not differ from characterised by the presence of a hyaline eosinophilic globule indent-
those with other large cell carcinomas in age, smoking history, clinical ing the nucleus.552 The globule represents a tangle of intermediate
presentation or pattern of relapse.379,380,382,540 However, they are reputed filaments, both vimentin and cytokeratins (Fig. 12.1.39).553,554
to fare badly compared with large cell carcinoma in general,379–381,540 Rhab­doid foci are also found in lung tumours showing varying
although this is disputed.382 lines of differentiation, where they are thought to represent areas of
The tumour is usually centrally located and often shows an exo- dedifferentiation.555,556Not surprisingly, therefore, rhabdoid tumours
phytic, endobronchial pattern of growth and a well-defined edge (Fig. appear to carry a poor prognosis, although numbers of analysed cases
12.1.37). Carcinoma-in-situ can often be recognised in the adjacent are small.557,558
or distant bronchial epithelium. Histologically, basaloid carcinoma
displays a lobular or anastomosing trabecular pattern with peripheral
palisading. The tumour cells are small, cuboidal or fusiform with
scanty cytoplasm and a hyperchromatic nucleus devoid of prominent ADENOSQUAMOUS CARCINOMA
nucleoli, as in the basaloid variant of squamous cell carcinoma por-
trayed in Figure 12.1.22D. Mitoses are frequent (over 25 per 10 high- Many non-small cell carcinomas of the lung show ultrastructural
power fields) and there is often centrilobular comedo-like necrosis. evidence of both squamous and glandular differentiation but the
The stroma may show abundant hyaline basement membrane-like diagnosis of adenosquamous carcinoma is reserved for tumours that
material, myxoid change or, rarely, chondroid or osseous metaplasia. show both squamous and adenocarcinomatous differentiation on
There is no squamous differentiation: if it is present the tumour is light microscopy (Fig. 12.1.40).559–562 These are rare but the exact
classified as a basaloid variant of squamous cell carcinoma (see p. incidence is uncertain because until recently there were no agreed
549). Basaloid carcinoma expresses high-molecular-weight cytokerat- criteria as to how much of the minor component should be present:
ins typical of bronchial basal cells (cytokeratins 1, 5, 6 and 14) but however, the current WHO classification130 stipulates at least 10%.

564
 Tumours Chapter | 12 |

A B

C D

Figure 12.1.38  Lymphoepithelial carcinoma. (A) The tumour is an undifferentiated large cell carcinoma that shows a heavy lymphoid infiltrate.
(B) Cytokeratin (MNF116) and (C) lymphocyte (CD3) staining distinguishes the two components of the tumour. (D) EBERS in situ hybridisation
demonstrates the Epstein–Barr virus.

Figure 12.1.39  Rhabdoid variant of large cell carcinoma. Large cell Figure 12.1.40  Adenosquamous carcinoma. The tumour shows evidence
carcinoma cells show indentation of nuclei by a hyaline eosinophilic of both squamous and glandular differentiation, with each component
globule. making up more than 10% of the whole.

565
 Pathology of the Lungs

Alveoli entrapped within squamous carcinomas may be mistaken for

tumour acini408 but their lining cells are smaller and more uniform
than those lining tumour acini.
Clinically and macroscopically, adenosquamous carcinomas
resemble adenocarcinomas.563 They are often peripheral tumours that
metastasise widely, often showing the same intermingling of the
two components in the metastases as in the primary tumour. The
prognosis is poor, worse than for either pure squamous cell carcinoma
or pure adenocarcinoma.561,562

SARCOMATOID CARCINOMA

Occasional carcinomas show foci of malignant spindle or giant cells,

suggesting that the tumour is composed of a mixture of carcinoma
and sarcoma. Such tumours were formerly thought to result from the
merging of separate carcinomas and sarcomas (so-called collision
tumours), or were considered to represent carcinomas merely exhibit-
ing exuberant stromal growth. The current view is that they represent
carcinomas showing connective tissue differentiation. This is an exten-
sion of the widely accepted concept of tumour heterogeneity used to
explain tumours of mixed epithelial phenotype, such as adenosqua-
mous carcinoma and the combined subgroup of small cell carcinoma.
What appears to be a sarcomatous element may seem to stream from
an obvious epithelial element (Fig. 12.1.41) and there is now consid-
erable electron microscopic and immunohistochemical evidence that
tumours that appear to be of mixed epithelial and connective tissue
phenotype, or composed only of what appears histologically to be
sarcoma, are entirely epithelial.564–566 Molecular studies are in accord
with this, showing identical mutations in the spindle cells and more
obviously in the epithelial components.567,568 Epithelial–mesenchymal
transition is controlled by various transcription factors, several of
which have been shown to be upregulated in sarcomatoid carcinomas
of the head and neck.569 The term ‘sarcomatoid carcinoma’ is therefore
appropriate and could well supplant older terms such as carcinosar-
coma and pulmonary blastoma. The latter are inaccurate but are
retained in the WHO classification for historic reasons. Figure 12.1.41  Sarcomatoid carcinoma. The tumour consists of
Some sarcomatoid carcinomas consist entirely of spindle or giant squamous and spindle cells, the latter obviously derived from the
cells and for these the terms spindle cell carcinoma and giant cell adjacent squamous cell carcinoma. Both components gave a strongly
carcinoma are appropriate. Spindle cell carcinoma was formerly positive immunoreaction for cytokeratin.
classed as a variant of squamous cell carcinoma but it is now appreci-
ated that spindle cell change may be found in any type of non-small
cell carcinoma (Fig. 12.1.43), including giant cell carcinoma. This has
led to the introduction of the term ‘pleomorphic carcinoma’ for a nature of the tumour is only recognisable by the application of
tumour that combines spindle and/or giant cell carcinoma with any immunohistochemistry to demonstrate cytokeratin or other epithelial
of the more usual patterns of non-small cell carcinoma.570 Occasionally markers. It thus corresponds to both spindle cell and giant cell
there is an even greater degree of connective tissue differentiation so carcinoma. Biphasic sarcomatoid carcinoma combines an obvious
that bone, cartilage or muscle is formed. The WHO classification epithelial component (e.g. glandular or squamous cell carcinoma)
retains the inaccurate term ‘carcinosarcoma’ for sarcomatoid carcino- with a malignant stroma (spindle cell or giant cell). If the stroma
mas containing such heterologous elements, although it recognises shows chondroid, osseous or myogenic differentiation the tumour is
them as being basically epithelial in nature. In one form of carcino­ classified as a heterologous biphasic sarcomatoid carcinoma (corre-
sarcoma the neoplastic glands and stroma have an embryonic appear- sponding to carcinosarcoma and blastoma); if not, it is termed a
ance so that the tumour bears a spurious resemblance to fetal lung in homologous biphasic sarcomatoid carcinoma (corresponding to
its canalicular phase of development: the traditional (but inaccurate) pleomorphic carcinoma). This classification has the merit of being
term ‘pulmonary blastoma’ is retained for this pattern in the WHO understood by those unversed in the historic development of our
classification.130 In one of the largest series of sarcomatoid carcinomas, understanding of lung tumours. It is also familiar to general histo­
58 cases were classified as pleomorphic carcinoma, 10 as spindle cell pathologists because it is applied to similar tumours that are
carcinoma, 3 as giant cell carcinoma, 3 as carcinosarcoma and 1 as encountered in the upper aerodigestive and genitourinary systems.
pulmonary blastoma.571 The two classifications are compared in Table 12.1.13.
An alternative classification to that advocated by WHO recognises Sarcomatoid carcinomas are rare, accounting for about only 1% of
only monophasic and biphasic sarcomatoid carcinomas, with the all lung malignancies.570,571 Patients are usually elderly and have been
latter subdivided into homologous and heterologous varieties.572,573 heavy smokers.571 They typically give a short history, yet have bulky
A monophasic sarcomatoid carcinoma is one in which the epithelial tumours. The prognosis is generally poor.573 Even tumours that appear

566
 Tumours Chapter | 12 |

Table 12.1.13  Sarcomatoid carcinoma. Corresponding

terminology used by Wick and colleagues572,573 and the World
Health Organization130

Wick et al. World Health Organization

Monophasic Spindle cell

Giant cell
Biphasic
Homologous Pleomorphic carcinoma
Heterologous Blastoma

Squamous cell
carcinoma 6%
None (’pure’ spindle
Figure 12.1.43  Giant cell carcinoma. The tumour cells are poorly
cell carcinoma) 10%
cohesive and there is a rich polymorph infiltrate. Multinucleate tumour
giant cells are evident.
Giant cell
carcinoma 35%

of spindle cell carcinoma that closely mimics an inflammatory myofi-

Large cell broblastic tumour. It shows a proliferation of cytologically bland neo-
carcinoma 17%
plastic spindle cells in a myxoid background while lymphocytes and
plasma cells surround or infiltrate the tumour. However, a dearth of
neutrophils, eosinophils and foam cells together with small foci of
necrosis and invasion of bronchi and blood vessels all favour sarco-
matoid carcinoma.
Giant cell carcinoma is a non-small cell carcinoma composed of
very large cells that are frequently multinucleate. The many nuclei
Adenocarcinoma 32% are large, pleomorphic and often multilobed. The mitotic rate is
Figure 12.1.42  Frequency of patterns found to be associated with high. The tumour cells are poorly cohesive and show a marked
spindle cell carcinoma, illustrating the diversity that led to the tendency to dissociate from each other (Fig. 12.1.43).577,578 There is
introduction of the term ‘pleomorphic carcinoma’.570 generally a rich inflammatory infiltrate, usually of neutrophils,
which frequently invade the tumour cells.305 This phenomenon was
initially thought to represent phagocytosis by the tumour cells,579
but more probably reflects emperipolesis580 (active penetration of the
to be operable have a worse571 or similar574 prognosis to large cell leukocytes into the tumour cells, in contrast to passive engulfment).
carcinoma of the lung, which is itself poor. The inflammation is not necessarily associated with necrosis and is
Signs and symptoms are related to tumour localisation. Haemoptysis, seen in metastases as well as the primary growth. Neutrophil seques-
fever due to recurrent pneumonia, cough and progressive dyspnoea tration within the tumour may be associated with peripheral granu-
are common with endobronchial lesions. Peripheral tumours may be locytosis and even a leukaemoid reaction. The granulocytosis is not
asymptomatic and only discovered incidentally on chest radiography, dependent upon bone marrow metastases. An unidentified chemo­
but most eventually cause pleuritic pain. attractant is presumably responsible for both the granulocytosis and
Spindle cell carcinoma is a non-small cell carcinoma that consists the sequestration of neutrophils within the tumour.305 The phenom-
only of spindle-shaped tumour cells (Fig. 12.1.42). It is a rare tumour enon is also seen in the inflammatory sarcomatoid carcinoma, men-
but is nevertheless the commonest spindle cell malignancy appear to tioned above. The tumour cells often coexpress cytokeratin, vimentin,
be in the lung. When encountering a tumour of such pattern one carcino­embryonic antigen and TTF-1. By electron microscopy aggre-
should therefore think of spindle cell carcinoma before considering a gates of paranuclear filaments may be seen but otherwise the tumour
diagnosis of primary pulmonary sarcoma. It is distinguished from cells possess few tonofibrils and are very poorly differentiated. Only
sarcoma by its expression of epithelial markers such as cytokeratin, very occasional desmosomes are identified, which is in accordance
epithelial membrane antigen and carcinoembryonic antigen.565,575 with the poor cohesiveness of the tumour cells.581 The differential
Difficulty may be encountered in distinguishing spindle cell carci- diagnosis of giant cell carcinoma includes not only other types of lung
noma from synovial sarcoma because they both express epithelial carcinoma, but also primary and metastatic malignant fibrous histio-
markers but synovial sarcoma also expresses the bcl-2 oncogene and cytoma, pleomorphic rhabdomyosarcoma, metastatic adrenocortical
shows t(X;18)(p11.2;q11.2) translocation. When there is pleural carcinoma and other pleomorphic malignant tumours, most of which
involvement it is particularly difficult to distinguish spindle cell car- can be distinguished by their own distinctive markers.
cinoma from sarcomatoid mesothelioma. Pankeratin, calretinin and Pleomorphic carcinoma is a poorly differentiated non-small cell
thrombomodulin are frequently expressed in both, while neither carcinoma in which spindle cell carcinoma and/or giant cell carci-
commonly expresses cytokeratin 5/6 or WT1, but some difference is noma form at least 10% of what would otherwise be a pure squamous
reported for smooth-muscle actin (positive in 60% of sarcomatoid cell, adeno- or large cell carcinoma (Fig. 12.1.44), or a carcinoma
mesotheliomas compared with only 10% of sarcomatoid carcino- consisting only of spindle and giant cells.570,582 Immunostaining
mas).576 Inflammatory sarcomatoid carcinoma is an unusual variant for epithelial markers to exclude sarcoma may be undertaken if

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 Pathology of the Lungs

Figure 12.1.44  Pleomorphic carcinoma consisting of a mixture of

glandular and spindle cell growth.

the tumour lacks an obvious epithelial component. In these

circumstances distinction from a mesothelioma of sarcomatoid
pattern is particularly difficult for the sarcomatoid component of the
carcinoma may express mesothelial markers such as podoplanin and
calretinin.583 Pseudoangiosarcomatous carcinoma is a variety of pleo-
morphic carcinoma in which squamous cell carcinoma is accompa-
nied by an angiosarcomatoid component showing anastomosing
channels lined by anaplastic cells focally aggregated in pseudopapil-
B
lae. The channels contain erythrocytes and occasionally form ‘blood
lakes’, thus simulating an angiosarcoma. However, the lining cells
Figure 12.1.45  Carcinosarcoma (biphasic sarcomatoid carcinoma with
express epithelial rather than endothelial markers and represent the
heterologous elements). (A) An excised carcinosarcoma showing largely
pulmonary counterpart of pseudovascular adenoid squamous cell car- exophytic growth. (B) Microscopy shows a mixture of squamous and
cinoma that one may see in other organs. Distinction from pleurop- spindle cell carcinoma, the latter exhibiting chondroid differentiation.
ulmonary angiosarcoma is based on the carcinoma’s lack of atypical
endothelial cells, negative immunostaining for vascular markers and
the presence of at least focal areas of squamous cell carcinoma.
Carcinosarcomas (heterologous type of biphasic sarcomatoid tumours cause cough, haemoptysis and recurrent chest infection
carcinomas) are malignant tumours that contain both epithelial and whereas peripheral lesions may be asymptomatic until they reach the
connective tissue elements, with the latter showing heterologous pleura and give rise to effusion or pleurisy.
differentiation into bone, cartilage or smooth muscle. They are similar By definition these tumours are biphasic, composed of an intimate
to those described in the upper aerodigestive tract, the urogenital mixture of epithelial and connective tissue (Fig. 12.1.45C). The
organs and other sites as carcinosarcomas, biphasic sarcomatoid demarcation between the two may be sharp or poorly defined. The
carcinomas or malignant mixed müllerian tumours. The first descrip- most frequent epithelial element is squamous cell carcinoma, fol-
tion of pulmonary carcinosarcoma is attributed to Kika in 1908.584 lowed by adenocarcinoma, large cell carcinoma, small cell carcinoma
Immunocytochemistry and electron microscopy (see below) support and carcinoid tumour but glandular differentiation is commoner in
the view that carcinosarcoma is basically an epithelial tumour that the rarer peripheral growths (Table 12.1.14).591,592 The connective
shows varying degrees of mesenchymal differentiation. In line with tissue component usually consists of undifferentiated spindle cells in
this, molecular studies have shown that the epithelial and sarcoma- which there are foci of malignant osteoid, cartilage, striated muscle or
toid components have a common genome.568,585 Further support fat.565,587,588,593,594 These connective tissue elements are clearly malig-
derives from experiments involving the transplantation of human nant, in contrast to the osteocartilaginous stromal metaplasia that is
lung carcinomas into inbred mice, in which environment the epi­ recorded in occasional squamous cell carcinomas.371 Such differentia-
thelial neoplasms showed connective tissue differentiation.586 tion may be sparse, rendering the distinction from spindle cell carci-
Pulmonary carcinosarcomas occur in the same type of patient as noma and undifferentiated sarcoma difficult. Furthermore, the relative
the more common forms of lung cancer, namely elderly or middle- proportions of carcinoma and sarcoma vary considerably: it should
aged cigarette smokers, and carry a similarly poor prognosis.587,588 The therefore be borne in mind that sarcomas of the lung are very rare
male : female ratio is about 7 with a mean and median age 65 years.589 and before making such a diagnosis the lesion should be sampled
Two-thirds arise in the walls of large airways and form polypoid endo- widely to exclude the possibility that the tumour is a carcinosarcoma
bronchial lesions (Fig. 12.1.45A, B)590 but some grow into large of predominantly sarcomatous pattern, particularly if it has the char-
intrapulmonary masses that may invade the chest wall.591 Central acteristic endobronchial growth pattern of a central carcinosarcoma.

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Table 12.1.14  Pathological features of 46 cases of

carcinosarcoma591

Endobronchial (n = 32) Peripheral (n = 14)

Epithelial Squamous 29 (91%) Squamous 6 (43%)

component Glandular 3 (9%) Glandular 7 (50%)
Other 1 (7%)
Mesenchymal Undifferentiated spindle Undifferentiated
component cell 26 (81%) spindle cell 11
(79%)
Differentiated 6 (19%) Differentiated 3
(21%)

Differentiated includes chondrosarcoma and rhabdomyosarcoma.

The malignant epithelial cells frequently express cytokeratin, epi-

thelial membrane antigen, carcinoembryonic antigen and TTF-1, and
the mesenchymal cells vimentin, but any of these markers may be
found in either component.565,566,595–597 Electron microscopy may also
show epithelial features such as desmosomes in the spindle cell com-
ponent, further emphasising the close relation between carcino­
sarcoma and spindle cell carcinoma.565,566
The metastases of a carcinosarcoma may consist of carcinoma or
sarcoma or both.595,598 If the epithelial component is glandular, pleural
involvement may lead to confusion with a mesothelioma of mixed
pattern but the identification of mucus and carcinoembryonic antigen
excludes mesothelioma.593
The term ‘pulmonary blastoma’ was coined by Spencer599 in 1961,
superseding Barnard’s earlier one of embryoma of lung.600,601 At that
time it was thought that the peripheral part of the lung was of mes-
enchymal origin and Spencer considered pulmonary blastomas to be
analogous to nephroblastomas in that both their epithelial and mes-
enchymal components were derived from a common mesodermal
blastema. The embryological basis for this concept is now known to
be false (see p. 40). Occasional reports of tumours intermediate in
structure between blastoma and carcinosarcoma598,602–604 suggest that
blastomas are related to carcinosarcomas,565 and hence to spindle cell
carcinomas. It has been suggested that the well-differentiated fetal
adenocarcinoma represents one-sided epithelial development of a
pulmonary blastoma, but this is unconvincing and it is therefore
considered with other adenocarcinomas on page 554. Pleuropul­
monary blastoma, a purely connective tissue tumour of the young that
is described on page 623, is now considered to represent the true
blastoma of the lung. Figure 12.1.46  Pulmonary blastoma. A 20-cm partly necrotic and
Pulmonary blastoma is a rare tumour that affects males three times haemorrhagic tumour occupies much of the lower lobe. (Courtesy of Dr PF
more commonly than females. It may occur at any age from child- Roberts, formerly of Norwich, UK.)
hood to the ninth decade with the mean age being about 40 years,
earlier than that of carcinosarcoma but considerably later than blasto-
mas of other organs. Blastomas may reach a considerable size before uniform, small, dark, oval or spindle-shaped nuclei and scanty cyto-
cough, haemoptysis or chest pain causes the patient to seek attention, plasm (Fig. 12.1.47): both components are malignant and either or
or they may be discovered incidentally by radiography. Pulmonary both may be seen in the metastases. The mesenchymal cells tend to
blastomas vary greatly in their behaviour but the prognosis is gener- be arranged more compactly around the epithelial tubules, which are
ally unfavourable: the overall 5-year survival is only 16%.605 lined by cuboidal or columnar cells with clear glycogen-rich cyto-
Pulmonary blastomas are generally peripheral growths and often plasm; the appearances closely resemble first-trimester fetal lung,
form large well-demarcated masses with foci of cystic change and hence the term blastoma.599,607,608 The stromal component shows focal
haemorrhage (Fig. 12.1.46). However, up to a quarter are similar to differentiation into cartilage, bone, fat and smooth or striated muscle
carcinosarcomas in forming polypoid endobronchial tumours.605,606 in up to 25% of cases (see Fig. 12.1.47C).606,609 In some tumours the
Microscopically, they are biphasic tumours composed of branching epithelial element shows squamous differentiation. Other examples
epithelial tubules or cords set in an undifferentiated stroma. The latter have had melanomatous,610 small cell carcinoma611 or yolk sac com-
is formed of loosely arranged polygonal cells which have fairly ponents.612 Transition to carcinosarcoma is also described.598,602–604

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 Pathology of the Lungs

Immunohistochemistry and electron microscopy support the view

that pulmonary blastomas are true mixed tumours: epithelial markers
are confined to the epithelial elements and connective tissue markers
to the stromal component.565,607–609,613–616 However, the features they
share with carcinosarcoma indicate that they represent a further type
of sarcomatoid carcinoma.

PROGNOSTIC FACTORS

Staging: the role of the pathologist

The appalling prognosis of carcinoma of the lung has already been
touched upon, when it was noted that the best overall 5-year survival
rates are no better than 14% (see Fig. 12.1.1, p. 532). This poor
outlook is due to a combination of late presentation, early metastasis
A
and a poor sustained response to chemotherapy. Surgeons can achieve
5-year survival rates of 50%, but only by being extremely rigorous in
assessing operability and thereby excluding many patients (up to
80%).9 Staging is therefore extremely important in both treatment and
prognosis. Some believe it to be the only significant predictor of
survival.617
An early step in the spread of a carcinoma is the transition from in
situ to invasive growth, recognition of which can sometimes be dif-
ficult, in which case staining for constituents of the epithelial base-
ment membrane such as laminin and type IV collagen can be helpful.618
Similarly the integrity of lymphatic and capillary endothelium can
be investigated with antibodies to factor VIII-related antigen, Ulex
europeus, CD31 and CD34.
The accurate assessment of metastasis requires histology and a
variety of tissues suspected of harbouring metastatic tumour may be
submitted to the laboratory for this purpose. Mediastinal lymph
nodes are now more often sampled by ultrasound-guided trans­
bronchial or transoesophageal needle aspiration than mediastinos-
copy or mediastinotomy.317,619 They are usually targeted because they
B are enlarged, although histology shows that the correlation between
size and involvement by tumour is poor.620,621 However, positron emis-
sion tomography has led to more accurate targeting of involved areas.
If the tumour is known to be a small cell carcinoma, bone marrow
may be aspirated. The histological detection of micrometastases in
these tissues may be helped by the use of epithelial or neuroendocrine
markers.622,623 Molecular techniques have also been used for this
purpose.624 However, the clinical impact of applying these special
techniques is questionable.625,626
After surgery, pathological staging provides a useful adjunct to the
clinical assessment of tumour size and lymph node involvement.627
Protocols for the examination of specimens from patients with lung
cancer have been drawn up by several institutions. Whichever is
followed the resection specimen should be dissected and sampled in
such a way that, apart from ensuring adequate typing of the tumour,
all questions pertaining to the pathological tumour stage can be
answered. As a routine, the bronchial resection margin, the peri­
bronchial lymph nodes within the lung, the hilar lymph nodes, the
resection margins of the large vessels and the pleura nearest to the
C tumour should be sampled. Lung tissue away from the tumour should
also be sampled to detect occult spread and for the assessment of
Figure 12.1.47  Pulmonary blastoma. (A) The tumour consists of conditions such as asbestosis that might have led to the development
malignant epithelial elements, resembling those seen in fetal lung, set in of the tumour. Any further nodules should also be examined. The full
a sarcomatous stroma. (B) High power shows epithelial tubules within a pathological TNM classification is shown in Table 12.1.15, regional
dense blastomatous stroma. (C) Elsewhere the malignant stroma shows lymph node nomenclature in Box 12.1.6, stage grouping in Table
chondroid differentiation.
12.1.16 and the effect of stage in Figure 12.1.48.628–632
Carcinoma-in-situ at the bronchial resection margin carries a risk
of stump recurrence and is often assessed by frozen section before

570
 Tumours Chapter | 12 |

Table 12.1.15  The 2009 (7th edition) lung cancer staging system: definitions of the descriptors631,632

Descriptors Definitions

T Primary tumour
T0 No primary tumour
T1 Tumour ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, not more proximal than the lobar bronchus
T1a Tumour ≤2 cm in greatest dimension
T1b Tumour >2 but ≤3 cm in greatest dimension
T2 Tumour >3 but ≤7 cm in greatest dimension or tumour with any of the following: invades visceral pleura, involves main
bronchus ≥2 cm distal to the carina, atelectasis/obstructive pneumonia extending to hilum but not involving the entire
lung
T2a Tumour >3 but ≤5 cm in greatest dimension
T2b Tumour >5 but ≤7 cm in greatest dimension
T3 Tumour >7 cm
or directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura or parietal pericardium
or tumour in the main bronchus <2 cm distal to the carina
or atelectasis/obstructive pneumonitis of entire lung
or separate tumour nodules in the same lobe
T4 Tumour of any size with invasion of heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body or
carina;
or separate tumour nodules in a different ipsilateral lobe

N Regional lymph nodes

N0 No regional node metastasis
N1 Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes, including involvement by
direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph
nodes

M Distant metastasis
M0 No distant metastasis
M1a Separate tumour nodules in a contralateral lobe
or tumour with pleural nodules or malignant pleural dissemination
M1b Distant metastasis

Special situations
TX, NX, MX T, N or M status not able to be assessed
Tis Focus of in situ cancer
T1 Superficial spreading tumour of any size but confined to the wall of the trachea or mainstem bronchus

surgery is completed.633 If the tumour is close to, but not obviously tumours of the same pattern in separate lobes might be either
through, the pleura, an elastin stain is useful to delineate the deep independent M0 growths or represent a single M1 tumour. It is now
margin of the pleura.634,635 Penetration of the outer visceral pleural recommended that such tumours in the same lung be classed T4,
elastic layer is regarded as the minimum criterion of penetration (Fig. but M1a if both lungs are affected. Molecular techniques have
12.1.49).636 A classification of the extent of pleural invasion is shown been applied in such cases. One such study found that discordant
in Table 12.1.17.637 and concordant genotypic profiles exist in morphologically similar
Staging becomes problematical when a lobectomy specimen synchronous adenocarcinomas of the lung.639 In two other
contains two carcinomas of the same histological pattern.638 If they studies genomic profiling contradicted the clinicopathological stage
are independent growths they may both be T1 but, if one is considered in 4 of 22 cases and 3 of 6 cases repectively.640,641 In practice, patients
to be a metastasis of the other this advances the stage to T3. Similarly, with such T4 or M1 tumours are generally treated surgically and have

571
 Pathology of the Lungs

100
Box 12.1.6  Regional lymph node numbering for the
purpose of staging lung cancer628,629

N2 lymph nodes Ia
80
Superior mediastinal lymph nodes

Cumulative proportion surviving (%)

1. Highest mediastinal
2. Upper paratracheal Ib
3. Pre- and retrotracheal
60
4. Lower paratracheal
IIa
Aortic lymph nodes
5. Subaortic IIb
6. Paraaortic (ascending aorta or phrenic) 40
Inferior mediastinal lymph nodes
IIIa
7. Subcarinal
8. Paraoesophageal (below the carina)
9. Pulmonary ligament 20 IIIb

N1 lymph nodes
10. Hilar IV
11. Interlobar
0
12. Lobar
0 1 2 3 4 5
13. Segmental
Years after treatment
14. Subsegmental
Figure 12.1.48  Survival of patients with carcinoma of the lung according
Above the highest mediastinal nodes and unnumbered are the scalene and to pathological stage: cumulative proportion (%) surviving up to 5 years
supraclavicular lymph nodes, involvement of which categorises the tumour as after treatment. (Data from the International Union Against Cancer632.)
N3, and above these the cervical lymph nodes, involvement of which
categorises the tumour as M1.

better outcomes than lung cancer patients with tumours designated

Table 12.1.16  Stage grouping and survival of pTNM subsets T4 on the basis of invasion of mediastinal structures or M1 because
after treatment for lung cancer631,632 of extrapulmonary metastases.
Large inoperable tumours may be reduced to an operable size by
Stage pTNM Deaths/ 5-year Median chemotherapy or irradiation, a process known as neoadjuvant
grouping subset total survival survival therapy.642 The extent of these changes should be incorporated in the
(%) (months) pathologist’s report of the resection specimen. Successful neoadjuvant
therapy results in haemorrhagic necrosis of the tumour. The necrosis
Ia T1 N0 M0 1168/3666 73 119 is generally bordered by chronic inflammatory granulation tissue in
which foamy macrophages, foreign-body giant cells and cholesterol
Ib T2a N0 M0 1450/3100 58 81
crystal clefts may be seen. Alternatively, the tumour site may show
IIa T1 N1 M0 or 1485/2579 46 49 only a fibrous scar of non-specific appearance. Occasionally, the
T2a N1 M0 or tumour appears quite viable but is of a less malignant pattern than
T2b N0 M0 was seen in the preoperative biopsy. For example, only adenocarcinoma-
in-situ may be found postoperatively in a patient whose preoperative
IIb T2b N1 M0 or 1502/2252 36 31
T3 N0 M0
biopsy showed invasive tumour.643 Similar changes may be en­­
countered in pulmonary metastases (see p. 686).
IIIa T1 N2 M0 or 2896/3792 24 22 The pathologist should attempt to identify and sample lymph
T2 N2 M0 or nodes at the hilum of the resection specimen, involvement of these
T3 N1 M0 or taking the tumour stage to N1. The laboratory will usually receive
T3 N2 M0 or several separate specimens of higher lymph node stations, all num-
T4 N0 M0 or bered according to the internationally approved classification shown
T4 N1 M0 in Box 12.1.6.631,632 The assessment of these will decide whether stage
IIIb T1 N3 M0 or 263/297 9 13 N2 has been reached. It is usually sufficient for the pathologist to
T2 N3 M0 or record the presence or absence of tumour in each of these. Some
T3 N3 M0 or surgeons wish to know whether the lymph node capsule has been
T4 N2 M0 or breached but the higher nodes are often received piecemeal. There is
T4 N3 M0 some evidence that direct spread to N1 nodes has a better prognosis
than metastatic spread to these nodes644and, similarly, that intrapul-
IV Any T Any N 224/266 12 17
M1
monary N1 lymph node involvement is better than extrapulmonary
N1 disease.645

572
 Tumours Chapter | 12 |

Histological type and grade cell carcinomas as inoperable and only divide them according to
whether spread is limited or extensive but it is now recommended
Bearing in mind that stage is far more important than any other that these tumours be fully staged by the TNM system. Adenocarcinoma
prognostic factor,617 histological type, subtype and grade cannot be is recognised as having more metastatic potential than squamous
con­sidered to have a major impact, but all have some relevance cell carcinoma and with this cell type it is worth extending pre­
to prognosis.361,646–651 In regard to tumour typing, interobserver vari- operative screening procedures for metastases to include the brain.
ability is reported to be small325,362 but grading is more subjective. Within adenocarcinoma, mucin-forming varieties are recognised to be
The worst histological type, small cell carcinoma, has a 5-year survival the more aggresive.426 Histological typing is also important in regard
rate of only 4% (Fig. 12.1.50).652 Many oncologists regard all small to treatment; small cell carcinoma generally is considered the only
type that responds to chemotherapy, if only temporarily. However, the
neoadjuvant chemotherapy for non-small cell carcinoma shows that
these tumours are also chemosensitive,642 albeit to a lesser extent than
small cell carcinoma. Considerable attention is being paid today to
the implications of neuroendocrine differentiation in non-small cell
carcinomas, in particular to the possibility that such differentiation
may be associated with the chemosensitivity shown by small cell
carcinoma: the limited evidence for this is discussed under large cell
neuroendocrine carcinoma (see p. 563).537,539

Other prognostic factors

As well as tumour stage, histological type and grade, various other
factors, listed in Box 12.1.7, have been reported to carry prognostic
significance, albeit rather limited.97,102,214,248–254,525,653–694 However,
reports tend to be conflicting. Furthermore, this discordance is com-
pounded by the heterogeneity of lung tumours, which is found to
apply to the results of these more sophisticated investigations as much
A as to simple histological typing. Therefore, if it were planned to intro-
duce any of these techniques into routine laboratory practice quite
extensive standardised sampling of the tumour would be required.695,696
Oncogene expression also appears to be linked to prognosis.697–699
Not all groups have found a positive correlation,700–702 but expression
of the ras oncogene in lung tumours is widely reported to auger a poor
prognosis.703–706 Similar findings are reported in respect of Her2/neu

Table 12.1.17  Classification of visceral pleural invasion637

PL0 Tumour located within the lung parenchyma or only

superficially invading in the pleural connective tissue,
but not beyond the elastic layer of the visceral pleura
PL1 Tumour invades the visceral pleura beyond the elastic layer
B
PL2 Tumour invades to visceral pleural surface
Figure 12.1.49  Pleural penetration. Elastin stains clarify the relation of a
peripheral growth to the pleura. (A) This pulmonary carcinoma (right) PL3 Tumour invades the parietal pleura or the chest wall
abuts but does not penetrate the outer elastin layer of the visceral pleura Correlation between PL and T status: T1 = PL0; T2 = PL1 or PL2; T3 = PL3.
whereas in (B) another carcinoma broaches this elastin layer.

Squamous cell

Adenocarcinoma

Small-cell

Large-cell

30 20 10 0 0 10 20 30
Men (%) Women (%)
Figure 12.1.50  Five-year-survival rates (%) of lung cancer according to histological type.652

573
 Pathology of the Lungs

which faulty genetic regulation may influence tumour growth is in the

Box 12.1.7  Putative prognostic factors for lung cancer production of receptors for specific growth factors. An example of this
other than tumour stage, histological type and grade is the strong expression of EGFR demonstrated in pulmonary
DNA content653–655
squamous cell carcinoma.722
As well as the control of these recognised oncogenes, the total
Ploidy656–658
genetic make-up of a tumour may be mapped by microarrays and by
Nuclear/cytoplasmic ratio659
comparing these results with the subsequent course and response to
Proliferation markers660–663 treatment in large series it may be possible to predict how subsequent
Nucleolar organiser regions664–666 tumours are likely to behave.723,724 This is leading to molecular
Telomerase activity667 classifications of tumours, the clinical importance of which is likely
Apoptosis668 to rival that of histological category. As yet, however, it is not known
Tumour doubling time669 whether tumours are genetically homogeneous so that a sample can
Tumour-specific markers525,670,671 be used to predict the behaviour of the whole.328
Oestrogen receptor672
Inflammatory response673–677
Fibrosis97,102
Vascularity678–682 DEVELOPMENTS IN TREATMENT
Vascular invasion683,684
Cell adhesion molecule expression685–688
The traditional treatment of lung cancer is threefold: surgery for those
Autocrine production of immunosuppressive oncogenes689 patients whose tumours appear to be operable after extensive staging,
Disruption of the epithelial basement membrane690,691 aggressive chemotherapy for most small cell carcinomas (typically
Secretion of metalloproteinases692–694 with etoposide and cisplatin), and palliative or radical chemotherapy
Autocrine production of growth factors214,248–254 and/or radiotherapy for inoperable non-small carcinoma. Neoadjuvant
chemotherapy extends this by reducing the extent of the tumour to
operable proportions, so providing curative treatment to patients
formerly offered only palliation.642 Postoperative (adjuvant) chemo­
therapy also improves survival.725 New chemotherapeutic drugs are
constantly being introduced and aggressive chemotherapy is being
(EGFR2, c-erbB2).707 Mutations of genes that control cell growth and increasingly offered to patients with inoperable non-small cell carci-
apoptosis, such as p53, RB and bcl-2, are found in many lung neo- noma.726,727 However, acting as they do against all dividing cells,
plasms,663,705,708–713 with obvious implications for the growth of the healthy as well as cancerous, side-effects generally limit their dose.
tumour. For example, squamous cell carcinomas of the lung express- Fortunately, totally new anticancer treatments that act more specifi-
ing the Forkhead box M1 (FoxM1) transcription factor are poorly cally are being introduced.343,723,728 A favourable feature is that some
differentiated, metastasise earlier and have more malignant potential are far less toxic. These tend to retard tumour growth rather than kill
than other tumours of this type.229 Furthermore, genetic abnormalities cancer cells, leading to disease stabilisation rather than regression, but
enhancing tumour growth may be induced by the very chemotherapy they often act synergistically with conventional chemotherapeutic
aimed at eliminating the tumour. For example, amplification of c-myc agents.
is more often present in small cell carcinomas from patients who have Many of these new agents act by modifying transduction pathways
relapsed after chemotherapy than in newly diagnosed patients; important in the continued growth of cancer cells.729 They include
patients in relapse who showed amplification had shorter survivals antibodies against both growth factor receptors on the surface of the
than those who did not.714 tumour cell and small-molecule inhibitors of the receptor’s cyto­
Drug resistance is a major problem in chemotherapy, and one that plasmic domain.730 TK activation is an important growth signal for
is compounded by the observation that tumours that acquire resist- lung cancer731 and members of the epidermal growth factor family
ance to one drug often simultaneously become resistant to a variety such as HER2/neu, which act as TK receptors, are targeted by the
of other structurally unrelated drugs. Such multidrug resistance is monoclonal antibodies cetuximab and trastuzumab and the small-
under genetic control. The genes responsible encode glycoproteins in molecule TK inhibitors gefitinib and erlotinib. In combination with
the cell membrane that eliminate various drugs from the cell and can conventional chemotherapy, gefitinib is proving particularly effective
be detected immunocytochemically.715–717 Pemetrexed is effective only in prolonging survival from lung cancers that express the appropriate
in carcinomas showing non-squamous histology and the presence of gene mutation.206–210,344,732–736 Conversely, mutation of K-ras, which
ERCC1 protein in tumour cells implies resistance to cis-platinum- encodes downstream of epidermal growth factor, and high ERCC1
based therapy. EGFR-targeted TK inhibitors show better response in expression are associated with resistance to TK inhibitors.737,738 Genetic
patients with certain mutations (exons 19 and 21) whilst there are markers of sensitivity to specific cytotoxic agents are proving useful in
other mutations that confer resistance (exon 20). guaging the likelihood of response to traditional chemotherapy.
One mechanism whereby aberrant gene expression may be linked Examples include ERCC1 and BRCA1 for platinum, RRM1 for gemcit-
to tumour aggressiveness is overelaboration of growth factors. En­­ abine and thymidilate synthase for antifolates (such as peme-
dothelin, for example, is a growth factor that has been demonstrated trexed).739,740 Trials of chemotherapy targeting those patients with
in large amounts in squamous cell and adenocarcinoma of the lung cancers containing ELM4-ALK gene rearrangement are also in
lung,253 and transforming growth factor beta-1 is reported to be a progress.229
prognostic factor for pulmonary adenocarcinoma.718 Over 30 other The rapamycin derivative RAD001 (Everolimus) is effective in inhib-
growth factors are known to be synthesised by small cell lung cancer.719 iting the Akt/mammalian target of rapamycin (mTOR) pathway,
Some growth factors, notably gastrin-releasing peptide (human which is frequently activated in small cell lung cancer, and following
bombesin), evince autocrine activity by stimulating the proliferation the demonstration that it inhibits the growth of cell lines of small cell
of the cancer cells that produce them.720,721 A further mechanism by lung cancer, is likely to progress to clinical trials.227

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12.2  Other epithelial tumours

with ‘cylindromas’ (adenoid cystic carcinomas of tracheobronchial

CHAPTER CONTENTS
gland origin, see p. 601), as well-differentiated bronchial tumours.3
Carcinoid tumours, tumourlets and neuroendocrine These two tumours came to be known as the carcinoid and
cell hyperplasia 593 cylindromatous types of bronchial adenoma, but this nomenclature
Carcinoid tumours 593 was abandoned when it was realised that their histogenesis differed
and that both were of at least low-grade malignancy.
Atypical carcinoid tumours 597
It is now appreciated that carcinoid tumours are neuroendocrine
Tumourlets and neuroendocrine cell hyperplasia 598 neoplasms of low-grade malignancy, related to a variety of more
Tracheobronchial gland (salivary gland-type) malignant bronchopulmonary tumours that also show evidence of
tumours 601 such differentiation.4–6 These include small cell carcinoma, atypical
Adenoid cystic carcinoma 601 carcinoid and large cell neuroendocrine carcinoma. Evidence of
Mucoepidermoid carcinoma 603 neuro­endocrine differentiation can also be found in occasional squa-
mous cell and adenocarcinomas but: its presence there does not
Mucous gland adenoma 604
appear to be of any clinical significance.7,8 Neuroendocrine tumours
Oncocytoma 605 can all generally be distinguished with ease but together they form a
Pleomorphic adenoma 605 spectrum and occasional examples are difficult to classify precisely.
Epithelial–myoepithelial carcinoma 605 Carcinoids, the microscopic tumour-like hyperplasias of the bron-
chopulmonary neuroendocrine cells known as tumourlets and neu-
Acinic cell carcinoma 606
roendocrine cell hyperplasia are considered in this chapter while
Papillomas 606 carcinomas showing neuroendocrine differentiation are dealt with in
Solitary papilloma 606 Chapter 12.1.
Recurrent respiratory papillomatosis 607
Adenomas 608
Epidemiology and aetiology
Papillary adenoma 608
About 12% of all carcinoids arise in the lung but less than 1% of lung
Alveolar adenoma 608 tumours are carcinoids.9 The sex incidence is equal and they occur
Sclerosing pneumocytoma (sclerosing over a wide age range.10,11 The mean age is about 50 years, significantly
‘haemangioma’) 610 lower than that for carcinoma of the lung. About 8% develop in the
Pulmonary thymoma 612 second decade, making them the commonest primary pulmonary
References 613 tumour of childhood.12,13 Carcinoid tumours are not related to
smoking or environmental pollution: it is not known what promotes
their formation but they are sometimes associated with multiple foci
of neuroendocrine cell hyperplasia and tumourlets, which are dealt
with next.14,15 They do not appear to de-differentiate into small cell or
CARCINOID TUMOURS, TUMOURLETS AND large cell neuroendocrine carcinomas, although focal carcinoid
NEUROENDOCRINE CELL HYPERPLASIA differentiation is sometimes observed within otherwise classic small
cell carcinoma.

Carcinoid tumours
The term ‘carcinoid’ was introduced in 1907 to distinguish certain Clinical features
previously described low-grade intestinal neoplasms from adenocar- Most patients with bronchopulmonary carcinoid tumours present
cinomas.1,2 Bronchial carcinoids were subsequently described, together with cough, haemoptysis or symptoms referable to the consequences

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 Pathology of the Lungs

of collapse or pneumonia distal to airway obstruction.10,11 Sometimes

there is wheezing, or even stridor, and these features have occasionally
been mistaken for asthma. Small central tumours and those in the
periphery of the lung may be asymptomatic and only discovered
by chance. Occasionally a polypoid carcinoid may be coughed up
spontaneously and no trace of its origin found on bronchoscopy.
Very occasionally, bronchial carcinoids present with metastatic
deposits or with a variety of paraneoplastic endocrine syndromes,
including Cushing’s syndrome, acromegaly or the carcinoid
syndrome.16–20 In contrast to their gastrointestinal counterparts,
bronchopulmonary carcinoids may cause the carcinoid syndrome
in the absence of metastases, although these are usually present.
This is because they release their secretions directly into the systemic
circulation rather than into portal vessels. For the same reason, the
endocarditis that forms part of the carcinoid syndrome affects valves
on the left side of the heart rather than the right. Bronchopulmonary
carcinoids may also be associated with pituitary, parathyroid and
pancreatic islet cell tumours as part of a multiple endocrine neo­
plasia syndrome known as MEN1.21

Gross appearances
Most bronchopulmonary carcinoids arise in the walls of central
airways where they are seen on bronchoscopy as smooth cherry-red
nodules that protrude into the airway. The bulk of the tumour often
extends between the bronchial cartilages to invade the adjacent lung
but sometimes the tumour grows entirely into the lumen of the
airway, forming an endobronchial polyp. A combination of endo-
bronchial and intrapulmonary growth may also be found, giving the
tumour a dumb-bell or cottage-loaf appearance (Fig. 12.2.1A). Those
that extend into the lung usually have a well-defined, rounded border.
Bronchopulmonary carcinoids are notorious for bleeding profusely if
A
biopsied, although this is not the experience of all groups.10 The cut
surface of the tumour has a soft pinkish-tan or yellow appearance, or
is haemorrhagic. A minority of bronchopulmonary carcinoids arise in
the periphery of the lung (Fig. 12.2.1B).22 Occasionally there are
multiple tumours.23–25 These are particularly likely to be associated
with multiple tumourlets, hyperplasia of bronchiolar neuroendocrine
cells, a peripheral location and, rarely, obliterative bronchioli-
tis.14,15,26,27 However a minority of isolated carcinoids also present in
a peripheral location. These tend to be circumscribed lesions and may
have no obvious association with an airway.

Histological appearances
Microscopy shows that carcinoid tumours have a thin fibrous capsule
that is often incomplete. They may also exhibit infiltrative activity (Fig.
12.2.2). Several histological patterns, which may be present in com-
bination, are recognised (Box 12.2.1).28 The commonest patterns are
the trabecular and the mosaic.29,30 In the former the tumour cells are
arranged in interlocking cords or ribbons while in the latter they form
nests or islands separated by a delicate fibrovascular stroma (Fig.
12.2.3). The tumour cells are uniform and generally polygonal, with
a moderate amount of eosinophilic cytoplasm and round nuclei B
having finely granular chromatin and inconspicuous nucleoli. Necrosis
is not seen and mitoses are not readily evident, numbering less than Figure 12.2.1  Bronchial carcinoid tumours. (A) A central carcinoid
2/2 mm2. If either necrosis or a higher mitotic rate is identified, the tumour that is partly endobronchial but has mainly grown into the
tumour is classified as an atypical carcinoid (see below) or, if 11 or surrounding lung. Note its well-circumscribed edge. (B) A well-
more mitoses per 2 mm2 are evident, a large cell neuroendocrine circumscribed 15 mm diameter carcinoid tumour located in the periphery
of the lung.
carcinoma (see p. 563).
About 40% of bronchial carcinoids are biphasic, being made up of
groups of neuroendocrine cells surrounded by S-100-positive
sustentacular cells, a feature that is also found in paragangliomas and
which has caused these carcinoids to be termed ‘paraganglioid’.31,32 An

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 Tumours Chapter | 12 |

Box 12.2.1  Histological patterns of bronchopulmonary

carcinoid tumours
Classic patterns
Mosaic (insular)
Trabecular
Variants
Paraganglioid
Adenopapillary
Clear cell
Oncocytic
Melaninogenic
Spindle cell
A Atypical

The pattern may vary within a tumour but to a limited degree histological
pattern correlates with site; central tumours tend to be trabecular and
peripheral growths mosaic or spindle cell.22

Figure 12.2.2  Bronchial carcinoid tumours showing infiltrative activity.

(A) Typical carcinoid tumours have a thin fibrous capsule that is often
incomplete. (B) Infiltration of cartilage may be seen in typical carcinoids. A

alternative view is that these tumours are not carcinoids at all

but paragangliomas. Support for this view comes from the
identification of scanty ganglion cells in a few examples, leading to
the introduction of the term ‘pulmonary gangliocytic paraganglioma’
(see also p. 638).33–35 Sustentacular cells are less common in the more
malignant neuroendocrine tumours.32
Some carcinoid tumours have an adenopapillary pattern, with small
amounts of mucin contained within either tumour cells or gland
lumina (Fig. 12.2.4).28,30,36 Peripheral tumours tend to show a spindle
cell pattern in which groups of fusiform cells are separated by a rich
network of blood vessels (Fig. 12.2.5).22,29,37 Other carcinoid tumours
have abundant clear38 (Fig. 12.2.6) or eosinophilic cytoplasm (Fig.
12.2.7),39–41 the latter representing oncocytic change, something that
may also be seen in occasional tracheobronchial gland tumours and
in glomangiomas. Clear cell carcinoids may be confused with benign B
clear cell tumours (see p. 625), but the immunohistochemical and
ultrastructural features, which are outlined below, are very different. Figure 12.2.3  Bronchial carcinoid tumours. (A) Trabecular pattern, in
Melanin is occasionally evident within the tumour cells42–48 (Fig. which the tumour cells form anastomosing cords. (B) Mosaic pattern, in
12.2.8) and rare examples contain rod-shaped crystalloid cytoplasmic which the tumour cells are arranged in nests. In both patterns the groups
inclusions.49 Argentaffin stains are seldom positive but argyrophilia of tumour cells are separated by a delicate vascular stroma, nuclei are
can often be demonstrated. regular and there are no atypical features.

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 Pathology of the Lungs

Figure 12.2.4  Bronchial carcinoid tumour of adenopapillary pattern. Figure 12.2.7  An oncocytic bronchial carcinoid tumour. The tumour cells
have abundant deeply eosinophilic cytoplasm.

Figure 12.2.5  A peripheral pulmonary carcinoid tumour of spindle cell

pattern. Figure 12.2.8  A bronchial carcinoid tumour in which many of the
tumour cells contain melanin.

Cartilage and bone may form in the stroma of bronchial carcinoid

tumours (Fig. 12.2.9).50 This has been variously ascribed to the tumour
infiltrating the perichondrium of the bronchial cartilage or to release
of various growth factors by the tumour. Apudamyloid is also occa-
sionally found in the stroma of carcinoid tumours.51,52 Stromal vascu-
larity may be very marked, with dilated sinusoidal vessels separating
groups of tumour cells to give an appearance resembling that of a
paraganglioma, the distinction from which is based on the immuno-
cytochemical demonstration of cytokeratin (see below). Alternatively,
the hypervascularity may suggest a glomus tumour, which is
distinguished by immunocytochemistry and electron microscopy.53

Ultrastructure
Electron microscopy shows that the cytoplasm contains abundant
dense-core neurosecretory granules, which range from 100 to
250 nm in diameter and vary in shape and electron density (Fig.
Figure 12.2.6  A bronchial carcinoid tumour of clear cell pattern. 12.2.10).4–6,54–57 Epithelial features include desmosomes and

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 Tumours Chapter | 12 |

occasional bundles of tonofilaments. Oncocytic tumours are charac-

terised by closely packed mitochondria in addition to neurosecretory
granules, but it may not be possible to demonstrate both in the
same cells.39–41

Immunohistochemistry
Immunohistochemistry may be used to identify markers of neuroendo­
crine differentiation.54,56,58,59 None of the antibodies currently avail­
able is totally specific,60 the best probably being CD56, synaptophysin,
chromogranin and N-cadherin.61–67 Other specific components of the
neurosecretory granules include biologically active amines and pep-
tides such as serotonin, calcitonin, gastrin-releasing peptide (human
bombesin), adrenocorticotrophic hormone (ACTH), vasoactive intes-
tinal polypeptide and leu-enkephalin. Differences between central
and peripheral carcinoids are described, the latter more frequently
expressing immunoreactivity for gastrin-releasing peptide, calcitonin
Figure 12.2.9  A bronchial carcinoid tumour in which there is stromal and ACTH.59,68 One bronchial carcinoid contained eight different hor-
bone formation. mones.69 The ability to produce more than one hormone may account
for variations in granule size seen in a single cell.57 However, neuro­
endocrine tumours may even store multiple peptides within a single
granule.70 Occasional tumours show evidence of dual exocrine and
endocrine (so-called amphicrine differentiation71), for example,
neuro­endocrine granules have been identified in the same tumour
cells as type II pneumocyte lamellar bodies, Clara cell granules and
mucous vacuoles.72,73 The intermediate filaments in the neuroendo-
crine cells consist of cytokeratin.74 Although the lung marker thyroid
trans­cription factor-1 (TTF-1) is expressed by small cell carcinoma and
large cell neuroendocrine carcinoma, reports of its expression by car-
cinoid tumours, tumourlets and neuroendocrine cell hyperplasia
vary.75–77 However, positive staining of a carcinoid for TTF-1 makes an
origin in the gastrointestinal tract or thymus unlikely.76,77

Behaviour
Typical carcinoids are of low-grade malignancy and infiltration of
adjacent lung or bronchus is often seen. However, it is important to
distinguish typical and atypical carcinoids as the latter carry a worse
prognosis (see below). Nuclear pleomorphism is sometimes apparent
in typical carcinoids but, as with other endocrine tumours, this is a
poor indicator of metastatic potential. It is likely that most early series
failed to exclude tumours that would now be regarded as atypical
carcinoids, and therefore overestimated the tendency for them to
metastasise. In a series of 101 bronchial carcinoids, 10 of the 12
that metastasised were histologically atypical.11 Typical carcinoid
tumours metastasise to hilar nodes in only 6–10% of cases,59,78,79 and
distant metastases, which may involve liver, lung, brain, adrenal or
bone, are even less common. Deposits in bone may be osteosclerotic.
Treatment usually requires lobectomy or, if the tumour involves the
main bronchus, pneumonectomy. However, more limited procedures
are sometimes feasible and a correct biopsy diagnosis is therefore
important.

Atypical carcinoid tumours

Atypical carcinoids make up about 11% of bronchopulmonary carci-
noid tumours.22 An early report suggested that peripheral carcinoids
were more likely to be atypical80 but more recent larger studies have
failed to confirm this.81 Up to 70% of atypical carcinoids eventually
metastasise.22,59,78,79,82,83 There is little effective treatment for metastatic
Figure 12.2.10  Bronchopulmonary carcinoid tumour. Electron microscopy disease as carcinoid tumours lack the chemosensitivity of small cell
shows a wealth of dense-core neuroendocrine granules. carcinomas84 and the somatostatin analogues that are successfully
employed in controlling the advance of metastatic islet cell tumours
are only occasionally effective.85 The 5-year survival rate is about 60%,

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 Pathology of the Lungs

nucleoli, hyperchromasia, hypercellularity and disorganisation, as

well as the afore-mentioned necrosis and increased mitotic activity,78
but some of these additional features are of little prognostic impor-
tance. Nuclear pleomorphism, for example, may be found in other-
wise unexceptional carcinoids that behave in an indolent manner.
Necrosis and increased mitotic activity are the most reliable pointers
to atypical behaviour. Mitoses number 3–10 per 2 mm2 (about 10
high-power fields); more than 10 indicates small cell or large cell
neuroendocrine carcinoma (see Table 12.1.12, p. 563).86 Within a
group of atypical carcinoids, those with 6–10 mitoses per 2 mm2 were
more aggressive than those with 2–5, and patients with tumours
measuring over 3.5 cm also fared badly.81
Electron microscopy shows that atypical carcinoids contain fewer
dense-core granules than typical carcinoids, but more than small cell
carcinomas. The immunohistochemical features are generally similar
to those of typical carcinoids, but with increasing malignancy there is
a progressive loss of chromogranin and N-cadherin positivity, loss of
heterozygosity and increased incidence of gene abnormalities.67,87,88
A Also, the C-terminal peptide of human pre-bombesin is detectable in
the majority of atypical tumours whereas it can only be shown in a
small number of typical carcinoids.89 Increasing atypicality is also
associated with loss of the S-100-positive sustentacular cells that char-
acterise many typical carcinoid tumours.31,90 Aneuploidy occurs in
both typical and atypical carcinoids but is commoner in the latter.91–94
Proliferative activity assessed by expression of the Ki-67 antigen is
higher in atypical than in typical carcinoids.95 All these features cor-
relate with the observed behaviour of atypical carcinoids, which is
intermediate between that of typical carcinoids and small cell carci-
noma. Thus, in the spectrum of neuroendocrine tumours of the lung,
atypical carcinoids come between typical carcinoid and the neuro­
endocrine carcinomas in terms of their pathological features, natural
history and prognosis (Table 12.2.1).

