NEXT LEARNING CENTER

NEXT LEARNING CENTER

PATHOLOGY;

WORK BOOK

By
Dr. Priyanka Sachdev

CENTERS IN INDIA :
1 DELHI • KERALA
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GENERAL PATHOLOGY

Cell Adaptations
Adaptations →
• Are reversible
• Structural responses to physiologic stress (e.g.,
pregnancy) and pathologic stress
• During which new but altered steady states are
achieved
• Allowing the cell to survive and continue to
function

5 Types of Adaptations
1. Hypertrophy→ Increase in the size of cells
2. Hyperplasia → Increase in number of cells
3. Atrophy → Decrease in the size of cells /
shrinkage of cells
4. Metaplasia→ Transformation of one adult cell
type with another
5. Dysplasia → ‘Disordered cellular development’

Hyperplasia
• Increase in the number of cells , not size of cell,

Physiologic hyperplasia
1. Hyperplasia of female breast at
puberty, pregnancy and lactation

2. Enlarged size of the uterus in

pregnancy is an example of
physiologic hypertrophy as well as
hyperplasia.
3. Compensatory hyperplasia →

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• Regeneration of the liver following partial hepatectomy.

• Following nephrectomy on one side, there is hyperplasia of nephrons of the
other kidney.

Pathologic hyperplasia
1. Endometrial hyperplasia following oestrogen excess
2. Benign prostatic hyperplasia due to DHT (dihydrotestosterone)
3. Formation of skin warts from hyperplasia of epidermis due to HPV

Hypertrophy
• Increase in the size of cells, not number of cells

Physiologic hypertrophy
1. Enlarged size of uterus in pregnancy is an eg of physiologic hypertrophy as well as
hyperplasia.
2. Hypertrophy of skeletal muscle e.g. hypertrophied muscles in athletes and manual
labourers.

Pathologic hypertrophy
1. Hypertrophy of cardiac muscle occurs in
Systemic hypertension, Aortic valve disease
2. Hypertrophy of smooth muscle e.g.
Cardiac achalasia (in oesophagus), Pyloric
stenosis (in stomach).

Atrophy
• Decrease in cell size and number of cells

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Physiologic atrophy
• Atrophy of thymus in adult life.
• Atrophy of ovary after menopause.
• Atrophy of brain with ageing.
• Decrease in the size of the uterus that occurs shortly after
parturition

Pathologic atrophy
1. Starvation atrophy → general
weakness, emaciation known as
cachexia seen in cancer and severely
ill patients.
2. Ischaemic atrophy → atrophic
kidney in atherosclerosis of renal
artery, Atrophy of the brain in
cerebral atherosclerosis.
3. Neuropathic atrophy → e.g.
Poliomyelitis,Motor neuron disease
4. Disuse atrophy → e.g. Wasting of
muscles of limb immobilised in cast,
Atrophy of the pancreas in obstruction
of pancreatic duct.
5. 5. Endocrine atrophy → eg. Hypopituitarism may lead to atrophy of thyroid, adrenal
and gonads
6. Pressure atrophy → eg. Erosion of the skull by meningioma, Erosion of the sternum
by aneurysm of arch of aorta.
7. Idiopathic atrophy → where no obvious cause is present

Metaplasia
• A reversible change in which one mature/adult cell type is
replaced by another mature/adult cell type

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Squamous metaplasia
Normal columnar epithelium → squamous epithelium

EXAMPLES
1. In bronchus (normally lined by pseudostratified
columnar ciliated epithelium) in chronic smokers.
2. In gallbladder (normally lined by simple columnar
epithelium) in cholelithiasis.
3. In prostate (normally lined by simple columnar
epithelium) in chronic prostatitis
4. In uterine endocervix (normally lined by simple
columnar epithelium) in prolapse of the uterus

Columnar metaplasia
Normal squamous epithelium → columnar epithelium

EXAMPLES
1. Barrett’s oesophagus → change of normal
squamous epithelium to columnar epithelium
due to GERD
2. Cervical erosion → Ectocervix - change of
normal squamous epithelium to columnar
epithelium due to increased exposure of the
cervical epithelium to estrogen

Dysplasia
• Disordered cellular development

Cytological changes
1. Increased number of layers
2. Disorderly arrangement of cells from basal layer to
surface layer
3. Loss of basal polarity i.e. nuclei lying away from
basement membrane
4. Cellular and nuclear pleomorphism
5. Increased nucleocytoplasmic (N/C) ratio
6. Nuclear hyperchromatism
7. Increased mitotic activity

• Full thickness dysplasia is known as carcinoma in

situ (Precurssor of cancer)

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Reversible Vs Irreversible Cell Injury

Irreversible Injury – Nuclear Changes

• Pyknosis
Nuclear shrinkage and increased
basophilia
• Karyorrhexis
Fragmentation of the pyknotic
nucleus
• Karyolysis
Fading of basophilia of chromatin

Reversible injury Irreversible Injury

Cell membrane – Swell – Do not swell
– Intact – Distrups
– Blebs
ER – Swell – Lysis
Ribosomes – Dispersion – Dispersion
Mitochondria – Swell – Swells
– Small densities – Large densities
Lysosomes – Autophagy – Rupture
Nucleus – Clumping – Pyknosis, Karyolysis,
Karyorrhexis

Cell Death
• Apoptosis → Suicide
• Necrosis → Murder

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Apoptosis → Cell Suicide

• It is a pathway of cell death that is induced by a
tightly regulated intracellular program in which
cells destined to die activate enzymes (caspase)
degrade the cells own nuclear DNA and
cytoplasmic proteins.
• The cell is phagocytosed
• There is no leakage outside
• So, there is no inflammation
Extrinsic pathway → Initiation phase
• It is initiated through specific receptors called death receptors
1. Fas protein (CD95)
2. TNF receptors

Fas receptor (Death receptor)

↓
Fas protein (CD95) binds with it
↓
Multiple Fas receptors come together
↓
Cytoplasmic death domain FADD formed
↓
Activate pro- caspsase 8 and 10 to active caspase 8 and 10

Intrinsic pathway → Initiation phase

Stimuli→ DNA damage (beyod repair)

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Stimuli (DNA damage)

↓
Anti apoptotic molecules Bcl-2 , Bcl-x ,Mcl -1 are
lost
↓
Replaced by pro-apoptotic molecules like Bak,
Bax, Bim, Bad
↓
Increased mitochondrial permeability (MPT)
↓
Release to cytochrome C into cytoplasm
↓
Activates Apaf-1 along with procaspase-9
↓
Activated caspase-9

Execution phase
• It is a convergence point for both
extrinsic and intrinsic pathways.

Morophological changes in apoptosis

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Diagnosis
1. Apoptosis markers
• Annexin-V is a recombinant protein with high affinity for phospholipid like
phosphatidylserine.
• Phosphatidylserine is a phospholipid present on inner surface membrane normally but it
is flipped to outer surface during apoptosis thus become a marker of apoptosis.

2. Agarose gel electrophoresis:

• Fragmented DNA shows Step Ladder Pattern,which is due to
internucleosomal cleavage of DNA by endonuclease
• During karryorrhexis endonuclease activation leaves short DNA
fragments regularly spaced in size.

Apoptosis (Suicide) Necrosis (Murder)

• Single cells or small clusters of cells • Often contiguous cells
• Cell shrinkage • Cell swelling
• Pyknosis and karyorrhexis • Karyolysis, pyknosis,and
• Intact cell membrane karyorrhexis
• Cytoplasm retained in apoptotic bodies • Disrupted cell membrane
• Inflammation absent • Cytoplasm leaked
• Inflammation present

Necrosis
• Necrosis is death of cells and tissues in the living animal
• Necrosis is defined as a localised area of death of tissue followed later by degradation
of tissue by hydrolytic enzymes liberated from dead cells
• Accompanied by inflammatory reaction

Remember
• Necrosis usually affects a group of contigous cells (in contrast
to apoptosis which involves a single cell).
• There are inflammatory changes in the surrounding tissue (in
contrast to apoptosis where there in no inflammatory changes).

Coagulative necrosis
• Most common type of necrosis

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• Architectural outlines persist but cellular and nuclear details are lost (Ghost cells /
Tombstone)
• Type of tissue can be recognized

Causes:
• Ischemia due to thrombosis/ embolism in all organs except brain
• Mild burns (thermal injury)
• Zenker's degeneration necrosis

Grossly
• Focus in the early stage is pale, firm, and slightly swollen

Microscopically
1. Conversion of normal cells into their ‘tomb stones’ i.e. outlines of the cells are
retained and the cell type can still be recognised but their cytoplasmic and
nuclear details are lost

Liquefactive (Colliquative) necrosis

• Semi-fluid material → Architectural details as well as cytoplasmic and nuclear
details are lost

Causes:
• Pyogenic bacterial infections attract neutrophils. Bacterial and leukocytic enzymes
liquefy dead cells and tissues.
• Ischemic necrosis of brain

Gross appearances
• Soft with liquefied centre containing necrotic debris with a cyst
wall

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Microscopic appearance:
1. No architectural or cellular details are visible
in the area of necrosis.
2. The necrotic area usually appears as a cavity
containing a mass of necrotic neutrophils,
bacteria and tissue debris
3. The entire necrotic mass is surrounded by a cyst
wall formed by proliferating capillaries and
inflammatory cells

Caseous necrosis (cheese like)

• Dead tissue is converted into a homogenous, granular mass resembling cottage cheese.
• Their architectural details as well as cytoplasmic and nuclear details are lost

Cause:
• Mycobacterium tuberculosis
• Syphilis
• Histoplasma
• Coccidioimycosis

Gross appearance
• Foci of caseous necrosis resemble dry cheese and are soft, granular and
yellowish.

Microscopically
1. Centre of the necrosed focus contain
structureless, eosinophilic material having
scattered granular debris of disintegrated
nuclei
2. The surrounding tissue shows characteristic
granulomatous inflammatory reaction

Fat necrosis
• Death of adipose tissue in a living animal

Causes
• Pancreatic (acute pacreatitis), Breast (Traumatic), Mesentry (Inflammmation)

Grossly
• Fat necrosis appears as yellowish-white and firm
deposits.
• Formation of calcium soaps imparts the necrosed foci
firmer and chalky white appearance

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Microscopically
1. The necrosed fat cells have cloudy appearance
2. They are surrounded by an inflammatory reaction.
3. Formation of calcium soaps is identified in the tissue
sections as amorphous, granular and basophilic
material

Fibrinoid Necrosis
• Fibrinoid necrosis is characterized by deposition of fibrin-like material which has the
staining properties of fibrin
• The fibrin like material is deposited in wall of blood vessels

Causes
• Immunologic injury of vessel wall

Microscopically
1. Fibrinoid necrosis is identified by brightly eosinophilic, hyaline-like
deposition in the vessel wall.
2. Necrotic focus is surrounded by nuclear debris of neutrophils
(leucocytoclasis)
3. Local haemorrhage may occur due to rupture of the blood vessel.

Gangrene
• Gangrene is necrosis of tissue associated with superadded putrefaction
GANGRENE = Necrosis + Putrefaction

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TYPES
1. “Dry” gangrene – less
bacterial superinfection; tissue
appears dry
2. “Wet” gangrene – abundant
bacterial superinfection; tissue
looks wet and liquefactive

FEATURE DRY GANGRENE WET GANGRENE

1. Site Commonly limbs Commonly in bowel
2. Mechanisms Arterial occlusion Blockage of both venous
drainage and arterial obstruction
3. Macroscopy Organ dry, shrunken and black Part moist , soft, swollen, rotten
and dark
4. Putrefaction Limited due to very little Marked due to stuffing of organ
blood supply with blood
5. Line of demarcation Present Absent
6. Bacteria Bacteria fail to survive Numerous present
7. Prognosis Better due to little septicaemia Poor due to profound toxaemia

Remember
• Dry gangrene -> Variant of Coagulative necrosis
• Wet gangrene -> Liquifactive necrosis is superimposed on coagulative necrosis

Gas Gangrene
• Special form of wet gangrene caused by gas-
forming clostridia (gram-positive anaerobic
bacteria)

Grossly
• Swollen, oedematous, painful and crepitant
due to accumulation of gas bubbles of carbon
dioxide within the tissues formed by
fermentation of sugars by bacterial toxins

Pathologic calcification
• Insoluble inorganic calcium salts are a normal constituent of bones and teeth.

• Deposition of calcium salts in tissues other than osteoid or enamel is called

pathologic or heterotopic calcification

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Sites of calcification - Dystrophic:

Dead tissues
• Caseation eg. Tuberculosis
• Dead parasites like trichinosis,
Onchocercosis.
• Fat necrosis
• Infarcts
• Thrombi
• Haematoma

Sites of calcification - Metastatic:

Inflammation
• It is a body defense reaction in order to eliminate or limit the spread of injurious agent,
followed by removal of the necrosed cells and repair of damaged tissue
• White blood cells or leukocytes are the body’s major infection-fighting cells.

Classification
ACUTE CHRONIC
Rapid onset Late onset
Short duration Longer duration
Odema Granuloma formation
Neutrophils Macrophage, lymphocyte

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Cardinal Signs
Latin English
Rubor : redness
Calor : ↑ed local temperature Celsus
Tumor : swelling
Dolor : pain
Functio laesa: loss of function → Virchow

Vascular Events
1. Transient vasoconstriction of arterioles
2. Persistent progressive vasodilatation
3. Elevate the local hydrostatic pressure
4. Increased vascular permeability
5. Slowing or stasis

1. Transient vasoconstriction of arterioles

2. Persistent progressive vasodilatation

3. Elevate the local hydrostatic pressure

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4. Increased vascular permeability

Mechanism Vasculature Response Pathogenesis

1. Endothelial gaps Venules Immediate Histamin
transient
2. Direct endothelial injury All levels Immediate Direct injury
prolong
3. Leukocyte mediated injury Venules Delayed Activated WBC
prolong
4. Transcytosis Venules Histamin and VEGF
5. Leaky new blood vessels - VEGF

5. Slowing or stasis

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Cellular Events
1. Margination and pavementing
2. Rolling
3. Adhesion
4. Transmigration (diapedes)
5. Chemotaxis
6. Phagocytosis

Mechanism of rolling and adhesion → Complementary adhesion molecules

(CAM)

Endothelial Molecule Leukocyte Molecule Major Role

1. P-selectin Sialyl-Lewis X Rolling
2. E-selectin Sialyl-Lewis X Rolling and adhesion
3. GlyCam-1 (CD34) L-selectin Rolling
4. ICAM-1 B2 integrins Adhesion
5. VCAM-1 B1 integrins Adhesion
6. PECAM-1 (CD-31) PECAM-1 (CD-31) Diapedesis (trasmigration)

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Transmigration (diapedes)
• Escape out into the extravascular space; this is known as transmigration
• Also known as diapedesis
• Passive phenomenon
• PECAM

Chemotaxis
• Unidirectional oriented along a chemical gradient

Potent chemotactic substance →

i) Leukotriene B4 (LT-B4)
ii) Components of complement system (C5a and C3a )
iii) Cytokines (Interleukins, in particular IL-8)

• C5a is the most powerful chemoattractant (chemokine)

Phagocytosis
This sequence was appreciated by Metchnikoff (1880)
1. Recognition and Attachement
2. Engulfment
3. Killing and degradation

Killing and degradation

3 Steps
Step 1
• NADPH-oxidase present in the cell membrane of phagosome reduces oxygen to
superoxide ion (O2-)
• O2 − − − − − − − − − → O2-
• This is known as respiratory burst

Step 2 → Superoxide is subsequently converted into H2O2:

Step 3

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MPO-dependent killing
• The enzyme MPO acts on H2O2 in the presence of halides (chloride, iodide or
bromide) to form hypohalous acid (HOCl, HOI, HOBr).

• This is called H2O2-MPO-halide system and is more potent antibacterial system

MPO-independent killing
Mature macrophages lack the enzyme MPO and they carry
out bactericidal activity by producing OH– ions from H2O2
➢ In the presence of O2 (Haber-Weiss reaction)
➢ In the presence of Fe++ (Fenton reaction)

Chronic Inflammation
➢ Chronic inflammation is a response of prolonged
duration (weeks or months) in which inflammation, tissue injury and attempts at
repair (fibrosis) coexist, in varying combinations.

Granulomatous Inflammation
• Formation of granuloma is a type IV hypersensitivity reaction

1. Engulfment by macrophages

Macrophages engulf the antigen

↓
Try to destroy it
↓
But antigen is poorly degradable
↓
These cells fail to digest and degrade the antigen

2.Activation of CD4+ T cells

Macrophages failed to deal with the antigen

↓
Present antigen to CD4+ T lymphocytes
↓
CD4+ T lymphocyte activated
↓
Release lymphokines
↓
IL-1, IL-2, interferon-Y, TNF-α

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3. Release of Cytokines
1. IL-1 and IL-2 stimulate proliferation of more T cells.
2. Interferon-γ activates macrophages and transform it into
epitheloid cells
3. TNF-α promotes fibroblast proliferation

Multinucleate giant cells

• Formed by fusion of adjacent epithelioid cells
• May have 20 or more nuclei.

Special Forms of Granuloma

Naked Granulomas
• These granulomas may not have surrounding rim of
mononuclear cells
• composed of epithelioid histiocytes and multinucleated giant
cells
• No or only sparse infiltrate of mononuclear cells at the
periphery.
• e.g. sarcoidosis

Stellate granuloma
• Star shaped Granuloma
• Granuloma with central neutrophilic infiltrates.
Examples
• Cat scratch disease
• LGV (lymphogranuloma venereum)

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Durck's granuloma:
• Seen in cerebral malarial caused by Plasmodium
falciparum.
• Blood vessels packed with rings of P. falciparum.

Fibrin ring granuloma / doughnut granuloma

• On H and E staining, the fibrin ring granuloma consists of
→
o Sentral lipid vacuole (usually washed-out during
fixing and staining, leaving only an empty hole)
o Surrounded by a dense red fibrin ring and
epithelioid macrophages. (Resembles like
doughnut)
• Eg .- Coxiella burnetii

Examples Of Granulomatous Inflammation

BACTERIAL
1) Tuberculosis Mycobacterium tuberculosis
2) Leprosy Mycobacterium leprae
3) Syphilis Treponema pallidum
4) Granuloma inguinale (Donovanosis) C. donovani
5) Brucellosis (Mediterranean fever) Brucella abortus
6) Cat scratch disease Coccobacillus
7) Tularaemia Francisella tularensis
8) Glanders Actinobacillus mallei

FUNGAL
1. Actinomycosis Actinomycetes israelii
2. Blastomycosis Blastomyces demtitidis
3. Cryptococcosis Cryptococcus neoformans
4. Coccidioidomycosis Coccidioidesimmitis

PARASITIC
1. Schistosomiasis (Bilharziasis) Schistosoma mansoni,
haematobiumjaponicum

MISCELLANEOUS
1.Sarcoidosis Unknown
2.Crohn's disease Unknown
3. Silicosis Silica dust
4.Berylliosis Metallic beryllium
5.foreign body granulomas Talc, suture, oils, wood splinter etc

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Healing
Regeneration
• Parenchyma replaced by parenchymal cells of
the same type
• Restoration of normal structure and function

Repair
• Parenchyma replaced by fibrous tissue
• Restoration of normal shape and function is
impaired
• Result - scar

Repair
• Repair is the replacement of injured tissue by fibrous tissue
1) The inflammatory phase:
a) Clot
b) Inflammation
2) The proliferative phase:
a) Epithelialization
b) Fibroplasia Granulation tissue
c) Angiogenesis
3) The maturation phase: scar

Inflammatory phase

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I. Inflammatory Phase
• Immediate (1 day to 3 days)

End product of Proliferation Phase

Granulation tissue consists of triad of:
1. Proliferating blood vessels (neovascularization)
2. Proliferating fibroblasts and collagen
3. Non-specific inflammation.

Maturation Phase
• 3 weeks to 2 years
• During the maturation phase, fibroblasts leave the wound

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• New collagen forms which increases tensile strength to wounds

• Collagen is remodeled into a more organized matrix.
• Tensile strength increases for up to one year following the injury.
• Tensile strength never reaches the normal strength of unwounded tissue (i.e., 100%).
- Maximum strength is 70-80% of normal tissue. (at end of 3 months)

End product of Maturation Phase

• Final product of the healing process is a scar → avascular and acellular mass of
collagen serves to restore tissue continuity, strength and function.

Healing of Skin Wounds

FEATURE PRIMARY UNION SECONDARY UNION

1. Cleanliness of wound Clean Unclean
2. Infection Uninfected May be infected
3. Margins Surgical, clean Irregular
4. Sutures Used Not used
5. Healing Scanty granulation tissue Exuberant granulation tissue
6. Outcome Neat linear scar Contracted irregular scar
7. Complications Infrequent Frequent

Oedema
• Oedema is defined as abnormal and excessive accumulation of fluid in the
interstitial tissue space

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Effusion
• Effusions is defined as abnormal and excessive accumulation of fluid in body
cavities

Causes and examples of oedema

FEATURE TRANSUDATE EXUDATE

Definition Protein-poor , cell-poor fluid Protein-rich , cell-rich fluid
Character Non-inflammatory oedema Inflammatory oedema
Protein content Low (less than 1 gm/dl) High ( 2.5-3.5 gm/dl)
Glucose content Same as in plasma Low (less than 60 mg/di)
Specific gravity Low (less than 1.015) High (more than 1.018)
pH > 7.3 < 7.3
LDH Low High
Cells Few cells Many cells
Examples Oedema in congestive cardiac failure Purulent exudate such as pus

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Hyperaemia And Congestion

Localised increase in the volume of blood within dilated
vessels of an organ or tissue.

Hyperamia
• Increased volume of blood from arterial dilatation (i.e.
increased inflow) is called hyperaemia (active process)
• Affected tissues turn red (erythema) because of increased delivery of oxygenated blood.

Congestion
• Increased volume of blood from impaired venous drainage
(i.e. diminished outflow) is called congestion (passive
process )
• Affected tissues turn blue (cyanosis) because of increased
delivery of deoxygenated blood.

HYPEREMIA CONGESTION
1. Active process Passive process
2. Vasodilatation of artery Impaired venous blood flow
3. During exercise & in inflammation Venous obstruction & cardiac failure
4. Oxygenated blood (Red,Erythema) Deoxygenated blood (Blue,Cyanosis)

Congestion
• In left-sided heart failure →
pulmonary congestion (CVC lungs)

• In right-sided heart failure →

systemic venous congestion (CVC of
systemic organs →Liver, spleen)

CVC Lung
Grossly→
• The lungs are heavy and firm in consistency
• Cut surface is dark and rusty brown in colour→ brown
induration of the lungs.

Microscopically
• The alveolar capillaries are congested.
• Initially, the excess fluid collects in the interstitial lung spaces
in the septal walls (interstitial oedema).
• Later, the fluid fills the alveolar spaces (alveolar oedema).

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• There are hemosiderin-containing macrophages in lung alveoli. These macrophages are

called heart failure Cells

Remember
• Heart failure cells are present in the lungs and NOT in the heart.
• These are hemosiderin laden macrophages.

