Neoplasia & Growth Disorders

 For the sake of survival on exposure to stress, the cells make adjustments with
the changes in their environment (i.e. adapt) to the physiologic needs
(physiologic adaptation) and to non-lethal pathologic injury (pathologic
adaptation). In general, the adaptive responses are reversible on withdrawal of
stimulus. However, if the irritant stimulus persists for long time, the cell may
not be able to survive and may either die or progress further into cancer. The
common term used for all malignant tumours is cancer. Hippocrates
(460-377 BC) coined the term karkinos for cancer of the breast. The word
‘cancer’ means crab, thus reflecting the true character of cancer since ‘it sticks
to the part stubbornly like a crab’.
 Defined as 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 is called oncology (oncos =tumour, logos = study).All
tumors (benign & malignant) have 2 basic components:
 Parenchymal cells, composed of epithelial tumour cells & determines the nature &
evolution of the tumour.
o ‘oma’ is added to denote a benign tumour E.g. C.T tumors like fibroma,
chondroma, osteoma, and epithelial-origin tumors like adenoma, papilloma, polyp.
o ‘carcinoma’ denotes malignant tumours of epithelial origin. E.g. basal cell
carcinoma, squamous cell carcinoma etc.
 Mesenchymal cells, composed of connective tissue.
o ‘sarcoma’ denotes malignant tumours non-epithelial in origin. E.g. fibrosarcoma,
chondrosarcoma, osteosarcoma etc.
 Special categories of tumours:
 Mixed tumours,
i) Tumours having both epithelial & mesenchymal tissue e.g. pleomorphic
adenoma.
ii) Adenosquamous carcinoma is the combination of adenocarcinoma (glands)
and squamous cell carcinoma in the endometrium (uterus).
 Teratoma, tumours made up of a mixture of various tissue types arising from
totipotent cells derived from the three germ cell layers—ectoderm, mesoderm
and endoderm. Most common sites for teratomas are ovaries and testis
(gonadal teratomas). But they occur at extra-gonadal sites as well, mainly in
the midline of the body such as in the head and neck region, mediastinum etc.
 Blastomas, or embryomas are a group of malignant tumours which arise from
embryonal cells which would normally form blastema of the organs and tissue
during embryogenesis. These tumours occur more frequently in infants and
children e.g. neuroblastoma, nephroblastoma (Wilms’ tumour), retinoblastoma
etc.
 Hamartoma, benign tumour which is made of mature but disorganised cells of
tissues belonging to the particular site or organ e.g. hamartoma of the lung
consists of mature cartilage, mature smooth muscle and epithelium. Thus, all
mature differentiated tissue elements which comprise the bronchus are present
in it but are jumbled up as a mass.
 Choriostoma, not a true tumour, i.e not belonging to the site of origin.
Differences between normal cell and cancer cell
i) Cancer cells disobey the growth controlling signals in the body & proliferates rapidly.
ii) Cancer cells escape death signals and achieve immortality.
iii) Imbalance between cell proliferation and cell death in cancer causes excessive growth.
iv) Cancer cells lose properties of differentiation and thus perform little or no function.
v) Due to loss of growth controls, cancer cells are genetically unstable & develop newer
mutations.
vi) Cancer cells overrun their neighbouring tissue and invade locally.
vii) Cancer cells have the ability to travel from the site of origin to other sites in the body
where they colonise and establish distant metastasis.
 Cancer cells originate by clonal proliferation of a single progeny of a cell
(monoclonality). Cancer cells arise from stem cells normally present in the tissues in
small number and are not readily identifiable.
TUMOUR ANGIOGENESIS: In order to provide nourishment o growing tumour, new
blood vessels are formed from pre-existing ones (angiogenesis). The new capillaries add to
the vascular density of the tumour which has been used as abmarker to assess the rate of
growth of tumours and hencebgrade the tumours. However, if the tumour outgrows its
blood supply as occurs in rapidly growing tumours or tumour angiogenesis fails, its core
undergoes ischaemic necrosis.
TUMOUR STROMA: The collagenous tissue in the stroma may be scanty where the
tumour is soft and fleshy (e.g. in sarcomas, lymphomas) or excessive where the tumour is
hard and gritty (e.g. infiltrating duct carcinoma breast). Growth of fibrous tissue in
tumour is stimulated by basic fibroblast growth factor (bFGF) elaborated by tumour cells.
A) Predisposing epidemiologic factors or cofactors which include a number of
endogenous host factors and exogenous environmental factors:
1. FAMILIAL AND GENETIC FACTORS. It has long been suspected that
familial predisposition and heredity play a role in the development of cancers.
i) Retinoblastoma:About 40% of cases are familial & show an autosomal
dominant inheritance. Familial form of retinoblastoma is due to missing of a
portion of chromosome 13 where RB gene is normally located. This results in
a genetic defect of absence of RB gene, the first ever tumour suppressor gene.
ii) Neurofibromatosis or von Recklinghausen’s disease: Characterised by multiple
neurofibromas and pigmented skin spots (cafe au lait spots).
iii) Cancer of the breast. Female relatives of breast cancer patients have 2 to 6
times higher risk of developing breast cancer. Inherited breast cancer comprises
about 5-10% of all breast cancers. There are two breast cancer susceptibility
genes, BRCA-1 and BRCA-2. Mutations in these genes appear in about 3% cases
and these patients have about 85% risk of development of breast cancer.
