Neoplasia

• Neoplasia : Process of new growth.

• Neoplasm : A new growth is called neoplasm.
• Tumor : A swelling. Originally described for
inflammation as one of five classic sign. But
now the term is equated with neoplasm.
• Cancer : A common term for all malignant
neoplasm.
• Neoplasm : According to British Oncologist
Willis
“A neoplasm is an abnormal mass of tissue, the
growth of which exceeds and is uncoordinated
with that of normal tissues and persist in the
same excessive manner after cessation of
stimuli which evoke the change.” It is
purposeless, virtually autonomous and preys on
• All neoplasm have two basic component :
1) Proliferating neoplastic cells that form the
parenchyma.
2) Supporting stroma : Made up of connective
tissue and blood vessels.
Desmoplasia : Formation of abundant
collagenous stroma, the formation of which is
stimulated by the parenchymal cells.
Nomenclature :
In general, benign tumor are designated by
attaching
the suffix- oma to the cells of origin. Tumors
of mesenchymal cells generally follow this
role. Example : Fibroma, Lipoma, Chondroma,
Osteoma.
• In contrast, the nomenclature of benign epithelial
tumor is more complex . They are variously
classified , some based on their cells of origin,
others on microscopic or macroscopic growth
pattern. Example of benign epithelial tumor :
• Adenoma : Benign epithelial neoplasm that
form glandular pattern as well as tumor derived
from glands but not necessarily producing
glandular pattern.
• Papilloma : Benign epithelial neoplasm
producing microscopically or macroscopically
visible finger-like or warty projection from
epithelial surfaces .
• Papillary cystadenoma : When papilla protrude
into cystic space.
 Nomenclature of malignant
tumor
• Sarcoma : Malignant tumor of
mesenchymal tissue.
• Carcinoma : Malignant tumor of epithelial
cells derived from any of the three germ
cell layers.
• Adenocarcinoma : Epithelial tumor
producing glandular growth pattern.
 Some important tumor and
tumor like conditions.
• Mixed tumor : Divergent differentiation of
single line of parenchymal cells. Example :
Pleomorphic adenoma of salivary gland,
Fibroadenoma of breast, Wilms’ tumor.
• Teratoma : Tumor composed of variety of
parenchymal cell types representative of
more than one germ layer, usually all three.
They arise from totipotential stem cells
and so are principally encountered in the
gonads.
• Choristoma : Ectopic rest of normal tissue.
Example : Pancreatic tissue in the mucosa of
small intestine, Adrenal tissue under the kidney
capsule.
• Hamartoma : Aberrant differentiation may
produce a mass of disorganized but mature
specialized cells or tissue indigenous (Native)
to the particular site. So hamartoma in lung may
contain cartilage, blood vessels, bronchial type
structure and lymphoid tissue but they does not
form organoid structure of lung tissue.
• Some tumor which end with suffix oma but are
not benign : Melanoma, Seminoma, Hepatoma.
 Classification of tumor
• Tumor can classified in the following way :
• 1) Naked eye appearance.
• 2) Histogenetic
• 3)Histological
• 4)Behavioural
• 5)Aetiological
• 6)Functional.
• Naked eye appearance : Annular, Fungating
(Cauliflower), Scirrhous, Encephaloid, Medullary
etc.
 Histogenetic
• Composed of one parenchymal cell type:
1) Composed of one parenchymal cell type:
Benign Malignant
Mesenchymal origin
Connective tissue Fibroma Fibrosarcoma
Lipoma Liposarcoma
Chondroma
Chondrosarcoma
Osteoma Osteosarcoma
 Benign Malignant
Endothelial and related tissue
Blood vessels Hemangioma Angiosarcoma
Lymph vessels Lymphangioma
Lymphangiosarcoma
Synovium Synovial sarcoma
Mesothelium Mesothelioma
Brain coverings Meningioma

Blood and related cells

Hematopoietic cells Leukaemia
Lymphoid tissue Lymphoma

Muscle
Smooth Leiomyoma Leiomyosarcoma
Striated Rhabdomyoma
Rhabdomyosarcoma
 Benign Malignant
Epithelial origin
Straified Squamous Squamous cell Squamous or
papilloma epidermoid
carcinoma
Basal cells Basal cell
carcinoma
Epithelial lining of Adenoma Adenocarcinoma
Glands or ducts Papilloma Papillary
carcinoma
Cystadenoma
Cystadenocarcinoma.
Respiratory epithelium Bronchial adenoma
Bronchogenic ca.
Renal epithelium Renal tubular adenoma Renal cell ca.
Liver cells Liver cell adenoma Hepatocellular
ca.
Urinary tract Transitional cell papilloma Transitional
cell ca.
 Benign Malignant
More than one Pleomorphic Malignant
Mixed
Neoplastic cell type- adenoma (Mixed tumor
of
Usually derived from tumor of salivary
salivary
one germ cell Layers. gland origin) gland
origin