CVC Liver
Grossly→
• The liver is enlarged and tender
• Capsule is tense.
• Cut surface shows characteristic nutmeg
appearance due to red and yellow mottled
appearance, corresponding to congested centre of
lobules and fatty peripheral zone respectively

Microscopically→
• The central veins is distended and filled with blood.
• The centrilobular hepatocytes undergo degenerative changes
and Centrilobular haemorrhagic necrosis occurs.
• The peripheral zone of the lobule is less severely affected by
chronic hypoxia and shows fatty change in the hepatocytes
• So nutmeg appearance
CVC Spleen
Grossly→
• Congested, tense and cyanotic
• Sectioned surface is gray tan

Microscopically→
• Red pulp is enlarged due to marked sinusoidal dilatation
• Sinusoids may get converted into capillaries (capillarisation of
sinusoids).
• Some of haemorrhages overlying fibrous tissue get deposits of
haemosiderin pigment → Gamna-Gandy bodies

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Remember
• CVC of lung → heart failure cells (hemosiderin laden macrophages)
• CVC of liver produces nut-meg liver
• CVC of spleen is characterized by presence of Gamna-Gandy bodies

Thrombosis
• Thrombosis is the formation of a blood clot (solid mass) in the
unruptured CVS from the constituents of flowing blood , obstructing the
flow of blood through the circulatory system

Pathophysiology
• Virchow described three primary events which predispose to
thrombus formation (Virchow’s triad):
1. Endothelial injury
2. Altered blood flow (Stasis or turbulance)
3. Hypercoagulability of blood
Types of Thrombi
1. Cardiac thrombi (vegetations)
2. Arterial thrombi
3. Venous thrombi

Feature Arterial thrombus Venous thrombus

Pathogenesis Endothelial injury or turbulence Stasis

Blood flow Active Sluggish
Sites Coronary, cerebral , femoral arteries Superficial and deep leg veins
Propagation Retrograde manner Antegrade manner
Lines of Zahn Present Absent
Microscopic Pale platelet layer alternating with RBC mixed with relatively less
dark red cell layer so also called as platelets, so also called as red thrombi
white thrombi
Occlusion Incomplete Complete
Complications lschemia and infarction Edema and ulceration

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Embolism
• An embolus is a detached intravascular solid, liquid, or gaseous
mass that is carried by the blood from its point of origin to a distant
site, where it often causes tissue dysfunction or infarction.
• The transported intravascular mass detached from its site of origin is
called an embolus
Depending upon the matter in the emboli

Depending upon whether infected or not:

Depending upon the source of the emboli

Depending upon the flow of blood

Types
i) Arterial circulation→ Arterial (systemic) thromboembolism
ii) Venous circulation → Pulmonary Thromboembolism

Effects of arterial emboli

➢ Infarction of the organ
➢ Gangrene in the lower limbs
➢ Myocardial infarction may occur following coronary embolism.
➢ Sudden death may result from middle cerebral artery embolism

Effect of venous embolism

• Obstruction of pulmonary arterial circulation leading to pulmonary
embolism

Pulmonary Thromboembolism
• Pulmonary embolism is the most common and fatal form of venous
thromboembolism
• There is occlusion of pulmonary arterial tree by thromboemboli

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Pathogenesis
Embolus in vein
↓
Flows through venous drainage into the larger veins (SVC and
IVC)
↓
Right side of the heart (RA → RV)
↓
Pulmonary artery
↓
Pulmonary embolism

• If the thrombus is large, it is impacted at the bifurcation of the main

pulmonary artery (saddle embolus)
• Multiple small emboli→ Particularly affecting lower lobes of lungs

Shock
Shock is the clinical syndrome that results from poor tissue perfusion
➢ In this condition tissues in the body do not receive enough oxygen and nutrients to allow
the cells to function.
➢ This ultimately leads to cellular death
➢ May progress to organ failure
➢ Finally, to whole body failure
➢ Death.

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1. Hypovolaemic shock
• Most common form of shock
• Occurs due to decreased blood volume

Causes
i) Acute haemorrhage
ii) Dehydration from vomiting's, diarrhoea
iii) Burns
iv) Excessive use of diuretics
v) Acute pancreatitis

Pathogenesis
• Occurs from inadequate circulating blood volume due to various causes,

Symptoms
1. Increased heart rate (tachycardia)
2. Low blood pressure (hypotension)
3. Low urinary output (oliguria to anuria)
4. Alteration in mental state (agitated to confused to lethargic)

3 stages→
i) Mild hypovolemia or stage I (< 20% volume loss): Only mild tachycardia is there
with normal BP.
ii) Moderate hypovolemia or stage II (20-40% volume loss): Tachycardia with normal
BP in supine position but hypotension in erect posture.
iii) Severe hypovolemia or stage III (> 40% volume loss): Classical signs of shock
appear e.g. tachycardia, hypotension, disorientation etc.

2. Cardiogenic shock
• caused by inadequate pumping action of heart
• Cardiogenic shock occurs when 40% or more of the left ventricle is destroyed.

Causes
i) Deficient emptying e.g.
a) Myocardial infarction
b) Cardiomyopathies
c) Rupture of the heart, ventricle or papillary muscle
d) cardiac arrhythmias
ii) Deficient filling e.g.
a) Cardiac tamponade from haemopericardium
iii) Obstruction to the outflow e.g.
a) Pulmonary embolism
b) Ball valve thrombus
c) Tension pneumothorax
d) Dissecting aortic aneurysm

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Pathogenesis
• There is acute circulatory failure
• sudden fall in cardiac output from acute diseases of the heart without actual reduction
of blood volume (Normovolaemia)

Symptoms
• Decreased cardiac output has its effects in the form of decreased tissue perfusion
(tissue hypoxia)
• Movement of fluid from pulmonary vascular bed into pulmonary interstitial space
initially (interstitial pulmonary oedema) and later into alveolar spaces (alveolar
pulmonary oedema)

3. Septic (Toxaemic) shock

Causes
i) Gram-negative septicaemia (endotoxic shock) e.g.
Infection with E.coli, Proteus, Klebsiella, Pseudomonas and Bacteroides
ii) Gram-positive septicaemia (exotoxic shock) e.g.
Infection with streptococci, pneumococci

Pathogenesis
Triggering factor →
• Gram positive bacteria → Lipotheichoic acid and superantigens (staphylococcal
TSST, streptococcal pyrogenic exotoxin).
• Gram negative bacteria → Endotoxin (lipopolysaccaride)

• Vasodilatation → hypotension → causes hyperdynamic circulation in septic

shock, in contrast to hypovolaemic and cardiogenic shock
• Increased vascular permeability→ Inflammatory oedema

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Septic shock has two different stages

1. Early hyperdynamic stage
• It is characterized by vasodilatation (decreased peripheral resistance),
Tachycardia, normal to increased cardiac output, and warm extrimities.
2. Late hypodynamic stage
• It is characterized by vasoconstriction, decreased output, and oliguria (renal
failure).

Genetics
• Out of a total number of 46 chromosome→
a) 22 pairs of chromosomes are homologous and are called
autosomes.
b) 23rd pair is alike only in the females (have 2 similar X
chromosomes) whereas in a male there is one X
chromosome and one Y chromosome. The X and Y are
therefore referred to as sex chromosomes.

Normal chromosome complement

a) 46, XX for female
b) 46, XY for male

Autosomal Dominant (AD) Inheritance Diseases

Vo Familial Hypercholesterolemia Autosomal DOMINANT Hai

Vo Von Willebrand Disease

Familial Familial Adenomatous Polyposis
Hypercholesterolemia Hypercholesterolemia (Familial)
Autosomal Adult polycystic kidney
D Dystrophia myotonica
O Osteogenesis imperfecta
M Marfan syndrome
I Intermittent porphyria
N Neurofibromatosis-1
A Achondroplasia
N Neurofibromatosis – 2
T Tuberous sclerosis
Hai Huntington’s disease; Hereditary spherocytosis

Autosomal Recessive (AR) Inheritance Diseases

ABCDEFGH SPW

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A - Albinism, Alpha 1 Antitrypsin Deficiency

B - Beta Thalassemia
C - Cystic Fibrosis, CGD, CAH
D - Deafness(SNHL), Dubin Johnson
E - Enzyme Deficiencies(Glycogen Storage And Lysosomal Storage)
F - Friedrich's Ataxia, Fanconi Anemia
G - Galactosemia
H - Hemochromatosis, Hurler syndrome
S - Sickle Cell Disease
P - Phenylketonuria
W - Wilson's disease
X - Linked Dominant Disorders
FAIR
F - Facial (oro) syndrome
A - Alports
I - Incontinenta pigmento
R - Resistant rickets

X - Linked Recessive Disorder

GRAHAM BELL

G - G6 PD deficency
R - Retinitis pigmentosa
A - Androgen insensitivity
H - Hemophilia A & B, Hydrcephalus
A - Adrenoleucodystrophy
M - Menkes disease
B - Beckers & duchennes musculardystrophy, Blindness (color blindness)
E - Emery- Dreifuss dystrophy
L - Lesch nyhan syndrome
L - Lowe disease

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Types Of Chromosomes

Cytogenetic Abnormalities
• The gametes contain half the number of
chromosomes (haploid) and are
represented as (23, X) or (23, Y).
• An exact multiple of haploid
chromosomes is called Euploidy
(2n, 3n, 4n etc).
• When exact multiple of haploid
chromosomes is not present, it is
called Aneuploidy.
• Genome mutations involve loss or gain
of whole chromosomes, giving rise to
monosomy or trisomy.

Cytogenetic disorders involving Autosomes

Down Syndrome (Trisomy 21)

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Patau syndrome (Trisomy 13)

Edwards syndrome (Trisomy 18)

Lyon hypothesis (X chromosome inactivation)

1. Only one of the X chromosomes is genetically active
2. Other X of either maternal or paternal origin undergoes
heteropyknosis and is rendered inactive
Barr body (X chromatin)
• Inactive X is seen in interphase nucleus as a darkly
staining small mass in contact with the nuclear
membrane.
• Used to test genetic femaleness.
• Number of Barr bodies = (N-l) (where N number of
X chromosomes)

Genotype Number of Barr bodies

In normal male (XY) (1 – 1 = O Barr body)
In normal female (XX) (2 - 1 = 1 Barr body)
In turner syndrome (XO) (1 – 1 = 0 Barr body)
In Klinefelter syndrome (XXY) (2 - 1= 1 Barr body)
Superfemale (XXX) (3 – 1 = 2 Barr bodies)

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Klinefelter Syndrome : (47,XXY)

Turner Syndrome (45; XO)

AMYLOIDOSIS
• Amyloidosis refers to a variety of condition in which amyloid proteins are abnormally
deposited extracellularly between the cells in various organs / tissues.
• Amyloid is a protein that has an alteration in its secondary structure which imparts it
a particular insoluble form

Physical nature
Electron microscopy:
• Nonbranching fibrils with diameter 7.5-10 nm and
indefinite length
X Ray crystallography / Infrared spectroscopy:
• Cross β pleated sheet conformation

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Chemical Nature of Amyloid

AL Protein
• AL amyloid fibril protein is derived from immunoglobulin light chain
• AL type of fibril protein is seen in plasma cell dyscrasias (multiple myeloma)
• It is included in primary systemic amyloidosis

AA Protein
• AA fibril protein is derived from larger precursor protein in the serum called SAA
(serum amyloid associated protein)
• SAA is an acute phase reactant protein synthesised in the liver, in response to chronic
inflammatory conditions
• AA fibril protein is found in secondary amyloidosis

Aβ₂m β₂ microglobulin Hemodialysis

AA SAA Familial mediterranean fever
ATTR Transthyretin Familial amyloidotic
polyneuropathies, Senile
cardiomyopathy
Aβ Aβ protein precursor (AβPP) Alzheimer's disease
APrP Prion protein Spongiform encephalopathy
A Cal Calcitonin Medullary carcinoma of thyroid
A IAPP Islet amyloid polypeptide Type II diabetes, Insulinomas
AANF Atrial natriuretic factor Isolated atrial amyloid

Diagnosis of Amyloidos → Biopsy

• Best sites for biopsy are rectum and abdominal fat
• Other sites of biopsy are salivary glands, gingiva , skin, tongue, bone marrow and
stomach.

Staining Characteristics of Amyloid

STAIN APPEARANCE
1. H&E Pink, hyaline, homogeneous
2. Methyl violet / Crystal violet Metachromasia: rose-pink
3. Congo red Light microscopy: pink-red
Polarising light: Apple green birefringence
4. Thioflavin-T/Thioflavin-S Ultraviolet light: fluorescence
5. Immunohistochemistry Immunoreactivity: Positive
(antibody against fibril protein)

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Congo Red
• Visible light → Pink red colour
• Polarised light → Apple-green birefringence
(due to cross-B-pleated sheet configuration)

Organs
Kidneys
➢ It is the most common form of systemic amyloidosis.
➢ It is the most serious form of organ involvement.
➢ The earliest pathological change seen in renal amyloidosis is
thickning of the glomerular basment membrane.
➢ Results in abnormal increase in permeability of the glomerular
capillaries → proteinuria and nephrotic syndrome

Spleen
i) Sago spleen → Amyloid deposition is limited to splenic
follicles (White pulp) → produces topioca like granules
ii) Lardoceous spleen → Amyloid depositon spares the follicles
and involves the walls of the splenic sinuses (Red pulp)

Hypersensitivity
• Hypersensitivity is defined as an exaggerated state of normal immune response which
results in adverse effects on the body.

Type I: Anaphylactic (Atopic) Reaction

• Eczema
• Hay fever
• Asthma (atopy)
• Urticaria
• Anaphylactic shock
• Acute dermatitis
• Theobald smith phenomenon
• PK (Prusnitz Kunster) reaction
• Casoni's skin test
• Schultz Dale phenomenon

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Type II: Antibody-Mediated (Cytotoxic) Reaction

My Blood Group Is RH Positive

My Myasthenia gravis
Blood Blood transfusion reactions
Group Goodpasture syndrome and Graves' disease
Is Insulin resistant diabetes, ITP
R Rheumatic fever
H Hyperacute graft rejection
Positive Pernicious anemia and Pemphigus vulgaris

Type V (Stimulatory Type) Reaction

• It is a modification of Type II hypersensitivity reaction.
• Antibodies interact with antigens on cell surface that leads to cell proliferation and
differentiation instead of inhibition or killing.
• Antigen-antibody reaction enhances the activity of affected cell.

Example
1. Grave’s disease
2. Myasthenia gravis

Type III: Immune Complex Mediated (Arthus) Reaction

SHARP

S Serum sickness, Schick test and SLE

H Henoch-Schonlein Purpura
A Arthus reaction
R Reactive arthritis, Raji assay
P Polyarteritis nodosa (PAN) and Post Streptococcal glomerulonephritis (PSGN)

Type IV: Delayed Hypersensitivity (T Cell-Mediated) Reaction

John gave TU LIP and Pop Corn to Hashi

John mote reaction

Tuberculin reaction
LePromin reaction
Pernicious anaemia
Contact dermatitis
Hashimoto thyroiditis

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Remember
• Types I, II and III →Antibody-mediated
• Type IV → Cellular immunity

Transplant
1. Autograft (autogenic graft): Graft from self
2. Isograft (syngraft): Graft from genetically
identical person, e.g. identical twin
3. Allograft (homograft or allogenic graft): Graft
from genetically unrelated member of same
species
4. Xenograft (heterograft): Graft from different
species

Graft versus host (GVH) reaction

• Graft mounts an immune response against the host (i.e.,
recipient) and rejects the host
(In contrary to the usual situation of graft rejections, in
which the recipient mounts an immune response against
the graft antigens)
• Runt disease in animals

Conditions for GVHD

1. Graft must contain immunocompetent T cells (e.g. stem cells or bone marrow or thymus
transplants)
2. Recipient may be immunologically suppressed and therefore cannot mount immune
response against the graft.

Neoplasia → Neoplasm
An abnormal mass of tissue
➢ The growth of which exceeds and is uncoordinated
with that of the normal tissues
➢ Persists in the same excessive manner even after
cessation of the stimuli which evoked the change.

Nomenclature
a) Benign tumors
b) Malignant tumors

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Benign tumors
Benign tumors are designed by attaching the suffix – oma

• Papilloma - Benign tumor with finger-like projections

• Adenoma - Benign epithelial tumor arising from glands or forming a glandular pattern

Exceptions
Malignant neoplasms with suffix - Oma –
1. Melanomas
2. Seminoma
3. Mesothelioma
4. Lymphoma

TISSUE OF ORIGIN BENIGN MALIGNANT

Epithelial Tumours
1. Squamous epithelium Squamous cell papilloma Squamous cell carcinoma
2. Transitional epithelium Transitional cell papilloma Transitional cell carcinoma
3. Glandular epithelium Adenoma Adenocarcinoma
4. Hepatocytes liver cell adenoma Hepatoma (Hepatocellular
5. Placenta (Chorionic Hydatidiform mole carcinoma)
epithelium) Choriocarcinoma
6. Neuroectoderm Naevus
Melanoma (Melanocarcinoma)

TISSUE OF ORIGIN BENIGN MALIGNANT

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Mesenchymal Tumours
1. Adipose tissue Lipoma Liposarcoma
2. Adult fibrous tissue Fibroma Fibrosarcoma
3. Embryonic fibrous tissue Myxoma Myxosarcoma
4. Cartilage Chondroma Chondrosarcoma
5. Bone Osteoma Osteosarcoma
6. Synovium Benign synovioma Synovial sarcoma
7. Smooth muscle Leiomyoma Leiomyosarcoma
8. Skeletal muscle Rhabdomyoma Rhabdomyosarcoma
9. Blood vessels Haemangioma Angiosarcoma
10. Lymph vessels Lymphangioma Lymphangiosarcoma
11. Meninges Meningioma Invasive meningioma
12. Lymphoid tissue Pseudo lymphoma Malignant lymphomas
13. Nerve sheath Neurofibroma Neurogenic sarcoma

Tetratoma
• Teratoma arise from totipotent cells
• Teratomas are germ cell tumors commonly composed of multiple cell
types derived from 3 germ layers → ectoderm, mesoderm and
endoderm
• A teratoma is a rare type of germ cell tumor that may contain
immature or fully formed tissue, including teeth, hair, bone and
muscle.

Not actual tumors (neoplasms)

Hamartoma
• It is a focal developmental malformation
• It represents a mass of disorganized but mature specialized cells indigenous / native to
the particular site
e.g.
a) Hamartoma of lung consists of mature cartilage,
mature smooth muscle and epithelium
b) Hamartoma of spleen consists of red and white pulp

Choristoma
• Ectopic islands of normal tissue.
• Thus, choristoma is heterotopia but is not a true tumour
Eg.
a) Osteocartilaginous choristoma of the tongue
b) Pancreatic tissue in mucosa of stomach

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Benign versus Malignant tumour

1. Rate of growth
• Benign tumour cells → Less mitotic rate (more doubling time)
• Malignant tumour cells → Increased mitotic rate (less doubling time) and slower
death rate ie. cell production exceeds the cell loss.

2. Clinical Features
Benign tumours Malignant tumours
• Slow growing • Grow rapidly
• May remain asymptomatic (e.g. • May ulcerate on the surface
subcutaneous lipoma) • Invade locally into deeper tissues
• May produce serious symptoms (e.g. • May spread to distant sites
meningioma in the CNS) (metastasis)
• Systemic features such as weight
loss, anorexia and anaemia

3. Gross Features
Benign tumours Malignant tumours
• Spherical or ovoid in shape. • Irregular in shape
• Encapsulated or well-circumscribed • Poorly-circumscribed
• Freely movable • Extend into the adjacent tissues.
• More firm and uniform • Sarcomas typically have fishflesh
• Surrounding tissue compressed like consistency while carcinomas
are generally firm
• Surrounding tissue invaded

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4. Microscopic Features
Lack of differentiation
OR
Presence of Anaplasia

Anaplasia
• Anaplasia is lack of differentiation
• Characteristic feature of malignant tumours
• Anaplasia is considered as a hallmark of malignant
transformation,
• It is irreversible

Features of anaplasia
1. Loss of polarity 6. Nucleolar changes
2. Pleomorphism 7. Mitotic figures
3. N:C ratio 8. Tumor giant cells
4. Anisonucleosis 9. Cytoplasm increased mucin
5. Hyperchromatism 10. DNA anuploidy

5. Spread Of Tumours
1. Local invasion (direct spread)
2. Metastasis (distant spread)

• Benign tumour → Neither show local invasion nor

Metastasis
• Malignant tumour → Show local invasion as well
as Metastasis

➢ Metastasis is the most reliable feature of a

malignant tumor
➢ Invasiveness is the 2nd most reliable sign of
malignancy (after metastasis)
FEATURE BENIGN MALIGNANT
Clinical And Gross Features
1. Boundaries Encapsulated or well- Poorly-circumscribed and
circumscribed irregular
2. Surrounding tissue Compressed Invaded

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3. Size Usually small Often larger

4. Secondary changes Occur less often Occur more often

Microscopic Features
1. Basal polarity Retained Lost
2. Pleomorphism Absent Present
3. N / C ratio Normal Increased
4. Anisonucleosis Absent Present
5. Hyperchromatism Absent Present
6. Mitosis May be present but are always Mitotic figures Increased and
typical mitoses are generally atypical and
abnormal
7. Tumour giant cells Present without nuclear atypia Present with nuclear atypia
8. Chromosomal abnormalities Infrequent Invariably present

Growth Rate Slow Rapid

Local Invasion Compresses the surrounding Infiltrates and Invades the
tissues without Invading adjacent tissues
Metastasis Absent Frequently present
Prognosis Local complications Death- metastatic complicatio
Metastasis (Distant Spread)
➢ Spread of tumour by invasion in such a way that discontinuous secondary tumour
mass/masses are formed at the site of lodgement away from primary site
➢ It is the most reliable feature of a malignant tumor
➢ Benign tumours do not metastasise
➢ All Malignant tumours can metastasise Except
1. Gliomas of CNS
2. Basal cell carcinoma of the skin

Routes of Metastasis
Cancers may spread to distant sites by following pathway
1. Lymphatic spread
2. Haematogenous spread
3. Transcoelomic spread

• Carcinomas metastasise by lymphatic route

• Sarcomas metastasise by haematogenous route

1. Lymphatic Spread
• Common route for carcinoma

Pattern of lymph node involvement

• The pattern of lymph node involvement follows the natural routes of lymphatic
drainage producing regional nodal metastasis

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• The first node in a regional lymphatic that receives lymph flow from the primary tumor is
called sentinel lymph node.
• Sentinel lymph node is useful in breast cancer, vulvar cancer and melanoma.
• Sometimes local lymph nodes may be bypassed because of venous lymphatic
anastomosis → skip metastasis
• In the lymph node tumor cells lodge in first in subcapsular sinus

Virchow’s lymph node

• Virchow’s lymph node is nodal metastasis to left supraclavicular lymph node from
cancers of abdominal organs e.g., cancer stomach, colon, and gallbladder.
• It is the thoracic duct end node
• It receives afferent lymphatic drainage from the left head, neck, chest, abdomen, pelvis,
and bilateral lower extremities, which eventually drains into the jugulo-subclavian
venous junction via the thoracic duct

2. Haematogenous Spread
• Common route for sarcomas

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• Veins are more commonly involved than arteries because veins have thinner walls that
can be penetrated readily (In contrast arteries have thicker walls)
• Liver and lung are the most frequent organs involved in hematogenous spread because
• All portal area drainage flows to the liver
• All caval blood flows to the lung

Remember
• Most common site of metastasis is LIVER
• 2nd most common site of metastasis is LUNG

3. Transcoelomic spread
i) Direct seeding into body cavities or surface
• Tumour clusters of tumour cells break off to be carried in the coelomic fluid and are
implanted elsewhere in the body cavity
• Most common cavity involved is peritoneal
cavity, but other cavities may also be involved,
e.g., pleural, pericardial, joint space,
subarachnoid.