Molecular biology and genetics of carcinoids

Comparative genomic hybridisation has shown frequent chromo-
somal abnormalities at 11q13 (the site of the MEN1 gene) in both
typical and atypical carcinoids, a point of distinction from small cell
carcinoma and neuroendocrine large cell carcinoma.96,97 Further dif-
B ferences between carcinoids and the higher-grade neuroendocrine
carcinomas include low Rb and p53 inactivation and a low incidence
Figure 12.2.11  Atypical carcinoid. Increased malignant potential is of 3p and 17p deletions in the carcinoids and differences in the ratio
suggested by (A) mitoses numbering more than 2/mm2 and (B) foci of
of bcl2:bax proteins.88,98,99 These differences support the opinion
punctate necrosis (right of centre).
that typical and atypical carcinoids are more closely related to each
other than to large cell neuroendocrine carcinoma and small cell
carcinoma.88,100–105 Differences between typical and atypical carcinoids
which is closer to that of typical carcinoids (95%) than that of large are relatively rare but, in general, atypical carcinoids show more exten-
cell neuroendocrine carcinomas and small cell carcinomas (2%). The sive genetic alterations than typical carcinoids. For example, atypical
peak age incidence (56 years, range 19–75 years) is also intermediate carcinoids have more often shown DNA underrepresentation at 10q
between that of typical carcinoid tumours (50 years, range 19–75 and 13q.101
years) and small cell carcinoma (62 years, range 30–79 years) and they
are more often seen in smokers than are their more benign
counterparts. Ectopic endocrine activity is commoner with atypical Tumourlets and neuroendocrine
than typical carcinoids.
Macroscopically, atypical carcinoids tend to be related to airways
cell hyperplasia
like their typical counterparts, but are more infiltrative. Microscopically, While neuroendocrine cells are abundant in fetal lung, few are found
they are recognised by increased mitotic activity and necrosis being in adult lungs where they are normally scattered singly and sparsely
seen in a tumour with the characteristic cellular make-up and trabec­ along the bronchial basement membrane. Occasionally however
ular or mosaic architecture of a carcinoid (Fig. 12.2.11). The necrosis aggregates of neuroendocrine cells are encountered in adult lungs,
is usually punctate and confined to the centres of cell groups, and it occurring either as clusters of cells or as linear arrays along the base-
may lead to focal dystrophic calcification. The atypical features may ment membrane. If such aggregates are confined by the basement
not be apparent in small biopsies as they are often focal. Atypical membrane the process is termed neuroendocrine cell hyperplasia
tumours were originally defined as carcinoids that showed any one or whereas if they penetrate the basement membrane the term tumourlet
a combination of features that included pleomorphism, prominent is used (for lesions up to a size of 5 mm; beyond 5 mm they are

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Table 12.2.1  A comparison of typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma

Typical carcinoid Atypical carcinoid Large cell neuroendocrine Small cell carcinoma
carcinoma

Behaviour
Local invasion Present Present Present Present
Lymphatic metastases Occasional Not infrequent Frequent Usual
Distant metastases Rare 45–70% >50% 90–100%
5-year survival 95% 60% 27–35% 2%

Histology
Architecture Well-organised Focal loss Moderate loss Poor
Necrosis None Focal Abundant Abundant
DNA deposition on vessels None None None Frequent

Cytology
Mitoses Not seen (<2/10 HPF) Common (2–10/10 HPF) Numerous (>10/10 HPF) Numerous (>10/10 HPF)
Pleomorphism Usually absent Moderate Marked Small cell
Argyrophilia Common Variable – Rare
Neuroendocrine markers Common, diffuse Common, diffuse Common, often patchy Common, often patchy

Aetiology
Role of smoking None Weak Strong Strong
Male : female ratio 0.8 : 1 2 : 1 2.5 : 1 Declininga
Mean age (years) 50 56 63 62

Ultrastructure
Granule numbers Many Moderate numbers – Scanty
Granule size (nm) 150–250 80–140 – 80–140
a
The male : female ratio of small cell carcinoma was formerly high but has been constantly dropping as more women smoke.
HPF, high-powered field.

regarded as carcinoid tumours) (Figs 12.2.12 and 12.2.13).106 cell hyperplasia and tumourlets include pulmonary hypertension,114
Neuroendocrine cell hyperplasia is more commonly found in bronchopulmonary dysplasia,115 chondroid ‘hamartomas’116and
association with neuroendocrine tumours of the lung than with non- various causes of focal pulmonary scarring.117,118 However, they are not
neuroendocrine tumours and within the spectrum of neuroendocrine particularly associated with diffuse interstitial fibrosis.
tumours it is especially associated with peripheral carcinoids.26,107 It has generally been assumed that neuroendocrine cell hyperplasia
The term ‘tumourlet’ was coined by Whitwell108 but Liebow had and tumourlets are pathological curiosities devoid of any clinical
earlier noted their histological resemblance to carcinoid tumours and import but this view has had to be revised following reports of their
referred to them, perhaps more accurately, as atypical carcinoid pro- association with clinically significant obstructive airway disease.14,26,119,120
liferations.109 However, Whitwell’s term ‘tumourlet’ is in more general Histological examination in such cases has shown fibrous obliteration
use. Opinion is divided on the nature of tumourlets but the secondary of bronchioles associated with diffuse idiopathic neuroendocrine cell
cases probably represent hyperplasia whereas a preneoplastic state is hyperplasia and multiple tumourlets (Fig. 12.2.14). This syndrome
envisaged for those patients with diffuse idiopathic pulmonary has been termed diffuse idiopathic pulmonary neuroendocrine cell
neuroendocrine cell hyperplasia (see below). Tumourlets seldom, if hyperplasia.27,106,119 It is suggested that in these cases the tumourlets
ever, metastasise and if similar deposits are found in the hilar are the cause rather than an effect of the fibrosis, the fibrosis being
lymph nodes110–112 or the pulmonary lesions are larger than 5 mm, mediated by the secretion of fibrogenic cytokines such as gastrin-
they are classified as carcinoid tumours. releasing peptide (human bombesin) by the tumourlets.119 Similar
postulates were advanced in a report of interstitial pulmonary fibrosis
associated with diffuse neuroendocrine hyperplasia that extended out
Clinical features from the bronchioles to fill many alveoli.121 It is now considered that
Tumourlets are most frequently associated with bronchiectasis and are diffuse neuroendocrine cell hyperplasia represents a preneoplastic
often multiple.113 Other conditions associated with neuroendocrine lesion leading to carcinoid tumours, mainly typical but occasionally

599
 Pathology of the Lungs

A B

Figure 12.2.12  Neuroendocrine cell hyperplasia. (A) A focus of neuroendocrine cell hyperplasia is present in the basal layer of the respiratory
epithelium, limited by the basement membrane. (B) The hyperplastic cells are more easiliy visualised by immunohistochemistry and are demonstrated
here with an immunoperoxidase stain for chromogranin.

extreme end of type MEN1 syndrome,122 with mutation at the associ-

ate gene being seen frequently in carcinoid tumours (see above).
Until recently tumourlets and foci of neuroendocrine hyperplasia
have been too small to be detected radiologically but with improved
imaging technology this is no longer the case and increasing numbers
are being identified, often leading to them being biopsied to exclude
metastatic disease.27,123

Microscopy
Tumourlets are minute, tumour-like proliferations that are generally
discovered incidentally. They arise in close proximity to bronchioles
as multiple nests of cells separated by narrow connective tissue septa
(see Fig. 12.2.13). Their cells are uniform and have regular, round,
oval or spindle-shaped nuclei with finely dispersed chromatin.
Electron microscopy shows that the cytoplasm contains granules of
typical dense-core type, averaging 100 nm in diameter.124 The
immunohistochemical features are identical to those of normal
bron­chopulmonary neuroendocrine cells and of carcinoid tumours
(see above).58,59,125
The relationship between tumourlets and bronchioles can often be
clearly seen and it is likely that tumourlets arise from bronchiolar
neuroendocrine cells.126,127 Bronchiolar epithelium may directly
overlie the cell clusters, or the bronchiole may be distended by the
tumourlet. In lungs in which tumourlets have been identified, markers
such as synaptophysin or chromogranin usually reveal many more but
smaller clusters of cells within the basal layer of the bronchiolar epi-
thelium. Examination of lungs resected for carcinoid tumours or car-
cinoma may also show a significant increase in the number of
neuroendocrine cells, including clusters large enough to disturb and
narrow small airways.15,119 Occasionally, otherwise typical carcinoid
Figure 12.2.13  Tumourlet. A neuroendocrine cell aggregate composed tumours may be accompanied by multiple fully formed
of small oval cells has infiltrated the peribronchiolar lung parenchyma. tumourlets.14

atypical,27 but not to other neuroendocrine tumours. No genetic

markers have been identified that might distinguish diffuse idiopathic Differential diagnosis
neuroendocrine cell hyperplasia from neuroendocrine cell hyper­ Tumourlets differ from carcinoid tumours only in their size. An arbi-
plasia secondary to lung damage, although diffuse idiopathic trary upper size limit of 5 mm has been adopted.106 Tumourlets may
neuroendocrine cell hyperplasia is seen in occasional patients at the be confused with meningothelioid nodules (see p. 700). Unlike

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tumourlets, the latter are not related to air spaces but are situated
within the interstitium, generally near septal veins: they lack neuroen-
docrine features. Localised regenerative proliferations of bronchiolar
epithelium have sometimes been termed tumourlets, but they usually
consist of stratified squamous epithelium and lack the pattern of a
true tumourlet; they also are devoid of any neuroendocrine features.

Prognosis
Diffuse idiopathic neuroendocrine cell hyperplasia generally pursues
a benign course but the condition is slowly progressive and the
subsequent obliterative bronchiolitis has occasionally necessitated
transplantation.120

A
TRACHEOBRONCHIAL GLAND (SALIVARY
GLAND-TYPE) TUMOURS

The mixed seromucous glands of the trachea and bronchi are similar
to the minor salivary glands and give rise to the same range of
tumours.128 Many are of low-grade malignancy and the term ‘bron-
chial adenoma’, previously used to cover both tracheobronchial gland
tumours and bronchial carcinoid tumours,3 has therefore been
abandoned despite them very rarely occurring in combination.129
Tracheobronchial gland tumours are less common than bronchial
carcinoids, in a ratio of 1 : 10, and most are either adenoid cystic
carcinomas or mucoepidermoid tumours. Pleomorphic adenoma, the
commonest tumour of the major salivary glands, is rare in the lower
respiratory tract. It is probable that some central adenocarcinomas
arise in tracheobronchial glands, although the site of origin of these
aggressive tumours can rarely be identified with confidence and claims
that they have a distinctive morphological pattern130,131 are not entirely
convincing.
B
Tracheobronchial gland tumours are usually central lesions that
tend to protrude into the airway lumen, causing such symptoms as
cough and haemoptysis, possibly of long duration. Alternatively, there
may be a history of repeated episodes of pneumonia. Occasionally a
tracheobronchial gland tumour is coughed up spontaneously.132
Clinical evaluation to exclude metastasis from a salivary gland primary
is always prudent, particularly if the lung tumour is peripheral or one
of many.

Adenoid cystic carcinoma

Adenoid cystic carcinoma, formerly known as cylindroma, has an
equal sex incidence and is a tumour of middle age (mean about 50
years), being extremely rare under the age of 30.128,133,134 Clinical
features are as outlined above.

Pathological features
C Adenoid cystic carcinomas most often involve the lower trachea or
large bronchi but some are peripheral, presumably derived from
Figure 12.2.14  Diffuse idiopathic neuroendocrine cell hyperplasia. (A) A glands in small bronchi.135,136 They are slowly growing infiltrative
dilated bronchiole shows chronic obstructive changes. (B) At the lower tumours that thicken and narrow the airway wall. They form poorly
border of (A) there is a small focus of neuroendocrine cell hyperplasia defined, sessile, nodular growths that may ulcerate centrally but more
and fibrosis. (C) An elastin stain shows that this represents fibrous
usually infiltrate extensively beneath an intact mucosa, ultimately
obliteration of a branching bronchiole. This was just one of many such
involving adjacent lung tissue and hilar lymph nodes by direct inva-
foci identified throughout the explanted lung of a patient undergoing
lung transplantation for obstructive lung disease. sion.136 Perineural infiltration is a characteristic feature.
Pulmonary adenoid cystic carcinomas are identical in their
microscopical appearances to those encountered in other sites, which

601
 Pathology of the Lungs

include salivary gland, breast, skin, oesophagus, cervix uteri and

prostate. The tumour cells form well-demarcated groups within which
small cysts give a cribriform or tubular appearance (Fig. 12.2.15). The
cysts may contain alcianophilic connective tissue mucin, secreted by
their lining myoepithelial cells. Serial sections show that these spaces
are continuous with the stroma of the tumour. Whilst most of this
secretion is mucoid and haematoxyphil, in places it becomes eosino­
philic and hyaline, forming connective tissue cylinders that gave the
tumour its former name of cylindroma. Closely packed, small, dark
myoepithelial cells form the dominant cell population, but there are
also true ducts lined by slightly larger cells that secrete periodic acid–
Schiff (PAS)-positive epithelial mucin.137 As in the salivary glands,
these tumours may occasionally be more solid and of higher grade.
The immunocytochemical profile of adenoid cystic carcinoma reflects
its myoepithelial nature, the tumour cells staining for cytokeratin,
vimentin and actin; S-100 staining may also be positive (Table 12.2.2).
The cysts contain components of basement membrane which may
stain for laminin, fibronectin and type IV collagen.134,138,139 Molecular
studies have shown polysomy of chromosome 7 in one-third of cases
but neither amplification nor mutation of the epidermal growth factor
A
receptor (EGFR) gene.140 KIT protein expression is frequently found
but KIT-activating mutations are not seen.141

Differential diagnosis
The histological features are usually sufficiently distinctive to allow a
confident diagnosis but in small biopsies it may be difficult to
distinguish adenoid cystic carcinoma from adenocarcinoma, basaloid
carcinoma, small cell carcinoma and lymphoma. Identification
of a myoepithelial phenotype is then helpful.

Treatment and prognosis

The central location of adenoid cystic carcinomas and their predi­
lection for submucosal and perineural spread make it difficult to treat
these tumours effectively. Despite this, resection is the treatment of
choice, with stenting, local ablation and radiotherapy forming alterna-
tive options for tumours that cannot be completely resected. Because B
of their growth pattern it is particularly important that the resection
margins are checked by frozen section before closure. Nevertheless, Figure 12.2.15  Adenoid cystic carcinoma of bronchial gland origin.
local recurrence is frequent, often after a period of years, and may (A) The tumour is almost wholly endobronchial. (B) Histologically, these
eventually lead to fatal pulmonary infection. Metastases are uncom- tumours are identical to those that arise in the salivary glands. Microcysts
mon but may develop in lymph nodes, bone, kidney, liver, brain give the tumour a cribriform pattern.
and lung.135

Table 12.2.2  Immunohistochemistry of tracheobronchial gland tumours

Adenoid cystic Mucoepidermoid Pleomorphic adenoma Acinic cell tumour

carcinoma tumour

Cytokeratin +++ +++ +++ +++

S-100 protein + − ++ −
Actin +++ − ++ −
Vimentin ++ − ++ −
Glial fibrillary protein − − ++ −
Chromogranin − − − −

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 Tumours Chapter | 12 |

Figure 12.2.16  Low-grade mucoepidermoid carcinoma. (A) Endobronchial tumour occludes the airway. (B) At low power, this endobronchial tumour
shows a mixed solid and glandular pattern. Many of the tumour acini are distended by mucus, in which there is focal dystrophic calcification.  
(C) An island of tumour beneath the surface epithelium consists of intermediate and goblet cells.

Mucoepidermoid carcinoma gross appearances vary according to the degree of malignancy. Low-
grade tumours form smooth, partly cystic, polypoid masses that
Mucoepidermoid carcinomas comprise 0.1–0.2% of primary lung project into the lumen of the bronchus (Fig. 12.2.16A) and may have
tumours.142 All ages are affected, although approximately 50% of cases a papillary stucture.150 They grow by expansion and compress
present before 30 years of age and 20% before 20 years. There is a surrounding tissue. The overlying bronchial mucosa, which may show
female sex predominance.143 The tumours show a spectrum of malig- squamous metaplasia, is generally intact. More aggressive tumours
nancy.128,133,142–150 Low- and high-grade variants are recognised, the tend to be less clearly defined, irregular and solid: they infiltrate
former comprising about 80% of these neoplasms. Younger patients surrounding lung and more closely resemble the commoner
generally have low-grade tumours, most of which are cured by surgical carcinomas of the lung.
resection. The high-grade tumours are generally found in patients over
the age of 30 years and prove fatal in 23% of cases.143 Although
typically presenting with symptoms of obstruction, occasional patients Microscopy
may be misdiagnosed as having asthma.151 Imaging classically reflects The essential microscopic feature of mucoepidermoid carcinomas is
airway obstruction and an endobronchial mass, sometimes with that they contain both glands and squamous elements (Fig. 12.2.16B,
punctate calcification.152 C). The glands are lined by a mixture of mucous and non-secretory
columnar cells, and contain epithelial mucus that may calcify or even
Gross features ossify.143 The mucous cells are also found mixed with the squamous
Mucoepidermoid carcinoma most commonly arises in the main, lobar cells in a sheet-like arrangement. The squamous cells are linked by
or segmental bronchi but occasional examples are peripheral.149 The intercellular bridges but keratinisation is not seen.144 Sheets of regular,

603
 Pathology of the Lungs

polygonal cells with abundant eosinophilic cytoplasm and known as

transitional or intermediate cells merge with the mucous and squa-
mous cells and may be the dominant component. In some tumours
the cells have abundant clear cytoplasm or, rarely, show oncocytic
change.153 Occasional examples display a prominent lymphoplasma-
cytic infiltrate.154 Low-grade tumours lack cellular atypia and mitoses,
features that are seen particularly in the squamous component of the
more malignant tumours. Genetic analysis has shown a variety of
translocations including t(11;19)(p22;q13), t(11;19)(q14–21;p12)
and t(11;19)(q21;p13) that lead to the deve­lopment of a novel fusion
oncogene, MECT1-MAML2.152,155–157 The last of these gene rearrange-
ments was found in 10/10 well-differentiated bronchopulmonary
mucoepidermoid carcinomas, 3 of 7 poorly differentiated such
tumours and in none of the several adenosquamous, squamous or
adenocarcinomas examined, thus proving to be of use in both diag-
nosis and prognosis.157

Differential diagnosis A
The histological features are usually sufficiently distinctive to permit
a confident diagnosis but separation from mucous gland adenoma
and carcinoid may be difficult in small biopsies or on frozen section.
Immunohistochemistry may help exclude carcinoid tumours but, in
practice, as long as the surgeons are aware that they are dealing with
a low-grade malignancy or benign tumour and that bronchoplastic
resection is an option, definitive classification may wait until examina-
tion of the resection specimen.
High-grade tumours show a more infiltrative growth pattern (Fig.
12.2.17) and it is difficult to draw absolute distinctions between high-
grade mucoepidermoid carcinoma and adenosquamous carcinoma,
both of which have a dual cell population. However, adenosquamous
carcinomas tend to arise in the periphery of the lung whereas muco­
epidermoid carcinomas arise in major airways. Frank keratinisation
with the formation of keratin pearls suggests adenosquamous carci-
noma rather than mucoepidermoid carcinoma whereas the presence
of abundant cells that are transitional in appearance between squa-
mous and mucous cells, foci of the more characteristic low-grade
pattern and a lack of in situ carcinoma in the overlying epithelium all
favour mucoepidermoid carcinoma. The differential diagnosis also B
includes necrotising sialometaplasia, a reactive, non-invasive process
that generally follows prolonged tracheal intubation (see p. 51).158
Figure 12.2.17  High-grade mucoepidermoid carcinoma. (A) An
endobronchial tumour occludes a segmental bronchus and an adjacent
lymph node is greatly enlarged by metastastatic tumour. (B) The
Treatment and prognosis intermediate cells are of acinar pattern, pleomorphic and mitotically
active and there is some resemblance to an adenocarcinoma.
Surgical resection is the treatment of choice for both low-grade and
high-grade tumours, with bronchoplastic surgery an option in low-
grade cases. The prognosis of low-grade tumours is generally excellent,
although nodal involvement and metastases have occasionally been
reported.143,147,159 The prognosis in children appears to be slightly
better than in adults, probably reflecting a higher incidence of low- bronchi as smooth, rounded, polypoid tumours (Fig. 12.2.18A). The
grade tumours in younger patients.12,145 The prognosis for high-grade overlying bronchial mucosa is usually intact and the cut surface may
tumours is variably reported142,143,160 but about 25% of patients with show irregular microcystic spaces filled with mucus. Invasion of bron-
these tumours develop metastases, typically in lymph nodes, bone or chial wall or lung parenchyma is not seen and these tumours tend to
skin. Some patients with unresectable disease have responded favour- remain superficial to the bronchial cartilage. Surgical resection, ideally
ably to EGFR-targeted therapy.161 by bronchoplastic resection, is curative.
Microscopically, glands, which sometimes form small cysts, are
lined by columnar or cuboidal mucous cells and contain mucin (Fig.
Mucous gland adenoma 12.2.18B). More solid areas consist of tubular or acinar structures or
aggregates of mucus-filled cells. The intermediate and squamous cells
Mucous gland adenoma, or cystadenoma, is one of the rarest tumours of a mucoepidermoid carcinoma are not seen but the identification
of tracheobronchial glands and one that has no direct counterpart in by electron microscopy of occasional squamous, myoepithelial and
the salivary glands.128,132,162–164 Reported examples cover a wide age oncocytic elements indicates a possible overlap with low-grade
range, including childhood. They arise in main, lobar or segmental mucoepidermoid carcinoma.163,164

604
 Tumours Chapter | 12 |

normal bronchial glands, oncocytic change affects small groups of

cells in ducts and acini and is seen more frequently with increasing
age.166 Bronchial carcinoids (see Fig. 12.2.7), glomus tumours,
mucoepidermoid carcinomas and acinic cell carcinomas are all
occasionally oncocytic, and recognition of their true nature may
depend upon the use of mucous stains, immunocytochemistry or
electron microscopy.167
Pure oncocytomas are exceedingly rare in the airways.128,167–169 Some
reported cases have been very small incidental lesions in which the
oncocytes formed acinar or tubulopapillary patterns.128,168 Grossly,
oncocytomas usually form well-demarcated, solid nodules ranging in
size from 1 to 3.5 cm. They are generally solitary but multiple pulmo-
nary oncocytomas have been described.170 Histologically, the onco-
cytic tumour cells are arranged in sheets or nests. They show little
mitotic activity and no necrosis. Focal infiltrative growth may be noted
at the periphery of lesions but this is not regarded as indicating malig-
nancy.169 The tumour cells stain focally for cytokeratin and vimentin,
but not for actin, S-100 or neuroendocrine markers.169 The absence
of neuroendocrine markers helps exclude oncocytic carcinoid.
Granular cell tumours resemble oncocytomas but are S-100-positive
and cytokeratin-negative.
Oncocytoma carries an excellent prognosis. Lymph node metastasis
is recorded in one case but 2 years after lobectomy the patient was
free of disease.171

A
Pleomorphic adenoma
Pleomorphic adenoma, which is the commonest tumour of major
salivary glands, is rare in the lower respiratory tract.172–176 The histo-
logical features are similar to those seen in the salivary gland tumour
except that ducts are relatively sparse: microscopy shows epithelial and
myoepithelial cells in a myxoid or chondroid stroma (Fig. 12.2.19).
The tumour cells react strongly with antibodies to cytokeratin and
variably for vimentin, actin, S-100 protein and glial fibrillary acidic
protein (see Table 12.2.2).173 Occasional tumours show cytological
atypia or local infiltrative activity and these tumours are prone to
metastasise.128,173,177 Frankly carcinomatous elements may also be seen
arising from a pleomorphic adenoma (carcinoma ex pleomorphic
adenoma). Some rare malignant endobronchial myxoid tumours
resemble extraskeletal myxoid chondrosarcomas but probably
represent a variant of pleomorphic adenoma.178

Epithelial–myoepithelial carcinoma
Terms such as adenomyoepithelioma and myoepithelioma have been
previously applied to this tumour but it is of low malignant potential
B
and the name epithelial–myoepithelial carcinoma is therefore recom-
mended.106 It is particularly rare in the lower respiratory tract: no more
Figure 12.2.18  Mucous gland adenoma. (A) Endoscopic view. (Courtesy of
than 30 cases have been recorded.179–191 Age at presentation ranges
Dr Gaafar, Alexandria, Egypt.) (B) The tumour consists solely of glands lined
from 33 to 71 years, with no sex predominance.
by cytologically bland mucus-secreting columnar cells.

Pathological features
Grossly, the tumour either protrudes into the bronchus or forms a
Oncocytoma
large intrapulmonary mass. The cut surface may be solid or gelatinous.
Oncocytes, or oxyphil cells, have abundant, finely granular, eosino­ Microscopically, both epithelial and myoepithelial elements are
philic cytoplasm due to the presence of numerous closely packed usually present (Fig. 12.2.20), although purely myoepithelial tumours
mitochondria. These organelles are very striking when examined by also occur and some also show pneumocytic differentiation.192 The
electron microscopy but may also be demonstrated by their affinity typical tubule is lined by two cell types, an inner layer of cytokeratin-
for phosphotungstic acid haematoxylin, with which they stain dark positive epithelial cells surrounded by an outer mantle of myo­
blue. Oncocytes are also distinguished by their strong expression of epithelial cells, the latter expressing smooth-muscle actin and S-100
cytokeratin 14.165 Oncocytes occur in the thyroid, parathyroid and antigen. The outer cells may in turn be surrounded by a rim of PAS-
salivary glands and give rise to oncocytic tumours in all these sites. In positive basement membrane material. In purely myoepithelial

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 Pathology of the Lungs

Acinic cell carcinoma

The histological appearances of this rare tumour are identical to those
of its salivary gland counterpart. It is an indolent growth and the
prognosis is good.193 The pattern is generally solid but reticulin sur-
rounds groups of tumour cells and outlines an acinar or glandular
pattern. The tumour cells are regular and have a poorly staining
slightly basophilic, vacuolated or granular cytoplasm.194,195 Diastase
PAS reactions are generally weak. Electron microscopy shows dense
cytoplasmic granules of about 500 nm diameter, as seen in the serous
acini of the tracheobronchial glands.194,195 The differential diagnosis
includes carcinoid tumour, paraganglioma and benign clear cell
tumour.

PAPILLOMAS

Several types of tumour show a tendency to endobronchial growth,

which means that they grow predominantly into the lumen of the
airways (Fig. 12.2.21). They include squamous cell carcinomas,196
basaloid carcinomas, carcinoids,36 some tracheobronchial gland
neoplasms,150 carcinosarcomas, occasional metastases, inflammatory
polyps and the papillomas that are dealt with here.

Solitary papilloma
Solitary papillomas are generally squamous cell in type but glandular
papillomas and mixed squamous and glandular papillomas are also
recognised.197 Sometimes a bronchial papilloma of mixed squamous
and mucous cell type is continuous with a mucous cell adenoma of
an underlying bronchial gland.198
Aetiological factors concerned in the development of solitary
squamous cell papillomas include human papillomavirus, which is
found in over 50% of cases,197,199–202 and cigarette smoking, perhaps
acting in combination. The patients are generally middle-aged or
elderly men. Types 16 and 18 papillomavirus are involved in these
Figure 12.2.19  Pleomorphic adenoma of the bronchus. Glandular
solitary tumours, rather than the types 6 and 11 found in
structures are set in an abundant myxoid stroma showing chondroid papillo­matosis.200,201 About one-third show cytologic atypia and there
differentiation. is a spectrum of microscopic appearances, ranging from a simple
benign, cytologically bland papilloma with or without an inflamed
hyaline stroma to the invasive papillary squamous cell carcinoma
discussed in Chapter 12.1.198 In solitary squamous papillomas, the
areas, the tumour cells vary from polygonal to spindle-shaped and epithelial covering may show the whole range of changes described
generally form solid nodules separated by a hyaline stroma. in the development of squamous cell carcinoma in flat bronchial
epithelium: squamous metaplasia, dysplasia, carcinoma-in-situ and
invasive tumour. In general, older patients are more likely to have
Differential diagnosis lesions that are malignant. Most are cured by excision, but about
The differential diagnosis includes several other types of tracheobron- 20% recur.197
chial gland neoplasm. Pleomorphic adenomas often contain myo­ Papillomas clothed entirely by mucous, simple columnar or ciliated
epithelial cells and ducts, but chondroid or myxochondroid elements cells are termed glandular (or columnar cell) papillomas (Fig.
usually predominate.173 Adenoid cystic carcinomas may resemble 12.2.22).106,203,204 They generally develop in the larger conductive
epithelial–myoepithelial carcinomas with a predominantly ductal airways but peripheral examples are recorded.204a The age range is
pattern, but are more infiltrative and cribriform areas are usually also wide – 26–74 years.205 Most are cured by excision but occasional cases
present. Epithelial–myoepithelial carcinoma may also enter the recur197 and some show foci of adenocarcinomatous change.204a
differential diagnosis of pulmonary clear cell tumours (see Table Unusual glandular papillomas containing multiple cysts have been
12.3.1, p. 626).187 described in association with von Hippel–Lindau syndrome.206
Mixed squamous and columnar cell papillomas are rare. They are
commoner in male smokers, as with squamous papillomas, and may
Treatment and prognosis show cytologic atypia. No such cases have recurred.197
Surgical resection is the treatment of choice. Epithelial–myoepithelial Some bronchial tumours resemble papillary urothelial tumours and
carcinomas are generally indolent growths but recurrence or have been called transitional cell papillomas.198,207 Tumours of this
metastasis has been recorded in purely myoepitheliomatous cases name are well known in the nose, where they are also known as
that showed brisk mitotic activity, necrosis and atypia.186,187 schneiderian, Ringertz or inverted papilloma. Earlier editions of the

606
 Tumours Chapter | 12 |

A B

C D

Figure 12.2.20  Epithelial–myoepithelial carcinoma. (A) The tumour shows a mixture of tubules (right) and a more solid spindle cell proliferation (left).
(B) The tubules are lined by an inner layer of epithelial cells surrounded by an outer layer of myoepithelial cells which have a clear cytoplasm. The
myoepithelial cells stain for both S-100 (C) and smooth-muscle actin (D).

World Health Organization’s histological classification of lung papil­lomavirus infection is common and recurrent respiratory
tumours referred to transitional cell papillomas208 whereas the current papil­lomatosis is rare, other factors probably contribute to patho­
edition uses the term ‘inverted papilloma’.106 However, specialists in genesis. For example, an association with HLA DRB1*0301 has
nasal pathology do not accept that the bronchial tumours are the been reported.213–215,217,218
same as those seen in the nose, where they are regarded as polyps The onset is generally before the age of 11 years and most examples
showing squamous metaplasia209: those in the bronchi are a subtype regress before puberty. However, repeated laser therapy may first be
of squamous cell papilloma and comparing them to tumours of the required because the lesions are prone to recur. If left untreated, the
nose or urinary tract is best avoided. lesions may enlarge, spread and endanger the airway (Fig. 12.2.23).219
Multiple laryngeal, tracheal and bronchial papillomas cause hoarse-
ness, stridor and respiratory obstruction, whilst the rare pulmonary
Recurrent respiratory papillomatosis lesions appear on chest radiographs as solid or cystic rounded
Recurrent respiratory papillomatosis most commonly affects the nodules.217
larynx. Only 5% of patients have involvement of the trachea or large The papillomas have a narrow connective tissue stalk covered by
bronchi, and fewer than 1% have more distal lung involvement.210,211 non-keratinising stratified squamous epithelium. There is no atypia
The human papillomavirus is an aetiological factor, types 6 and 11 but certain cytological changes typical of a genital condyloma caused
having been identified in the lesions.212–217 Infection is believed to by the human papillomavirus may be found, namely koilocytosis,
be acquired at birth during vaginal delivery. However, since which is characterised by irregular nuclear shrinkage, binucleation

607
 Pathology of the Lungs

Figure 12.2.21  Endoscopic view of a tracheobronchial papilloma.

(Courtesy of Dr Gaafar, Alexandria, Egypt.)

Figure 12.2.23  Papillomatosis spreading along the wall of the trachea:

bronchoscopic appearances. (Reproduced from Haussinger et  al. (2003)219 by
permission of Elsevier.)

ADENOMAS

Papillary adenoma
Papillary adenomas are rare well-circumscribed parenchymal lesions.
Affected patients are usually asymptomatic, the lesions being found
incidentally on imaging. The tumours may be encapsulated and
are typically soft solid masses that range from 1 to 4 cm in size.
Multiple type II cell papillary adenomas are recorded in a child with
neurofibromatosis.229
The lining cells are cuboidal or columnar (Fig. 12.2.25). They stain
Figure 12.2.22  A bronchial papilloma of glandular type in which the for cytokeratins, TTF-1, surfactant apoproteins, carcinoembryonic
epithelium consists of columnar mucous cells. antigen and epithelial membrane antigen (EMA) and have the
ultrastructural features of either Clara cells or type II alveolar epithelial
cells or both these cell types.198,230–235
and perinuclear clearing (Fig. 12.2.24).220 The papillomatous pro­ Papillary adenomas are distinguished from sclerosing pneumo­
liferation may extend into the soft tissues surrounding the airways, cytoma by lacking the varied architecture of the latter and by the
even though there are no cytological features of malignancy. Such TTF-1 and EMA staining being limited to the surface epithelium. They
extension has been termed invasive papillomatosis.221 In the are distinguished from alveolar adenoma by their papillary growth
lung clusters of squamous cells fill several adjacent alveoli without pattern and focal ciliated or Clara cell morphology. Metastases also
destroying their walls. Continued growth leads to expansion of the need to be excluded, especially those from the thyroid. Occasionally,
alveoli and compression of the surrounding lung. In larger invasive papillary adenomas show infiltrative growth, in which case their
lesions, central cavitation occurs, with the danger of secondary distinction from papillary adenocarcinoma is uncertain and they are
infection. probably best classified as low-grade adenocarcinomas.
Frank malignant change to squamous cell carcinoma, characterised
by atypia, keratinisation and infiltrative growth, supervenes in about
Alveolar adenoma
2% of cases. Smoking and irradiation, the latter used in the past to
treat the papillomatosis, appear to promote this complication, which This tumour often resembles a lymphangioma microscopically
has been recorded in patients whose ages have ranged from 6 to 35 and some examples have probably been reported as such.236,237 Its
years.220,222–227 Malignant change has been associated with type 11 epithelial nature was established in 1986 by a combination of electron
papillomavirus infection followed by increased expression of p53 and microscopy and immunocytochemistry.238 Only a few have been
Rb proteins.228 reported since.239–244 One group compared the lesion to the sclerosing

608
 Tumours Chapter | 12 |

Figure 12.2.26  Alveolar adenoma forming a well-circumscribed 13-mm

peripheral nodule. (Courtesy of Dr M Jagusch, formerly of Auckland, New
Zealand.)

Figure 12.2.24  Bronchial papillomatosis. (A) The papillae are covered by

well-differentiated non-keratinising squamous epithelium. (B) High
magnification shows nuclear shrinkage with perinuclear vacuolation
indicative of papilloma virus infection.

Figure 12.2.27  Alveolar adenoma. Irregular spaces, deceptively

resembling lymphatics, are separated by fibrous septa of varying
thickness with flattened lining cells. (Courtesy of Dr M Jagusch, formerly of
Auckland, New Zealand.)

pneumocytoma described below and suggested that it was a variant

of the latter.245
The mean age of the patients reported to date is about 60 years.
They have all had solitary peripheral lung lesions, measuring up to
2 cm in diameter, most of which were discovered incidentally as a
radiographic ‘coin lesion’.238,239 None has recurred after local excision
or lobectomy.243
Alveolar adenomas are well-circumscribed tumours with a solid
grey or haemorrhagic appearance on the cut surface (Fig. 12.2.26).
Microscopy typically shows irregular spaces, empty or filled with PAS-
positive eosinophilic material (Fig. 12.2.27). Occasional lesions may
be solid and mimic a sclerosing pneumocytoma.245–247 The spaces are
lined by flattened or cuboidal cytokeratin-positive cells that have the
ultrastructural features of type I and II alveolar epithelial cells (Fig.
Figure 12.2.25  Papillary adenoma. The tumour consists of papillae lined 12.2.28). They also stain for surfactant apoprotein and TTF-1. However
by cytologically bland pneumocyte-like cells. It differs from sclerosing they are negative for the Clara cell marker, CC10243 and they do
pneumocytoma by its lack of stromal cells. not express endothelial markers. This latter finding helps exclude

609
 Pathology of the Lungs

Figure 12.2.28  Alveolar adenoma. The cells lining the spaces stain for Figure 12.2.29  Sclerosing pneumocytoma forming a well-circumscribed
cytokeratin, showing that the tumour is an adenoma rather than a peripheral tumour. It shows microcystic change and is yellow because of
lymphangioma. Immunoperoxidase stain. its high lipid content. (Courtesy of Dr M Jagusch, formerly of Auckland, New
Zealand.)

lymphangioma which the tumour may mimic morphologically.

The spaces are separated by fibrous septa that are generally thin but
may show exuberant connective tissue proliferation so that a mesen-
chymal neoplasm with cystic change enters the differential diagnosis.
There may also be focal lymphoid infiltration or central stellate
scarring.

SCLEROSING PNEUMOCYTOMA
(SCLEROSING ‘HAEMANGIOMA’)

This unusual lung tumour was first described in 1956248 under the
name sclerosing haemangioma, a term that reflects two common
histological features, sclerosis and vascular proliferation, that are both
now thought to represent secondary changes in an essentially
epithelial neoplasm. This view is based on immunohistochemical and
ultrastructural evidence that the tumour cells are type II pneumocytes:
they stain for epithelial rather than endothelial markers and have
ultrastructural features characteristic of type II cells.249–264
The term ‘sclerosing pneumocytoma’ is therefore more appropriate
than sclerosing haemangioma,251 although the latter is still preferred Figure 12.2.30  Sclerosing pneumocytoma showing a typically mixed
by the World Health Organization for historic reasons.106 It is solid, papillary, haemorrhagic and sclerotic architecture.
suggested that these tumours are related to the peripheral
papillary adenoma and the alveolar adenoma described above.239
Several authors have proposed that they are hamartomatous246,249,265 metastasis is recorded.245–247 One example was observed over a period
but rare reports of them metastasising to hilar lymph nodes245–247,266 of 47 years, at which stage it occupied the whole of the left thoracic
and evidence of clonality support them being neoplastic.267 cavity but had not metastasised.273

Clinical features Pathological features

Patients with sclerosing pneumocytoma range from 13 to 83 years of Sclerosing pneumocytomas are well-circumscribed but not en­­
age, with a peak incidence in the fifth decade and the ratio of females capsulated tumours: they show expansile growth and compress
to males being about 5 : 1.246,250,251,255,268 The preponderance of females rather than infiltrate the adjacent lung. The cut surface is variegated,
is reflected in the demonstration of oestrogen and progesterone recep- with red well-vascularised areas and yellow foci amid firmer grey
tors on the tumour.269,270 Most of the patients with these receptors tissue (Fig. 12.2.29). Most tumours are peripheral and solitary, but
have been Asian.258 Most patients are asymptomatic, but some com- multiple lesions have been reported and occasionally there is promi-
plain of cough or haemoptysis. Imaging typically shows a solitary nent endobronchial growth.250,271,274,275 Rare cystic examples are also
circumscribed mass that may rarely be calcified or cystic, while haem- recorded.276
orrhagic variants are sometimes identifiable by nuclear magnetic reso- Histologically, the tumours may be papillary, solid, sclerotic or
nance. Alternatively, multiple small nodules may be found.271,272 The angiomatoid. One of these patterns may predominate but they more
tumours are generally benign but, as noted above, hilar lymph node commonly seen in combination (Fig. 12.2.30).261 In the papillary

610
 Tumours Chapter | 12 |

Figure 12.2.31  Sclerosing pneumocytoma. The tumour comprises

cuboidal lining cells, which have eosinophilic cytoplasm, and more
rounded stromal cells that have either eosinophilic or clear cytoplasm.

areas the covering cells have moderate amounts of lightly eosinophilic

cytoplasm and oval, slightly irregular nuclei with a single nucleolus
(Fig. 12.2.31). Mitoses are rare and atypia is unusual. These cells may
be continuous with normal bronchiolar epithelium. They stain for
cytokeratin, EMA, TTF-1 and surfactant (Fig. 12.2.32).260,261 A second
cell type forms the stroma of the papillae and often fills the inter­
papillary spaces. These cells are rounded and uniform with distinct
cell borders. Significant pleomorphism is exceptionally rare. They
contain centrally located cytologically bland nuclei with fine chroma-
tin. Their cytoplasm is either eosinophilic or clear (see Fig. 12.2.31). B
These cells, like those covering the surface of the papillae, express EMA
and TTF-1 but not surfactant or cytokeratin (see Fig. 12.2.32).245,260–263
The two cell types show an identical pattern of monoclonality.267 By
electron microscopy the surface cells contain lamellar bodies similar
to those of type II pneumocytes whereas the round cells contain
electron-dense structures that possibly represent lamellar body precur-
sors.261 Molecular studies suggest that the Wnt/β-catenin pathway is
involved in the pathogenesis of these tumours.277
Secondary changes include haemorrhage, haemosiderosis, foamy
macrophage accumulation, sclerosis, focal dystrophic calcification,
cystic degeneration and even a granulomatous reaction (Fig.
12.2.33).278 The formation of ‘giant lamellar bodies’ is a further sec-
ondary change. These structures represent extracellular accumulations
of surfactant material arranged in lamellar fashion and forming
roughly spherical bodies that measure up to 25 µm in diameter.279
They are not specific to sclerosing pneumocytomas but are
encountered most frequently in these tumours. C
Occasional patients have multiple small sclerosing pneumocytomas
intimately related to multiple tumourlets.271 Figure 12.2.32  Sclerosing pneumocytoma. Only the surface tumour cells
stain for cytokeratins (A) but both surface and stromal cells stain for
epithelial membrane antigen (B) and thyroid transcription factor-1 (C).
Differential diagnosis
The most important distinction is from adenocarcinoma of the lung.
A dual cell population, variegated patterns, a characteristic immu-
nophenotype and a lack of cytological atypia all favour sclerosing
pneumocytoma. One study suggests that the diagnosis can be confi-
dently made at frozen section.280

611
 Pathology of the Lungs

A C

Figure 12.2.33  Sclerosing pneumocytoma. Secondary features include (A) sclerosis, (B) foamy macrophage accumulation, (C) angiomatoid change and
(D) dystrophic calcification.

Epithelioid haemangioendothelioma is another tumour

characterised by sclerosis and a papillary structure, but it is generally PULMONARY THYMOMA
multifocal and differs in its radiographic appearances and natural
history as well as microscopically: furthermore its stromal cells express It is rare to encounter primary thymomas outside the mediastinum
endothelial rather than epithelial markers (see p. 636). but examples have been described in the neck, trachea, thyroid,
Sclerosing pneumocytomas characterised by sheets of clear cells lung and pleura, sometimes associated with thymic rests in these
may be mistaken for the benign clear cell tumour of the lung tissues.281–289 The diagnosis of thymoma in such sites requires
described on page 625 and also for metastatic renal cell carcinoma careful review of the clinical and radiological findings to exclude
but are distinguished from both these tumours by their TTF-1 and metastasis or direct spread from a primary mediastinal lesion (see
EMA positivity and from the benign clear cell tumour by failing to Fig. 12.6.15, p. 688).
express HMB45. Clear cell carcinoma of the lung is distinguished by Patients with pulmonary or pleural thymomas may be asympto-
showing malignant features and lacking the two cell types seen in matic or complain of chest pain, weight loss or breathlessness. One
sclerosing pneumocytoma. Papillary adenoma and alveolar adenoma patient with an intrapulmonary thymoma had myasthenia gravis.281
similarly lack these two cell types. Radiology shows a circumscribed central or peripheral pulmonary

612
 Tumours Chapter | 12 |

nodule, a pleural nodule, pleural thickening or pleural effusion. phoma or small cell carcinoma, and those of spindle cell pattern for
Occasionally there are multiple intrapulmonary tumours, or a localised fibrous tumour. Thymoma carries a better prognosis than
thymoma may involve the pleura diffusely in the manner of a many of these and a correct histological diagnosis is therefore impor-
mesothelioma.288 tant. Except in the case of lymphoepithelial carcinoma, the mixed
Pulmonary thymomas are identical to those that arise in the thymus cellularity of a thymoma is helpful in suggesting the correct diagno-
but are not so clearly encapsulated. Infiltrative growth is therefore sis.284 The lymphocytes within a thymoma express CD1a whereas
more difficult to assess. Some invasive tumours prove to be inoperable those within a lymphoepithelial carcinoma or those reacting to a
and others have metastasised.287 However, most pulmonary thy­ carcinoma do not. TTF-1 staining would indicate carcinoma of the
momas are slowly growing tumours that can be cured by surgical lung, being found in about 30% of pulmonary large cell undifferenti-
resection. ated carcinomas but not in thymomas, while CD5 is more commonly
Predominantly epithelial thymomas arising in the lung are likely to expressed in thymomas.290,291 Positive immunostaining for cytokeratin
be mistaken for carcinoma, those of mixed cellularity for lympho­ generally distinguishes spindle cell thymomas from both localised
epithelial carcinoma, those predominantly lymphocytic for lym- fibrous tumour and lymphoma.

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haemangiomas and tumourlets. A report Primary intrapulmonary neoplasms

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 Chapter 12 

12.3  Soft-tissue tumours

CHAPTER CONTENTS
INFLAMMATORY MYOFIBROBLASTIC
Inflammatory myofibroblastic tumour (‘plasma cell TUMOUR (‘PLASMA CELL GRANULOMA’,
granuloma’, ‘inflammatory pseudotumour’) 620 ‘INFLAMMATORY PSEUDOTUMOUR’)
Pleuropulmonary blastoma 623
Benign clear cell tumour (‘sugar tumour’) 625 Many different names have been applied to this tumour, reflecting its
‘Hamartoma’ (chondroid hamartoma, varied cellular composition on the one hand and the confusion that
adenochondroma, mixed mesenchymoma) 626 has existed over its nature on the other. It has been variously termed
Lipoma, chondroma and fibroma 627 plasma cell granuloma, postinflammatory pseudotumour, xanthoma,
Carney’s triad 628 xanthomatous pseudotumour, fibrous histiocytoma or histiocytoma,
mast cell tumour or mast cellgranuloma and the current term, inflam-
Histiocytoma 629 matory myofibroblastic tumour.1–14a The lungs are a common site of
Leiomyoma and fibroleiomyoma 629 origin but, these tumours have also been reported in many other sites,
Angiomyolipoma 630 including the mesentery, mediastinum, soft tissue, larynx, stomach,
Myelolipoma 630 oesophagus, intestine, liver, genitourinary tract, central nervous
system, nerve, heart, skin and breast.
Miscellaneous sarcomas 630
Vascular tumours and proliferations 632
Haemangioma and lymphangioma 632 Aetiology15
Haemangiomatosis and lymphangiomatosis 632 Inflammatory myofibroblastic tumours form a neoplastic subgroup of
Pulmonary telangiectasia 634 the rather nebulous and broad category of ‘inflammatory pseudo­
Pulmonary peliosis 634 tumours’, which also includes several non-neoplastic fibroinflamma-
tory mass lesions. Previous reports that they can be induced
Haemangiopericytoma 634
experimentally by irritants16,17 and that in humans they represent
Glomus tumour 634 organising pneumonia18 or are the result of antecedent infection12,29
Kaposi’s sarcoma 635 probably relate to the non-neoplastic varieties of inflammatory pseu-
Epithelioid haemangioendothelioma 636 dotumour rather than inflammatory myofibroblastic tumour. The
possibility that some infective agents, particularly Epstein–Barr virus
Non-chromaffin paraganglioma (chemodectoma) 638
and human herpesvirus-8, may play a role in the development of
Sarcoma of the major pulmonary blood vessels 638 inflammatory myofibroblastic tumours is not incompatible with them
Neural tumours 640 being neoplastic.22–25
Nerve sheath tumours 640 In an early review of 118 cases no instances of malignant change
Granular cell tumour 640 were identified26 but reports of vascular invasion,27 sarcomatous
change with distant metastasis,12,28,29 chromosomal translocations,
Meningioma 641
aneuploidy and monoclonality have steadily accumulated.30–37
Ependymoma 642 Particularly notable is the identification of the 2p23 chromosomal
References 642 aberrations associated with expression of anaplastic lymphoma kinase

620
 Tumours Chapter | 12 |

(ALK) in 33% of pulmonary ‘pseudotumours’ and of identical

clonality in separate lesions, features that support a neoplastic process
capable of distant metastasis.34,38 The predominant view today is that
these tumours are either myofibroblastic or fibroblastic reticulum cell
neoplasms of low malignant potential.13,39
The term ‘inflammatory pseudotumour’ remains in use but is only
properly applied as a generic term to lesions such as localised foci of
organising pneumonia, malakoplakia (p. 216), mycobacterial spindle
cell tumour (p. 212), atypical mycoses of tumour-like configuration
and the lesions of hyper-IgG4 disease (p. 485). The following account
of inflammatory myofibroblastic tumour is necessarily based on the
existing literature and may need to be modified as more soundly
based series are described.

Clinical features
The age range stretches from the first year of life to the eighth
decade but most patients are less than 40 years old and many are
children.7,12,40 This lesion is one of the commonest primary lung
tumours seen in young people.41 Females outnumber males but there
are no significant racial or geographical differences.
About half the patients are asymptomatic, the lesion being
discovered as a chance radiological finding. Other patients complain
of cough, haemoptysis, chest pain or dyspnoea, sometimes accompa-
nied by systemic features that are possibly related to interleukin pro-
duction by the lesion, namely low-grade pyrexia, weight loss,
microcytic hypochromic anaemia, polyclonal hyperglobulinaemia
and a raised erythrocyte sedimentation rate.42 Hypercalcaemia has also
been recorded, apparently caused by the tumour secreting calcitriol.43
High-resolution computed tomography typically shows a solitary
mass with sharp regular borders, or if the tumour is endobronchial,
obstructive pneumonia or atelectasis.44

Gross appearances
The lesions occur with equal frequency on the two sides and are
slightly more common in the lower lobes. There are instances of
bilateral tumours, multiple lesions in the same lung, satellite nodules
about the main mass and the simultaneous occurrence of pulmonary
and extrapulmonary lesions.7,27,40,45–47a There may be endobronchial
extension with disruption of bronchial cartilage and polypoid
protrusion into the lumen.2,7,9,10 Peripheral lesions often invade the Figure 12.3.1  Inflammatory myofibroblastic tumour occupying the major
chest wall or mediastinum. part of the lower lobe with a satellite nodule at the hilum.
The lesions form rounded masses that can measure less than 1 cm
or occupy the whole hemithorax.7,12,48 They are sharply circumscribed
and generally of firm consistency with a yellow, tan or grey cut surface
(Fig. 12.3.1). Other examples may be softer and more fleshy, or even the periphery of the lesion where they often extend into adjacent lung
mucoid. Focal calcification, haemorrhage or necrosis may be apparent as an interstitial infiltrate, sometimes forming lymphoid follicles.
in the larger examples.14 Russell bodies are often found in areas rich in plasma cells. There is
no capsule and incorporation of lung tissue into the expanding mass
may result in the presence of epithelial inclusions. The pulmonary
Histopathology architecture is generally effaced and vascular, perineural and bronchi-
There are two major histological patterns, fibrohistiocytic and inflam- olar invasion may be evident (Fig. 12.3.3). Histiocytes and foam cells,
matory, but these are the ends of a spectrum and both are often seen together with Touton giant cells, may either be interspersed with
in the same tumour. Generally, the tumours are composed of cellular spindle cells or form discrete clusters. Some inflammatory myofibrob-
fibrous tissue heavily infiltrated by plasma cells, histiocytes, lym- lastic tumours consist largely of plump histiocytes set in a loose
phocytes and foam cells in varying proportion (Fig. 12.3.2).7,9,11,12,17 myxoid stroma in which there are few inflammatory cells.9 Some
Mast cells occasionally predominate.4,5 Eosinophils and neutrophils such examples have been incorrectly termed histiocytomas or
are infrequent. Most lesions have a prominent spindle cell component xanthomas3,6,8,9,11 but it is important that such examples are
with a variable degree of collagenisation. There is often hyalinisation, diagnosed correctly so that clinicians are aware of their more
occasionally calcification and rarely ossification.7,49 Central necrosis malignant growth potential.
with the formation of a small cavity is occasionally seen. In more Immunocytochemistry demonstrates the presence of vimentin and
cellular areas, there may be a woven or ‘storiform’ pattern, mitoses actin in most cases, and cytokeratin in about one-third, consistent
may be seen and rare examples show frank sarcomatous transform­ with the spindle cells being myofibroblasts.13 Immunocytochemistry
ation. Plasma cells and lymphocytes tend to be most conspicuous at also demonstrates the polytypic nature of the plasma cells,50–52

621
 Pathology of the Lungs

A B

Figure 12.3.2  Inflammatory myofibroblastic tumour – variations in morphology. (A) Many plasma cells and lymphocytes are mixed with the
myofibroblastic cells. (B) Inflammatory areas merge with areas of dense hyaline fibrosis. (C) Focal collections of foam cells are seen. (D) Hyaline fibrosis
with osseous metaplasia.

substantial numbers of CD68-positive cells and in about half the mycobacteria and have the phenotype of macrophages rather than
cases cytoplasmic ALK, which correlates well with the presence of ALK myofibroblasts.
gene rearrangements detected by in situ hybridisation.25,34,36,37 In a sclerosing pneumocytoma (see p. 610), large numbers of foam
Ultrastructural studies6,9,11,16,17,48,50,53,54 confirm that the spindle cells cells and fibrosis may produce an appearance similar to the
have the features of myofibroblasts, uncommitted mesenchymal xanthomatous variety of inflammatory myofibroblastic tumour but
cells or fibroblasts, and that the histiocytes may contain numerous there are also papillary formations and angiomatoid areas that are
myelin figures resulting from phagosomal activity. not seen in the latter and the stromal cells stain for epithelial mem-
brane antigen (EMA) and thyroid transcription factor-1 (TTF-1).
Lymphomas (see p. 659) are not so well circumscribed as inflam­
Differential diagnosis matory myofibroblastic tumours and like plasmacytomas (see p. 666)
The differential diagnosis of inflammatory myofibroblastic tumour comprise a dense and often monotonous infiltrate of atypical mono-
includes mycobacterial spindle cell tumour, sclerosing pneumo­ clonal cells, although they may show marked central sclerosis. In the
cytoma, lymphoma, plasmacytoma, localised organising pneumonia, commonest primary lymphoma of the lung, marginal zone
amyloid tumour, hyalinising granuloma, intrapulmonary localised lymphoma of mucosa-associated lymphoid tissue origin, lympho­
fibrous tumour, malignant fibrous histiocytoma, follicular dendritic epithelial lesions are often prominent and the dense infiltrate
cell tumour, lymphoepithelial carcinoma, spindle cell carcinoma, mainly comprises CD20-positive B lymphocytes.
localised fibromuscular scar and invasive fibrous tumour of the Organising pneumonia may produce a chronic inflammatory mass
trachea. but this is generally irregular in outline, and a connective tissue stain
Mycobacterial spindle cell tumours, as seen in acquired immuno- will reveal the underlying lung architecture to be intact.
deficiency syndrome (AIDS) patients (see p. 212), resemble the lesion Although hyaline areas resemble amyloid, stains for this substance
now being considered but the spindle cells contain numerous are negative.7 Hyalinising granuloma (see p. 699) differs from in­­

622
 Tumours Chapter | 12 |

Follicular dendritic cell tumours, which may extend into the lungs
from the mediastinum or more rarely arise in the lungs (see p. 653),
closely resemble the fibrohistiocytic variant of inflammatory myo­
fibroblastic tumour and may only be distinguished by the use of
dendritic cell markers such as CD21 and CD35; confusion between
these two entities may have led to some reports of malignant change
in extrapulmonary inflammatory myofibroblastic tumours.
Intrapulmonary localised fibrous tumours are identical to those that
occur in the pleura (see p. 730) and are usually subpleural. They also
lack the inflammatory component of myofibroblastic tumours and
their CD34 positivity is a further distinguishing feature.
Invasive fibrous tumour of the trachea61 is not a well-defined entity
and some examples may have represented inflammatory myo­
fibroblastic tumours.
Lymphoepithelial carcinoma and inflammatory spindle cell carci-
noma (see pp. 564 and 567) are both distinguished by their cytologi-
cal atypia. Markers have to be interpreted with caution in this context:
A cytokeratin immunoreactivity is frequently patchy in spindle cell car-
cinoma and often positive in inflammatory myofibroblastic tumour
while although ALK1 confirms the latter when positive it is often
negative.