Renal anlage Wilms tumor

More than one
Neoplastic cell type- Mature teratoma
Immature
 Histological classification
• Well-differentiated
• Moderately differentiated
• Poorly differentiated
• Undifferentiated
 Behavioural classification
• Benign tumor
• Malignant tumor
• Tumors of intermediate malignancy
• Latent cancer
• Dormant cancer
• Occult carcinoma.
• Carcinoma-in-situ.
 Tumors of intermediate
malignancy
• These tumor does not fit either into benign or
malignant group. These are locally invasive
tumor but show little or no tendency to
metastasize. These are :
• Basal cell carinoma.
• Carcinoid tumor
• Giant cell tumor
• Astrocytoma, Oligodendroglioma.
• Invasive mole
• Myeloproliferative disorder
• Ameloblastoma
• Craniopharyngioma.
• Latent cancer : These tumor show histological
characteristic of malignancy but are clinically
silent and does not metastasize. e.g : Prostatic
carcinoama.
• Dormant cancer : It is the late appearance of
metastasis after the successful removal of
primary tumor.
• Occult carcinoma : These are also clinically
silent carcinoma but diagnose first from
metastasis. Such as papillary thyroid carcinoma
may be first detected from metastatic lymph
node.
• Aetiological classification : Since the
cause of most carcinoma is not known,
this classification is at present impractical.
• Functional classification : Some author
classify tumor according to hormone
production :
• Insulinoma
• Glucagonoma.
• Gastrinomas.
 Biology of tumor growth
• Biology of tumor growth can be divided
into four phases
1) Malignant change in the target cells
called transformation
2) Growth of the transformed cells
3) Local invasion
4) Distant metastasis
 Differentiation and anaplasia
• Differentiation refers to the extent to which
neoplastic cells resemble comparable normal
cells, both morphologically and functionally; lack
of differentiation is called anaplasia. Malignant
tumor composed of undifferentiated cells are
said to be anaplastic. Lack of differentiation or
anaplasia is marked by : Pleomorphism,
Increased nuclear cytoplasmic ratio, Loss of
polarity, Hyperchromasia, Irregular nuclear
membrane, chromatin is coarsely clumped and
distributed beneath the nuclear membrane,
parachromatin clearing, increased mitosis,
abnormal mitosis, Large nucleoli, Tumor giant
• Dysplasia- Means a loss of the uniformity of cells
as well as a loss in their architectural orientation. It
is seen principally in epithelium. Dysplastic cells
show considerable pleomorphism and often
hyperchromatic nuclei that are abnormally large
for the size of the cells. Mitotic figure are more
abundant and may be found in all levels including
surface cells but show normal pattern. It does not
necessarily progress to cancer. e.g. Adjacent to
foci of invasive carcinoma, Long term cigarette
smoking, Barett esophagus.
• Carcinoma in situ-when dysplastic changes are
marked and involve the entire thickness of the
epithelium, but the lesion is confined to normal
tissue and not cross the basement membrane, it is
considered a preinvasive neoplasm and is referred
 Rate of growth: Time for a detectable
tumor mass

• The original transformed cell of 1m

diameter must undergo at least 30
population doublings to produce 109 cells
(approx.1gm) and only ten further
doublings are required to produce a tumor
containing 1012 cells (aprox.1kg), which is
the maximum size compatible with life. By
the time a solid tumor is clinically
detected, it has already completed a major
portion of its life cycle.
 Rate of growth of a tumor
• It depends on three main factors:
• 1. The doubling time of tumor cells
• 2. The fraction of tumor cells that are in
replicative pool
• 3. The rate at which the cells are shed and
lost
in the growing lesion.
• Growth of tumor is not commonly associated
with shortening of cell cycle time. The
proportion of cells within the tumor population
that are in the proliferative pool is referred to as
the growth fraction. Some leukemias,
lymphomas and small cell carcinoma of lung
have a relatively high growth fraction and their
clinical course is rapid, comparing breast cancer
and colon cancer have low growth fraction, they
tend to grow slowly. During the early
submicroscopic phase of tumor growth, the vast
majority of transformed cells are in proliferative
pool. As the tumor continue to grow, cells leave
the proliferative pool owing to shedding, lack of
nutrients, or apoptosis, by differentiating and by
• Most cells within cancer remain in the G1 and Go
phases. Thus, by the time a tumor is clinically
detectable, most cells are not in the replicative
tool. Even in some rapidly growing tumor, the
growth fraction is only bout 20 %.
• Now the question is, How long does it take for
one transformed cell to produce a clinically
detectable tumor of 109 cells?
• If every one of the daughter cell remain in cell
cycle and no cells were lost, the anticipated
answer is 90 days (approx.1gm , 30 population
doublings, cell cycle of 3 days) which is the
smallest cinically detectable mass. In reality, the
latent period before the clinically detectable
tumor is unpredictable and much larger than 90
• After a tumor is clinically detectable, the average
doubling time for cancer of lung and colon is
about 2-3 months. Range of doubling time value
is extremely broad varying from 1 month for
some childhood cancer to more than 1 year for
certain salivary gland tumors.