Eg. Carcinoma of the stomach seeding to both

ovaries (Krukenberg tumour)

ii) Spread via cerebrospinal fluid

• Malignant tumour of the ependyma and leptomeninges may spread by release of
tumour fragments and tumour cells into the CSF and produce metastases at other sites in
the central nervous system.

iii) Implantation
• Spread of some cancers by implantation by surgeon’s scalpel, needles, sutures, and
direct prolonged contact of cancer of the lower lip causing its implantation to the
apposing upper lip.

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Mechanism Of Metastasis
8 steps

Genetic regulators (genes)

Normal cell growth, 4 regulatory genes:
i) Proto-oncogenes are growth-promoting genes
ii) Anti-oncogenes or tumour suppressor genes are growth-inhibiting or growth
suppressor genes.
iii) Apoptosis regulatory genes control the programmed cell death.
iv) DNA repair genes regulate repair of DNA damage that has occurred during mitosis and
also control the damage to proto-oncogenes and antioncogenes.

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In cancer
i) Overstimulation of proto-oncogenes
ii) Inhibition of tumour-suppressor genes

Proto-oncogenes
• Proto-oncogenes were discovered by Harold Varmus and Michael Bishop.
• Normal genes required for cell proliferation
• They act under proper physiological stimuli

Oncogenes

Proto-oncogenes
(Normal genes required for cell proliferation and differentiation)
↓ Mutation
Oncogenes
(Genes promoting autonomous cell growth in cancer cells)
↓
Oncoproteins
(Proteins lacking regulatory control and responsible for promoting cell growth)

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Tumour sppressor genes

• Tumor suppressor genes are the genes whose products down regulate the cell cycle and
thus apply brakes to cellular proliferation
• So, loss of function of tumor suppressor genes results in uncontrolled cell proliferation
and carcinogenesis.
GENE ASSOCIATED HUMAN TUMOURS
1. RB Retinoblastoma, osteosarcoma
2. p53 (TP53) Most human cancers, common in Ca lung, head and neck,
colon, breast
3. TGF-b and its receptor Ca pancreas, colon, stomach
4. APC and b-catenin proteins Ca colon
5. Others
i. BRCA 1 and 2 Ca breast, ovary
ii. VHL Renal cell carcinoma
iii. WT 1 and 2 Wilms' tumour
iv. NF 1 and 2 Neurofibromatosis type 1 and 2

Carcinogens and Carcinogenesis

• Carcinogenesis means mechanism of induction of tumours
• Agents which can induce tumours are called carcinogens

Physical Carcinogenesis
Ultraviolet Light
• Source → Sunlight
• has three subtypes
1. UV-A is 320-400 nm
2. UV-B is 280- 320 nm
3. UV-C is 200 - 280 nm
• UV-C gets filtered by ozone layer
• UV-B is the most carcinogenic UV ray to reach the earth
(UV-B is Bad for humans as it causes cancers)

Cancers
Skin cancers—
1. Squamous Cell carcinoma
2. Basal cell carcinoma (most common cancer)
3. Melanoma
Mechanism
Exposure to UV rays
↓
Pyrimidine dimers in DNA
↓
Mutation in oncogenes and tumor suppressor genes
↓

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Cancer

Ionising Radiation
• Source→ x-rays, y rays, α rays, β particles

Cancers
1. All forms of leukaemias (except chronic lymphocytic leukaemia CLL)
2. Cancers of the thyroid (most commonly papillary carcinoma)
3. Others → skin, breast, ovary, uterus, lung, myeloma, and salivary glands

Remember → CLL is the only leukemia NOT associated with ionizing

radiation exposure.

Mechanism
Exposure to ionizing radiation
↓
dislodge ions from water
↓
Formation of highly reactive free radicals
↓
DNA damage
↓
Cancer
ULTRAVIOLET LIGHT IONISING RADIATION
• Source Sunlight X-ray, a-ray, b-ray
(UV-B is Carcinogenic)
• Cancers Skin Cancers → -All leukaemia's (except CLL)
-BCC -Thyroid tumours
-SCC
-Meanoma
• Mechanism Pyrimidine dimers in DNA Reactive free Radical Formation

Remember
• The most radiosensitive cell in the blood is the lymphocytes
• The least radiosensitive cell in the blood is the platelets

Chemical Carcinogenesis
Types of chemical carcinogens
➢ Direct-acting carcinogens → induce cellular transformation without undergoing any
prior metabolic activation

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➢ Indirect-acting carcinogens or procarcinogens → require metabolic conversion within

the body so as to become ‘ultimate’ carcinogens

Stages In Chemical Carcinogenesis

3 stages →
1. Initiation
a) Metabolic activation c) Target molecules mutations
b) Reactive electrophiles d) The initiated cell
2. Promotion
3. Progression

Tests For Chemical Carcinogenicity

Ames’ Test
• Evaluates the ability of a chemical to induce mutation in the
mutant strain of Salmonella typhimurium that cannot
synthesise histidine.
• Such strains of mutant Salmonella typhimurium are
incubated with the potential carcinogen
• If the chemical under test is mutagenic, it will induce
mutation in the mutant strains of S. typhimurium in the
functional histidine gene

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• It will be reflected by the number of bacterial colonies growing on histidine-free culture

medium

Chemical carcinogens Associated cancer or neoplasm

• Alkylating agents • AML , bladder cancer
• Androgens • Prostate cancer
• Aromatic amines (dyes) (aniline • Bladder cancer
dyes)
• Arsenic • Cancer of the lung, skin
• Asbestos • Cancer of the lung, pleura,
Peritoneum,Mesothelioma
• Estrogens • Cancer of the endometrium liver breast
• Ethyl alcohol • Cancer of liver, esophagus, head, neck
• Tobacco (including smokeless) • Cancer of upper aerodigestive tract,
bladder
• Vinyl chloride • Liver cancer (angiosarcoma)
• Chromium and nickel • Lung cancer
• Benzene • Leukemia, Hodgkin’s lymphoma
• Nitrates • Gartric cancer
• Aflatoxin • Liver cancer

Biologic Carcinogenesis
Infectious agent Tumors
Virus HPV Cervical, vulvar & penile cancers (squamous cell
carcinoma)
EBV Nasopharyngeal carcinoma, Burkitt’s lymphoma,
Hodgkin’s lymphoma
HBV, HCV Hepatocellular carcinoma
HIV Kaposi sarcoma, NHL, squamous cell carcinoma
HTLV-1 Adult T- cell leukemia
HHV-8 Kaposi sarcoma, primary effusion lymphoma
Bacteria H. Pylori Gastric Cancer
Parasite Schistosomiasis Bladder cancer (squamous cell)
Clonorchis sinensis Liver cancer (HCC), bile duct carcinoma
(cholangiocarcinoma), Pancreatic cancer
Opisthorchis viverrine Bile duct carcinoma (cholangiocarcinoma)
Fasciola hepatica Bile duct carcinoma (cholangiocarcinoma)

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Paraneoplastic Syndrome
• A group of conditions developing in patients with advanced cancer which are neither
explained by direct and distant spread of the tumour
• About 10 to 15% of the patients with advanced cancer develop paraneoplastic syndromes
• Sometimes PNS may be the earliest manifestation of a latent cancer.

• Paraneoplastic Syndrome is a disease or a symptom that is a consequence of cancer, but

not due to the presence of local cancer cells.
1.
CLINICAL SYNDROME UNDERLYING CANCER i. MECHANISM
1. ENDOCRINE
SYNDROME

i. Hypercalcaemia -Lung (sq. cell Ca), kidney, breast, -Parathormone-like protein

Adult T-cell leukaemia-lymphoma -Vitamin D
-Lung (small cell carcinoma),
pancreas, neural tumours
ii. Cushing's syndrome -Lung (small cell Ca), prostate, -ACTH or ACTH-like substance
intracranial tumour -ADH or atrial natriuretic factor
iii. Inappropriate anti-diuresis -Pancreas (islet cell tumour), -Insulin or insulin-like substance
iv. Hypoglycaemia mesothelioma, fibrosarcoma -Serotonin, bradykinin
-Bronchial carcinoid tumour,
v. Carcinoid syndrome carcinoma pancreas, stomach -Erythropoietin
-Kidney, liver, cerebellar
vi. Polycythaemia haemangioma

2. NEUROMUSCULAR -Immunologic
SYNDROMES -Thymoma -Immunologic
i. Myasthenia gravis -Lung (small cell Ca), breast
ii. ii. Neuromuscular disorders
3. OSSEOUS, JOINT,
SOFT TISSUE
i. Hypertrophic Lung Not known
osteoarthropathy
ii. Clubbing of fingers Lung Not known

4. HAEMATOLOGIC
SYNDROMES
i. Thrombophlebitis Pancreas, lung, GIT Hypercoagulability
(Trousseau's phenomenon)
ii. Non-bacterial thrombotic
endocarditis Advanced cancers Hypercoagulability
iii. Disseminated
intravascular coagulation
(DIC) AML, adenocarcinoma Chronic thrombotic phenomena
iv. Anaemia
Unknown
5. GASTROINTESTINAL Thymoma
SYNDROMES
i. Malabsorption
Hypoalbuminemia
Lymphoma of small bowel

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6. RENAL SYNDROMES
i. Nephrotic syndrome Advanced cancers Renal vein thrombosis, systemic
amyloidosis
7. CUTANEOUS
SYNDROMES
i. Acanthosis nigricans Stomach, large bowel Immunologic
ii. Seborrheic dermatitis Bowel Immunologic
iii. Exfoliative dermatitis Lymphoma Immunologic

8. AMYLOIDOSIS
i. Primary Multiple myeloma Immunologic (AL protein)
ii. ii. Secondary Kidney, lymphoma, solid tumours AA protein

• Most common tumor associated with paraneoplastic syndrome is small cell carcinoma
of lung
• Hypercalcemia is the most comon paraneoplastic syndrome. Most commonly it is caused
by parathyroid hormone related peptide
• Cushing’s syndrome is most common endocrinopathy. It is usually due to production of
ectopic ACTH by small cell carcinoma lung(most common), carcinoid tumor
(neuroendocrine tumor), pancreatic tumor (islet cell tumor), and medullary carcinoma of
thyroid.

Diagnosis of Cancer
1. Histological method
2. Cytological method
3. Histochemistry and Cytochemistry
4. Immunohistochemistry (IHC)
5. Electron microscopy
6. Tumour markers

3. HISTOCHEMISTRY AND CYTOCHEMISTRY

1. Basement membrane/collagen ‐ Periodic acid-Schiff (PAS)

‐ Reticulin
‐ Van Gieson
‐ Masson's trichrome

2. Glycogen ‐ PAS with diastase loss

3. Glycoproteins, glycolipids, glycomucins ‐ PAS with diastase persistence
4. Acid mucin ‐ Alcian blue
5. Argyrophilic/argentaffin granules ‐ Silver stains
6. Nucleolar organiser regions (NORs) ‐ Colloidal silver stain

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4. Immunohistochemistry (Ihc)
TUMOUR IMMUNOSTAIN
1. Epithelial tumours (Carcinomas) i. Pankeratin (HMW-K, LMW-K)
ii. Epithelial membrane antigen (EMA)
iii. Carcinoembryonic antigen (CEA)
iv. Neuron-specific enolase (NSE)

2. Mesenchymal tumours (Sarcomas) i. Vimentin (general mesenchymal)

ii. Desmin myogenic)
iii. Myoglobin (for skeletal myogenic)
iv. a-1-anti-chymotrypsin (for malignant fibrous
histiocytoma)
v. CD34 (endothelial marker)
3. Melanoma i. HMB-45 (most specific)
ii. Vimentin
iii. S-100

4. Lymphoma i. Leucocyte common antigen (LCA/CD45)

ii. Pan-B (Immunoglobulins, CD20)
iii. Pan-T (CD3)
iv. RS cell marker for Hodgkin’s (CD15, CD30)

i. Neurofilaments (NF)
5. 5. Neural and neuroendocrine tumours ii. NSE
iii. GFAP (for glial tumours)
iv. Chromogranin (for neuroendocrine)

6. Tumour Markers (Biochemical Assays)

• Some tumor produce or elicite the production of markers that can be measured in the
serum or urine or other body fluids.
• Tumor markers are biochemical indicators of the presence of a tumor.

Tumor Markers Tumor Types

Hormones
Human chorionic gonadotropin Trophoblastic tumors, nonseminomatous testicular
tumors
Calcitonin Medullary carcinoma of thyroid
Catecholamine and metabolites Pheochromocytoma and related tumors
Oncofoetal Antigens
a-Fetoprotein Liver cell cancer, nonseminomatous germ cell
tumors of testis
Carcinoembryonic antigen Carcinomas of the colon, pancreas, lung, stomach,
and heart

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Isoenzymes
Prostatic acid phosphatase Prostate cancer
Neuron-specific enolase Small-cell cancer of lung, neuroblastoma
Specific Proteins
Immunoglobulins Multiple myeloma and other gammopathies
Prostate-specific antigen and Prostate cancer
prostate-specific membrane antigen
Mucins and Other Glycoproteins
CA-125 Ovarian cancer
CA-19-9 Colon cancer, pancreatic cancer
CA-15-3 Breast cancer

Hematology
Red Cell Indices
PCV in L/L
1. MCV = Normal value = 82-96 fL
RBC count/L

Hb/L
2. MCH = Normal range = 27-33 Pg.
RBC count/L

Hb/dl
3. MCHC = Normal value = 33-37 gm/dL
PCV in L/L

4. RDW = Degree of Anisocytosis Normal value = 11.5 to 14.5.

5. PCV = Blood volume proportion occupied by RBC

Normal value = 45% for men and 42%for women

Anemia
• Anaemia is defined as reduced haemoglobin concentration in blood below the lower
limit of the normal range for the age and sex of the individual.
• The lower extreme of the normal haemoglobin is taken as →
➢ 13.6 g/dl for males
➢ 12.0 g/dl for females
➢ 15 g/dl for newborns

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Morphology of RBC
Normal RBC is biconcave with diameter of 7 to 8 um.
• Biconcave shape is due to spectrin protein.
• The hemoglobin of red cells is located peripherally, leaving an area of
central pallor equal to approximately 30-35% of diameter of the cells
( Central 1/3rd pallor)
• The lifespan of red cells is 120 + 30 days.

Variations In Size
• RBC of normal size → Normocytic
• When red cell diameter is greater than
9 μm they are referred as macrocytes
• When red cell diameter is less than 6
μm they are referred as microcytes

• On smear size of RBC is compared

with small lymphocyte
Variations In Colour
• RBC with normal hemoglobin content (color)
(Central 1/3rd pallor) → Normochromic
• When area of central pollar is greater than 50% of
diameter, it is referred as hypochromic

• Variation is size of RBCs is known as anisocytosis

• Variation in shape of RBCs is known as
poikilocytosis

• Thalassemia, Hemoglobinopathies
• Post splenectomy
Target cells
• Liver disease
• Artefact

• G6PD deficiency
Bite cells • Unstable haemoglobin disorders
• Oxidative drugs

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• Sickle cell anemia

Sickle cell
• S-beta thalassemia

• Myelofibrosis
Teardrop cell
• Underlying marrow infiltrate

• Abetalipoproteinemia
• Liver disease
Spurr cell (Acanthocyte)
• Post splenectomy
• McLeod blood group phenotype

• Usdaia
Burr cell (Echinocyte) • Artefact
• Liver disease

• Haemoglobin C disease
Burr cell (Echinocyte)
• Haemoglobin SC disease

• Chronic liver disease

Rouleaux formation • Malignant lymphoma, Multiple myeloma
• Chronic inflammatory disease

• Cold autoimmune haemolytic anemia

• Paroxysmal cold hemoglobinuria
RBC agglutination
• IgM associated lymphoma
• Multiple myeloma

Classification Of Anaemias
Morphologic Classification
i) Microcytic, hypochromic
ii) Normocytic, normochromic
iii) Macrocytic, normochromic

Pathophysiological/ Etiological Classification

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RBC Inclusion Bodies

Morphology Composition Seen in

1. Howell Jolly bodies Nuclear rem. Splenectomy

2. Pappenhiemer body Ferritin agg. Ferritin excess

3. Heinz bodies Denatured Hb. G6PD def.

4. Cabot ring Iron & Arginine rich Pernicious anemia

histone
5. Basophilic stippling Agg. of ribosomes or LUNATIC
rRNA

Howell Jolly bodies Pappenheimer body Heinz bodies

Cabot ring Basophilic stippling

Hemolytic Anemia
• Haemolytic anaemias are defined as anaemias resulting from an increase in the rate of
red cell destruction

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Types

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Extravascular Hemolysis Intravascular Hemolysis

• Hereditary spherocytosis • Paroxysmal nocturnal hemoglobinuria
• Thalassemia • G-6-PD deficiency
• Sickle cell anemia • Clostridial toxin
• Autoimmune hemolytic anemia • Falciparum malaria
• Drug induced immune hemolytic • Mechanical injury to red cells
anemia • Defective cardiac valves
• G-6-PD deficiency • Thrombin in microcirculation
• Sickle cell anemia (minor)

Remember
• In G-6-PD deficiency both extravascular and intravascular hemolysis occur
• In Sickle cell anemia, usually there is extravascular hemolysis but intravasacular
hemolysis can also occur

Hereditary Spherocytosis
• Autosomal dominant inheritance
• Red cell membrane is abnormal

Membrane skeleton consists

Spectrin, (chief protein component responsible for
biconcave shape)which has two subunits a and β
This spectrin is attached to cell membrane at two sites→
1. Spectrin binds to ion transporter,
band 3 of membrane with the help of
ankyrin and band 4.2
2. Spectrin binds to glycophorin A of
the membrane by protein 4.1 and
actin

• Mutation most commonly involves the gene coding for →

Ankyrin > Band-3 > Spectrin >Band 4.2 (also called paladin)

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Remember
• Most common defect in hereditary Spherocytosis is in Ankyrin.
• Most common defect in hereditary elliptocytosis is in spectrin.

Morphology of RBC
• Blood film shows the characteristic abnormality of erythrocytes in the form of
microspherocytes

Special test
1. Osmotic fragility test / Pink test is helpful in testing the spheroidal nature of red cells
• RBCs lyses more readily in solutions of low salt concentration i.e. osmotic fragility
is increased

2. Direct Coombs’ (antiglobulin) test is negative so as to distinguish this condition from

acquired spherocytosis of AIHA in which case it is positive.

3. A characteristic feature of HS is increase in MCHC due to dehydration caused by loss of

K+ and water.
• Hereditary spherocytosis is the only important anemia in which MCHC is
increased.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

Anemias
• X-linked recessive disorder
• It is characterized by hemolytic anemia on exposure to
oxidative stress
Oxidant stress
a) Viral and bacterial infections
b) Certain drugs (antimalarials Primaquine, sulfonamides,
nitrofurantoin, aspirin, vitamin K)
c) Metabolic acidosis

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d) Ingestion of fava beans (favism)

Normal person Person with G6PD deficiency

↓ ↓
Oxidant stress Oxidant stress
↓ ↓
G6PD present NADPH is not generated in HMP shunt
↓ ↓
NADPH is generated in HMP shunt Oxidized glutathione is not converted to
↓ Reduced glutathione
Oxidized glutathione is converted to Reduced ↓
glutathione RBCs are not protected from oxidant injury
↓ ↓
Reduced glutathione protects RBCs from oxidant Intravascular and extravascular hemolysis
Morphology injury
↓
1. Heinz bodies →
No hemolysis
• Precipitate of denatured Hb. in RBC due to oxidative
stress)
• Revealed by supravital staining.
2. Bite cells (eaten RBCs by splenic macrophages)

Paroxysmal Nocturnal Haemoglobinuria (PNH)

• Acquired intrinsic defect in the cell membrane.
• PNH results from acquired mutation that inhibits synthesis of
Glycosylphospatidylinositol (GPl)

Pathogenesis
2 anchoring proteins called complement regulating proteins →
1. Decay accelerating factor (DAF, CD55)
2. A membrane inhibitor of reactive lysis (MIRL, CD59)

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Myeloid progenitor cell lineage (RBCs, WBCs,

platelets)

Mutation of PIG-A (phosphatidyl inositol glycan)

gene

Synthesis of glycosyl phosphatidyl inositol (GPI) does

not occur

Deficiency of GPI results in absence of complement

regulating proteins
(CD55, CD59) on blood cells

Blood cells become unusually sensitive to

complement mediated lysis

Intravascular hamolysis

Clinical features
1. The hemolysis is→
a) Paroxysmal (intermittent attacks)
b) Nocturnal (occurs in the night) → Because during sleep the pH of blood gets
slightly reduced and acidic medium leads to activation of the complement.
2. Pancytopenia

3. Thrombosis
• Due to absence of CD-59 on platelets, this results in externilization of
phosphotidylserine →thrombosis

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Triad of PNH
1. Hemolysis
2. Pancytopenia
3. Thrombosis
Screening test
1. Ham test
2. Sucrose lysis test
2. Sucrose lysis test
Confirmatory test
Flow cytometry
• Bimodal distribution of the red cells

Autoimmune Haemolytic Anaemia (AIHA)

• Autoimmune hemolytic anemia is caused by autoantibodies directed against a red cell
antigen.

Types
1. ‘Warm’ Antibody AIHA
• Most common form of autoimmune hemolytic anemia.
• Antibody react with RBC at 37°C.
• Most causative antibodies are of the IgG class
• Extravascular hemolysis

2. ‘Cold’ Antibody AIHA

1. Cold agglutinin disease
• Antibodies react with RBC at 0° to 4°C.

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• Caused by cold agglutinin IgM antibodies.

• Extravascular hemolysis

2. Paroxysmal cold haemoglobinuria (PCH)

• Antibodies react with RBC at 0° to 4°C.
• The autoantibodies are of IgG class, also known as Donath-Landsteiner
antibody
• Intravascular hemolysis occur
IgM antibody directed against the I antigen of IgG (Donath-Landsteiner) antibody directed
RBC against the P antigen of RBC
↓ ↓
bind to I antigen of RBC at 4 degree C bind to P antigen of RBC at 4 degree C
↓ ↓
Fix complement on RBC (transient reaction) Antigen antibody complex on the red blood cell
↓ activates complement
C3b acts as an opsonin ↓
↓ Large amount of membrane attack complex
It enhances the phagocytosis of RBCs in (MAC)forms
phagocytic system of liver and spleen ↓
↓ Destroys red cells directly in blood vessel
Extravascular hemolysis ↓
Intravascular hemolysis
Warm AIHA Cold AIHA Cold AIHA
CAD PCH
Temperature 370C 40C 40C
Ab. IgG IgM IgG
(Donath-Landsteiner)
Hemolysis Extrinsic Extrinsic Intrinsic

Warm antibody type Cold antibody type

Mostly IgG; rarely IgA Mostly IgM, rarely IgG
Causes Causes
• Primary (Idiopathic) • Primary (Idiopathic)
• SLE, rheumatoid arthritis • Mycoplasma infection,
• B cell lymphoid neoplasms • Infectious Mononucleosis Lymphoid
• Drugs (a-methyldopa, penicillin) neoplasms
• Paroxysmal cold hemoglobinuria
(IgG)
Mechanism of hemolysis Mechanism of hemolysis
Extravascular hemolysis (in spleen) Extravascular hemolysis in cold agglutinin
Intravascular hemolysis in cold hemolysins
The antibody is active at 37°C Antibodies reacts at 4-6°C,
dissociate at 30°C or above

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Morphology
• Prominent spherocytosis in the peripheral blood film.
Special test
1. Positive direct Coombs’ (antiglobulin) test for presence of warm
antibodies on the red cell, best detected at 37°C.
2. A positive indirect Coombs’ (antiglobulin) test at 37°C may indicate presence of large
quantities of warm antibodies in the serum.
Sickle Cell Anaemia
Haemoglobinopathies
2 types:
1. Qualitative disorders in which there is structural abnormality in synthesis of
haemoglobin e.g. sickle cell syndrome
2. Quantitative disorders in which there quantitatively decreased globin chain
synthesis of haemoglobin e.g. thalassaemias

Sickle Cell Anaemia

• Sickle cell anaemia (SS) is a homozygous state of HbS in the red cells
• In this an abnormal gene is inherited from each parent.