Course of the disease

In most cases growth is slow and occasional instances of arrested
growth62 or spontaneous resolution are recorded.40 Indeed, some cases
of calcified fibrous pseudotumour of the lung may represent involuted
inflammatory myofibroblastic tumours.57 The majority of lesions are
resected before the diagnosis has been established and this is usually
curative. Attempts at enucleation may be followed by recurrence,26
possibly with mediastinal extension mimicking sclerosing mediastin­
itis.7 If the pleural surface is involved and the tumour is adherent to
chest wall or mediastinum, excision may be difficult and the usual
good prognosis adversely affected. Infiltration of vessels at a distance
from the main tumour mass has been reported and occasionally death
is due to extension into pulmonary veins or oesophagus.19,27,50,54
Exceptional instances of sarcomatous change have been referred to
above.12,29,63
B The histological features provide a poor prediction of behaviour.
Aneuploidy appears to correlate better with a more aggressive course64
Figure 12.3.3  Inflammatory myofibroblastic tumour. (A) Invasion of the while in one series of extrapulmonary inflammatory myofibroblastic
chest wall with widespread perineural infiltration. (B) Vascular invasion tumours a combination of aneuploidy, atypia, ganglion-like cells and
may also be seen, in this instance within the lung parenchyma. p53 expression was identified as providing the best predictor of
aggressive behaviour.65 Another group reports that ALK reactivity is
associated with local recurrence but not metastasis.66

flammatory myofibroblastic tumour in being less cellular and showing

less intense inflammation with what inflammation is present being
more pronounced peripherally; affected patients are older and the PLEUROPULMONARY BLASTOMA
geographical distribution of the two diseases is different.
Inflammatory myofibroblastic tumour lacks the focal calcification Unlike other tumours that have been termed pulmonary blastoma
of a calcifying fibrous pseudotumour but rare cases showing a (see p. 569) pleuropulmonary blastoma lacks an epithelial compo-
combination of patterns suggest that the two lesions are related, a nent and consists entirely of primitive blastema showing varying lines
possi­bility that is discussed further on page 733.55–58 of sarcomatous differentiation. These tumours may be pulmonary,
When fibrohistiocytic elements predominate, inflammatory myofi- pleural or mediastinal and are largely confined to childhood.67–71 In
broblastic tumour needs to be distinguished from fibrosarcoma and the past they have been reported under a variety of terms, including
on addressing this problem one group found necrosis, bizarre giant cystic blastoma and sarcomas or malignant mesenchymoma arising
cells, numerous mitoses, high cellularity and poor circumscription to in congenital cysts.72–79
be more significant histological features of malignancy than nuclear Pleuropulmonary blastoma appears to be the true embryonic
pleomorphism and atypical mitoses.59 Others rely on inflammatory tumour or blastoma of the lung. This is supported by cytogenetic
myofibroblastic tumours lacking cytological atypia, pleomorphism analysis, which has revealed a variety of chromosomal alterations,
and abnormal mitoses, or recommend p53 oncogene identification as including partial trisomy of chromosome 2q, trisomy of chromosome
an indicator of malignancy.51,60 Occasional cases may however undergo 8 and loss of heterozygosity on chromosome 11 involving the Wilms
sarcomatous transformation. tumour gene WT2. These abnormalities show some overlap with those

623
 Pathology of the Lungs

of hepatoblastoma, embryonal rhabdomyosarcoma and Wilms

tumour.80,81 It is also noteworthy that pleuropulmonary blastoma has
been reported in association with familial cystic nephroma and a
variety of other tumours or tumour precursors in approximately 25%
of cases.82–84 Pleuropulmonary blastoma evidently heralds a constitu-
tional and heritable predisposition to dysplastic or neoplastic disease,
indicating that family members need to be counselled and monitored
accordingly.83 Several families have shown heterozygous germline
mutations in DICER1, a gene that encodes an endoribonuclease
critical to the generation of regulatory RNAs. The DICER-1 protein
is found in the blastematous component of tumours.85

Clinical features
Patients are usually less than 12 years old and of either sex but rare
cases have been reported in adults.86 The patient may be asymptomatic
but there is usually chest pain, breathlessness and fever. Imaging
shows a cystic or solid peripheral mass or masses, possibly
accompanied by pneumothorax.67–69,71,87,88 The cystic tumours are
generally found in the youngest patients.71

Pathological features
Pleuropulmonary blastomas from large multilobed masses that may
be difficult to resect. Cystic (type 1), partly cystic (type 2) and solid
A
(type 3) varieties are described.71 The cysts may be unilocular or
multilocular. In the type 2 lesions the solid component may be
limited to a nodule of tumour protruding into the cyst. The solid areas
sometimes show necrosis and haemorrhage.
Microscopically, small round or spindle-shaped blastematous cells
comprise the malignant component and in the cystic varieties these
cells are typically concentrated immediately beneath a non-neoplastic
lining of entrapped respiratory epithelium in a so-called cambium
layer (Fig. 12.3.4). Solid areas consist of sheets of a similar blastema,
but often with a greater degree of pleomorphism, mitotic activity and
divergent sarcomatous differentiation resulting in foci of rhabdo­
myosarcoma or chondrosarcoma (Fig. 12.3.5). Very cellular areas
alternating with others composed of looser myxoid tissue may result
in an appearance resembling that of a Wilms tumour.

Differential diagnosis
Low-grade cystic examples resemble both mesenchymal cystic hamar-
toma and type 4 congenital cystic adenomatoid malformation, so
much so that it is questionable whether these represent separate enti-
ties (see pp. 74 and 61). In the few published cases of type 4 congeni-
tal cystic adenomatoid malformation small areas of cellular
blastematous proliferation may be seen89 and these cases are certainly
B
better classified as type 1 pleuropulmonary blastomas.71 Staining with
desmin may be helpful as it highlights foci of rhabdomyomatous
Figure 12.3.4  Pleuropulmonary blastoma. Cystic (type 1) variant. (A) The
differen­tiation, although care is needed to distinguish these from tumour forms a multiloculated cyst. Even at low power, foci of stromal
normal muscle.71,89,90 The distinction is vital so that the child can cellularity are identifiable. (B) Stromal hypercellularity sometimes forms a
benefit from adequate surgery and follow-up care.91 subepithelial ‘cambium’ layer (top).
The differential diagnosis of high-grade pleuropulmonary blasto-
mas depends upon the proportion of blastema and sarcoma, and
includes undifferentiated sarcoma, synovial sarcoma, rhabdomyo­
sarcoma, chondrosarcoma, malignant teratoma and metastatic Wilms Treatment and prognosis
tumour. Pleuropulmonary blastoma is distinguished from malignant The long-term survival is 25–50%,67 with the solid variety and those
small cell tumour of the thoracopulmonary region (Askin tumour or involving the pleura or mediastinum having a particularly poor prog-
primitive neuroectodermal tumour (PNET), see p. 737) by its location nosis.71 Five-year survival for type 1 pleuropulmonary blastoma is
in the periphery of the lung rather than the chest wall, cystic nature 83% compared to 42% for types 2 and 3.71 Younger patients are more
and focal sarcomatous differentiation, while in doubtful cases CD99 likely to have surgically resectable lower-grade tumours. Complete
staining and chromosomal analysis may be helpful. Well-differentiated surgical resection is important because, although progression of type
fetal adenocarcinoma and pulmonary blastoma are excluded by the 1 tumours to types 2 and 3 is not inevitable, these tumours tend to
absence of malignant epithelial elements. recur in a more malignant form.91–93 The requirement for family

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 Tumours Chapter | 12 |

A A

Figure 12.3.6  Benign clear cell tumour. Trabeculae of cells with clear
cytoplasm are separated by thin-walled sinusoidal vessels. (A) Low power;
(B) high power.

B of the lung. Upper and lower lobes are equally affected. Although
initially believed to be unique to the lung, examples of clear cell
Figure 12.3.5  Pleuropulmonary blastoma. Solid (type 3) variant. tumour have now been reported in the trachea, pancreas, ligamentum
(A) Recurrence of a cystic type 1 pleuropulmonary blastoma in solid form. teres hepatis, rectum, uterus, vulva, breast and heart, a few of which
(B) Microscopy shows undifferentiated sarcoma with marked have exhibited aggressive behaviour, sometimes metastasising to the
pleomorphism. lungs.99,117–123 Certain abdominopelvic sarcomas of perivascular epi-
thelioid cells appear to represent further malignant examples of
members to be counselled and investigated appropriately is outlined extrapulmonary clear cell tumours.101,124 In the lungs, lobectomy,
above, especially in relation to the DICER-1 mutation, which conveys wedge resection or even simple enucleation is generally curative, but
a risk of tumours at other sites and in other family members.85 in one case widespread metastases resulted in death 17 years after
resection.110,125

BENIGN CLEAR CELL TUMOUR Pathology

(‘SUGAR TUMOUR’) On gross inspection the tumour has a sharp outline and lacks any
obvious connection with major airways, blood vessels or pleura. The
This is a particularly rare tumour that is now thought to be one of cut surface is often haemorrhagic: otherwise it is a translucent pinkish-
several that derive from a putative perivascular epithelioid cell (PEC, grey, and not yellow, as are many renal carcinomas. Necrosis is rare;
and hence PEComa).94,95 The tumour is sometimes encountered in it was present in the only case that metastasised and may therefore
patients with tuberous sclerosis, which links it to other neoplasms and auger malignancy.110,125–127
proliferations such as lymphangioleiomyomatosis that also show evi- The microscopic appearances are rather uniform, consisting of
dence of PEComatous differentiation.96–101 sheets and cords of large polygonal or spindle cells with distinct out-
Benign clear cell tumours span a wide age range (8–73 years, mean lines and abundant clear cytoplasm that is generally rich in glycogen
49 years) and have an equal sex incidence.97,102–116 Most patients are (Fig. 12.3.6), a feature that has given rise to the colloquial term ‘sugar
asymptomatic and the tumour is often an incidental finding in chest tumour’. A few reticulin fibres representing type IV collagen surround
radiographs, where it is seen as a solitary ‘coin lesion’ in the periphery individual tumour cells.116 Nuclei are hyperchromatic and often have

625
 Pathology of the Lungs

Table 12.3.1  Features of benign clear cell tumour and other pulmonary clear cell tumours

Tumour Glycogen Fat Mucin Vessels NE HMB45 S-100 CK CK7 EMA TTF1

Benign clear cell tumour + − − Sinusoidal − + + − − − −

Metastatic renal cell carcinoma + + − − − − − + - + −
Clear cell carcinoma and clear cell − − − − − − − + + + +
adenocarcinoma of the lung
Clear cell carcinoid − − − Sinusoidal + − +a + + + −/+
Sclerosing pneumocytoma − + − − − − − + + + +

+, present; −, absent; NE, neuroendocrine: HMB45, human melanin black 45; CK, cytokeratin, EMA, epithelial membrane antigen, TTF1, thyroid transcription factor-1.
a
Positive in sustentacular cells.

irregular outlines. Binucleate, or even multinucleate, cells may be nective and epithelial tissues normally found in the lung but their
present. Mitoses are generally absent. Although the cytoplasm is rarity in childhood and continued growth in adult life favour them
characteristically clear it may contain fine eosinophil granules which being neoplasms, albeit benign. The identification of chromosomal
sometimes appear to radiate from the nucleus. Lipochrome is found rearrangements (6p21 and 12q14–15) similar to those found in
in some tumour cells. A rich blood supply is evident in many parts of lipomas and leiomyomas also favours neoplasia rather than
the tumour, taking the form of large thin-walled sinusoidal vessels malformation.136–139 Terms such as adenochondroma, adenofibroma140
that lack a muscle coat (see Fig. 12.3.6). Hyaline connective tissue may and fibroadenoma141 imply a benign mixed neoplasm but the role
form around or within vessel walls and occasionally this progresses played by the epithelial components may also be questioned. It is
to more extensive fibrosis with calcification. Inclusions lined by notable that the chromosomal rearrangements referred to above are
bronchiolar or alveolar epithelium probably represent entrapment of confined to the mesenchymal component. Also, it is now appreciated
adjacent lung tissue. that epithelial structures are commonly entrapped in many lung
Electron microscopy generally confirms the presence of glycogen tumours, both primary and metastatic,142,143 and it is likely that this
but reports are otherwise inconsistent.105,108,111,116 However, ultra­ is how the epithelial clefts of the so-called adenochondroma or chon-
structural evidence of melanogenesis113 is in line with human melanin droid hamartoma should be regarded. A name that reflects a purely
black-45 (HMB45) being consistently and diffusely expressed, a mesenchymal nature appears appropriate and, since these tumours
feature that benign clear cell tumours share with lymphangioleio­ display a variety of connective tissues, the term ‘mesenchymoma’
myomatosis (see p. 293) and angiomyolipoma (see p. 630).94,116,128,129 has been recommended.134 However, the term ‘hamartoma’ is well
CD1a is a further marker found in all these lesions.130 entrenched and continues to be used.

Differential diagnosis Clinical features

The importance of this lesion lies in its distinction from clear These tumours are fairly common, constituting about 8% of all ‘coin’
cell carcinoma of the lung, either primary (see p. 562) or metastatic lesions in chest radiographs.143a In an unselected postmortem series,
from the kidney or elsewhere.131 The major differences are outlined an incidence of 1 in 400 was found.144 The age range is wide but they
in Table 12.3.1. The characteristic vascular pattern is helpful, the are rare in children; the peak age incidence is the sixth decade and
wide thin-walled sinusoids of the benign tumour contrasting with they are commoner in men.134 Sequential radiographs show that most
the thick-walled narrow arterioles of a carcinoma. Renal carcinomas first develop in adult life and slowly increase in size thereafter (at a
owe their seemingly empty cytoplasm to the presence of both rate of up to 5 mm/year).145 Most are paren­chymal and asymptomatic
glycogen and fat and it is useful to be able to demonstrate the latter but about 8% are endobronchial134 and cause coughing, dyspnoea,
if reserve tissue is available. A diastase-controlled periodic acid–Schiff haemoptysis, obstructive pneumonia or collapse.146,147 Multiple
stain is also useful in distinguishing mucus-secreting adeno­ lesions are uncommon, as is involvement of the trachea134,148–151; mul-
carcinomas of solid pattern from the glycogen-rich benign tumour. tiplicity raises the possibility of Carney’s triad (see below).152 An
Chemodectoma, carcinoid and haemangiopericytoma all contain accompanying carcinoma of the lung is encountered more frequently
sinusoidal vessels on occasion but lack significant quantities of than expected134,153 but this may be fortuitous, the carcinoma causing
glycogen and only haemangiopericytoma has reticulin surrounding the chest to be investigated so that an asymptomatic ‘hamartoma’ is
individual cells. revealed. Sarcomatous change is recorded but is exceptionally rare.154
One study identified a high incidence of associated congenital anoma-
lies and benign tumours, prompting the authors to envisage a ‘pul-
monary hamartoma syndrome’.155 In another study, the lung adjacent
‘HAMARTOMA’ (CHONDROID to six of 38 resected chondroid hamartomas showed areas resembling
HAMARTOMA, ADENOCHONDROMA, the so-called placental transmogrification described on page 703.156
MIXED MESENCHYMOMA) Others have described ‘tumourlets’ in association with chondroid
hamartomas.157
Despite their popular name – chondroid hamartoma – it is likely that
these lesions are benign connective tissue neoplasms rather than
Pathological features133–135
tumour-like malformations.132–135 They are widely regarded as being There are no significant pathological differences between parenchymal
hamartomatous because of their disorganised mix of the various con- and endobronchial growths, although the proportions in which the

626
 Tumours Chapter | 12 |

Fatty 5%
Osseous 3% Fibroblastic 12%

Chondroid 80%

Osseous 8%
Fatty 33%

Chondroid 50%
Fibroblastic 8%
Figure 12.3.7  The predominant tissue in a series of 154 ‘hamartomas’
comprising 142 parenchymal (top) and 12 endobronchial (bottom)
tumours.134 Figure 12.3.8  A ‘hamartoma’ of the lung forming a 4.5-cm tumour that
‘shelled out’ at operation. Note the clefts intersecting the pale
cartilaginous tissue.
various connective tissues are represented differ (Fig. 12.3.7) and
epithelial clefts are less prominent in endobronchial than paren­
chymal tumours.133,158,159 Most measure 1–3 cm in diameter but they
range up to 9 cm. They lack a capsule but are sharply circumscribed
and shell out easily at operation (Fig. 12.3.8), after which there is little
risk of recurrence. Most are lobulated and the predominant tissue is
cartilage (Fig. 12.3.9), which may calcify or undergo osseous change.
Other connective tissues commonly found include fat, fibrous tissue
and loose mesenchyme with a myxoid appearance (Fig. 12.3.10).
These various components are usually present in combination,
together with cells of transitional form.135 The lesions may come close
to the bronchial cartilage but there is no continuity with this tissue,
as there is in tracheobronchopathia osteochondroplastica; fibro-
myxoid spindle cells probably represent the progenitor mesenchymal
element.135 The connective tissue components are quite regular
cytologically and show no evidence of malignancy. Intersecting
the connective tissue lobules are clefts lined by ciliated pseudo­
stratified columnar epithelium, which is quite normal cytologically.
The retention of cilia is notable as these are usually lost when Figure 12.3.9  A ‘hamartoma’ composed of mature cartilage intersected
respiratory epithelium becomes neoplastic. by clefts lined by respiratory epithelium.

Differential diagnosis
There is a close genetic relationship between ‘hamartoma’ and other bronchoplastic resection. Recurrence is rare134 and sarcomatous
benign mesenchymal tumours such as lipoma, chondroma and transformation even rarer.154
fibroma (which are discussed below) but these entities can be excluded
histologically because they consist of just one mesenchymal tissue.
More difficulty may be encountered if metastatic teratoma is removed
from the lung following successful chemotherapy and submitted
LIPOMA, CHONDROMA AND FIBROMA
for pathological examination with inadequate clinical information
(see pp. 686 and 690). If the proposed nature of the ‘hamartomas’ (mixed mesenchymomas)
outlined above is accepted, they are obviously closely related to
benign connective tissue neoplasms composed of a single tissue –
Treatment and prognosis lipoma,160–163 chondroma,164,165 fibroma,166 fibromyxoma167 and
The parenchymal tumours are often enucleated or removed by osteoma,168 for example – none of which is common in the lungs.133
wedge resection but lobectomy may be undertaken if there is chronic Like the mixed mesenchymomas, all these neoplasms may either lie
parenchymal damage. Endobronchial lesions are generally treated by entirely within the lung substance or protrude into major bronchi

627
 Pathology of the Lungs

myxomas of various organs, blue naevi and tumours of the pituitary,

adrenal cortex and Sertoli cells.
In a review of 79 patients with Carney’s triad, 85% were female,
22% presented with three tumours and 78% with two tumours. The
commonest combination was one that included gastric and pulmo-
nary tumours. Intervals up to 26 years between detection of the first
and second components were noted but the mean was 8 years. In half
the patients there were multiple chondromas, involving either one or
both lungs. A total of 13% of patients died of the disorder (but none
of pulmonary chondroma) and some cases were familial.173 Similar
findings are reported in other large series.172 Early recognition of the
syndrome is important in view of the malignant potential of the
gastric lesions and paragangliomas. Pulmonary metastases from one
or other of these may be difficult to distinguish from chondromas
clinically but calcification in pulmonary opacities is a useful radio-
graphic pointer to the opacities being chondromas.
The chondromas have no malignant potential. They differ from
chondroid ‘hamartomas’ in lacking both epithelial clefts and other
connective tissue components (Fig. 12.3.12 and Table 12.3.2) and in
being encapsulated. However, the presence of a little respiratory
epithelium at the edge of the chondromas persuaded Carney that
they derive from bronchial cartilage,173 a further difference from
‘chondroid hamartomas’, which are believed to derive from precursor
fibromyxoid cells.135
Concurrent duodenal stromal tumour, pulmonary chondromatous
‘hamartoma’ and pancreatic islet cell tumour in a 63-year-old man
have been reported as a possible variant of Carney’s triad.174
Adrenocortical adenomas may also be associated with Carney’s triad173
but the significance of this observation is uncertain as these tumours
are very common in the general population.

HISTIOCYTOMA

Pulmonary lesions that have all the features of benign fibrous histio-
Figure 12.3.10  A ‘hamartoma’ formed of myxoid fibrous tissue and fat cytomas, as described in other sites, have been widely regarded as
as well as cartilage. forming part of a plasma cell granuloma–histiocytoma complex, but
most would now be regarded as inflammatory myofibroblastic
tumours (see p. 620) and every effort should be made to confirm this
diagnosis. Nevertheless, true fibrous histocytomas very rarely occur
in the lungs. Most ‘cystic fibrohistiocytic tumours’ of the lungs are
(Fig. 12.3.11), but the proportion of lipomas and chondromas that metastases from low-grade cellular fibrous histiocytomas (see
are endobronchial is higher than the 8% found with the so-called p. 686).175
hamartomas. Epithelial clefts are not found in single-tissue benign
mesenchymal tumours, which resemble in every way their counter-
parts that occur more commonly in other parts of the body. Like
chondroid hamartomas, they appear to have no malignant potential:
the rare primary pulmonary fibrosarcomas, liposarcomas, chondro­ LEIOMYOMA AND FIBROLEIOMYOMA
sarcomas and osteosarcomas (dealt with below) are believed to
be sarcomatous from their outset. A diagnosis of primary pulmonary leiomyoma or fibroleiomyoma
should be advanced only with caution. Pulmonary tumours corre-
sponding to these terms often prove to be multiple and confined to
middle-aged women with uterine fibroids, representing examples of
Carney’s triad
so-called benign metastasising leiomyomas of the uterus (see p. 686).
This is a rare combination of three unusual neoplasms that affects In the rare instances in which the patient is male, a history of previous
young women.164,165,169–172 The patients are generally in the second or surgery for a ‘soft-tissue tumour’ can often be elicited. True primary
third decade, the youngest recorded being a girl aged 9 years. The three leiomyomas developing in the lungs are distinctly rare.176–181
tumours are pulmonary chondroma, extra-adrenal paraganglioma Patients with a pulmonary leiomyoma may be of any age, from
(chemodectoma) and gastric stromal tumour (epithelioid leiomyo­ infancy onwards. The sex incidence is equal. The tumours may involve
sarcoma). Carney’s triad is therefore quite different from Carney’s the airways or be peripheral, the former usually giving rise to symp-
syndrome, which lacks a pulmonary component and comprises toms resulting from obstruction while the latter are often discovered

628
 Tumours Chapter | 12 |

A B

Figure 12.3.11  (A) Endobronchial and (B) parenchymal lipomas. (B courtesy of Dr JT Gmelich, formerly of Pasadena, USA.)

by chance in an asymptomatic person. Pulmonary leiomyomas and

leiomyosarcomas developing in AIDS are referred to below under
miscellaneous sarcomas.
Pulmonary leiomyomas resemble those encountered in other sites
in every way (Fig. 12.3.13). They show a well-developed fascicular
pattern and lack features suggesting malignancy, such as atypia,
haemorrhage and necrosis. Immunostaining for smooth-muscle actin
supports the diagnosis.
Leiomyomas of the lung are well-circumscribed tumours, in con-
trast to the more frequently seen fibromuscular scars that are stellate
in outline and lack a definite edge. These may be rich in smooth
muscle and are often considered to be smooth-muscle hamartomas,
but if there is any appreciable degree of fibrosis a more likely explana-
tion is that they represent old scars in which there is prominent reac-
tive smooth-muscle hyperplasia. Diffuse changes of this nature are
often seen in end-stage diffuse pulmonary fibrosis and the term ‘mus-
cular cirrhosis of the lung’ has been used for this (see p. 269). A
case reported as ‘diffuse fibroleiomyomatous hamartomatosis’182 is
possibly just a further example of ‘muscular cirrhosis’. Pulmonary
lymphangioleiomyomatosis is another diffuse infiltrative process Figure 12.3.12  Pulmonary chondroma as a component of Carney’s triad.
rather than a circumscribed tumour (see p. 293). Other conditions to The tumour is composed solely of benign chondroid elements. (Courtesy of
be distinguished from leiomyoma include the CD34-positive intra­ Dr TV Colby, Scottsdale, USA.)

629
 Pathology of the Lungs

matosis, two conditions that are sometimes associated with extra­

Table 12.3.2  The chondromas of Carney’s triad compared to
pulmonary angiomyolipomas.186 Angiomyolipomas express the
chondroid ‘hamartomas’172
melanocyte marker HMB45 and CD1a, which are also found in the
‘perivascular epithelioid cells’ of lymphangioleiomyomatosis
Carney’s triad Chondroid
(see p. 293) and the benign clear cell tumour of the lung that is dealt
chondromas ‘hamartomas’
with above.130,187 A histogenetic relationship is envisaged, which
Mean age 25 years 59 years also encompasses a variety of clear cell neoplasms of the soft tissues.
They are collectively known colloquially as PEComas.94,101,188
Sex 88% female 60% male Angiomyolipomas have been regarded as hamartomas rather than
Multiple lesions 52% 2% neoplasms but the demonstration of clonality casts doubt upon
this.189,190
Central : peripheral 15 : 85 8 : 92
Fibrous pseudocapsule 93% 0
Invaginated epithelium 2% 99%
MYELOLIPOMA
Fat and fibromyxoid tissue Not found Commonly present

Myelolipoma is best known as a tumour of the adrenal glands

and examples arising in the lungs are distinctly unusual.191 They are
usually small and asymptomatic, being discovered by chance at
necropsy or when radiography is undertaken for unrelated reasons.
They consist of mature fat and haemopoietic tissue, occasionally with
a thin rim of trabecular bone. Some have been contiguous with a
bronchial cartilage but the cartilage has shown no evidence of calcifi-
cation or ossification. Unlike foci of extramedullary haemopoiesis
they are solitary, well circumscribed and unassociated with a blood
disorder. They are quite benign. It is suggested that they may represent
metaplasia rather than neoplasia.

MISCELLANEOUS SARCOMAS

Primary bronchopulmonary sarcomas are rare, outnumbered by car-

cinomas 700 to 1.192,193 However, they are quite diverse and represent
a diagnostically challenging group of neoplasms that need to be
distinguished from sarcomatoid carcinoma of the lung and secondary
sarcoma invading the lungs from adjacent structures or metastasis­
ing from distant sites.194 Immunohistochemistry is helpful here.
Cytokeratin positivity permits the recognition of sarcomatoid
Figure 12.3.13  Pulmonary leiomyoma involving airway wall. The tumour,
which was resected from the lung of a male patient, consists of
carcinomas and mesotheliomas while CD34 immunohistochemistry
cytologically bland spindle cells with abundant eosinophilic cytoplasm, as faci­litates the identification of solitary (localised) fibrous tumours.
seen in leiomyomas arising in other sites. Immunocytochemical markers also allow a more confident character­
isation of certain sarcomas as being of muscular, vascular or neural
origin. This has led to the re-categorisation of tumours that on purely
morphological grounds were formerly described as malignant fibrous
pulmonary localised fibrous tumour (see p. 730), nerve sheath histiocytoma, haemangiopericytoma and fibrosarcoma. Molecular
tumours, which are S-100-positive, inflammatory myofibroblastic techniques are also useful in the study of soft-tissue tumours,
tumour, which generally shows a lymphoplasmacytic infiltrate, and permitting the recognition of characteristic translocations in tumours
epithelial–myoepithelial carcinoma (see p. 605), which expresses such as synovial sarcoma.
epithelial as well as muscle markers. Except for a few notable exceptions that have arisen in chil-
dren,74,195,196 sarcomas of the lung generally affect the middle-aged and
elderly. They usually appear to arise without antecedent lesions but
occasional examples have developed in bronchial cysts74,197 and arte-
riovenous fistulas,198 or after radiation therapy.199 However, most, if
ANGIOMYOLIPOMA not all, of those ‘arising’ in bronchial cysts would now be recognised
to be pleuropulmonary blastomas. More recently, leiomyosarcomas
Angiomyolipomas are rare benign tumours composed of a mixture of have been encountered in many organs, including the lung, in
small to medium-sized blood vessels, smooth muscle and fat, all of association with Epstein–Barr virus in AIDS196,200 and following
which appear quite mature. They are most commonly found in the transplantation.201
kidney, but have been reported in a variety of other sites, including Most pulmonary sarcomas show smooth muscle or fibrous differ-
the lung.183–185 One pulmonary angiomyolipoma developed in a entiation or are anaplastic.194,202–205 The commonest histological
patient suffering from tuberous sclerosis but not lymphangioleiomyo- subtype is storiform pleomorphic but the inflammatory and giant cell

630
 Tumours Chapter | 12 |

Figure 12.3.14  Synovial sarcoma of the lung. (A) A circumscribed, soft and focally haemorrhagic mass fills half a lobe. (B) Microscopy shows a
monophasic synovial sarcoma surrounding residual entrapped air spaces. (C) Staining for thyroid transcription factor-1 confirms that gland-like
structures are indeed entrapped lung elements and not part of a biphasic synovial sarcoma.

subtypes may also be encountered in the lung.206 They contain foam Other rare varieties include liposarcoma,220 rhabdomyosar-
cells, giant cells and myofibroblasts as well as fibroblasts and have to coma,221,222 chondrosarcoma,223 osteosarcoma,224,225 giant cell
be distinguished from inflammatory myofibroblastic tumour (see tumour,226 alveolar soft-part sarcoma227 and angiosarcoma.228,229
above) by the usual cytological criteria of malignancy. Myxoid change may be prominent in several of these sarcomas.230,231
Synovial sarcomas of both monophasic spindle cell and biphasic Sarcomas arising in the major pulmonary blood vessels are described
pattern have been described as arising in the lung205,207–214: they express on page 638. Occasionally a pulmonary sarcoma may elaborate mul-
cytokeratins and the bcl-2 oncogene and show the t(X;18)(p11.2;q11.2) tiple mesenchymal elements such as bone, cartilage and striped
translocation seen in synovial sarcomas of soft tissues (Fig. 12.3.14). muscle and is best described as a malignant mesenchymoma.232
Solitary fibrous tumours may be wholly intrapulmonary (see Fig. A distinction is generally made between endobronchial and
13.28, p. 731).215–217 They characteristically express CD34, although intrapulmonary sarcomas, the endobronchial tumours presenting
less so in the more malignant examples. earlier and consequently having a better prognosis.233,234 Small
Malignant nerve sheath tumours arising in the lung as opposed to intrapulmonary sarcomas may metastasise early but large intra­
other intrathoracic sites are particularly rare218,219 and, in the absence pulmonary growths are equally lethal due to direct invasion of the
of von Recklinghausen’s disease, may be mistaken for fibrosarcoma. chest wall and mediastinum. Tumour grade and mitotic activity give
They are dealt with more fully on page 640. a good indication of the degree of malignancy.203,235

631
 Pathology of the Lungs

two of their capillary haemangiomas expressed both these markers in

VASCULAR TUMOURS AND PROLIFERATIONS a mutually exclusive manner, leading the authors to reca­tegorize these
lesions as combined haemangiolymphangiomas.250 Sometimes a hae-
mangioma forms a pedunculated endobronchial tumour. More often
Haemangioma and lymphangioma
it is an asymptomatic parenchymal mass (Fig. 12.3.16) but there is
Haemangiomas and lymphangiomas of the lung are very rare.236–249a always the danger of life-threatening haemorrhage. Pulmonary lym-
Most reports comprise single cases but one German group was able phangiomas cause non-specific symptoms such as cough or dyspnoea
to retrieve 13 haemangiomas (five capillary and eight cavernous) and or are discovered by chance radiographically.249a
two lymphangiomas from their archives.250 Some of the cases reported
before immunocytochemistry was available were possibly examples
of alveolar adenoma (see p. 608) or sclerosing pneumocytoma (see
Haemangiomatosis and lymphangiomatosis
p. 610),241 the distinction from which can now be made by immuno- Pulmonary haemangiomatosis is a rare condition in which the lungs
histochemical staining for endothelial markers (see below), cytokerat- may be affected diffusely or by multifocal nodules. The diffuse form
ins, EMA and TTF-1. Pulmonary haemangiomas and lymphangiomas is most frequently encountered in very young children as part of a
resemble the commoner tumours found elsewhere: they form circum- generalised vascular malformation affecting many viscera and soft
scribed lesions consisting of dilated, closely apposed, endothelium- tissues.251,252 The multifocal form is more often confined to the lungs
lined vascular spaces which share adventitial connective tissue but lack and, although often congenital, it may present in later life.253,254
a media (Fig. 12.3.15). Histologically, they differ only in their content Pulmonary lesions manifest themselves by causing haemoptysis,
– blood or lymph – but it is notoriously difficult to tell whether the shortness of breath, haemorrhagic pleural effusions and pneumonia.
presence of blood is genuine or artefactual, justifying the use of the Vascular fragility and thrombocytopenia due to platelet trapping both
non-committal term ‘angioma’ unless specific markers for haeman- contribute to the haemorrhage. The lungs are infiltrated diffusely or
gioendothelium, such as factor VIII, CD31 or CD34, and for lym- in a multifocal manner by a network of vascular spaces of varying size.
phangioendothelium, such as Fli-4 or D2–40, are employed. Using The infiltration is particularly prominent where there is abundant
CD34 and D2–40, the German group referred to above found that connective tissue – beneath the pleura, in interlobular septa and

Figure 12.3.16  Haemangioma of the lung. A well-circumscribed tumour

Figure 12.3.15  Lymphangioma of the lung. A localized mass composed composed of many blood-filled channels is seen at the hilum of the lung.
of interweaving vascular channels devoid of blood. (Courtesy of Dr T Jelihovsky, Sydney, Australia.)

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A B

C D

Figure 12.3.17  Haemangiomatosis. (A) High-resolution computed tomography shows a lobulated mass in the lung. (B and C) The bronchial wall and
alveolar parenchyma are diffusely infiltrated by anastomosing vascular channels. (D) CD31 stain demonstrates that the channels have an endothelial
lining.

around airways. Arteriovenous communication is not a feature and the lower lobes. The lung markings represent a proliferation of anas-
the disease is not hereditary. It thus differs from arteriovenous fistula tomosing endothelium-lined channels along pulmonary lymphatic
and hereditary haemorrhagic telangectasia (see below). It should routes, especially the pleura and interlobular septa, accompanied by
also be distinguished from pulmonary peliosis (see below), and from spindle cells which stain for smooth-muscle actin. The histological
pulmonary capillary haemangiomatosis (see p. 429). Tracheobronchial appearances resemble those of congenital lymphangiectasia (see
haemangiomatosis (Fig. 12.3.17) is recorded in blue rubber bleb p. 77) but differ in the greater number of lymphatics while the
disease (see p. 482) accompanying the more usual cavernous haeman- prominent vascular lumina distinguish the condition from lym-
giomas of the skin and gastrointestinal tract.255 phangioleiomyomatosis (see p. 293). Haemangiomatosis is distin-
A similar condition involving lymphatic channels is known as lym- guished by the use of the immunomarkers described above. There may
phangiomatosis (Fig. 12.3.18).243,256–258 Although generally a disorder be associated abnormalities of the thoracic and retroperitoneal lym-
of children, lymphangiomatosis may first present in adult life.259 It phatics.259,260 In one example the lungs were compressed by a mass of
causes shortness of breath, tiredness and chylous effusions. Chest dense connective tissue containing numerous dilated lymphatic path-
radiographs show bilateral reticular infiltrates, often more marked in ways which invaded the chest wall and diaphragm.261 Pulmonary

633
 Pathology of the Lungs

anabolic steroids, which is often the case with peliosis hepatis. The
pulmonary lesion was an unexpected postmortem finding in one case
but another patient died of haemoptysis from rupture of a peliotic
lesion in the lungs. Pulmonary peliosis consists of multiple, irregularly
distributed, thin-walled blood spaces of variable size.

Haemangiopericytoma
The histological boundaries between haemangiopericytoma and
localised fibrous tumour have become increasingly blurred and
A
it is likely that most of the tumours reported as pulmonary haem­
angiopericytomas235,268–274 were intrapulmonary localized fibrous
tumours or synovial sarcomas. These are described on pages 730
and 631 respectively and no further attention will be paid to
haemangiopericytoma.

Glomus tumour
Rare instances of glomus tumour (glomangioma) have been reported
in the trachea,275–281 bronchi282 and lung,283–290 suggesting that the
specialised arteriovenous anastomoses familiar in the nailbeds also
exist in the lower respiratory tract. The histological appearances are
identical to those of glomus tumours elsewhere and for the most part
they are similarly benign in their behaviour. The affected patients were
adults who were asymptomatic or presented with cough or non-
specific symptoms and were found to have well-demarcated nodules
B in their major airways or lungs.

Figure 12.3.18  Lymphangiomatosis. (A) The pleura is markedly thickened

and the interlobular septa are unduly prominent. (B) Lymphangiomatosis.
An interlobular septum is thickened by the presence of numerous
Pathology
lymphatics. Glomus tumours consist of a network of vessels of capillary size sur-
rounded by small, uniform, rounded cells with moderate amounts of
eosinophilic or clear cytoplasm, set in a hyaline or myxoid stroma.
Occasionally they undergo oncocytic transformation.278 The nuclei are
round with finely dispersed chromatin and indistinct nucleoli (Fig.
lymphangiomatosis may also form part of the Klippel–Trenaunay 12.3.19). A reticulin or periodic acid–Schiff stain reveals a fine base-
syndrome, the more common manifestations of which are soft- ment membrane network surrounding individual tumour cells.
tissue hypertrophy, angiomas and varicosities (see pp. 77 and 482). Immunohistochemical stains are positive for vimentin and actin,
Gorham’s syndrome represents a destructive non-neoplastic vascular weakly so for desmin and negative for cytokeratins, melanocytic
proliferation of bone that may invade the lung if it involves the tho- markers (HMB45, S-100 protein) and CD31. Markers of endothelium
racic skeleton, as described on page 737. (factor VIII-related antigen, CD34) stain the vasculature but not the
tumour cells. On electron microscopy there is abundant basement
membrane and the cells contain prominent cytoplasmic filaments
Pulmonary telangiectasia with dense bodies and rows of pinocytotic vesicles,275,276,283 features
Telangiectasias are localised dilatations of small precapillary blood very similar to those of smooth muscle, although there is little
vessels, which in the lungs may be so small that they are not evident resemblance on light microscopy.
on chest radiographs. Multiple pulmonary telangiectasias occur in two
unrelated conditions, hereditary haemorrhagic telangiectasia (Rendu–
Osler–Weber disease, see p. 481) and cirrhosis of the liver. Patients Differential diagnosis
with liver failure due to cirrhosis occasionally present with hypoxia
due to pulmonary shunts through vascular lesions analogous to cuta- Many of the immunohistochemical and ultrastructural features of
neous spider naevi, casts of which show them to consist of both glomus cells are also seen in pericytes but these cells are more elon-
dilated existing vessels and newly formed channels.262–265 gated, and have long processes and far fewer myofilaments and dense
bodies. Glomus cells, pericytes and smooth-muscle cells are closely
related291 but the differential diagnosis is unlikely to include haem­
angiopericytoma and leiomyoma. However, the distinction from car-
Pulmonary peliosis cinoid tumour (see p. 593) may be difficult by light microscopy,
Peliosis is well known in the liver as a rare vascular anomaly of un­­ particularly in a small biopsy.288 Helpful histological features are the
certain aetiology. Extrahepatic peliosis is exceptional but, very rarely, distinctive reticulin pattern of a glomus tumour and the absence of
pulmonary involvement has been reported in association with similar immunohistochemical staining for cytokeratins and neuroendocrine
lesions in the liver and spleen.266,267 One such patient was receiving differentiation.

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been recognised as a risk factor. Groups at particular risk now include

transplant recipients, patients being treated for leukaemia or
lymphoma, and those suffering from AIDS.292–298 These patients suffer
from a particularly aggressive disseminated form of the disease. Up to
70% of AIDS patients in the USA formerly developed Kaposi’s
sarcoma,299–301 but the proportion is now less. A notable feature is that
these cases are almost all men who acquired their human immuno-
deficiency virus (HIV) by homosexual contact, whereas the tumour is
rare in AIDS patients infected with HIV by intravenous injec-
tion.292,302–305 This suggests sexual transmission of a causative agent,
presumably a virus distinct from, but often transmitted with, HIV.306
This is supported by a reduction in the incidence of the tumour as
homosexual promiscuity lessens and by the identification of human
herpesvirus-8 in lesional tissue from patients Kaposi’s sarcoma.307–314
DNA sequences unique to this virus appear to be preferentially associ-
ated with Kaposi’s sarcoma, serosal lymphoma, some inflammatory
myofibroblastic tumours and multicentric Castleman’s disease.315
Their identification in bronchoalveolar lavage fluid appears to be
A highly sensitive and specific for pulmonary involvement by Kaposi’s
sarcoma.316
Following the identification of human herpesvirus 8-associated
Kaposi sarcoma in the Uygurs of Xinjiang, northwest China, a sero-
logical survey of the region identified the virus in a high proportion
of the population, leading to speculation that it had been carried
thither (or thence) by travellers on the ancient silk road connecting
Europe and China.317

Clinical features
The sporadic European form of the disease is characterised by purple
macules on the skin of the legs and feet. It generally runs an indolent
course. Visceral lesions are present in 10–20% of patients, with lymph
nodes, gastrointestinal tract, liver, lungs, heart, bone and spleen
involved in descending order of frequency.318 Very rarely, predomi-
nantly pulmonary involvement is seen without skin lesions.294,319–321
In Africa, Kaposi’s sarcoma accounts for up to 15% of all tumours and
is more aggressive: lymphoadenopathy and pulmonary involvement
are common.322,323
Pulmonary involvement by Kaposi’s sarcoma is often overlooked,
B partly because coexisting opportunistic infections blur the clinical and
radiographic appearances and partly because open-lung biopsy is
Figure 12.3.19  An endobronchial glomus tumour. (A) The tumour often thought necessary to make the diagnosis. In most cases, visceral
surrounds entrapped gland ducts. (B) The tumour cells have clear lesions are preceded by cutaneous disease but this is not always
cytoplasm, are cytologically bland and are in close apposition to true.297,298,319,321,322 About 16% of one group of HIV-positive patients
capillaries. had bronchial lesions but no mucocutaneous disease.324
The commonest symptom of pulmonary Kaposi’s sarcoma is breath-
lessness, which may be accompanied by cough, wheezing or haemop­
tysis. Pleural effusion is frequently present. Chest radiographs
show diffuse pulmonary infiltrates, fine nodularity or a combination
Prognosis of the two. The changes are often bilateral.325 Mucosal lesions may be
Most pulmonary glomus tumours are benign. Only a few glomangio­ seen at bronchoscopy as bright red raised areas. The prognosis in AIDS
sarcomas are recorded in the lung, some disseminating widely to is adversely affected by the development of pulmonary Kaposi’s
extrapulmonary sites.282,286,289 Their malignant nature is evidenced his- sarcoma as this introduces the added risks of pulmonary haemor-
tologically by brisk mitotic activity, cytological atypia and necrosis. rhage, pulmonary oedema due to lymphatic obstruction and airway
narrowing.

Kaposi’s sarcoma
Pathology320,322,326,327
Epidemiology and aetiology At autopsy, multiple small haemorrhagic nodules are found scattered
Kaposi’s sarcoma was initially known as a rare sporadic disease of throughout the lungs and visible in the tracheobronchial mucosa or
elderly European men, usually of Italian or Jewish ancestry, and as a on the visceral pleura. The nodules may aggregate to form larger
more frequent disease affecting younger men, and occasionally masses.
women and children in central and east Africa. More recently the Histologically, there is often interstitial infiltration in addition to
disease has become more widespread and immunodeficiency has the nodules visible macroscopically. Low-power microscopy reveals a

635
 Pathology of the Lungs

contrast to other forms of the disease it forms a diffuse infiltrate and

seldom produces a mass lesion. The inflammatory form is particularly
common in AIDS patients.
Diagnosis by bronchial or transbronchial biopsies requires a high
index of suspicion.326,327 The inflammatory form of Kaposi’s sarcoma
is particularly likely to be mistaken for inflammatory granulation
tissue, but with a knowledge of the different variants of the disease
and of its distribution, the diagnosis should be evident. Mycobacterial
spindle cell pseudotumour also enters the differential diagnosis and,
as both conditions are predisposed to by severe immunodeficiency,
they may coexist. The mycobacterial lesion consists of shorter spindle-
shaped or even polygonal cells with voluminous eosinophilic cyto-
plasm. It lacks the blood-filled slit-like spaces seen in Kaposi’s sarcoma
and mitoses are not observed. The component cells are histiocytic,
staining for CD68 and strongly with the Ziehl–Nielsen method, but
A not for the vascular markers such as CD31 and CD34, which are
evinced by Kaposi’s sarcoma.

Epithelioid haemangioendothelioma
Dail and Liebow provided the first comprehensive description of this
tumour but mistakenly believed it to be epithelial in type and named
it ‘intravascular bronchioloalveolar tumour’.332,333 Earlier reports had
suggested a possible decidual origin334 and other examples had been
mistaken for chondrosarcoma. The endothelial nature of the neoplas-
tic cells was established by the identification of Weibel–Palade bodies
in the cytoplasm by electron microscopy335,336 and the later demon-
stration of immunoreactivity for factor VIII-related antigen.333,337,338
This led to the introduction of terms such as sclerosing angiogenic
tumour,336 sclerosing interstitial vascular sarcoma,339 sclerosing epi­
thelial angiosarcoma340 and low-grade sclerosing angiosarcoma.338
The neoplasm was also included among the so-called histiocytoid
B haemangiomas.341 Soft-tissue342,343 and hepatic338,344,345 counterparts
were then recognised, and nomenclature was standardised by the
Figure 12.3.20  (A) Kaposi’s sarcoma surrounds and infiltrates a adoption of the term ‘epithelioid haemangioendothelioma’. It is
pulmonary artery and its accompanying bronchiole in a patient with now included in the spectrum of angiosarcomas as one of the
acquired immunodeficiency syndrome (AIDS). (B) Higher magnification less malig­nant members. A non-random chromosomal translocation
shows the tumour to consist of spindle cells separated by slit-like vascular t(1:3)(p36.3;q25) has been identified.346
spaces.

Clinical features
Although pulmonary epithelioid haemangioendothelioma occurs
characteristic distribution of the infiltrative disease along lymphatic over a wide age range (12–71 years) and in both sexes, about 50% of
pathways: the interlobular septa and visceral pleura are thickened and patients are less than 40 years of age and 80% are female.333,347
a cuff of neoplastic tissue forms around arteries and their accompany- Oestrogen receptors have been detected in a minority of tumours.348
ing airways (Fig. 12.3.20). The infiltrate consists of spindle cells and Symptoms are slight at first but shortness of breath slowly increases.
variable numbers of inflammatory cells, particularly plasma cells. The Occasionally the tumour presents as a solitary pulmonary nodule349
spindle cells closely resemble fibroblasts or endothelial cells and may but initial chest radiographs usually show numerous small nodular
form a network of irregular vascular channels. Red blood cells are opacities, mostly less than 1 cm in diameter, scattered throughout
often scattered between the spindle cells or may be present in the both lungs. Calcification is not usually evident radiographically and
vascular spaces. Obvious features of malignancy are often lacking but hilar lymphadenopathy is uncommon. The nodules enlarge only
scanty mitoses are usually evident. The histogenesis of Kaposi’s slowly and patients may survive for as long as 15 years after diagnosis
sarcoma is still debated but it is likely that the malignant cells are before dying of restrictive pulmonary failure. One patient presented
endothelial, originating either in lymphatics or in blood vessels.328–331 with hypertrophic pulmonary osteoarthropathy and following
The tumour cells express the haemangioendothelial markers CD31, treatment with azathioprine remained well with no apparent
CD34 and factor VIII and the lymphangioendothelial marker D2–40. pro­gression for 16 years.350
The infiltrate extends into the walls of airways but the bronchial epi- Unusual intrathoracic forms of the disease include an anterior
thelium usually remains intact. Arteries and veins appear to offer more mediastinal mass, diffuse pleural thickening resembling malignant
resistance, although some separation of muscle fibres may occur. The mesothelioma,351–353 a solitary peripheral calcified nodule,351 wide-
intervening lung shows non-specific features such as alveolar oedema, spread vascular occlusion resulting in pulmonary hypertension,354
haemosiderosis and the development of lymphoid aggregates. A alveolar haemorrhage and pleural effusion.355 Diffuse pleural thicken-
variant of Kaposi’s sarcoma, described as ‘inflammatory’301 or ‘poly- ing and widespread vascular occlusion are seen more often in men.
morphous’,326 is characterised by a predominant infiltrate of They indicate more aggressive growth and a correspondingly worse
lymphocytes and plasma cells with inconspicuous spindle cells: in prognosis.356,357

636
 Tumours Chapter | 12 |

B
Figure 12.3.21  Epithelioid haemangioendothelioma forming multiple
pulmonary nodules and thickening the pleura diffusely in the manner of Figure 12.3.22  Epithelioid haemangioendothelioma. (A) The tumour
a mesothelioma. (Courtesy of Dr CGB Simpson, Aberystwyth, UK.352) nodules are more cellular at the periphery, where they protrude into
neighbouring air spaces, giving them a micropolypoid structure. (B) The
centres of the nodules show hyaline sclerosis, and sometimes
calcification.

Pathology
At autopsy, the lungs are studded by multiple hard nodules and the
pleura may be diffusely thickened (Fig. 12.3.21). Microscopically, the
nodules have a central core of myxoid or hyaline connective tissue, is demonstrable both in the cytoplasm and within vacuoles (Fig.
which may show central calcification, chondrification or ossification 12.3.24).335–338 Positive reactions are usually obtained with other
(Fig. 12.3.22). Elastin stains reveal compressed alveolar walls and endothelial markers, including Fli-1, CD 31 and CD34.359
obliterated vessels. Congo red staining may be positive but the Extension within the lung may occur by lymphatic spread, produc-
characteristic birefringence and dichroism of amyloid are absent. The ing appearances similar to those seen in cases of lymphatic permea-
nodules are more cellular at the periphery where the stroma contains tion by carcinoma (so-called carcinomatous lymphangitis – see
single, or small clusters of tumour cells. Tumour cell nuclei are oval p. 682),351 and the pleura may be involved diffusely, resulting in a
with dispersed granular chromatin and a small nucleolus; they lack gross appearance that resembles that of a mesothelioma (see Fig.
atypia and mitoses are infrequent. The cytoplasm is abundant, 12.3.21).351–353 Extrathoracic spread is rare but extrapulmonary depos-
eosinophilic and often contains vacuoles, which may coalesce to its are recorded in sites such as the liver, bone and skin.333,338,344,348,349,360
form an intracellular lumen (Fig. 12.3.23). These minature lumina The characteristic micropolypoid structure is not seen outside the lung
sometimes contain a few red blood cells but if not they are apt to be and is evidently a product of the alveolar architecture.
confused with the mucin vacuoles of an adenocarcinoma.358 With such a slow-growing multifocal tumour, the identification of
At the periphery, the nodules extend into adjacent bronchioles and a solitary deposit in the liver raises the question whether the pulmo-
alveoli as papillary processes that are often clothed by cuboidal cells nary lesions are metastases from an occult hepatic primary.361,362 Based
(see Fig. 12.3.23). In paraffin sections these are not clearly distinguish- on a study of basement membrane composition it has been claimed
able from stromal cells but marked differences are evident on electron that the pulmonary tumours represent multicentric primary growths
microscopy.335,336 The surface cells are type II alveolar epithelial cells rather than metastases,363 but this issue is unsettled.348 There are cases
and are presumably reactive. The tumour cells have ultrastructural in which the multiple pulmonary lesions have developed long after
features more suggestive of vasoformative cells in that they contain epithelioid haemangioendothelioma has been diagnosed in an
Weibel–Palade bodies, and immunoreactive factor VIII-related antigen extrapulmonary site.352,364

637
 Pathology of the Lungs

Differential diagnosis
The differential diagnosis includes lesions containing cartilage or
myxoid connective tissue, such as chondroid ‘hamartoma’, metastatic
chondrosarcoma and sclerosing pneumocytoma. Sclerosing pneumo-
cytoma is typically a solitary lesion and contains sclerotic areas and
papillary processes that may resemble those of epithelioid
haemangioendothelioma, but the presence of prominent vascular
spaces in the sclerosing pneumocytoma usually enables the
distinction to be made.