2. RACIAL AND GEOGRAPHIC FACTORS.
i) White Europeans & Americans develop malignancies of the lung, breast, colon.
ii) Black Africans, on the other hand, have more commonly cancers of the skin,
penis, cervix and liver.
iii) Japanese have five times higher incidence of carcinoma of the stomach than
the Americans.
iv) Indians of both sexes have higher incidence of carcinoma of the oral cavity and
upper aerodigestive tract, while in females carcinoma of uterine cervix and of the
breast run parallel in incidence.
v) Penile cancer is rare in the Jews and Muslims as they are customarily
circumcised.
vi) 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.
3. SEX: most tumours are generally more common in men than in women except
cancer of the breast, gallbladder, thyroid and hypopharynx.
4. HORMONES AND CANCER:
i) OESTROGEN: Women receiving oestrogen therapy and women with
oestrogen-secreting granulosa cell tumour of the ovary have increased risk of
developing endometrial carcinoma. Adenocarcinoma of the vagina is seen
with increased frequency in adolescent daughters of mothers who had
received oestrogen therapy during pregnancy.
ii) CONTRACEPTIVE HORMONES: associated with increased risk of
developing breast cancer.
iii) HORMONE-DEPENDENT TUMOURS:
i) Prostatic cancer usually responds to the administration of oestrogens.
ii) Breast cancer may regress with oophorectomy, hypophysectomy or on
administration of male hormones.
 To achieve DNA replication and division, the cell goes through a tightly
controlled sequence of events known as the cell cycle. The cell cycle consists of
G1 (presynthetic), S (DNA synthesis), G2 (premitotic), and M (mitotic) phases.
Quiescent cells that have not entered the cell cycle are in the G0 state. The cell
cycle has multiple checkpoints, particularly during emergence from G0 into
G1 and the transition from G1 to S phase.
 Progression through the cell cycle, particularly at the G1-S transition, is
regulated by proteins called cyclins, so called because of the cyclic nature of
their production and degradation, and associated enzymes, the cyclin
dependent kinases (CDKs).
 The activity of CDK regulated by CDK inhibitors (CDKIs), which enforce cell
cycle checkpoints i.e., a surveillance mechanisms that are sensing for any
damage to DNA and these quality control checks are called checkpoints. The
G1-S checkpoint monitors the integrity of DNA before DNA replication,
whereas the G2-M checkpoint checks DNA after replication and monitors
whether the cell can safely enter mitosis. When cells sense DNA damage,
checkpoint activation delays the cell cycle and triggers DNA repair
mechanisms. If DNA damage is too severe to be repaired, the cells are
eliminated by apoptosis, or enter a non-replicative state called senescence.
 Carcinogenesis or oncogenesis or tumorigenesis means mechanism of induction
of tumours (pathogenesis of cancer); agents which can induce tumours are
called carcinogens (etiology of cancer). The subject of etiology and
pathogenesis of cancer is discussed under the following headings:
A. Molecular pathogenesis of cancer (genes and cancer)
B. Chemical carcinogens
C. Physical carcinogens and radiation carcinogenesis
 In normal cell growth, there are 4 normal regulatory genes:
i. Proto-oncogenes are growth-promoting genes i.e. they encode for cell
proliferation pathway.
ii. Anti-oncogenes are growth-inhibiting or growth suppressor genes.
iii. Apoptosis regulatory genes control the programmed cell death.
iv. DNA repair genes are those normal genes which regulate the repair of DNA
damage that has occurred during mitosis and also control the damage to
proto-oncogenes and antioncogenes.
 In cancer, the transformed cells are produced by 4 abnormal regulatory genes:
i) Activation of growth-promoting oncogenes causing transformation of cell
(mutant form of normal protooncogene in cancer is termed oncogene).
ii) Inactivation of cancer-suppressor genes (i.e. inactivation of anti-oncogenes)
permitting the cellular proliferation of transformed cells.
iii) Abnormal apoptosis regulatory genes.
iv) Failure of DNA repair genes.
1. EXCESSIVE AND AUTONOMOUS GROWTH: GROWTH PROMOTING
ONCOGENES.
Mutated form of normal protooncogenes in cancer is called oncogenes.
Protooncogenes become activated oncogenes by following mechanisms:
• By mutation in the protooncogene which alters its structure and function.
• By retroviral insertion in the host cell.
• By damage to the DNA sequence that normally regulates growth-promoting
signals of protooncogenes resulting in its abnormal activation.