Pathogenesis
Haemoglobin
↓
β-globin chain gene mutation (chromosome11)
↓
Single point mutation at sixth position of β-globin
chain (mis-sense mutation)
↓
Substution of a valine residue for a glutamic acid
residue
↓
Sickle hemoglobin (HbS) instead of HbA

Consequences of Sickling

Deoxygenation of HbS-containing RBC

↓
Polymerisation of deoxygenated HbS
↓
Elongated rod-like polymers fibres align

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↓
Distort the RBC into classic sickle shape (Sickling)
↓
Express higher levels of adhesion molecules (abnormally sticky)
↓
Vaso occlusion of microcirculation

With repeated episodes of

deoxygenation and sickling With membrane damage
↓ ↓
Membrane damages permanently Water comes out of the cell
↓ ↓
RBC become irreversibly sickled Intracellular dehydration
↓ ↓
Difficulty in passing through Increased MCHC
splenic sinusoids → Spleenic
Sequestration
↓
Rapid phagocytosis
↓
Extravascular Haemolysis →
Haemolytic anaemia
Factors determining rate of sickling
1. Amount of HbS and interaction with other Hb
2. Hemoglobin concentration of RBC
3. Intracellular dehydration
4. Decrease in pH
5. The length of time red cell are exposed to low oxygen tension
Clinical Features
1. Anaemia
• Irreversible sickle cells have difficulty in passing the splenic sinusoids,
sequestration, and rapid phagocytosis.
• Anemia is associated with Jaundice reticulocytosis.

2. Vaso-occlusive phenomena
• Reversible sickle cells express higher levels of adhesion molecules and are
abnormally sticky , So responsible for occlusion of microcirculation
• Vasoocclusive symptoms are the most common manifestations of sickle cell
anemia.
A. Bone

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a. Hand foot syndrome

b. Avascular necrosis of femoral head
c. Prominent cheek bones
d. Crew cut appearance of skull
e. Fish mouth appearance of vertebra

B. Lungs → Acute chest syndrome characterized

by cough, fever and chest pain
C. Brain →seizures or stroke
D. Skin →leg ulcers
E. Penis → stagnation in corpora cavernosa leads to priapism
F. Aplastic crises
• Occurs from the infection of red cell progenitors by parvovirus B19→ sudden
worsening of the anemia
G. Spleen
• In the initial stages, there is splenomegaly due to congestion
and trapping of red cells in the vascular sinusoids
• Prolonged hypoxia and infarction can lead to
autosplenectomy

Screening
Sickling Test

Diagnosis
1. Peripheal smear

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2. ESR
• ESR is usually increased in all anemia except in sickle cell anemia where ESR is
decreased because there is no rouleaux formation.

3. Haemoglobin electrophoresis
• HbS moves Slowly towards Anode.
• HbA moves faster towards Anode
Interpretation→
• Formation of 1 band is suggestive of sickle cell
anemia
• Formation of 2 bands are suggestive of sickle
cell carrier or trait.

Thalassaemias

• Quantitative abnormalities of polypeptide globin chain synthesis

• Reduced synthesis of one or more of the globin polypeptide chains.

Classification
• α Thalassaemia→ Absent or reduced synthesis of α globin chain
(chromosome 16) with normal β -chain synthesis.
• β Thalassaemia→ Absent or reduced synthesis of β globin chain
(chromosome 11) with normal α -chain synthesis

Classification of a-thalassaemias
TYPE HB Electrophoresis Genotype Clinical
Syndrome
1. Hydrops foetalis 3-10 gm/dl Hb Barts Deletion of Fatal in utero or in
four a-genes early infancy
2. HbH disease 2-12 gm/dl HbF , HbH Deletion of three Haemolytic
a-genes anaemia
3. -Thalassaemia 10-14 gm/dl Almost normal Deletion of Microcytic
trait two a-genes hypochromic
blood
picture but no
anaemia
4. -Thalassaemia Normal Normal Deletion of Asymptomatic
Carrier One a-genes

Classification of b-thalassaemias
TYPE HB Electrophoresis Genotype Clinical Syndrome

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Severe anaemia,
HbA(0-50%),
1. -Thal major <5 gm/dl thal/thal requires
HbF(50-98%)
transfusions
Severe anaemia, but
Multiple
2. -Thal intermedia 5-10 gm/dl Variable regular transfusions
mechanisms
not required
10-12 HbA2(4-9%), Usually,
3. -Thala minor A/thal
gm/dl HbF (1-5%) asymptomatic

β thalassemia
• Absent or reduced production of β globin chain
• Reduced formation of HbA in the red cells.

Molecular pathogenesis
Point Mutations of β-globin gene resulting from single base
changes

Clinical features of β -Thalassaemia major

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Lab Diagnosis of β -Thalassaemia major

Perpheral smear

Bone marrow examination

a) Hypercellular with erythroid hyperplasia
b) Reversal of normal M:E ratio (1:3)
c) Pink inclusions are seen in the normoblasts (caused by a chain accumulation).

Osmotic fragility test

Increased resistance to saline haemolysis i.e. decreased osmotic fragility

NESTROF Test
Naked Eye Single Tube Red cell Osmotic Fragility

Haemoglobin electrophoresis
1. Since β chains are not produced but y chains are synthesized normally → increased
amounts of HbF (90%).
2. Increased amount of HbA2
3. Almost complete absence of HbA

Skull X-ray
Widening of the diploe gives rise to →
➢ Crew cut appearance on skull X-ray
➢ Hair on end appearance

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α thalassemia
Molecular pathogenesis
• Deletion of one or more of the α -chain genes located on short arm of chromosome 16.

Iron Deficiency Anaemia

• Most common cause of anemia worldwide and in India

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Normal iron metabolism

Regulation of iron absorption

When body is replete with iron When body iron stores is low
↓ ↓
High hepcidin levels Hepcidin synthesis falls
↓ ↓
Inhibit iron absorption into the blood Facilitates iron absorption into the bloo

Factors of Iron absorption

Factors increasing absorption Factors decreasing absorption
• Ferrous form (Fe2+) • Ferric form (Fe3+)
• Acid (HCI) in the stomach • Achlorhydria (absence of HCI
• Ascorbic acid secretion)
• Amino acid and sugars in the food • Alkaline food (pancreatic secretions)
• Iron deficiency • Phytates, tannates and phosphates in
• Physiological conditions diet
(pregnancy and hypoxia) • Iron overload
• Tetracyclines and EDTA
• Inflammatory disorders

Don’t Forget
• Iron is transported is blood in combination with a glycoprotein transferrin.
• Iron is stored as ferritin or haemosiderin.

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Clinical Features
a) Nails (koilonychias or spoon-shaped nails)
b) Tongue (atrophic glossitis)
c) Mouth (angular stomatitis)
Plummer-Vinson syndrome

Laboratory Findings
Blood picture

a) Reticulocyte count → normal but may be slightly low

b) Indices
• Diminished MCV (below 50 fl)
• Diminished MCH (below 15 pg)
• Diminished MCHC (below 20 g/dl)
c) Leucocytes → TLC and DLC normal
d) Platelets → normal

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Bone marrow findings

a) Marrow cellularity
• Increased due to erythroid hyperplasia
• Myeloid-erythroid ratio decreased
b) Erythropoiesis
• Small normoblasts. (micronormoblast)
• Cytoplasmic maturation lags behind nuclear maturation
c) Marrow iron (Prussian blue reaction) → Deficient

Biochemical findings
a) Serum iron level → Low (50 μg/dl)
b) Serum ferritin level → Low
(Indicating poor tissue iron stores)
c) Total iron binding capacity (TIBC) →
High
d) Transferrin saturation → Low (below
15%)

Differential diagnosis
Test Iron Chronic Thalassaemia Sideroblastic
Deficiency Disorders Minor Anaemia
1. MCV, MCH, Reduced Low normal- Very low Very low (except
MCHC to-reduced MCV raised in
acquired type)
2. Serum iron Reduced Reduced Normal Raised
3. TIBC Raised Low-to-normal Normal Normal
4. Serum ferritin Reduced Raised Normal Raised (complete
saturation)
5. Marrow-iron stores Absent Present High High
6. Iron in normoblasts Absent Absent Present Ring sideroblasts
7. Hb electrophoresis Normal Normal Abnormal Normal

Sideroblastic Anaemia

Sideroblastic anemia is a type of anemia in which the body has adequate amount of iron
but is unable to corporate it into hemoglobin.

Mitochondrial Enzymes defect activity in erythroblasts

↓
Iron enters into the mitochondria
↓

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Cannot be utilized to synthesize heme

↓
Iron accumulates in mitochrondria of erythroblasts
↓
Ringed sideroblast
Types of Sideroblast

Types of

Sideroblastic Anaemias
Hereditary sideroblastic anaemia
• A rare X-linked disorder associated with defective enzyme activity of aminolevulinic
acid (ALA) synthetase required for haem synthesis.

Acquired sideroblastic anaemia

• Previous chemotherapy
• Irradiation
• Myelodysplasia
• Myelproliferative disorders
• Drugs→ Alcohol, isoanizid, choramphenicol, pyridoxine deficiency, lead poisoning

Laboratory diagnosis
Blood picture
a) Haemoglobin → Fall
b) RBC → Hypochromic anaemia which may be microcytic or normocytic
(dimorphic).
c) Reticulocyte count → normal but may be slightly low
d) Indices → (MCV, MCH and MCHC) → Reduced in hereditary type but
MCV is often raised in acquired type.
e) Leucocytes → TLC and DLC normal
f) Platelets → normal

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Bone marrow findings

1. Marrow cellularity
• Increased due to erythroid hyperplasia
• Myeloid-erythroid ratio decreased
2. Erythropoisis → Erythroid hyperplasia
3. Marrow iron
• Raised
• Pathognomonic ring sideroblasts are present.

Biochemical Findings
a) Serum iron level → Raised
b) Serum ferritin level → Raised
c) Total iron binding capacity (TIBC) → normal 33%
d) Transferrin saturation → Increased

Anaemia of Chronic Disorders

a) In patients of a variety of chronic systemic diseases in which anaemia develops
secondary to a disease process but there is no actual invasion of the bone marrow.
b) The severity of anaemia is usually directly related to the primary disease process.
c) The anaemia is corrected only if the primary disease is alleviated

Laboratory diagnosis
Blood picture
a) Haemoglobin → Fall
b) RBC → Normocytic normochromic
c) Reticulocyte count → normal but may be slightly low
d) Indices → MCHC is slightly low.
e) Leucocytes → TLC and DLC normal
f) Platelets → normal
Bone marrow findings
a) Marrow cellularity

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• Increased due to erythroid hyperplasia

• Myeloid-erythroid ratio decreased
b) Erythropoisis → Normal erythroid maturation
c) Marrow iron → Raised
Biochemical Findings
a) Serum iron level → Reduced
b) Serum ferritin level → Increased
c) Total iron binding capacity (TIBC) → Normal or decreases
d) Transferrin saturation → Decrease
Others
a) Acute phase reactants (gamma-globulin, C3, haptoglobin, a1-antitrypsin and fibrinogen)
→ Raised
b) ESR → Raised

Megaloblastic Anaemias (Vitamin B12 And Folate Deficiency

• The megaloblastic anaemias are disorders caused by impaired DNA synthesis

• Vit B12 and folic acid are required for DNA synthesis.
• So megaloblastic anaemia is due to deficiency of
vit. B12 and folic acid

Inadequate DNA synthesis

↓
Defective nuclear maturation
↓
Maturation of the nucleus lag behind to that of the cytoplasm
↓
Nuclear/Cytoplasmic asynchrony
↓
Formation of megaloblasts and macrocytes

• Vit. B12 is also involved in the conversion of methylmalonyl CoA to succinyl CoA
which is required for the formation of normal neuronal lipids.
• So, deficiency of vitamin B12 (but not of folic acid) results in neurological features

Clinical Features
1. Anaemia (In both vit.B12 and folate def.)
2. Neurologic manifestations (only in vit.B12 def. Not in folate def.) →
➢ Subacute combined degeneration of the spinal cord
➢ Peripheral neuropathy

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➢ Numbness, paraesthesia, weakness, ataxia, poor finger coordination and

diminished reflexes.

Laboratory findings
Blood picture
a) Haemoglobin concentration → Fall
b) RBCs
• Macrocytosis
• Macroovalocytes
• Anisocytosis
• Poikilocytosis
• Tear drop cells
• Basophilic stippling
• Cabott Ring
• Howell-jolly bodies (Evidence of defective
erythropoiesis)
c) Reticulocyte count → Low to normal
d) Absolute values
• Elevated MCV (above 120 fl)
• Elevated MCH (above 50 pg)
• Normal or reduced MCHC (because
hemoglobin content in the cell is increased
proportiante to increase in the size of RBC)
e) Leucocytes
• Hypersegmented neutrophils (having more than 5 nuclear lobes) → First
manifestation of megaloblastic anemia
f) Platelets → Bizarre forms of platelets may be seen.

Bone marrow findings

a) Marrow cellularity
• Hypercellular → erythroid hyperplasia
• Decreased myeloid-erythroid ratio
b) Erythropoiesis
• Megaloblastic erythropoiesis
• Nuclear maturation lags behind that of
cytoplasm
c) Marrow iron →Increase

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Biochemical findings
a) Serum iron → Normal or elevated
b) Serum ferritin → Normal or elevated

Special Tests for for vit. B12 deficiency

Schilling test
a) To detect vitamin B12 deficiency
b) To distinguish and detect lack of IF and
malabsorption syndrome.

• Radioisotope used for labeling B12 is either 58Co or

57Co.

Schilling Test
58
Co-Cbl W/intrinsic After 5 Days W/Pancreatic
Factor of Antibiotics Enzymes
Pernicious Reduced Normal Reduced Reduced
Anemia
Bacterial Reduced Reduced Normal Reduced
overgrowth
Chronic pancreatitis Reduced Reduced Reduced Normal

Special Tests for for folate deficiency

Urinary excretion of FIGLU
• Folic acid is required for conversion of formiminoglutamic acid (FIGLU) to glutamic
acid in the catabolism of histidine.
• Thus, on oral administration of histidine, urinary excretion of FIGLU is increased if
folate deficiency is present

Histidine
↓
Formiminoglutamic acid (FIGLU)

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↓ Folic acid
Glutamic acid
Pernicious Anaemia
Autoantibodies against gastric parietal cells
↓
Atrophy of gastric mucosa
↓
IF absent
↓
No absorption of Vitamin B 12
↓
Vitamin B 12 deficiency
↓
Pernecious anemia

Aplastic Anaemia

• Aplastic anaemia result from aplasia of the bone marrow

• In aplastic anaemia, there is pancytopenia i.e. simultaneous
presence of
1. Anaemia
2. Leucopenia
3. Thrombocytopenia

Etiology
1. Primary aplastic anaemia
a) Fanconi's anaemia (congenital)
b) Immunologically-mediated (acquired)
2. Secondary aplastic anaemia
a) Drugs e.g. with antimetabolites (methotrexate), mitotic inhibitors (daunorubicin),
alkylating agents (busulfan), nitroso urea, anthracyclines.

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b) Toxic chemicals e.g. benzene derivatives, insecticides, arsenicals.

c) Infections e.g. infectious hepatitis, EB virus infection, AIDS, other viral illnesses.

Laboratory findings
Blood picture
a) Haemoglobin → Fall
b) Red cells → Normocytic normochromic anaemia
c) Reticulocyte → reduced or zero
d) WBC → Leucopenia The absolute granulocyte count is particularly low (below 1500/μl)
with relative lymphocytosis.
e) Platelet → Thrombocytopenia

Bone marrow picture

Cellularity →
• A bone marrow aspirate → ‘dry tap’.
• A trephine biopsy → Hypocellular or aplastic
marrow due to replacement by fat.
• Haematopoietic stem cells bearing CD34
marker are markedly reduced or absent.

Leukemias And Lymphomas

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• Leukemia is used for lymphoid neoplasms presenting with widespread involvement of

the bone marrow usually accompanied by the presence of large number of tumour
cells in the peripheral blood.
• Lymphoma is used to describe proliferations arising as discrete tissue masses
(lymph nodes, spleen, or extranodal tissues).
• Lymphoma may have leukemia and vice versa.

Classification of Leukemias

Classification of Lymphomas
WHO categorise various lymphoid neoplasms into five categories based on clinical features and
morphology

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FEATURE HODGKIN'S NON-HODGKIN'S

1. Cell derivation B-cell 90% B
10% T
2. Nodal involvement Localised, may spread to Disseminated nodal
contiguous nodes Spread
3. Extranodal spread Uncommon Common
4. Bone marrow involvement Uncommon Common
5. Constitutional symptoms Common Uncommon
6. Chromosomal defects Aneuploidy Translocations, deletions
7. Spill-over Never May spread to blood
8. Prognosis Better Bad
(75-85% cure) (30-40% cure)

Chronic Myeloid Leukemia (CML)

• CML is an acquired disease of haemopoietic stem cell that is characterized by→
1. Leucocytosis with granulocytic immaturities
2. Basophilia
3. Splenomegaly
4. Distinct chromosomal abnormality - Philadelphia (Ph’) chromosome.

Age→ CML presents in old age (> 50 years )

Pathogenesis
• Translocations t(9;22) / ABL-BCR Translocation → Philadelphia chromosome

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In Translocation
ABL gene (normal location on chromosome 9)
↓
Translocated to chromosome 22
↓
It fuses with BCR (breakpoint cluster region)
gene
↓
ABL-BCR hybrid gene → Philadelphia
chromosome
↓
210 KD fusion protein
↓
Abnormal signal transduction even without
growth factors
↓
Uncontrolled mitosis
↓
CML

Phases of CML
CML (Triphasic leukemia)
I. Chronic phase II. Accelerated phase III. Blast crisis
(one or more of the following)
1. Bone marrow or peripheral blood 1. Blast cells 10-19% 1. Blast count > 20%
< 10% of blast cells.
2. BCR-ABL [t(9;22)] fusion genes 2. Basophilia ≥ 20% 2. Extramedullary blast cells (-
present chloromas)
3. Thrombocytopenia or 3. Large clusters of blast cell on bone
thrombocytosis, nonresponsive to marrow biopsy
treatment
4. Leukocytosis or splenomegaly-non-
responsive to treatment
5. Cytogenetic changes - Trisomy 8,
isochromosome some 17q;
Philadelphia chromosome
duplication, etc.

Clinical Features
1. Due To Bone Marrow Failure→
a) Anaemia producing pallor, lethargy, dyspnoea.
b) Bleeding manifestations causing spontaneous bruises, petechiae, bleeding from
gums and other bleeding tendencies.
c) Infections
2. Symptoms due to hypermetabolism such as weight loss, lassitude, anorexia, night
sweats.
3. Splenomegaly is massive.

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Blood Picture
a) Anaemia→ Normocytic normochromic
b) Thrombocytopenia
c) White blood cells →
• Marked leucocytosis (approx
200,000/μl or more)
• Immature Neutrophils ((band forms,
metamyelocytes, myelocytes,
promyelocytes)
• Basophilia
• Eosinophilia

Bone Marrow Examination

a) Cellularity→ Hypercellularity (proliferating myeloid cells)
b) Myeloid cells The myeloid cells predominate in the bone marrow with increased
myeloid-erythroid ratio
c) Erythropoiesis → Reduced
d) Megakaryocytes → Megakaryocytes are normal but are usually smaller in size

Cytogenetics
• Cytogenetic studies on blood and bone marrow cells show the characteristic
chromosomal abnormality called Philadelphia (Ph) chromosome seen in 90-95% cases
of CML.

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• Ph chromosome is formed by reciprocal balanced translocation between part of long

arm of chromosome 22 and part of long arm of chromosome 9
→ t(9;22) → BCR/ ABL fusion gene

Cytochemistry
• Reduced scores of neutrophil alkaline phosphatase (NAP) which
helps to distinguish CML from myeloid leukaemoid reaction (in
which case NAP scores are elevated )

Treatment
1. Treatment Of Anaemia And Haemorrhage
a) Anaemia and haemorrhage → fresh blood transfusions and platelet
concentrates.
b) Patients with severe thrombocytopenia → regular platelet transfusions
2. Imatinib oral therapy
a) Competitively inhibit ATP binding site of the ABL kinase→ inhibits signal
transduction BCR/ABL fusion protein
b) Induces apoptosis in BCR/ ABL-positive cells and eliminates them
3. Allogenic bone marrow (stem cell) transplantation

Acute Myeloid Leukaemia (AML)

• Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by infiltration
of malignant myeloid cells into the blood, bone marrow and other tissues.

Age→ Peak age group is 15 to 40 years.

Pathophysiology
• AML develops due to inhibition of maturation of myeloid stem cells due to mutations
a) t(8;21)
b) t(15;17)
c) inv(16)

FAB Classification
FAB CLASS OLD NAME

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M0: Minimally differentiated AML

M1: AML without maturation
M2: AML with maturation
M3: Acute promyelocyte leukaemia
M4: Acute myelomonocytic leukaemia (Naegeli type)
M5: Acute monocytic leukaemia (Schilling type)
M6: Acute erythroleukaemia (DiGuglielmo's syndrome)
M7: Acute megakaryocyte leukaemia
M0:
• Myeloid lineage blasts
• MPO Negetive
M1:
• Myeloblasts without maturation
• > 3% blasts MPO or SBB positive
M2:
• AML is the Commonest type of AML
• t (8;21) is present
• maximum incidence of chloroma
M3:
• t (15; 17) seen
• Auer rods are seen
• AML is associated with disseminated intravascular coagulation (DIC)
M4:
• Inversion 16 present
• Presence of both myeloblasts and monoblasts
M5:
• t (9;11)
• Highest incidence of tissue infiltration, organomegaly, and lymphadenopathy

M6:
• Abnormal erythroid precursors are seen
M7:
• Least common type of AML
• Commonest type of AML in Down syndrome
• Megakaryocytes are seen
• Release of platelet derived growth factor (PDGF) causes myelofibrosis

Clinical Features
1. Due To Bone Marrow Failure→
a) Anaemia producing pallor, lethargy, dyspnoea.
b) Bleeding manifestations causing spontaneous bruises, petechiae, bleeding from
gums and other bleeding tendencies.
c) Infections
2. Due to organ infiltration by leukaemic cells →

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a) Pain and tenderness of bones (e.g. sternal tenderness)

b) Lymphadenopathy and enlargement of the tonsils
may occur.
c) Splenomegaly
d) Hepatomegaly
e) Leukaemic infiltration of the kidney
f) Gum hypertrophy due to leukaemic infiltration of
the gingivae is a frequent finding in AML M4 and
AML M5
g) Chloroma or granulocytic sarcoma is a localised tumour forming mass occurring in
the skin of orbit (Proptosis) , frequent finding AML M2
h) Meningeal involvement

Lab diagnosis
Blood Picture
1. Anaemia→ Normocytic normochromic
2. Thrombocytopenia (Acute promyelocytic
leukaemia (M3) associated with DIC).
3. White blood cells →
• Exceed 100,000/μl
• Myeloblasts with Ayur rods present (Faggot cells→ Maximum in M3)

Bone Marrow Examination

a) Cellularity → Hypercellular
b) Leukaemic cells
• The diagnosis of AML is based on myeloblasts
more than 20% of cells in the marrow
• Auer rods (Represent abnormal azurophilic
granule) present in myeloblasts → definite
evidence of myeloid differentiation.
c) Erythropoiesis → Reduced
d) Megakaryocytes → Reduced or absent

Cytogenetics
a) M2 → t(8;21)

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b) M3 → t(15;17)
c) M4 → inv(16)

Cytochemistry
a) Myeloperoxidase (MPO) → Positive (Negative in M0 myeloblasts)
b) Sudan Black → Positive
c) Non-specific esterase (NSE) → Positive in monocytic series (M3 ,M4 and M5).
d) Periodic acid-Schiff (PAS) → Negative (Positive in M6).
e) Acid phosphatase → Negative (Diffuse reaction in M4 and M5).