Non-chromaffin paraganglioma
(chemodectoma)
A Paraganglia of the head, neck and thorax are closely aligned with the
parasympathetic nervous system and blood vessels such as the carotid
arteries, aorta and the main pulmonary arteries, locations that fit well
with their proposed chemoreceptor function. They are not well
described in the lungs. The existence of chemoreceptors on intrapul-
monary blood vessels is based on functional observations365 backed
up by a single morphological description of ‘glomera’ (paraganglia,
chemoreceptors) in the outer coats of pulmonary arteries at their
branching points closely related to adjacent nerves (see p. 23).366
Primary pulmonary paragangliomas could develop from such struc-
tures. However, most intrathoracic paragangliomas arise outside the
lung367–370 or, if intrapulmonary, eventually prove to be metastases
from an occult growth in the neck. Apart from the so-called multiple
minute chemodectomas of the lung described separately (see meningo­
thelioid nodules, p. 700), few cases of primary pulmonary paragan­
glioma have been reported, and it is debatable whether these represent
paragangliomas or carcinoids.371–377 Carcinoids and paragangliomas
both contain dense-core granules, which are indistinguishable in size
and structure. The nature of the dense-core granules is obscure but
one reputed pulmonary paraganglioma was shown to contain
noradrenaline (norepinephrine),378 whilst a few others have secreted
B catecholamines.379,380 Cytokeratin immunocytochemistry was for-
merly thought to provide a clear means of distinguishing carcinoids
Figure 12.3.23  Epithelioid haemangioendothelioma. (A) The tumour from paragangliomas but it is now recognised that positive reactions
nodules have a micropolypoid structure at their periphery. (B) Vacuolation may be obtained with both.381–384 Paragangliomas are characterised by
of tumour cells is sometimes evident, probably representing primitive S-100-positive sustentacular cells surrounding cells with neuroendo-
angiogenesis. crine characteristics but this feature is also described in a substantial
number of bronchopulmonary carcinoids. However, some workers
prefer to regard tumours of this description as paragangliomas and
have substantiated this claim by demonstrating scanty ganglion cells
in occasional examples, terming these tumours gangliocytic
paragangliomas.385–387 These few examples have included both a
central peribronchial tumour of Zellballen pattern and peripheral
spindle cell growths. All have been benign. One was responsible for
Cushing’s syndrome.387

Sarcoma of the major pulmonary

blood vessels
A rare form of sarcoma arises within the pulmonary trunk, the main
pulmonary arteries or the right side of the heart and gives rise to mul-
tiple pulmonary tumours.388–398 Less commonly, similar tumours arise
in the pulmonary veins, the chambers on the left side of the heart or
the aorta and metastasise via the systemic circulation.178,227,395,399–402

Clinical features
Figure 12.3.24  Epithelioid haemangioendothelioma. The tumour cells Patients with sarcoma of the pulmonary arteries cover a wide age
stain for the endothelial marker CD31. range, from 21 to 80 years, but most tumours occur between the ages

638
 Tumours Chapter | 12 |

Figure 12.3.25  Pulmonary trunk sarcoma. (A and B) A pulmonary artery is plugged and almost totally occluded by metastatic tumour, which consists
of (C) undifferentiated spindle cell sarcoma. (Courtesy of Dr W Kenyon, Liverpool, UK.)

or 45 and 65 and there appears to be a predominance of females. 12.3.25a, b). It may spread from the arteries to present as a diffuse
Radiation induction is recorded.403 Dyspnoea, chest pain and cough pulmonary infiltrate.229
may be accompanied by episodes of haemoptysis, syncope, a systolic In biopsy material, pathologists often misinterpret the pulmonary
murmur or right ventricular dilatation and failure.404 Plain chest radio­ deposits as infarcts, haemorrhagic pneumonia or haemorrhage as
graphy shows increased hilar shadowing and hypoperfusion of the many are well vascularised and liable to bleed. Other deposits,
lung fields, often leading to a mistaken diagnosis of pulmonary however, are more solid. Some tumours consist of a fairly uniform
thromboembolism.405–407 Weight loss, fever and anaemia are addi- population of polygonal or spindle cells whereas others show marked
tional features more suggestive of malignancy.408 Diagnosis during life pleomorphism and giant tumour cells (Fig. 12.3.25c). They are most
has been unusual but modern imaging techniques, such as angio­ frequently termed undifferentiated, pleomorphic or intimal sarcomas
graphy and computed tomography, make this possible.409,410 but other terms reflect their ability to differentiate in a number of
Fragmentation and tumour embolization result in multiple pulmo- directions and include, in descending order of frequency, leiomyo­
nary metastases, which appear as peripheral rounded nodules or sarcoma, rhabdomyosarcoma, chondrosarcoma, fibromyxosarcoma,
masses. Metastatic sites beyond the lungs include lymph nodes, brain, mesenchymoma (containing mixed elements), osteosarcoma, myxo-
diaphragm, thyroid and pancreas. sarcoma, angiosarcoma and malignant fibrous histiocytoma.411 Thus,
some tumours show the formation of bone or cartilage. The few
examples subjected to electron microscopy have shown striated388 or
Pathology smooth muscle392,412 or have been undifferentiated.413 Occasional
At surgery or autopsy the pulmonary trunk is distended by soft, grey, cases are examples of epithelioid angiosarcoma,394 and are likely to
polypoid tumour, often mixed with thrombus. This frequently extends be confused with poorly differentiated carcinoma, particularly pseudo­
distally into one or both main pulmonary arteries and, less often, vascular variants414: both carcinoma and epithelioid angiosarcoma
proximally to involve the pulmonary valve and right ventricular express cytokeratin415 but only the latter expresses endothelial markers.
outflow tract. Sometimes the tumour appears to arise in the right The prognosis is usually poor but some well-differentiated myo­
ventricle or atrium. The intima and media of the pulmonary trunk fibroblastic tumours have been associated with prolonged patient
are infiltrated but often quite superficially. In about half the cases survival and rare examples reported under terms such as myxoma
tumour extends directly into smaller intrapulmonary branches (Fig. appear to have been benign.416

639
 Pathology of the Lungs

It is uncertain what proportion of patients with intrapulmonary

nerve sheath tumours have neurofibromatosis but most have no other
features of the disease. Such patients are often asymptomatic, their
tumours having reached a considerable size by the time they are dis-
covered on a routine chest radiograph. Others have chest symptoms
attributable to the obstructive effect of the tumour. Some lesions are
visible bronchoscopically as a polypoid mass bulging into the lumen
of an airway, and this may cause bronchiectasis.425 The airways may
also be affected diffusely and require stenting421 or there may be
multiple endobronchial lesions.426 A unique case of multiple neuro­
fibromas has been described with severe hypoxaemia due to right-
to-left shunts within the tumours.427
In addition to these true neoplasms, traumatic (amputation) neu-
romas may be observed, generally at bronchoscopy following pulmo-
nary resection when they are liable to be mistaken for recurrence of
the original tumour or a stitch granuloma.428 They resemble similar
lesions encountered elsewhere, consisting of disorganised, hyper-
trophic bundles of axons surrounded by Schwann cells, perineurium,
A fibroblasts and collagenous scar tissue.

Granular cell tumour

Granular cell tumours were first described by Abrikossof in 1926 and
in the respiratory tract shortly afterwards.429–431 They were initially
considered to be of striated muscle origin but a neural derivation is
now thought more likely432–435 and the original term ‘granular cell
myoblastoma’ has therefore been modified. The tongue is the com-
monest site but they occur in many other locations, including the lip,
skin, breast, muscle, neurohypophysis and other viscera. A small
proportion, about 8%, arise in the tracheobronchial tree or the
periphery of the lung.436–442

Clinical features
Patients with bronchopulmonary granular cell tumour range in age
from 20 to 47 years (median 45 years) and show no sex predilec-
tion.439,442 The tumours are either incidental findings or cause obstruc-
tive symptoms or haemoptysis. A small number of patients have
B
multiple pulmonary lesions438 and some have associated soft-tissue
granular cell tumours.438,440 Imaging usually shows obstructive
Figure 12.3.26  Neurofibroma. (A) As in the skin, the tumour surrounds
changes. At bronchoscopy, granular cell tumours usually appear as
rather than destroys glands. (B) The tumour consists of cytologically
bland wavy spindle cells, and mast cells are evident in the stroma.
endobronchial nodules at points of bifurcation but others are plaque-
(Courtesy of Dr A Herbert, London, UK.)
like. They range in size up to 6.5 cm in diameter.

Pathology
NEURAL TUMOURS Bronchoscopic biopsy is usually diagnostic, showing the characteristic
cells lying directly beneath the epithelium, which may undergo
squamous metaplasia. The tumour cells are closely packed in cords,
Nerve sheath tumours
sheets or nests. They are polygonal or spindle-shaped and have small,
Posterior mediastinal or paravertebral nerve sheath tumours are fairly densely staining nuclei and abundant, coarsely granular, eosinophilic
common but in the lower respiratory tract tumours of nerve sheath and periodic acid–Schiff-positive cytoplasm (Fig. 12.3.27A). Nerve
origin are distinctly rare.219,235,417–422 They develop in both sexes and fibres may be seen among the tumour cells. Infiltration of the adjacent
may be endobronchial or parenchymal.235 They comprise both lung is often seen and lymph nodes may be directly involved but
neurofibromas and neurilemmomas (schwannomas), some of which metastasis is not a feature.
are malignant. Neurofibromas are more frequent in men, whereas Ultrastructurally, the cytoplasmic granules are consistent with them
schwannomas are more common in women. The gross, microscopical, being of lysosomal autophagic or cell membrane origin432,433,443 and
immunocytochemical and ultrastructural appearances are identical to the presence of axons and an incomplete basement membrane around
those of nerve sheath tumours elsewhere (Fig. 12.3.26). Melanin pro- the cells is thought to point to a Schwann cell origin.444 This is sup-
duction is occasionally encountered423 and rhabdomyoblastic differ- ported by the immunohistochemical demonstration of S-100 neural
entiation is recorded in rare malignant nerve sheath tumours protein (Fig. 12.3.27B).432,442,445 Negative reactions are obtained for
(so-called triton tumours) of the lung.424 cytokeratin and neuroendocrine markers.

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 Tumours Chapter | 12 |

Figure 12.3.28  Meningioma of the lung. There was no evidence of an

intracranial lesion and electron microscopy supported the diagnosis.
(Courtesy of Dr TV Colby, Scottsdale, USA.)

Meningioma
Occasional meningiomas, identical to those found within the
B cranium but apparently primary to the lungs, have been
described.446–458 It has been suggested that they arise from ectopic
Figure 12.3.27  A granular cell tumour that formed a bronchial polyp. arachnoid cells,452 but it is likely that arachnoid-like cells are an in­­
(A) The tumour is composed of polygonal cells with abundant herent part of the normal lung (see p. 23) and that this is the source
eosinophilic cytoplasm. (B) The tumour cells are strongly positive for
of the pulmonary tumours. This relates them to the meningo­
S-100 protein.
thelioid nodules (so-called multiple minute chemodectomas, see
p. 700) but pulmonary meningiomas are generally solitary and are
not minute.459
Differential diagnosis
Granular cell tumours may be confused with oncocytic carcinoid
Clinical features
tumours (see p. 595) or oncocytic tumours of bronchial gland origin The reported cases have ranged from 51 to 70 years of age. The patients
(see p. 605). Carcinoid tumours are typically much more vascular have generally been asymptomatic, their tumour being discovered on
than granular cell tumours. Electron microscopy of oncocytic tumours routine chest examination. The tumours have generally been solitary
shows closely packed mitochondria rather than the autophagic but in one case there were multiple pulmonary meningiomas and the
granules of granular cell tumours. Some carcinoid tumours may stain patient also had neurofibromatosis.448
weakly for S-100 protein but both carcinoid tumours and bronchial
gland tumours also stain for cytokeratin whereas granular cell tumours
Pathology
do not.
The tumours are well circumscribed but are not encapsulated.
They have no obvious connection with airways, blood vessels or
Prognosis pleura. Histologically, they consist of sheets of regular ovoid or
Granular cell tumours generally grow slowly and no malignant exam- spindle cells forming the ‘menigothelial whorls’ and psammoma
ples are described in the lung. Nevertheless, effective therapy usually bodies characteristic of the intracranial growths (Fig. 12.3.28).
requires formal resection. Immunohistochemistry shows that the tumour cells stain positively

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 Pathology of the Lungs

for vimentin and EMA but negatively for cytokeratin and S-100 Ependymoma
protein. Electron microscopy shows complex cellular interdigitations
and many desmosomes. Rare examples of ependymomas occurring outside the central nervous
system have been described in the pelvis and posterior mediastinum
and, in one patient only, the lung.461 This was an elderly woman who
Differential diagnosis also had a small cell carcinoma treated by chemotherapy and it is
An occult primary in the cranium obviously needs to be excluded uncertain whether the ependymoma represented metaplastic change
before the diagnosis of primary pulmonary meningioma can be in the carcinoma, perhaps due to the chemotherapy, or whether it
countenanced. The degree of atypia is of no significance as some arose in ectopic ependyma. The tumour had the usual morphology of
metastases appear quite benign histologically, giving rise to the term a malignant ependymoma and showed strong immunoreactivity for
‘benign metastasising meningioma’.460 glial fibrillary protein with less intense staining for vimentin, EMA
and S-100 protein.

Treatment and prognosis

Treatment is by surgical resection, following which recurrence is
very rare.456

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12.4  Lymphoproliferative disease

ment before the various lymphomas that affect the lungs.1 Whereas
CHAPTER CONTENTS
the lungs are often involved in disseminated nodal lymphomas of all
Intrapulmonary lymph nodes 653 types, primary pulmonary lymphoma is relatively rare, accounting for
Lymphoid hyperplasia 653 less than 0.5% of all primary lung neoplasms. There are several varie-
ties but marginal-zone non-Hodgkin lymphoma of mucosa-associated
Follicular bronchiolitis 654
lymphoid tissue (MALT) origin makes up approximately 80% of the
Lymphoid interstitial pneumonia 655 total and diffuse large B-cell non-Hodgkin lymphoma approximately
Nodular lymphoid hyperplasia 656 15%.2–6 The other 5% comprises lymphomatoid granulomatosis,
Lymphoproliferative disease complicating severe plasmacytoma, Hodgkin lymphoma, anaplastic large cell lymphoma,
immune impairment 657 CD56-positive (natural killer cell) lymphoma,7,8 the CD21- and
Marginal-zone B-cell lymphoma of MALT type 659 CD35-positive follicular dendritic cell tumour,9,10,11solitary mast cell
tumours of the lung,12,13 Langerhans cell sarcoma14 and exceptional
Diffuse large B-cell non-Hodgkin lymphoma 660 cases that appear to be of follicle centre cell origin and are therefore
Lymphomatoid granulomatosis 664 directly comparable to nodal lymphomas.15
Hodgkin disease 666
Plasmacytoma 666
Large cell anaplastic lymphoma 667 INTRAPULMONARY LYMPH NODES
Intravascular lymphoma (angiotropic lymphoma) 667
Secondary pulmonary involvement by The lymphoid elements of the lung consist of intrapulmonary lymph
lymphoproliferative disorders 668 nodes and airway-associated lymphoid tissue, details of which are
Pulmonary problems in leukaemia 668 provided on p. 26. The two are best considered separately.
Intrapulmonary lymph nodes have a normal follicular and sinusoidal
Angiofollicular lymph node hyperplasia (giant
architecture, and may undergo all those changes encountered in
lymph node hyperplasia, Castleman’s disease) 669
lymph nodes elsewhere. In the lungs they are also often heavily pig-
References 669 mented with carbon. Most are situated at the hilum but they may be
found anywhere in the lung, occasionally as far out as the pleura (Fig.
Lymphoproliferative disease is a useful term as it covers lymphoid 12.4.1). In one necropsy study intrapulmonary lymph nodes were
infiltrates of the lung of questionable status as well as those that are identified in 18% of patients.16 They are generally asymptomatic and
evidently reactive or neoplastic. Until recently those of questionable discovered incidentally on chest radiographs, following which they
status included lymphoid interstitial pneumonia and so-called may be excised to exclude cancer, increasingly so since the advent of
pseudolymphoma but the application of modern laboratory tech- high-resolution computed tomography (HRCT).17,18 Otherwise they
niques has clarified the nature of both these conditions. However, the are of no clinical significance.
emergence of seemingly malignant posttransplantation and acquired
immunodeficiency syndrome (AIDS)-related lymphoid lesions that
regress when immunity is restored has again blurred the distinction
between lymphoid hyperplasia and neoplasia. LYMPHOID HYPERPLASIA
In this chapter we follow the World Health Organization (WHO)
classification of extranodal lymphomas, considering reactive lesions Hyperplasia of the airway-associated lymphoid tissue may be seen in
and lymphoproliferative disease complicating severe immune impair- a variety of diseases and is often no more than an epiphenomenon.

653
 Pathology of the Lungs

Box 12.4.1  Conditions associated with follicular

bronchiolitis and lymphoid interstitial pneumonia
Collagen vascular disease, especially rheumatoid21,25
Sjögren’s syndrome26–28
Pernicious anaemia29
Autoimmune haemolytic anaemia26,30
Chronic active hepatitis31
Primary biliary cirrhosis32,33
Myasthenia gravis26
Acquired immunodeficiency syndrome (AIDS), particularly AIDS
affecting children34–37
Congenital immunodeficiency syndromes
Allogeneic bone marrow transplantation38
Allergy, including asthma21

tissue.19,21,22 There may be extension of the process into the bronchi-

olar epithelium and into the walls of neighbouring alveoli but the air
spaces are spared. In extreme cases the lymphoid follicles are evenly
distributed throughout the lung, perhaps even involving the pleura,
Figure 12.4.1  An intrapulmonary lymph node lies just beneath the when the term ‘diffuse lymphoid hyperplasia’ has sometimes been
pleura. applied,23 but this process does not otherwise differ materially from
follicular bronchiolitis.19,24

Thus, lung tumours and many focal pulmonary infections are often Clinical features
attended by a chronic inflammatory infiltrate comprising a mixture of
Patients commonly present in middle age. They complain of breath-
lymphocytes, plasma cells and histiocytes, sometimes with lymphoid
lessness and cough and suffer from recurrent episodes of fever or
follicles. Such an infiltrate is also a general feature of viral, rickettsial
pneumonia.21 There are several clinical association, which are listed
and Mycoplasma pneumonia. Similarly, extrinsic allergic alveolitis is
in Box 12.4.1.21,25–38 The sexes are affected equally, apart from the
characterised by an interstitial lymphoid infiltrate that histologically
patients in whom follicular bronchiolitis is associated with connective
may closely resemble lymphoid interstitial pneumonia. Chronic inter-
tissue disorders, in which females predominate.21,25,39 Chest X-ray find-
stitial inflammation is particularly marked in obstructive pneumonia.
ings are similar to those seen in lymphoid interstitial pneumonia, but
It is also a component of all patterns of chronic idiopathic interstitial
HRCT typically shows bilateral centrilobular and peribronchial
pneumonia, although the intensity of the infiltrate varies consid­
nodules rather than ground-glass opacification.25,33,39,40
erably, being light in desquamative interstitial pneumonia, moderate
in cellular non-specific interstitial pneumonia and heavy in lymph­
oid interstitial pneumonia. Expansion of the bronchus-associated Aetiology
lymphoid tissue is particularly conspicuous in follicular bronchiecta- Follicular bronchiolitis is associated with a range of conditions
sis. However, all these conditions have their own specific features that similar to that found with lymphoid interstitial pneumonia. Their
facilitate their recognition. aetiology is probably similar and is therefore dealt with together (see
Hyperplasia of the pulmonary lymphoid tissue also occurs in the p. 655).
absence of any accompanying morphological pointers to its aetiology,
although the conditions with which it is associated often provide a
clue to its causation. Three forms are recognised: follicular Pathological features
bronchiolitis, lymphoid interstitial pneumonia and nodular lym- Follicular bronchiolitis is characterised by prominent peribronchial
phoid hyperplasia.19,20 The first of these is centriacinar, the second and peribronchiolar lymphoid follicles with only minor interstitial
diffuse and the last forms a localised tumour-like nodule. Castleman’s inflammatory component (Fig. 12.4.2). Hyperplastic follicles may
disease may also present as primary pulmonary disease, but more also be seen in the interlobular septa and the visceral pleura.
commonly involves the lung as part of a multiorgan disorder and is Compression of the airways may lead to an obstructive endogenous
discussed below under secondary involvement. lipoid pneumonia or secondary infection with pus in the bronchioles
Although follicular bronchiolitis and lymphoid interstitial pneu- and the alveoli showing focal organising pneumonia.
monia are traditionally regarded as distinct, they frequently coexist
and have overlapping clinical and histological features. Both are
encompassed by the term ‘diffuse pulmonary lymphoid hyperplasia’. Differential diagnosis
The differential diagnosis of follicular bronchiolitis is from the other
forms of bronchiolitis described in Chapter 3. It also has to be distin-
Follicular bronchiolitis
guished from follicular bronchiectasis, a term used when prominent
Follicular bronchitis/bronchiolitis consists of a predominantly centri- follicular hyperplasia accompanies airway dilatation. Lymphoid fol-
acinar lymphocytic infiltrate with abundant germinal centres. It rep- licles may also be prominent in the middle-lobe syndrome (see p. 92),
resents an expansion of the normally sparse peribronchiolar lymphoid but this is a localised disease. Extrinsic allergic alveolitis may also

654
 Tumours Chapter | 12 |

Clinical features
The age and sex distribution tend to reflect the associated diseases
listed in Box 12.4.1 so the age range is broad. Cases have been
described in both infants and the elderly but most cases occur in
middle age. There is a slight female preponderance21 and occasionally
there is a familial pattern of inheritance.42,43 Most patients have cough
and dyspnoea accompanied by systemic symptoms such as weight loss
and low-grade pyrexia.28 Many also have hypergammaglobulinaemia
but some show low levels of gammaglobulins.26,32,44–47 Pulmonary
function tests show a restrictive defect.28 Chest radiographs show
ground-glass opacities or reticular, coarse reticulonodular or fine retic-
ulonodular opacities19,26,32,45 while HRCT may also show cystically
dilated air spaces, which occasionally dominate the image.28,47–50

Aetiology
The aetiology of lymphoid interstitial pneumonia is probably multi-
factorial as there is evidence that both viruses and immune processes
A
contribute. The viruses include Epstein–Barr virus (EBV)51–53 and in
children particularly human immunodeficiency virus (HIV).51,54–57 The
identification of monoclonal gammopathy in some patients44 and of
clones of lymphoid cells with high sequence homology to auto­
reactive lymphocytes suggests autoimmunity58 while the association
with congenital immunodeficiency suggests further pathways of
lymphocyte dysregulation.46,59 In the acquired immunodeficiency of
HIV infection, high levels of chemokines such as interleukin-18 may
be in part responsible for recruitment of inflammatory cells into
the interstitium.60

Pathological features
The involved lung tissue may appear consolidated on gross inspection
but microscopy shows that it is the alveolar walls that are affected
rather than the air spaces, being expanded by an interstitial infiltrate.
The infiltrate is predominantly composed of small lymphocytes but
B
these are mixed with plasma cells, a few larger mononuclear cells and
histiocytes (Fig. 12.4.3). The distribution is typically diffuse but may
Figure 12.4.2  Follicular bronchiolitis. (A) A lymphoid follicle is closely be similar to that encountered in the more diffuse forms of pulmonary
related to a small bronchiole, compressing the lumen. (B) The bronchiolar
lymphoma, being particularly prominent in relation to lymphatics
lumen contains retained proteinaceous debris and cholesterol because of
narrowing by hyperplastic lymphoid follicles. and thus most marked around bronchovascular bundles, bordering
interlobular septa and beneath the pleura. It also forms rounded
nodular aggregates about small intralobular vessels but the alveolar
walls are nevertheless considerably thickened (see Fig. 12.4.3).
show prominent peribronchial lymphoid follicles, but there are Lymphoid follicles are frequent and there may be poorly formed
usually granulomas and a significant interstitial inflammatory granulomas.23,26 The follicles largely consist of B cells (see Fig. 12.4.3)
component. but the interstitial infiltrate predominantly comprises T cells.
Occasionally there is local deposition of amyloid (Fig. 12.4.4).23,61
Molecular studies show no immunoglobulin heavy-chain restriction
Treatment and prognosis or gene rearrangement.19,22,23,32,62,63 Lymphoid interstitial pneumonia
Most patients respond well to corticosteroid therapy, although non- may occasionally overlap with follicular bronchiolitis (see above);
resolving alveolar collapse, fibrosis and even bulla formation may these two conditions represent different patterns of lymphoid hyper-
occur. Occasional cases show obliterative bronchiolitis but this prob- plasia and are seen together particularly in patients with connective
ably represents an independent manifestation of an associated tissue disorders (Fig. 12.4.5).19,22,24
connec­tive tissue disorder rather than progression of the follicular
bronchiolitis.
Differential diagnosis
The differential diagnosis includes both reactive conditions and inter-
Lymphoid interstitial pneumonia
stitial patterns of low-grade B-cell lymphoma. The former include HIV
Lymphoid (or lymphocytic or lymphoplasmacytic) interstitial pneu- and EBV infection. In comparison with the other idiopathic interstitial
monia is characterised by a prominent, diffuse, alveolar infiltrate of pneumonias the infiltrate of lymphoid interstitial pneumonia is much
lymphocytes and plasma cells.41 Occasional cases are idiopathic but denser and is generally not accompanied by any significant degree
it is generally associated with a variety of clinical conditions that of fibrosis. It most closely resembles cellular non-specific interstitial
reflect impaired immunity (Box 12.4.1).21,25–27,28–31,32–36,21,37,38 pneumonia, from which it is only distinguished by a subjective

655
 Pathology of the Lungs

A B

C D

Figure 12.4.3  Lymphoid interstitial pneumonia. (A) A heavy infiltrate of small lymphocytes cuffs the intralobular blood vessels and thickens the alveolar
walls. (B) Although the alveolar walls are markedly expanded, there is little involvement infiltration of the air space. (C) At high power, the interstitial
infiltrate comprises small round lymphocytes, plasma cells and histiocytes. (D) CD20 staining shows tight aggregates of B cells, mainly within follicles
(compare with the lymphomatous infiltration in Fig. 12.4.15a).

assessment of the intensity of the infiltrate, which is less marked in studies, taking advantage of molecular techniques, suggest that apart
non-specific interstitial pneumonia. Extrinsic allergic alveolitis is also from the cases complicating AIDS,51,52,66 lymphomatous change is
characterised by a predominantly T-cell infiltrate with occasional unusual.28 The prognosis is therefore better than was formerly believed,
granulomas, but a peribronchiolar concentration of the infiltrate and although it remains unpredictable.45 Some patients recover com-
the presence of organising pneumonia distinguish it from lymphoid pletely, others remain stable46 or slowly progress to end-stage fibrosis50
interstitial pneumonia.64 Extrinsic allergic alveolitis, sarcoidosis and and some die within months.19,32,45 One group reported that 7 of 15
lymphoid interstitial pneumonia are compared in Table 6.1.6 patients died with a median survival of 11.5 years.28 Causes of death
(p. 281). Distinguishing these conditions is greatly facilitated by cor- include progression to interstitial fibrosis and infection.47 Treatment
relation with clinical data, especially the HRCT findings (Table is usually with corticosteroids, with or without cytotoxic therapy.
12.4.1).65 The distinction of lymphoid interstitial pneumonia from Patients with symptomatic HIV-related lymphoid interstitial pneumo-
marginal-zone lymphomas of MALT origin is considered on p. 660. nia have improved following highly active antiretroviral therapy.67

Treatment and prognosis

Older reports probably included cases that were lymphomatous from
Nodular lymphoid hyperplasia23,68,68a
the outset, which would explain why the condition has been regarded Over the last two decades, it has become apparent that most localised
as having a propensity to evolve into frank lymphoma. More recent lymphoid lesions arising in the lung are marginal-zone non-Hodgkin

656
 Tumours Chapter | 12 |

Figure 12.4.4  Lymphoid interstitial pneumonia. Rare cases may be Figure 12.4.6  Nodular lymphoid hyperplasia. A pulmonary nodule is
associated with the deposition of either amyloid or, as in this case, light composed of hyperplastic germinal centres interspersed by a mixed
chains. infiltrate of plasma cells and small lymphocytes. The features are similar
to those of marginal-zone lymphomas of mucosa-associated lymphoid
tissue (MALT) origin, but no evidence of clonality was found on
immunohistochemistry or molecular analysis.

vity at the periphery is quite limited. Atypical cells are not seen.
Immunochemistry shows that the reactive follicles are populated by
B cells expressing both κ and λ light chains while the interfolli­
cular lymphocytes are largely T cells. Staining for bcl-2 protein is
negative and no immunoglobulin heavy-chain gene rearrangement is
detectable.

Differential diagnosis
Nodular lymphoid hyperplasia differs from lymphoid interstitial
pneumonia in being focal rather than diffuse. The principal alterna-
tives are inflammatory myofibroblastic tumour (see p. 620) and
Figure 12.4.5  Histological overlap in lymphoid hyperplasia. On the left,
marginal-zone non-Hodgkin lymphoma of MALT type (see below). It
the inflammatory infiltrate is mainly interstitial, whereas on the right
there is follicular bronchiolitis. differs from inflammatory myofibroblastic tumour in lacking spindle
cells. The distinction from marginal-zone non-Hodgkin lymphoma of
MALT type is particularly difficult and often uncertain without molec-
ular studies but any significant degree of infiltrative activity along side
lymphomas.4,15,69 However, a few prove to be polyclonal and reactive
adjacent lymphatics would favour lymphoma.
in nature and the term ‘nodular lymphoid hyperplasia’ is now applied
to these, having superseded pseudolymphoma.

LYMPHOPROLIFERATIVE DISEASE
Clinical features
COMPLICATING SEVERE
Patients have a mean age of 65 years (range 19–80) and show a slight
female preponderance.68 The lesions are generally chance radiographic
IMMUNE IMPAIRMENT
finding. Symptoms include cough, shortness of breath and pleuritic
pain. Most lesions are solitary and, if multiple, unilateral. Surgical The spread of AIDS and the development of organ transplantation
resection is curative. have both seen the appearance of a remarkable spectrum of lympho-
proliferative disease from which the lungs have not been spared. The
chief pulmonary manifestations have been lymphoid hyperplasia,
Pathological features including lymphoid interstitial pneumonia (see above), and a variety
Nodular lymphoid hyperplasia forms a well circumscribed nodule of lesions that have many of the features of lymphoma.70–73 In the case
measuring up to 6 cm, which is of fleshy or rubbery consistence of posttransplantation lymphoproliferative disease, which is touched
and usually subpleural. Histologically, lymphoid follicles are well upon again in Chapter 11 (see p. 521), some of these lesions regress
developed and plasma cells are prominent between the follicles (Fig. when immunosuppressive therapy is withdrawn or even reduced,
12.4.6). There may be extensive central scarring. Any infiltrative acti­ while in the case of AIDS-related lymphomas tumour grade appears

657
 Pathology of the Lungs

Table 12.4.1  Clinical and pathological characteristics of lymphoid interstitial pneumonia, cellular non-specific interstitial pneumonia
and extrinsic allergic alveolitis65

Lymphoid interstitial Cellular non-specific Extrinsic allergic alveolitis

pneumonia interstitial pneumonia

Age Wide age range 26–50 years Wide age range

Sex Female preponderance in adults Male preponderance Dependent on causative agent

Associated diseases
Autoimmunity Common Fairly common No

Immunodeficiency Common (especially in HIV+ve May be seen in HIV+ve patients No

children)
Idiopathic disease Rare Fairly common No
Amyloidosis Rare No No
Environmental allergens No No Yes
Hypogammaglobulinaemia Common No No
Lavage lymphocytosis Common Common Common

Imaging
Chest radiograph Ground-glass or reticulonodular Non-specific, variable Variable (dependent on stage of disease)
shadowing shadowing May wax and wane on serial radiographs
Occasionally normal May be normal
HRCT Spectrum of randomly distributed Ground-glass opacification Subacute disease characterised by
nodules (1–4 mm) through to without architectural ground-glass opacification and poorly
ground-glass opacification with the disturbance or defined centrilobular nodularity.
latter sometimes accompanied by honeycombing Expiratory scans show air-trapping
thin-walled cystic air spaces reflecting bronchiolitis
Chronic disease shows fibrosis of
non-specific pattern and distribution

Histopathology
Distribution Diffuse Diffuse Often centrilobular
Inflammation Severe interstitial infiltrate Mild interstitial infiltrate Variable interstitial infiltrate
Architecture Little architectural destruction No architectural destruction May be lost in chronic disease
Interstitial fibrosis Rare None May be present in chronic disease
Interstitial cell types Small round lymphocytes, plasma cells, Small round lymphocytes, Small round lymphocytes, plasma cells,
histiocytes plasma cells, histiocytes, histiocytes, some fibroblasts
some fibroblasts
Granulomas Rare No Common
Organising pneumonia Rare Rare (less than 10% of cases) Common (70% of cases)

HIV, human immunodeficiency virus; HRCT, high-resolution computed tomography.

to vary with the patient’s immune status, the more severely clonal B-lymphocyte proliferation, a clone of malignant cells may
immu­nodepleted developing more aggressive neoplasms.74 emerge. The resultant B-cell tumours are often high-grade and notable
Lymphoproliferative disease complicating profound immuno­ for affecting extra­nodal tissues, including the lungs on occasion.75,80,81
suppression generally involves B cells: T cells are poorly represented. There is a particularly high risk of pulmonary involvement, around
The B-cell proliferation is probably attributable to T-lymphocyte 60%, after heart–lung transplantation. Transplantation of lungs alone
deficiency for in normal individuals T cells control the division of B carries less of a risk.
cells. T-cell deficiency also permits the proliferation of latent EBV Lung involvement by these high-grade tumours generally takes
infection. This virus is a further stimulus to B-cell proliferation and the form of multiple nodules that are relatively well circumscribed
its constituents have been identified in most of the resultant and show extensive necrosis. Histologically, the lesions may be
tumours.75–79 It would appear that after a period of unchecked poly- monomorphic or polymorphic: the former consist of immuno­

658
 Tumours Chapter | 12 |

Figure 12.4.7  Marginal-zone lymphoma of mucosa-associated lymphoid Figure 12.4.8  Marginal-zone lymphoma of mucosa-associated lymphoid
tissue (MALT) origin. High-resolution computed tomography shows an tissue (MALT) origin. Bronchial washings show a moderately dense
area of consolidation with ground-glass changes at its periphery. Air infiltrate of small lymphocytes, which proved to be of B-cell phenotype.
bronchograms are present within the consolidation.

blasts or large or small non-cleaved lymphoid cells, whilst the Aetiology

latter consist of a variety of cell types, including immunoblasts,
Whereas gastric marginal-zone lymphomas of MALT origin show a
centroblast-like and centrocyte-like cells, plasmacytoid cells and his-
strong relation to Helicobacter pylori infection, less is known of the
tiocytes. The infiltrate tends to involve blood vessels, so that the fea-
aetiology of the comparable tumours arising in the lungs. However,
tures may resemble those of lymphomatoid granulomatosis (see
there is evidence that smoking,89 autoimmune disorders,76,90 immuno­
below).81 AIDS-related lymphoma of the pleura is considered sepa-
suppressive therapy,91,92 AIDS, tuberculosis93 and hepatitis C94 may all
rately on page 734.
play a role. Neoplastic change in the bronchus-associated lymphoid
tissue is therefore likely to be multifactorial. These associations are all
characterised by an expansion of the bronchus-associated lymphoid
MARGINAL-ZONE B-CELL LYMPHOMA tissue and this is probably a common factor in the pathogenesis of
OF MALT TYPE these tumours.
Molecular studies have shown various translocations, trisomy
of chromosome 3 and mutation of the bcl-10 gene.95–99 The
Clinical features commonest translocations are t(11;18)(q21;q21), t(14;18)(q32;q21)
More than 80% of patients with these tumours are over 40 years of and t(1;14)(p22;q32), being seen in 40%, 5–25% and 8% of pulmo-
age. The mean age is about 55 years; children are rarely affected.15 nary marginal-zone lymphomas respectively.99 They result in fusion,
There is a slight male preponderance. The majority of patients are and hence inactivation, of genes concerned in apoptosis, or overex-
asymptomatic at presentation, the disease being first detected on pression of oncogenes such as bcl-10 and MALT-1.99
routine radiographs. Other patients suffer from cough, dyspnoea,
chest pain and haemoptysis, sometimes accompanied by malaise,
weight loss or pyrexia.2 Paraproteinaemia is present in up to 20% of Pathological features
cases and this is usually of IgM type (macroglobulinaemia).82 Evidence The macroscopic appearances vary from a localised tan or grey tumour
of Sjögren’s syndrome or, less often, another connective tissue dis­ to areas of apparent pulmonary consolidation (Fig. 12.4.9). Preserved
order such as lupus erythematosus, may be present,27 and there may bronchovascular bundles can sometimes be seen on the cut surface.
be a history of lymphoma in other extranodal sites, such as the gas- Microscopically, the tumours consist of small lymphocytes, which
trointestinal tract, salivary glands, orbit or skin. Some patients have may be centrocyte-like, lymphocyte-like or monocytoid, although all
systemic (‘type B’) symptoms such as fever, weight loss and night are thought to be variations of the same neoplastic cell (Fig. 12.4.10A).
sweats. Imaging shows variable patterns, with unilateral or bilateral They first proliferate around the bronchovascular bundles and then
disease, isolated or multiple opacities, diffuse infiltration, reticulo­ spread out in the connective tissue planes alongside blood vessels and
nodular shadowing and pleural effusions. HRCT scans typically show their accompanying lymphatics. At this stage there is prominent
multiple or solitary areas of consolidation, with associated air bron- involvement of the interlobular septa (Fig. 12.4.10B) and there may
chograms and haloes of ground-glass shadowing at lesion margins be pleural infiltration. As the disease progresses there is invasion of
(Fig. 12.4.7).83 Mediastinal lymphadenopathy is unusual.5 Diagnosis the alveolar walls, which are first expanded and then destroyed leading
is possible with cytological specimens (Fig. 12.4.8) or small biop- to filling of the air spaces and obliteration of the alveolar architecture
sies,4,84–86 but more often a surgical lung biopsy and correlation with (Fig. 12.4.10C, D).100 This ultimately results in a tumour mass in
HRCT data are needed. Immunohistochemistry, flow cytometry and which only the larger airways and blood vessels are spared. The latter
molecular analysis may be required.87,88 may be infiltrated101 but not on the scale seen with the angiocentric

659
 Pathology of the Lungs

clonality.4 The bcl-2 oncogene is not expressed in the follicle centre

cells but is positive in the colonising neoplastic lymphocytes. The
neoplastic cells are also CD5- and CD10-negative. If there is nodal
involvement the features there are those of nodal marginal-zone B-cell
non-Hodgkin lymphomas.105,106

Differential diagnosis
The principal histological difficulty lies in distinguishing this type of
lymphoma from lymphoid interstitial pneumonia. These conditions
share many histological features but involvement of alveolar spaces,
destruction of alveolar walls, the presence of giant lamellar bodies and
infiltration of the pleura and bronchial cartilage all favour lymphoma.
Immunohistochemical characterisation of the infiltrate is of consider-
able help for whereas the small lymphocytes in lymphoid interstitial
pneumonia are predominantly T cells, the interstitial infiltrate in
marginal-zone lymphoma has a predominantly B-cell phenotype
(compare Figs 12.4.3D and 12.4.11D).4,6,19 Finally, molecular studies
may provide firm supportive evidence; amplification of the immuno­
globulin heavy chain gene favours lymphoma and identification of
the chromosomal translocations described above points to marginal-
zone B-cell lymphoma of MALT type.
Distinguishing lymphoma from nodular lymphoid hyperplasia is
described above (p. 657). Distinguishing primary from secondary
lymphoma depends upon clinical data. Lymphocyte-rich variants of
thymoma (WHO type B1) involving the lung may resemble lym-
phoma but are easily recognised by their cytokeratins CD3 and CD1a
positivity.107
In cases of lymphoma with extensive amyloid deposition, the
intensity of the lymphocytic infiltration, lymphatic tracking and
pleural invasion are all clues to the lymphomatous nature of the
disease.
Clinically, the differential diagnosis often includes local or
multifocal mucinous adenocarcinoma and organising pneumonia,
in which case a cytological specimen or endoscopic biopsy showing
a dense lymphocytic infiltrate with the appropriate immunopheno-
Figure 12.4.9  Marginal-zone lymphoma of mucosa-associated lymphoid
type may be sufficient to identify marginal-zone lymphoma.
tissue (MALT) origin. The tumour forms a cream-coloured mass which is
less dense peripherally, in keeping with the ground-glass changes at the
edges of the mass noted on high-resolution computed tomography in
Figure 12.4.7. Treatment and prognosis
These tumours are either stage Ie (confined to the lungs) or IIe (Ie
plus hilar/mediastinal involvement) and resection has often resulted
lymphoproliferative disorders. Ultimately, the tumour cells also infil- in prolonged remission.108 In some elderly patients with asympto-
trate the pleura and bronchial cartilage. Hyaline sclerosis is common matic disease, a ‘wait and watch’ policy is often appropriate for these
and lymphoid follicles are often evident, particularly when stains for indolent tumours. The 5-year survival exceeds 90%.3,4,15,109Metastases
the CD21 marker of follicular dendritic cells are employed (Fig. involve other mucosal sites rather than lymph nodes.2,4 Recurrence is
12.4.11). Epithelioid and giant cell granulomas may rarely be observed associated with a tendency towards transition to diffuse large B-cell
(Fig. 12.4.12) and lymphoepithelial lesions are often present, recogni- lymphoma.15 Extensive pulmonary involvement that is not amenable
tion of which is facilitated by cytokeratin staining (Fig. 12.4.13). Giant to resection is associated with a worse prognosis. Chlorambucil is the
lamellar bodies derived from type II pneumocytes may be seen within medical treatment of choice.109
the tumour, possibly related to airway obstruction (Fig. 12.4.14).102
Amyloid is present in up to 10% of cases.5,6,103,104 Necrosis is rarely
observed.
DIFFUSE LARGE B-CELL
Immunohistochemistry
NON-HODGKIN LYMPHOMA
The more numerous B lymphocytes can be identified with stains for
CD20 or CD79a and the background reactive T cells with CD3 (Fig.
Clinical features
12.4.15A, B). Immunostains for κ and λ light chains may provide Diffuse large B-cell non-Hodgkin lymphoma forms about 20% of
evidence of clonality but are successful in only a minority of cases, pulmonary lymphomas. The age range is similar to that of marginal-
less so than at any other site where lymphomas of this type arise.100 zone non-Hodgkin lymphoma of MALT origin but the patients are
However, amplification of the immunoglobulin heavy-chain gene by usually symptomatic at presentation, complaining of cough,
the polymerase chain reaction may provide firmer evidence of mono- haemoptysis, dyspnoea and systemic (‘B’) symptoms such as fever,

660
 Tumours Chapter | 12 |

A B

C D

Figure 12.4.10  Marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT) origin. (A) The tumour is composed of a monotonous sheet of
small mature lymphocytes. (B) At its periphery, the tumour has spread primarily along the pulmonary lymphatics. (C) As the lymphoma expands, so the
interstitium becomes increasingly widened and alveoli are filled by tumour cells. (D) Centrally, alveolar walls are destroyed, but as yet bronchovascular
bundles are preserved.

weight loss and night sweats. Imaging shows solid masses, which Pathological features
are often multiple.
Macroscopically, areas of pulmonary involvement typically form solid
or necrotising cream-coloured masses. Microscopically, the lung archi-
tecture is destroyed by sheets of tumour cells that have large irregular
vesicular nuclei and moderate amounts of cytoplasm. The cells are
Aetiology pleomorphic and there are many mitoses (Fig. 12.4.16). Lymphoid
It is likely that these tumours represent blastic transformation of follicles, lymphoepithelial lesions and granulomas are seldom evident
marginal-zone non-Hodgkin lymphomas of MALT origin, probably but bronchial MALT may be found in the distant non-involved lung.
through further mutation. There is a rare association with fibrosing Foci of marginal-zone non-Hodgkin lymphomas of MALT origin may
alveolitis and connective tissue diseases. Diffuse large B-cell lympho- be seen.4 The neoplastic cells are of B-cell phenotype, mixed with
mas are also found in immunodeficient individuals, notably those reactive T cells. Evidence of monoclonality is occasionally obtained
undergoing immunosuppression following organ transplantation or by demonstrating heavy-chain gene amplification with the
suffering from AIDS.4,73,76,90,110 poly­merase chain reaction.4

661
 Pathology of the Lungs

Table 12.4.2  Clinical and pathological characteristics of lymphoid interstitial pneumonia, mucosa-associated lymphoid tissue (MALT)
lymphoma, nodular lymphoid hyperplasia and lymphomatoid granulomatosis65

Lymphoid interstitial MALT lymphoma Nodular lymphoid Lymphomatoid

pneumonia hyperplasia granulomatosis

Age Wide age range Usually between 50 and 19–80 years 4–80 years
70 years
Sex In adults, female Slight male preponderance Slight male preponderance Male preponderance
preponderance

Associated diseases
Autoimmunity Common Rare None None
Immunodeficiency Common (especially HIV+ve Rare None Occasional
children)
Amyloidosis Rare Rare None None

Imaging
Chest radiograph Ground-glass or Consolidation (single or Variably sized nodules Multiple bilateral nodules (may be
reticulonodular multifocal) (occasionally multiple) cavitating)
shadowing. Occasionally Air bronchograms
normal
HRCT Spectrum of randomly Consolidation (single or Not known Cavitating nodules, sometimes
distributed nodules multifocal) with ground with peripheral ground-glass
(1–4 mm) through to glass at periphery of attenuation
ground-glass opacification lesions. Air
with the latter sometimes bronchograms
accompanied by
thin-walled cystic air
spaces

Histopathology
Architecture Heavy diffuse interstitial Consolidated mass Single or multiple nodules Multiple nodules, usually with
infiltrate with little (alveolar + interstitial) focal necrosis
architectural destruction May be multifocal, or Infiltrate usually angiocentric
rarely diffuse
Cell type Mainly T lymphocytes with Mainly B lymphocytes Mainly T lymphocytes with Mainly T lymphocytes with some
lesser numbers of plasma (lymphocyte-like, some plasma cells and plasma cells and histiocytes, and
cells and histiocytes plasmacytoid and/or histiocytes a variable population of atypical
monocytoid) B cells
Germinal centres Yes Yes Yes Occasional (secondary reactive
phenomenon)
Dutcher bodies No Yes No No
Monoclonality No Yes No Yes

HIV, human immunodeficiency virus; HRCT, high-resolution computed tomography.

Differential diagnosis lymphoma are negative.111 Sclerosing mediastinal B-cell lymphoma

may invade the lung but the anatomical position of the main mass
There are few difficulties in identifying the confluent sheets of blast
and the younger age of these mediastinal tumours enable them to be
cells of a high-grade lymphoma, other than distinguishing the
distinguished from the pulmonary growths.
con­dition from other undifferentiated neoplasms, which may be
accomplished by applying stains for lymphocyte markers (CD45),
cytokeratins, alpha-fetoprotein, and epithelial membrane antigen. A
surgical lung biopsy may be required to identify the angiocentric
lesions of lymphomatoid granulomatosis but, although both are Treatment and prognosis
B-cell proliferations, B cells are comparatively scarce in lymphomatoid Extensive involvement of the lung usually precludes resection and
granulomatosis and they are usually positive for EBV, while those in most patients require combination chemotherapy. Five-year survival
immunocompetent patients with diffuse large B-cell non-Hodgkin figures range from 0 to 60%.3,4,15

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 Tumours Chapter | 12 |

Figure 12.4.11  (A) Marginal-zone lymphoma of mucosa-associated

lymphoid tissue (MALT) origin in which there are prominent reactive B
lymphoid follicles. (B) The follicles are particularly well demonstrated with
the CD21 marker of follicular dendritic cells (immunoperoxidase stain for Figure 12.4.13  Lymphoepithelial lesions in a marginal-zone lymphoma of
CD21). mucosa-associated lymphoid tissue (MALT) origin. These lesions may be
difficult to recognise in haematoxylin and eosin stains (A) but are readily
apparent in sections immunostained for cytokeratin (B).

Figure 12.4.14  Giant lamellar bodies in a marginal-zone lymphoma of

mucosa-associated lymphoid tissue (MALT) origin. A low-grade lymphoma
Figure 12.4.12  Tuberculoid granulomas in a marginal-zone lymphoma of of MALT origin contains abundant giant lamellar bodies within the
mucosa-associated lymphoid tissue (MALT) origin. alveolar spaces.

663
 Pathology of the Lungs

Figure 12.4.16  Diffuse large B-cell lymphoma. (A) The tumour is very
cellular and shows focal necrosis. (B) At high power, the neoplastic B cells
show considerable cellular pleomorphism and mitotic activity.
B

Figure 12.4.15  Marginal-zone lymphoma of mucosa-associated lymphoid dominant T-cell phenotype, rearrangement of the T-cell receptor genes
tissue (MALT) origin. (A) The cells within the interstitium are could be identified in only a minority of cases116–120 and it was subse-
predominantly CD20-positive, (B) with variable numbers of admixed quently shown that the scanty atypical cells were of B-cell phenotype,
CD3-positive T lymphocytes. (Compare with lymphoid interstitial often with rearrangement of the immunoglobulin heavy-chain
pneumonia in Fig. 12.4.3D).
gene.121–124 EBV was localised to the atypical B cells81,120–123,125–127 and
lymphomatoid granulomatosis is now regarded as representing a
T-cell-rich, EBV-driven, angiocentric B-cell proliferation, distinct from
polymorphic reticulosis.121
LYMPHOMATOID GRANULOMATOSIS Note has to be taken however of occasional cases that are histologi-
cally identical to lymphomatoid granulomatosis yet consist entirely
of T cells. These are generally not associated with EBV and may
Aetiology and nomenclature re­present peripheral T-cell lymphomas.122 Other lymphomas may also
Lymphomatoid granulomatosis is a rare disease characterised by show an angiocentric pattern resembling that seen in lymphomatoid
a necrotising, angiocentric, polymorphous and usually atypical granulomatosis.7 Thus, what appears to be a distinct morphological
lymphoid infiltrate that typically forms tumour-like masses in the entity may be mimicked by various lymphoproliferative diseases
lungs, brain, skin and other tissues. It was first described by Liebow showing angiocentricity and secondarily involving the lung, the
in 1972, the rather ambiguous term chosen reflecting initial uncer- identification of which will probably become important as
tainty concerning the nature of the condition.112–114 treatment evolves.22
Early attempts to characterise the lymphoid cells established that Conversely, what were initially described as separate conditions are
the majority were T cells and the condition was therefore included, now widely regarded as different grades of lymphomatoid granulo-
together with polymorphic reticulosis (lethal midline granuloma of matosis. Thus, based on the degree of atypia and necrosis, benign
the nose), in a spectrum of so-called postthymic T-cell prolifera- lymphocytic angiitis and granulomatosis128–130 is now considered to
tions.115,116 However, although further studies substantiated the pre- be the lowest grade of lymphomatoid granulomatosis while the

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 Tumours Chapter | 12 |

highest grade conforms to what has been termed angiocentric

lymphoma.101,116,131

Clinical features
Patients with lymphomatoid granulomatosis cover a wide age range
but most are middle-aged with the median age at diagnosis being in
the sixth decade: men are affected twice as frequently as women.132–135
Most patients present with pyrexia, weight loss and general malaise
in addition to chest symptoms such as cough, chest pain and dys­
pnoea. About a quarter have neurological symptoms at presentation
and half develop an erythematous, macular rash or subcutaneous
nodules some time during their illness.136 An appreciable degree of
lymphadenopathy is unusual. CD4 lymphocyte counts may be low.133
Chest radiographs and HRCT scans typically reveal bilateral, multiple,
rounded masses, located in the middle and lower zones.137 These vary
in size and may coalesce or cavitate; they are frequently mistaken for
metastases. Unilateral lesions or a diffuse infiltrative process are less
often seen. Hilar node enlargement is not a feature in the early stages
of the disease, although lymph node involvement is present in
22% of cases at autopsy114and can be more readily recognised as
malignant than the lesions in the lungs.
Lymphomatoid granulomatosis may also present in other organs.
Neurological symptoms may result either from similar involvement
of small vessels in the central nervous system or peripheral nerves or
from the formation of tumour-like masses in the brain. In the kidney
there may be a diffuse interstitial infiltrate or distinct tumours138 but,
in contrast to Wegener’s granulomatosis, there is no glomerulo­
nephritis. Other affected sites include skin, liver, spleen, adrenals,
heart, pancreas, gastrointestinal tract and pancreas.114 Extra­
Figure 12.4.17  Lymphomatoid granulomatosis forming large fleshy
pulmonary lesions generally resemble those in the lungs but in
masses within the lung. (Courtesy of Dr P King, Johannesburg, South Africa.)
the skin it is unusual to find cells bearing the EBV genome. This
has led to suggestions that the skin lesions may be caused by cytokines
released by lesions elsewhere rather than direct involvement.139 present in significant numbers and sarcoid-like granulomas are not a
Extrapul­monary involvement is unusual in benign lymphocytic feature.
angiitis and granulomatosis. The degree of cellular atypia varies considerably, from lymphocytes
with irregular, folded nuclei in lymphomatoid granulomatosis to
larger blast-like cells with prominent nucleoli and condensed
Aetiology
marginal chromatin in angiocentric lymphoma. The lesions are graded
Apart from its close association with EBV, the aetiology of lymphoma- 1–3 on the degree of lymphocytic atypia, the presence of necrosis and
toid granulomatosis is obscure, although the patients sometimes have the polymorphic/monomorphic nature of the infiltrate, grade 3
obvious underlying defects in their cell-mediated immunity. These lesions being synonymous with angiocentric lymphomas.116 The B-cell
may be congenital, as in the Wiskott–Aldrich syndrome,140 or acquired, proliferation index correlates well with histological grade.148
as in AIDS,141 angiogenic myeloid metaplasia142 and the treatment of
other forms of lymphoma.143,144 There is also some similarity between Differential diagnosis
lymphomatoid granulomatosis and posttransplantation lympho­
proliferative disorders (see p. 521): both are essentially angio­centric In contrast to true vasculitis, in which the vessel wall is destroyed by
B-cell proliferations, both bear the EBV genome and both vary in their a necrotising inflammatory process, vascular involvement is character-
clonality, but they differ in the proportion of reactive T cells.145,146 It ised by separation of the components of the wall by the infiltrating
appears likely that impaired immunity underlies the development of cells. This is usually best seen in the intima, which becomes greatly
both these diseases. thickened as the infiltrate lifts the endothelium and obliterates the
lumen. Similar cells infiltrate the alveolar and bronchiolar walls,
giving rise to additional non-specific reactive changes, such as
Pathological features organising intra-alveolar fibrinous exudates, proliferation of alveolar
Macroscopically, the lungs contain nodules of pinkish-grey tissue, the epithelial cells and bronchiolitis obliterans. However, the cardinal
largest of which show central necrosis and cavitation (Fig. 12.4.17). feature that distinguishes lymphomatoid granulomatosis from other
Alternatively, areas of confluent consolidation may be seen. The pleura granulomatous vasculitides is the presence of the atypical B
is frequently thickened but effusions are unusual. lymphocytes. These are poorly represented in the lower grades. Gene
Microscopically, most cases show broad tracts of necrosis separated rearrangement studies may be of value in doubtful cases.123 Distinction
by a mixed angiocentric infiltrate that includes usually scanty from diffuse large B-cell non-Hodgkin lymphomas is discussed above.
pleomorphic atypical lymphoid cells (Fig. 12.4.18). While most of the IgG4-related systemic sclerosing disease (see p. 485) is a further condi-
lymphocytes stain for T-cell markers,147 the atypical lymphoid tion that may be confused with lymphomatoid granulomatosis. It is
cells stain as B cells, analogous to the findings in T-cell-rich B-cell characterised by a sclerosing vasculitis and a heavy infiltrate of
lymphomas. The B cells may also be positive for CD30 but are IgG4-bearing plasma cells, the recognition of which is key to the
negative for CD15. Eosinophils and giant cells are not usually diagnosis.