•  Generally speaking, growth rate of tumors

correlates with their level of differentiation, and
so most malignant tumors grow rapidly than
benign tumors with many exceptions e.g.
leiomyomas.
 Invasion
• Benign tumor does not have the capability to
infiltrate, invade, or metastasis and usually have
capsule and a well-defined cleavage plane in
contrast to malignant tumor.
• There are some unencapsulated benign tumor.
These are : Haemangioma, leiomyoma,
lymphangioma, Neurofibroma.
• The growth of malignant tumor is accompanied
by progressive infiltration, invasion, and
destruction of the surrounding tissue. Next to the
development of metastasis, invasiveness is the
most reliable factor that differentiates malignant
 Metastasis
• Metastases are tumor implant discontinuous
with the primary tumor. Metastases
unequivocally marks a tumor as malignant. The
invasiveness of cancers permits them to
penetrate into blood vessels, lymphatic and body
cavities providing the opportunity to spread.
• All cancer can metastasize except malignant
neoplasm of glial cells in CNS, called gliomas,
basal cell carcinoma, Ameloblastoma.
• Generally, the more rapidly growing and the
larger the primary tumor the greater the
likelihood that it will metastasize though
exception occurs. Approx. 30% patient with solid
tumors (excluding skin cancers other than
melanomas) present with metastasis.
• Pathways of spread:
• 1.Lymphatic spread.
• 2. Haematogenous.
• 3. Direct seeding of body cavities or surfaces-
Krukenberg tumor.
Lymphatic spread :Carcinomas mainly and also
sarcoma use this route of metastasis. Tumor do not
contain any functional lymphatics but lymphatic
vessels located around tumor margin are sufficient
for the lymphtic spread of tumor cells. The pattern
of lymph node involvement follow the natural route
of lymphatic drainage.
Skip metastasis : Metastasis bypassing the local
lymph node due to venous-lymphatic anastomoses
or becauseinflammation or radiation has obliterated
lymphaticChannels.
Sentinel node : It is the first node in regional lymphatic
basin that receives lymph flow from the primary
tumor. E.g breast cancer, spread of melanomas,
colon cancer, and other tumors.
• Haematogenous-Typical of sarcomas but can
also be used by carcinomas. Liver and lung are
most commonly involved.
• Carcinoma which metastasize through
hematogenous route are : Renal cell carcinomas,
Hepatocellular carcinomas, Carcinoma of
Prostate and Thyroid etc.
• Spread through body cavity : Peritoneal cavity
mostly involved but other cavity such as pleural,
pericardial, subarachnoid space and joint spaces
may also involved. Ovarian cancer mostly
involve peritoneal cavity. Sometimes mucous
secreting appendiceal carcinomas fill the
peritoneal cavity with gelatinous neoplastic
mass refferred as pseudomyxoma peritonei.
 Difference between benign and
malignant tumor
Characteristics Benign Malignant
1)Neoplastic
cells.
a) Well- Well-
Differentiation differentiated differentiated to
undifferentiated
b)Pleomorphis Absent Often present
m
c)Orientation of No loss of Loss of
neoplastic cells orientation. orientation.
d)Nuclear Normal Increased (May
2) Rate of Grow and Most cancers
growth expand slowly grow rapidly
3) Size Usually small Usually larger.
4)Haemorrhage Little tendency Common
and necrosis
5)Capsule Mostly Not capsulated.
encapsulated.
6)Local No local Locally
Invasion invasion invasive
7)Metatasis Never occur Frequent
metastasis.
8) Clinical Usually not fatal Almost
effects invariably fatal.
 Causes of Cancer
Most cancer in adults arise spontaneously in
response to an unknown stimulus but in a few cases
certain preceding causes can be identified. The
factors generally recognised as possible cause of
human neoplasia are :
• 1) Chemical carcinogen.
• 2) Radiations.
• 3) Viruses.
• 4) Hereditary predisposition
• 5) Non- hereditary predisposition
• 6) Hormonal Imbalance.
• 7) Geographic and enviromental factors.
Chemical carcinogens :
The major chemical carcinogens are as follows :
1) Direct acting agents : These are activation
independent and in general these are weak
carcinogens. But they are important because many
therapeutic agents fall into this category. Example :
Dimethyl Sulfate, Anticancer drugs
(Cyclophosphamide, Chlorambucil, busulfan,
Melphalan).
2) Polycyclic Aromatic Hydrocarbon : These are most
potent carcinogen. They require metabolic
activation. e.g :Benzanthracine, Dibenzanthracine,
Benzopyrene, Smoked meat and fish.
3) Aromatic amines, Amides, Azo Dyes : 2-
• Natural Plant and Microbial Products
Aflatoxin
Griseofulvin
Safrole
Betel nuts.