Prognostic factors of AML

Good prognosis Bad prognosis
• Age <40 years • Age <2 years or >55 years
• M2, M3, M4 forms of AML • M0, M6, M7 forms of AML
• Blast cell with Auer rods • Complex karyotypes
• TLC < 25 X 109/L • TLC > 100X109/L
• t (15;17), t(8;21), inv 16 • Deletions 5q, 7q
• Rapid response to therapy • Delayed response to therapy
• Leukemia without preceding MDS • AML with preceding MDS or anticancer drug
exposure

Acute Lymphoblastic Leukemia / Lymphoma

TYPES →
1. Pre B-cell ALL
2. Pre T-cell ALL
Age
• Pre B-cell ALL → 3-5 years
• Pre T-cell ALL → Adolescent male

Pathogenesis
Pre B cell ALL
• Hyperdiploidy (i.e., more than 50 chromosomes)
• Hypodiploidy (chromosome number less than 50).
• Balanced t (12;21) translocations involving genes ETV6 and RUNX1.
Pre T cell ALL
• t(9;22) translocations involving genes BCR and ABL

L1 ALL L2 ALL L3 ALL

Commonest type of ALL having Next common type having worse Rarest type of ALL with the worst
the best prognosis prognosis. prognosis.

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Large, heterogenous blast, indented Large homogenous blast, abundant

Small homogenous blast, scanty nuclei, one or more nucleoli, basophilic cytoplasm with prominent
cytoplasm, indistinct nucleoli moderately abundant cytoplasm, cytoplasmic vacoulation staining
minimal cytoplasmic vacoulation positive with Oil Red '0'.

Clinical Features
1. Due To Bone Marrow Failure→
a) Anaemia producing pallor, lethargy, dyspnoea.
b) Bleeding manifestations causing spontaneous bruises, petechiae, bleeding from gums
and other bleeding tendencies.
c) Infections
2. Due to organ infiltration by leukaemic cells →
1. Bone pain and tenderness → Resulting from infiltration of the subperiosteum.
2. Generalized lymphadenopathy, splenomegaly and hepatomegaly→ neoplastic
infiltration of these tissues.
3. Compression of large mediastinal vessels or airway → In Pre-T ALL of thymus.
4. CNS manifestation (Headache, vomiting, nerve palsies)→ Due to meningeal
involvement.
5. Testicular involvement

Lab diagnosis
Blood Picture
a) Anaemia
b) Thrombocytopenia
c) White blood cells →
• Leucopenia to- normal TLC to
leucocytosis
• Large number of circulating
lymphoblasts

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Bone Marrow Examination

a) Cellularity → Hypercellular
b) Leukaemic cells
• FAB diagnostic criteria → > 30 % blasts in bone marrow
• WHO criteria → > 20% blast in bone marrow
c) Erythropoiesis → Reduced
d) Megakaryocytes → Reduced

Cytogenetics
• Hyperdiploidy
• Hypodiploidy
• Trisomy 4, 7,10
• t (9;12)
• t (12;21)
• t (9;22)
• t (4;11)

Cytochemistry
a) Periodic acid-Schiff (PAS): Positive
b) Acid phosphatase: Focal positivity in leukaemic blasts in ALL.
c) Myeloperoxidase: Negative
d) Sudan Black: Negative
e) Non-specific esterase (NSE): Negative

Prognostic factors
Criteria Good Bad
1. Age 2-10 years <2 years; > 10 years
2. Gender Female Male
3. Race White Black
4. CNS, mediastinum, Absent Present
testicular involvement
5. Peripheral blood blast <100000 >100000
count
6. Cytogenetics a. Hyperdiploidy (>50 a. Hypodiploidy (<50
chromosomes) chromosomes)
b. Trisomy 4, 7, 10 b. t (8:14)
c. t (9:12) and t(12:21) c. t (1:19)
d. t (9:22)
e. t (4:11)

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Chronic Lymphocytic Leukaemia (CLL)

• CLL and SLL are identical neoplasms arise due to an abnormal neoplastic proliferation
of B cells.
• CLL is defined as an absolute lymphocyte count more than 5000 per mm3.
• Some patient may not have lymphocytosis and are classified as SLL
➢ CLL involves primarily bone marrow and blood
➢ SLL involves lymph nodes.
Age
• Median age of 60 years

Pathogenesis
• Deletions of 13q, 11q, and 17p
• Trisomy 12q
• Most common chromosomal change in CLL is deletions 13q (good prognosis).

Clinical Features
1. Due To Bone Marrow Failure→
a) Anaemia producing pallor, lethargy, dyspnoea.
b) Bleeding manifestations causing spontaneous bruises, petechiae, bleeding from
gums and other bleeding tendencies.
c) Infections
2. Enlargement of superficial lymph nodes is a very common finding. The lymph nodes
are usually symmetrically enlarged, discrete and non-tender.
3. Splenomegaly and hepatomegaly

Blood Picture
a) Anaemia → Normocytic normochromic
b) Thrombocytopenia
c) White blood cells →
• Marked leukocytosis (50,000-200,000/ μl).
• More than 90% of leucocytes are mature small
lymphocytes.

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• Smudge or basket cells (degenerated forms) are present due to damaged nuclei
of fragile malignant lymphocytes.

Smudge or basket cells

• Slide artefact formed by deficiency of cytoskeletal protein Vimentin, which is required
for rigidity and integrity of cells

Immunophenotyping
• CLL is a tumor of mature B-ceIls
• Therefore it expresses the B-cell markers such as CD19 ,CD20 and surface IgM and
IgD
• In addition CD 23 and CD5 are also present

Lymph Node Biopsy

Prognosis
Poor prognosis →
1. Deletions of 11q or 17p and trisomy 12.
2. Expression of ZAP-70 protein that augments immunoglobulin receptor signalling
activity.
3. Presence of notch1 mutations.

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Hodgkins Lymphoma
Types of RS Cells

WHO Classification of Hodgkins lymphoma

The classification is based on Immunophenotyping of RS cells

Classic subtypes Non classical

• Nodular sclerosis • Lymphocyte predominant
• Mixed cellularity
• Lymphocyte-rich
• Lymphocyte depletion

Nodular sclerosis Mixed cellularity Lymphocyte rich Lymphocyte Lymphocyte

depleted predominant
(non classical
HL)
‒ MC type ‒ MC type in ‒ Associated
India with HIV
‒ M=F ‒ M>F ‒ M>F ‒ M>F ‒ M>F
‒ Lacunar ‒ Classical RS ‒ Classical RS ‒ Pleomorphic ‒ LH
cell RS cell cells cells RS cell (popcorn
cells) RS cell
‒ CD15 + ‒ CD15 + ‒ CD15 + ‒ CD15 + ‒ CD20 +
CD30+ CD30+ CD30 + and CD30+ BCL6 +,
CD20- EMA +
‒ CD15—,
CD30-
‒ No ‒ Associated ‒ Associated ‒ Associated ‒ Not
association with EBV with EBV with EBV associated
with EBV with EBV
‒ Excellent ‒ Prognosis ‒ Good to ‒ Poor ‒ Excellent
prognosis very good excellent prognosis prognosis
prognosis
‒ Adolescent ‒ Biphasic ‒ Old age ‒ Old age ‒ Young males
(young and > group group
55 years)

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Ann Arbor Staging

Each of these stages is divided into A & B category.

• A category —> Without symptoms
• B category —> With symptoms such as unexplained weight loss, unexplained fever &
night sweats

Bleeding Disorders
A group of disorders characterised by defective haemostasis with abnormal bleeding.
• Spontaneous
• Excessive external or internal bleeding following trivial trauma

Classification
1. Haemorrhagic diathesis due to vascular abnormalities
2. Haemorrhagic diathesis related to platelet abnormalities
3. Disorders of coagulation factors
4. Haemorrhagic diathesis due to fibrinolytic defects
5. Combination of all these as occurs in disseminated intravascular coagulation (DIC)

Haemorrhagic diatheses due To Platelet Disorders

a) Due to reduction in the number of platelets →
thrombocytopenias (Quantitative defect)
b) Due to defective platelet functions (Qualitative
defect)

Thrombocytopenias
• Thrombocytopenia is defined as a reduction in the
peripheral blood platelet count below the lower limit of normal i.e. below 150,000/μl
though spontaneous bleeding is seen usually when the count falls below 20,000 cells/ μl
• There is prolonged BT with normal PT and aPTT

Types
1. Megakaryocytic thrombocytopenia

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2. Amegakaryocytic (hypoplastic) thrombocytopenia

CAUSES

Immune Thrombocytopenic Purpura (ITP)

• Immunologic destruction of platelets by autoantibodies of class IgG
• Destruction of platelets in ITP is type II hypersensitivity reaction
• Due to peripheral platelet destruction there is compensatory increase in
megakaryoctyes in bone marrow

Acute ITP
• In children (2-6 year)

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• No sex predilections
• Following recovery from a viral infection
• Duration of disease is 4-6 weeks.

Viral antigens
↓
Formation of IgG antibodies against viral antigens
↓
Antibodies Cross react with platelets
↓
Immunologic destruction of platelets
↓
Thrombocytopenia
Chronic ITP
• More commonly in adults
• More common in females
• Duration of disease is > 6 months

• By formation of anti-platelet autoantibodies

• These antibodies are directed against target antigens on the platelet glycoproteins, Gp IIb-
IIIa and Gp Ib-IX complex.

Clinical Features
• Petechial haemorrhages
• Easy bruising mucosal bleeding
• Menorrhagia in women
• Nasal bleeding
• Bleeding from gums
• Melaena
• Haematuria
• Intracranial haemorrhage

Laboratory Findings
1. Platelet count → Reduced
2. BT → Increased
3. Blood film → Occasional platelets which are often large
in size
4. Bone marrow → Increased number of megakaryocytes
5. Anti-platelet IgG antibody → can be demonstrated on
platelet surface or in the serum of patients

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Thrombotic Thrombocytopenic Purpura (TTP) / Moschcowitz disease

Pentad →
1. Microangiopathic hemolytic anemia
2. Thrombocytopenia
3. Neurological symptoms (platelet thrombin in cerebral vessels)
4. Renal dysfunction
5. Fever

Deficiency of enzyme called

ADAMTS.13 (vWF metalloprotease) that degrades vWF
↓
Multimers of vWF accumulate in plasma
↓
Promote platelet thrombus formation throughout the microcirculation
↓
TTP
Clinical Features
• Petechial haemorrhages
• easy bruising mucosal bleeding
• menorrhagia in women
• nasal bleeding
• bleeding from gums
• melaena
• haematuria
• Intracranial haemorrhage

• Formation of microthrombi →Neurological symptoms and Renal dysfunction and

Microangiopathic haemolytic anaemia

Laboratory Findings
1. Platelet count → Reduced
2. BT → Increased
3. Blood film → Occasional platelets which are often large in size
4. Bone marrow → Increased number of megakaryocytes
5. Biopsy (e.g. from gingiva) → Typical microthrombi in arterioles, capillaries and venules

Hemolytic uremic syndrome (HUS)

Triad →
1. Microangiopathic hemolytic anemia
2. Renal failure (microangiopathy of kidney involving glomerular capillaries and
arterioles).
3. Thrombocytopenia (due to platelet consumption)

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Typical (epidemic, classical, diarrhea-positive) HUS

Episode of acute gastroenteritis caused by E. coli strain 0157: H7

↓
Shiga-like toxin into the circulation
↓
Alters endothelial cell function
↓
Platelet activation and aggregation
↓
Typical HUS

TTP HUS
ADAMT 13 ↓ Normal
CNS involvement + Not affected
Renal involvement + +++
Age Adult Children

Platelet Function Defect Disorders

• It is characterised by normal platelet count with defect in function of platelet
• Bleeding time prolonged but platelet count will be normal

Defective Platelet Adhesion

Bernard-Soulier syndrome →
• An autosomal recessive disorder due to
deficiency or dysfunction of glycoprotein Ib-IX
• Thus there is defect in platelet adhesion
• Platelet aggregation is normal in response to
standard agonists like collagen, ADP or
thrombin
• But platelets fail to aggregate in response to
ristocetin (as ristacetin facilitates binding of
vWF and Gp Ib-IX).

Defective Platelet Aggregation

Glanzmann’s disease→
• Autosomal recessive disorder due to deficiency/dysfunction of glycoprotein Ilb-IIIa
• Thus, there is defective platelet aggregation
• At birth present with increased bleeding from umbilical cord stump.

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Coagulation Disorders
1. Classic haemophilia or haemophilia A (due to inherited deficiency of factor VIII)
2. Christmas disease or haemophilia B (due to inherited deficiency of factor IX)
3. Von Willebrand’s disease (due to inherited defect of von Willebrand’s factor)

Classic Haemophilia (Haemophilia A)

• Inherited deficiency of factor VIII
• X linked recessive trait
➢ Manifests clinically in males
➢ Females are usually the carriers
Pathogenesis
• Quantitative reduction of factor VIII
Functions of factor VIII →
a) Factor VIII regulates the activation of factor X in intrinsic
coagulation pathway
b) Factor VIII circulates in blood complexed to another larger
protein, von Willebrand’s factor (vWF), which comprises 99%
of the factor VIII-vWF complex.

Christmas Disease (Haemophilia B)

• Inherited deficiency of factor IX (Christmas factor or plasma thromboplastin
component)
• Haemophilia B is rarer than haemophilia
• X linked recessive trait
➢ Manifests clinically in males
➢ Females are usually the carriers
Pathogenesis
• Quantitative reduction of factor IX

Clinical Features
• Easy bruising mucosal bleeding
• Menorrhagia in women
• Nasal bleeding
• Bleeding from gums
• Melaena
• Haematuria
• Intracranial haemorrhage
• Fascial hemorrhages can result in the formation of blood filled cysts with calcification
and proliferation of fibroblasts giving the appearance of a tumor (pseudotumor
syndrome).

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• Petechiae are characteristically absent in hemophilia.

Laboratory Findings
i) BT is prolonged
ii) PT is normal.
iii) APTT is prolonged.
iv) Specific assay for factor VIII or factor IX shows lowered activity.

Disseminated Intravascular Coagulation (DIC)

• DIC is a common acquired coagulation disorder resulting due to excessive activation of

the coagulation system, usually due to massive tissue injury or sepsis.
• The normal anticoagulants and fibrinolytic systems are overwhelmed and cannot control
the coagulation activation which becomes systemic, resulting in disseminated
microvascular thrombi formation.
Also known as
• Defibrination syndrome
• Consumption coagulopathy
• Thrombo-haemorrhagic disorder

Etiology
1. Massive tissue injury in obstetrical syndromes (e.g., abruptio placentae, amniotic fluid
embolism, retained dead foetus), massive trauma, metastatic malignancies, surgery.
2. Infections Especially endotoxaemia, gram-negative and meningococcal septicaemia,
certain viral infections, malaria, aspergillosis.
3. Widespread endothelial damage in aortic aneurysm, haemolytic-uraemic syndrome,
severe burns, acute glomerulonephritis.
4. Carcinoma: Pancreas, Stomach, Prostate, Lung, Acute promyelocytic leukemia

Pathogenesis

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Clinical Features
There are 2 main features of DIC—
1. Bleeding as the most common manifestation
2. Organ damage due to ischaemia caused by thrombosis

Laboratory Findings
1. Platelet count → Low
2. BT, PT, APTT, TT → Prolonged
3. Plasma fibrinogen levels → Reduced
4. Fibrin degradation products (FDPs) → raisead
5. Factor V and factor VIII → Decreased in
concentration
6. Blood film shows MAHA (fragmented R.B.C. -
schistocytes)

Systemic Pathology

Blood Vessels
Atherosclerosis
• Atherosclerosis is an thickening and hardening of
large and medium-sized muscular arteries due to
involvement of tunica intima
• It is characterised by fibrofatty plaques or
atheromatous plaques
• An atheromatous plaque protrude into vessel
lumens consists of a raised lesion with a soft core of
lipid (mainly cholesterol and cholesterol esters)
covered by a fibrous cap

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Most commonly affected arteries in decreasing order

Mnemonic → ACP Delhi Traffic IS Cute
Abdominal aorta > Coronaries (LAD>RCA>LCX) > Poplitial > Descending thorasic >
Internal carotid> Cerebral arteries (circle of willis)

Pathogenesis
Reaction-to-Injury Hypothesis
1) Endothelial injury
2) Migration of leukocytes
3) Smooth muscle cell migration and
proliferation
4) Maturation of plaque

1) Endothelial injury

Stages of development of atheromatous plaque

1. Type I (Initial/Fatty dot) lesion
2. Type II lesion (fatty streaks)
3. Type III (intermediate) lesion
4. Type IV (atheroma) lesion
5. Type V lesion (fibroatheroma or mature atherosclerosis)
6. Type VI (complicated) lesion

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Clinical Effects
1. Slow luminal narrowing causing ischaemia and atrophy.
2. Sudden luminal occlusion causing infarction necrosis.
3. Propagation of plaque by formation of thrombi and emboli.
4. Formation of aneurysmal dilatation and eventual rupture.

Aneurysms And Aortic Dissection

Aneurysms
• An aneurysm is defined as a permanent abnormal dilatation of a blood
vessel or heart occurring due to congenital or acquired weakening or
destruction of the vessel wall

Clinical features
1. Thrombosis
2. Thromboembolism
3. Rupture of the vessel
4. Compression of neighbouring structures

Classification
A. Depending upon the composition of the wall
1. 1 True aneurysm composed of all the
layers of a normal vessel wall.
2. False aneurysm having fibrous wall and
occurring often from trauma to the vessel
(pulsating hematoma)

B. Depending upon the shape

1. Saccular 4. Serpentine or varicose
2. Fusiform 5. Racemose or circoid
3. Cylindrical

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Based on pathogenetic mechanisms

1. Atherosclerotic (arteriosclerotic) aneurysms → most common type.
Wall weakness due to atherosclerosis
2. Syphilitic (luetic) aneurysms → Wall weakness due to tertiary stage
of the syphilis.
3. Mycotic aneurysms → Wall weakness due to microbial infection
(misnomer)

Atherosclerotic Aneurysms
• Most common type
• Most common site → Abdominal aorta (infrarenal)
• Most frequently fusiform in shape

Syphilitic (Luetic) Aneurysms

• Develops in the tertiary stage of syphilis
• Most common site → Thoracic aorta (particularly the aortic ring)
• It may extend proximally into the aortic valve causing aortic
incompetence
• Mostly saccular in shape

Pathogenesis
Tertiary syphilis
↓
Inflammatory infiltrate around the vasa vasorum of the adventitia
↓
Endarteritis obliterans
↓
Ischaemic injury to the media
↓
weakening of wall
↓
• Contraction of fibrous scar with in the vessel wall may lead to wrinkling of the
intervening segments of arotic intima → Tree - barking.
• There is characteristic linear calcification of the ascending aorta.
• Aortic valve insufficiency results in cardiac hypertrophy and the name given to such
heart is Cor bovinum/ Cow heart because of increased size of heart.

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Aortic Dissection
• Aortic dissection occurs when blood separates
the laminar planes of the media to form a blood-
filled channel within the aortic wall

Pathogenesis
Weakened aortic media→
i) Hypertensive state About 90% cases of dissecting aneurysm have hypertension (40 to
60 years old)
ii) Non-hypertensive cases (young persons)
a) Marfan’s syndrome (Cystic medial degeneration)
b) Iatrogenic trauma during cardiac catheterisation or coronary bypass surgery.
c) Pregnancy

Morphologic Features
Double - barrel aorta

Classification
1. Stanford classification
2. DeBakey Classification

Clinical features
1. Sudden onset of excruciating pain, (can be confused with MI)
2. Retrograde dissection into the aortic root → Aortic incompetency
3. The most common cause of death is rupture of the dissection into the pericardial, pleural,
or peritoneal cavities.

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Vasculitis
• Inflammation of vessel wall is called vasculitis.

Antineutrophilic cytoplasmic antibody (ANCA)

• ANCA are heterogenous group of autoantibodies directed against antigens which are
found within the primary granules of neutrophil

Cytoplasmic ANCA (c-ANCA) Perinuclar ANCA (p-ANCA)

• Against proteinase 3. • Against myeloperoxidase.
• It is found in • It is found in microscopic
Wegner’s polyangitis, chrug-strauss
granulomatosis syndrome

Based on type of inflammation

Vasculitis granulomatous inflammation Vasculitis with necrotizing inflammation
• Giant cell arteritis • Polyarteritis nodosa
• Takayasu's disease • Microscopic polyangitis
• Wegner's granulomatosis • Wegner's granulomatosis
• Churg strauss syndrome • Churg strauss syndrome

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Raynaud's Phenomenon
• Raynaud’s phenomenon refers to episodic pallor of digits of the hands or feet.
• Raynaud phenomenon results from exaggerated vasoconstriction (abnormal spasm ) of
arteries and arterioles in the extremities, particularly the fingers and toes, but also
occasionally the nose, earlobes, or lips.

CVS
Ischaemic Heart Disease (IHD)/ Coronary Artery Disease
(CAD)
• Ischaemic heart disease (IHD) arise from Imbalance between the myocardial supply
and demand for oxygenated blood.

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Angina Pectoris
• Angina pectoris is a symptom complex of IHD characterized by
paroxysmal and recurrent attacks of substernal or precordial
chest discomfort caused by transient myocardial ischemia
• The levels of cardiac markers remains unchanged

Types
Classical (stable) angina
• It is the most common form of angina
• It is caused by the reduction of coronary
perfusion to a critical level due to coronary
atherosclerosis without plaque rupture.
• Chest discomfort occurs on exertion
• Chest discomfort occurs on exertion
• relieved by rest.
• When patient is asked to localize the sensation, he/she will typically place their hand
over the sternum with clenched fist → Levine’s sign
• Chest discomfort typically lasts 2-5 minutes.
• Stable angina is usually crescendo - decrescendo in nature.

