NEOPLASIA, cancer, Benign and malignant tumor

NEOPLASIA
Mithun Venugopal. A
Assistant Professor
Dept. Of Pathology

What is a Neoplasia?
The term ‘neoplasia’ means new growth; the new growth
produced is called ‘neoplasm’ or ‘tumour’.
All ‘new growths’ are not neoplasms.
Embryogenesis, regeneration and repair, hyperplasia, hormonal
stimulation.

NORMAL CELLS
The proliferation and maturation of cells in normal adults is controlled.
Cells proliferate throughout life (Labile Cells)
(hematopoietic stem cells, skin cells, GIT)
Cells with limited proliferation (Stable Cells)
(liver, endocrine glands, kidney)
Cells do not replicate (Permanent Cells)
(neurons, heart cells, RBC)
On the other hand, neoplastic cells lose control and regulation of
replication and form an abnormal mass of tissue.
3
TYPES
OF
CELLS

Define Neoplasm
A neoplasm or tumour is ‘a mass of tissue formed as a result
of abnormal, excessive, uncoordinated, autonomous and
purposeless proliferation of cells even after cessation of
stimulus for growth which caused it’.
The branch of science dealing with the study of neoplasms
or tumors is called Oncology (oncos=tumour, logos=study).

Neoplastic Cells differs from Normal Cells
An abnormal mass of tissue differs from the normal in:
1.Growth
2.Differentiation
3.Organization
4.Function

COMPONENTS
1.Neoplastic Cells:
Constitutes tumour parenchyma.
Classification and biologic behavior is based on this.
2.Reactive Stroma:
Constitutes connective tissue, blood vessels, cells of
immune system.
Growth and spread are dependent on stroma.

CLASSIFICATION
1.Benign: When they are slow growing and localized
without causing much difficulty to the host.
2.Malignant: When they proliferate rapidly, spread
throughout the body and may eventually cause death of
the host.
The common term used for all malignant tumors is cancer. The word
‘cancer’ means crab, thus reflecting the true character of cancer since
‘it sticks to the part stubbornly like a crab’.

BENIGN TUMOURS
Nomenclature can be based on:
Microscopic Pattern (Example: Adenoma (derived from glandular)
epithelium, may or may not form gland)
Cells of Origin (Example: Renal tubular adenoma)
Macroscopic Architecture (Example: papilloma (tumour with finger like
projections), cystadenoma (tumour is predominantly cystic), polyp
(tomour with visible projections)
The nomenclature can be a combination of these three patterns. For example
‘adenomatous polyp’ when on microscopy it is gland forming and macroscopically it
is a polyp structure.

MALIGNANT TUMOURS
Sarcomas: Tumour arising from solid mesenchymal tissues. Example:
fibrosarcoma (malignant tumour of fibrous tissue), chondrosarcoma
(malignant tumour of cartilage), leiomyosarcoma (malignant tumour of
smooth muscle).
Carcinoma: Tumour of epithelial origin. Example: squamous cell carcinoma
(malignant tumour of squamous cell epithelium), adeno carcinoma
(malignant tumour of glandular epithelium).
Leukemias: Tumour arising from blood forming cells. Example: AML, CML,
ALL, CLL.
Lymphomas: Tumour arising from the lymphoid cells. Example: Hodgkins
and Non-hodgkins lymphoma.

CANCER Vs CARCINOMA
Cancer is a common term used to describe all malignant
neoplasm (epithelial as well as mesenchymal).
Carcinoma is a specific term used to describe malignancies
arising from epithelial cells.

OTHER TYPES OF TUMOURS
Mixed tumours: single neoplastic cell can differentiate into different
types of cells. Example: pleomorphic adenoma of salivary gland.
Teratoma: tumours contain mature or immature cells which are
derived from more than one germ cell layer (ectoderm, endoderm,
mesoderm). These tumours originate from totipotential germ cells
(ovary, testis, embryonic rests).
Hamartoma: benign masses where the cells are disorganized.
Contain cells indigenous to the involved site. Example: hamartoma of
lung and heart.