Others
Nitrosamine and amides
Insecticides, Fungicides.
 Radiation
• Ultraviolet Rays
• Ionizing Radiation
-Electromagnetic (X-rays, γ rays)
-Particulate radiation (α particles, β
particles
protons, neutrons)
 Viruses
• DNA viruses :
• 1) Human papillomavirus (HPV): HPV causes
genital, laryngeal and skin warts.
Skin cancer in patient with
epidermodysplasia verruciformis.
In situ and invasive cancer of vulva and
uterine cervix.
2) Epstein-Barr virus : African form of Burkitt
Lymphoma, Nasopharyngeal carcinoma,
Immun-oblastic lymphoma, Some Hodgkin
• 3) Hepatitis B virus : Hepatocellular
carcinoma.
• 4) Herpes simplex type-2 : Cancer of uterine
cervix.
• 5) Cytomegalovirus : gastrointestinal
neoplasm in patient with AIDS.
• 6) Kaposi sarcoma herpes virus (KSHV) :
AIDS associated Kaposi’s sarcoma.
• RNA virus :
• HTLV-1 : Adult T-cell leukaemia /lymphoma.
• Hepatitis C Virus : Hepatocellular carcinoma.
• Helicobacter pylori : Gastric carcinoma,
Genetic predisposition to cancer
• For a large number of cancer, there exist
not only environmental influence but also
hereditary predisposition. Genetic
predisposition to cancer can be divided into
three categories :
• 1) Inherited cancer syndrome: The inherited
mutation is usually a point mutation
occurring in a single allele of a tumor
suppressor gene. Example : RB gene
Retinoblastoma
• APC Familial adenomatous
polyp
• NF1,NF2 Neurofibrmatosis 1 and 2
• BRCA1, BRCA2 Breast and ovarian tumor.

Defective DNA repair syndrome : These condtion

have an autosomal recessive pattern of
inheritance. This group include :
Xeroderma pigmentosum
Ataxia telangectasia
Bloom syndrome
Fanconi anaemia.
• Familial cancers : Cancer may occur in certain
family without a clearly defined pattern of
inheritance. Virtually all common type of cancer
can occur in familial form. Example : Carcinoma
of colon, breast ovary, brain, pancreas and
melanoma. It is likely that familial susceptibility
to cancer may depend on multiple low-
penetrance allele, each contributing to only a
small increase in the risk of tumor development.
 Nonhereditary predisposing condition
• Chronic inflammation and cancer : In 1883
Virchow proposed that cancer develops at sites of
chronic inflammation. There is increased risk of
cancer development in patient with variety of
gastrointestinal chronic inflammatory disease.
These include Ulcerative colitis, Crohn’s disease,
Viral hepatitis.
• Precancerous conditions : Certain non-neoplastic
condition have such a well defined association
with cancer that they are termed Precancerous
conditions. Such conditions are : Chronic atrophic
gastritis of pernicious anaemia, Solar keratosis,
Cell-cycle
 Cell-cycle checkpoint
• Cell cycle has its own internal control, called cell-
cycle checkpoint. There are two main checkpoint,
one at the G1/S transition and another at G2/M
transition.
The G1/S checkpoint check for DNA damage. If DNA
damage is present, the DNA repair mechanism are
put in motion. If the damage is not reparable,
apoptotic pathway are activated to kill the cell. Thus
G1/S checkpoint prevents the replication of cells
that have defects in DNA. DNA damaged after its
replication can still be repaired as long as the
Checkpoint in cell cycle
 G2/M checkpoint monitor the completion
of DNA replication and check whether
the cell can safely initiate mitosis and
separate sister chromatid. This
checkpoint is particularly important in
ionizing radiation. In the G1/S checkpoint,
cell cycle arrest is mediated by p53
• Arrest of the cell cycle in the G2/M
checkpoint involves both p53 dependent
and independent mechanism. Defect in
 Molecular Basis of cancer
• List of fundamental principle of molecular
basis :
• Nonlethal Genetic damage lies at the heart of
carcinogenesis. Such genetic damage (or
mutation) may be acquired by the action of
environmental agents such as chemicals,
radiation and viruses or it may be inherited in
germline.
•  A tumor is formed by the clonal expansion
of a single precursor cells that has incurred
the genetic damage i. e. tumors are
• Four classes of normal regulatory gene—the
growth promoting protooncogenes, the growth-
inhibiting tumor suppressor gene, genes that
regulate programmed cell death (apoptosis)
and gene that are involved in DNA repair.
Mutant allele of protooncogene are considered
dominant because they can transform cells
despite the presence of their normal counterpart.
In contrast, both allele of tumor suppressor gene
must be inactivated. So, tumor suppressor gene
are recessive oncogene.
• A disability to DNA repair genes can predispose
to mutation in genome and hence to neoplastic
proliferation.
 