665
 Pathology of the Lungs

predominance.152–157 Most patients complain of breathlessness and

cough and about half also have systemic symptoms such as weight
loss and fever. Chest radiographs may show multiple nodules or soli-
tary tumours with cavitation in some of the larger lesions. Following
treatment, relapse occurs in the majority of cases, either in the lungs
or elsewhere. Solitary tumours are less frequently associated with
systemic symptoms and have a better prognosis than bilateral
growths.155

Pathological features
The microscopic appearances are typical of Hodgkin disease, usually
of either nodular sclerosing or mixed cellularity type. Bronchi are
frequently involved, with resultant obstructive changes distally, but
presentation as an endobronchial lesion is rare.158 Larger lesions
A usually undergo extensive central necrosis. Away from the nodules, a
lymphatic or vascular distribution of spread is discernible, the pleura
may be infiltrated and atypical cells may be found in air spaces.154 As
in other organs, the lesions of Hodgkin disease may be accompanied
by sarcoid-like epithelioid and giant cell granulomas.159

Differential diagnosis
The differential diagnosis of pulmonary Hodgkin disease includes
necrotising granulomatous inflammation, particularly Wegener’s
granulomatosis, sarcoidosis and infection, Langerhans cell histio­
cytosis, undifferentiated carcinoma and other forms of malignant
lymphoma. Wegener’s granulomatosis can be excluded if clearly atypi-
cal lymphoid cells are present. Large numbers of eosinophils may
cause Langerhans cell histiocytosis to be considered, but the extensive
necrosis is not a feature of this disorder and the Langerhans cells lack
the malignant characteristics of mononuclear Hodgkin cells and
Reed–Sternberg cells. Undifferentiated carcinomas occasionally
B
appear extremely pleomorphic, sometimes with the multilobed nuclei
and large nucleoli of Reed–Sternberg cells. Neutrophils are frequently
Figure 12.4.18  Lymphomatoid granulomatosis. (A) The wall of a small
present in undifferentiated carcinomas but eosinophils are seldom a
pulmonary blood vessel is heavily infiltrated. (B) Atypical lymphoid cells
infiltrate the intima of a pulmonary artery but do not destroy the vessel feature. In debatable cases, immunostaining for keratin intermediate
wall. Immunostaining shows that, although many T cells are present, the filaments and leukocyte common antigen can be decisive.
atypical cells are B cells. Exclusion of other forms of malignant lymphoma may be impos-
sible when only standard histological preparations are available:
immunocytochemistry, which has often been lacking in reported
cases, may be required. Some forms of T-cell lymphoma may simulate
Treatment and prognosis Hodgkin disease by showing extreme degrees of cellular pleo­
morphism and a background of reactive inflammatory cells.
Survival varies from a few months to many years, according to grade,
but is generally short.114,122,123 High-dose corticosteroids, cyclophos-
phamide and combination chemotherapy have been used, and good
responses to interferon-alpha 2b,127 bone marrow transplantation
and, in line with the B-cell nature of the lesion, response to anti-CD20
PLASMACYTOMA
(rituxiab) have been achieved.149,150
Extramedullary plasmacytomas are rare tumours. The majority occur
in the upper respiratory tract and only 6% arise in the bronchi or
lungs.160–165 Some earlier cases may have represented inflammatory
HODGKIN DISEASE myofibroblastic tumours,166,167 whilst others were probably marginal-
zone lymphomas of MALT origin showing predominantly plasma­
Primary pulmonary Hodgkin disease is very uncommon, much cytoid differentiation.
rarer than secondary involvement.151 The diagnosis is only justified if Only about 7% of patients with multiple myeloma have intra­
hilar lymph nodes are uninvolved and disease elsewhere has been thoracic disease168 and this is rarely confined to the lung. However,
excluded. pulmonary plasmacytoma occasionally precedes or accompanies
other manifestations of disseminated disease.169,170 The presence of
a paraprotein is not necessarily indicative of multifocal disease: re­­
Clinical features, treatment and prognosis
section of a solitary intrapulmonary plasmacytoma may be followed
Reported cases cover a wide age range (18–82 years, mean 43 years) by disappearance of a circulating paraprotein,171 or of urinary Bence
and, as with nodal Hodgkin disease, the age incidence is bimodal, Jones protein.172 However, as in myelomatosis, the gammopathy
with peaks at 21–30 and 60–80 years of age.152 There is a slight female may lead to renal failure.165

666
 Tumours Chapter | 12 |

Pathological features
Microscopically, plasmacytomas consist of sheets of plasma cells:
many may appear normal but others have multiple nuclei and some
show nuclear pleomorphism. The spindle-shaped and inflammatory
cells seen in inflammatory myofibroblastic tumours are lacking.
Immunohistochemical investigation confirms the diagnosis by dem-
onstrating light-chain restriction. Occasionally, amyloid is found in
the stroma,160 or there is material that resembles amyloid but fails to
stain as such and consists of monotypic immunoglobulin.163,173
Sometimes the plasma cells are overshadowed by numerous macro-
phages distended by large amounts of ingested immunoglobulin
(crystal-storing histiocytosis), which renders the cytoplasm eosino­
philic and can be shown to be monoclonal (see Fig. 12.7.5,
p. 700).174,175 Monoclonality needs to be verified as similar appear-
ances can be produced by reactive conditions that result in excessive
immunoglobulin production.176

Prognosis A
The overall 2- and 5-year survival rates of pulmonary plasmacytomas
are 66% and 40%, respectively.177

LARGE CELL ANAPLASTIC LYMPHOMA

Large cell anaplastic lymphoma characteristically involves the lymph

nodes or skin, but rare cases are limited to the lungs.178–181 The tumour
is considered to be a T-cell lymphoma, although many cases fail to
express the typical T-cell phenotype, being CD3- and CD45-negative.
However, on molecular analysis most show clonal rearrangement of
the T-cell receptor genes. The large, pleomorphic tumour cells are also
CD15-negative and sometimes epithelial membrane antigen-positive.
CD30 expression is a characteristic feature and many cases also stain
for large cell lymphoma kinase (ALK). A t(2:5)(p23:35) translocation
involving the ALK gene may be demonstrated. EBV is not detected.
Negative reactions for cytokeratins distinguish large cell anaplastic
lymphoma from primary or secondary carcinoma, conditions for
which it is most easily mistaken. Patient ages range from childhood
to the seventh decade with the sexes affected equally. Radiographic B
features include nodules, masses, air space consolidation, pleural
effusion, cavitations and cystic change. Response to treatment is Figure 12.4.19  Intravascular lymphoma. (A) Atypical lymphoid cells are
variable. evident within the small blood vessels of the lung. (B) With CD 20
staining the tumour is categorised as an intravascular large B-cell
lymphoma. (Courtesy of Dr AC Wotherspoon, London, UK.)
INTRAVASCULAR LYMPHOMA
(ANGIOTROPIC LYMPHOMA)
process may present as interstitial lung disease185,189 or even obstruc-
Intravascular (or angiotropic) lymphoma is to be distinguished from tive airway disease with air trapping.190 Affected patients are usually
the angiocentric lymphoma described above. It was originally consid- in the fifth to seventh decades of life. Chest radiographs may be
ered to represent a form of malignant ‘angioendotheliomatosis’ but normal or show non-specific infiltrates. Laboratory findings are also
is now recognised to be a lymphoma of unusual distribution, the often unhelpful. Despite the presence of numerous malignant cells
malignant cells being almost exclusively confined to the lumen of within small blood vessels, only rarely are they identified in blood
capillaries and small arteries and veins throughout the body.182,183 films. Most cases are diagnosed postmortem but the disease is rela-
The lung is generally involved at a late stage of the disease but rare tively sensitive to combination chemotherapy if treated early.187
cases are reported in which the process is apparently confined to the
lungs.184–187 Pathological features
Microscopic examination shows a proliferation of neoplastic round
Clinical features or spindle-shaped cells confined to capillaries and small arteries and
Intravascular lymphoma usually presents with fever and features veins throughout the body. Affected vessels may show intimal fibrosis.
referable to the skin or central nervous system.182 However, involve- The neoplastic cells have large, vesicular, indented nuclei, eosinophilic
ment of the pulmonary vasculature is sometimes so extensive that nucleoli and moderate amounts of cytoplasm. They are usually B cells
pulmonary hypertension is the presenting feature.188 Alternatively, the and stain for the appropriate lymphoid markers (Fig. 12.4.19) but

667
 Pathology of the Lungs

occasional cases have been reported to have a T-cell phenotype.

Monoclonality may be demonstrated with immunohistochemical Box 12.4.2  Causes of breathlessness in leukaemia
stains for κ and λ chains and by gene rearrangement studies.186,191 Leukaemic infiltration
The neoplastic cells lack CD29 (beta1-integrin), a molecule integral
Infection
to lymphocyte trafficking, which presumably underlies the peculiar
Cytotoxic drug damage
intravascular localisation of this neoplasm.192 Gene mutations on
Irradiation injury
chromosome 1 and trisomy 18 have also been reported.193
Graft-versus-host disease
Alveolar haemorrhage
Differential diagnosis
The differential diagnosis of angiotropic lymphoma includes meta-
static carcinoma and melanoma, leukaemia and lymphoid interstitial
pneumonia. The first of these are distinguished by immunohisto-
chemical identification of lymphoma, epithelial cell and melanocyte Box 12.4.3  Pulmonary complications found at autopsy in
markers (CD45, cytokeratin, S-100 and HMB45). Leukaemia may be 71 adult bone marrow transplant recipients215
distinguished by reference to blood counts and bone marrow
examination and lymphoid interstitial pneumonia by the intra­ Infectious complications
vascular rather than interstitial location of the cells. Bacterial bronchopneumonia 13
Aspergillosis 11
Cytomegalovirus pneumonia 2
Candida infection 1
SECONDARY PULMONARY INVOLVEMENT
BY LYMPHOPROLIFERATIVE DISORDERS Non-infectious complications
Diffuse alveolar damage 35
Diffuse alveolar haemorrhage 10
Secondary involvement of the lung in patients with nodal lymphoma
Amyloidosis 9
is common and may be due to direct invasion from involved media­
Pulmonary embolism 5
stinal lymph nodes or metastasis via the blood stream or lymphat- Lymphoma/leukaemia 4
ics.151 At presentation only about 12% of patients with Hodgkin Bronchiolitis obliterans 2
disease and 4% of patients with non-Hodgkin lymphoma have radio- Organising pneumonia 2
graphic evidence of lung involvement194 but the figure is much higher Aspiration 1
in patients dying with disseminated disease.195 Whereas non-Hodgkin Alveolar proteinosis 1
lymphomas tend to involve the lungs in a diffuse fashion, following
the perivascular and pleural lymphatics, the pulmonary lesions of
Hodgkin disease are often nodular, and polypoid endobronchial
masses are occasionally seen.158,195
Less commonly, angioimmunoblastic lymphadenopathy may also plantation is preceded by whole-body irradiation and introduces the
involve the lungs, when the microscopic features are similar to those possibility of both radiation injury and graft-versus-host disease.
in the lymph nodes, showing a mixed infiltrate of plasma cells and Haemostasis may also be impaired and these patients are liable to
immunoblasts and hyperplasia of the capillary endothelium.196–198 suffer diffuse alveolar haemorrhage. There are therefore six possible
Multiple myelomatosis is another condition that may involve the lungs conditions to consider when such patients complain of breathlessness
and be associated there with the deposition of material similar to that (Box 12.4.2). In one autopsy study of adult patients treated by bone
better known in the renal tubules.199 Lymphocytic infiltrates of the marrow transplantation, pulmonary complications were the com-
lung, pleura and hilar lymph nodes are also described in Waldenstrom’s monest cause of death: the detailed findings are listed in Box 12.4.3.215
macroglobulinaemia.200,201 Systemic mast cell disease has also presented as Another group reported that the important late-onset non-infectious
diffuse parenchymal lung disease.202 Cutaneous T-cell lymphoma pulmonary complications of haemopoietic stem cell transplantation
(mycosis fungoides or Sézary syndrome) involves the lungs in about were bronchiolitis obliterans, organising pneumonia and interstitial
two-thirds of cases at autopsy. The interstitial infiltrate of convoluted pneumonia and that, whereas the organising pneumonia responded
or cerebriform cells follows the bronchovascular bundles in a lym- to corticosteroids, fewer than 15% of the patients with interstitial
phatic distribution and may form nodular aggregates203 or simulate pneumonia survived 1 year while the bronchiolitis obliterans carried
pneumonia.204 A similar lymphatic distribution is described in malig- a 61% mortality.216
nant histiocytosis205–207 and leukaemia.208,209 The chest radiograph is generally non-specific and seldom of help
in distinguishing these conditions and even after full haematological
and microbiological investigations the diagnosis may remain
uncertain. However, bronchoalveolar lavage is generally of value in
PULMONARY PROBLEMS IN LEUKAEMIA dis­tinguishing leukaemic infiltration, opportunistic infections and
haemorrhage, the last of these being characterised by haemosiderin-
Respiratory distress often develops in advanced leukaemia and in laden macrophages as well as fresh blood. If bronchoalveolar lavage
these circumstances it can be difficult clinically to distinguish leuk­ is not diagnostic, the histopathological appearances of leukaemic
aemic infiltration of the lungs from opportunistic infection and from infiltration, infection and cytotoxic damage are sufficiently distinctive
the cytotoxic effects of antileukaemic chemotherapy.210 Furthermore, to make biopsy a worthwhile procedure,217–221 particularly as these
the chemotherapy may well have been augmented with bone marrow three categories of disease fit well with the therapeutic regimens
transplantation.210–213 Posttransplantation lymphoproliferative disease available to the clinician, namely, further antileukaemic drugs, anti­
is rare with bone marrow transplantation and, although usually microbials and corticosteroids respectively. It matters little to patient
extranodal, seldom affects the lungs.214 However, bone marrow trans- management that the pathological changes induced by radiotherapy

668
 Tumours Chapter | 12 |

and antileukaemic drugs are virtually identical, or that they are extrathoracic sites. Some patients have multicentric disease. Two his-
difficult to distinguish from some of the features of graft-versus-host tological patterns are described, hyaline-vascular and plasma cell. The
disease. hyaline-vascular pattern is much the commoner. It is seen more often
Leukaemic infiltration of the lungs initially involves the bronchi- in the localised form of the disease and generally forms a mass lesion
oloalveolar bundles, interlobular septa and pleura, wherein run the that is either asymptomatic or causes pressure effects. The plasma cell
lymphatics, but it later spills out into the air spaces. Micronodular pattern is more often seen in multicentric disease. This is a systemic
aggregates of leukaemic cells may form, as in secondary involvement disease that is characterised by fever, sweating, fatigue, anaemia,
of the lung by lymphoma,209 and rarely myeloid leukaemia may lymph­adenopathy, hepatosplenomegaly, skin rashes, an elevated
present as a granulocytic sarcoma of the lungs.222–224 In some cases of erythrocyte sedimentation rate, polyclonal hypergammaglobulinae-
myeloid leukaemia coming to autopsy with very high white blood cell mia and bone marrow plasmacytosis. Pulmonary involvement results
counts, diffuse accumulations of leukaemic cells are found filling in diffuse reticulonodular infiltrates involving the bronchovascular
minor blood vessels, especially those of the lungs, a process known bundles and interlobular septa, often accompanied by thin-walled
as leukostasis.225 Lysis of these many leukaemic cells may develop cysts and occasionally by subpleural nodules or bronchiectasis.258,261
within 48 hours of the initiation of chemotherapy, releasing toxic In contrast to the solitary form of the disease, which is quite benign
metabolites that may ultimately lead to diffuse alveolar damage.226 and usually cured by surgery, the multicentric variety has an aggressive
Chronic lymphocytic leukemia may also occasionally extend into the course with a mean survival of 5 years: some patients with multicen-
lung parenchyma in a bronchiolocentric fashion, mimicking bronchi- tric disease develop lymphoma.262–265 Others are AIDS patients who
olitis.227 High-grade transformation (Richter syndrome) causing bron- are also suffering from Kaposi’s sarcoma and in these patients
chial obstruction due to massive peribronchial lymphadenopathy and DNA sequences of the Kaposi sarcoma virus (human herpesvirus-8)
bronchial infiltration is also described.228 have been identified within the Castleman’s disease, raising the
The spectrum of opportunistic infection is wide but, as well as possibility of this virus playing a causative role in both diseases.266
the common bacterial pneumonias, invasive aspergillosis, cyto­ The same virus is incriminated in body cavity-based lymphoma (see
megalovirus infection and Pneumocystis pneumonia are particularly p. 734), which is also recorded in association with multicentric
common.220,229–231 Herpes, parainfluenza and respiratory syncytial Castleman’s disease.267
virus pneumonias are also recorded.231–234 Infection is a likely cause
of the bronchiolitis obliterans organising pneumonia that has been
reported in bone marrow recipients.235–237 Pathological features
The pathology in the cytotoxic group consists of interstitial pneu- In the hyaline-vascular variant, which is the type most likely to be seen
monitis, diffuse alveolar damage and vascular disease.38,217–220 It carries in the lungs, there are prominent lymphoid follicles of abnormal
a high mortality.238 Biopsy shows lymphocytic infiltration and fibrosis pattern. The germinal centres are reduced in size and contain increased
of the alveolar walls, oedema, fibrinous exudates, haemorrhage and numbers of follicular dendritic cells and reduced numbers of follicular
hyaline membranes. Regenerating alveolar epithelium may show centre cells. The reduced germinal centres are surrounded by an
atypia, regardless of whether cytomegalovirus is present.239 Small expanded layer of mantle cells arranged in concentric layers, resulting
blood vessels show organising thrombus and intimal thickening, in an onion-skin appearance. Blood vessels enter the germinal centres
sometimes resulting in pulmonary veno-occlusive disease.240,241 It is while between the follicles there are increased numbers of high-
probable that such changes reflect the toxicity of antileukaemic drugs endothelial venules and clusters of plasmacytoid monocytes
or whole-body irradiation rather than graft-versus-host disease for (Fig. 12.4.20).
they occur in the absence of the better-known extrapulmonary mani- The plasma cell variant is characterised by a dense interstitial infil-
festations of this condition and occur with syngeneic as well as allo- trate of plasma cells and lymphocytes (Fig. 12.4.21).258 It overlaps
geneic grafts.242,243 However, some patients develop obstructive airway
disease a year or more after the marrow transplant, and this may be
a manifestation of graft-versus-host disease211,244–249 mediated by
tumour necrosis factor.250 Biopsy shows lymphocytic bronchiolitis
and bronchitis with bronchiolitis obliterans of constrictive
pattern.237,244,246,248,251 Lymphoid interstitial pneumonia is also recorded
and it is suggested that this is also a manifestation of graft-versus-host
disease.38,252
Late manifestations of bone marrow transplantation include the
development of solid tumours but the risk of lung cancer does not
appear to be increased.253 However, impaired lung function of un­­
certain nature can be detected in many long-term survivors who are
free of respiratory symptoms.254

ANGIOFOLLICULAR LYMPH NODE

HYPERPLASIA (GIANT LYMPH NODE
HYPERPLASIA, CASTLEMAN’S DISEASE)

Clinical features and prognosis

Angiofollicular lymph node hyperplasia typically affects mediastinal Figure 12.4.20  Hyaline vascular variant of Castleman’s disease. Germinal
lymph nodes but the condition has also been reported in the trachea,255 centres within the bronchial mucosa-associated lymphoid tissue (MALT)
the lung,256–258 the pleura259 and the chest wall,260 in addition to many contain prominent hyalinised capillaries.

669
 Pathology of the Lungs

A B

Figure 12.4.21  Plasma cell variant of Castleman’s disease. (A) Lymphoid cells infiltrate the parenchymal interstitium and an interlobular septum. (B)
The infiltrate is markedly plasma cell-rich and proved to be polyclonal in nature.

histologically with both lymphoid interstitial pneumonia and ants of lymphoma. Such nodularity argues against lymphoid inter­
marginal-zone lymphoma of MALT origin. Ancillary investigations are stitial pneumonia, which does not usually have aggregations of
required to exclude the latter, along the line of those undertaken for plasma cells. Ultimately the diagnosis may be easier to make on any
nodular lymphoid hyperplasia, as the lesions may form solid masses lymph nodes that may be involved.
that are rich in plasma cells and therefore mimic plasmacytoid vari-

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12.5  Miscellaneous tumours

CHAPTER CONTENTS Pathological features

Tracheobronchial melanomas are generally polypoid but occasional
Melanoma 677
‘flat’ examples are reported.3 Microscopically, they are identical to
Germ cell tumours 677 those that occur elsewhere, being predominantly pigmented, probably
References 678 because amelanotic melanomas in the lung are likely to be interpreted
as anaplastic carcinomas (Fig. 12.5.1). If there is no pigmentation, or
Six tumours were listed as miscellaneous in the 2004 World Health if pigmented carcinoid tumour is suspected, the presence of S-100
Organization/International Association for the Study of Lung Cancer protein and HMB-45 antigen, the absence of cytokeratin expression
Histological Classification of Lung Tumours, of which we have dealt and neuroendocrine markers, and the identification of melanosomes
with two (sclerosing ‘haemangioma’ and thymoma) in Chapter 12.2 by electron microscopy are helpful diagnostic features.
(Other epithelial tumours) and two (‘hamartoma’ and benign clear
cell tumour) in Chapter 12.3 (Soft-tissue tumours), as we believe this
reflects their histogenesis more accurately. This leaves only melanoma Differential diagnosis
and germ cell tumours to be considered in this chapter. Strict criteria must be applied before a diagnosis of primary malignant
melanoma of the lower respiratory tract can be accepted.8 Very few
reported cases withstand close scrutiny. There should be no evidence
of a current or previous primary melanoma elsewhere and any previ-
MELANOMA ously resected lesions of the skin, adjacent mucosal surfaces or the eye
should be reviewed. The phenomenon of spontaneous regression of
Whereas melanoma commonly metastasises to the lungs, primary an extrapulmonary melanoma after metastasis has occurred bedevils
bronchopulmonary melanoma is extremely rare. Embryologically, the exclusion of a bronchial melanoma having such an origin.
melanocytes derive from the neural crest. They are not a normal Junctional change in bronchial epithelium is regarded as the best
feature of the lower respiratory tract and descriptions of a blue naevus1 histological evidence of a primary bronchial origin, particularly if it
and primary melanomas of the bronchi are therefore surprising, is well away from the tumour because neoplastic melanocytes may
particularly one arising in an albino patient.2–13 Whether these directly infiltrate the overlying epithelium and mimic junctional acti­
tumours can be presumed to arise from ectopic melanocytes is not vity. True junctional change has been well described in only a few
entirely clear since melanin production is documented in bronchop- melanomas of the lower respiratory tract.2,3,6,9 In a review of 18
ulmonary carcinoid tumours,14–18 which are thought to be of endo- previously published cases, only two were considered to be proven,
dermal rather than neural crest origin. Melanin pigmentation has also eight were thought to be near proven, four probable and four
been recorded in a bronchial schwannoma,19 a pulmonary blastoma20 improbable.6
and ‘pecomas’ such as the benign clear cell tumour of the lung (see
p. 625).21

Clinical features, treatment and prognosis GERM CELL TUMOURS

Age at presentation ranges from 29 to 80 years (median 51 years) and
there is no sex predilection.7,11 The tumours nearly always involve large Primary germ cell tumours of the lung are extremely rare22–40a and the
bronchi or the trachea and the patients complain of persistent cough possibility of metastasis should always be excluded. Germ cell tumours
and haemoptysis or symptoms attributable to obstructive pneumonia. of the anterior mediastinum arise in the thymus and the presence of
Treatment is surgical but the prognosis is poor.10 thymic tissue in several reported cases of intrapulmonary teratoma

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Pancreatic enzymes released from a teratoma may erode adjacent

tissue and this has been a frequent cause of haemoptysis.40a Surgical
treatment is the treatment of choice. Prognosis depends on
tumour type.

Pathological features and differential diagnosis

Pulmonary teratomas tend to be large and cystic, and may be partly
or entirely endobronchial, resulting in bronchiectasis.34 The cysts are
often in continuity with the bronchi. About two-thirds are benign and
consist solely of mature tissues such as skin (with its usual append-
ages, including hair), bronchus, pancreas (which is also a frequent
feature of mediastinal teratomas), cartilage and neural tissue.
Malignant primary teratomas of the lung show the usual variety of
differentiated and anaplastic tissues.
Some of the reported malignant germ cell tumours have been
choriocarcinomas associated with elevated levels of serum human
chorionic gonadotrophin,29–31,37,40 and a few of these have arisen in
infants22 or men.25,31,39 They have displayed the usual mixture of
cytotrophoblastic and syncytiotrophoblastic elements.
Figure 12.5.1  Melanoma. A primary endobronchial lesion shows Other pulmonary germ cell tumours have contained yolk sac ele-
malignant polygonal cells, within which only a little melanin pigment can ments and secreted α-fetoprotein.32,36 Mixed yolk sac and blastema-
be seen. (Courtesy of Dr TV Colby, Scottsdale, USA.) tous differentiation is also described.33,35 The immunohistochemical
demonstration of β-human chorionic gonadotrophin and α-
fetoprotein is of little value as these trophoblastic markers may be
seen in carcinoma of the lung.42 It is notable that some of the few
suggests that these may have originated in heterotopic thymic primary choriocarcinomas of the lung reported in men have been
tissue.24,26 combined with carcinoma of more conventional pattern,39 suggesting
that they represent carcinomas showing unusual differentiation rather
than primary germ cell tumours.
Clinical features, treatment and prognosis The differential diagnosis also includes metastatic teratoma, either
Pulmonary germ cell tumours show a wide age range (3 months to by direct spread from a mediastinal tumour (see Fig.12.6.14, p. 687)
68 years) and a slight female preponderance.26 They are also more or blood-borne. In the latter context, it is important to remember that
prevalent in the upper lobes and on the left side.34,38 The presenting chemotherapy may ablate all the malignant elements of the tumour
symptoms are usually not specific, apart from the expectoration of so that the pulmonary metastases may only contain totally mature
hair, a dramatic but rare manifestation of a cystic pulmonary tera­ elements and appear quite benign (see Fig.12.6.13, p. 687).43,44
toma.28,41 Choriocarcinomas are often haemorrhagic and one that Pleuropulmonary blastoma, pulmonary blastoma and carcinosar-
arose in the lungs caused diffuse pulmonary haemorrhage.40 coma do not form the organoid structures seen in a teratoma.

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19. Rowlands D, Edwards C, Collins F. 29. Tanimura A, Natsuyama H, Kawano M, 38. Asano S, Hoshikawa Y, Yamane Y, et al. An
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bronchus. J Clin Pathol 1987;40:1449–55. Hum Pathol 1985;16:1281–4. bronchiectasia containing various kinds of
20. Cohen RE, Weaver MG, Montenegro HD, 30. Pushchak MJ, Farhi DC. Primary primordium: a case report and review of the
et al. Pulmonary blastoma with malignant choriocarcinoma of the lung. Arch Pathol literature. Virchows Archiv 2000.
melanoma component. Arch Pathol Lab Lab Med 1987;111:477–9. APR;436(4):384–388 2000;436:384–8.
Med 1990;114:1076–8. 31. Sullivan LG. Primary choriocarcinoma of 39. Chen FS, Tatsumi A, Numoto S. Combined
21. Gaffey MJ, Mills SE, Zarbo RJ, et al. Clear the lung in a man. Arch Pathol Lab Med choriocarcinoma and adenocarcinoma of
cell tumor of the lung – 1989;113:82–3. the lung occurring in a man – Case report
immunohistochemical and ultrastructural 32. Hunter S, Hewan-Lowe K, Costa MJ. and review of the literature. Chest
evidence of melanogenesis. Am J Surg Primary pulmonary alpha-fetoprotein- 2001;91:123–9.
Pathol 1991;15:644–53. producing malignant germ cell tumor. Hum 40. Shintaku M, Hwang MH, Amitani R.
Pathol 1990;21:1074–6. Primary choriocarcinoma of the lung
Germ cell tumours 33. Siegel RJ, Bueso-Ramos C, Cohen C, et al. manifesting as diffuse alveolar hemorrhage.
22. Kay S, Reed WG. Chorioepithelioma of the Pulmonary blastoma with germ cell (yolk Arch Pathol Lab Med 2006;130:540–3.
lung in a female infant seven months old. sac) differentiation: report of two cases. 40a.  Macht M, Mitchell JD, Cool C, et al. A
Am J Pathol 1955;29:555–60. Mod Pathol 1992;4:566–70. 31-year-old woman with hemoptysis and an
23. Pound AW, Willis RA. A malignant teratoma 34. Morgan DE, Sanders C, McElvein RB, et al. intrathoracic mass. Chest 2010;138:213–19.
of the lung in an infant. J Pathol Intrapulmonary teratoma: a case report and 41. Ustun MO, Demircan A, Paksoy N, et al. A
1969;98:111–14. review of the literature. J Thorac Imaging case of intrapulmonary teratoma presenting
24. Day DW, Taylor SA. An intrapulmonary 1992;7:70–7. with hair expectoration. Thorac Cardiovasc
teratoma associated with thymic tissue. 35. Miller RR, Champagne K, Murray RCN. Surg 1996;44:271–3.
Thorax 1975;30:582–6. Primary pulmonary germ cell tumor with 42. Boucher LD, Yoneda K. The expression of
25. Hayakawa K, Takahashi M, Sasaki K, et al. blastomatous differentiation. Chest trophoblastic cell markers by lung
Primary choriocarcinoma of the lung. Acta 1994;106:1595–6. carcinomas. Hum Pathol 1995;26:1201–6.
Pathol Jpn 1977;27:123–35. 36. Kakkar N, Vasishta RK, Banerjee AK, et al. 43. Madden M, Goldstraw P, Corrin B. Effect of
26. Holt S, Deverall PB, Boddy JE. A teratoma Primary pulmonary malignant teratoma chemotherapy on the histological
of the lung containing thymic tissue. with yolk sac element associated with appearances of testicular teratoma
J Pathol 1978;126:85–9. hematologic neoplasia. Respiration metastatic to the lung: correlation with
27. Jamieson MPG, McGowan AR. 1996;63:52–4. patient survival. J Clin Pathol
Endobronchial teratoma. Thorax 37. Aparicio J, Oltra A, Martinez-Moragon E, 1984;37:1212–14.
1982;37:157–9. et al. Extragonadal nongestational 44. Cagini L, Nicholson AG, Horwich A, et al.
28. Filho JCC, Coehlo JCMR. Benign lung choriocarcinoma involving the lung: a Thoracic metastasectomy for germ cell
teratomas. Report of two cases. J. report of three cases. Respiration tumours: long term survival and prognostic
Pneumologia 1985;11:82–8. 1996;63:251–3. factors. Ann Oncol 1998;9:1185–91.

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 Chapter 12 

12.6  Secondary tumours of the lungs

oesophagus, chest wall, breast, thyroid or abdomen. No particular

CHAPTER CONTENTS
route is followed, other than penetration of the fused pleurae.
Routes of tumour spread to the lungs 680 Alternatively, there may be retrograde spread through pulmonary lym-
Direct extension 680 phatics once the lymphatic pathway is obstructed by tumour emboli
in the mediastinal lymph nodes. Further dissemination within pul-
Metastasis 680
monary lymphatics may be widespread and this is one route (but not
Patterns of tumour spread within the lungs 681 the commonest) by which secondary tumours produce the character-
Blood-borne metastases 681 istic appearances of so-called lymphangitis carcinomatosa (see below).
Lymphatic spread within the lung 682 Direct invasion of the lungs along veins is rare as this entails inva-
sion of pulmonary veins between the lungs and the left atrium and
Intra-alveolar spread 683
retrograde venous extension into the lungs. Direct extension along the
Interstitial spread 684 pulmonary arteries is also rare but is occasionally seen with sarcomas
Primary or metastatic tumour? 684 originating in the pulmonary trunk or the right side of the heart
Gross appearances 685 (see p. 638).
Histological appearances 685
Ultrastructural features 688 Metastasis
Cytochemistry 688 With their vast capillary network and unique position in the
Immunocytochemistry 688 circulation it is not surprising that the lungs are frequently the site of
Molecular techniques 690 metastatic tumours. The incidence of lung involvement in metastatic
Effects of secondary lung tumours and their clinical disease is second only to that of the liver; pulmonary metastases are
features 691 found at necropsy in 30–50% of patients dying of cancer.1 The com-
moner extrathoracic tumours may be ranked in the following descend-
Prolonged survival despite metastatic disease 691
ing order in regard to the frequency with which they metastasise to
References 691 the lungs: kidney, skin, breast, thyroid, pancreas, prostate, stomach,
uterus and colon (Box 12.6.1). Tumours of the lung itself and certain
rare tumours, notably choriocarcinoma and osteosarcoma, also com-
monly metastasise to the lungs. Some tumours with a high tendency
ROUTES OF TUMOUR SPREAD TO THE LUNGS to metastasise to the lungs are not themselves common. Therefore
they are not the first to be considered when trying to identify the
Extrapulmonary neoplasms may involve the lungs by direct extension origin of pulmonary metastases. Thus, an order of frequency different
or by metastasis. Direct extension may be through the pleura or along from the above applies when considering possible sites of origin
lymphatic or blood vessels. Metastasis is by way of the pulmonary or following the identification of pulmonary metastases (see Box 12.6.1).
bronchial arteries and possibly within the lungs via the airways (aerial If these organs are grouped regionally it is found that the genitouri-
metastasis). nary tract accounts for 28% of pulmonary metastases, the gastro­
intestinal tract for 28%, the breasts for 17% and sarcomas for 11%.2
In a patient with sarcoma or melanoma elsewhere, even a solitary
Direct extension
pulmonary lesion is most often a metastasis. Conversely, if the patient
Direct invasion of the lungs through the pleura complicates primary has a nodal lymphoma, a solitary parenchymal lesion in the lung is
or metastatic growths in the pleura, mediastinal lymph nodes, thymus, more likely to be an independent primary carcinoma.3

680
 Tumours Chapter | 12 |

Box 12.6.1  Primary tumour sites ranked in descending Box 12.6.2  Patterns of secondary tumour growth in the
order of frequency according to the propensity of their lungs
tumours to metastasise to the lungs (left) and the
likelihood of a pulmonary metastasis having originated Blood-borne metastases
in a particular site (right) Solitary nodule
Multiple nodules
1 Kidney 1 Breast Massive tumour embolism
2 Skin 2 Colon Microangiopathy
3 Breast 3 Pancreas
4 Thyroid 4 Stomach Diffuse lymphatic permeation (lymphangitis
5 Pancreas 5 Skin carcinomatosa)
6 Prostate 6 Kidney Endobronchial metastases
7 Stomach 7 Ovary
8 Uterus 8 Prostate Intra-alveolar spread
9 Colon 9 Uterus Diffuse air space
Lepidic growth
The difference between the two columns is largely accounted for by differences
in the frequency of cancer developing in these sites: thus tumours of the kidney Interstitial growth
frequently metastasise to the lungs but are not as common as tumours of the
breast, colon, pancreas, stomach or skin. Other factors include selective
attachment of tumour cells to endothelium based on particular cell surface
components

PATTERNS OF TUMOUR SPREAD

Metastases in the lung almost all arise from tumour emboli arrested WITHIN THE LUNGS
in small pulmonary arteries.4 Bronchial arterial dissemination is far
less common but may account for some endobronchial metastases. Secondary growth in the lung may take the form of discrete nodules,
Groups of tumour cells enter the circulation by invasion of small diffuse lymphatic permeation, diffuse consolidation, endobronchial
peripheral veins or through the thoracic duct, and generally come to growth or massive tumour embolism (Box 12.6.2).11–13 Metastases in
rest in pulmonary arteries between 400 and 800 µm in diameter.5 the pleura are usually multinodular but occasionally form a
Occasionally there is widespread occlusion of medium-sized continuous sheet and mimic the appearances of a mesothelioma.
pulmonary arteries by tumour or tumour-associated thrombus They are dealt with in Chapter 13 (see p. 736).
(see below).
Pulmonary arteries are less resistant to invasion by malignant
tumour than their counterparts in the systemic circulation.6
Nevertheless, although microscopic emboli are very common in the Blood-borne metastases
lungs, most fail to establish themselves. In many cases of abdominal
carcinoma, malignant cells in the lungs are only to be found in throm- Discrete tumour nodules
bus within the pulmonary arteries, and many of these intraluminal Metastases in the lung commonly take the form of discrete nodules
malignant cells are degenerate.1 Although viable cells within tumour or well-circumscribed masses, which are generally multiple and bilat-
emboli are in the minority, it is of course these which invade the walls eral (Fig. 12.6.1). They affect the lower lobes more often than the
of the pulmonary arteries to form secondary lung tumours, and then upper, and are commonest in the outer parts of the lungs, in accord-
promote further tumour dissemination via the pulmonary veins and ance with the distribution of blood within the lungs and with the sites
systemic arteries. It is very unusual to encounter widespread systemic of embolic lodgement.1,5,14,15 Metastatic deposits may be of any size,
metastases in the total absence of tumour deposits in the lungs. and whereas they are sometimes all the same size, in other cases
Systemic dissemination is dependent as much on pulmonary growths of many different sizes are seen. Although metastatic tumours
metastases invading pulmonary venules as single cancer cells travers- are generally multiple, solitary deposits forming ‘coin lesions’ may be
ing the lung capillaries. encountered.15a Pulmonary metastases generally have well-
Although the high incidence of lung involvement in metastatic circumscribed margins, in contrast to the ill-defined in­­filtrating edge
disease owes much to the special position of the lungs in the circ­ usually seen with primary malignant lung tumours. On its cut surface
ulation, other factors are also involved. Many cancers display charac- a metastasis is generally white and opaque but may show necrosis and
teristic organ colonisation patterns that do not conform to simple haemorrhage. Cavitation and calcification are occasionally seen.16
mechanical trapping. Organ preferences of metastatic spread appear Appearances indicative of the site of origin are considered below.
to be influenced by selective attachment of tumour cells to endo­
thelium, based on particular cell surface components.7 This appears
to be under genetic control. For example, in breast cancer certain genes
selectively facilitate the establishment of metastases in the lung
Massive tumour embolism
whereas others mediate skeletal metastasis.8 On the other hand hyper- Tumour emboli occluding the main pulmonary arteries are rare12 but
oxic injury to the pulmonary endothelium increases the number of tumours such as renal cell carcinomas and hepatocellular carcinomas
pulmonary metastases.9 An intriguing correlation between cigarette have a propensity to invade the systemic veins and may present with
smoking and a high risk of breast cancer metastasising to the lungs massive tumour embolism. This may also occur with tumours arising
has been noted.10 in the right side of the heart and pulmonary trunk (See p. 638).

681
 Pathology of the Lungs

Figure 12.6.2  Embolic choriocarcinoma occludes the pulmonary arteries.

Figure 12.6.1  Pulmonary metastases forming well-circumscribed masses.

Microscopic tumour angiopathy

Microscopic tumour emboli are found in up to 26% of cancer patients
coming to autopsy,12,17–19 typically occluding small muscular pulmo-
nary arteries and arterioles (Fig. 12.6.2). Symptoms are generally
similar to those seen with lymphangitic spread (see below)11 but rarely
the emboli may be sufficiently extensive to cause pulmonary hyper­
tension and right ventricular failure.20–23 This is alternatively termed
Figure 12.6.3  Carcinomatous microangiopathy. Tumour has filled the
carcinomatous thrombotic microarteriopathy or carcinomatous pul-
lumen of a small pulmonary artery in a man with occult gastric
monary endarteritis (Fig. 12.6.3).19 Carcinomas of the stomach and carcinoma who died of rapidly progressive pulmonary hypertension.
breast are the commonest tumours to have this effect but it may also
be seen with tumours of the liver and placenta. The emboli may
consist purely of tumour cells, a mixture of cells and fibrin, or show
severe fibrointimal hyperplasia with scanty tumour cells. The last of pale threads of tumour tissue filling these vessels (Fig. 12.6.4).26 A
these patterns is particularly characteristic of metastatic gastric adeno- network of occluded lymph channels is clearly visible on the visceral
carcinoma.13 It has been attributed to the expression of osteopontin pleural surface whilst on the cut surface the bronchoarterial bundles
(a multi­functional cytokine and adhesive protein), platelet-derived in the centres of the acini and the veins in the interlobular septa are
growth factor and vascular endothelial growth factor, by the cuffed by tumour spreading along their accompanying lymphatics.
tumour.24,24a Such arteriopathy is generally first diagnosed postmor- The bronchus is richly supplied with lymphatics and fibreoptic
tem but is sometimes detected by lung biopsy or from examining bronchial biopsy may detect lymphatic permeation even when
material obtained at pulmonary artery catheterisation.25 Survival in bronchoscopy is normal.27
such patients has seldom exceeded 12 weeks.19–23 Although lymphangitis carcinomatosa may be produced by direct
extension from tumour deposits in hilar lymph nodes, a more
common source of involvement is multiple minute tumour emboli
Lymphatic spread within the lung reaching the lungs via the pulmonary arteries and subsequently invad-
ing the lymphatics.1,5,28 The main evidence for this is the high inci-
‘Lymphangitis carcinomatosa’ dence of tumour emboli within small pulmonary arteries and the
The major route of spread within the lung of both metastatic and frequent absence of marked hilar lymph node enlargement in lym-
primary tumours is along lymphatics. When very marked this results phangitis carcinomatosa. There is also a high incidence of minute
in so-called lymphangitis carcinomatosa, a condition in which the blood-borne tumour emboli in organs other than the lung in this
entire lymphatic system of the lungs is brought into sharp relief by condition, notably in the bone marrow. In one case, previous thoraco­

682
 Tumours Chapter | 12 |

Figure 12.6.4  ‘Lymphangitis carcinomatosa’. (A) Tumour fills lymphatics throughout the lung, thickening the interlobular septa and periarterial sheaths.
(B) Pleural lymphatics permeated by tumour. (Courtesy of Dr GA Russell, Tunbridge Wells, UK.) (C) Microscopy shows tumour filling the periarterial
lymphatics.

plasty, which reduces pulmonary perfusion as well as ventilation,

appeared to have caused the lung on that side to be spared the wide-
spread lymphatic permeation present in the other.29 Tumours most
likely to give rise to lymphangitis carcinomatosa are those arising in
the stomach, pancreas, breast and colon, and in the lung itself.

Endobronchial metastases
In following lymphatics to the hilum of the lung, neoplastic cells may
occlude mucosal lymph channels and thereby develop into secondary
tumours in the main air passages, so simulating primary growths of
the bronchus. Sometimes these metastases protrude into the lumen
of the bronchus (Fig. 12.6.5).30,31 Such endobronchial metastases
are encountered with a wide variety of tumours but most commonly
originate from growths in the intestine, cervix uteri and breast.30
Primary tumours of the bronchus with a propensity to grow in
this way include carcinosarcomas, carcinoids and bronchial gland
tumours.

Intra-alveolar spread
Microscopical examination of the growing edge may show tumour
extending into the lumen of neighbouring alveoli, by which means it Figure 12.6.5  Metastatic osteosarcoma showing endobronchial growth.

683
 Pathology of the Lungs

Figure 12.6.8  Metastatic adenocarcinoma of the pancreas growing

along the alveolar walls and simulating adenocarcinoma-in-situ (formerly
in bronchioloalveolar cell carcinoma).
Figure 12.6.6  Metastatic carcinoma growing from one alveolus to the
next without disturbing the alveolar architecture.

Lepidic spread
A further route of tumour spread within the alveolar tissues of the
lung is one in which the tumour cells grow along the surface of
alveolar walls. The tumour replaces the alveolar epithelium, usually
in a layer no more than one cell thick. Neither the alveolar walls nor
the air spaces are obliterated; the tumour uses the alveolar walls as a
supporting scaffold (Fig. 12.6.8). This is termed a lepidic growth
pattern. It is the pattern of growth found with adenocarcinoma-in-situ
(formerly bronchioloalveolar cell carcinoma, see p. 536), but is one
that may be adopted by any adenocarcinoma, either primary or meta-
static.40,41 Pancreatic, gastric and colorectal growths are the common-
est metastatic tumours to grow in this way. Because it does not destroy
the lung tissue, this growth is likely to mimic an area of pneumonic
consolidation both radiographically and on macroscopical examina-
tion of the cut surface of the lung. There may be a single area of diffuse
involvement or multiple foci may develop in both lungs. A mucoid
appearance may be evident, depending on the secretory status of the
tumour. Considerable controversy attends the possibility of aerial
Figure 12.6.7  Poorly cohesive cells of metastatic carcinoma fill the metastases accounting for the frequent multifocal distribution of
alveolar spaces, mimicking desquamative interstitial pneumonia. primary lung tumours which evince this pattern of growth but in cases
of metastatic tumour vascular dissemination provides an adequate
explanation.
spreads from one air space to the next (Fig. 12.6.6). When this occurs
the alveolar septa are generally compressed. Only older parts eventu-
ally are obliterated. Elastin stains often demonstrate the skeletal Interstitial spread
remains of alveolar septa in what appears to be solid tumour tissue.
Another extralymphatic route of tumour spread in the alveolar tissues
Alternatively, non-cohesive tumour cells may fill many alveoli
of the lung is within the alveolar interstitium, which is correspond-
without affecting the alveolar walls, resulting in appearances that
ingly thickened (Fig. 12.6.9). The air spaces are eventually obliterated
simulate desquamative interstitial pneumonia (Fig. 12.6.7).32,33 This
by this encroachment. Total destruction of the alveolar architecture
is distinguished by careful attention to the cytological features of the
may take place in the older parts of the tumour as with intra-alveolar
free cells, aided by the immunocytochemical demonstration of cyto­
growth.
keratin, which is present in carcinoma and mesothelioma cells but
not in the macrophages of desquamative interstitial pneumonia.32
This pattern has been shown to be non-angiogenic, the tumour cells
depending on the pre-existent alveolar capillaries rather than inducing
neoangiogenesis.34 Some metastatic breast and renal carcinomas PRIMARY OR METASTATIC TUMOUR?
showing such non-angiogenic alveolar spread have apparently been
confined to the lungs, with obvious implications regarding prognosis The development of metastatic disease long after the primary growth
and treatment.35,36 Such non-angiogenic spread is also seen with some has been eradicated is well recognised42 but mention of previous
primary pulmonary tumours. It indicates a relatively favourable operations is often neglected when a new specimen is submitted to
prognosis whatever the tumour.34,37–39 the laboratory.

684
 Tumours Chapter | 12 |

Figure 12.6.10  Metastatic melanoma. The heavy pigmentation of this

tumour provides a strong clue to its nature.

often grossly haemorrhagic and smooth-muscle tumours may display

a recognisable fascicular pattern.42a,b

Histological appearances
Sometimes the microscopic pattern gives a clear indication of an
extrapulmonary derivation, but often the tumour is anaplastic or the
pattern of differentiation is one seen in both pulmonary and extrapul-
Figure 12.6.9  Metastatic mesothelioma growing within the alveolar monary primary growths. All the common carcinomas of the lung
walls. may be mimicked microscopically by metastases. Adenocarcinomas
are broadly similar whether they arise in lung, alimentary tract or the
female genital tract. Adenosquamous carcinomas of lung and uterus
are similar histologically while squamous cell carcinomas are identical
A multiplicity of growths in the lungs always suggests metastatic regardless of origin. Similarly, recognising the source of anaplastic
disease but solitary metastases are not uncommon and the question large cell carcinomas is a common histopathological problem wher-
whether a given tumour is primary or metastatic arises particularly in ever they are encountered, and even small cell carcinomas may arise
patients with a solitary lung nodule. Up to 9% of solitary lung nodules outside the lungs.42c However, there are some purely morphological
prove to be metastases. characteristics that may point to particular types of tumour arising in
Whether the lung is the site of single or multiple growths, the lungs themselves rather than in some other parts of the body and
recognition of the site of origin assumes particular clinical importance these will now be described.
where there is site-specific therapy. Testicular teratoma and carcinoma Squamous cell carcinoma of the bronchus arises in foci of dysplasia
of the breast, ovary, prostate and thyroid fall into this category. and develops through an in-situ phase. Such lesions are multifocal
Familiarity with the histological appearances of tumours is of limited and recognition of these premalignant changes in the surface epithe-
help in the hunt for the primary site for there can be no certainty in lium of neighbouring airways may help in deciding that a squamous
distinguishing, for example, one adenocarcinoma from another by cell carcinoma is primary rather than metastatic. Continuity between
this means. invasive and apparently in-situ carcinoma is less helpful because
metastases can erode a bronchus and replace the surface epithelium
to mimic pre-existent in situ carcinoma.
Adenocarcinoma presents particular difficulties in distinguishing
Gross appearances
primary from secondary growths.3,43 Scarring may suggest the possibil-
The gross appearances are seldom informative with regard to the tissue ity of a primary scar cancer but it is notoriously difficult to prove that
of origin but obvious mucin secretion, melanin production (Fig. such fibrosis antedates the tumour (see p. 534). Central fibrosis may
12.6.10) or bone or cartilage formation may be helpful on occasion. be a consequence of tissue destruction in either primary or metastatic
Similarly, the metastases of choriocarcinomas and angiosarcomas are pulmonary tumours, rather than the cause of the tumour, whilst

685
 Pathology of the Lungs

metastases sometimes develop in lung scars. However, premalignant

epithelial atypia suggests that a tumour is a primary scar cancer rather
than a metastasis.
Some metastases appear quite benign and are therefore likely to be
mistaken for primary growths. So-called benign metastasising
leiomyoma of the uterus is a notable example of this.44–49 Obviously,
a tumour that metastasises to the lung cannot be truly benign but in
this entity neither the primary growth nor its metastases shows any
microscopic evidence of malignancy whatsoever (Fig. 12.6.11).
Primary leiomyoma of the lung is rare and, before such a diagnosis is
contemplated, metastatic tumour must be excluded, particularly in a
middle-aged woman with multiple lung tumours. Some may evolve
from benign tumour emboli released at myomectomy, some from
intravenous leiomyomatosis of the myometrium50 and some may
represent metastases of a very well-differentiated leiomyosarcoma.
Very rarely, the patient is male, and the primary tumour then arises in A
sites such as the skin.51 The metastases may be discovered by chance
radiographically, appearing as multiple rounded opacities in an indi-
vidual with no respiratory complaints. They grow quite slowly in the
lungs, leading to gradually increasing breathlessness and eventually
fatal respiratory failure. The median survival is quoted as 94 months
after excision of the pulmonary metastases, compared with 22 months
with metastatic leiomyosarcoma.48 During pregnancy or after
oophorectomy or the menopause, growth is even slower or may stop
completely.52,53 Antioestrogen drugs may be beneficial; in this, and the
almost exclusively female predilection, the condition resembles
pulmonary lymphangioleiomyomatosis (see p. 293) but the latter is
characterised radiographically by an interstitial infiltrate rather
than multiple discrete opacities.
Other tumours that have metastasised despite entirely benign
histological appearances include thymoma,54 giant cell tumours of
bone,55 dermatofibroma,56 adenomyoepithelioma of the breast57 and
meningioma.58 B
Secondary changes within metastases may also confuse the unwary
pathologist. For example, metastases in the lung often engulf pre-
existent structures and the survival of entrapped air spaces in a meta-
static sarcoma must not be mistaken for the epithelial component of
a primary mixed tumour such as pulmonary blastoma or carcinosar-
coma.51,59 Obstruction of engulfed air spaces may lead to marked cystic
change,60–65 occasionally resulting in pneumothorax, haemopneumo­
thorax or pneumomediastinum.66 This change appears to be particu-
larly common in the condition of ‘benign metastasising leiomyoma’
described above (see Fig. 12.6.11) and metastatic endometrial stromal
sarcoma.65 It may also have led to some low-grade metastatic sarcomas
being described as primary pulmonary tumours under terms such as
multiple cystic fibrohistiocytic tumour or mesenchymal cystic hamar-
toma62,63,67: most cases classified as such have been shown to represent
metastatic cellular fibrous histiocytomas (Fig. 12.6.12). They show a
male predominance and long-term survival despite extensive disease.68
A further trap for the pathologist arises from the surgeon withhold-
ing information that the patient has had a testicular teratoma treated
by chemotherapy. Subsequent metastases are thought to be worth
excising and the pathologist can give useful prognostic information,
or, if ignorant of the clinical circumstances, make a totally wrong C
diagnosis. For example, complete chemotherapeutic ablation may
result in totally necrotic tissue encompassed by granulation tissue, the Figure 12.6.11  ‘Benign metastasising leiomyoma’ of the uterus.
whole resembling a granuloma. Alternatively, fibrous scars may be the (A, B) This was one of many pulmonary nodules in a woman with uterine
only remnants of successfully treated metastases. In other cases fibroids. No cytological evidence of malignancy was apparent in any of
metastases consist only of well-differentiated tissues with limited the uterine or pulmonary tumours. (C) The pulmonary metastases of
growth potential. All these findings indicate that chemotherapy has these tumours may be cystic.
been successful, whereas viable malignant tumour indicates that it
has failed.69,70
On occasion, chemotherapy results in metastatic teratoma being
reduced to such well-differentiated cartilage that the residual tumour

686
 Tumours Chapter | 12 |

Figure 12.6.13  Pulmonary metastasis of testicular teratoma excised after

chemotherapy. Histologically, the tumour appears entirely benign,
indicating that the chemotherapy has been successful and that the
prognosis is favourable. In this example, the predominant component of
the tumour is cartilage and it is easy to see how the lesion could be
erroneously diagnosed as a chondroid hamartoma if the necessary clinical
information was lacking.

Figure 12.6.14  Secondary teratoma. This differentiated teratoma

infiltrated the lung directly from the mediastinum.

C
closely mimics a ‘hamartoma’ (Fig. 12.6.13).69,71 At other times suc-
Figure 12.6.12  Metastatic cellular fibrous histiocytoma. (A) Multiple cessful chemotherapy causes cystic change and, if there is also chemo­
thin-walled cystic masses are present within the lung in a case originally resistant cartilage, a bronchogenic cyst may be simulated.72 In these
diagnosed as mesenchymal cystic hamartoma.67 It was later found that circumstances immunocytochemical study of the epithelial elements
the patient had a cellular fibrous histiocytoma resected over a decade along the lines described below is helpful because, whereas a teratoma
earlier. (B, C) The walls of the cysts consist of a cytologically bland
may express both intestinal and respiratory markers, the former are
fibrohistiocytic proliferation and the diagnosis was revised to metastatic
cellular fibrous histiocytoma. not found in these primary lesions.
Teratomas spreading directly from the mediastinum need also to be
considered (Fig. 12.6.14), as does direct spread from a thymoma into
the lung (Fig. 12.6.15).
Other secondary tumours that may mimic primary lung growths
include low-grade endometrial stromal sarcoma60,65,73,74 and clear cell
odontogenic carcinoma.75

687
 Pathology of the Lungs

Figure 12.6.16  A positive immunoperoxidase reaction for surfactant

apoprotein enables this pleural deposit of adenocarcinoma to be
recognised as having originated in the lung.