Blastoma: Blastomas or embryomas are a 193 group of malignant
tumours which arise from embryonal or partially differentiated cells
which would normally form blastema of the organs and tissue during
embryogenesis. These tumours occur more frequently in infants and
children. Example: neuroblastoma, nephroblastoma.
Choristoma: excess of normal tissue in abnormal location. Example:
pancreatic tissue mass found in stomach or small intestine.
OTHER TYPES OF TUMOURS

BENIGN Vs MALIGNANT
FEATURES BENIGN TUMOUR MALIGNANT TUMOUR
1. GROSS
a. Boundaries Encapsulated/well
circumscribed
Irregular/poorly
circumscribed
b. Surrounding tissue Often compressed Usually invaded by cancer
cells
c. Size Usually small Often larger
d. Secondary changes
(hemorrhage, necrosis,
etc.)
Less often More often

BENIGN Vs MALIGNANT
2. MICROSCOPY
a. Pattern Usually resembles the
tissue of origin closely
Often poor resemblance to
tissue of origin
b. Basal polarity Retained Often lost
c. Pleomorphism Usually not present Often present
d. Neucleo-Cytoplasmic
ratio
Normal Increased
e. Aniso neucleosis Absent Generally present
f. Hyper chromatism Absent Often present

BENIGN Vs MALIGNANT
g. Mitoses May be present but are
always typical mitoses
Mitotic figures increased
and are generally atypical
and abnormal
h. Tumour giant cells May be present but
without nuclear atypia
Present with nuclear atypia
i. Chromosomal
abnormalities
Infrequent Invariably present
j. Function Usually well maintained May be retained, lost or
become abnormal

BENIGN Vs MALIGNANT
3. GROWTH RATE Usually slow Usually rapid
4. LOCAL INVASION Often compresses the
surrounding tissues
without invading or
infiltrating them
Usually infiltrates and
invades the adjacent
tissues
5. METASTASIS Absent Frequently present
6. PROGNOSIS Local complications Death by local and
metastatic complications

Oncogenes
An oncogene is a mutated gene that has the potential to
cause cancer.
Before an oncogene becomes mutated, it is called a proto-
oncogene, and it plays a role in regulating normal cell
division.
Cancer can arise when a proto-oncogene is mutated into
an oncogene and causing the cell to divide and multiply
uncontrollably.

Oncogenes
Proto-oncogenes encode proteins that function to
stimulate cell division, inhibit cell differentiation, and halt
cell death. All of these processes are important for normal
human development and for the maintenance of tissues
and organs.
Oncogenes, however, typically exhibit increased
production of these proteins, thus leading to increased cell
division, decreased cell differentiation, and inhibition of cell
death; taken together, these phenotypes define cancer
cells.

Oncogenes
Examples:
HER2 gene in breast cancer.
BCR/ABL1 gene in chronic myeloid leukemia.
CMYC gene in Burkitts lymphoma.
NMYC gene in small cell lung cancer and neuroblastoma.
EGFR and EML4AK genes in adenocarcinoma of the lung.

HALLMARKS OF CANCER
1. Self sufficiency in the growth signals.
2. Insensitivity to antigrowth/growth inhibitory signals.
3. Evasion of apoptosis.
4. Limitless replication potential.
5. Sustained angiogenesis.
6. Ability to invade and metastasize.
7. Reprogramming energy metabolism.
8. Evasion of immune system.

Self sufficiency in the growth signals
Oncogenes: they promote unregulated proliferation /autonomous cell
growth (Self sufficiency in the growth signals).
Proto oncogenes: the unmutated genes from which the oncogenes
develop after mutation.

Insensitivity to antigrowth/growth
inhibitory signals
Tumour suppressor genes produce tumour suppressor proteins which
regulate the cell growth by applying breaks to cell proliferation (growth
inhibition).
Failure of growth inhibition is seen in carcinogenesis.
Loss of function of these tumour suppressor genes is a key event in
carcinogenesis.

TUMOUR SUPPRESSOR GENES AND ASSOCIATED TUMOURS
GENE LOCATION FUNCTION ASSOCIATED
TUMOURS
RB Nucleus (13q14) Cell cycle Retinoblastoma,
osteosarcoma
TP53 Nucleus (17p13) DNA repair,
apoptosis
Carcinoma of lung
colon, head, neck
and breast
APC Cytosole Cell-cell
recognition
Carcinoma of
colon
BRCA 2 Nucleus DNA repair Carcinoma of
breast and ovary

Both normal alleles of
Tumour Suppressor Gene
(TSG)
Normal function of Tumour
Suppressor Gene (TSG)
One normal allele active
Another abnormal allele
(inactive) of TSG
(HETEROZYGOUS)
Normal function of TSG
Both abnormal alleles
(inactive) of TSG – deletion,
mutation, etc.
(LOSS OF HETEROZYGOSITY)
Loss of function of TSG
TUMOUR

Evasion of apoptosis
Apoptosis is cell death.
To divide and grow uncontrollably, the cancer cells has to escape the
normal cell death.
This is achieved by either disrupting the balance between pro-
apoptotic and anti-apoptotic factors or by impairing the death receptor
signaling.