• Carcinogenesis is a multistep process at both
the phenotypic and the genetic levels. A
malignant neoplasm has several phenotypic
attributes, such as excessive growth, invasion
and metastasis. These characteristics are
acquired in a stepwise fashion, a phenomenon
called tumor progression. At the molecular level,
progression results from accumulation of
genetic lesions.
 Essential alteration for malignant
transformation
• Genetic damage that lie in the heart of
carcinogenesis is related with seven
fundamental changes in cell physiology that
together determine malignant phenotype. These
changes are :
• 1) Self sufficiency in growth signals-Tumors
have the capacity to proliferate without external
stimuli usually as a consequence of oncogenic
activation.
• 2)Insensitivity to growth inhibitory signal.
• 3) Evasion of apoptosis.
• 4) Defects in DNA repair.
• 6) Sustained angiogenesis.
• 7) Ability to invade and metastasis.
 Gene related with neoplastic transformation
• Self sufficiency in growth signals-Oncogene :Gene
that promote autonomous cell growth of cancer cell
are called oncogene and their normal cellular
counterparts are called protooncogenes.
• Protooncogene are normal cellular gene that
promote and regulate cellular proliferation and
differentiation.
• Oncogenes are characterized by the ability to
promote cell growth in the absence of normal
mitogenic signals. Their products, called
oncoprotein, resembles the normal products of
protooncogene with the exception that
oncoproteins are devoid of important regulatory
 Insensitivity to growth inhibitory signal :
Tumor suppressor gene
• The protein that apply brakes to cell proliferation
are the products of tumor suppressor gene. The
term “tumor suppressor gene” is a misnomer
because the physiologic function of these gene
is to regulate normal cell growth, not to prevent
tumor formation. As the loss of function of these
gene is associated with many tumor formation
so the name tumor suppressor gene persist. The
tumor suppressor gene were discovered by
studying rare diseases such as retinoblstoma.
• 60 % of retinoblstomas are sporadic and the
remaining 40 % are inherited.
• To explain the inherited and sporadic occurrence of
an apparently identical tumor, Knudson proposed
his “two hit” hypothesis of oncogenesis. In
hereditary cases, one genetic change (first hit) is
inherited from an affected parent and is therefore
present in all somatic cells of the body, whereas the
second mutation (second hit) occurs in one of the
many retinal cells (already carry the first mutation).
In sporadic cases both mutations (hits) occur
somatically within a single retinal cell, whose
progeny then form the tumor.
• Patient with familial retinoblastoma are also at
greatly increased risk of developing osteosarcoma
and other soft tissue sarcoma. As retinoblastoma
develop only when both the RB gene are lost it is
• Other genes that function as tumor suppressor
genes include p53, NF-1 gene, NF-2 gene, VHL
gene, PTEN gene etc.
p53 gene is called guardian of genome
• p53 act in G1/S checkpoint. When cells sustain
DNA damage, p53 undergoes conformational
changes and induces the expression of genes
that shut down the cell cycle until DNA damage
is repaired, so damaged DNA is not duplicated.
When DNA damage repair is not possible then
p53 initiate apoptosis of cell. In view of these
activities, p53 has been rightfully called the
“Guardian of the genome”. p53 is the most
common target in human cancer. Over 50% of
human tumor contains mutation in this gene.
Homozygous loss of p53 allele occur in virtually
every type of cancer including carcinoma of
colon, lung and breast.  p53 mutation are
common in a variety of tumor suggest that p53
acts as a critical gatekeeper against the
formation of cancer. Indeed, it is evident that
p53 acts as a “molecular policeman” that
prevents the propagation of genetically
damaged cells. p53 functions primarily by
controlling the transcription of several other
protein. Mutation of p53 will produce defective
protein that blocks the activity of several other
protein.
 Evasion of Apoptosis
• Cell survival is conditioned by genes that
promote and inhibit apoptosis. BCL-2 gene is
prototype in this category. In 85% of follicular
variety of B cell lymphoma carry a characteristic
t (14;18) in which BCL-2 gene from 18 is
translocated to immunoglobulin heavy chain
locus on 14. In this new location the normal
control of BCl-2 gene is lost and there is
overexpression of BCl-2 gene. BCL-2 protein
prevents apoptosis. As there is overexpression
of BCl-2 so the cells is protected from apoptosis
and there is accumulation of B lymphocytes.
 DNA repair gene
• We are continuously exposed to naturally
occurring DNA-damaging agent such as ionizing
radiation, sunlight, dietary carcinogen but cancer
is a relatively rare outcome of such encounter.
This fortunate state results from ability of
normal cell to DNA repair by DNA repair gene.
Those born with inherited mutation of DNA repair
proteins are at a greatly increased risk of
developing cancer, known as genetic instability
syndromes. Moreover, Defects in repair
mechanisms are present in sporadic human
cancers.
• DNA repair genes themselves are not oncogenic,
but their abnormalities allow mutations in other
genes during the process of normal cell division.
Typically genomic instability occur when both
the copy of these genes are lost. In this respect
they resemble tumor suppressor gene. The
disorder of this group are :
• Hereditary non-polyposis cancer syndrome.
Xeroderma pigmentosum
Ataxia telangectasia
Bloom syndrome
Fanconi anaemia.
 Chromosomal changes
• Specific chromosomal abnormalities have been
identified in most leukaemias and lymphomas
and also in non-haematopoietic tumors. Two
types of chromosomal rearrangements can
activate protooncogenes –translocation and
inversions.
• Translocation can activate protooncogenes in
two ways :
• 1) Specific translocation results in
overexpression protooncogenes by removing
them from their regulatory elements.
• The translocation allow normally unrelated
sequence from two different chromosomes to
recombine and form hybrid genes that encode
growth promoting hybrid protein.
• Gene amplification- activation of
Protooncogenes associated with over
expression of their products may result from
reduplication and multiplication of their DNA
sequences. Such amplification may produce
several hundred copies of the Protooncogene in
the tumor cells. The amplified gene can be
detected by molecular hybridization and
appropriate DNA probe. In some cases the
amplified gene produces Chromosomal changes
that can be identified microscopically.
• Two mutually exclusive pattern are seen

• a. Double minutes-multiple small

Chromosome like structures.