Unstable angina
• Unstable angina is due to disruption of atherosclerotic plaque with thromosis.
Unstable angina is defined as chest discomfort that has at least one of the three feature→
• It occurs at rest and lasting > 10 min.
• It is severe and of new onset (i.e. within prior 4-6 weeks).
• It occurs with a crescendo pattern
• The chest discomfort of US is described as pain (in contrast to stable angina).

Prinzmetal variant angina

• Due to focal spasm in right coronary artery
• Pain occurs at rest.

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Myocardial Infarction (MI)

• Infaction (ischemic necrosis) of myocardium of heart due to decreased blood supply

Etiopathogenesis
i) Coronary atherosclerosis
ii) Superadded changes in coronary atherosclerosis
iii) Vasospasm
Types of Infarcts
i) Full-thickness or transmural, when they involve the
entire thickness of the ventricular wall.
ii) Subendocardial when they occupy the inner
subendocardial half of the myocardium

Location Of Infarcts
• Depends on which branch of coronary artery is obstructed

Gross
• Necrotic area can be visualized after 2-3 hours by
immersion of tissue slices in a solution of
triphenyltetrazolium chloride (TTC)
➢ Non infarcted myocardium →TTC
imparts brick red color to it where the
dehydrogenases enzymes are preserved.
➢ Infarcted area → unstained pale zone
Microscopy
0- ½ Hour → Normal
½- 4 Hours → Waviness

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4-12 Hours → CN
12-24 Hours → CN + few neutrophils
1-3 Days → CN + brisk neutrophils
3-7 Days → Neutrophils ↓ + Macrophages ↑
7-10 Days → Granulation tissue at margin
10-14 Days → Granulation tissue well established
2-8 Weeks → Collagen
> 2 Months → Scar

Diagnosis
ECG changes

Serum cardiac markers

• Cardiac markers are intracellular enzymes that leak out of dead necrotic cells
Enzyme Seen at Peak Return to Comment
normal

Myoglobin 2 hours 24 hours Earliest marker to be detected, not

specific
CPK-MB 2-4 hours 24 hours 48-72 hours Sensitive and specific; Marker of choice
for reinfarction
Troponin (T 2-4 hours 48 hours 7-10 days Most sensitive and specific marker
or I)
AST/SGOT Within 12 48 hours 4-5 days Not specific
hours
LDH 24 hours 4-5 days After 10 days Only marker raised after 10
days, Not specific

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Endocarditis
• Endocarditis is an inflammation of the inner layer of the heart, i.e.
endocardium
• Usually involve the heart valves (native or prosthetic).

Rheumatic Fever Non-bacterial Libman Sack’s Infective Endocarditis

Thrombotic Endocarditis (SLE) (Marantic)

• Small, warty • Small (1-5 mm) • Medium sized • Large

(small)

• Firm • Friable (produce • Flat, Verrucous • Friable (easily

emboli) detachable)

• Friable (but less • Irregular • bulky

than those of • Irregular
NBTE)
• Along lines of • Along lines of • On surface of cusps • On upper surface
closure closure both surfaces of cusps
• Sterile • Sterile • Sterile • Non-Sterile
(bacteria)
• No destruction of • No destruction • Destructive, may • Ulcerates or
under-lying valves • No Inflammation damage valve or perforates
or myocardium myocardium
underlying valve
(ormyocardium)
• Seen in Rheumatic • Seen in • Seen in SLE • Seen in I.E.
fever hypercoagulabie
states

Rheumatic fever

• Rheumatic fever (RF) is a systemic, post-streptococcal, nonsuppurative inflammatory

disease, principally affecting the heart, joints, central nervous system, skin and
subcutaneous tissues.

Pathogenesis
• It is an autoimmune response associated with streptococcal infection, but it is not
caused by bacteria directly effects
• Molecular mimicry and cross-reactivity between streptococcal M protein and the
human endogenous molecules forms the basis of autoimmune damage to human target
tissues in RHD

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Revised Jones Criteria

MAJOR MINOR GAS Infection

Carditis Fever GAS on Throat swab (Culture)

Arthritis Arthralgia Anti-streptolysin O titre (ASOT)

Anti-deoxyribonuclease B (Anti-
Sydenham’s Chorea ↑ PR interval on ECG
DNase B)

ESR ≥30mm/hr. or CRP

Erythema marginatum
≥30mg/L

Subcutaneous nodules

• 2 MAJOR manifestations
OR
• 1 MAJOR and 2 MINOR manifestations
+
• Evidence of preceding Group A streptococcal infection (within 3 weeks before ARF symptoms)

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Rheumatic heart disease → Pancarditis

Rheumatic Valvulitis
• Formation of characteristic vegetations or verrucae
• Small (1 to 3 mm in
diameter)
• Multiple
• warty
• Soft and firm
• Sterile, bland

Valves
• Commonest valve to involve → Mitral valve (Causing MR)
• 2nd commonest valve to involve → Aortic valve
• 3rd commonest valve to involve → Tricuspid valve
• Least frequently involved value → Pulmonary valve

• Location → chiefly along the line of closure of the

leaflets and cusps.
• Deformity →Chronic healed mitral valve in RHD is
characteristically ‘fish mouth’ or ‘button hole’
stenosis.

Rheumatic Mural Endocarditis

• The lesions are seen most commonly as MacCallum’s patch
• It is endocardial surface in the posterior wall of the left atrium just above the
posterior leaflet of the mitral valve

Rheumatic Myocarditis
• The most characteristic feature is the presence of distinctive Aschoff bodies.
• Aschoff bodies are pathogmatic of RHD

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Aschoff bodies→ Granulomas with →

1. Central fibrinoid necrosis
2. Surrounded by palisade of Anitschkow cells and
multinucleate Aschoff cells.
3. There is infiltration by lymphocytes, plasma cells and
fibroblast
• Neutrophils (polymorphonuclear cells) are
characteristically absent

Rheumatic Pericarditis
• The usual finding is fibrinous pericarditis
• Two separated surfaces are shaggy due likened to ‘bread
and butter appearance’

Extracardiac Lesions
Migratory Polyarthritis
• Earliest manifestation within 2 weeks with H/O sore throat
• Most common Manifestation (75%)
• Involves larger joints: the knees, ankles, wrists & elbows
• Rheumatic joints: hot, red, swollen & exquisitely tender
• Migratory in nature
• No deformity: non-erosive arthritis
• A dramatic response to even small doses of salicylates is another characteristic feature of
the arthritis

Chorea
• St. Vitus’dance
• Damage to caudate nucleus
• Prepubertal girls (8-12 yrs)
• A long latency period (1-6 months) between
streptococcal pharyngitis & the onset of chorea

Clinical maneuvers to elicit features of chorea include

1) demonstration of milkmaid's grip (irregular
contractions of the muscles of the hands while
squeezing the examiner's fingers)
2) spooning and pronation of the hands when the
patient's arms are extended
3) wormian darting movements of the tongue upon
protrusion
4) examination of handwriting to evaluate fine motor movements

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Erythema Marginatum
A rare (<3% of patients with acute rheumatic fever) but characteristic rash
of acute rheumatic fever
• Erythematous
• serpiginous
• macular lesions with pale centers
• Not pruritic
• Trunk & extremities, not on the face
• Skin- bathing suit distribution
• Migrating from place to place.
• No residual scarring occurs.

Subcutaneous Nodules
• Consist of firm nodules approximately 1 cm in diameter along the
extensor surfaces of tendons near bony prominences
• It is often seen in association with carditis
• Painless and Nontender nodules
• They last for a week and disappear spontaneously.

Atypical Verrucous (Libman-sacks) Endocarditis

• It is one of the manifestations of ‘collagen diseases’
• Characteristic lesions of Libman-Sacks endocarditis are seen in
50% cases of systemic lupus erythematosus (SLE)

Grossly
• Characteristic vegetations
• The vegetations of atypical verrucous endocarditis are
• Medium sized (1 to 4 mm in diameter)
• Multiple
• FLAT
• Granular
• Sterile, bland

• Valve → occur most frequently on the mitral and tricuspid valves

• Location → occur on both surfaces of affected valves, in the valve pockets and on the
adjoining ventricular and atrial endocardium.
• Deformity → The vegetations are Unlike vegetations of RHD, the healed vegetations of
Libman-Sacks endocarditis do not produce any significant valvular deformity.

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Non-bacterial Thrombotic Endocarditis (NBTE)

• Non-bacterial thrombotic,endocarditis is an involvement of the heart valves by sterile
thrombotic vegetation
• Seen in patients having hypercoagulable state

Grossly
Vegetations/ verrucae of NBTE→
• Small (1 to 5 mm in diameter),
• More friable than the vegetations of RHD.
• Sterile, bland
• Valves → chiefly mitral, and less often aortic and tricuspid
valve.
• Location → Occur along the line of closure of the leaflets
• Deformity → Organised and healed vegetations appear as
fibrous nodules

Infective (Bacterial) Endocarditis

FEATURE ACUTE SUBACUTE

1. Duration <6 weeks >6 weeks

2. Most common Staph, aureus, (b- Streptococcus viridans
organisms streptococci
3. Virulence of organisms Highly virulent Less virulent
4. Previous condition of Usually previously Usually previously damaged
valves normal
5. Lesion on valves Invasive, destructive, Usually not invasive or
suppurative suppurative
6. Clinical features Features of acute systemic Splenomegaly, clubbing of
infection fingers, petechiae

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The vegetations are→

• Large
• Grey-tawny to greenish
• Irregular
• Single or multiple
• Typically friable

• Valve → The lesions are found most frequently on the

• Mitral > aortic > both mitral and aortic valves > rarely on
the valves of the right heart.
• Location → atrial surface of atrioventricular valves and
ventricular surface of the semilunar valves (Upper surfaces
of cusps)

Deformity →
• Ulceration or perforation of the underlying valve leaflet
• Myocardial abscesses
• Most destructive vegetations are of infective endocarditis

Extracardiac complications
• In ABE there is appearance of painless, non-tender subcutaneous
maculopapular lesions on the pulp of the fingers called
Janeway’s spots.
• In SABE, there are painful, tender nodules on the finger tips of
hands and feet called Osler’s nodes

Modified Duke criteria

Major
• Blood culture(s) positive for a characteristic organism or persistently positive for an
unusual organism
• Echocardiography identification of a valve-related or implant-related mass or abscess, or
partial separation of artificial valve
• New valvular regurgitation

Minor

Pathologic Criteria

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CNS
Meningitis

Cob web
Cloudy or
Naked eye Clear and Clear or slightly (fibrin
frankly
appearance colorless turbid coagulum on
purulent
standing)
Elevated
CSF 60-150 mm Elevated (Above Elevated (Above
(Above 300
pressure water 180 mm water) 250 mm water)
mm water)
0-4 100-10,000 10-100 100-1000
Cells
lymphocytes/ul Neutrophils/ul lymphoctes/ul lymphoctes/ul
Markedly
Glucose 50-80 mg/dl Normal Reduced
reduced
Markedly
Protein 15 - 45 mg/dl Elevated Elevated
Elevated
Causative
Tubercle bacilli
Bacteriology Sterile Organisms Sterile
Present
present
Brudzinsk’s Sign
• A Positive Brudzinsk’s sign occurs when flexion of the
Neck causes involuntary flexion of the Knee and Hip
Joints.

Special stains
• Tubercle bacilli may be found on
microscopy of by ZN staining in
tuberculous meningitis.
• Capsulated cryptococci may be found on
India ink preparation

Tumours of CNS
2 types →
1. Originate in the brain or spinal cord → Primary tumours
2. May spread to the brain from another primary site of cancer→ Metastatic tumours

Metastasis to brain
• Metastasis to brain are the most common brain tumor

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• Most common primary malignancy metastatizing to brain is lung carcinoma > breast >
skin (melanoma) > kidney (genitourinary) and GIT cancers.

Gliomas
• The term glioma is used for all tumours arising from neuroglia

Glioma types
i) Astrocytomas → From astrocytes
ii) Oligodendroglioma → From oligodendrocytes
iii) Ependymoma → From ependyma

Astrocytomas → Astrocytomas are the most common type of gliomas

WHO classification
1. WHO Grade I (Pilocytic) Astrocytoma → Most common in children and good
prognosis
2. WHO Grade II (Fibrillary) Astrocytoma
3. WHO Grade III (Anaplastic) Astrocytoma
4. WHO Grade IV Astrocytoma (Glioblastoma Multiforme)→ Most common in
adult and Poor prognosis

WHO Grade I Astrocytoma → Pilocytic astrocytoma

• Occur in Children
• Site → Cerebellum and brainstem
• Surgical treatment is curative in 80 to 100% of cases
• They have a good prognosis.

Gross →
• Usually well circumscribed

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• Commonly cystic (myxoid or mucoid appearance)

Microscopy →
a) Rosenthal fibers are intracytoplasmic
inclusions which are compact areas of
condensed mass of glial fibrillary acidic protein
(GFAP)

WHO Grade IV Astrocytoma (Glioblastoma Multiforme)

• 6th decade of life
Site → Cerebral hemispheres (temoral and frontal lobes)

Gross →
• Variegated appearance with haemorrhages and necrosis.
• Also known as butterfly tumor since it crosses midline.

Microscopy →
a) The tumour cells are poorly-differentiated
round cells, pleomorphic cells and giant cells.
b) Mitoses are frequent
c) Pseudopalisading necrosis seen
d) Microvascular endothelial proliferation is
marked

Oligodendroglioma
• Most common site → cerebral hemisphere white matter (80 to 90% supratentorial)

Gross →
• Well-circumscribed, grey-white gelatinous mass with Foci of
haemorrhages and calcification
Microscopy →
a) The tumour is characterised by uniform cells
b) Tumour cells have round to oval nuclei surrounded by a
clear halo of cytoplasm → Fried Egg appearance
c) Endothelial cell hyperplasia
d) Foci of calcification

Ependymoma
Most common site →
i) In the first two decades of life → fourth ventricle
ii) In adults most common site → spinal cord (associated with
neurofibromatosis
type 2)

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Gross→
• Ependymoma is a well-demarcated tumour

Microscopically
• Tumour is composed of uniform epithelial (ependymal) cells
forming rosettes and perivascular pseudorosettes.
• Blepharoplasts representing basal bodies of cilia may be
demonstrated in the cytoplasm of tumour cells

Pilocytic Glioblastoma Oligodendrogliom

Ependymoma
astrocytoma Multiforme a

Cerebral Cerebral Cortex

MC site Cerebellum 4th Ventricle
hemisphere (white matter)

‒ Well
Butterfly
Gross circumscribed Gelatinous mass Well demarcated
tumor
‒ Cystic

‒ Pleomorphic
Rosettes ,
‒ Pseudopalisadi ‒ Fried egg cell
Microscopy Rosenthal fibres Pseudorosettes
ng necrosis ‒ Calcification
Blepharoplasts
‒ Mitosis

Meningioma
• Meningiomas arise from the cap cell layer of the arachnoid.
• Most common sites are: lateral cerebral convexities, midline along the falx cerebri
and olfactory groove.
• Meningiomas are generally solitary.
• Increased frequency in patients with neurofibromatosis 2 and are often multiple in these
cases.
• 2nd to 6th decades of life
• Female preponderance.

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Gross →
• Well-circumscribed mass of varying size (1-10 cm in
diameter).
• The overlying bone usually shows hyperostosis

Microscopically
a) Conspicuous whorled pattern of tumour cells, often
around central capillary-sized blood vessels.
b) Some of the whorls contain psammoma bodies due to
calcification of the central core of whorls

Medulloblastoma
• Occur exclusively in the cerebellum.
• Most common primary malignant brain tumour in childhood.
• These are undifferentiated tumor because they have both glial and neuronal features
• Dissemination through the CSF forms nodular masses at some distance from primary
tumor and this is termed "drop metastases'"

Gross→
• They are midline in children and lateral in adults.
• Protrudes into the fourth ventricle as a soft, grey-white
mass or invades the surface of the cerebellum

Microscopy →
a) Small round blue tumor cells
b) Homer-Wright pseudo-rosettes → groups of tumor cells
arranged in a circle around a fibrillary center

Schwannomas (Neurilemmomas)
• Arise from cranial and spinal nerve roots.
• Solitary nodule
• Multiple schwannomas occur in von Recklinghausen’s disease
• Association with Neurofibromatosis type 2
• Acoustic schwannoma → schwannoma of 8th nerve (Most common)
• Invariably benign

Gross →
• Encapsulated, solid tumour
• Produces eccentric enlargement of the nerve root from
where it arises

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• Does not infiltrate the peripheral nerve

Microscopy →
Two areas seen histologically →
a) Antoni A pattern → dense and compact cellular
areas show palisaded nuclei called Verocay bodies
b) Antoni B pattern → Loose acellular areas

BREAST
Stomal Breast Tumours
FIBROADENOMA
• Most common benign tumour
• 15 to 30 years of age
• Clinically appears as a solitary,discrete, freely mobile nodule within
the breast.

Gross
• Small (2-4 cm diameter)
• Solitary
• Well encapsulated,spherical mass.
• The cut surface is firm, grey-white, slightly myxoid and may show
slit-like spaces formed by compressed ducts.

Microscopy
The arrangements between fibrous overgrowth and ducts may produce two
types of patterns →
1. Intracanalicular pattern
• The stroma compresses the ducts so that they are reduced to slit-
like clefts lined by ductal epithelium

2. Pericanalicular pattern
• Encircling masses of fibrous stroma around the patent or
dilated ducts.

Phyllodes Tumour (Cystosarcoma Phyllodes)

• Phyllodes = leaf-like
• Aggressive clinical behaviour.
• 30 to 70 years of age. (peak 60 years)

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Grossly
• 10-15 cm in diameter
• Round to oval, bosselated
• Less fully encapsulated than a fibroadenoma.
• The cut surface is grey-white with cystic cavities, areas of
haemorrhages, necrosis and degenerative changes

Microscopy
• Extremely hypercellular stroma and stromal
overgrowth accompanied by benign ductal structures
→ typical Leaf like architechture
• Thus, phyllodes tumour resembles fibroadenoma
except for marked stromal overgrowth

WHO Classification Benign PT Borderline PT Malignant PT

Stromal cellularity Modest Modest Marked

Cellular pleomorphism Little Moderate Marked

Mitoses Few, if any Intermediate Numerous (>10/HPF)

Margins Well circumscribed Intermediate Invasive

(Pushing)
Stromal pattern Uniform stromal Heterogenous stromal Marked stromal
distribution distribution overgrowth
Heterologous stromal Rare Rare Not uncommon
distribution
Overall average 60 20 20
distribution (%)

Breast Carcinoma
Introduction
• Cancer of the female breast is among the commonest of human cancers throughout the
world
• Highest in the perimenopausal age group

Clinical features
• Clinically, the breast cancer usually presents as a solitary, painless, palpable lump
detected by self-examination.

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Triple technique

Risk Factors
1.Geographic and racial factors
• The incidence of breast cancer is 4-6 times higher in developed countries and low in
developing countries of Asia and Africa

2. Family history
• First-degree relatives (mother, sister,daughter) of women with breast cancer have 2 to 6-
fold higher risk of development of breast cancer.

3. Menstrual and obstetric history

• Total length of menstrual life is directly related to increased risk.
• Thus, there is increased risk of breast cancer development in women who had
1. Early menarche
2. Nulliparity
3. Delayed menopause

4. Estrogen exposure
• Menopausal hormone therapy increases the risk of breast cancer
• Reducing endogenous estrogens by oophorectomy decreases the risk of developing
breast cancer by up to 75%.
• Drugs that block estrogenic effects (e.g., tamoxifen) or block the formation of estrogen
(e.g., aromatase inhibitors) also decrease the risk of breast cancer.

5. Fibrocystic change
• 5-fold higher risk of developing breast cancer subsequently.

6. Dietary factors
i) Consumption of large amounts of animal fats, high calorie foods.
ii) Cigarette smoking.
iii) Alcohol consumption.

7. Exercise
• Protective effect for women who are physically active.

8. Breast density

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• Women with very dense breasts on mammography have a four- to six-fold higher risk of
breast cancer compared to women with the lowest density.

9. Environmental toxins
• Environmental contaminants such as organochlorine pesticides have estrogenic effects
on humans.

10. Radiation exposure

• Radiation to the chest, whether for cancer therapy, due to atomic bomb exposure, or
nuclear accidents, results in a higher rate of breast cancer.

11. Genetic Factors

1. BRCA 1 gene →
• Located on chromosome 17
• Breast and ovarian cancer in inherited cases

2. BRCA 2 gene →
• Located on chromosome 13
• Breast and ovarian cancer in inherited cases

3. Mutation in p53 →
• Tumour suppressor gene , located on chromosome 17

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Invasive Breast Carcinoma

Invasive Duct Carcinoma (IDC)
a) Anaplastic tumour cells forming solid nests, cords,poorly-
formed glandular structures and some intraductal foci.
b) Infiltration of tumour cells into diffuse fibrous stroma and
fat.
c) Invasion into perineural spaces
d) Lymphatic and vascular invasion.

Invasive Lobular Carcinoma (ILC)

a) A characteristic single file (Indian file) linear
arrangement of stromal infiltration by the tumour cells
b) Tumour cells → round and uniform, regular with
very little pleomorphism and infrequent mitoses.

Paget’s Disease of The Nipple

• Eczematoid lesion of the nipple associated with an invasive or non-
invasive ductal carcinoma of the underlying breast.
• The nipple bears a crusted, scaly and eczematoid lesion with a palpable
subareolar mass
• It is a malignant lesion

The tumour cells from the underlying ductal carcinoma

↓
Migrated up into the lactiferous ducts
↓
Invaded the epidermis of nipple
↓
Producing skin lesions
Grossly
• The skin of the nipple and areola is crusted, fissured and ulcerated with oozing of
serosanguineous fluid from the erosions

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Histologically
• Presence of Paget’s cells singly or in small clusters in the epidermis
• These cells are larger than the epidermal cells, spherical, having hyperchromatic
nuclei with cytoplasmic halo

Molecular classification
ER/PR Her-2

Luminal A + -
Luminal B + +
Basal - -
Her-2 Positive - +

TNM Staging

ENDOCRINE SYSTEM
Graves’ Disease
• Most common cause of endogenous Hyperthyroidism
• Autoimmune disorder presenting clinically with feature of hyperthyroidism
• 20 and 40 years of age.
• Women > men.

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Pathogenesis
• characterized by the production of autoantibodies thyroidstimulating
immunoglobulin (TSI) against TSH receptor.

Antibodies against TSH receptors (Thyroid stimulating

immunoglobulins (TSI) and longacting thyroid stimulator
(LATS)
↓
When antibodies react with TSH receptor
↓
Thyroid cells are stimulated
↓
Form excess thyroid hormone (hyperthyroidism)
↓
TSH is suppressed and T3, T4 (free and bound) is raised

Histologically
1. Epithelial hyperplasia and hypertrophy as seen by
increased height of the follicular lining cells and
formation of papillary infoldings of piled up
epithelium into the lumina of follicles which are small.
2. Colloid is markedly diminished and is lightly
staining, watery and finely vacuolated.
3. The stroma shows accumulation of lymphoid cells.

Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis)

• Autoimmune disorder that results in
destruction of the thyroid gland and
gradual and progressive thyroid failure
• Most common cause of hypothyroidism
• 45 and 65 years of age
• Women > men.