Limitless replication potential
Normal cell – limited cell division
(due to the loss of telomere in
each cell division).
Telomere protect the
chromosome from damage and
once the telomere is completely
loss, the cell undergoes death.
Cancer cells - activate enzyme
telomerase - make telomere long
and prevent cell death.

Sustained Angiogenesis
Angiogenesis - process by which new blood vessels form (delivery of
oxygen and nutrients to the body’s tissues).
The process of angiogenesis is controlled by chemical signals in the body
(vascular endothelial growth factor (VEGF).
Solid tumors need a blood supply for their growth. Tumors promote
angiogenesis by producing chemical signals.
Tumors can also stimulate nearby normal cells to produce angiogenesis
signaling molecules.
The resulting new blood vessels “feed” growing tumors with oxygen and
nutrients, allowing the tumor to enlarge and the cancer cells to invade nearby
tissue, to move throughout the body, and to form new colonies of cancer cells,
called metastases.

Ability to Invade and Metastasize
Major cause of cancer related morbidity and mortality.
This damage or destroy vital structures.
Invasion: direct extension and penetration by tumour cells into
neighboring tissues.
Metastasis: spread tumour to sites that are physically discontinuous
with the primary tumour.

Reprogramming energy metabolism
Normally energy (ATP) is produced by 2 mechanisms:
1. Oxidative phosphorylation in mitochondria (oxygen
dependent process) - production of 36 ATP.
2. Glycolysis in cytoplasm (oxygen independent process) -
production of 2ATP.
So in the presence of adequate oxygen ATP is generated by oxidative
phosphorylation and as oxygen decreases this shifts to glycolysis
(anaerobic glycolysis).

In early 20th century a German physiologist ‘Otto Heinerich Warburg’
observed that the cancer cells had increased rates of glycolysis despite
the availability of adequate oxygen levels.
He called that effect as aerobic glycolysis or Warburg effect.
The metabolic intermediates of aerobic glycolysis provides raw
material for the synthesis of cellular components in these rapidly
dividing tumour cells.
Release of lactic acid lowers the extracellular pH which favors the
tumour invasion and suppresses the immune effectors.
Reprogramming energy metabolism Cont.

MORPHOLOGY OF NEOPLASTIC CELLS
1. DIFFERENTIATION:
It is defined as the extent of morphological and functional resemblance
of parenchymal tumour cells to corresponding normal cells.
If the deviation of neoplastic cell in structure and function is minimal as
compared to normal cell, the tumour is described as ‘well-differentiated’
such as most benign and low-grade malignant tumours.
‘Poorly differentiated’, ‘undifferentiated’ or ‘dedifferentiated’ are
synonymous terms for poor structural and functional resemblance to
corresponding normal cell.

2. ANAPLASIA:
Anaplasia is the lack of differentiation and is a characteristic feature
of most malignant tumours.
Depending upon the degree of differentiation, the extent of
anaplasia is also variable i.e. poorly differentiated malignant tumours
have high degree of anaplasia.

As a result of anaplasia, following noticeable morphological and
functional alterations in the neoplastic cells are observed.
Loss of polarity
Pleomorphism
N:C ratio
Anisonucleosis
Hyperchromatism
Nucleolar changes
Mitotic figures
Functional (Cytoplasmic) changes

Loss of polarity
Normally, the nuclei of epithelial cells are oriented along the
basement membrane which is termed as basal polarity.
This property is based on cell adhesion molecules, particularly
selectins.
Early in malignancy, tumour cells lose their basal polarity so that the
nuclei tend to lie away from the basement membrane.

Pleomorphism
The term pleomorphism means variation in size and shape of the
tumour cells.
The extent of cellular pleomorphism generally correlates with the
degree of anaplasia.
Tumour cells are often bigger than normal but in some tumours they
can be of normal size or smaller than normal.