Figure 12.6.15  Secondary thymoma. Tumour has infiltrated the lung

directly from the thymus.
profile and secondly upon their molecular weights. Thus 1–8 repre-
sent basic cytokeratins of progressively increasing molecular weight
while 9–20 are similarly ranked among the acidic cytokeratins.
Ultrastructural features Some particular problems that lend themselves to immunocyto-
chemical elucidation will now be considered.
Electron microscopy might be thought to reveal cytological features
indicative of a particular cell type or tissue but, apart from the Birbeck
granules of Langerhans cells and the Weibel–Palade bodies of endo­ Pulmonary versus extrapulmonary adenocarcinoma
thelial cells, there are few such marker organelles. However, in trying Primary adenocarcinoma may be recognised by the immuno­
to identify the origin of an adenocarcinoma the identification of Clara cytochemical demonstration of thyroid transcription factor-1 (TTF-1),
cell granules or lamellar (surfactant) bodies is indicative of a primary napsin A, surfactant apoprotein or Clara cell antigens (Fig. 12.6.16).84–
origin in the lung: conversely, terminal webs are diagnostic of intesti- 93b
Conversely, these markers enable the lungs to be recognised as the
nal carcinomas.76 Glycocalyceal bodies and microvillous core rootlets origin of tumours in other organs (Fig. 12.6.17).94 TTF-1 is the more
are characteristic of adenocarcinomas of the gastrointestinal tract but sensitive lung marker and its antibody is the method of choice for
are also found on occasion in primary lung carcinomas.77–79 establishing origin in the lung, although being both a lung and
thyroid marker, it may need to be supplemented by thyroglobulin and
Cytochemistry surfactant apoprotein on occasion.86,91 It is applicable to frozen as well
as paraffin sections.95 Attention should be confined to the nuclei as
Cytochemical characterisation of mucin has been utilised to distin- cytoplasmic TTF-1 immunoreactivity is occasionally encountered as a
guish primary and secondary mucus-secreting adenocarcinomas80,81 non-specific feature in various neoplasms.96 TTF-1 is relatively specific
but the specificity is low. However, a diastase-controlled periodic acid– for lung and thyroid.89,90,92,97–103 It is positive in the nuclei of up to
Schiff stain identifying both mucin and glycogen can be useful in 76% of primary adenocarcinomas of the lung (but seldom in muci-
distinguishing primary and secondary clear cell carcinomas. Clear cell nous varieties) and 40% of large cell carcinomas.92,93b
carcinoma of the kidney contains glycogen but no mucin whereas Immunocytochemical markers specific for other organs occasion-
some pulmonary clear cell carcinomas are mucin-rich. If a clear cell ally help in identifying an extrapulmonary origin, e.g. thyroglobulin,
tumour evinces no features of malignancy such as excessive mitotic prostate-specific antigen, hepatocyte paraffin-1, renal cell carcinoma
activity and necrosis, the possibility of benign clear cell tumour of the marker and kidney-specific cadherin,104,105 while a mammary origin is
lung (see p. 625) arises: like a renal metastasis, this stains for glycogen likely if a lung tumour expresses oestrogen receptors and cystic disease
rather than mucin. In this case any available reserve tissue should be fluid protein-15.93b,106–109 Similarly, the immunocytochemical demon­
utilised for a fat stain, with a positive reaction favouring a renal origin. stration of CDX-2 strongly favours an adenocarcinoma as having
There are also vascular differences between these tumours, the originated in the large bowel110,111 (except in the case of primary
metastases of a renal carcinoma lacking the thin-walled wide colloid carcinoma of the lung, which also expresses CDX-2).112 A
sinu­soids that characterise the benign clear cell tumour of lung panel of immunocytochemical markers that proved useful in
(see Table 12.3.1, p. 626). Immunocytochemistry is also helpful. distinguishing adenocarcinomas of various origin is shown in
Table 12.6.1.82 Other proposed discriminants are of less value. For
example, villin is expressed in a substantial proportion of pulmonary
Immunocytochemistry
as well as gastrointestinal adenocarcinomas,113,114 while the Wilms
Immunocytochemistry is very helpful in distinguishing primary and tumour suppressor gene WT-1 is expressed in pulmonary adeno­
metastatic tumours in the lung, particularly carcinomas and especially carcinomas as well as renal, ovarian and mesothelial neoplasms.115
adenocarcinomas.82,83 Identification of the various cytokerains is A useful website for assessing the specificities and sensitivities
important in this and it is worth noting how these are classified. Their of antibodies in relation to primary sites is available at http://
enumeration is not random but is based firstly upon their acid–base e-immunohistochemistry.info.

688
 ered on page 722. The expression of cytokeratin 7 and 20 applied in
combination is shown in Box 12.6.3.

Pulmonary versus extrapulmonary clear cell tumours

In distinguishing primary and secondary clear cell tumours, immuno-
histochemistry augments the mucin, fat and glycogen stains referred
to above. Renal cell carcinoma reacts for the broad-spectrum cyto­
keratins detected by Cam 5.2 but is distinguished from primary clear
cell carcinoma of the lung by failing to stain for TTF-1 or cytokeratin-7,
and from the benign cell tumour of the lung by failing to stain for
HMB45 (see Table 12.3.1, p. 626). Renal cell carcinoma antigen and
kidney-specific cadherin may also be helpful.104,105,121

Pulmonary versus extrapulmonary

neuroendocrine neoplasms
Small cell carcinomas have been described in many organs other than
the lungs and may of course metastasise to the lungs. TTF-1 and the
A neuroendocrine markers CD56, chromogranin and synaptophysin
are of limited value as they are expressed by small cell carcinomas
wherever they arise.
However, the distinction between primary and metastatic small cell
carcinomas is of limited importance if it is assumed that the patient
has extensive disease and is to be treated systemically irrespective of
where the tumour arose. Similarly with large cell neuroendocrine
carcinomas: if staging identifies deposits in extrapulmonary organs
as well as the lungs the patient will be referred for appropriate
chemotherapy irrespective of the site of origin.
With the less malignant carcinoid tumours, CD56 and TTF-1 are
again of debatable utility, the former being universally expressed and
the latter variably so, positivity being reported in 0–69% of cases,
with more peripheral than central carcinoids being positive.122–124
Cytokeratin-20 and CDX2 are of more value as these markers are
frequently positive in gastrointestinal carcinoids and islet cell tumours
but not in bronchopulmonary carcinoids.122 Metastatic islet cell
tumours also react for neurosecretory protein-55.125 Medullary
carcinoma of the thyroid may be distinguished from carcinoids
by its expression of calcitonin104 and the identification of stromal
amyloid in some cases.
B Paraganglioma is distinctly rare in the lung (see p. 638) and when
a patient appears to have a primary paraganglioma of the lung cyto­
Figure 12.6.17  (A) Non-small cell carcinoma in a hilar node in a patient keratin positivity usually indicates that it is a carcinoid or subsequent
with a pulmonary mass and a history of previous breast carcinoma.  
events suggest that it has metastasised from sites such as the glomus
(B) The tumour cells seen in (A) stain for thyroid transcription factor-1,
indicating metastasis from the lung.
jugulare. When considering the possibility of carcinoid tumour or any
neuroendocrine tumour of cribriform pattern, metastatic adeno­
carcinoma of the prostate needs to be kept in mind and prostate-
specific markers sought.126
Individual cytokeratins can be helpful in narrowing the list of
potential primary sites in a TTF-1-negative adenocarcinoma, particu-
Pulmonary versus extrapulmonary
larly if a combination of cytokeratins 7 and 20 is used.116,117 Thus,
while adenocarcinomas arising in the lung, endometrium, thyroid squamous cell carcinoma
and breast are generally cytokeratin 7-positive and cytokeratin While the high specificity and relatively good sensitivity of TTF-1 make
20-negative, the converse is seen with colonic carcinomas. However, it a valuable antibody in distinguishing primary and metastatic
mucinous adenocarcinoma of lepidoic pattern (formerly bronchiolo­ adenocarcinomas, it is of limited value with squamous cell carcino-
alveolar carcinoma) differs from other adenocarcinomas of the mas because these tumours generally fail to stain for this epitope,
lung in that it is generally cytokeratin 20-positive. It is also TTF-1 irrespective of site of origin. However, cytokeratin-5/6 is a sensitive
negative and may therefore be confused with metastatic bowel cancer and specific marker for primary pulmonary growths of this phenotype
growing in this fashion but it lacks the CDX-2 reactivity found with (Table 12.6.2).127 Also, there is a high chance that a squamous cell
bowel cancer.118 Pulmonary adenocarcinomas showing enteric differ- carcinoma positive for cytokeratin-7 has originated in the uterine
entiation may fail to stain for TTF-1 and surfactant apoprotein but cervix because most other squamous cell carcinomas (but not
usually retain cytokeratin-7 expression; they also fail to stain for the several tumours of other phenotype) fail to express this epitope.116
enteric marker CDX-2.119,120 The combination of cytokeratins 7 and 20 Similarly, p16 is almost always strongly expressed in squamous cell
does not distinguish pulmonary adenocarcinoma from pleural carcinomas of the cervix but less frequently in such growths arising in
mesothelioma of epithelioid pattern, techniques for which are consid­ the lungs.128

689
 Pathology of the Lungs

Table 12.6.1  A panel of immunostains that correctly predicted the site of origin of 75% of 314 test samples of metastatic
adenocarcinoma of known primary site82

TTF-1 CDX2 CK7 CK20 CEA MUC2 MUC5AC ER GCDFP15

Lung (n = 50) + − + − − − − −
Colorectal (n = 50) − + − +
or − + − − + +
Ovary (n = 14) − − + − + −
Breast (n = 50) − − + − +
or − − − − − +
Pancreas (n = 50) − − + + +
Bile duct (n = 50) − − + + +
Stomach (n = 50) − + + −

TTF-1, thyroid transcription factor-1; CK, cytokeratin; CEA, carcinoembryonic antigen; MUC, mucin; ER, oestrogen receptor; GCDFP, gross cystic disease fluid protein.

Box 12.6.3  CK7/CK20 combinations Table 12.6.2  Expression of cytokeratins (CK) 5, 6 and 7 in
squamous cell carcinomas
CK7+/CK20−
Adenocarcinoma of lung Primary site CK 5/6 CK 7
Small cell carcinoma of lung
Lung Positive Negative
Squamous cell carcinoma of cervix
Adenocarcinoma of endometrium Cervix uteri Negative Positive
Non-mucinous carcinoma of ovary Other Negative Negative
Epithelioid mesothelioma
CK7−/CK20+
Adenocarcinoma of large bowel
CK7−/CK20− Table 12.6.3  Antibodies for undifferentiated malignancies
Squamous cell carcinoma of lung
Adenocarcinoma of prostate EMA HMB-45 LCA PLAP
Thymoma
Carcinoma + − − −
Renal carcinoma
Hepatocellular carcinoma Melanoma − + − −

CK7+/CK20+ Lymphoma − − + −
Mucinous carcinoma of ovary Germ cell neoplasm − − − +
Transitional cell carcinoma
EMA, epithelial membrane antigen; HMB-45, human melanin black-45; LCA,
Adenocarcinoma of pancreas
leukocyte common antigen (CD45); PLAP, placental-like alkaline phosphatase.

Undifferentiated malignancy of uncertain origin differentiated tissues of benign appearance and that if cartilage is
the predominant element a diagnosis of bronchogenic cyst or
Undifferentiated large cell carcinoma is a common pattern of primary
‘hamartoma’ may be considered in the differential diagnosis.
lung tumour that may be mimicked by certain undifferentiated non-
Attention to the epithelial elements can be helpful here for whereas
epithelial malignancies metastasising to the lung. Important examples
a teratoma may include respiratory epithelium (complete with cilia
include melanoma, lymphoma and germ cell tumours. Key screening
and expressing respiratory markers such as TTF-1) there may also
antibodies that distinguish these undifferentiated growths are shown
be gastrointestinal epithelium expressing markers such as CDX2
in Table 12.6.3. Others include the germ cell-specific transcription
foreign to the lung.
factors OCT3/4, NANOG and SOX2.129

Metastatic teratoma simulating primary Molecular techniques

chondroid lesions In the future, immunocytochemistry will be augmented by molecular
It has been mentioned above that successful chemotherapy may result techniques: organ-specific gene profiles that enable adenocarcinomas
in the metastases of a teratoma being composed wholly of well- of the lung, colon and ovary to be distinguished have already been

690
 Tumours Chapter | 12 |

identified130 and the recognition of cytogenetic aberrations has transfer, but is only occasionally severe enough to cause respiratory
enabled a endometrial synovial sarcoma metatasising to the lung to failure.135 Widespread pulmonary artery occlusion may cause pulmo-
be correctly categorised.131 Similarly, molecular techniques have been nary hypertension (see patterns of spread above)5,136–141 while repeated
used to distinguish specific human papillomavirus genotypes in episodes of tumour embolism may result in recurrent infarction.142
patients with squamous cell carcinoma in both the lung and other Massive tumour embolism has proved fatal143,144 or necessitated
organs in which these tumours originate, identical genotypes favour- emergency embolectomy.145 Even successful chemotherapy is not
ing pulmonary metastasis and dissimilar genotypes favouring inde- without its complications; an arteriovenous fistula has been reported
pendent tumours.132 One group found that this allowed almost certain in an ablated pulmonary metastasis.146
discrimination in 57% of cases.133 Others have successfully distin-
guished pulmonary from head and neck squamous cell carcinomas
by applying molecular techniques to routine specimens.133a
PROLONGED SURVIVAL DESPITE
METASTATIC DISEASE
EFFECTS OF SECONDARY LUNG TUMOURS
AND THEIR CLINICAL FEATURES The prognosis in patients with secondary lung tumours is of course
very poor but instances of prolonged survival147 and even spontaneous
The capillary bed of the lungs is an effective filter of tumour emboli regression are well known. Spontaneous regression of metastatic
and secondary tumours in the lungs are therefore the usual immediate tumours is commonest with renal carcinomas148,149: it sometimes
source of metastases in other organs, except of course those that reach follows resection of the primary tumour,150 whilst in other cases
the liver via the portal circulation. Pulmonary metastases, like primary hormonal influences are possibly responsible.53,148
tumours in the lung, may also result in non-neoplastic systemic Although chemotherapy and radiotherapy are the mainstays of
disturbances, such as hypertrophic pulmonary osteoarthropathy and treatment of metastatic disease there is increasing interest in the resec-
blood eosinophilia.134 tion of solitary and even multiple pulmonary metastases.70,151–154 An
Local effects on the lung are inevitable if there is extensive International Registry for Lung Metastases has shown an actuarial
replacement of lung tissue, but it is remarkable how few symptoms survival after complete metastasectomy of 36% at 5 years, 26% at 10
pul­monary metastases generally cause. The commonest effects are years, and 22% at 15 years.155 Favourable prognostic indicators are
compression of the lung and mediastinal shift by an effusion caused solitary metastases, prolonged interval between primary tumour and
by pleural rather than pulmonary metastases, and terminal broncho­ metastasis, completeness of resection and certain tumour types such
pneumonia. The latter is largely attributable to general debility but as metastatic teratoma, breast carcinoma and melanoma.70,156–158
pneumonia and abscess formation may also follow airway obstruction Incomplete resection does not usually offer any survival advantage but
by secondary lung tumours. Haemoptysis is seldom severe except with the ‘debulking’ of certain tumours, for example metastatic thyroid
metastatic choriocarcinoma or angiosarcoma. Massive pulmonary tumours resistant to chemotherapy, helps control symptoms and may
metastases result in a significant reduction in lung volume, whilst also prolong survival.159 Opinions currently differ on the value of
lymphangitis carcinomatosa renders the lung stiff and impairs gas metastatectomy for metastatic bowel cancer.160,161

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100. Comperat E, Zhang F, Perrotin C, et al. 113. Tan JY, Sidhu G, Greco MA, et al. Villin, pancreatic endocrine tumors and
Variable sensitivity and specificity of TTF-1 cytokeratin 7, and cytokeratin 20 pheochromocytomas from gastrointestinal
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2007;60:941–3. of rootlets: An electron microscopic and 127. Jerome Marson V, Mazieres J, Groussard O,
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Pathol 2004;35:697–710. 118. Goldstein NS, Thomas M. Mucinous and Pathol 2007;31:836–45.
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A persistent pulmonary lesion following

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12.7  Tumour-like conditions

CHAPTER CONTENTS
REGENERATIVE CONDITIONS
Regenerative conditions mimicking neoplasia 696 MIMICKING NEOPLASIA
Amyloid tumour 696
Light-chain deposition disease 698 Throughout the lower respiratory tract regenerative processes may be
Crystal-storing histiocytosis 698 so atypical that carcinomatous transformation has to be considered
in the differential diagnosis. This impression is often augmented by
Bronchial inflammatory polyp 699
excessive mitotic activity and metaplasia. Thus, at the alveolar level
Hyalinising granuloma 699 necrotising lesions such as infarcts and the granulomatoses may be
Multiple minute meningothelioid nodules 700 bordered by foci of atypical squamous hyperplasia that are easily
Multifocal micronodular type II pneumocyte mistaken for squamous cell carcinoma. Similarly, damage to the
hyperplasia 701 bronchial epithelium is often followed by atypical regeneration that
Bullous placentoid lesion (placental is easily mistaken for carcinoma, particularly when exfoliated cells are
transmogrification) 703 being examined. Bronchoscopy inevitably involves bronchial injury
and cytopathologists have to be aware of the atypicalities that follow
References 703
this procedure. Necrotising lesions of the larynx are sometimes
accompanied by atypical regeneration that involves both the surface
epithelium and the submucosal glands: the term ‘necrotising
sialometaplasia’ has been applied to this and to a similar process
involving the trachea in patients with herpetic tracheitis undergoing
This chapter deals with certain tumour-like lesions of the lower respi- repeated intubation (see p. 97).
ratory tract, these being non-neoplastic processes that present as
masses or nodules within the lung and thereby simulate true neo-
plasms. However, several such lesions are considered in other chap-
ters, for example endometriosis under systemic disorders and localised AMYLOID TUMOUR
areas of organising pneumonia, Langerhans cell histiocytosis and
lymphangioleiomyomatosis under diffuse parenchymal diseases. Amyloidosis of the lower respiratory tract may develop as part of
Similarly, inflammatory pseudotumour is dealt with in the chapter on generalised amyloidosis or in isolation (Table 12.7.1).1–5 Pulmonary
soft-tissue neoplasms (Chapter 12.3) under the title inflammatory involvement in generalised amyloidosis is dealt with on page 489 and
myofibroblastic tumour, following recognition that at least some of this section deals only with amyloidosis confined to the lower respira-
these lesions are neoplastic rather than reactive. Tumourlets are not tory tract. The disease is usually confined to either the lung paren-
considered to be neoplastic but are nevertheless considered with the chyma or the major airways but occasionally affects both.6 It generally
related carcinoid tumours, as in the context of diffuse neuroendocrine takes the form of tumour-like nodules. In the airways the tumours
cell hyperplasia they are probably preneoplastic (see p. 598). The term may be solitary or multifocal, whereas parenchymal tumours are
‘pseudolymphoma’ has simply become obsolete. usually solitary. Rarely, however, there may be extensive pulmonary

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Table 12.7.1  Bronchopulmonary amyloidosis

Form Type Clinical features

Diffuse parenchymal (as part AL Cardiorespiratory failure

of systemic amyloidosis) Poor prognosis
Nodular parenchymal AL Often asymptomatic
(limited to the lungs)
Tracheobronchial (limited to AL Dyspnoea, wheeze
the major airways) Requires repeated resection

involvement with extension to the hilar lymph nodes and involve-

ment of adjacent structures,7,8 including the pleura.9–11
Other forms of amyloid confined to the lower respiratory tract
include rare examples of amyloid in the stroma of tumours –
apudamyloid in the case of neuroendocrine tumours12–14 and immu-
noamyloid in the case of lymphomas.15–21 Amyloid has also been
described in the lymphoid interstitial pneumonia associated with
Sjögren’s syndrome22,23 and in similar pulmonary infiltrates associated
with macroglobulinaemia.24 The corpora amylacea described on page
320 also consist of amyloid.

Clinical features
The age range of patients with amyloid tumours is wide but most are
middle-aged. There is no sex predilection and the lesions are not
related to smoking. Tracheobronchial and parenchymal forms of
amyloid are distinguished because they differ markedly in their
symptomatology, but pathologically amyloid tumours of the main
airways are identical to those situated in the periphery of the lung.
The former obstruct major airways and cause coughing, breathless-
ness, wheezing and even stridor, whereas the latter often form an
asymptomatic mass that is discovered by chance radiographically,
and is then suspected of being malignant. Occasionally there is promi-
Figure 12.7.1  Localised pulmonary amyloid consisting of a mass of
nent cystic change.21 eosinophilic amorphous material.

Pathology
Amyloid tumours consist of crumbling eosinophilic amorphous
material that exhibits the characteristic dichroism and birefringence
of amyloid when stained with Congo red. The amyloid is often partly
calcified or even ossified and is surrounded by foreign body giant cells,
lymphocytes and plasma cells (Figs 12.7.1–12.7.3).2,8 The plasma cells
are polyclonal and the amyloid is of the immune or AL type, as it is
when the lungs are involved in generalised amyloidosis (see Table
12.7.1).25 This may be confirmed by the congophilia being resistant
to prior potassium permanganate treatment,2,26 immunohisto­
chemistry27,28 or full chemical analysis.29 As there is no evidence of
generalised disease, it is likely that the immunoamyloid is formed
locally by the surrounding plasma cells rather than resulting from
circulating immunoglobulin light chains. Support for this is provided
by a case in which amyloid nodules were associated with polyclonal
light-chain deposits, both of which were confined to the lungs.30 The
polyclonality of the associated plasma cells favours the likelihood that
isolated pulmonary amyloid represents a local hyperimmune response
to an unknown antigen. However, others consider that the condition
represents a focal clonal immunocyte dyscrasia.5

Differential diagnosis
Figure 12.7.2  Pulmonary amyloid tumour showing a vigorous foreign-
The calcification and ossification that are often evident in amyloid body giant cell reaction to the amyloid and a lymphoplasmacytic
tumours (see Fig. 12.7.3) probably underlie erroneous suggestions infiltrate.

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 Pathology of the Lungs

disorder or in isolation, either diffusely or in nodular form, and both

frequently reflect an underlying lymphoplasmacytic dyscrasia or
neoplasia. Furthermore, they are virtually identical histologically.
However, LCDD deposits lack the β-pleated sheet configuration of
amyloid and therefore fail to stain with Congo red.

Clinical features
The patients reported to date have been adults of either sex, aged from
20 to 80 years.30,34,36–41 Most complained of exertional dyspnoea and
cough. Chest radiographs showed nodular, diffuse or cystic lung
disease, the latter being responsible for multiple pneumothoraces in
one patient.40,42

Pathological features
Grossly, pulmonary LCDD may form a solitary mass, multiple nodules
Figure 12.7.3  A pulmonary amyloid tumour showing prominent or gross cystic change affecting all parts of both lungs. Histologically
dystrophic calcification. Together with ossification this has led to the condition is characterised by an interstitial deposition of amor-
erroneous claims that tracheobronchopathia osteochondroplastica phous eosinophilic material, which in the case of nodular disease is
represents a form of tracheobronchial amyloidosis.
attended by a prominent foreign-body giant cell reaction. There may
also be a lymphoplasmacytic infiltrate but this is seldom prominent
that tracheobronchopathia osteochondroplastica develops from unless the LCDD complicates a plasmacytoma. The eosinophilic
multifocal tracheobronchial amyloidosis.31–33 Although their broncho­ material stains well with periodic acid–Schiff reagents but not with
scopic appearances may be similar the two conditions are in fact Congo red. Electron microscopy shows electron-dense deposits on the
quite different. Apart from the characteristic features of tracheobron- epithelial and endothelial basement membranes and the interstitial
chopathia, described on page 94, Congo red staining is generally elastin. In contrast to amyloid, the deposits are granular rather than
reliable in distinguishing the two. fibrillary. Immunofluorescent microscopy has generally shown κ-
Caseous tuberculosis may also be suspected, but the correct diag- chain restriction, or in a case in which there was coexistent amyloid
nosis can be made without Congo red and Ziehl–Neelsen stains from deposition, a mixture of κ and λ chains.30
the nature of the surrounding reaction. The foreign-body giant cells
engulfing the amyloid are a very characteristic feature whereas the Course of the disease
epithelioid and giant cell granulomas of tuberculosis are lacking.
A more difficult distinction is that from amyloid-producing lympho- Patients with solitary lung nodules have done well following
mas, particularly plasmacytomas.15–20 Features suggesting lymphoma excisional biopsy while those with multiple nodules or diffuse
include lymphatic tracking by the cellular infiltrate, sheet-like clusters disease have generally experienced slow progression. However, in
of plasma cells, reactive follicles and light-chain restriction.19 patients with cystic disease lung function deteriorated so rapidly as
Amyloid-like nodules associated with light-chain deposition consist to necessitate lung transplantation within as little as 2 years
of electron-dense granular material rather than the fibrils seen in (Fig. 12.7.4).40
amyloidosis and fail to stain with Congo red (see below).34
Pulmonary hyalinising granuloma may also mimic an amyloid
tumour but is composed of dense lamellar collagen rather than amor-
CRYSTAL-STORING HISTIOCYTOSIS
phous material and does not stain with Congo red.

This condition generally represents the storage of immunoglobulin

Treatment and prognosis light chain in crystalline form within histiocytes. This results from the
Tracheobronchial amyloid tumours are generally removed piecemeal, excessive production of immunoglobulin, usually within a plasma­
and incompletely, so that they require repeated surgery whereas cytoma but occasionally in relation to a marginal-zone lymphoma
re­currence of a resected parenchymal tumour, although recorded,35 as well as reactive conditions.43–48 The underlying tumour may be
is unusual. Laser therapy has also been used for extensive airway overshadowed by sheets of histiocytes, the cytoplasm of which is
involvement. Localised amyloidosis has a much better prognosis distended by refractile, eosinophilic crystalline inclusions (Fig.
than systemic amyloidosis and it is therefore important to exclude 12.7.5B). Electron microscopy shows that the cytoplasm contains a
involvement of other organs. It is also important to ensure that the multitude of rhomboid and needle-shaped crystals (Fig. 12.7.5C, D).
amyloid is of AL type as other types require different treatment and Immunostaining for CD68 and immunoglobulin confirms the nature
might also require relatives to be screened for inherited forms of the of both the cells and their inclusions. Crystal-storing histiocytosis due
disease.11 to the accumulation of Charcot-Leyden crystals is so far unique to the
colon despite eosinophilia affecting the lung more commonly.49
The differential diagnosis includes storage disorders such as
Gaucher’s and Niemann–Pick’s diseases (see p. 491), malakoplakia
LIGHT-CHAIN DEPOSITION DISEASE (see p. 216) and granular cell tumour (see p. 640). All these conditions
are characterised by cells swollen by eosinophilic cytoplasmic inclu-
Light-chain deposition disease (LCDD) and amyloidosis have much sions but in none are the inclusions so obviously crystalline, refractile
in common. Both diseases may affect the lung as part of a systemic or composed of immunoglobulin. Granular cell tumours also differ

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 Tumours Chapter | 12 |

matory polyposis complicating bronchiectasis is recorded in a patient

with cystic fibrosis.51 Inflammatory polyps have no malignant
potential and may resolve with antibiotic treatment.52 Alternatively,
they may be excised at bronchoscopy while chronic lung damage has
occasionally necessitated lobectomy.50

HYALINISING GRANULOMA

Hyalinising granuloma is a rare condition of unknown aetiology.

Most cases have been reported from the new world.53–58 There are few
reports from Europe59 or Asia.60,61

Clinical features
Most patients are middle-aged, with a mean between 40 and 45 years.
A
They are either asymptomatic or have mild breathlessness, cough,
chest pain, low-grade pyrexia and general malaise. The radiographic
appearances, those of single or multiple pulmonary nodules, are
usually interpreted as representing primary or secondary neoplasms.
The nodules tend to enlarge slowly and the disease has a benign
course.

Aetiology
The microscopical appearances of hyalinising granuloma have been
likened to those of sclerosing mediastinitis and a common aetiology
is suggested by the simultaneous occurrence of pulmonary hyalinising
granuloma and sclerosing mediastinitis or retroperitoneal fibrosis, or
sometimes all three conditions.53,56,59,60 Associated immunological
abnormalities include the presence of antinuclear antibodies,
rheumatoid factor, antimicrosomal and anti-smooth-muscle anti­
bodies, circulating immune complexes and Coombs-positive haem­
olytic anaemia.53–55 Other clinical associations include systemic
B idiopathic fibrosis,60 synchronous lymphoma,62,63 Castleman’s
disease64 and multiple sclerosis.65
An abnormal response to chronic infection, such as tuberculosis or
Figure 12.7.4  Light-chain deposition disease. Computed tomograms
taken 3 years apart showing progressive pulmonary cystic change. histoplasmosis, has been suggested as the cause of hyalinising
(Courtesy of Dr C Danel, Paris, France and reproduced by permission of the granuloma but, although skin tests may be positive, culture and stains
American Journal of Respiratory and Critical Care Medicine.40) for microbes are invariably negative.53,56 The apparent predilection
of this condition for North America is compatible with there being
an unusual infective agent but it may denote unwillingness to
make the diagnosis of an unfamiliar and debatable entity in other
in reacting for S-100 rather than CD68. The prognosis is that of the countries.
underlying condition.

Pathology
BRONCHIAL INFLAMMATORY POLYP The nodules may be single (about one-third of cases), or multiple and
bilateral, and vary from a few millimetres to 15 cm in diameter.53 They
Inflammatory polyps of the bronchus have a core of oedematous con- are well circumscribed and may be subpleural or lie deep within
nective tissue covered by respiratory epithelium (Fig. 12.7.6). They the lung parenchyma. Cavitation and calcification are unusual
are reactive and often show a heavy acute or chronic inflammatory features.53,56,57
infiltrate. In infancy they may be caused by trauma from suction at Microscopically, the centre generally consists of hyaline collagen
the time of delivery.50 The surface epithelium may be replaced by arranged in a distinctive pattern of concentric lamellae, sometimes
granulation tissue or show squamous metaplasia or goblet cell hyper- with focal calcification or ossification (Fig. 12.7.7).56 The periphery is
plasia but these changes are focal, unlike the squamous, glandular and more cellular, showing an infiltrate of lymphocytes, plasma cells,
mixed papillomas described on page 606. histiocytes, fibroblasts and occasional giant cells. Blood vessels may
Inflammatory polyps may cause collapse or hyperexpansion, the be infiltrated by the inflammatory cells or incorporated into the
latter more common in infancy. They are usually solitary but inflam- sclerotic area where they are encircled by the hyaline lamellae. The

699
 Pathology of the Lungs

A B

C D

Figure 12.7.5  Crystal-storing histiocytosis in primary plasmacytomas of the lung. (A, B) The tumour is largely replaced by sheets of histiocytes, the
cytoplasm of which is distended by eosinophilic crystalline inclusions. (C, D) In a similar case, electron microscopy shows that the cytoplasm contains a
multitude of rhomboid and needle-shaped crystals. Immunostaining for CD68 and immunoglobulin confirms that the cells are histiocytes and that their
inclusions represent immunoglobulin. (Courtesy of Dr D Owen, formerly of Winnipeg, Canada and Dr B Kazzaz, formerly of the The Hague, Netherlands43.)

original report included lesions that stained for amyloid53 but Treatment and prognosis
subsequent workers have excluded such cases56 and electron micros-
There is no specific treatment but symptomatic lesions may be
copy has not confirmed the presence of amyloid.55
resected. The prognosis is good and morbidity may be more
frequently encountered in relation to fibrosis at other sites.
Differential diagnosis
Hyalinising granuloma is to be distinguished from amyloidosis (see
above), necrobiotic (rheumatoid) nodules (see p. 473) and Wegener’s
granulomatosis (see p. 438). The necrosis seen in active examples MULTIPLE MINUTE
of the last two of these entities is lacking but their healed lesions MENINGOTHELIOID NODULES
can closely resemble hyalinising granuloma. Sclerosing lymphomas
may be excluded by immunohistochemistry. Infections such as tuber-
culosis and histoplasmosis need to be excluded as far as is possible Histogenesis and epidemiology
by culture and appropriate stains. Inflammatory myofibro­blastic Multiple microscopic lung tumours that resembled chemodectomas
tumour may have densely sclerotic foci, rendering its distinction dif- (paragangliomas) were first described in 196066 and were long known
ficult in small biopsies, but in resection specimens the myofibroblastic as minute pulmonary chemodectomas or chemodectomatosis.67
areas characteristic of this tumour are generally evident, while in However, electron microscopy fails to show the dense-core granules
hyalinising granuloma inflammation is confined to the periphery of of chemoreceptor cells but demonstrates complex interdigitating cell
the lesion. processes, prominent desmosomes and cytoplasmic tangles of fibrils.

700
 Tumours Chapter | 12 |

Figure 12.7.7  Pulmonary hyalinising granuloma. A mass of densely

fibrotic tissue with a peripheral rim of chronic inflammation. The fibrotic
tissue consists of thick interweaving collagen bundles.

unusual.74 An incidence of 1 in every 200–300 autopsies is reported,

but this can be increased to around 1 in 25 if a specific search is
made.66,68,75–77 They are more common in patients with thrombo­
embolic disease, other forms of chronic pulmonary disease in which
scarring occurs and cardiac failure.75,76,78 They also appear to be com-
moner in people who reside at high altitude.73 A tendency to
pulmonary oedema may be the linking factor. The age range is wide
but most patients are in their fifth or sixth decade.78 There is a female
preponderance of about 5 to 1, in connection with which it is notable
that the lesions bear a progesterone receptor.78,79

Pathology
Meningothelioid nodules measure up to 3 mm in diameter. They are
occasionally visible beneath the pleura or on the cut surface of the
lung but most are discovered only when randomly selected tissue is
B examined microscopically. They are situated in the pulmonary inter-
stitium close to the walls of veins, causing distension of adjacent
Figure 12.7.6  Inflammatory polyp. (A) A mixed polyp protrudes into a alveoli. They consist of aggregated small nests of closely packed cells
segmental bronchus. (B) The polyp is lined by respiratory epithelium and separated by collagen and elastic tissue (Fig. 12.7.8). The cells have
there is moderate chronic inflammation of the stroma. moderate amounts of lightly eosinophilic cytoplasm and often appear
elongated. Nuclei are oval or reniform, and vesicular, with a small
nucleolus, so differing from the finely dispersed chromatin pattern of
tumourlets.
There is a marked ultrastructural and immunohistochemical resem- Unlike chemodectomas, sustentacular cells are not present and,
blance to meningeal arachnoid granulations and meningiomas,68–72 unlike tumourlets, argyrophilia and immunohistochemical stains for
in which context it is of interest that a few primary pulmonary men- neuroendocrine markers are negative. Meningothelioid nodules stain
ingiomas have been reported (see p. 641). The term ‘meningothelioid for epithelial membrane antigen, progesterone receptor79 and vimen-
(or arachnoid) nodules’ is therefore preferred to minute pulmonary tin but not for cytokeratin, S-100 or actin. The location of tumourlets
chemodectomas. Some authors suggest that they have a similar func- adjacent to small airways rather than veins is another helpful point of
tion to the meningeal arachnoid granulations that absorb cerebro­ distinction.
spinal fluid and return it to the dural veins: it is suggested that in the
lung they may return interstitial fluid to the pulmonary veins and so
minimise the danger of pulmonary oedema.73 Clonality and loss of
MULTIFOCAL MICRONODULAR TYPE II
heterozygosity have been reported but not so frequently as in menin-
giomas.72 Reported increases in their number and size probably PNEUMOCYTE HYPERPLASIA
represent hyperplasia induced by local changes in perfusion, rather
than neoplasia. They are confined to the lung and have no malignant Micronodular type II pneumocyte hyperplasia is largely, though
potential. not exclusively, confined to patients with tuberous sclerosis, of
These lesions are generally found fortuitously at autopsy or in sur­ which it is a particularly rare manifestation.80–88 It may be seen
gical samples. Dyspnoea with diffuse radiographic opacification is in otherwise normal lungs or in association with pulmonary

701
 A B

Figure 12.7.8  Meningothelioid nodule (so-called minute pulmonary chemodectoma). (A) Islands of round to oval cells lie within a fibrous stroma.
(B) The cells have oval nuclei and eosinophilic cytoplasm without clear cell boundaries.

A
A

Figure 12.7.9  (A) Low- and (B) high-power views of micronodular type II B
cell hyperplasia in tuberous sclerosis.
Figure 12.7.10  Bullous placentoid lesion, (A) Multiple papillary processes
as seen leaving a spurious resemblance to chorionic villi few clotted by
an attenuated cytokeratin-positives and TTF-1-positives epithelium. The
core of the papillae contain a mix of connective tissues, including fat,
which is will seen in (B). (Courtesy of Professor D.W. Henderson, Adelaide,
702
Australia.)
 Tumours Chapter | 12 |

lymphangioleiomyomatosis. Unlike lymphangioleiomyomatosis, it represents a localised accumulation of papillary processes that bear
affects tuberous sclerosis patients of either sex and the hyperplastic only a superficial histological resemblance to chorionic villi, being
type II cells fail to stain for HMB-45.87 The condition is multifocal and clothed by an attenuated layer of epithelium rather than trophoblast,
microscopic and usually of no clinical significance. However, in rare as shown by cytokeratin immunocytochemistry.
cases the lesions are of an appreciable size and so numerous that Patients are typically young to middle-aged adults90,92,93 who
pulmonary function is severely compromised.89 The hyperplastic cells often present with pneumothorax related to an associated bullous
stain for cytokeratin, surfactant apoprotein and epithelial membrane component.91,92 The lesion is widely regarded as being reactive to
antigen. They show no atypia and appear to be devoid of any malig- the bullous change but this is disputed as the lung seldom shows
nant potential (Fig. 12.7.9). bullous change elsewhere, suggesting that the converse may be
more correct, namely that the bullous change is the result of the
placentoid lesion.93,94 Attention has therefore switched to the intersti-
tial cores of the papillary processes. These contain a variety of connec-
tive tissues, including fibroblasts, fat, smooth muscle, clear cells,
BULLOUS PLACENTOID LESION (PLACENTAL blood vessels and lymphatics (Fig. 12.7.10), giving rise to suggestions
TRANSMOGRIFICATION) that the lesion is a benign connective tissue tumour or tumour-like
process sharing some features with the common ‘chondroid hamar-
The nature of this rare lesion is poorly understood but the name by toma’ described on page 626.92,95,96 This suggestion derives support
which it is best known, placental transmogrification,90 is inaccurate: from the lesion being identified adjacent to six of 38 resected ‘chon-
the term ‘placentoid’91 is to be preferred to ‘placental’ for the condition droid hamartomas’.95

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MG. Micronodular hyperplasia of type-II Placental transmogrification of the lung
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83. Popper HH. Micronodular hyperplasia of Placental transmogrification of the lung, a
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1992;20:281. emphysema: clinicopathological study of

705
 Chapter 13 

Pleura and chest wall

CHAPTER CONTENTS Pleural fibromatosis (desmoid tumour) 732

Calcifying fibrous pseudotumour 732
Normal structure and function of the pleura 707 Desmoplastic small round cell tumour 733
Pleural effusions 709 Pleural lymphoma 734
Hydrothorax 709 Synovial sarcoma 734
Chylothorax 709 Vascular tumours 735
Haemothorax 710 Nerve sheath tumours 735
Biliothorax (thoracobilia) 710 Other primary sarcomas of the pleura 735
Silicone thorax 710 Thymoma 735
Pneumothorax 710 Carcinoma 735
Inflammation and fibrosis of the pleura Secondary tumours of the pleura 736
(pleuritis, pleurisy) 712
Pleural splenosis 736
Empyema thoracis (pyothorax) 713
Chest wall disease 736
Tuberculosis of the pleura 713
Chest wall tumours 736
Connective tissue disorders 714
Malignant small cell tumour of the
Nodular histiocytic/mesothelial hyperplasia 714 thoracopulmonary region (Askin tumour) 737
Non-malignant asbestos-induced pleural disease 715 Mesenchymal hamartoma of the chest wall 737
Benign asbestos pleurisy and pleural effusion 715 Gorham’s syndrome 737
Asbestos-induced pleural fibrosis 715 References 737
Blesovsky’s disease (folded lung, rounded
atelectasis) 715
Pleural plaques 716
Pleural tumours 717
NORMAL STRUCTURE AND FUNCTION
Mesothelioma 717
OF THE PLEURA
Well-differentiated papillary mesothelioma 729
Multicystic mesothelioma (multicystic mesothelial The lung is surrounded by a smooth glistening membrane, the visceral
proliferation) 729
pleura, which is reflected at the hilum over the mediastinum and the
Adenomatoid tumour 729 inside of the chest wall as the parietal pleura. The potential space thus
Solitary fibrous tumour of the pleura created extends from the root of the neck, 3 cm above the midpoint
(localised fibrous tumour) 730 of the clavicle, down behind the abdominal cavity and the kidney as

©
2010 Elsevier Ltd
DOI: 10.1016/B978-0-7020-3369-8.00013-6 707
 Pathology of the Lungs

the costodiaphragmatic recess as far as the 12th rib. The two layers of CHEST WALL LUNG
the pleura are in close contact and slide easily over each other because
of a thin mucinous film between them. Although this facilitates
respiratory movements, there is little respiratory embarrassment if the Pleural
pleural space is obliterated. Indeed, elephants and other large animals space
that generate large negative intrathoracic pressures lose their pleural Pulmonary
Systemic
cavities early in development without suffering any evident respiratory or bronchial
capillary
disability. The pleural cavities have therefore been called ‘an capillary
anatomical luxury and a pathological hazard’.1
Each pleural surface consists of connective tissue covered by a single
layer of flattened mesothelial cells which secrete fluid rich in hyaluronic
acid. However, most of the pleural fluid (which normally amounts to To right Pleuro- To left
atrium lymphatic atrium
no more than a few millilitres) is a transudate of blood plasma with
a protein concentration of less than 2 g/dl, mainly albumin. Although stoma
the parietal and visceral layers of the pleura both receive blood from
systemic arteries – distal branches of the intercostal and bronchial
arteries respectively – the visceral layer is largely supplied by pulmo­ Lymphatic Lymphatic
nary vessels and, because of the different pressures in the systemic and
pulmonary circulations, most of the pleural fluid enters through the
parietal pleura. Initial views that it was absorbed by the visceral pleura
were based on the false assumption that the two pleurae were mor­ To hilar lymphatic
phologically similar and that Starling principles would apply. In fact To thoracic and right
Parietal Visceral nodes
the parietal and visceral pleurae differ considerably in structure.2,3 lymphatic ducts
pleura pleura
Whereas the connective tissue of the parietal pleura is thin and
capillaries and lymphatics within this tissue are no more than a few Figure 13.1  The normal formation and drainage of pleural fluid. Pleural
fluid is normally derived from the high-pressure systemic blood vessels  
microns from the pleural space, the connective tissue of the visceral
in the parietal pleura and most of it leaves the pleural space through
pleura is relatively thick. The pulmonary blood vessels lie deep to the
stomata in the parietal pleura. This changes when the pulmonary venous
pleura and are separated from the pleural space by as much as 60– pressure rises (as in left heart failure) and when the pulmonary
70 µm. Furthermore, the parietal pleura is equipped with specialised vasculature is unduly leaky (as in pneumonia), in which circumstances
stomata, described below, which provide a direct exit from the pleural fluid enters the pleural space through the visceral pleura (the inner
space.4 Under normal circumstances most of the fluid therefore both elastin layer of which is represented here by the thin red zigzag line).
enters and leaves the pleural space through the parietal pleura (Fig.
13.1).
The uptake of macromolecules and particles less than 4 nm in
diameter probably takes place by passive diffusion through the gap
beneath which there is a connective tissue network, which, as noted
junctions that connect many mesothelial cells5 and by active vesicular
above, is thicker in the visceral pleura than in the parietal pleura. In
transport across the mesothelial cytoplasm.6,7 Larger particles are
the parietal pleura the amount and distribution of elastin are irregular
mainly cleared in the caudal portions of the parietal pleura. The sys­
whereas in the visceral pleura a thin inner and a thick outer elastic
temic lymphatic network is particularly rich here, and mesothelial and
lamina can generally be discerned. Thus, the visceral pleura comprises
lymphatic endothelial cells are in direct apposition, without an inter­
five layers (Fig. 13.2):
vening basement membrane. Here too, stomata in the parietal pleura
provide a direct connection between the pleural cavity and the under­ 1. The flattened mesothelium and its basement membrane
lying lymphatics.8 Over the lower mediastinum the stomata are associ­ 2. A thin submesothelial layer of loose connective tissue
ated with collections of macrophages and lymphoid cells, visible 3. A thin outer layer of elastin, which is continuous around the
macroscopically as pale spots known as Kampmeier’s foci. Particles lobe and does not dip into the interlobular septa
up to about 10 µm are absorbed by the stomata-membrana- 4. A thicker layer of loose connective tissue in which are found
cribriformis complex, a process that is monitored by the lympho­ the pleural veins, the pleural arteries (which are branches of the
reticular cells of Kampmeier’s foci. Many particles are rapidly cleared systemic bronchial arteries) and the pleural lymphatics. The
by this route9 but some are retained in Kampmeier’s foci to form lymphatics are valved whereas the veins are not, the opposite to
what are termed black spots.10–12 what appertains elsewhere in the body
Mesothelial cells express epithelial markers such as cytokeratin and 5. A relatively thick layer of elastin, which dips into the
are joined by desmosomes which contribute to the formation of either interlobular septa and is continuous with the elastic tissue of
tight or gap junctions. However, many mesothelial cells merely overlap the peripheral alveoli.
one another, like lymphatic endothelial cells. Pinocytotic vesicles are Mesothelial cells are readily damaged and desquamate in large
plentiful in the cytoplasm which also contains rough endoplasmic numbers in many pathological conditions. Unlike epithelium, meso­
reticulum and bundles of fine filaments. The mesothelial cell surface thelial repair does not solely involve centripetal migration of ad­­
is not smooth but bears long, slender microvilli measuring up to 3 µm jacent cells, as evidenced by the fact that large and small pleural
in length and 0.3 µm in width, suggesting an absorptive function. The lesions heal in exactly the same time. Mesothelial repair depends
numbers of microvilli vary from cell to cell. They are sparse over the upon the differentiation of submesothelial connective tissue cells15–19
ribs but increase towards the base of the lung and are more numerous and exfoliated mesothelial cells resettling on the denuded areas20,21 as
on the visceral than the parietal pleura.13 With their surface muco­ well as the centripetal migration of adjacent mesothelial cells.21,22
polysacharide coat, microvilli may also counter frictional forces.14 Macrophages also settle out from the pleural fluid23,24 but do not
Except at the stomata in the parietal pleura described above, both appear to differentiate into mesothelial cells.15,25 Differentiation
layers of mesothelium rest upon a continuous basement membrane, of proliferating submesothelial cells involves the acquisition of cytok­

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 Pleura and chest wall Chapter | 13 |

likely to develop when cardiac failure is accompanied by pulmonary

venous hypertension than when there is systemic venous hyper­
tension. Thus pleural effusion is common with left ventricular failure
but rare with cor pulmonale.
Exudates are of varying aetiology, being the result of pleural or
pulmonary irritation from any cause. The irritation is often due to
acute infection, which is usually pneumonic but may be a pulmonary
or subdiaphragmatic abscess. Other causes include acute pan­
creatitis,32 rheumatoid disease, lupus erythematosus, tuberculosis,
pulmonary infarction, a drug reaction (notably to practolol, methy­
sergide and bromocriptine), non-malignant asbestos pleurisy, cancer
and lymphatic obstruction or deficiency, and even pleural amyloido­
sis.33 Acute irritation typically leads to an accumulation of neutrophils
in the fluid and chronic disease to increased numbers of lymphocytes.
Pleural exudates due to defective lymphatic drainage are also rich in
lymphocytes. A predominance of eosinophils is occasionally found,
even in the absence of blood eosinophilia. The most common
associations of an eosinophil-rich pleural effusion are malignancy,
infection and trauma but often no cause can be identified.34 Exudates
caused by cancer and pulmonary infarction are commonly blood-
Figure 13.2  The normal visceral pleura at its intersection with an stained.26 The presence of tumour markers in the exudate may
interlobular septum. The visceral pleura comprises five layers, the contribute to the diagnosis.35
presence and thickness of which vary regionally: (1) the surface Ascites may also result in pleural effusion due to ascitic fluid cross­
mesothelium and its basement membrane; (2) a thin layer of connective ing the diaphragm, in which case the nature of the pleural effusion is
tissue; (3) a prominent outer elastin layer; (4) a band of collagen; and (5) similar to that of the ascitic fluid from which it derives. The passage
an inner elastin layer (which is continuous with the alveolar elastin). is through mesothelium-lined channels, which are generally micro­
Whereas the outer layer of elastin forms a continuous band around each
scopic but may measure up to 5 mm.36 The sudden development of
lobe, the inner elastin layer turns inwards wherever interlobular septa join
a pleural effusion in association with ascites secondary to a pelvic
the pleura. In decortication it is the collagen layer that forms the plane of
cleavage but it is the outer elastin layer that needs to be addressed when tumour is known as Meig’s syndrome (see p. 495). Hydrothorax is
assessing tumour spread (see tumour staging, p. 571). also recorded in patients with ascites secondary to cirrhosis36 and in
those undergoing peritoneal dialysis.37 Ovarian stimulation under­
taken for in vitro fertilisation is a more recently recognised cause of
pleural effusion accompanying ascites.38

eratin antigens, markers of mesothelial cells not normally found in

connective tissue; this complicates the interpretation of immunocyto­ Chylothorax
chemical stains used to distinguish granulation tissue from mesothe­
lioma of sarcomatous pattern (see p. 728).17 The accumulation of chyle in the pleural space is due to obstruction
or rupture of the thoracic duct.39 Rupture is usually traumatic whilst
obstruction may be developmental, neoplastic or surgical, or due to
rare conditions such as lymphangioleiomyomatosis (see p. 293),
PLEURAL EFFUSIONS angiofollicular lymphoid hyperplasia (Castleman’s disease, see p.
669) or the yellow-nail syndrome.40 Chyle is rich in dietary fat and a
Pleural effusions may be serous (hydrothorax), bloody (haemo­ chylous effusion appears milky (Fig. 13.3A). Diagnosis involves cho­
thorax) or chylous (chylothorax), or consist of frank pus (pyothorax lesterol and triglyceride measurement in the pleural fluid.
or empyema thoracis). Most are caused by malignancy or infec­ Pseudochylothorax may develop in a long-standing serous exudate:
tion.26 Their rapid therapeutic removal occasionally alters pulmonary this also looks milky and has a high content of cholesterol but it lacks
haemodynamics to such an extent that pulmonary oedema or even the triglycerides and chylomicrons found in chyle.41 Complications
pulmonary haemorrhage results.27,28 include malnutrition, immunosuppression and respiratory distress.