Pathogenesis
• Hashimoto thyroiditis is caused by a
breakdown in self-tolerance to thyroid
autoantigens.

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HISTOLOGY
1. There is extensive infiltration of the parenchyma by a
mononuclear inflammatory infiltrate containing small
lymphocytes, plasma cells, and well-developed germinal
centers
2. The thyroid follicles are atrophic
3. Thyroid follicles are lined by epithelial cells with abundant
eosinophilic, granular cytoplasm, termed Hürthle cells

Thyroid tumours
4 types→
1. Papillary Thyroid Carcinoma Introduction
2. Follicular Thyroid Carcinoma Gross
3. Medullary Thyroid Carcinoma Microscopy
4. Anaplastic Carcinoma
Papillary Thyroid Carcinoma
• Papillary carcinoma is the most common type of thyroid carcinoma
• Thyroid carcinomas arising after radiation or in thyroglossal cyst

Histologically
1. Papillary pattern → Papillae composed of fibrovascular
stalk and covered by single layer of tumour cells is the
predominant feature.
2. Tumour cells → Ground glass or optically clear
appearance or Orphan Annie eye nuclei and clear or
oxyphilic cytoplasm
• Intranuclear inclusins (Pseudoinclusions) or
intranuclear grooves -» the diagnosis of papillary
carcinoma is based on these nuclear features.
3. Psammoma bodies → small, concentric, calcified spherules
called psammoma bodies in the stroma.

Follicular Thyroid Carcinoma

• Follicular carcinoma is the 2nd common type of thyroid cancer

Microscopically
1. Follicular pattern follicles of various sizes
2. The tumour cells have hyperchromatic nuclei and the
cytoplasm resembles that of normal follicular cells.

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3. Vascular invasion and direct extension

Hurthle cell or oncocytic carcinoma is a varriant of follicular carcinoma.

Medullary Thyroid Carcinoma

• Derived from parafollicular or C-cells present in the thyroid
• Tumour cells of medullary carcinoma secrete calcitonin, the hypocalcaemic
hormone.
Familial occurrence

Histologically
1. Tumour cells → Nests of tumour cells separated by
fibrovascular septa.
2. The tumour cells are uniform
3. Amyloid stroma → The tumour cells are separated by
amyloid stroma derived from altered calcitonin which
can be demonstrated by immunostain for calcitonin.
4. Aeas of irregular calcification but without regular
laminations seen in psammoma bodies

Anaplastic Carcinoma
• One of the most malignant tumour in human
• The tumour is predominantly found in old age (7th-8th decades)
• The tumour is widely aggressive and rapidly growing
• Extensive invasion of adjacent soft tissue, trachea and oesophagus. These features
include: dyspnoea, dysphagia and hoarseness, in association with rapidly-growing tumour
in the neck.

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Diabetes Mellitus
• Diabetes mellitus (DM) is a group of metabolic
disorders sharing the common feature of
hyperglycemia
• DM is diagnosed when blood glucose levels becomes too
high

Pathogenesis of Type 1 DM
• Body can not make enough INSULIN
• They kill body’s own cells → Autoimmunity

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In DM – I
↓
There is genetic abnormality and
Environmental trigger
↓
Loss of self-tolerance
↓
Self-reactive clonal T cells are not killed or
deleted in thymus
↓
Attack β-cells of pancreas (β-cells act as
autoantigens)
↓
Decrease insulin
↓
Increase glucose in blood (Hyperglycemia)

Pathogenesis Of Type 2 DM
Type 2 diabetes is a complex disease that involves an interplay of genetic and
environmental factors and a proinflammatory state.

Genetic component
+
Constitutional factors such as obesity, hypertension, and level of physical activity play
contributory role
↓
Insulin resistance on target organ
↓
Hyperglycaemia

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Clinical Features

Diagnosis Of Diabetes
URINE TEST
1. Glucosuria
2. Ketonuria

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Revised criteria for diagnosis of diabetes (as per American Diabetes Association)

Glycosylated haemoglobin (HbA1C)

• Long-term assessment of degree of glycaemic control is better monitored by
measurement of glycosylated haemoglobin (HbA1C)
• Glycosylated haemoglobin (HbA1C) is a minor haemoglobin component present in
normal persons.
• This is because the non-enzymatic glycosylation of haemoglobin takes place over 90-120
days, lifespan of red blood cells.
• HbA1C assay, therefore, gives an estimate of diabetic control and compliance for the
preceding 3-4 months.
• Normal value < 6.5 %
• A glycated hemoglobin (HbA1C) level ≥ 6.5% → diabetics
• It is recommended that HbA1C be maintained below 7% in diabetic patients.

GIT
Achalasia (Cardiospasm)
Normal physiology
• Normally, LES is closed
• But during swallowing → LES is relaxed due to → Release of nitric oxide

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Pathogenesis

Triad of Achalasia
Achalasia cardia is a motor disorder of esophageal smooth
muscles, characterized by:
i) Failure of relaxation of LES with swallowing
ii) Increased resting tone of LES
iii) Aperistalsis

Types
1. Primary achalasia → Congenital Myenteric plexus damage
2. Secondary achalasia
Chagas’ disease (sleeping sickness)
↓
Trypanosoma cruzi infection
↓
Destruction of the myenteric plexus,

Morphologic Features
1. Dilatation above the short contracted terminal segment of the oesophagus

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2. Muscularis propria of the wall is hypertrophied as a result of obstruction, or thinned out

due to dilatation.
3. Secondary oesophagitis

Investigations
Screening test
Cholecystokinin (CCK) test:
• CCK normally causes a fall in the sphincter pressure
(because of the relaxant effect of inhibitory
neurotransmitters like VIP and nitric oxide)
• In achalasia cardia it causes paradoxical increase in LES
tone (loss of inhibitory neurons).
1.Barium swallow
• Cucumber oesophagus / Bird beak’ / rat tailed’ appearance
• Megaesophagus (diffuse esophageal dilatation or sigmoid
esophagus)

2. Oesophagoscopy:
• LES: Lower oesophageal sphincter is closed, with air insufflation. It has a
'rosette' appearance

3. Oesophageal manometry:
• Manometry is the diagnostic procedure of choice
• Hypertensive lower oesophageal sphincter (LOS)
• Increased resting pressure in the oesophagus

Complication of achalasia cardia

• Precancerous condition → Squamous cell carcinoma is the most common type
identified in a patient with achalasia.

Barrett’s Oesophagus
• This is a condition in which due to reflux oesophagitis, stratified squamous
epithelium of the lower oesophagus is replaced by columnar epithelium (columnar
metaplasia).

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Repeated reflux
↓
Shifting of the oesophago-gastric junction upwards
↓
Further increases the reflux
↓
Intestinal metaplasia of lower oesophagus

Incidence of malignancy
• High-grade dysplasia may progress to invasive
adenocarcinoma of the oesophagus in up to 20% cases
• Barrett's esophagus is the single most important risk
factor for adenocarcinoma of esophagus.
• Therefore, surveillance endoscopic biopsies are advised.
• Barrett’s oesophagus is a premalignant condition

Carcinoma Of Oesophagus
• Carcinoma of the oesophagus is diagnosed late
• More commonly in men
• Over 50 years of age.
Site
• Lower 1/3 > Middle 1/3rd > Upper 1/3rd

Etiology

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Squamous Cell (Epidermoid) Carcinoma

• Comprises 90% of primary oesophageal cancers.
• It is the most common type of esophageal carcinoma world wide and in India
• Occurs in 6th to 7th decades of life
• More common in men than women.

Site → Middle 1/3 > Lower 1/3 > Upper 1/3

Microscopically
• Tumour cell are arranged in sheets
• Tumour cells are large with hyperchromatic nuclei and high N/C
ratio
• Intracellular and extracellular keratinization is seen
• Keratin Pearls are commonly seen.

Adenocarcinoma
• Constitutes less than 10% of primary oesophageal cancer.
• It is the most common type of esophageal carcinoma in USA.
• 4th to 5th decades.
• More common in men than women.

Site → Lower 1/3 > Middle 1/3

Risk factor
• The single most important riskfactor for adenocarcinoma of esophagus is Barrett’s
esophagus

Microscopically
• Tumor cells are arranged in glandular pattern
• Tumour cells produce mucin and form glands mostly with
intestinal-type morphology
• Sometimes tumors are composed of diffusely infiltrative signet-
ring cells (similar to those seen in diffuse gastric cancers)

Adenosquamous type
• The pattern in which there is an admixture of adenocarcinoma
and squamous cell carcinoma.

Most common site for

• Squamous cell carcinoma → Middle 1/3 > Lower 1/3 > Upper 1/3

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• Adenocarcinoma is → Lower 1/3 > Middle 1/3

• Overall esophageal carcinoma → Lower 1/3

Gastritis
Gastritis is the inflammation of the gastric mucosa
Chronic gastritis
• It is characterized by the presence of chronic mucosal inflammatory changes leading
eventually to mucosal atrophy and intestinal metaplasia, usually in the absence of
erosions.
TYPES
1. Type A gastritis (Autoimmune gastritis)
2. Type B gastritis (H. pylori-related)
3. Type AB gastritis (Mixed gastritis)

Type A gastritis (Autoimmune gastritis)

Site
• Involves mainly the body-
fundic mucosa

Type B gastritis (H. pylori-related)

• Commonly due to infection with H. pylori
• Also called hypersecretory gastritis due to excessive secretion of acid,
• Associated peptic ulcer.
• Unlike type A gastritis, this form of gastritis has no autoimmune basis nor has
association with other autoimmune diseases.

Site
• Mainly involves the region of antral mucosa
• However, it is misnomer as the inflammatory process may progress to body and
fundus and causing pangastritis

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Peptic Ulcers
• Ulcers are defined histologically as a breach in the mucosa of the alimentry tract that
extends through the mucularis mucasea into the submucosa or deep.
Risk factors
1. Psychological stress
2. Physiological stress as in the following:
i) Shock
ii) Severe trauma
iii) Septicaemia
iv) Extensive burns (Curling’s ulcers in the posterior aspect of
the first part of the duodenum).
v) Intracranial lesions (Cushing’s ulcers developing from
hyperacidity following excessive vagal stimulation).
vi) Drug intake (e.g. aspirin, steroids, butazolidine,indomethacin).
vii) Local irritants (e.g. alcohol, smoking, coffee etc).

Types
1. Gastric ulcer
2. Duodenal ulcers

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Microscopically
1. Necrotic zone— lies in the floor of the ulcer
2. Superficial exudative zone
3. Granulation tissue zone
4. Zone of cicatrisation

Complications
1. Haemorrhage/ Bleeding
• Most frequent complication.
• More common in posterior wall duodenal ulcers
• Result in iron deficiency anaemia.
• ‘coffee ground’ vomitus or melaena.

2. Perforation
• Second most common complication
• Most common cause of death in peptic ulcer
• More common in anterior wall duodenal ulcers

3. Malignant transformation
• A chronic duodenal ulcer never turns malignant
• Less than 1% of chronic gastric ulcers may transform into carcinoma

Remember
• Cushing ulcer → associated with intracranial injury or an increase in ICT .They are
usually located in Stomach, Duodenum (proximal part), Esophagus
• Curling ulcers → associated with burns.Occur in proximal duodenum.

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Investigations
• Screening test: Urea breath test (radiolabeled urea
is broken down to radiolabeled CO2 by urease
enzyme which is detected by breath analyzer, thus
suggesting presence of H. pylori infection)
• Gold standard: Staining of H. pylori with silver
stain or Warthin starry stain
• Most specific investigation: Culture of bacteria (done on Skirrow’s medium)
Gastric Carcinoma
• Adenocarcinoma is the most common malignancy of the stomach
• 4th to 6th decades of life
• Men > women.
Etiology
Environmental factors Genetic factors Host factors
• H. pylori infection • Family history of gastric cancer • Chronic gastritis
• Nitrites in diet • Blood group A • Intestinal metaplasia
• Nutritional (vitamin C, E) • Hereditary non polyosis colon cancer • Partial gastrectomy
deficiency syndrome (HNPCC) • Gastric adenoma
• Smoking • Familial gastric cancer syndrome • Barrett's esophagus
(due to E-cadherin mutation) • Menetrier disease

Site

I. Early Gastric Carcinoma (EGC)

• Limited to the mucosa and submucosa.
• Prognosis is quite good; 5-year survival rate being 93-99%.

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II.
Advanced Gastric Carcinoma
• When the carcinoma crosses the basement membrane into the muscularis propria or
beyond
• The prognosis is generally poor
• 5-year survival rate being 5-15%

Advanced gastric carcinoma has following 5 patterns:

i) Ulcerative carcinoma
ii) Fungating (polypoid) carcinoma
iii) Scirrhous carcinoma (Linitis plastica)
iv) Colloid (Mucoid) carcinoma
v) Ulcer-cancer

Inflammatory Bowel Disease

Crohn’s Disease
Crohn’s disease may involve any portion of the gastrointestinal tract but affects most commonly
terminal ileum which may extend into the caecum and sometimes into the ascending colon

Grossly

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1. ‘skip areas’.
2. Hose pipe
3. ‘serpiginous ulcers’. → deep fissuring into the bowel wall
4. Intervening surviving mucosa is swollen giving ‘cobblestone
appearance’.
• Bowel adhesions and serositis.
• Fistula or sinus tract formation.
5. Strictures are common
6. Serosa may be studded with minute granulomas.
7. Screening test is presence of anti-Saccharomyces cerevisae
antibody

Histologically

Ulcerative Colitis
• Begins in the rectum, and in continuity extends upwards into the sigmoid
colon, descending colon, transverse colon, and sometimes may involve the
entire colon.
• In severe cases entire colon may be involved —> Pancolitis
• It is a disease of continuity, and skip lesions are not found.
• Distal ileum develop muscosal inflammation -» backwash ileitis.

Grossly
• Continuous involvement
• Garden hose appearance and Pipe stem appearance
• The intervening intact mucosa may form inflammatory
‘pseudopolyps.’
• In sever cases of UC, toxic damage to the muscularis propria and
neural plexus lead to complete shutdown of neuromuscular
function —> colon progressively swells to create toxic megacolon
• Carcinoma.

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Histologically

LIVER
Hepatitis

Common mode(s) of
Type Causative agent Incubation period
transmission
Hepatitis A Enterovirus 72 (picornavirus) 15-45 days Faecal-oral sexual
Sexual, perinatal,
Hepatitis B Hepadnavirus 30-180 days
percutaneous
Hepatitis G Hepacivirus (Flavivirus) 15-160 days Percutaneous
Sexual, perinatal,
Hepatitis D Viriods like 30 - 180 days
percutaneous
Hepatitis E Galcivirus (alphavirus like) 15-60 days Faecal-oral

FEATURE HEPATITIS HEPATITIS HEPATITIS HEPATITIS HEPATITIS

A B C D E
Agent HAV HBV HCV HDV HEV

Year identified 1973 1965 1989 1977 1980

Viral particle 27 nm 27 nm 30-60 nm 35-37 nm 32-34 nm

Genome RNA, ss, DNA, ss/ds RNA, ss, RNA, ss, circular RNA, ss,
linear linear circular linear

Morphology Morphology Double- Enveloped Enveloped, Icosahedral,

shelled, replication non-enveloped
Enveloped defective

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Spread Faeco-oral Parenteral, Parenteral, Parenteral, close Water-borne

close contact close contact contact
Incubation 15-45 days 30-180 days 20-90 days 30-50 days (In 15-60 days
period superinfection)
Antigen(s) HAV HBsAg HCV RNA HBsAg HEV
HBcAg C 100-3 HDV
HBeAg C 33c
HBxAg NS5
Antibodies anti-HAV anti-HBs anti-HCV anti-HBs anti-HEV
anti-HBc anti-HDV
anti-Hbe
Severity Mild Occasionally Moderate Occasionally Mild
severe severe
Chronic None Occasional Common Common None
hepatitis
Carrier state None <1% <1% 1-10% Unknown
Hepatocellular No + + ± None
carcinoma
Prognosis Excellent Worse with Moderate Acute good; Good
age chronic poor

Hepatitis B virus (Serum Hepatitis)

HBs Anti HBs Ab HBe Anti HBe Ab Anti HBc Ab

Ag Ag

Acute HBV + - + IgM

(high infectivity)
Acute HBV + - + IgM
(low infectivity)
Chronic HBV + - + IgG
(high infectivity)

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Chronic HBV + - +
(low infectivity)
Recovery - + - + IgG

Immunized - + - IgG

Hepatitis D virus
• HDV is a defective virus for which HBV is the helper.
• Replication is defective and can cause infection only when encapsulated by HBs Ag

Acute Hepatitis

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Chronic Hepatitis

Cirrhosis
MORPHOLOGIC ETIOLOGIC

I. Micronodular 1. Alcoholic cirrhosis (the most common, 60-70%)

(nodules less than 3 mm) 2. Post-necrotic cirrhosis (10%)
II. Macronodular 3. Biliary cirrhosis (5-10%)
(nodules more than 3 mm) 4. Pigment cirrhosis in haemochromatosis (5%)
III. Mixed 5. Cirrhosis in Wilson's disease
6. Cirrhosis in a-1 –antitrypsin deficiency
7. Cardiac cirrhosis
8. Indian childhood cirrhosis (ICC)
9. Cirrhosis in autoimmune hepatitis
10. Cirrhosis in non-alcoholic steatohepatitis
11. Miscellaneous forms of cirrhosis (metabolic, infectious, GI,
infiltrative) diseases
12. Cryptogenic cirrhosis

Causes of Micronodular cirrhosis

Indian childhood cirrhosis
Alcoholic cirrhosis
Hemochromatosis
Cirrhosis associated with biliary obustruction
Cirrhosis associated with jejunoileal bypass
Venous outflow obstruction → veno - occlusive disease, Budd-chiary syndrome.
Causes of Macronodular cirrhosis

Post necrotic cirrhosis (after viral hepatitis)

Wilson disease

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Alcoholic Liver Disease and Cirrhosis

1. Alcoholic Steatosis (Fatty Liver)

2. Alcoholic Steatohepatitis

3. Alcoholic Cirrhosis

Hepatocellular Carcinoma
• Most common primary malignant tumour of the liver.
• M > F ( 4:1)
• 5th to 6th decades of life
• Tumour supervenes on cirrhosis in 70-80% of cases

Etiopathogenesis
1. Relation to HBV infection
2. Relation to HCV infection

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3. Relation to cirrhosis
4. Relation to alcohol
5. Mycotoxins
6. Chemical carcinogens

Grossly

Microscopically→

Fibrolamellar Carcinoma
• Variant of the HCC
• young people of both sexes
• Occurs in the absence of cirrhosis.
• Prognosis of fibrolamellar carcinoma is better than HCC (more favourable prognosis)

RENAL SYSTEM
Nephritic Syndrome
1. Haematuria
2. Proteinuria
3. Hypertension
4. Oedema
5. Oliguria
• Most common cause of nephritic syndrome is rapidly progressive glomerulonephritis

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Nephrotic Syndrome
1. Heavy proteinuria
2. Hypoalbuminaemia
3. Oedema
4. Hyperlipidaemia
5. Lipiduria
6. Hypercoagulability

• Most common cause of nephrotic syndrome in children is minimal change disease

Remember
• Cause of edema in nephrotic syndrome: Hypoalbuminemia (hypoproteinemia).
• Cause of edema in nephritic syndrome: Salt (sodium) and water retention

Pathogenesis Of Glomerular Injury

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Glomerulonephritis

Acute Glomerulonephris
• Acute Proliferative GN (APGN)
• Poststreptococcal Glomerulonephritis (PSGN)

Etiopathogenesis
Group A β-haemolytic streptococci
↓
Pharyngitis or skin infection
↓
Comes to kidney through blood
↓
Bacteria gets deposited on visceral podocytes (Planted Ag)
↓
Antibodies against bacteria are formed in – situ
↓
Ag – Ab complexes are formed in – situ with complement deposition
↓
Subepithelial deposits are seen on EM

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Gross
• Petechial haemorrhages on the surface→ flea-bitten kidney

Light microscopic findings

Glomeruli → Enlarged and hypercellular

Electron microscopy
subepithelial deposits → dense irregular deposits (‘humps’)

Immunofluorescence microscopy
• IgG and complement C3 granular deposits

Clinical Features
• Acute nephritic syndrome

Rapidly Progressive Glomerulonephritis (RPGN)

Also known as Characterised by formation of ‘crescents’ (crescentic GN)
Etiopathogenesis
1. Type I→ (anti-GBM type)
2. Type II→ Post-infectious RPGN
3. Type III→ Pauci-immune RPGN (Cellular immunity→ ANCA positive

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Light microscopic findings

• ‘Crescents’ on inside of Bowman’s capsules.
• Pathogmatic
• Formed by proliferation of parietal cells and by
migration of monocytes and macrophages
• Neutrophils and lymphocytes present.

Electron microscopy
• Type I → Linear deposits along GBM
• Type II→ Electron-dense sub epithelial granular
deposits
• Type III → No deposits

Immunofluorescence microscopy
• Type I→ linear pattern→ containing IgG + C3
• Type II→Granular pattern → consisting of IgG + C3
• Type III→ Scanty or no deposits

Clinical Features
• Nephritic syndrome and Acute renal failure

Minimal Change Disease (MCD)

• Nephrotic syndrome with no apparent change in glomeruli by light microscopy →
Minimal Change Disease (MCD)
• Also known as lipoid nephrosis→ fatty changes in the tubules
• Foot process disease → EM - flattened podocytes
• No deposits (nil deposit disease).
• Most common cause of nephrotic syndrome in children (80% cases)

Gross
• Kidneys are of normal size and shape

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Light microscopic findings

1. Glomeruli
• No apparent abnormality
• Slight increase in the mesangial matrix
2. Tubules
• Lipid vacuolation and hyaline droplets in the cells
of proximal convoluted tubules and, hence called as
‘lipoid nephrosis’.

Electron microscopy
• Diffuse flattening (effacement) of foot processes of
the visceral epithelial cells (podocytes)
• No deposits

Immunofluorescence microscopy
• No deposits (nil deposit disease).

Clinical features
• Nephrotic syndrome with massive and highly selective proteinuria
Prognosis
• Characteristically responds to steroid therapy.Long-term prognosis is very good

Membranous Glomerulonephritis
• Characterised by widespread thickening of the glomerular capillary wall →
Epimembranous Nephropathy

Etiopathogenesis
Antigen appears to be gp 330 - component of podocyte (Fixed Ag.)
↓
Ab are formed against it
↓
Form immune complexes in podocytes (In situ deposition against fixed AG)
↓
ARF

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Light microscopic findings

• Diffuse thickening of the glomerular BM
• Deposits are incorporated into enormously thickened
basement membrane, producing ‘duplication’ of
GBM
• No cellular proliferation in the glomerular tufts.

Electron microscopy
• subepithelial location → ‘spikes’

Immunofluorescence microscopy
• Granular deposits consisting of IgG associated with complement C3.

Clinical Features
• Nephrotic syndrome in an adult.

Membranoproliferative Glomerulonephritis (MPGN)

Etiopathogenesis
1. Type I or classic form (70% cases) → immune deposits in the subendothelial position.
2. Type II or dense deposit disease (30% cases) → electron-dense material in the lamina
densa of the GBM.
3. Type III (rare )

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Light microscopic findings

1. Glomeruli
• Enlarged
• Mesangial cellular proliferation and increase in
mesangial matrix.
• GBM is considerably thickened
• ‘Double contour’, splitting, or ‘tram track’
appearance.