N:C Ratio
Generally, the nuclei of malignant tumour cells show more
conspicuous changes.
Nuclei are enlarged disproportionate to the cell size so that the
nucleocytoplasmic ratio is increased from normal 1:5 to 1:1.

Anisonucleosis
Just like cellular pleomorphism, the nuclei too, show variation in size
and shape in malignant tumour cells.

Hyperchromatism
Characteristically, the nuclear chromatin of malignant cell is increased
and coarsely clumped.
This is due to increase in the amount of nucleoprotein resulting in
dark-staining nuclei, referred to as hyperchromatism.
Nuclear shape may vary, nuclear membrane may be irregular and
nuclear chromatin is clumped along the nuclear membrane.

Nucleolar changes
Malignant cells frequently have a prominent nucleolus or nucleoli in
the nucleus reflecting increased nucleoprotein synthesis.

Mitotic figures
The parenchymal cells of poorly- differentiated tumours often show
large number of mitoses as compared with benign tumours and well-
differentiated malignant tumours.
As stated above, these appear as either normal or abnormal mitotic
figures.

Tumour Giant Cells
Multinucleate tumour giant cells or giant cells containing a single large
and bizarre nucleus, possessing nuclear characters of the adjacent
tumour cells, are another important feature of anaplasia in malignant
tumours.

Functional (Cytoplasmic) changes
Structural anaplasia in tumours is accompanied with functional
anaplasia as appreciated from the cytoplasmic constituents of the
tumour cells.

GRADING AND STAGING OF CANCER
‘Grading’ and ‘staging’ are the two systems to predict tumour
behaviour and guide therapy after a malignant tumour is detected.
Grading is defined as the gross and microscopic degree of
differentiation of the tumour, while staging means extent of spread of
the tumour within the patient. Thus, grading is histologic while staging is
clinical.

GRADING
Cancers may be graded grossly and microscopically.
Gross features like exophytic or fungating appearance are indicative of
less malignant growth than diffusely infiltrating tumours.
However, grading is largely based on 2 important histologic features:
the degree of anaplasia, and the rate of growth.
Based on these features, cancers are categorised from grade I as the
most differentiated, to grade III or IV as the most undifferentiated or
anaplastic.

Many systems of grading have been proposed but the one described by
Broders for dividing squamous cell carcinoma into 4 grades depending
upon the degree of differentiation is followed for other malignant
tumours as well.
Broders’ grading is as under:
Grade I: Well-differentiated (less than 25% anaplastic cells).
Grade II: Moderately-differentiated (25-50% anaplastic cells).
Grade III: Moderately-differentiated (50-75% anaplastic cells).
Grade IV: Poorly-differentiated or anaplastic (more than 75%
anaplastic cells).
GRADING

STAGING
The extent of spread of cancers can be assessed by 3 ways— by
clinical examination, by investigations, and by pathologic examination
of the tissue removed.
Two important staging systems currently followed are: TNM staging
and AJC staging.

TNM Staging
T for primary tumour, N for regional nodal involvement, and M for
distant metastases.
Was developed by the UICC (Union Internationale Contre Cancer,
Geneva).
For each of the 3 components namely T, N and M, numbers are added
to indicate the extent of involvement, as under:
T0 to T4: In situ lesion to largest and most extensive primary tumour.
N0 to N3: No nodal involvement to widespread lymph node
involvement.
M0 to M2: No metastasis to disseminated haematogenous
metastases.

AJC Staging
American Joint Committee staging divides all cancers into stage 0 to IV,
and takes into account all the 3 components of the preceding system
(primary tumour, nodal involvement and distant metastases) in each
stage.
TNM and AJC staging systems can be applied for staging most
malignant tumours.