Hydrothorax Yellow-nail syndrome

Serous effusions may be clear or cloudy, the former usually denoting This syndrome, first described in 1964, consists of chylous effusions,
a transudate low in protein content and the latter a protein-rich lymphoedema of varied distribution and yellow discoloration and
exudate. The traditional demarcation point between transudates distortion of the nails, all of which are attributed to defective
and exudates is 3 g protein/dl but pleural fluid-to-serum ratios of lymphatic drainage (Fig. 13.3B).42 It is often associated with
protein, lactic dehydrogenase and cholesterol are now widely repeated pulmonary infections, bronchiectasis and an immuno­
used.29–31 logical disorder such as lymphopenia, hypogammaglobulinaemia or
Transudates develop in cardiac failure, overhydration, constrictive macroglobulinaemia.42–47 Although widely regarded as representing a
pericarditis and fibrosing mediastinitis, the fluid accumulation result­ hereditary disorder, the family history is generally negative and the
ing from an imbalance between hydrostatic and osmotic forces in each clinical features are seldom evident before adult life: the median
case. In cardiac failure the effusion is commonly unilateral. It is often age at diagnosis is 61 years (range 18–82 years).48,49 The yellow
stated that the right side is more frequently involved than the left but nails may return to normal if the pulmonary problems are treated
several studies have failed to confirm this. Pleural effusion is more successfully.49

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 Pathology of the Lungs

Figure 13.3  Yellow-nail syndrome. (A) A chylous pleural exudate aspirated from a patient with the yellow-nail syndrome. (B) Dilated pleural lymphatics
in another patient with the syndrome. (B courtesy of Dr Fiona Roberts, Glasgow, UK)

Haemothorax to trauma, a fractured clavicle or rib lacerating the parietal pleura and
allowing the ingress of air through an associated wound of the skin.
Haemorrhage into a pleural sac may follow trauma to the chest, Sometimes, the local blood vessels may also be damaged and the
pulmonary embolism or spontaneous rupture of an aneurysm of the condition becomes one of haemopneumothorax. In surgical opera­
thoracic aorta.50 Occasionally, rupture of an emphysematous bulla is tions on the thorax the pleural sac is often opened and allowed to fill
followed by haemopneumothorax, with blood and air escaping simul­ with air. Formerly, air was deliberately introduced into the pleural sac
taneously from the damaged lung into the sac.51 Thoracic endo­ in the treatment of chronic respiratory tuberculosis, to collapse and
metriosis may also cause haemopneumothorax (see p. 495). thus rest the lung (artificial pneumothorax). Further consideration
Carcinomatous involvement of the pleura typically causes a blood- will be limited to air entering the pleural sac through the visceral
stained pleural effusion but seldom gives rise to frank haemorrhage. pleura. Such pneumothoraces may be open or closed: in the former,
the aperture remains patent, so that air can pass freely into and out
Biliothorax (thoracobilia) of the sac; in the latter, the opening soon becomes sealed, and thus
traps the air that has entered. Once the air leak has been sealed, the
The removal of gallstones from the pleural cavity is one of the air in the pleural sac is gradually absorbed over the ensuing weeks –
more unusual thoracic operations.52 Such calculi enter the thorax oxygen first and nitrogen later. Occasionally, and particularly in older
by producing a cholecystopleural fistula. The accompanying bile is people, the tissues near the orifice act as a valve, allowing air to enter
liable to cause a chemical pleuritis resulting in severe respiratory but not to escape. In these cases pressure builds up in the sac, dis­
insufficiency. placing the structures of the mediastinum to the opposite side, with
consequent grave embarrassment of respiration. This is known as
pressure or tension pneumothorax and constitute a medical
Silicone thorax
emergency.
Pleural nodules representing a foreign-body reaction to silicone is
described in a woman whose breast implant had burst and who had
Clinical features
subsequently undergone cardiac surgery, which admitted the silicone
into the pleural cavity.53 Pneumothorax is usually sudden in onset, and often occurs during
physical exertion. It is generally unilateral. Bilateral pneumothorax is
more serious since there is interference with the inflation of both
lungs. The onset is painful, and quickly followed by shortness of
PNEUMOTHORAX breath, especially in patients with emphysema or other extensive
chronic pulmonary disease that already impairs their respiratory
Air may enter the pleural sac through either the chest wall or the capacity. In the cases in which the tissues create a valve at the site of
visceral pleura. In the former case the condition is almost always due perforation, the pneumothorax may build up slowly without any

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 Pleura and chest wall Chapter | 13 |

Box 13.1  Causes of pneumothorax

Air entry through the chest wall

Trauma
Air entry through the visceral pleura
Emphysema
Langerhans cell histiocytosis
Lymphangioleiomyomatosis
Cystic fibrosis
Thoracic endometriosis
Lymphoid interstitial pneumonia
Light-chain deposition disease
Marfan’s syndrome
Ehlers–Danlos syndrome
Birt–Hogg–Dubé syndrome
Necrotising pneumonia, as with Pneumocystis

Figure 13.4  A bulla, rupture of which had caused pneumothorax,

sudden symptoms; in these instances the displacement of the associated with a focus of fibrosis, the so-called apical cap. The overlying
mediastinum is apt to be greater. visceral pleura is oedematous and contains pockets of air. These
represent interstitial emphysema and are termed blebs, in contrast to
bullae, such as that seen to the left, which represent enlarged alveolar
Epidemiology spaces.
Epidemiological studies show that men are affected more than women
(in a ratio of 2.4 : 1), that there is a biphasic age distribution and that
most deaths occur in older patients.54 Cigarette smoking increases the
risk in a dose-dependent manner55 and cannabis use further increases Pneumothorax causes a reactive mesothelial hyperplasia associated
this risk.56,57 with an inflammatory infiltrate that is frequently rich in eosinophils
and is sometimes called `reactive eosinophilic pleuritis’.64,65 The in­­
filtrate is superficial, penetrating only a short distance into the sub­
Pathogenesis and pathological features
stance of the lung beneath the pleura: this distinguishes the process
Escape of air into the pleural space from the lungs may be due to from eosinophilic granuloma of the lung and eosinophilic pneumo­
trauma or some pathological change in the lungs, usually emphysema. nia. Small blood vessels may be involved but limitation of the process
It causes the lung to collapse and if bilateral may prove fatal (see to the subpleural region of the lung distinguishes it from a true vas­
Fig. 7.2.7, p. 377). Other conditions in which pneumothorax occur culitis. Reactive type II pneumocyte hyperplasia may also develop and
particularly frequently are listed in Box 13.1. A sudden drop in atmos­ be atypical enough to arouse suspicion of adenocarcinoma.66
pheric pressure may be the precipitating factor and occasionally loud If air is maintained in the pleural cavity for many months, as was
music has also had this effect, pressure changes presumably being once customary in the treatment of pulmonary tuberculosis, the
again responsible.58,59 mesothelium may undergo extensive squamous change. It is uncertain
Pneumothorax also occurs in healthy young individuals who appear whether this represents metaplasia of the mesothelium, extension of
to have normal lungs. This is known as idiopathic spontaneous pneu­ metaplastic bronchial epithelium through a bronchopleural fistula or
mothorax. When treatment in such cases has necessitated thora­ implantation of skin, but progression to malignancy has been noted.67
cotomy it has usually been found that at the apex of the lung there is In cystic fibrosis, focal replacement of the visceral pleural meso­
an area of fibrosis, 2–3 cm in its greatest dimension, surmounted by thelium by ciliated columnar or squamous epithelium has been
one or more bullae up to 1 cm or so in diameter.60,61 A hole may be described, possibly due to rupture of bronchiectatic abscesses68 and
found in the pleural surface adjoining the bullae, or one of the bullae perhaps contributing to the pathogenesis of pneumothorax in this
may have a tear in its wall. Microscopy shows subpleural alveolar col­ condition.69 Unexplained columnar or mucous cell metaplasia of the
lapse and fibrosis, and an accumulation of chronic inflammatory cells pleura has also been reported.70
(Fig. 13.4), but no evidence of tuberculosis or other specific disease.
Such lesions are not uncommon. They were identified in 15 (6%) of
250 young, healthy adults undergoing bilateral thoracoscopic sym­
Pleurodesis
pathectomy for hyperhidrosis.62 It has been suggested that, since most If a patient suffers from repeated pneumothoraces, it may be necessary
of these patients are tall, thin men, the changes in the apical region to obliterate the pleural cavity, a procedure termed ‘pleurodesis’. This
of the lungs – demonstrably affected bilaterally in some cases – may may be effected surgically, by stripping the pleura, or by the in­­
be developmental in origin and possibly related to rapid somatic stillation of sclerosing substances such as talc or tetracycline.
growth. Their tall build will result in the apices of these individuals’ Intractable pleural effusions may also require such treatment,
lungs being particularly poorly perfused when they stand erect. This especially in the palliation of malignant effusions. However, before
ischaemia may damage the apices directly or contribute to the fibrosis performing pleurodesis consideration should be given to the possibil­
by impairing the resolution of any inflammatory process.63 Because ity of the underlying condition requiring lung transplantation at some
the apical changes are frequently bilateral, there is often recurrence future date as pleurodesis would make this technically difficult. The
on the opposite side. histological observation of numerous birefringent crystals in a fibrotic

711
 Pathology of the Lungs

pleura indicates that pleurodesis has been undertaken in the past

(Fig. 13.5). Neoplasia involving the chest wall 2 years after talc pleu­
rodesis is recorded but the tumour was an adenocarcinoma of the
peripheral lung rather than a pleural mesothelioma71 and is therefore
likely to have been coincidental, particularly as no mesotheliomas
developed in any of 80 patients who had undergone talc pleurodesis
22–35 years previously.72 Although commercial talc is often contami­
nated by tremolite asbestos and talc miners have developed mesothe­
lioma, cosmetic talc and that used in medicine are rigorously screened
to ensure their purity; they appear to be entirely non-carcinogenic
but there are reports of acute lung enjury following pleural
talc insufflation.73,73a

INFLAMMATION AND FIBROSIS OF THE

PLEURA (PLEURITIS, PLEURISY)
A
Inflammation of the pleural sac can develop in many conditions (Box
13.2). Usually, it is secondary to inflammation of one of the adjoining
thoracic or subdiaphragmatic structures, particularly the lungs.
Sometimes, it is a manifestation of systemic lupus erythematosus or
another connective tissue disorder (see below). Asbestos and certain
drugs may also cause pleural inflammation and fibrosis (see pp. 715
and 391). Silicotic nodules developing along the pleural lymphatics
have been likened to pearls or drops of candle wax74 while eosi­
nophilic pleuritis as a reaction to air in the pleural cavity has been
mentioned above. Occasionally, no cause is evident.75
Acute inflammation of the pleura commences with hyperaemia,
which is followed by exudation of fluid and leukocytes into the sac.
Initially, before the exudate has fully formed, the pleurisy is dry (fibri­
nous pleurisy). This is accompanied by considerable pain on breath­
ing and a rub that is audible on auscultation. With the development
of an exudate (serofibrinous pleurisy) the visceral and parietal pleural
surfaces separate and the pain and rub diminish. If the cause is bac­
terial, the serofibrinous exudate may be replaced by suppuration, the
cavity becoming filled by pus – the condition known as empyema
thoracis or pyothorax (see below).
In many cases of serofibrinous pleurisy the inflammation regresses B
as time or treatment brings about recovery from the underlying
disease. In such cases, the exudate is absorbed, and unless the pleura
has been extensively denuded of its mesothelium the sac recovers its
smooth lining. Where mesothelium has been lost, adhesions may
form between the lung and the chest wall: at first the adhesions are
fibrinous, but later, through organisation, they become fibrous. In this
way, part or all of the cavity may be obliterated. This generally occa­
sions no great functional disadvantage. However, an appreciable
degree of diffuse fibrous thickening of the pleura of any cause impairs
movement of the chest. Accordingly, bilateral diffuse pleural fibrosis
has important clinical consequences. The causes are as numerous as
those of pleuritis (see Box 13.2) but asbestos is particularly important
and the condition is therefore dealt with below under the heading of
non-malignant asbestos-induced pleural disease.
The organisation of surface fibrin often involves the development
of abundant granulation tissue and this may mimic sarcomatoid
meso­thelioma. The expression of keratin by such spindle cells is gen­
erally taken as evidence that they are mesothelial rather than fibrob­
lastic, but it is not necessarily indicative of mesothelioma because
reactive submesothelial spindle cells stain similarly.17 However, cytok­
eratin staining is a useful marker of malignancy if it is positive in C
irregular cells in the deeper parts of the process for, as granulation
tissue matures away from the surface, the intensity of the cytokeratin Figure 13.5  Talc pleurodesis. (A) A linear inflammatory infiltrate is seen
staining lessens. within densely fibrotic pleura. (B) The inflammation is of foreign-body
granulomatous type. (C) Polarisation readily identifies birefringent talc
crystals amongst the macrophages and giant cells.

712
 Pleura and chest wall Chapter | 13 |

ones being the anaerobic or microaerophilic Streptococcus milleri, pep­

Box 13.2  Causes of pleural inflammation and fibrosis tostreptococci, peptococci, Fusobacterium nucleatum, Bacteroides
Infection, particularly of the lungs melaninogenicus, B. fragilis, clostridia, Escherichia coli and Pseudomonas
aeruginosa.76–79 Klebsiella pneumoniae is common in patients with dia­
Other pulmonary lesions, e.g. infarction
betes mellitus80 whereas in children Staphylococcus aureus is common,
Connective tissue disease
the empyema generally complicating underlying staphylococcal pneu­
Drug reaction
monia or pneumatocele (see p. 182). If it complicates a staphylococcal
Asbestos pneumatocele the empyema may be associated with pneumothorax.
Pneumothorax This combination is known as pyopneumothorax and may also
Sarcoidosis develop when a cavitating rheumatoid nodule establishes a broncho­
Pancreatitis pleural fistula.81,82 Empyema may also follow thoracotomy, or less
Post cardiac injury (Dressler’s syndrome) commonly thoracocentesis, penetrating injuries or rupture of the
Radiation oesophagus during instrumentation or by a sharp foreign body.
Renal failure Blood-borne and transdiaphragmatic infection are rare causes of
Trauma empyema.
Malignancy
In empyema thoracis the whole of the sac or merely a part, usually
the lower part, may be filled with thick viscous pus (see Fig. 13.6).
Sometimes the pus is confined to an interlobar fissure. Organisation
of parts of the exudate leads to the formation of firm adhesions that
restrict spread of the infection and localise the pus. Alternatively,
the pus may extend into the lung and rupture into a bronchus, leading
to the sudden dissemination of infected material throughout the
bronchial tree. If the patient survives this, there remains a chronic
bronchopleural fistula. Occasionally, the pleural infection erodes the
chest wall, leading to discharge of pus through the skin (empyema
necessitans).
Empyema thoracis is a serious condition which, if inadequately
treated, has a high mortality. Sometimes infection is overcome without
intervention, and the pus is eventually replaced by granulation tissue
and fibrous tissue. Even in favourable cases the damage to the serosa
is severe: when the suppuration subsides, fibrous adhesions develop
and eventually obliterate the cavity. The lining of the cavity may
undergo calcification during the succeeding years. Malignant change
is a further complication (see pleural sarcoma and pleural lymphoma,
p. 734).

Tuberculosis of the pleura

Pleural involvement is common in tuberculosis, usually taking the
form of an effusion in an apparently healthy young person soon after
the primary infection. Pleural involvement may also complicate
obvious active pulmonary tuberculosis or even apparently healed
disease. The effusion is usually clear but occasionally blood-tinged. It
contains numerous lymphocytes. Tubercle bacilli may be demonstra­
ble, for the condition is truly infective rather than an allergic reaction
as was once thought. Occasionally there is a dry painful pleurisy.
The pleura may be infected directly or by blood-borne spread from
either the Ghon focus or caseous hilar lymph nodes. Bilateral effusion
suggests blood spread but one pleural cavity may be infected directly
Figure 13.6  Empyema thoracis. There is shaggy fibrinopurulent from the other, as may the pericardium.
thickening of both pleural surfaces over the lower lobe.
In the early stages of a tuberculous pleurisy the appearance of the
visceral and parietal serosal surfaces does not differ greatly from that
seen in the usual serofibrinous form of pleurisy. Discrete miliary
granulomas may stud the pleura but more often there is diffuse surface
Empyema thoracis (pyothorax) involvement. However, typical tubercles can be seen histologically.
Empyema thoracis represents a collection of pus in the pleural space Pleural biopsy with both histological and bacteriological examination
(Fig. 13.6). It is usually a complication of pneumonia and, with the has a sensitivity of greater than 90%,83 confirming that the condition
advent of antibiotics, is now rare. When it does occur there is is infective rather than allergic. Ultimately, there is caseation and, in
usually some underlying debilitating condition such as diabetes or time, this may undergo calcification.
alcoholism, chronic lung disease such as bronchiectasis or carcinoma, Even before effective antituberculosis drugs were available, such an
or the patient is on long-term immunosuppressive therapy. In about effusion usually disappeared within 3–4 months, leaving at most a
a third of cases the condition is associated with a necrotising pneu­ minor degree of obliteration of the costophrenic angle in the radio­
monia or ‘primary’ lung abscess, due to aspirated anaerobes (see graphs. However, some patients developed extensive thick rigid ad­­
pp. 189–191). Often there is a mixture of bacteria, the predominant hesions with consequent restriction of pulmonary ventilation.

713
 Pathology of the Lungs

A more severe form of tuberculous infection of the pleura may

develop in the course of postprimary tuberculosis if a tuberculous
cavity erodes into the pleural sac. The result is the condition conven­
tionally described as a tuberculous empyema (see Fig. 5.3.8, p. 202),
although the semifluid matter that collects is caseous and not true pus,
except when there is a simultaneous or subsequent infection by pyo­
genic bacteria. The exudate in the pleural sac becomes encased in a
thick, fibrosing layer of tuberculous granulation tissue. The same con­
dition may result from rupture of a juxtavertebral abscess in cases of
tuberculosis of the thoracic spine. Similarly, tuberculosis of a rib may
be complicated by pleural effusion or ‘empyema’. Bronchopleural
fistula may be present in association with tuberculous ‘empyema’. This
increases the liability to secondary infection, which in some cases is
caused by fungi.84
The formerly common establishment of an artificial pneumothorax
to rest a tuberculous lung has been mentioned above. Other manipu­ A
lations favoured in the past for the same purpose included the re­­
section of several ribs (thoracoplasty) or the introduction of some
inert material into the pleural sac, a procedure known as plombage:
decades later, patients may find worm-like threads of wax in their
sputum,85 or pathologists unfamiliar with this outdated procedure
may be surprised to find at autopsy one side of a deceased elderly
patient’s chest largely filled with what look remarkably like white bil­
liard balls. More often, complications such as infection led to the
removal of the plombe within a few years of its insertion.86 Various
forms of plombage material were favoured: plastic in the form of
sponge or lucite spheres, packets of shredded plastic and injections
of paraffin wax or vegetable oil (oleothorax).87 The development of
carcinoma of the lung underlying lucite spheres is mentioned on
page 735.

Connective tissue disorders

B
Pleural involvement is common in rheumatoid disease and systemic
lupus erythematosus, but rare in systemic sclerosis, polymyositis and
Figure 13.7  (A) A rheumatoid nodule is seen discharging into the pleural
dermatomyositis.88
space, following which (B) the palisade of histiocytes fronts the pleural
space rather than the centre of a granuloma.
Rheumatoid disease
Pleurisy and pleural effusions are the most common of the several
respiratory manifestations of rheumatoid disease (see Box 10.1, pulmonary involvement in frequency. The pleural effusions are
p. 473). The pleural inflammation may be non-specific or represented usually bilateral and the fluid is an exudate rich in proteins. Glucose
by classic rheumatoid nodules.89 Sometimes a subpleural rheumatoid con­centrations are normal. The cells are usually unremarkable but
nodule discharges into the pleural space and the characteristic occasionally lupus erythematosus cells may form. These are phago­
palisade of cells forms a linear pattern over the surface of the pleura cytes that have taken up effete nuclear material so that their own
(Fig. 13.7).90 An effusion, unilateral or bilateral, generally forms. nuclei are stretched around a large haemotoxyphil inclusion. Biopsy
This is an exudate, rich in immunoglobulins and other proteins, shows non-specific chronic inflammation or fibrosis.
and sometimes cloudy or opalescent due to a high cholesterol
content. Glucose levels in the fluid are low, apparently due to impaired
glucose transport.91 Lymphocytes are the predominant leukocytes, Nodular histiocytic/mesothelial hyperplasia
but sometimes there is a unique microscopical pattern – a com­
Nodular histiocytic/mesothelial hyperplasia is found on serosal sur­
bination of large elongated multinucleate cells, cholesterol crystals,
faces as small discrete aggregates of histiocytes intermingled with
clumps of eosinophilic granular material and a dearth of mesothelial
occasional mesothelial cells. The condition is well known on the
cells.92–94 The elongated cells are believed to come from the
pericardium where the aggregates are often termed mesothelial/
palisade layer of the granuloma. Their bizarre shape makes them
monocytic incidental cardiac excresences (cardiac MICE), and upon
liable to be mistaken for carcinoma cells. Rheumatoid pleural
the peritoneum in hernial sacs. The aggregates are also found on
effusions are liable to become infected, sometimes resulting in
the pleura, probably developing in response to non-specific pleural
empyema. At other times a cavitating intrapulmonary rheumatoid
irritation.95 They are symptomless and of no clinical importance
nodule leads to the development of a bronchopleural fistula and
unless an unwary pathologist mistakes them for something more
pyopneumothorax.81,82
sinister, such as carcinoma or mesothelioma. Recognising the
numerous histiocytes as such is the key to the correct diagnosis;
Systemic lupus erythematosus these cells stain strongly for CD68 and greatly outnumber the
Pleurisy, with or without effusion, is among the most common calretinin- and cytokeratin5/6-positive mesothelial cells and any
visceral manifestations of systemic lupus erythematosus, far exceeding reactive thyroid transforming factor-1 (TTF-1)-positive pulmonary

714
 Pleura and chest wall Chapter | 13 |

epithelial cells present at the deeper aspect of a lesion on the

visceral pleura.96

NON-MALIGNANT ASBESTOS-INDUCED
PLEURAL DISEASE

Besides asbestosis, carcinoma of the lung and pleural meso­thelioma,

respiratory disease attributable to the inhalation of asbes­tos includes
pleurisy, which is generally accompanied by an effusion, and pleural
fibrosis.97 The latter takes several forms: distinctive plaques and less
distinct pleural fibrosis that may be focal or diffuse, and either
of no clinical consequence or responsible for particular clinical
syndromes.
In contrast to asbestosis and asbestos-induced lung cancer, both of
which generally require relatively high exposure levels, all pleural
diseases attributable to asbestos are associated with relatively low
asbestos burdens in the lung.98 Furthermore, it is very difficult to
identify asbestos in the pleural lesions themselves, although they are
attributable to asbestos inhalation.

Benign asbestos pleurisy and

pleural effusion
An exudative pleurisy may develop within 10 years of first contact with
asbestos and therefore be found in persons currently at work in the
industry. The effusion may be asymptomatic97 or the patient may
complain of pleuritic pain, sometimes accompanied by fever, leuko­
cytosis and an elevated blood sedimentation rate.99 The effusion is
usually small and blood-stained, giving rise to suspicion of malig­ Figure 13.8  Diffuse thick fibrous thickening of the pleura in an asbestos
nancy. It often resolves spontaneously, only to recur, perhaps on the worker. At the base of the lower lobe there is also a localised area of
pleural thickening (Blesovsky’s disease).
other side. It may progress to diffuse pleural fibrosis that requires
decortication.99 Asbestos-induced pleurisy is thought to play no part
in the development of pleural mesothelioma.

interstitial fibrosis but this should not be interpreted as asbestosis

Asbestos-induced pleural fibrosis unless there is also evidence of substantial asbestos exposure.
Asbestos-induced pleural fibrosis has to be distinguished from
Bilateral obliteration of the costophrenic angles is a common radio­
pleural plaque, which is described below, and from a cryptogenic form
graphic finding in healthy asbestos workers. It presumably reflects the
of bilateral fibrosing pleuritis that has been reported in a few patients
organisation of previous asymptomatic effusions. Pleural fibrosis of
in whom asbestos, systemic connective tissue disorders, tuberculosis
non-specific character is common in such workers, and in those
and all other recognised causes of pleural fibrosis have been
suffering from asbestosis a diffuse but thin fibrous thickening of
excluded.109 Such cryptogenic diffuse pleural fibrosis has been reported
the visceral pleura is almost invariably present. Indeed, apart from
in three sisters.110 In other patients it has been associated with a thin
the presence of asbestos in the lungs, this is one of the few
rim of subpleural fibrosis and been termed idiopathic pleuro­
pathological features that distinguish asbestosis from idiopathic
parenchymal fibroelastosis.111,112
pulmonary fibrosis.
This thin fibrous thickening of the visceral pleura is of no clinical
consequence but occasionally asbestos-exposed individuals develop Blesovsky’s disease (folded lung,
extensive, thick fibrosis of the pleura in the absence of asbestosis rounded atelectasis)
(Fig. 13.8) and this may severely compromise expansion of the
chest.24,100–104 It may be bilateral or limited to one side.105 The resultant Localised patches of pleural fibrosis may be important clinically, not
restrictive defect in lung function is responsible for incapacitating for their functional effects, but because they may mimic a peripheral
breathlessness and this form of pleural fibrosis is one of the industrial lung tumour radiographically. The contracture of the pleural scar
diseases recognised by several governments for compensation draws the adjacent lung tissue to it, causing a localised area of col­
purposes. Medicolegal definitions vary from country to country and lapse. The bases of the lungs are particularly affected (Figs 13.8 and
with time. In the UK the current definition is unilateral or bilateral 13.9 and Table 13.1). The collapsed lung often appears to be folded
diffuse pleural thickening with obliteration of the costophrenic upon itself and the resultant radiographic opacity has a comet’s tail
angle.106 Mesothelioma may develop in patients with such restrictive appearance. The condition is variously known as Blesovsky’s disease,
pleural fibrosis but the tumour is thought to arise independently. folded lung or rounded atelectasis.24,113–117a In 25% of cases the lesion
Although generally limited to the pleura, the fibrosis occasionally is bilateral.105 There is often a history of asbestos exposure, but like
extends into the chest wall107 and mediastinum.108 The lung paren­ the other forms of asbestos-induced pleural fibrosis, the condition is
chyma immediately beneath the thickened pleura may show diffuse thought to play no part in the pathogenesis of mesothelioma.

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 Pathology of the Lungs

Figure 13.9  Folded lung (Blesovsky’s disease). A white Y-shaped band of

scarred pleura is surrounded by collapsed lung. (Courtesy of Dr T Jelihovsky,
Sydney, Australia.)

Table 13.1  Lobar distribution of Blesovsky’s disease in 100

reported cases113

Right Left

Upper lobe 2 3
B
Middle lobe/lingual 11 10
Lower lobe 47 27 Figure 13.10  Pleural plaques. (A) The eviscerated thoracic cavity showing
pearly white and irregular plaques on the inner side of the chest wall. (B)
Microscopically, the plaques are practically acellular, consisting of hyaline
collagen that has a `basket-weave’ pattern. They provide strong evidence
Pleural plaques of asbestos exposure.
Pleural plaques are a further form of asbestos-induced pleural fibrosis,
described separately because of their distinctive pathological appear­
ance.24 Although they are occasionally found in persons with no examination in life.118 Pleural plaques are harmless and have no
history of asbestos exposure, the association with asbestos is a firm relation­ship to mesothelioma, or lung cancer, other than their
one, based on both epidemiological evidence118,119 and the identifica­ association with asbestos.123
tion of asbestos in the underlying lung.120 Pleural plaques therefore
provide strong evidence of asbestos exposure, which may be occupa­
tional or environmental. They occur after exposure to all types of Pathology
asbestos but anthophyllite is particularly potent. Plaques are common Plaques are localised raised areas that are generally multifocal and
in areas where the soil is contaminated with asbestiform minerals, for bilateral. They may occur on the visceral pleura or even the perito­
example parts of Finland and Greece.121,122 The longer and heavier the neum124 but usually affect the parietal pleura, particularly in relation
exposure, the more extensive the plaques, but even slight exposure can to the ribs and the central tendon of the diaphragm. They have an
be sufficient. Very few develop within 15 years of first exposure and irregular outline, a smooth shiny pearly-grey surface and a low profile,
most appear after 30 years. Postmortem studies show that plaques typically about 5 mm in height: their other dimensions are very vari­
are more common than can be appreciated from radiological able (Fig. 13.10A). Microscopically, plaques are hyaline, avascular and

716
 Pleura and chest wall Chapter | 13 |

almost acellular (Fig. 13.10B). In a pleural biopsy, even a small latter half of the twentieth century but such is the long latent interval
number of spindle cells in a hyaline lesion should suggest the possi­ between exposure and disease that these do not have an effect for
bility of paucicellular hyaline mesothelioma (see p. 722) rather than several decades. The durability of asbestos is another factor hampering
plaque. The hyaline collagen bundles have a characteristic pattern that efforts to reduce the incidence of mesothelioma. It is calculated that
is often likened to basket weave. Calcification is common. Inflammation the numbers mesotheliomas in the UK will triple between 1991 and
is not found, except at the periphery and there it is mild. 2020 and only then decline.131 In contrast, there is already a decline
in the incidence of mesothelioma in the USA where the use of amphi­
bole asbestos was restricted as early as the 1960s.132
Pathogenesis
Although the connection between asbestos and plaques is firmly
established, the pathogenetic mechanism is obscure. Organisation of Aetiology
exudates probably underlies the other less distinctive forms of pleural In the mid twentieth century it was increasingly suspected that meso­
fibrosis found in asbestos workers but it is difficult to envisage a thelioma was related to asbestos exposure and substance was given to
special type of exudate that may give rise to plaques. Furthermore, the this in 1960, when Wagner and colleagues showed a high incidence of
plaques are covered by an intact mesothelium and are not usually the tumour in the area near Kimberley, northern Cape province, South
attended by adhesions. It has been suggested that the parietal pleura Africa, where blue asbestos is mined.133,134 The relationship between
is particularly affected because it is abraded by asbestos fibres project­ asbestos exposure and mesothelioma was subsequently confirmed in
ing through the visceral pleura, but no such projections have been other countries where asbestos is mined and in those that import and
identified. A further possibility derives from consideration of the lym­ process the ore.135–139 Asbestos and similar fibrous substances are virtu­
phatic drainage of the pleural cavity, which is largely through the ally the only recognised causes of mesothelioma. Smoking does not
parietal pleura. Short asbestos fibres have been identified in the increase the risk of mesothelioma. Cases that can be attributed to
visceral pleura125 and it is likely that some reach the pleural cavity, causes such as radiation, chronic inflammation and scarring are ex­­
whence their disposal would be by the stomata and lymphatics of the ceptionally rare.140–146 Despite the predominant role of asbestosis,
parietal pleura (see p. 708). Any fibres arrested by the ribs or the there is evidence that simian virus 40 (SV40) may also play a role in
tendinous portion of the diaphragm would elicit submesothelial the development of mesothelioma, acting either independently or
fibrosis at these sites.24 Ferruginous bodies are not usually seen in the synergistically with asbestos. This virus contaminated monkey kidney
plaques but they have been recorded there.126 cells used in the manufacture of early batches of poliomyelitis vaccine
and may have reached humans in this way. SV40 sequences are selec­
tively expressed in many mesotheliomas, the development of which
has been attributed to the ability of the sequences to inactivate the p53
PLEURAL TUMOURS and Rb tumour suppressor genes and promote the secretion of various
growth factors.147–150 However, subsequent investigations have resulted
Pleuropulmonary blastoma is dealt with on page 623 and this section in both supportive and contrary findings151–156 and the relationship of
will consider only those tumours that are initially confined to the SV40 infection to development of mesotheliomas remains uncertain.
pleura, of which mesothelioma is by far the most important. The risk of mesothelioma is substantial in the mining, transport­
ation and processing of asbestos but is dose-related and can be mini­
mised by precautionary measures based on good industrial hygiene.157
Mesothelioma The principal manufacturing industries using asbestos are those pro­
ducing items such as specialised cement products, insulating materials
Mesotheliomas arise most commonly in the pleura but also develop and brake linings. All industries applying and refitting asbestos insula­
in the peritoneum and occasionally in the pericardium or tunica tion carry a potential risk and many cases have been seen in construc­
vaginalis of the testis.127,128 They are malignant neoplasms: the terms tion and demolition work, ship-fitting and other dockyard work, and
‘benign fibrous mesothelioma’ and ‘multicystic mesothelioma’ are railway carriage maintenance. Many joiners, heating engineers, boiler­
misnomers in that the former is not of mesothelial origin and the men, railwaymen and former naval servicemen have been exposed
latter is not neoplastic (see solitary fibrous tumour on page 730 and unknowingly158 whilst some exposure is para-occupational, incurred
multicystic mesothelioma on page 729). A benign mesothelial neo­ by men such as shipyard welders who work alongside those applying
plasm is encountered in the peritoneum and rarely in the pleura but or stripping asbestos. The families of asbestos workers are also at
is termed adenomatoid tumour rather than benign mesothelioma increased risk through being exposed to asbestos dust carried home
(see p. 729). Well-differentiated papillary mesothelioma is a low- on work clothes. Such exposure may occur very early in life.159 Others
grade mesothelioma that warrants separate consideration (see p. 729). appear to have developed mesothelioma because they live in the
vicinity of asbestos mines or factories, but it is always difficult to
exclude occupational, para-occupational or domestic exposure in such
Incidence cases.160,161 However, environmental exposure undoubtedly occurs in
Mesothelioma was very rare in the nineteenth and early twentieth parts of the world such as Turkey and the Metsovo region of Greece
centuries. Indeed, as late as the 1950s, some eminent authorities where the soil contains asbestos,121,122,162,163 and town dwellers are
denied its existence. However, it is now recognised to be one of the subjected to continuous low levels of asbestos exposure from sources
most important occupational diseases. Its incidence has been steadily such as brake linings. Thus, exposure to asbestos may be:
rising and in industrialised countries mesothelioma now accounts for • direct, from the handling of asbestos ore or its products
about 1% of all cancer deaths. The highest annual crude incidence • para-occupational, from working alongside asbestos workers, as
rates (about 30 cases per million) are observed in Australia, Belgium in shipyards
and the UK.129,130 • household, for example from the clothes of an asbestos worker
Measures to curtail exposure to its principal cause, asbestos, were • neighbourhood, from living near an asbestos mine or factory
introduced and progressively strengthened in many countries in the • ambient.

717
 Pathology of the Lungs

The carcinogenicity of asbestos depends on its physical properties The sex incidence of mesothelioma is also largely determined by
and it is notable that not all forms of asbestos carry the same risk of asbestos exposure, men greatly outnumbering women, a difference
mesothelioma.164 The various types of asbestos have been described that is not so marked in the rare cases where asbestos does not appear
on page 342, where a broad division was drawn between the serpen­ to be involved. In all other respects mesothelioma in women is
tine chrysotile (white asbestos) and the straight-fibred amphiboles, iden­tical to mesothelioma in men.195
crocidolite (blue asbestos), amosite (brown asbestos), anthophyllite, The cumulative dose of asbestos is of greater importance than the
tremolite and actinolite. Chrysotile accounts for more than 90% of all duration of exposure: short periods of high exposure can be very
asbestos used and of the others only crocidolite and amosite are now hazardous. Some women who developed mesotheliomas after making
produced commercially. The principal cause of mesothelioma in the military gas masks in Nottingham during the Second World War had
UK is crocidolite whilst in North America it is amosite. Chrysotile is only short periods of exposure, in some cases as little as 3 months,
thought not to cause mesothelioma165,166 and the few mesotheliomas but their exposure was heavy. Nevertheless, the level of exposure
associated with this form of asbestos are probably due to con­ necessary to cause pleural mesothelioma is far less than that required
tamination of the chrysotile by tremolite.167–169 Contamination with to cause asbestosis (Table 7.1.5, p. 346). Peritoneal tumours are gener­
tremolite is also the probable explanation of the occasional mesothe­ ally associated with relatively heavy exposure and the proportion of
liomas observed in talc and vermiculate miners167 and of mesothelio­ meso­theliomas arising in the peritoneum diminishes as occupational
mas reported in southeast Turkey amongst inhabitants of houses hygiene improves: in one asbestos manufacturing company the ratio
whitewashed with a non-asbestiform ore.170 of peritoneal to pleural tumours fell from 5 : 1 before 1921 to 1 : 3 after
The particular physical properties of asbestos that determine its 1950.196 The proportion of peritoneal cases has always been low in
carcinogenicity are fibre diameter, length and biodegradability. Its mining. Ingested asbestos fibres do not penetrate the walls of the
dimensions determine whether a fibre reaches the lung and all three gastrointestinal tract, and peritoneal mesothelioma is presumed to be
factors determine whether it is retained there or cleared. Fibres thinner caused by inhaled asbestos crossing both the pleura and the
than 0.25 µm and longer than 5 µm carry the greatest risk of meso­ diaphragm.197
thelioma.171 The curly chrysotile fibres tend to settle in large airways The assessment of asbestos load is described on page 344 but a
and to be eliminated by ciliary action, whilst those that reach the lung simple first step is to examine thick (20–30-µm) unstained sections
break up more readily than the amphiboles and are cleared more of the lungs for asbestos bodies. In cases of mesothelioma the
rapidly. Because of this a former chrysotile miner may ultimately have presence of as few as one asbestos body in a standard 5-µm thick
more tremolite than chrysotile in his lungs, although the tremolite is section of lung is regarded as evidence of substantial exposure,198–200
only a contaminant of the mined ore. obviating the need for more sophisticated procedures. However, an
The physical properties of asbestos not only govern whether it inability to identify asbestos bodies in histological sections does not
reaches, and is cleared from the lung, but are also responsible for its exclude asbestos causation.
carcinogenicity. Thus, whereas the injection of fibrous tremolite into Even after an exhaustive occupational history and the most detailed
the pleural cavity of rats produced mesotheliomas, an equal dose of analysis, no cause can be identified for some mesotheliomas. The
non-asbestiform tremolite did not.172 proportion of such cases varies considerably, probably depending
Fibrous minerals other than asbestos may have fibres of the same upon the degree of industrialisation so that in a non-industrialised
shape and size as the dangerous amphibole forms of asbestos. In country the low background incidence becomes important. In the UK
central Turkey a high incidence of mesothelioma is associated with and the USA, 10–20% of mesotheliomas appear to be unrelated to
environmental exposure to erionite, which is a fine fibrous form of asbestos exposure.201–206 One group reported that asbestos bodies were
the volcanic silicate, zeolite.125,173 In inhalation experiments, erionite identified in histological sections in 57% of mesothelioma cases, that
exceeds asbestos in its ability to induce mesotheliomas.174 Much atten­ the figure reached 83% when asbestos bodies were sought in lung
tion therefore centres on the many other naturally occurring fibrous digests by light microscopy and 89% when electron microscopy was
minerals, some of which are in commercial use as oil absorbents or used to identify coated and uncoated fibres in lung digests (Fig.
cat litter, and on synthetic fibres.175 Fortunately, many of these fibres 13.11).205,207 Another group, which confined their attention to a careful
are not in the respirable range but the potential dangers are shown by occupational history or the presence of asbestos bodies in lung
the high incidence of mesothelioma in rats injected with fibreglass sections, identified asbestos exposure in 87% of cases.206
and other fibres particles of respirable size.176–178 A variety of broncho­ Evidence that there is a low background of mesothelioma unrelated
pulmonary abnormalities is reported in workers exposed to fine to asbestos derives from several sources:
fibreglass 179 but so far at least there have been no convincing reports • Mortality trends in industrialised countries record an equal sex
of synthetic fibres causing cancer in humans.180–182 incidence in the early twentieth century.
Susceptibility to mesothelioma is probably influenced by genetic • The subsequent increase is largely confined to men.
factors. Thus, the prevalence of mesotheliomas induced ex­­ • Mesothelioma in childhood is rare, but well established.190–194
perimentally with asbestos was found to vary according to the strain • Although rare, associations with possible causes such as
of mice studied.183 Genetic factors are also suggested by the develop­ radiotherapy and chronic infection are recorded.140–145
ment of mesothelioma in families184,185 but it must be remembered
that one family member may inadvertently expose others to
asbestos, for example by bringing home soiled work clothes.
Pathogenesis
The age incidence of mesothelioma is largely determined by the Three main hypotheses have been adduced to explain the induction
time at which an individual is first exposed to asbestos and the latent of mesothelioma by asbestos: (1) an oxidative stress theory based on
interval between exposure and presentation, which is generally over the fact that macrophages release large amounts of free radicals when
20 years, with a mean of about 40 years, but may be as short as 15 they ingest asbestos fibres; (2) a chromosome-tangling theory that
years.186–188 Where environmental exposure occurs from birth, meso­ envisages asbestos fibres damaging chromosomes during cell division;
theliomas start to develop from about the age of 14.189 The cause of and (3) an absorptive theory that postulates carcinogens being con­
mesotheliomas occurring in younger children is unknown.190–194 centrated on the surface of the fibres.207a
Cases without evidence of asbestos exposure are touched upon again It is likely that most mesotheliomas commence as localised lesions
below. on the parietal pleura and evolve through a non-invasive phase

718
 Pleura and chest wall Chapter | 13 |

may result in superior vena caval compression, Horner’s syndrome or

recurrent laryngeal nerve palsy.226 Invasion of the spinal canal may
cause paraplegia.227 Chest radiographs typically show diffuse pleural
thickening on the affected side but at first the tumour may be localised
Asbestosis or multifocal. Symptoms due to metastases generally develop only
23%
terminally, if at all, but rarely they are the initial manifestation of the
AB’s on disease.228–230 Paraneoplastic syndromes include thrombocytosis due
H&E Stained
Sections to the production of interleukin-6 by the tumour, which may also be
19% responsible for in amyloidosis and pseudohyperkalaemia (high serum
AB’s on but normal plasma potassium levels).213,231–233
Fe-Stained Sections
15%
Pleural aspiration
Elevated AB Content
(%) in Lung Tissue Digests As well as relieving breathlessness, aspiration of pleural fluid can be
0 26% helpful diagnostically, particularly in the recognition of metastatic
23 Elevated Asbestos Fiber tumour.234,235 Its sensitivity in the diagnosis of mesothelioma depends
42 Content by SEM/EDXA upon the expertise of the cytologist and a biopsy is often preferred.236
6% Opinions vary as to the volume of fluid required for diagnosis of
57
83 malignancy but 50–60 ml appears to be a reasonable compro­
No Evidence of Asbestos Etiology mise.237,238 The International Mesothelioma Interest Group
89 11%
recommends that a cytological suspicion of mesothelioma be fol­
100
lowed by tissue confirmation supported by both clinical and radio­
Figure 13.11  Asbestos load in mesothelioma. In 23% of cases asbestosis logical data.239
is evident (ABs), in another 19% there is no pulmonary fibrosis but Exfoliated cells may be examined in films in the conventional way
asbestos bodies; can be identified in standard sections; in a further   or concentrated into cell blocks which may be sectioned for light or
15% asbestos bodies are detected when iron stains are employed; in a electron microscopy. Immunocytochemical procedures (see below)
further 26% asbestos body counts in lung digests are elevated; in a may be applied to either smears or sections of these cells.240–242 Pleural
further 6% excess asbestos fibre is found when lung digests are
fluid is particularly suitable for flow cytometry, cytogenetic and
examined by scanning electron microscopy; leaving 11% in which a link
with asbestos cannot be established.205,207 H&E, haematoxylin and eosin; molecular studies and scanning electron microscopy.209a–244
Fe, iron; SEM, scanning electron microscopy; EDXA, energy-dispersive The cytological diagnosis of adenocarcinoma or other types of
X-ray analysis. (Courtesy of Professor V Roggli, Durham, USA.) metastatic tumour in serous effusions is often relatively straight­
forward for, in addition to reactive mesothelial cells, recognisable by
their microvillous border and denser perinuclear staining, a separate
population of malignant cells can be recognised.245–247 Adenocarcinoma
cells form clumps with a smooth border rather than a scalloped edge,
which is characteristic of mesothelioma.239 On the other hand, the
known as mesothelioma-in-situ (see below).208,209 These morpho­ distinction between benign and malignant mesothelial cells is
logical changes are preceded by molecular alterations that activate notoriously difficult.236 Reactive mesothelial cells can be alarmingly
receptors, inactivate tumour suppression and promote cell signalling. large and binucleate or multinucleate. The nuclear-to-cytoplasmic
Both asbestos exposure and SV40 transfection of human mesothelial ratio is often not significantly increased in mesothelioma but nuclear
cells cause genetic modifications such as AP-1 activation that favour irregularity and prominent multiple nucleoli may suggest malignancy.
cell growth and malignant change.150 The tumour suppressor genes A feature particularly suggestive of epithelioid mesothelioma is the
p 16 and p 21 are often inactivated in mesothelioma209a and several presence of papillary aggregates or morulae containing up to 100 or
autocrine growth factors have been identified in mesotheliomas. The so cells and having a scalloped edge (Fig. 13.12).
latter include platelet-derived growth factor, transforming growth Although attention is usually concentrated on the cellular com­
factor-β, vascular endothelial growth factor, tumour necrosis factor-α ponent, the supernatant fluid can also be informative. Many meso­
and inhibitors of apotosis210–220 while oncogenes identified within theliomas, but not carcinomas, secrete hyaluronic acid which can
mesotheliomas include p53, RAS and bcl-2.221–223 Mesotheliomas are then reach high levels in the pleural fluid.248,249 Some immunocyto­
often infiltrated by lymphoid cells that might be expected to suppress chemical tumour markers may be detected in pleural fluid. For
tumour growth but they include regulatory T cells that suppress an example, the demonstration of carcinoembryonic antigen (CEA) in a
efficient immune response.224 Chromosomal abnormalities are pleural effusion favours metastatic carcinoma.250–252 Conversely, raised
common but there is no single, specific defect, indicating a levels of soluble mesothelin favour mesothelioma.253,254
broad spectrum of heterogeneity, as reflected in the tumour’s
morphology.225,225a
Macroscopic features
Pleural mesothelioma is commoner on the right than the left, in a
Clinical features ratio of 3 : 2.206 The reason for this is poorly understood but may
Mesothelioma is more common in men, reflecting their greater depend upon differences in airway orientation, fibre burden, pleural
exposure to asbestos. It generally presents after the age of 50 years but area and chest wall movement on the two sides.
may arise at any age. Asbestos fibres reaching the pleural cavity are concentrated in
Patients with pleural mesothelioma complain of continuous chest Kampmeier’s foci (see p. 708)10 and thoracoscopy has shown that
pain due to infiltration of the chest wall and dyspnoea due to pleural meso­thelioma first develops in the parietal pleura where these foci are
effusion or encasement of the lung by tumour restricting chest move­ found, appearing there as multiple small grape-like nodules; involve­
ment. The effusion is often blood-stained. Mediastinal infiltration ment of the visceral pleura follows.208 Progression of the tumour

719
 Pathology of the Lungs

Figure 13.13  Pleural mesothelioma. Dense white tumour encases the

lung and spreads along a fissure.

Microscopic features
Needle biopsy of the pleura is often disappointing and a firm diag­
nosis of mesothelioma is sometimes not possible until thorascopic or
open biopsy, or even autopsy, is undertaken.262 Reactive mesothelial
cells may form loose aggregates and it is important that in small
biopsies these are not mistaken for true papillae, which are suggestive,
but not pathognomonic, of mesothelioma.246,263
B Despite their epithelioid appearance, mesothelial cells are of meso­
dermal origin and their malignant counterparts display a wide
Figure 13.12  Mesothelioma in a pleural aspirate. (A) The exfoliated diversity of differentiation, which has led to the alternative name of
malignant cells are clumped together in so-called morulae. (B) The cells mesodermoma being suggested.264–266 This diversity is reflected in the
stain strongly for epithelial membrane antigen, a feature supportive, but traditional histological classification of mesotheliomas as epithe­
not diagnostic, of malignancy.
lioid, sarcomatoid (or fibrous) and biphasic (or mixed).267 The epi­
thelioid type is the commonest in most series268,269 but widespread
sampling of the tumour, which is possible postmortem, increases the
proportion of biphasic tumours.270,271
A mixed (biphasic) pattern combining the epithelioid and sar­
results in coalescence of the nodules to form plaques and, ultimately, comatoid features described below is the classic pattern of meso­
a continuous sheet of tumour fusing the visceral and parietal pleura thelioma (Fig. 13.14). The two components often merge where they
and obliterating the pleural space (Fig. 13.13), except for occasional meet and the combination makes a distinctive picture that presents
residual loculi containing glairy fluid or blood. Areas of necrosis or few diagnostic problems (which are considered below).
haemorrhage and softer areas of mucoid consistency may be seen and In well-differentiated tumours of purely epithelioid type a tubulo­
occasionally the whole tumour appears gelatinous. In the late stage, papillary pattern is most commonly seen (Fig. 13.15), but the pattern
tumour encases the lung as a layer of dense white tissue up to several may be purely tubular, composed of well-formed glandular spaces, or
centimetres thick, which extends into fissures and infiltrates the purely papillary, in which small, irregular, cystic spaces are lined by
peripheral lung parenchyma so that at autopsy the lung has to be tumour cells and filled by papillary projections with delicate cores of
forcibly dissected from the chest wall. It is very rare for a mes­o­ con­nective tissue and a covering of tumour cells. As in other papillary
thelioma to remain localised and form a solitary mass; not surpris­ neoplasms, psammoma bodies (calcospherites) may be formed.
ingly, such localised mesotheliomas have a comparatively good Mesothelioma may also be strikingly glandular in morphology (Fig.
prognosis.255–260 A feature of mesothelioma that is often stressed is a 13.16). Individual tumour cells are generally cuboidal or polygonal
supposed predeliction to infiltrate along biopsy tracks or surgical with moderate amounts of eosinophilic cytoplasm and round nuclei
incisions, but this is a feature of all malignant tumours.261 Metastasis containing a single nucleolus. Sometimes they are peg-shaped, with
is late but at death may be widespread (see below). only a narrow base (Fig. 13.17). In many cases mitoses are infrequent

720
 Pleura and chest wall Chapter | 13 |

A
Figure 13.14  Biphasic mesothelioma comprising both epithelioid and
sarcomatoid elements.

B
A

Figure 13.16  Epithelioid mesothelioma in which the glands closely

resemble those of an adenocarcinoma. In (A) the stroma is fibrous while
in (B) it is myxoid.

Figure 13.15  Epithelioid mesothelioma of tubulopapillary pattern. (A) A

papillary pattern is seen on the surface while (B) a tubular pattern is seen Figure 13.17  Epitheliod mesothelioma in which some of the tumour
invading the stroma. cells are peg-shaped.

721
 Pathology of the Lungs

of the pleura for an otherwise typical mesothelioma in an asbestos

worker is inappropriate and may prejudice a justifiable claim for
industrial compensation.296 Lymphangiomatoid is another rare
pattern.297
Mesotheliomas frequently evince distinctive features when stained
for mucus or examined by immunocytochemistry or electron
microscopy. These procedures are often invaluable in the differential
diagnosis of a tumour involving the serous cavities of the body and
will now be considered.

Differential diagnosis of mesothelioma

The classic gross appearance of a pleural mesothelioma, that of a firm
pale tumour encasing the lung, may be mimicked by extensive pleural
fibrosis or by a peripheral carcinoma of the lung growing along
the pleura – so-called pseudomesotheliomatous carcinoma of the
lung,298–300 as well as other tumours growing in a similar manner
(see Fig. 12.3.21, p. 637).301,302 Each of the histological types of
mesothelioma presents its own diagnostic problems. A distinction
has to drawn between:
Figure 13.18  Mesothelioma-in-situ. This term should only be used when 1. biphasic mesothelioma and other biphasic tumours
there is unequivocal invasion adjacent to the surface proliferation (as
2. epithelioid mesothelioma and adenocarcinoma
there is on the right).
3. poorly differentiated epithelioid mesothelioma and poorly
differentiated squamous cell carcinoma
4. epithelioid mesothelioma and reactive mesothelial hyperplasia
5. sarcomatoid mesothelioma and other spindle cell tumours
and there may be little cellular pleomorphism. Occasionally there is
6. sarcomatoid mesothelioma and fibrosis.
atypia but no evidence of invasive activity; this appears to be a pre­
malignant state.272 The term ‘mesothelioma-in-situ’ has been intro­ These will now be considered in turn:
duced to describe such changes but it is recommended by its originators
that the term should only be used when the surface changes are Biphasic mesothelioma versus other biphasic tumours
accompanied by invasive tumour (Fig. 13.18).209 Vacuoles may
The distinctive biphasic pattern of the mixed type of mesothelioma
develop within the cytoplasm of tumour cells, compressing the nuclei
presents few diagnostic problems, but pleural involvement by sarco­
and simulating signet ring cell carcinoma.273 In some tumours the
matoid carcinoma303,304 or biphasic synovial sarcoma305–307 may need
glands are lined by flattened cells, giving the tumour a lace-like micro­
to be considered, although both are rare and generally form localised
cystic appearance (Fig. 13.19A). The stroma around the tumour cells
rather than diffuse growths. The key to distinguishing these tumours
is typically myxoid and may be abundant, with wide separation of the
from mesotheliomas of mixed pattern lies in their epithelioid com­
gland spaces, but may be sclerotic (see Fig. 13.16). Undifferentiated
ponent: if this is squamous, sarcomatoid carcinoma can be assumed,
epithelioid mesotheliomas often consist of sheets of cells with abun­
but if it is glandular the problem is similar to that encountered in
dant eosinophilic cytoplasm but few other characteristic features and
distinguishing metastatic adenocarcinoma from mesothelioma of
little intervening stroma (Fig. 13.19B). Alternatively there may be little
purely epithelioid type, which is considered next. The special tech­
cytoplasm and a focal resemblance to small cell carcinoma.274,275 The
niques considered in the next section are equally applicable to the
diversity of these tumours is shown by reports of focal trophoblastic
epithelial component of a sarcomatoid carcinoma or biphasic
differentiation and chorionic gonadotrophin secretion,276,277 or the
synovial sarcoma. Synovial sarcomas also stain strongly and diffusely
tumour having a deciduoid (Fig. 13.19C),146,233,278–282 small cell,274
for bcl-2 protein,308 which is only rarely expressed in meso­
rhabdoid283,284 or clear cell (Fig. 13.19D, E)285–287 phenotype. Their
thelioma, and they show an x:18 translocation, which is not seen
diversity is further emphasised by reports of chromogranin being
in mesothelioma.
demonstrated immunocytochemically in mesotheliomas of glandular
pattern288 and rare cases showing a marked lymphohistiocytoid
reactive infiltrate (Fig. 13.19F) being mistakenly diagnosed as Epithelioid mesothelioma versus adenocarcinoma
lymphomas.289–291 Mucin stains afford one of the simplest and most effective means of
In the sarcomatoid (fibrous) type of mesothelioma the cells are distinguishing epithelioid mesotheliomas from carcinomas (Table
spindle-shaped and set in a varying amount of collagenised stroma 13.2). Mesotheliomas do not produce the epithelial mucins so often
so that the cellularity varies greatly. Markedly pleomorphic, cellular seen in adenocarcinomas and the periodic acid–Schiff (PAS) stain is
foci showing mitotic activity are indistinguishable from other forms therefore a useful first step in this differential diagnosis (Fig. 13.22).
of undifferentiated sarcoma or the tumour may consist of bland The presence of PAS-positive mucin within tumour cells or glands is
spindle cells widely scattered in a densely collagenised stroma consti­ generally regarded as excluding a diagnosis of mesothelioma, although
tuting the so-called desmoplastic variant, which may be very difficult rare exceptions to this are reported in which crystals of hyaluronic acid
to distinguish from scar tissue (Fig. 13.20).291a Cartilaginous, osseous, are responsible for the PAS-positivity.128,273,309,310 PAS-positive material
muscular or fatty differentiation is occasionally seen and, if no epi­ in mesotheliomas may also represent basement membranes rather
thelioid elements are present, the tumour may resemble a primary than epithelial mucin.311 Attention should therefore be confined to the
sarcoma of one of these tissues (Fig. 13.21).264,265,292–296 However, it is contents of the glands or cytoplasmic vacuoles: finely granular cyto­
uncommon for these heterologous patterns to dominate the histologi­ plasmic PAS-positivity should be disregarded. Diastase predigestion
cal picture and the adoption of nomenclature such as osteosarcoma is essential because mesotheliomas are frequently rich in glycogen,

722
 Pleura and chest wall Chapter | 13 |

A B

C D

E F

Figure 13.19  Rarer variants of epithelioid mesothelioma. These include (A) microcystic, (B) solid, (C) deciduoid, (D and E) clear cell and
(F) lymphohistiocytoid. (E, cytokeratin stain.)

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 Pathology of the Lungs

A A

Figure 13.20  Sarcomatoid (fibrous) mesothelioma. (A) A cellular tumour

showing pleomorphism and cytological atypia. (B) The desmoplastic B
variant showing densely hyaline fibrosis and little cellularity. Here the
distinction from scar tissue depends on finding atypical cytokeratin- Figure 13.21  Sarcomatoid mesothelioma showing (A) cartilaginous and
positive spindle cells. A lack of zonation, a storiform pattern, numerous (B) osseous differentiation.
mitoses and foci of necrosis are further features suggestive of
malignancy.

occasionally to the extent that the tumour cells have abundant clear teristics. The first group includes antibodies against CEA, Leu-M1,
cytoplasm.312 B72.3, AUA1, BerEP4, MOC-31, claudin-4 and E-cadherin. Some of
The glycosaminoglycan hyaluronic acid is an acid mucopoly­ these reagents are not without their critics and it is best to employ a
saccharide produced by both normal and neoplastic mesothelial cells. panel of such antibodies. Hyaluronic acid may account for some
Alcian blue (pH 2.5) can be used to demonstrate its presence on the spuriously positive immunocytochemical results so these procedures
apical surface of tumour cells, and within glandular spaces and intra­ may be worth repeating after predigestion with hyaluronidase.314
cellular vacuoles: the staining is abolished by prior treatment with The commonest adenocarcinoma mimicking mesothelioma is that
hyaluronidase, in contrast to acidic glycoproteins produced by some arising in the underlying lung and antibodies specific to the lung such
adenocarcinomas.313 Attention must be confined to the epithelial as those reacting with surfactant apoprotein and TTF-1 are therefore
component because stromal glycosaminoglycans include hyaluronic helpful.315,316 The following sensitivities/specificities are quoted for
acid. Fixation in alcohol or cetyl pyridyl formalin is desirable as it pulmonary adenocarcinoma involving the pleura: TTF-1 72/100; CEA
preserves hyaluronic acid, which is water-soluble and may be leached 93/95; Ber-EP4 80/90; B72.3 80/93; E-cadherin 86/82.317
out by prolonged fixation in aqueous solutions. Monoclonal antibodies that react with mesotheliomas but seldom
Mucicarmine stains both epithelial mucin and hyaluronic acid and with adenocarcinomas include those directed against cytokeratin 5/6,
has no place in the distinction of mesothelioma from adeno­ thrombomodulin (CD141), calretinin, Wilms tumour product-1,
carcinoma unless hyaluronidase controls are employed.314 N-cadherin and podoplanin (D2-40).239,317,318,318a Initial enthusiasm
These traditional mucus stains are now widely augmented, or for HMBE1, OV632, mesothelin and CD44 hyaluronate receptor has
indeed replaced, by immunohistochemical staining (see Table 13.3). waned. More recently h-caldesmon and caveolin-1 have also been
Antibodies of diagnostic utility fall into two groups, those that recog­ reported as being highly specific for mesothelioma.319,320 With cal­
nise epithelial epitopes and those that recognise mesothelial charac­ retinin it is important to confine attention to the nuclei of the malig­

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Table 13.2  Staining characteristics of mesothelioma and

adenocarcinoma

Mesothelioma Adenocarcinoma

Cytoplasm contains glycogen but Glycogen content is small. May

no diastase-resistant PAS- contain diastase-resistant
positive material PAS-positive mucin
Alcianophilic hyaluronic acid in No hyaluronic acid within or on
glands or on tumour cell tumour cells
surface
CEA, Leu M1, BerEp4 and AUA1 CEA, Leu M1, BerEp4 and AUA1
negative positive
EMA positive at cell membrane EMA positive in cytoplasm and at
cell periphery
Cytokeratin 5/6, Cytokeratin 5/6, thrombomodulin
thrombomodulin and and calretinina negative A
calretinina positive
a
Attention should be confined to nuclear staining as cytoplasmic staining for
calretinin is non-specific.
PAS, periodic acid–Schiff; CEA, carcinoembryonic antigen; EMA, epithelial
membrane antigen.

Figure 13.22  Metastatic adenocarcinoma. A diastase-controlled periodic

acid–Schiff stain is strongly positive, confirming that the tumour is a
metastatic adenocarcinoma rather than an epithelioid mesothelioma.

nant cells as cytoplasmic staining is far less specific for cells of

mesothelial origin (Fig. 13.23). Podoplanin is specific for meso­
theliomas but whereas the staining is membranous with epithelioid
mesotheliomas, it is cytoplasmic with sarcomatoid mesotheliomas.321
The International Mesothelioma Interest Group recommends that
markers have either sensitivity or specificity greater than 80% for the C
lesion in question,239 although how many markers are required for
confident diagnosis remains a matter of debate.322 Figures quoted for Figure 13.23  Immunohistochemistry for epithelioid mesothelioma. In
epithelioid mesothelioma are shown in Table 13.3.317 contrast to metastatic adenocarcinomas, epithelioid mesotheliomas
Whilst these mesothelial markers are relatively dependable in dis­ typically stain for (A) calretinin (nuclear stain), (B) cytokeratin 5/6
(cytoplasmic stain) and (C) thrombomodulin (membrane stain).
tinguishing mesothelioma from adenocarcinoma, they are not so
dependable in relation to other carcinomas of the lung. They not
infrequently stain squamous cell, small cell, large cell and giant cell
carcinomas,323,324 but most of these are distinguishable on their mor­
phology and their expression of other epitopes such as TTF-1.