Electron microscopy
• Type I → Subendothelial deposits
• Type II → Intramembranous deposition
• Type II → Anywhere

Clinical Features
• 50% of the patients present with nephrotic syndrome
• 30% have asymptomatic proteinuria
• 20% have nephritic syndrome at presentation.

Focal Segmental GN and Focal Segmental Glomerulosclerosis

GN of-
i) Some, but not all, glomeruli (thus, it is focal)
ii) In the affected glomeruli, only a portion of capillary tuft is involved (thus, it is
segmental)

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Chronic Glomerulonephritis
• Also known as End-Stage Kidney, Chronic Kidney Disease
• Chronic GN is the final stage of a variety of glomerular diseases which result in
irreversible impairment of renal function.
Grossly
• Kidneys →small and contracted
• Cortical surface →diffusely granular
• On cut section → Cortex is narrow and atrophic, while the medulla is unremarkable.

Light Microscopically
1. Glomeruli
• Glomeruli are reduced in number
• show completely hyalinised tufts, giving
appearance of acellular, eosinophilic masses
which are PASpositive.
2. Tubules
• Atrophy of tubules
• Hyaline-droplets
• Interstitium → fibrosis
•
IgA Nephropathy
• Also known as Berger’s Disease, IgA GN
• Most common type of glomerulonephritis world wide
• Characterised by aggregates of IgA, deposited principally in the mesangium.
• Occurs after an upper respiratory tract infection or gastrointestinal infection

Light microscopy
Various patterns→
• Focal proliferative GN,
• Focal segmental glomerulosclerosis,
• Membranoproliferative GN

Electron microscopy,
• Granular electron-dense deposits are seen in the mesangium

Immunofluorescence microscopy
• Mesangial deposits of IgA, with or without IgG, and usually with C3 and properdin.

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Diabetic Nephropathy

1. Diabetic Glomerulosclerosis
1. Diffuse glomerulosclerosis
• Most common.
• There is involvement of all parts of glomeruli.

2. Nodular glomerulosclerosis
• Also called as Kimmelstiel- Wilson (KW) lesions or
intercapillary glomerulo sclerosis
• Pathognomonic (most specific)

2. Vascular Lesions
• Hyaline arteriolosclerosis affecting the afferent and efferent arterioles of the glomeruli

3. Tubular Lesions (Armanni-Ebstein Lesions)

• Epithelial cells of PCT → extensive glycogen deposits appearing as vacuoles

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Renal Cystic Disease / Polycystic Kidney Disease

Tumours of Kidney
Adenocarcinoma of Kidney
• Renal cell carcinoma is the most common malignant tumor of kidney.
• 50 to 70 years of age
• Male preponderance (2:1)

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Grossly
• Arises from the poles of the kidney (upper pole)
• Tumour is large, golden yellow and circumscribed.
• Cut section → ischaemic necrosis, cystic change and haemorrhages.

Microscopically
1. Clear cell type RCC
• Most common pattern (70% to 80% of RCC)
• Arises from PCT
• Tumour cells are arranged in solid pattern separated by
delicate vasculature
• Tumour cells have clear cytoplasm
• Clear cytoplasm of tumour cells is due to removal of
glycogen and lipid from the cytoplasm during processing of
tissues.
• Cytogenetic abnormality → deletion of short arm of
chromosome-3 (3p deletion) ie. VHL gene.

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2. Papillary type RCC

• 2nd most common
• Arises from DCT
• Tumour cells are arranged in papillary pattern over the
fibrovascular stalks.
• Psammoma bodies seen.
Cytogenetic abnormalities in papillary carcinoma are
1. Sporadic: Trisomy of 7,16,17; loss of Y chromosome (Y);
t (X:1).
2. Hereditary: Trisomy 7.

3. Chromophobe type RCC

• Arise from intercalated cells of cortical collecting ducts
• Tumour cells have prominent cell membranes and pale
eosinophilic cytoplasm
• A halo around the nucleus is seen (perinuclear halo)
• Cytogenetic abnormality includes Hypodiploidy or monosomy
due loss of multiple chromosomes:
1, 2, 6, 10, 13, 17, 21, & Y

4) Collecting duct (Bellini duct) carcinoma

• Least common type of RCC.
• Arises from medullary collecting duct.
• Cells have prominent fibrotic stroma.

Clinical Features→ Triad of

1. Gross haematuria (most common)
2. Flank pain
3. Palpable abdominal mass.

Wilms’ Tumour
• Also known as Nephroblastoma
• Embryonic tumour derived from primitive renal epithelial and mesenchymal
components
• Most common abdominal malignant tumour of young children,
• 1 to 6 years of age
• M=F

Etiology And Pathogenesis

1. Wilms’ tumour associated gene, WT1 gene, is located on chromosome 11p13.
2. Mutation between B-catenin pathway and WNT (wingless) signaling pathway.

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Grossly
• Tumour is usually large, spheroidal, replacing most of the
kidney.
• Solitary and unilateral but 5-10% cases bilateral tumour.
• On cut section → tumour shows characteristic variegated
appearance

Microscopically
Triphasic →
• Blastemal component → The tumour consists of
small, round ,blue, anaplastic tumour cells
• Epithelial component→ abortive tubules and poorly-
formed glomerular structures are present
• Mesenchymal elements → such as smooth and
skeletal muscle, cartilage and bone, fat cells and
fibrous tissue seen.

Clinical Features
• Palpable abdominal mass in a child detected by mother

Respiratory System

Chronic Obstructive Pulmonary Disease (COPD)

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Chronic Bronchitis
• Chronic bronchitis is a common condition defined clinically as persistent cough with
expectoration on most days for at least three months of the year for two or more
consecutive years.
Pathogenesis
• The cough is caused by over secretion of mucus due to increase in number and size of
submucosal gland of trachea and bronchi

Microscopically
1. Increased Reid index (normal 04 )
• Reid index is the ratio between thickness of
the submucosal mucus glands (i.e.
hypertrophy and hyperplasia) in the cartilage-
containing large airways to that of the total
bronchial wall
2. Goblet cells are increased
3. The bronchial epithelium may show squamous
metaplasia and dysplasia.
4. There is little chronic inflammatory cell infiltrate.

Clinical Features
1. Persistent cough with copious expectoration of long duration; initially beginning in a
heavy smoker with ‘morning catarrh’ or ‘throat clearing’ which worsens in winter.
2. Recurrent respiratory infections are common.
3. Dyspnoea
4. Patients are called ‘blue bloaters’ due to cyanosis
5. Features of right heart failure (cor pulmonale) are common.
6. Chest X-ray shows enlarged heart with prominent vessels.

Emphysema
• The WHO has defined pulmonary emphysema as combination
of permanent dilatation of air spaces distal to the terminal
bronchioles and the destruction of the walls of dilated air
spaces.
• Thus, emphysema is defined morphologically, while chronic
bronchitis is defined clinically.

Chronic Bronchitis Emphysema

Age 40-45 50-75
Dyspnea Mild; late Severe; early

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Cough Early; copious sputum Early; copious sputum

Infections Common Occasional
Respiratory insufficiency Repeated Terminal
Cor pulmonale Common Rare; terminal
Airway resistance Increased Normal or slightly increased
Elastic recoil Normal Low
Chest radiograph Prominent vessels; large heart Prominent vessels; large heart
Appearance Blue bloater Pink puffer

Bronchial Asthma
Asthma is a disease of airways that is characterised by
increased responsiveness of the tracheobronchial tree to a
variety of stimuli
↓
Widespread spasmodic narrowing of the air passages
↓
Relieved spontaneously or by therapy

• Asthma is an episodic disease manifested clinically

by
1. Paroxysms of dyspnoea,
2. Cough
3. Wheezing
• A severe and unremitting form of the disease termed status asthmaticus may prove fatal.

Pathogenesis
• Asthma is an example of type I hypersensitivity

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Sputum
1. The mucus plugs contain normal or degenerated respiratory
epithelium forming twisted strips called Curschmann’s
spirals.
2. The sputum usually contains numerous eosinophils and
diamond-shaped crystals derived from eosinophils called
Charcot-Leyden crystals.
3. Creola bodies: Ciliated columnar cells sloughed from
bronchial mucosa.

Bronchiectasis
• Bronchiectasis is defined as abnormal and irreversible
dilatation of the bronchi and bronchioles (greater than 2
mm in diameter) developing secondary to inflammatory
weakening of the bronchial walls.
• The most characteristic clinical manifestation of
bronchiectasis is persistent cough with expectoration of
copious amounts of foul-smelling, purulent sputum.

• Cut surface of the affected lobes shows characteristic

honey-combed appearance→ The bronchi are extensively
dilated, their walls are thickened and the lumina are filled
with mucus or mucopus.
Microscopically
1. Bronchi and bronchioles are dilated
2. The bronchial epithelium may be normal, ulcerated or
sloughed
3. The bronchial wall shows infiltration by acute and chronic
inflammatory cells
4. In the bronchial wall there is destruction of normal muscle
and elastic tissue with replacement by fibrosis

Kartagener's syndrome
Triad→
• Bronchiectasis
• Sinusitis
• Situs invertus (including
dextrocardia)

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Pneumonias
• Pneumonia is defined as acute inflammation of the lung parenchyma distal to the
terminal bronchioles (consisting of the respiratory bronchiole, alveolar ducts,
alveolar sacs and alveoli).
• Consolidation of lung

Classification
1. Bacterial Pneumonia →
• Lobar
• Lobular (Bronchopnemonia)
2. Viral pneumonia → Intertitial / atypical pneumonia
3. Fungal pnemonia

Bacterial Pnemonia
1. Lobar Pneumonia
• Lobar pneumonia is an acute bacterial infection of a
part of a lobe, the entire lobe, or even two lobes of one or both the lungs
• The condition is frequent in adults

4 pathologic phases of pnemonia

• Laennec’s divides lobar pneumonia into 4 sequen tial pathologic phases:
1. Stage of congestion (initial phase),
2. Red hepatisation (early consolidation),
3. Grey hepatisation (late consolidation)
4. Resolution

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2. Lobular Pneumonia / Bronchopneumonia

• Bronchopneumonia or lobular pneumonia is infection of the terminal bronchioles that
extends into the surrounding alveoli resulting in patchy consolidation of the lung.
• The condition is frequent at the extremes of life (i.e. in infancy and old age), in chronic
debilitating diseases and as a secondary infection following viral respiratory
infections

Grossly
• Patchy areas of consolidation affecting one or more lobes,
• Frequently found bilaterally
• More often involving the lower zones of the lungs due to
gravitation of the secretions.
• On cut surface, these patchy consolidated lesions are dry,
granular, firm, red or grey in colour, 3 to 4 cm in diameter,
slightly elevated over the surface

Histologically
i) Acute bronchiolitis.
ii) Suppurative exudate, consisting chiefly of neutrophils, in
the peribronchiolar alveoli.
iii) Thickening of the alveolar septa by congested capillaries
and leucocytic infiltration.
iv) Less involved alveoli contain oedema fluid.

Item Lobar pneumonia Lobular pneumonia

Age Young and adults Extremes of ages
Organism Mostly pneumococci Mixed organisms
Grossly Affects one or more than one Patchy, bilateral basal
lobe (Diffuse) affection of both lungs
Type of inflammations Fibrinous inflammation Suppurative inflammation
Mode of healing Resolution occurs in the Lysis & complications are
most cases most common

Viral/ Mycoplasma Pneumonia, Interstitial Pnemonia,

Primary Atypical Pneumonia
• Viral pneumonia is characterised by patchy inflammatory changes, largely confined to
interstitial tissue of the lungs, without any alveolar exudate.
• Also called interstitial pneumonitis due to interstitial location of the inflammation
• Also called primary atypical pneumonia, atypicality being the absence of alveolar
exudate which is commonly present in other pneumonias.

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Histologically
1. Hallmark of viral pneumonias is the interstitial nature of the
inflammatory reaction comprised by lymphocytes,
macrophages and some plasma cells.
2. There is thickening of alveolar walls due to congestion, oedema
and interstitial inflammation
3. Lack of alveolar exudate

Fungal / Mycotic Pneumonias

• Rare in healthy individuals, Common in immunosuppressed individuals

Microscopically
1. Interstitial pneumonitis
2. Thickening of the alveolar walls
3. No significant inflammatory exudate is seen in the air spaces.
4. Alveolar lumina contain pink frothy fluid having the organisms
5. By Grocott’s methenamine-silver (GMS) stain, the characteristic oval
or crescentic cysts, surrounded by numerous tiny black dotlike organism
P. jirovecii are demonstrable in the frothy fluid

Tumours of Lung
• Lung cancer is the most common cause of cancer related death.
• Occurs most often between ages 40 and 70 years.

Histological Types -→ 5 types

i) Squamous cell or epidermoid carcinoma

ii) Small cell carcinoma
iii) Adenocarcinoma (including bronchioalveolar carcinoma)
iv) Large cell carcinoma
v) Combined squamous cell carcinoma and adenocarcinoma (adenosquamous
carcinoma).

Clinical types
1. Small cell carcinomas, SCC (20-25%)
2. Non-small cell carcinomas, NSCC (70-75%) (includes squamous cell
carcinoma, adenocarcinoma, and large cell carcinoma)
3. Combined/mixed patterns (5-10%).

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Bronchogenic Carcinoma
Etiology
1. Smoking
2. Other Factors →
i) Radiation exposure
ii) Atmospheric pollution
iii) Occupational causes
iv) Dietary factors
v) Chronic scarring

Molecular Pathogenesis
i) EGFR mutations
ii) VEGF over expression

Remember
• Adenocarcinoma is the overall most common type of lung carcinoma
• Squamous cell (epidermoid) carcinoma is the most common type of lung carcinoma in
lndia
• Adenocarcinoma is the most common type of lung carcinoma in non-smokers and
females.
• Squamous cell carcinoma is the most common type of lung carcinoma in smokers and
males

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1. Squamous cell carcinoma

• Most common type of lung cancer in India
• Most commonly found in men and is closely related
with smoking history
• They arise centrally (hilar) from the segmental or
subsegmental bronchi

Histologically
• Characterized by the presence of keratinization
and intracellular bridges
• Keratinization may take the form of squamous
pearls (eddy pearl) or individual cells with
markedly eosinophilic dense cytoplasm.
• Marker of squamous cell carcinoma is cytokeratin

2. Small cell carcinoma (Oat-cell carcinoma)

• Small cell carcinoma have a strong relationship to cigarrete smoking (also squamous
cell carcinoma).
• They occur both in major bronchi (central) and in the periphery of lung.

Histologically
Tumour cells →
• Scant cytoplasm
• Ill defined cell borders
• Small -» Smaller than small resting lymphocytes
• High mitotic count
• Finely granular nuclear chromatin (salt and pepper
pattern)
• Absent or incospicuous nucleoli
• Necrosis is common and extensive.

• Marker → Neuroendocrine markers -> chromogranin, Synaptophysin,

Remember
• Small cell carcinoma of lung is the most aggressive and most malignant lung tumor,
with worst prognosis
• Most common site of metastasis is brain
• Small cell carcinoma is most common type of lung cancer associated with ectopic
horomone production and paraneoplastic syndrome
• It is the most common type of lung cancer responsive to chemotherapy and
radiotherapy

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3. Adenocarcinoma
• most common lung cancer, overall
• Most common type of lung cancer in women and nonsmokers
• Peripheral carcinoma

Types
i) Acinar → predominance of glandular structure
ii) Papillary→ pronounced macropapillary
configuration
iii) Bronchioalveolar / Lepidic → cuboidal to tall
columnar and mucus-secreting epithelial cells
growing along the existing alveoli
• Bronchioloalveolar carcinoma consists mucin
secreting bronchiolar cells, clara cells, or rarely
type II pneumocytes.
iv) Solid with mucin production
• Marker → CK 7

4. Large cell carcinoma

• Cells with large nuclei, prominent nucleoli and a moderate amount of cytoplasm.
• Located peripherally

Paraneoplastic syndromes in lung carcinoma

• Lung carcinoma can be associated with a number of paraneoplastic syndromes

Hormones or hormone-like factors elaborated include :

1. ADH →Causing SIADH
2. ACTH → Causing cushing syndrome
3. PTH (parathormone related peptide → Causing hypercalcemia
4. Calcitonin →Causing hypocalcemia
5. Gonadotropins →causing gynaecomastia
6. Lambert eaton syndrome
7. Acanthosis nigricons
8. Hypertrophic pulmonary oseoarthropathy (clubbing & periosteal reaction).

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IMP

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MGT
Pathological classification
1. Germ cell tumours (95%)
→ YESS PCT
2. Sex cord-stromal tumours
3. Combined forms

Clinical classification
1. Seminomatous
2. Non-seminomatous

FEATURE SGCT NSGCT

1 Primary Larger, confined to testis for Smaller, at times indistinct;
tumour sufficient time; testicular contour testicular contour may be
retained distorted
2 Metastasis Generally to regional lymph nodes Haematogenous spread early
3 Response to Radiosensitive Radioresistant
radiation
4 Serum markers hCG; generally low levels hCG, AFP, or both; high levels
5 Prognosis Better Poor

Etiologic Factors
1. Cryptorchidism
2. Dysgenetic gonads
3. Genetic factors
4. Orchitis
5. Trauma
6. Carcinogens

Classic Seminoma
• Commonest malignant tumour of the testis
• Corresponds to dysgerminoma in the female

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Grossly
• Larger tumour replaces the entire testis
• Cut section of the affected testis shows homogeneous, grey-
white lobulated appearance

Microscopically
1. Tumour cells arrangement → lobules.
2. Tumour cells cytology→
• Uniform in size
• Clear cytoplasm
• Well-defined cell borders.
• Cytoplasm contains variable amount of glycogen that
stains positively with PAS reaction.
• Nuclei are centrally located, large, hyperchromatic
and usually contain 1-2 prominent nucleoli.
3. Stroma shows a characteristic lymphocytic infiltration

Tumour markers
1. KIT
2. OCT4
3. Placental alkaline phosphatase (PLAP)
• They are negative for alpha-fetoprotein (AFP) and human chorionic gonadotropin
(HCG)

• Nodular hyperplasia (BPH)arises

from transitional zone (Middle lobe)
and produces urinary obstruction.
• Prostatic carcinoma is located in the
peripheral zone (posterior lobe)

Nodular Hyperplasia
• Benign nodular hyperplasia (BNH)
• Benign nodular hyperplasia (BPH)

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• Benign enlargement of prostate (BEP)

Histologically
Glandular hyperplasia→
• Exaggerated intra-acinar papillary infoldings with
delicate fibrovascular cores.
• Lining epithelium is two-layered
Fibrous and muscular hyperplasia → aggregates of spindle cells

Carcinoma Of Prostate
• Second most common form of cancer in males (1st → lung cancer)

Microscopically
Pattern
• In contrast to convoluted appearance of the glands
seen in normal and hyperplastic prostate, there is
loss of intra-acinar papillary convolutions.
• Groups of acini are either closely packed in back-
to-back arrangement without intervening stroma or
are haphazardly distributed.

Gland pattern
• Glands are lined by a single layer of cuboidal or
low columnar cells.
• Poorly differentiated tumours have little or no glandular arrangement but instead show
solid pattern.

Stroma
• Normally, fibromuscular sling surrounds the acini, whereas malignant acini have little or
no stroma between them.

Serum tumour markers

1. Prostatic acid phosphatase (PAP)
2. Prostate-specific antigen (PSA)

FGT

Invasive Cervical Cancer

• Most common gynaecological malignancy in the world

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Age → Bimodal peak →

1. 1st peak seen at 35-39 years.
2. 2nd peak seen at 55-60 years

Risk factors
1. Human Pappiloma virus infection
1. High risk HPV include 16,18,31,33,35,39,45,52,56,58,59,68
2. Low risk HPV associated with genital warts are subtypes 6 and 11.

2. Factors increasing the risk of sexually transmitted infections

• Coitus before 18 years of age
• Multiple sex partners
• Multiparity
• Poor personal hygiene
• Poor socioeconomic status

3. Smoking (predisposes to squamous cell CA).

4. Immunosuppressed individuals

5. Women on OCP or progesterone therapy for long time, are predisposed to

adenocarcinoma of endocervix

6. In utero exposure to diethylstilbestrol (DES).

Classification
1. Epidermoid (Squamous cell) carcinoma
2. Adenocarcinoma

Grossly
3 types of patterns:
1. Fungating,
2. Ulcerating
3. Infiltrating

Histologically

1. Epidermoid (Squamous cell) carcinoma

• This type comprises vast majority of invasive cervical
carcinomas (about 70%)
• Arises from the squamocolumnar junction.

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• Tumour cell are arranged in sheets

• Tumour cells are large with hyperchromatic nuclei and high N/C ratio
• Tumour cells are non-keratinising

2. Adenocarcinoma
• Adenocarcinomas comprise about 20-25% of cases.
• Arises from the endocervix
• Tumor cells are arranged in glandular pattern
• Tumour cells produce mucin and form glands

Screening
Pap Smear (Exfoliative Cytology)

Ovarian Tumours
Classification
I. Tumours of surface epithelium (common epithelial tumours)
II. Germ cell tumours
III. Sex cord-stromal tumours
IV. Miscellaneous tumours
• 65% of ovarian cancers are epithelial
• 35% of ovarian cancers are nonepithelial

Tumours Of Surface Epithelium

A. Serous tumours
1. Serous cystadenoma
2. Borderline serous tumour
3. Serous cystadenocarcinoma
B. Mucinous tumours
1. Mucinous cystadenoma
2. Borderline mucinous tumour
3. Mucinous cystadenocarcinoma
C. Endometrioid tumours
D. Clear cell (mesonephroid) tumours
E. Brenner tumours

Germ Cell Tumours

A. Teratomas
B. Dysgerminoma
A. Endodermal sinus (yolk sac) tumour
B. Choriocarcinoma
C. Others (embryonal carcinoma, polyembryoma, mixed germ cell tumours)

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Tumour markers
Epithelial cell Tumor-
• Serous variety → CA 125
• Mucinous variety → Ca 19-9,CEA
• Both serous and Mucinous variety → OCCA, OCA

Leiomyoma
• Also known as fibroids
• Most common uterine tumours of smooth muscle origin
• Benign

Etiology
• Stimulus to their proliferation is oestrogen.
• This is evidenced by increase in their size in pregnancy and high dose
oestrogen-therapy and their regression following menopause and castration

TYPES
1. within the myometrium → Intramural or interstitial
2. Beneath the serosa → subserosal
3. Underneath the endometrium → submucosal

Grossly
• Often multiple, circumscribed, firm, nodular, grey-white masses of variable size.
• On cut section → whorled pattern

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Histologically
• Whorled bundles of smooth muscle cells admixed with
variable amount of connective tissue.

Leiomyosarcoma
• Malignant tumour
Grossly
• Diffuse, bulky, soft and fleshy mass, or a polypoid mass
projecting into lumen

Histologically
• Whorled arrangement of spindle-shaped smooth
muscle cells having large and hyperchromatic nuclei
• The hallmark of diagnosis and prognosis is the number
of mitoses per high power field (HPF).

The essential diagnostic criteria are

• More than 10 mitoses per 10 HPF without cellular
atypia
OR
• 5-10 mitoses per 10 HPF with cellular atypia.

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NLC
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2
Psychiatry by Dr. Ankit Goel