Currently, clinical staging of tumours does not rest on routine radiography
(X-ray, ultrasound) and exploratory surgery but more modern techniques are
available by which it is possible to ‘stage’ a malignant tumour by non-
invasive techniques.
These include use of computed tomography (CT) and magnetic resonance
imaging (MRI) scan based on tissue density for locating the local extent of
tumour and its spread to other organs.
More recently, availability of positron emission tomography (PET) scan has
overcome the limitation of CT and MRI scan because PET scan facilitates
distinction of benign and malignant tumour on the basis of biochemical and
molecular processes in tumours.
DIAGNOSIS

PREDISPOSING FACTORS OF CANCER
1.FAMILIAL AND GENETIC FACTORS:
It has long been suspected that familial predisposition
and heredity play a role in the development of cancers.
Example: Retinoblastoma, Familial polyposis coli, Cancer
of the breast,

2. RACIAL AND GEOGRAPHIC FACTOR:
 Differences in racial incidence of some cancers may be
partly attributed to the role of genetic composition but are
largely due to influence of the environment and geographic
differences affecting the whole population such as climate,
soil, water, diet, habits, customs etc.
 White Europeans and Americans develop most commonly
malignancies of the lung, breast, and colon.
 Black Africans, on the other hand, have more commonly
cancers of the skin, penis, cervix and liver.
 Indians of both sexes have higher incidence of carcinoma of
the oral cavity and upper aero-digestive tract, while in
females carcinoma of uterine cervix and of the breast run
parallel in incidence.

3.ENVIRONMENTAL AND CULTURAL FACTORS:
Cigarette smoking
Alcohol abuse
Cancer of the cervix is linked to a number of factors
such as age at first coitus, frequency of coitus,
multiplicity of partners, parity etc.
Certain constituents of diet have also been implicated
in the causation of cancer. Overweight individuals,
deficiency of vitamin A and people consuming diet rich
in animal fats and low in fibre content are more at risk
of developing certain cancers such as colonic cancer.

4.AGE:
The most significant risk factor for cancer is age. Generally, cancers
occur in older individuals past 5th decade of life (two-third of all
cancers occur above 65 years of age), though there are variations in
age incidence in different forms of cancers.
Tumours in infancy and childhood are: neuroblastoma,
nephroblastoma, retinoblastoma, hepatoblastoma, rhabdomyo-
sarcoma, teratoma and CNS tumors.
5.SEX:
Apart from the malignant tumours of organs peculiar to each sex,
most tumours are generally more common in men than in women
except cancer of the breast, gall bladder, thyroid and hypopharynx.

CARCINOGENS
A carcinogen is any substance, agent, or organism that has the potential
to cause cancer.
Some carcinogens, such as UV rays from sunlight, occur naturally. Others
originate from artificial sources, such as cigarette smoke.
Most carcinogens cause cancer by producing mutations in a cell’s DNA.
Different carcinogens can cause different types of cancer.
Carcinogens do not necessarily cause cancer every time someone
interacts with them. However, exposure to a carcinogen can raise a
person’s risk of developing certain cancers.

Types of Carcinogens
Carcinogens are divided into three main categories.
Chemical carcinogens: These are carcinogens that release into the
environment through pollution, such as through car exhaust fumes,
industrial by-products, and cigarette smoke.
Physical or environmental carcinogens: These carcinogens come from
the environment. UV rays from sunlight and radiation from X-rays or
other radioactive materials are examples of physical carcinogens.
Biological carcinogens: These are microbial agents that can cause
cancer. Examples include human papillomavirus (HPV), Epstein-Barr, and
hepatitis B.

Examples of Carcinogens
Alcohol
Asbestos
Formaldehyde
Processed meat
Tobacco
UV rays
Arsenic
Chloroform
Coal dust and emissions
Nickel
Epstein-Barr virus
Hepatitis B virus
Hepatitis C virus
Human Papilloma Virus
HIV type-1
Helicobacter pylori
Aspergillus flavus
Oral contraceptives
X-rays and gamma rays

CARCINOGENESIS
Carcinogenesis or oncogenesis or tumorigenesis means
mechanism of induction of tumours (pathogenesis of
cancer) and agents which can induce tumours are called
carcinogens (etiology of cancer).

Etiology & Pathogenesis of Cancer
1. Molecular pathogenesis of cancer (genes and cancer)
2. Chemical carcinogens and chemical carcinogenesis
3. Physical carcinogens and radiation carcinogenesis
4. Biologic carcinogens and viral oncogenesis.

Radiation agents Non-radiation agents
UV light Mechanical injury to the tissue
X-rays Healed scars following burns or trauma
Radioactive isotopes
Protons

Parasites Fungus Bacteria
Schistosoma
haematobium
Aspergillus flavus Helicobacter pylori
Clonorchis sinensis

NEOPLASIA, cancer, Benign and malignant tumor

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