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Table 13.3  Sensitivities and specificities of epithelioid

mesothelioma markers versus adenocarcinoma317

Immunocytochemical Sensitivity Specificity

marker (%) (%)

Cytokeratin 5/6 83 85
Calretinin 82 85
N-cadherin 78 84
Wilms tumour product-1 77 96
Thrombomodulin 61 80
Figure 13.24  Transmission electron micrograph of an epithelioid
mesothelioma showing long curly microvilli intermingled with collagen.

Table 13.4  Ultrastructural distinction between mesothelioma (Table 13.4).332–337 Adenocarcinomas often contain secretory granules,
and adenocarcinoma which are never found in mesotheliomas. Conversely, mesotheliomas
generally have long, slender, curved microvilli that give a bush-like
Mesothelioma Adenocarcinoma appearance to the surface of the cells (Fig. 13.24) and differ from the
short stubby microvilli of an adenocarcinoma. The long microvilli are
Microvilli elongated, slender and Microvilli short and stubby with easily recognisable by scanning electron microscopy. They cover all
bushy without glyocalyceal glycocalyceal bodies. Generally free surfaces of the mesothelioma cells, including both intracellular
bodies. May mingle with confined to the luminal surface and intercellular lumina, and may come into direct contact with
collagen fibrils and seldom mingle with
stromal collagen through deficiencies in the basement membrane (see
collagen fibrils
Fig. 13.24), a feature that is rarely encountered in carcinomas. Neither
Apical tight junctions Terminal bars near lumen long curly microvilli nor contact between microvilli and collagen is
totally specific but either of these findings is very suggestive of
Long, well-developed Short, less well-developed
mesothelioma.338 At points of contact between mesothelioma cells,
desmosomes desmosomes
well-developed and often unusually long desmosomes are found.
Perinuclear tonofilaments Irregularly distributed Abundant intermediate filaments (tonofilaments) form bundles that
intermediate filaments may converge on cell junctions, or more characteristically are perinu­
clear. Large collections of glycogen and occasional fat droplets are
No mucin granules May contain mucin granules
often evident in the cytoplasm of mesothelioma cells. Tubular struc­
Abundant glycogen Variable amount of glycogen tures that possibly represent crystallised proteoglycan have been iden­
tified in the rare mesotheliomas referred to above as containing
Scanty fat droplets No fat
hyaluronidase-resistant PAS-positive droplets.310
Separation of small cell anaplastic mesothelioma274,275 from small
cell carcinoma involving the pleura339 depends upon wide sampling
Extrapulmonary carcinomas that may express some of these meso­ to identify more characteristic areas. The neuroendocrine markers
thelial markers include transitional cell and renal cell carcinomas, chromogranin, neuron-specific enolase, Leu-7 and neural cell adhe­
the latter exceptional in also failing to express the epithelial marker sion molecule (CD56) are not specific, being found in a proportion
CEA. Results obtained with mesothelial markers therefore need to be of mesotheliomas.288,340,341
viewed with some caution and assessed in conjunction with clinical, Flow cytometric ploidy studies have been conducted in the hope
radiological and morphological features.325,326 Separation of the rare of discriminating better between carcinoma and mesothelioma.
clear cell type of mesothelioma285–287 from metastatic clear cell carci­ Differences are reported but these are not absolute and therefore of
noma of the kidney can be problematical. One authority recommends limited use in individual cases: 47–78% of mesotheliomas are diploid
the mesothelioma markers cytokeratin 5/6, podoplanin and meso­ whereas 85–88% of carcinomas are aneuploid.342–344 Despite the rela­
thelin and the renal markers CD15 and RCC Ma.239 It is advisable to tive lack of aneuploidy in mesotheliomas, cytogenetic studies have
correlate these laboratory results with imaging studies. documented abnormal karyotypes in about three-quarters of cases but
In distinguishing peritoneal mesothelioma of epithelioid pattern no consistent abnormality has been identified.344 However, microarray
from serous carcinoma of the ovary a similar panel of antibodies may data assessing expression levels of a small number of genes as ratios
be employed but calretinin is more sensitive than thrombomodulin, have shown similar specificity to immunohistochemistry in distin­
cytokeratin 5/6 and BerEP4 than CEA.327 It is also worth adding guishing mesothelioma from metastatic adenocarcinoma.345
oestrogen receptor antibody as a specific marker of ovarian serous Many asbestos workers are also cigarette smokers and it is therefore
carcinoma.328,329 inevitable that occasional cases of synchronous pulmonary carcinoma
Electron microscopy is now used less than formerly but when the and mesothelioma will arise, necessitating particularly careful
sample is small (as in cell block preparations) or the histological and evaluation.346
immunohistochemical findings are of uncertain significance, it can
be very helpful in distinguishing mesotheliomas from other
Poorly differentiated epithelioid mesothelioma versus
tumours.330,331 Although epithelioid mesotheliomas have several poorly differentiated squamous cell carcinoma
ultrastructural features in common with adenocarcinomas, sufficient Specific markers of squamous cell carcinoma are as yet not as well
differences may be present to enable a confident diagnosis to be made substantiated as those for adenocarcinoma, which is unfortunate

726
 Pleura and chest wall Chapter | 13 |

Table 13.5  Immunohistochemical distinction of sarcomatoid mesothelioma, sarcoma and sarcomatoid carcinoma364,378

Pankeratin CK5/6 Calretinin Thrombomodulin SMA TTF-1 D2-40

Sarcomatoid mesothelioma 70% Rare 70% 70% 60% 0/10 87%

Sarcoma 17% Rare 17% 38% 58% Negative
Sarcomatoid carcinoma 90% Rare 60% 40% 10% Pulmonary may be positive 26%

SMA, smooth-muscle actin; TTF-1, thyroid transcription factor-1.

because without obvious evidence of keratinisation it may be difficult diagnosis, especially if the tumour is localised and there is no history
to distinguish squamous cell carcinoma from poorly differentiated of exposure to asbestos.362 Sarcomatoid mesotheliomas frequently
epithelioid mesothelioma. Furthermore, markers such as cytokeratin express broad-spectrum cytokeratins363 and this provides strong but
5/6 and calretinin that distinguish mesothelioma from adenocarci­ not infallible support for the tumour being a sarcomatoid meso­
noma are expressed by some squamous cell carcinomas.323,347 At thelioma rather than a sarcoma (Table 13.5),364 and helps in the
present discrimination is best achieved with a combination of the distinction of lymphohistiocytoid mesothelioma from lymphoma.
mesothelioma marker Wilms tumour suppressor gene-1 and the squa­ However, it has to be remembered that the submesothelial spindle
mous cell carcinoma markers p63 and MOC-31.239,348 cells of reactive pleural fibrosis also express cytokeratin18,365: attention
should therefore be concentrated on the deeper parts of the lesion.
Epithelioid mesothelioma versus reactive Conversely, between 16 and 40% of sarcomatoid mesotheliomas fail
mesothelial hyperplasia to stain for cytokeratin.128,366 It is therefore helpful that calretinin and
thrombomodulin react with some sarcomatoid as well as epithelioid
The epithelioid pattern of mesothelioma may be simulated both by
mesotheliomas,364,367 although their specificity and sensitivity in rela­
papillary hyperplasia of the surface mesothelium and by the presence
tion to primary pleural sarcomas and sarcomatoid carcinomas of lung
of groups of hyperplastic mesothelial cells trapped in granulation
are sufficiently low that they are of questionable diagnostic value.322
tissue beneath the surface. Cellular pleomorphism and mitotic activity
For example, calretinin often stains synovial sarcomas.368 However,
may be lacking in mesothelioma and there are often few other
podoplanin staining is more specific, decorating the cytoplasm of
pointers to malignancy. However, mesothelial inclusions entrapped
sarcomatoid mesothliomas but not staining synovial sarcomas.321
by granulation tissue differ from an invasive mesothelioma in that
Sarcomatoid mesothelioma also lacks the SYT-SSX fusion of synovial
they are often aligned parallel to the surface because they represent
sarcoma.369,370
the line of the former pleural surface, and they do not invade the fat
The diversity of differentiation seen with mesotheliomas means that
underlying the parietal pleura. Invasion of fat, muscle or lung is
the expression of markers such as vimentin and smooth-muscle actin
undoubtedly the best indicator of neoplasia.349,350 Caution is needed
does not exclude a diagnosis of mesothelioma, even if the tumour is
in the interpretation of non-invasive papillary proliferation of the
cytokeratin-negative.293,363,371,372 However, a combination of cytokeratin-
surface mesothelium in view of the possibility that it may represent a
negativity and CD34-positivity would favour localised fibrous tumour
premalignant state (see Fig. 13.15a and mesothelioma-in-situ209
of the pleura. Epithelioid haemangioendothelioma and other vascular
above). In effusions, macrophages may mimic exfoliated mesothelial
tumours may mimic mesothelioma both grossly and microscopically
cells, both reactive and malignant, but may be recognised by the inclu­
but can be distinguished by their positive endothelial markers (factor
sion of the macrophage marker CD68 in the immunohistochemical
VIII-related antigen, von Willebrand factor, CD31, CD34 and Ulex
panel. The spread of non-malignant mesothelial cells to regional
europaeus agglutinin).302,373–376
lymph nodes is another trap for the unwary.351–358
Sarcomatoid mesotheliomas also need to be distinguished from a
Immunohistochemistry has a limited role in the recognition of
variety of epithelial spindle cell tumours, notably the pleural
pleural malignancy. Epithelial membrane antigen (EMA) and p53 are
metastases of monophasic sarcomatoid carcinomas of the lung, renal
found more often in malignant mesothelioma than reactive hyper­
carcinomas of spindle cell or eosinophilic polygonal cell type, and
plasia, whereas the reverse is found with desmin,308,359,360 but many
melanomas. The last of these differs from mesothelioma in lacking
find these antibodies unhelpful in the individual case.349 The follow­
cytokeratins and staining for S-100 and HMB45 antigens. Lung
ing sensitivity/specificity fiqures are quoted: EMA 74/89; p53 58/91;
markers such as surfactant apoprotein and TTF-1 may occasionally be
desmin 83/83.317 The combination of EMA and p53 positivity, together
useful in distinguishing spindle cell carcinoma of the lung (see Table
with lack of desmin expression, may give additional weight to a
13.5)364 and wider sampling of many apparently monophasic sarco­
benign or malignant diagnosis, but should not override the morpho­
matoid carcinomas of the lung reveals that they are biphasic, permit­
logical features.349,361 When there is doubt a report of ‘atypical
ting a distinction based upon the properties of the epithelioid
mesothelial proliferation’ is recommended.350 It is likely that in
component,377 as described above. Of 13 other immunomarkers, one
the near future the definition of genetic abnormalities will con­
group reported that only D2-40 (antipodoplanin) stained most sar­
tribute to the distinction of malignant and reactive mesothelial
comatoid mesotheliomas (87%) and few sarcomatoid carcinomas of
proliferation.361a
the lung (26%), the specificity for mesothelioma being 75% (see Table
13.5).378 Sarcomatoid renal carcinoma may be very difficult to distin­
Sarcomatoid mesothelioma versus guish from mesothelioma, as there is some overlap in their immuno­
other spindle cell tumours histochemical profiles.325,326 If a renal origin is suspected it is perhaps
Sarcomatoid mesotheliomas may mimic a wide range of connective best to advise a non-invasive investigation of that area by computed
tissue tumours and it is necessary to consider these in the differential tomography or ultrasound.325,379 Thymomas involving the pleura may

727
 Pathology of the Lungs

also mimic mesothelioma in their gross structure but generally retain prognosis than the other histological types.208,269,400,402–406 They tend to
their distinctive microscopic morphology.380–383 behave like carcinomas and spread to the regional lymph nodes whilst
In mesotheliomas that appear purely sarcomatoid by light micros­ sarcomatoid mesotheliomas tend to behave like sarcomas and metas­
copy, electron microscopy may demonstrate the classic biphasic tasise to distant sites; mixed tumours have features of both,269,407 but
pattern by revealing cells with such epithelial features as desmosomes these differences are by no means absolute.394,408 The expression of
and microvilli.334,384,385 factors influencing epithelial mesenchymal transition is touched upon
below. Evidence has been presented that mesothelioma patients
Sarcomatoid mesothelioma versus fibrosis without a history of asbestos exposure survive slightly longer but it
Desmoplastic sarcomatoid mesotheliomas may mimic scar tissue very is uncertain whether this is independent of histological type.409,410
closely (see Fig. 13.20B)386 whilst cellular sarcomatoid mesotheliomas Adverse prognostic factors also include male sex, older age, advanced
may be impossible to distinguish from granulation tissue if, as is stage, weight loss, poor performance status208,406,411 and the expression
sometimes the case, they lack cellular pleomorphism and invasion is of proliferation markers.412–414
not evident in the area sampled. Cytokeratin may be expressed in Various staging systems are in use208,406,415 and protocols for examin­
either reactive or neoplastic fibrous pleural lesions because as sub­ ing mesothelioma specimens have been established.416 The latest TNM
mesothelial cells mature to replace lost mesothelial cells they acquire classification of pleural mesothelioma and stage groupings are shown
mesothelial characteristics.17,18,365 In the absence of invasion, features in Box 13.3 and Table 13.6.417 In assessing mesothelial inclusions in
suggestive of mesothelioma include:
• an absence of the zoning usually seen in reparative processes
whereby cellular granulation overlies denser scar tissue
• a storiform pattern
Box 13.3  TNM classification of pleural mesothelioma417
• necrosis
• numerous abnormal mitoses TX Primary tumour cannot be assessed
• severe cytological atypia. T0 No evidence of primary tumour
Conversely, elongated capillaries aligned at right angles to the T1 Tumour involves ipsilateral parietal pleura with or without
surface favour granulation tissue rather than mesothelioma.239,349 involvement of the visceral pleura
Often however wider sampling to identify frankly malignant foci may T1a Tumour involves ipsilateral parietal pleura. No involvement of
be the only solution. In such cases, orientation of the specimen at visceral pleura
the time of processing may help in distinguishing the organised T1b Tumour involves ipsilateral parietal pleura, with focal
maturation of granulation tissue from the more disorganised growth involvement of visceral pleura
pattern of a desmoplastic mesothelioma. T2 Tumour involves any of the ipsilateral pleura surfaces, with at
When sarcomatoid mesotheliomas invade the mediastinum the least one of the following:
appearances may mimic those of sclerosing mediastinitis,226 in which confluent visceral pleural tumour including the fissure
case cytokeratin staining may be helpful. invasion of the diaphragmatic muscle
Desmoplastic mesothelioma is seldom so lacking in cells as the invasion of lung parenchyma
hyaline pleural plaque, which is virtually acellular.
T3a Tumour involves any of the ipsilateral pleural surfaces, with at
least one of the following:
Spread and prognosis of mesothelioma invasion of endothoracic fascia
Instances of mesothelioma being operable are exceptionable.255,260 invasion of mediastinal fat
There is usually widespread pleural involvement at presentation. solitary focus of tumour invading soft tissue of chest wall
However, once the lung is surrounded, there is a period during which non-transmural involvement of pericardium
the tumour expands locally before metastasising and it is in cases T4b Tumour involves any of the ipsilateral pleural surfaces, with at
such as these that surgery in the form of pleurectomy or extrapleural least one of the following:
pneumonectomy is practised, sometimes preceded by neoadjuvant diffuse or multifocal invasion of soft tissues of the chest wall
chemotherapy.387 However, the place of radical surgery remains any involvement of rib
controversial,130 as does chemotherapy,388 although drugs such as
invasion through the diaphragm to the peritoneum
pemetrexed show promise in selected patients.389,390 Peritoneal meso­
invasion of any mediastinal organ
thelioma is similar, coating the abdominal viscera for some time
before disseminating more widely. It is unusual for patients to present direct extension to the contralateral pleura
because of distant metastases.228,391,392 Eventually however, dissemi­ invasion into the spine
nation may be widespread and should not detract from a diagnosis extension to the internal surface of the pericardium
of mesothelioma.393–396 pericardial effusion with positive cytology
If the tumour is pleural, there is ultimately invasion of the lung and invasion of the myocardium
lymphatic spread to the hilar lymph nodes.397 Infiltration of the dia­
NX Regional lymph nodes cannot be assessed
phragm results in spread to the peritoneum and upper abdominal
lymph nodes, particularly the pancreaticosplenic nodes. The parietal N0 No regional lymph node metastasis
pericardium is infiltrated and multiple deposits may develop in the N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes
opposite pleural cavity. Late in the disease, blood-borne metastases N2 Metastasis in subcarinal lymph nodes and/or ipsilateral internal mammary
may develop in the other lung, liver, adrenals, kidneys, brain, or mediastinal lymph nodes
meninges, bone, skeletal muscle and elsewhere.393–396 Most patients N3 Metastasis in contralateral mediastinal, internal mammary or hilar nodes
succumb within 2 years of diagnosis206,269,398–400 but exceptional cases and/or ipsilateral or contralateral supraclavicular or scalene lymph nodes
survive for more than 10 years.401 Notes: aT3 describes locally advanced but potentially resectable tumour.
To some extent the pattern of spread and prognosis are influenced b
T4 describes locally advanced, technically unresectable tumour.
by the histological type. Epithelioid mesothelioma has a slightly better

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 Pleura and chest wall Chapter | 13 |

Table 13.6  Stage grouping of pleural mesothelioma TNM

subsets

Stage T N M

IA 1a 0 0
IB 1b 0 0
II 2 0 0
III 1 or 2 1 0
1 or 2 2 0
3 0,1 or 2 0
IV 4 Any N 0
Any 3 0
Any Any 1

mediastinal lymph nodes it should be remembered that these are not Figure 13.25  Well-differentiated papillary mesothelioma. This tumour is
always neoplastic.351–358 composed of papillae in which a mainly single layer of cuboidal cells
The production of autocrine growth factors by mesotheliomas covers delicate connective tissue cores.
would be expected to exert an adverse influence on survival, and
several have been identified, including platelet-derived growth factor,
transforming growth factor-β and vascular endothelial growth
factor.210–217 An immediate consequence of autocrine activity would be
increased mitotic activity and the production of proliferating cell Multicystic mesothelioma (multicystic
nuclear antigen, both of which correlate with the degree of malig­
mesothelial proliferation)
nancy and may be of prognostic418 and future therapeutic value.419
Microarray data assessing expression levels of a small number of genes Multicystic mesothelioma is a rare but well-recognised condition of
as ratios have been used to identify patients with a better prognosis.420 the peritoneum,432,433 that has occasionally been described in the
However, the expression of osteopontin, a glycoprotein involved in pleura.434 Confusion as to its true nature has led to a plethora of
cell/matrix interactions and epithelial mesenchymal transition, is an names, but it is now recognised to be a reactive lesion and the term
adverse prognostic factor.421,422 Oncogenes such as p53, RAS and ‘multicystic mesothelial proliferation’ better reflects its true nature.
bcl-2 have been identified within mesotheliomas221–223 and the effec­ The prognosis is good but it is often difficult to eradicate completely
tiveness of antioncogenes such as veglin, which blocks the action of and the lesion is therefore prone to recur.
vascular endothelial growth factor, is being assessed in clinical trials. Patients with peritoneal lesions are generally young adult women
Other potential therapeutic targets overexpressed in mesothelioma with a history of pelvic inflammation or surgery. Typically, multicystic
include epidermal growth factor, YAP1, MUC1, p21/WAF1, nicotinic lesions attached to the pelvic organs rise up into the abdomen. The
acetyl choline receptor and mesenchymal–epithelial transition patient with pleural disease was a 37-year-old woman complaining of
factor.423–429 pleuritic pain. As a child she came into contact with asbestos insula­
tion but the condition is not thought to be related to this pollutant.
A large unilateral multicystic mass continuous with the parietal pleura
Well-differentiated papillary mesothelioma and tightly adherent to the visceral pleura was identified at
Well-differentiated papillary mesothelioma is a rare, low-grade variant thoracotomy: there were frequent connections between the cyst lining
of epithelioid mesothelioma. Most examples have arisen in the peri­ and the normal parietal pleura.434
toneum of young women but some have been pleural, predominantly Histologically the cysts were lined by a monolayer of flattened cells
affecting middle-aged or elderly patients of either sex.430,431 Some showing papillary infoldings. There was no invasive or mitotic activity.
patients give a history of asbestos exposure.275,430,431 The tumours may The lining cells stained with antibodies to cytokeratin and EMA while
be solitary but more often are multifocal. They generally grow slowly staining for factor VIII-related antigen and CEA was negative. Electron
and show no histological evidence of malignancy but occasional microscopy confirmed the mesothelial nature of the cyst lining.
examples pursue an aggressive course. Of 11 patients with a minimal Immunocytochemistry and electron microscopy are useful in
follow-up period of 24 months, survival ranged from 36 to 180 distinguishing this lesion from a lymphangioma, with which it is
months with an average of 74 months and a 10-year survival of 31%.431 readily confused.
Patients with pleural involvement present with dyspnoea due to
recurrent pleural effusions. Thoracoscopy shows the pleura to be
studded with firm nodules measuring less than 1 cm or that there is
Adenomatoid tumour
a single arborescent tumour measuring up to 5 cm. Histology shows Adenomatoid tumours are distinctive benign mesothelial tumours
papillae consisting of a single layer of bland cuboidal cells covering a that have mainly been described in the scrotum or in relation to the
delicate connective tissue core (Fig. 13.25). The surface cells have female generative organs. Despite the abundance of mesothelium in
small, regular nuclei. They do not contain nucleoli and mitoses are the pleura, adenomatoid tumours are rare in this site.435,436 They
rare. The cytochemical and ultrastructural features are those of an appear as small circumscribed nodules on imaging. Histologically, the
epithelioid mesothelioma, as described above. cells are often vacuolated, giving the tumours a lace-like appearance.

729
 Pathology of the Lungs

Immunocytochemical reactions and electron microscopical appear­

ances are those expected of a mesothelial tumour of epithelioid
pattern, as described above, and the distinction from an early localised
mesothelioma therefore arises. The sharp circumscription and bland
cytological features of an adenomatoid tumour are helpful in this
respect.

Solitary fibrous tumour of the pleura

(localised fibrous tumour)
In the past this tumour has been known as benign or localised meso­
thelioma because, although there is no obvious mesothelial differ­
entiation, early tissue culture experiments were thought to show
biphasic differentiation into ‘epithelial’ and mesenchymal elements.437
This may have been due to the inadvertent inclusion of normal meso­
thelial cells in the culture medium.438 An alternative proposal envis­
ages origin from subpleural mesenchyme and, despite some contrary
views,439,440 immunocytochemical and ultrastructural findings gener­
ally favour this theory. The tumour cells express vimentin and actin
intermediate filaments but not cytokeratin or EMA18,365,441–446 and the
ultrastructural features are those of fibroblasts or myofibro­
blasts.82,443,446–448 Occasional microvilli and poorly formed junctions
are described441,442,447,449 but it is difficult to distinguish neoplastic
Figure 13.26  Solitary fibrous tumour of the pleura, 9 cm in diameter,
mesothelial cells from inclusions of reactive mesothelium by electron
excised with its pedicle and a small portion of lung.
microscopy.439,450 Similarly, it may be difficult to decide whether cells
containing keratin intermediate filaments are an inherent part of the
tumour or mere inclusions of either mesothelium or alveolar epi­
thelium. However, the bulk of the evidence points to these cells
representing entrapment of non-neoplastic elements.451 Accordingly,
the term ‘solitary fibrous tumour’ is preferred.
Solitary fibrous tumour of the pleura differs from mesothelioma in
being unrelated to asbestos exposure and in having a much better
prognosis. Several hundred have now been reported.443,447

Clinical features
These tumours have a wide age range (8–86 years) but most are dis­
covered in middle-aged or older adults. There is no sex predilection.
Some patients are asymptomatic but the majority complain of chest
pain, cough and breathlessness. Many develop finger clubbing and
hypertrophic pulmonary osteoarthropathy. Some experience hypo­
glycaemic episodes due to the secretion of insulin-like growth
factors.443,452–455 Recurrent pleural effusion is also recorded.456

Pathogenesis
The insulin receptor pathway is consistently activated in these tumours,
which, together with their secretion of insulin-like growth factor-2 and
expression of p53, platelet-derived growth factors alpha and beta, and Figure 13.27  Solitary fibrous tumour of the pleura. The tumour has a
hepatocyte growth factor, suggests that their growth is maintained by broad base and is mainly encapsulated.
autocrine activity.457,458

Typically, solitary fibrous tumours of the pleura are well circum­

Pathological features scribed and have a smooth, often bosselated, surface covered by
The tumours occur with equal frequency on the left and right sides, serosa. They may attain a weight of 2–3 kg and a diameter of 30 cm
and three to four times as many arise from the visceral pleura as from or more. The cut surface is pale grey or white, often with a whorled
the parietal pleura. Often they are attached to the surface of the lung pattern. Small areas of softening or necrosis may be present in larger
by a pedicle and are mobile within the pleural cavity (Fig. 13.26). tumours and some have very vascular areas which may become
Tumours of the parietal pleura tend to be sessile with a broader base haemorrhagic.
(Fig. 13.27). Similar tumours are wholly intrapulmonary459–461 (Fig. Microscopically, the appearances are those of a low-grade spindle
13.28) whilst others arise in the mediastinum462 and more distant cell neoplasm of variable cellularity with the tumour cells dispersed
sites.444,463–482 Solitary fibrous tumours may also have been in­­ in a variably hyaline collagenous stroma (Fig. 13.29). The oval or
cluded in a series of invasive fibrous tumours of the trachea.483 spindle-shaped nuclei are fairly small and regular with finely dis­

730
 Pleura and chest wall Chapter | 13 |

Figure 13.28  An intrapulmonary solitary fibrous tumour, 12 cm in

diameter. (Courtesy of Dr W Downey, Melbourne, Australia.)

persed chromatin. In more cellular areas mitoses may be present, but

they are rarely numerous. A storiform pattern, reminiscent of malig­ B
nant fibrous histiocytoma, is sometimes seen. Very vascular areas may
resemble haemangiopericytoma, but often the vessels have a narrow
cuff of hyaline material. There may be focal, or even extensive, myxoid
change.484,485 Liposarcomatous differentiation is recorded as an excep­
tional feature.486 At the periphery, inclusions of non-neoplastic meso­
thelium or bronchioloalveolar epithelium are frequently present.
Another variable feature is the presence of microscopic irregular fis­
sures or small cysts, lined by flattened cells. Occasionally these spaces
are very conspicuous, giving a lace-like microcystic pattern (Fig.
13.30). Electron microscopy shows that their lining cells resemble the
other tumour cells and lack mesothelial or epithelial features. Rare
biphasic tumours are reported in which there are foci of malignant
epithelioid differentiation.487

Immunohistochemistry
Immunocytochemical features distinguishing solitary fibrous tumour
(positive reactions for vimentin and actin and negative reactions for
cytokeratin or EMA) have been mentioned above. In addition, positive
immunostaining for CD34 is obtained in about 80% of solitary
C
fibrous tumours: this is useful in distinguishing solitary fibrous
tumour from mesothelioma, malignant fibrous histiocytoma and
Figure 13.29  Solitary fibrous tumour of the pleura. (A) The tumour is
haem­angiopericytoma, in all of which CD34 reactivity is limited to encapsulated and of variable cellularity. (B) The stroma may be myxoid or
blood vessels.468,488,489 However, the higher the grade of a solitary fibrous. (C) The cells are rounded or spindle-shaped cells show no atypia.
fibrous tumour, the less likely is it to express CD34, and the more
likely to express p53.490 Solitary fibrous tumours may be distinguished
from inflammatory pseudotumours by positive staining for the p53

731
 Pathology of the Lungs

Figure 13.30  Solitary fibrous tumour of the pleura of varying cellularity

and showing microcystic degeneration. A

oncogene product,491 and from gastrointestinal stromal tumours, to

which they have been likened (both being positive for CD99), by their
failure to stain for CD117.492 Nerve sheath tumours rarely arise in the
pleura but the occasional examples reported in this site have resem­
bled solitary fibrous tumours both histologically and by showing
patchy CD34 positivity. However, they are distinguished by also
expressing S-100.493

Prognosis
The prognosis following resection is generally good but in a minority
there is local recurrence and then usually a fatal outcome.443,447,494–496
Exceptional cases present with widespread pleural dissemination.497
Hypercellularity, pleomorphism, necrosis and excessive mitotic activ­
ity (more than 4 mitoses per 10 high-power fields) (Fig. 13.31) suggest
that the lesion will behave aggressively443 but the most important
prognostic factor is the completeness of excision, fundamental to
which is the presence or absence of a pedicle. A staging system has B
been proposed and subsequently validated (Table 13.7).458,498 In
general, pedunculated tumours, which can be removed with their Figure 13.31  Malignant solitary fibrous tumour of the pleura. (A) In
attachment, do not recur.447,499 In a review of 360 previously reported places the tumour shows marked pleomorphism and mitotic activity.  
cases it was found that 88% behaved in a benign fashion after surgical (B) Here, the tumour cells are more rounded, but there is still
resection,447 while in another series of 223 cases, 45 patients (20%) considerable cellularity and mitoses are easily seen.
died due to invasion, recurrence or metastasis.443 In a third series, local
recurrence occurred in 6 of 40 cases and metastasis in 5, and tumour
size and cellularity correlated with malignancy.494 In a fourth series of
88 cases, 10% of patients died of their tumour and another 18% cells are myofibroblasts and therefore stain for vimentin, desmin and
experienced recurrence.458 smooth-muscle actin but lack the CD34-positivity of a solitary fibrous
tumour and the cytokeratin positivity of a desmoplastic sarcomatous
mesothelioma, the two lesions with which they are liable to be
Pleural fibromatosis (desmoid tumour) confused.502 Nuclear staining for β-catenin is positive in most (~80%)
Desmoid tumours, also known as aggressive fibromatosis or musculo­ desmoid tumours but also in a minority (~20%) of solitary fibrous
aponeurotic fibromatosis, generally arise in subcutaneous tissue but tumours.502,503 Recurrence is likely unless excision is wide but
origin in the pleura is also described, often following surgery or other metastasis is not a problem.
trauma.500,501 The pleural examples are liable to be confused with soli­
tary fibrous tumour, both clinically and histologically. They generally
form large localised growths with a broad-based attachment to either
Calcifying fibrous pseudotumour
the parietal or visceral pleura (Fig. 13.32A). The surface is bosselated Calcifying fibrous pseudotumour, as described in soft tissues, has also
but infiltrative activity is evident on the deeper aspect. The tumours been reported in the pleura, peritoneum and mediastinum.504–506 The
are firm and show a pale trabeculated pattern on their cut surface. patients with pleural tumours were young adults who were either
Histologically, they consist of hypocellular fibrous tissue: sparse asymptomatic or complained of chest pain. They had a plaque-like,
spindle cells are set in a collagenous stroma (Fig. 13.32B). The spindle well-circumscribed but non-encapsulated tumour of the visceral

732
 Pleura and chest wall Chapter | 13 |

Table 13.7  The de Perrot staging system for localised pleural

solitary fibrous tumours498

Stage 0 Pedunculated tumour with no histological evidence

of malignancy
Stage I Sessile tumour with no histological evidence of
malignancy
Stage II Pedunculated tumour with histological evidence of
malignancy
Stage III Sessile tumour with histological evidence of
malignancy
Stage IV Multiple synchronous metastases

Figure 13.33  Calcifying fibrous pseudotumour of the pleura. The tumour

consists of thick bundles of hyaline fibrous tissue in which there is focal
psammomatous calcification. (Courtesy of Dr A Gibbs, Penarth, UK.)

pleura. Multiple such tumours were identified in one case.507

Microscopically, these tumours are characterised by abundant hyaline
collagen containing sparse thin spindle cells and foci of psammom­
atous dystrophic calcification (Fig. 13.33). The nature of this lesion is
uncertain but it may represent the late stage of an inflammatory
myofibroblastic tumour, a possibility that derives some support from
the presence of sparse areas of lymphoplasmacytic infiltration, reactiv­
ity of both lesions for CD34 and factor XIIIa, and rare reports of cases
showing transitional features.508–511 Local excision appears adequate
A but it is suggested that if it behaves in a similar fashion to those in
the soft tissues, a low rate of local recurrence might be expected.504

Desmoplastic small round cell tumour

This is a rare tumour that typically presents with widespread ab­­
dominal involvement.512–514 It is not organ-related and appears to
be of mesothelial or submesothelial origin. A few examples arising
in the pleura or lung have been reported.515–517
The tumour generally affects children and young adults, and has a
male-to-female ratio of 4. The tumours that affect the pleura do so in
a diffuse manner so that the clinical, radiological and gross features
all mimic mesothelioma. However, there is no association with asbes­
tos and the histological features are quite different.
Microscopy shows discrete islands of small cells set in an abundant
desmoplastic stroma. The islands of tumour cells vary greatly in size
and shape and are sometimes necrotic. The tumour cells are uniform
but show many mitoses. They have little cytoplasm and round or oval
hyperchromatic nuclei with clumped chromatin and scanty nucleoli.
Pseudorosettes are present but no glands or tubules are evident,
although entrapped mesothelial islands may be seen.
B
Although the histological features are those of an anaplastic growth,
immunocytochemistry indicates diverse differentiation, with epi­
Figure 13.32  Pleural fibromatosis (desmoid tumour). (A) A discrete firm thelial, neuronal and myogenic expression.518 The most consistent
fibrous mass is present deep to the chest wall. (B) Microscopy shows a
immunocytochemical finding is strong focal dot-like positivity for
paucicellular, cytologically bland spindle cell proliferation with dense
background fibrosis, typical of fibromatosis. There is extension into the vimentin, corresponding to a collection of intermediate filaments
peripheral lung, in keeping with the infiltrative properties of this disorder. evident near the nucleus on electron microscopy. Other ultrastructural
The residual visceral pleura elastin can be seen as a corrugated line across features include numerous desmosomes, dense-core granules and
the centre of the image (arrow). occasional gland lumina with microvilli.519 Further positive reactions

733
 Pathology of the Lungs

are obtained with antibodies to desmin and less consistently to cytok­

Table 13.8  Comparison of primary effusion (body cavity-based)
eratin, EMA, neuron-specific antigen, S-100 and glial fibrillary acidic
and pyothorax-associated pleural lymphomas
protein. The tumour cells are negative for actin, lymphocyte markers
and mesothelial markers such as cytokeratin 5/6.
Primary effusion Pyothorax-
The differential diagnosis is firstly from mesothelioma, which this
(body cavity-based) associated pleural
tumour simulates in its gross form. The mixed keratin, vimentin and
neuron-specific enolase expression is compatible with a mesotheli­ pleural lymphoma lymphoma
oma, of which a small cell variant has been described, but the com­ Gross structure Effusion Mass lesion
bined histological, immunocytochemical and ultrastructural features
distinguish the two. There is a closer histological similarity to the Aetiology Immunosuppression, Chronic pleuritis,
malignant small cell tumour of the primitive neuroectodermal tumour typically in an   typically following
series (PNETs), first described in the chest wall (see below), but the HIV-positive male repeated artificial
diverse differentiation towards muscle, nerve and epithelium shown homosexual pneumothoraces
by immunocytochemistry in the tumour now under discussion is HIV status Positive Negative
wider than the purely neural differentiation of the PNETs.520 However,
both express CD99 and there is a close cytogenetic similarity, a HHV8 status Positive Negative
t(11;22)(p13;q11 or q12) translocation nearly matching the t(11;12) EBV status Positive Positive
(q24;q12) abnormality found in PNETs and Ewing’s sarcoma. 11p13
is the locus of the Wilms tumour suppressor gene and it is notable CD20/CD3 Negative/negative (null Positive/negative
that the desmoplastic small round cell tumour reacts with an antibody cell) (B-cell)
to the C-terminal region of the Wilms tumour protein WT1, in con­ HIV, human immunodeficiency virus; HHV, human herpesvirus; EBV, Epstein–
trast to PNETs, which fail to react with this antibody.521 The phenotype Barr virus.
of the desmoplastic small round cell tumour is intermediate between
the purely neural phenotype of the PNETs and the mixed but pre­
dominantly epithelial phenotype of a Wilms tumour, reflecting its
Ewings/PNET and WT1 gene fusion.522,523. Smears from the pleural fluid show dyscohesive, round to ovoid
The prognosis with pleural tumours appears to be as poor as that malignant lymphoid cells with large round nuclei. Some cells have
of patients with abdominal desmoplastic small round cell tumours. irregular or multiple nuclei. Many mitoses are evident. The cells
Of three patients with pleural tumours, two died 15 months and 2 express CD45 but neither B- nor T-cell antigens (i.e. they have a null
years respectively after presentation and the third was alive with cell phenotype).527–531 Although this lymphoma takes the form of an
tumour 18 months later.516 effusion, a tumour mass may develop late in the course of the
disease.531 Radiographs show a unilateral or bilateral pleural, peri­
cardial or peritoneal effusion, usually associated with slight serosal
thickening. The prognosis is poor, with treatment affording only
Pleural lymphoma
slightly improved survival.537
Most patients with pleural lymphoma have evidence of simultaneous
systemic involvement but occasionally the lymphoma appears to be
confined to this site.524 Two unusual lymphomas arise here. One
Pyothorax-associated lymphoma
complicates pyothorax and forms a mass lesion whereas the other is Pyothorax-associated lymphoma is an extranodal non-Hodgkin
seen in acquired immunodeficiency syndrome (AIDS) patients and is lymphoma of B-cell phenotype, rich in reactive T cells.538–542 In
generally manifest as a pleural, pericardial or peritoneal effusion. They contrast to primary effusion lymphoma, pyothorax-associated lym­
have become known as pyothorax-associated lymphoma and primary phoma forms a tumour mass. It has largely been reported from Japan
effusion (or body cavity-based) lymphoma respectively. Both are asso­ but a few cases have been reported from the west.540,543–548 Patients
ciated with Epstein–Barr virus but the primary effusion lymphoma is give a long history of chronic pleuritis, which has generally been
also associated with human herpesvirus 8 and human immunodefi­ consequent upon repeated artificial pneumothoraces for pulmonary
ciency virus (HIV), supporting the view that they are distinct entities tubercu­losis.548 Rarer causes of the pleuritis include asbestos.549 In
(Table 13.8).525 Reports of other types of lymphoma arising in the many cases there is evidence of Epstein–Barr virus infection and it is
pleura are quite exceptional.526 suggested that immunosuppressive cytokines or growth factors pro­
duced by the inflammatory cells favour the clonal evolution of
Epstein–Barr virus-infected B cells.536,540,546,550,551
Patients are elderly and present with chest pain, cough and haemop­
Primary effusion lymphoma tysis.548 Radiographs show a pleura-based mass. Histology shows a
(body cavity-based lymphoma) diffuse proliferation of large, mitotically active lymphoid cells, which
Most patients with primary effusion lymphoma are HIV-positive are usually CD20-positive but may show aberrant CD3 expres­
homosexual men with advanced AIDS who also test positively for sion.548,552 Necrosis and angioinvasion may be evident. Epstein–Barr
human herpesvirus 8.527–531 Occasional patients are human herpes­­ virus may be demonstrated, but not human herpesvirus 8.546 The
virus-8-positive but HIV-negative.530,532 An inflammatory effusion prognosis is poor – only 35% of patients survive 5 years.548
associated with human herpesvirus-8 may represent the precursor of
primary effusion lymphoma.530,533 Human herpesvirus-8 is also found
in Kaposi’s sarcoma and multicentric Castleman’s disease and there
Synovial sarcoma
are reports of patients who have developed both Castleman’s disease Synovial sarcoma is another tumour that may arise in the pleura,
and primary effusion lymphoma.534,535 Many patients with primary usually as a localised mass but occasionally involving the pleura dif­
effusion lymphoma also show evidence of Epstein–Barr virus fusely and so mimicking mesothelioma.305,306,369,553–555 The age range
co-infection.528,529,536 is wide (9–79 years, mean 42 years) and males are affected twice as

734
 Pleura and chest wall Chapter | 13 |

often as females. Reported examples have generally been aggressive

tumours, proving fatal within 3 years of initial diagnosis, although
occasional localised examples appear to have been cured by surgical
excision.
Both biphasic and monophasic examples have been reported,
resembling mesothelioma of mixed and sarcomatoid pattern respec­
tively. Localised monophasic examples need to be distinguished from
solitary fibrous tumour. Subtle differences are described: monophasic
synovial sarcomas are typically composed of closely packed spindle
cells arranged in interweaving bundles (so-called herringbone pattern).
The cells appear to overlap and numerous mitoses are evident, but
pleomorphism is not prominent, as is often the case in meso­
theliomas. Mesotheliomas and localised fibrous tumours are also gen­
erally less cellular than synovial sarcoma. Immunohistochemical
similarities to a mesothelioma of mixed pattern include positive reac­
tions for calretinin, EMA and cytokeratin but the epithelial compo­
nent of a synovial carcoma also stains for mucus and carcinoma
markers such as BerEP4, while the spindle cell component expresses
the bcl2 oncogene.553 Solitary fibrous tumours may also express bcl2 Figure 13.34  Thymoma seeding in the pleural space. A primary
but they also react for CD34. Cytogenetic analysis for the SYT-SSX mediastinal thymoma adheres to the medial surface of the lung and
many tumour seedlings are seen on the visceral pleura.
transcript resulting from t(X;18)(p11;q11) chromosomal translocation
is another approach to establishing the diagnosis, this being a char­
acteristic marker of synovial sarcoma: it can be accomplished on
paraffin-embedded tissues by fluorescence in situ hybridisation.556 or leiomyosarcoma,573–577 chondrosarcoma578,579 and malignant nerve
sheath tumour.563 However, pleural sarcomas of various type may
complicate chronic pleurisy.557,561,562
Vascular tumours
Vascular tumours such as angiosarcoma, epithelioid angiosarcoma Thymoma
and epithelioid haemangioendothelioma have been reported in the
pleura, generally mimicking the diffuse distribution of a meso­ Thymoma has been reported to have arisen in the pleura on occasion,
thelioma (see Fig. 12.3.21, p. 637).374,375,557–560 The sarcomas were presumably arising from ectopic thymic tissue.380–383,580 However, it is
partic­ularly aggressive growths. All had morphological features typical always difficult to exclude seeding of the pleura from an undetected
of these growths elsewhere in the body, including reactivity for the primary in the thymus (Fig. 13.34). The reported patients have been
endo­thelial markers factor VIII-related antigen, CD31 and CD34.302,373– adults complaining of chest pain, dyspnoea or loss of weight, or
376
Some angiosarcomas have complicated pyothoraces.561,562 occasionally free of symptoms, while the tumours have generally
formed localised masses or, less frequently, a diffuse mantle encasing
the lung in the manner of a mesothelioma. Growth has generally been
Nerve sheath tumours indolent but recurrence, metastasis and death from respiratory failure
The visceral pleura is innervated by branches of the vagus nerve and have all been reported. Histologically, the tumours have generally
the parietal pleura by the intercostal nerves, yet primary nerve sheath resembled those encountered in the thymus, showing lobules sepa­
tumours of the pleura are distinctly rare. Reports are limited to one rated by fibrous septa and composed of epithelial cells and lym­
of a malignant nerve sheath tumour that mimicked a mesothelioma563 phocytes in varying proportions. Cytokeratin 5/6 and thrombomodulin
and another describing two localised neurofibromas that mimicked (CD141) may be expressed, causing further confusion with meso­
solitary fibrous tumours.493 The latter showed patchy positivity for thelioma, but calretinin staining is negative.383 The lymphocytes
CD34 but were distinguished from solitary fibrous tumour by express­ are mainly CD3-positive T cells but CD1a, CD2 and CD99 may also
ing S-100. In contrast to their rarity in the pleura, nerve sheath tumours be demonstrated.383,581
are common in the posterior mediastinum and these may impinge
upon the pleura. They may also arise in the chest wall (see below).
Carcinoma
Rare instances of pleural ‘epidermoid’ (squamous cell) carcinoma are
Other primary sarcomas of the pleura recorded, all of which arose in pleural cavities that showed widespread
When considering the possibility of a primary tumour of the pleura squamous change following the induction of long-standing artificial
other than mesothelioma, it must be remembered that the versatility pneumothoraces.67,582 It is possible that the squamous change repre­
of malignant mesothelial cells enables them to mimic many other sented metaplasia of the mesothelium but implantation of epidermal
types of primary mesenchymal tumour; for example, osteogenic fragments is equally likely because numerous injections of air were
sarcomatous mesotheliomas may be indistinguishable histologically required to maintain these chronic pneumothoraces. Furthermore,
from primary osteogenic sarcoma.292 Features suggesting a non- some cases were associated with a bronchopulmonary fistula which
mesothelial sarcoma include the gross appearance of a localised mass, also showed squamous change and malignancy and in these a bron­
an absence of asbestos exposure and failure to stain for cyto­ chogenic origin cannot be excluded. The tumours were typically well
keratin,564,565 but none of these features is entirely reliable. Origin differentiated with abundant keratinisation; although of low grade
from the chest wall, diaphragm, mediastinum and lung needs to be they showed undoubted infiltrative activity with destruction of adja­
excluded. All these caveats need to be considered when evaluating cent tissues. Carcinoma is also reported in association with lucite ball
reports of pleural malignant fibrous histiocytoma,557,566–568 angio­ plombage, apparently arising in the periphery of the lung but closely
sarcoma,557 liposarcoma,569,570 rhabdomyosarcoma,571,572 leiomyoma associated with the lucite in the pleural cavity.583 Primary muco­

735
 Pathology of the Lungs

Figure 13.36  Schwannoma arising from an intercostal nerve.

marker of a pulmonary origin591 and TTF-1 as a marker of origin in

the lung or thyroid.
A pleural effusion in a patient with lung cancer does not necessarily
indicate that the tumour is inoperable. Other causes of a pleural
effusion in these patients include secondary infection, lymphatic and
venous obstruction and hypoproteinaemia. Involvement of the pleura
is more likely if the effusion is blood-stained, or the lung tumour is
Figure 13.35  Carcinoma of the lung permeating the pleural lymphatics. an adenocarcinoma.588
(Courtesy of W Edwards, Gordon Museum, Guy’s Hospital, London, UK.)

epidermoid carcinoma of the pleura is also recorded, apparently Pleural splenosis

arising spontaneously.584 Splenosis results from the implantation of fragments of splenic tissue
after traumatic rupture of this organ.592,593 The implantation is usually
Secondary tumours of the pleura on the peritoneum but if the diaphragm is also torn thoracic splenosis
is a further potential complication. This may affect the left pleural
Pleural metastases are common in patients with malignant tumours, cavity or pericardium. Splenosis has not been described in the right
the commonest primary neoplasms in descending order being adeno­ side of the chest or within the substance of either lung. The condition
carcinomas of the breast, lung, ovary, stomach, large bowel, carcinoma was first described as a chance autopsy finding in 1937594,595 and by
of the kidney, lymphoma, various sarcomas and melanoma.247 In 1994 only 22 cases had been reported. It is generally asymptomatic
many cases the primary site is not determined during life.247,585,586 and the interval between the trauma and the diagnosis of thoracic
Breast carcinoma generally first involves the parietal pleura underlying splenosis is long (9–32 years, average 20 years). In this time the
the affected breast587 whereas lung cancer more often involves the implant may grow into a large mass, which is only discovered by
visceral pleura, either by direct extension (see Fig. 12.1.10, p. 543) or chance when chest radiographs are taken for some other purpose. The
lymphatic permeation (Fig. 13.35 and Fig. 12.6.4B, p. 683).588 diagnosis is generally made when the lesion is excised and submitted
However, at autopsy metastases generally involve both pleural sur­ for histological examination. This shows all the components of
faces.589 Whatever the source, blood-borne metastases are generally normal splenic tissue, including both red and white pulp.596
multifocal (see Fig. 13.34) and commoner in the lower half of the
thorax.590 However, some peripheral adenocarcinomas of the lung,
and, more rarely, squamous carcinomas, spread over the pleural sur­
faces in a manner similar to mesothelioma and it may be difficult to CHEST WALL DISEASE
establish where in the lung such tumours have originated (pseudomeso­
theliomatous carcinoma).298–300 Thymomas may behave similarly.381
Chest wall tumours
In distinguishing between secondary adenocarcinoma of the pleura
and mesothelioma of epithelioid pattern, mucus stains, immuno­ The chest wall may be directly invaded by carcinoma of the breast or
histochemistry and electron microscopy are all helpful (see p. 722). lung, it may be the seat of metastases from more distant organs or it
Thymomas spreading on to the pleura should not cause any difficulty may be the site of origin of a range of primary soft-tissue tumour.
to the histopathologist, showing as they do the lobulation and mixed Attention here is confined to this latter group.597
cellularity that are typical of these tumours. They are distinguished Primary tumours of the chest wall include extra-abdominal desmoid
from pleural lymphomas by their epithelioid component staining for tumours (aggressive fibromatosis, sometimes developing at the site of
cytokeratin. The metastatic nature of some pleural tumours can be a previous thoracotomy),598,599 elastofibroma dorsi (which particularly
recognised because they carry site-specific markers that can be detected involves the scapular region), myositis ossificans600 and tumours
by immunocytochemistry; for example, surfactant apoprotein as a of muscle, fat, blood vessel, nerve sheath (Fig. 13.36) and bone.601,602

736
 Pleura and chest wall Chapter | 13 |

Figure 13.37  Chondrosarcoma of the rib. The tumour forms a

bosselated mass on the inner aspect of the anterior chest wall, but is
quite localised, a feature against it being a sarcomatoid mesothelioma
showing chondroid differentiation.

The bone tumours include multiple myeloma, chondroma, chon­

drosarcoma (Fig. 13.37), fibrous dysplasia and Langerhans cell
histio­cytosis. Of the soft-tissue sarcomas, about half are fibrous (fib­
rosarcoma or dermatofibrosarcoma protuberans), while liposarcoma
and nerve sheath malignancies each form 14%, 8% show muscle dif­
ferentiation, 4% are vascular and 2% are synovial.603 Some of these Figure 13.38  Malignant small cell tumour of the thoracopulmonary
tumours follow radiation for breast carcinoma or Hodgkin disease.604 region (Askin tumour). The tumour is composed of undifferentiated small
All are well described in texts devoted to skeletal and soft-tissue hyperchromatic cells.
tumours and attention here will be confined to two that have a par­
ticular predilection for the chest wall and a reactive condition that
may be mistaken for a neoplasm.
Extrathoracic examples have subsequently been described and col­
Malignant small cell tumour of the lectively they are now known as primitive neuroectodermal tumours
(and colloquially as PNETs), of which those arising in the thoraco­
thoracopulmonary region (Askin tumour)
pulmonary region comprise about a third. Suggestions that PNETs are
This high-grade tumour occurs predominantly in the first two decades related to Ewing’s sarcoma are supported by cytogenetic studies
of life (average age 14 years) and 75% of patients are female.605,606 showing that they carry the Ewing’s karyotype, a t(11;22)(q24;q12)
Solitary or multiple nodules occur in the chest wall, eroding the ribs translocation615 and frequently express the Ewing-specific antigen
and subsequently spreading to involve the pleura, pericardium, dia­ MIC2 (CD99).616–618 Malignant small cell tumour of the thoraco­
phragm and periphery of the lung. The tumour tends to recur locally pulmonary region also shows histological and cytogenetic similarities
and does not disseminate widely, but the prognosis is dismal, with to the desmoplastic small round cell tumour described above, but
a 2-year survival of 38% and a 6-year survival of only 14%.606 differs in failing to react with antibodies against the Wilms tumour
Rare examples develop entirely within the lung and are more protein WT1.521
amenable to surgery.607–609 Separation of PNETs and Ewing’s sarcoma from neuroblastoma is
The microscopic features are those of a malignant tumour com­ facilitated by their expression of MIC2, neuroblastomas being nega­
posed of sheets of undifferentiated small hyperchromatic cells, with tive for this antigen. However, chromosomal confirmation is desirable
rosettes of radially arranged cells around a central tangle of fibrillary because a small proportion of PNETs and Ewing’s sarcoma are also
cytoplasmic processes (Fig. 13.38). Electron microscopy reveals dense- MIC2-negative and positive reactions are obtained with occasional
core neurosecretory granules, and neuroectodermal markers such as rhabdomyosarcomas and synovial sarcomas.618 Separation of PNETs
S-100 protein, synaptophysin and neuron-specific enolase can be from lymphoblastic lymphoma may be effected by the application
shown by immunohistochemistry, evidence that the tumour is of of lymphocyte markers.619 Pleuropulmonary blastoma is distinguished
neural or neuroendocrine derivation.605,610–613 Further support for this by its location in the periphery of the lung rather than the chest
stems from the experimental induction of neuronal differentiation in wall, its cystic nature and focal sarcomatous differentiation, while
Askin tumour cell lines.614 However, the dense-core granules are scanty in doubtful cases CD99 staining and chromosomal analysis are
and the tumour therefore fails to stain for chromogranin.606 helpful.620

737
 Pathology of the Lungs

Mesenchymal hamartoma of the chest wall

This tumour-like malformation621–623 is a distinctive lesion that
presents at birth or soon after as an extrapleural chest wall mass with
involvement of one or more ribs. It was formerly thought to be neo­
plastic but is now recognised to be a malformation. The few deaths
that have been recorded are attributable to pressure effects on the
thoracic viscera by lesions that grew to fill much of the hemithorax.
Metastasis has not been observed. Former terms that are now
redundant include osteochondroma, osteochondrosarcoma,
chondroblastoma and mesenchymoma.
Growth may be rapid but spontaneous regression has been recorded.
The lesion is usually solitary but may be multifocal or even bilateral.
It generally forms a lobulated, well-circumscribed mass composed of
bone, cartilage and blood-filled cysts set in a myxoid matrix.
Aneurysmal bone cyst is the principal differential diagnosis but,
although this condition affects the young, it is infrequent in the
newborn and does not show the prominent cartilage seen in
mesenchymal hamartoma.

Gorham’s syndrome
This rare condition of unknown aetiology represents a florid pro­
A
liferation of thin-walled vascular channels that predominantly
involves bone and causes marked osteolysis (Fig. 13.39).624,625
Underlying soft tissues may be invaded, including the lung if the
disease is centred on a rib or vertebra. Respiratory function may be
further impaired by thoracospinal deformity or pleural effusion.626,627
Young adults of either sex are predominantly affected. The process
may arrest spontaneously and is therefore not considered to be neo­
plastic, yet the histological appearances are quite alarming. The vas­
cular channels are lined by plump atypical cells and together with
evident invasive activity the appearances suggest a malignant process,
either angiosarcoma or angiomatoid carcinoma, the latter condition
being excluded by negative epithelial and positive endothelial markers
(cytokeratin and CD34 respectively). Bilateral effusions, which may
be chylous because of thoracic duct involvement, and vertebral col­
lapse carry an adverse prognosis and may warrant radiotherapy, to
which the condition has sometimes responded.

Figure 13.39  Gorham’s syndrome. (A) Radiographs show osteolysis of

the left second to fifth ribs. (B) Microscopy shows loose connective tissue
in which there is a mild lymphocytic infiltrate and prominent vascular
proliferation. (Courtesy of Drs H Aziz and C. Lam, Gothenberg, Sweden.)

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