• b. Homogenous staining regions-

assembly of amplified genes into new
chromosomes; because the regions
containing amplified genes lack a normal
banding pattern, they appear Homogenous
in a G banded karyotype.
• Limitless replicative potential-After a fixed
number of divisions, normal cells become
arrested in a terminally nondividing state known
as replicative senescence by the action of a
specialized structure located at the ends of
chromosomes-telomeres. Reactivation of
telomerase in cells with abnormal genomes
confers an unlimited replicative capacity to cells
that have tumorigenic potential.

• Sustained angiogenesis- Tumor stimulate the

growth of host vessels. It is a requisite not only
for continued tumor growth, but also for
metastasis.
 Invasion and metastasis
• Biological hall mark of malignant tumor
• Major cause of cancer related morbidity
and mortality
• Metastatic cascade divided into two
phase
• 1) Invasion of the ECM and
• 2) vascular dissemination and homing of
tumor cells.
 Invasion of extracellular matrix
• A carcinoma breach the underlying basement
membrane then traverse interstitial connective
tissue
• penetration of vascular BM
• Gain access to the circulation
This cycle will be repeated when tumor cell
emboli extravasate at distant site.
Invasion of ECM is an active process that can
be resolved into several steps :
Detachment of the tumor cells from each other
Attachment to matrix component
Degradation of ECM
 Vascular dissemination and
homing of tumor cell.
• Once in the circulation, the tumor cell are
particularly vulnerable to destruction by innate
and adaptive immune response. Within the
circulation, tumor cells tend to aggregate in
clumps. This is favored by homotypic adhesion
among tumor cells as well as heterotypic
adhesion between tumor cells and blood cells
particularly platelets. Formation of platelet-
tumor aggregates may enhance tumor cell
survival and impartibility. Arrest and
extravasations of tumor emboli at distant sites
may involve adhesion to the endothelium,
• The site at which circulating tumor cells leave
the capillaries to form secondary deposit is
related, in part to the anatomic location of
primary tumor. But the natural pathway of
drainage do not wholly explain the distribution of
metastasis. For example, prostatic carcinoma
spread to the bone, bronchogenic carcinoma
tend to involve the adrenals and the brain, and
neuroblastomas spread to the liver and bone.
 Carcinogenesis
• Carcinogenesis is the process by which normal
cells are transformed to cancer cells. Several
sequential and concurrent cellular changes were
required for carcinogenesis. This idea received
support from experimental model of chemical
carcinogenesis in which the process of tumor
formation can be divided into distinct steps,
such as initiation and promotion. Study of
oncogene and tumor suppressor gene has
provide a firm footing for the concept of
multistep carcinogenesis.
• No single oncogene can fully transform a cell
but cells can generally be transformed by
combination of oncogenes.
• Most human cancer that have been analyzed
reveal multiple genetic alterations involving
activation of several oncogenes and loss of two
or more tumor suppressor gene.
• Gatekeeper and tumor suppressor gene :
Oncogenes and tumor suppressor gene directly
control tumor growth by functioning respectively
as accelerators and brakes for cellular
proliferation. They are known as gatekeeper
genes which regulate entry of gene into the
tumorigenic path. Genes that do not directly
control tumor growth but affect genomic
stability are called caretaker gene. Example :
Colorectal cancer
(Carcinogenesis)
 Chemical carcinogenesis.
• Carcinogenesis is a multistep process and this is
most readily demonstrated in experimental
models of chemical carcinogenesis, in which the
stages of initiation and progression during
cancer development have been described. The
classic experiments that allowed the distinction
between initiation and promotion were
performed on mouse skin and are outlined in
figure. The following concepts relating to the
initiation-promotion sequence have emerged
from these experiments :
Chemical carcinogenesis
• Initiation results from exposure of cells to a
sufficient dose of carcinogenic agent (initiator);
an initiated cell is altered, making it potentially
capable of giving rise to a tumor (groups 2 and 3)
. Initiation alone, however is not sufficient for
tumor formation.
• Initiation causes permanent DNA damage
(mutation). It is therefore rapid and irreversible
and has memory. This is illustrated in group 3, in
which tumors were produced even if the
application of the promoting agent was delayed
for several months after a single application of
initiator.
• Promoters can induce tumors in initiated cells,
but they are nontumorigenic by themselves
promoting agent is applied before rather than
after the initiating agent (group 4). This indicates
that, in contrast to the effects of initiators, the
cellular changes resulting from the application
of promoters do not affect DNA directly and are
reversible. The effects of promoters are
reversible is further documented in group 6, in
which tumor failed to develop in initiated cells if
the time between multiple applications of
promoter was sufficiently extended.
 Host defense against tumor-Tumor
immunity.
• Tumors are not entirely self and may be
recognized by the immune system. A number of
observer use the term Immune surveillance which
implies that A normal function of the immune
system is to survey the body for emerging
malignant cells and destroy them. This idea is
supported by many observations- occurrence of
lymphocytic infiltrates around tumors and in
lymph nodes draining the sites of cancer ; the
increased incidence of some cancers in
immunodeficient individuals ; and the direct
demonstration of tumor specific T cells and
antibodies in patients with malignancy.
• Tumor antigens : Initially, the tumor antigen were
broadly classified into two categories based on
their pattern of expression :
• 1) Tumor- specific antigens-present only on
tumor cells and not in any normal cells.
• 2) Tumor associated antigen-present on tumor
cells and also on some normal cells.
This classification, however, is imperfect
because many antigen thought to be tumor
specific turned out to be expressed on some
normal cell as well. The modern classification of
tumor antigens is based on their molecular
structure and source.
1)Products of mutated oncogenes or tumor
suppressor genes- Because these altered protein
are not present in normal cells, they do not
induce self tolerance. This product may be
recognized by CD8 T cells and also by CD4 T
cells.
2)Product of other mutated gene- Because of
genetic instability of tumor cells many different
genes may be mutated in these cells. Product of
these mutated genes are potential tumor antigen.
3)Over expressed or aberrantly expressed cellular
proteins : Some normal protein which are
expressed at low level in normal cells may be
overexpressed in tumor cells and may elicit
immune response. The possible explanation is
 Tumor cells may produce a normal protein that
are not expressed by that organ from which the
tumor arise but expressed by other organ or the
protein were expressed during development,
may elicit immune response. Example : MAGE
protein may be expressed by Melanoma,
carcinoma of bladder, breast, skin etc. But
normally these MAGE protein is expressed only
by testis.
4) Tumor antigen produced by oncogenic virus.
5) Oncofetal antigen : Oncofetal antigen are
protein that are produced at high level by cancer
cell and in normal fetal tissue but not by adult
tissue. Example : carcinoembryonic antigen
(CEA), Alpha fetoprotein (AFP).
 Cell type specific differentiation
antigens
• Tumor express molecules that are
normally expressed on cell of origin-called
differentiation antigens because they are
specific for particular lineages or
differentiation stages of various cell types.
• CD10 and CD 20 are expressed by
lymphoma of B cell origin. They are
normally typical self-antigens and don’t
induce immune responses in tumor
bearing hosts.
 Mechanism to escape or evade
the immune system
• Selective outgrowth of antigen-negative variant.
• Loss or reduced expression of MHC molecule.
• Lack of co stimulation.
• Immunosuppression : Many oncogenic agents
(Chemicals and ionizing radiation) suppresses host
immune response. Tumors or tumor product may
also be immunosuppressive
• Antigen masking : The cell surface antigen may be
hidden or masked by glycocalyx molecule.
• Apoptosis of cytotoxic T cells by Fas dependent
killing of T lymphocytes.
Antitumor effector mechanisms
  Cytotoxic T lymphocytes-against tumor antigens
is well recognized in experimentally induced
tumors. In human, they play a protective role
against virus induced tumors.
NK cells-They are lymphocytes that are capable
of destroying tumor cells without prior
sensitization.
Macrophages-Activated macrophages are
effective at killing tumor cells in vitro.
Antibodies-May kill tumor cells by activating
complement or ADCC.
 Effects of tumor on host
• Cancer are far more threatening to the host than
benign tumor. Neverthless both type of tumor can
cause problem because of (1) Location and
impingement on adjacent structures. (2) Functional
activity such as hormone synthesis (3) Bleeding and
secondary infection.
• (4) Initiation of acute symptoms caused by either
rupture or infarction.
• Local and Hormonal effect : Pituitary adenoma due
to its critical location may destroy remaining
pituitary. Gastric neoplasm may lead to obstruction.
Neoplasm of endocrine gland may produce
 Cancer Cachexia
• Patients with cancer commonly suffer
progressive loss of body fat and lean body mass
accompanied by profound weakness, anorexia
and anaemia. This wasting syndrome is known
as cachexia. There is little doubt that cachexia is
not caused by the nutritional demand of the
tumor. Anorexia is a common problem in
patients with cancer. Reduced food intake has
been related to abnormalities in taste and
central control of appetite, but reduced intake is
not sufficient to explain the cachexia of
malignancy.
• In patient with cancer, calorie expenditure often
remains high, and basal metabolic rate is
increased despite reduced food intake. By
contrast, in starvation there is adaptational
lowering of metabolic rate. Furthermore, in
cancer cachexia there is equal loss of fat and
muscle mass, whereas in starvation the muscle
mass is relatively preserved at the expense of fat
stores. Current evidence indicate that cachexia
result from the action of soluble factor such as
cytokines (TNF) produced by the tumor and by
the host in response to tumor.
 Paraneoplastic syndrome
• Symptom complex in cancer bearing patients
that cannot readily explained either by the local
or distant spread of the tumor or by the
elaboration of hormones indigenous to the tissue
from which the tumor arose, are known as
paraneoplastic syndrome. Paraneoplastic
syndrome are important to recognize for several
reasons :
• They may represent the earliest manifestation of
an occult neoplasm.
• In affected patients they may represent
significant clinical problem and may even be
fatal.
• Example of preneoplastic disorder :
Clinical syndrome Underlying cancer
Cushing syndrme Small cell carcinoma of
lung.
Pancreatic carcinoma
Hypercalcaemia Fibrosarcoma
Hepatocellular carcinoma.

Polycythaemia Renal carcinoma

Cerebellar haemangima

Hypertrophy osteo- Bronchogenic carcinoma.

arthopathy and
Clubing
 Grading and staging of cancer

• Grading of a cancer is based on the degree of

differentiation of the tumor cells and the number
of mitosis within the tumor as presumed
correlates of the neoplasm aggressiveness. Thus
cancer are classified as grades I to IV with
increasing anaplasia.
• The staging of cancer is based on the size of the
primary lesion, its extent of spread to regional
lymph node and the presence or absence of
blood-born metastasis.
• Two major staging system are currently in use,
one developed by the Union Internationale
Contre Cancer (UICC) and the other by the
American Joint Committee (AJC) on cancer
staging. The UICC employs a classification
called the TNM system—T for primary tumor, N
for regional lymph node involvement, and M for
metastasis. With increasing size, the primary
lesion is characterized as T1 to T4. T0 is added
to indicate an In situ lesion. N0 mean no nodal
involvement, whereas N1 to N3 would denote
involvement of an increasing number and range
of nodes. M0 signifies no distant metastases,
whereas M1 or sometimes M2 indicates the
presence of blood-borne metastases.
• The AJC employs somewhat different
nomenclature and divides all cancer into
stage 0 to IV, incorporating within each
stages the size of primary lesion as well
as the presence of nodal spread and
distant metastases.
• In general, staging has proved to be of
greater clinical value than grading.
 Laboratory diagnosis of cancer.
• For virtually every neoplasm, the experts have
characterized a number of subcategories for
Laboratory diagnosis of cancer . These are
mentioned below :
• Histologic and cytologic method : Clinical data
are mandatory for optimal diagnosis and the
specimen must be adequate, representative and
properly preserved. Several sampling
approaches are available:
• 1) Biopsy (2) Needle aspiration (3) Cytologic
smear.
• Biopsy may be excisional and incisional. Frozen
section diagnosis is sometimes desirable.
• Fine needle aspiration cytology :
• It is a less invasive, less expensive, reliable and
quick method of diagnosis. The procedure may
be :
• 1) Image guided (2) Non-guided.
• Cytologic smear :
• Pap smear.
• Brush cytology.
• Imprint cytology
• Cytology of body fluid etc.
• Immunohistochemistry :
• This procedure are used in the diagnosis and
management of following malignant neoplasm :
• 1) Categorization of undifferentiated malignant
tumor.
• 2) Categorization of Leukaemias and
Lymphomas : Immunohistochemistry in
conjunction with immunoflurescence has proved
useful in the identification and classification of
tumor arising from T and B lymphocytes.
• 3) Determination of site of origin of primary
tumor.
• 4) Detection of molecules that have prognostic
or therapeutic significance.
Intermediate filament which help in the
diagnosis by Immunohistochemictry
Intermediate filament Associated tumor
Keratin Carcinoma,
Mesothelioma
Desmin Muscle tumor both
smooth and striated.
Vimentin Mesenchymal tumor,
Some carcinoma
Glial filament Gliomatous tumor

Neurofilament Neuronal tumor

• Molecular diagnosis : Although molecular
method are not the primary modality of cancer
diagnosis, they are of considerable value in
selected cases. This procedure can be used in
the following condition :
• 1) Diagnosis of malignant neoplasm : Gene
diagnosis and diagnosis of translocation in
certain haematopoietic malignancy, round cell
tumor etc.
• 2) Prognosis of malignant neoplasm : Certain
genetic alteration are associated with poor
prognosis.
• 3) Detection of minimal residual disease by
applying PCR technique.
• Flow cytometry : Flow cytometry can rapidly
and quantitatively measure several individual cell
characteristics, such as membrane antigen and
DNA content of tumor cells. Identification of cell
surface antigens by flow cytometry is widely
used in the classification of leukaemias and
lymphomas.
• Tumor markers : Tumor marker are biochemical
marker detected in plasma or other body fluid
and are used for identification of the presence of
a tumor. They include cell-surface antigens,
cytoplasmic protein, enzymes and hormones.
Tumor marker cannot be used as primary
modalities for the diagnosis of cancer. Their
main utility as a laboratory test to support the
diagnosis. Some tumor marker are also of value
in determining response of therapy and relapse
The following are some selected tumor
marker.
Marker Associated cancer

Hormone : Human Trophoblastic tumor,

Chorionic Gonadotropin Non-seminomatous
testicular tumor.
Calcitonin Medullary carcinoma of
thyroid
Catecholamines and Pheochromocytoma and
metabolites related tumor
Ectopic hormone Paraneoplastic
syndrome
Oncofetal antigen

α- Fetoprotein Liver cell cancer,

Nonseminomatous germ
cell tumor of testis.
Carcinoembryonic Carcinoma of colon,
antigen Lung, Pancreas,
(CEA) Stomach & Heart
Isoenzymes

Prostatic acid Prostatic cancer

phosphatase
Neuron-specific enolase Small cell carcinoma of
Specific protein

Immunoglobulins Multiple myeloma and other

Gammopathies.
Prostate-specific antigen Prostate cancer

Mucins and other

Glycoprotein
CA-125 Ovarian cancer

CA-19-9 Colon cancer, Pancreatic

cancer.
Ca-15-3 Breast cancer