Transformation of proto-oncogene to oncogenes may occur by:
i) Point mutations i.e. an alteration of a single base in the DNA chain. The most
important example is RAS oncogene carried in many human tumours such as
bladder cancer, pancreatic adenocarcinoma.
ii) Chromosomal translocations i.e. transfer of a portion of one chromosome
carrying proto-oncogene to another chromosome and making it independent of
growth controls e.g. Philadelphia chromosome seen in 95% cases of chronic
myelogenous leukaemia in which c-ABL proto-oncogene on chromosome 9 is
translocated to chromosome 22.
Growth factors (GFs) were the first proto-oncogenes to be discovered which
encode for cell proliferation. They act by binding to cell surface receptors to
activate cell proliferation within the cell. GFs are small polypeptides elaborated
by many cells and normally act on another cell to stimulate its proliferation i.e.
paracrine action. However, a cancer cell may synthesise a GF and in this way
cancer cells acquire growth self-sufficiency (autocrine). The examples of such
tumour secreted GFs are as under:
a) Platelet-derived growth factor (PDGF-β)-: e.g. in gliomas and sarcomas.
b) Transforming growth factor- (TGF-α): e.g. in carcinoma and astrocytoma.
c) Fibroblast growth factor (FGF): e.g. in cancer of the bowel and breast.
d) Hepatocyte growth factor (HGF): e.g. in follicular carcinoma thyroid.
2. REFRACTORINESS TO GROWTH INHIBITION:GROWTH
SUPPRESSING ANTI-ONCOGENES
The mutation of normal growth suppressor anti-oncogenes results in removal of
the brakes for growth; thus the inhibitory effect to cell growth is removed and the
abnormal growth continues unchecked. In other words, mutated anti-oncogenes
behave like growth-promoting oncogenes.
Major anti-oncogenes (suppressed) implicated in human cancers are:
i) RB gene, known as the governor of the cell cycle and it is the first ever
tumour suppressor gene identified. RB gene is termed as master ‘break’ in
the cell cycle and is virtually present in every human cell. Other anit-
oncogenes are Wilm’s tumor gene, Neurofibroma gene etc.
Normally, RB gene product is a DNA-binding protein that is expressed in every
cell type examined, where it exists in an active hypophosphorylated state and an
inactive hyperphosphorylated state. The importance of Rb lies in its regulation of
the G1/S checkpoint, the portal through which cells must pass before DNA
replication.
 The initiation of DNA replication (S phase) requires the activity of cyclin
E/CDK2 complexes, and expression of cyclin E is dependent on the E2F family
of transcription factors. Early in G1 phase, Rb is in its hypophosphorylated
active form, and it binds and inhibits the E2F of transcription factors by,
preventing the cyclin E & CDK2 to act on E2F by the inihibitor called p27.
 Growth factor signaling leads to activation of cyclin D expression and
activation of CDK4/6 complexes. These complexes phosphorylate/inactivate Rb
& releasing E2F by inactivating the p27 inhibitor by the action of cyclin E &
CDK2. Therefore cyclin E helps in transcription DNA replication and
progression through the cell cycle from G1 to S phase.
 When the cells enter S phase, they are committed to divide without additional
growth factor stimulation. This phase is regulated by cyclin A and CDK2.
3. ESCAPING CELL DEATH BY APOPTOSIS: GENES REGULATING
APOPTOSIS AND CANCER
 TP53 gene, known as the guardian of the genome and is one of the most
commonly mutated genes in human cancers. The p53 protein prevents
neoplastic transformation by three interlocking mechanisms: activation of
temporary cell cycle arrest (termed quiescence), induction of permanent cell
cycle arrest (termed senescence), or triggering of programmed cell death
(termed apoptosis).
 BCL2 gene is seen in normal lymphocytes, but its mutant form was first
described in B-cell lymphoma and hence the name BCL.
Normally, TP53 mediates the cell cycle arrest in response to DNA damage by the
CDK inhibitor called p21. This p21 protein inhibits cyclin D–CDK4/6 complexes
and prevents hyperphosphorylation of inactive Rb, thereby arresting cells in the
G1 phase and it gives the cells “breathing time” to repair DNA damage. If DNA
damage is repaired successfully, p53 upregulates transcription of MDM2, leading
to inactivation of p21 by the protein p53 and it releases the cell cycle arrest.
If the damage cannot be repaired, the cell may enter p53-induced senescence or
undergo p53-directed apoptosis.
Cyclin D–CDK4/6 & cyclin E–CDK2 regulate the G1-to-S transition by phosphorylating the
Rb protein (pRb). Cyclin A–CDK2 and cyclin A–CDK1 are active in the S phase. Cyclin B–
CDK1 is essential for the G2-to-M transition. CDK inhibitors called INK4 inhibitors,
composed of p16, p15, p18, and p19, act on cyclin D–CDK4/6. The other inhibitors, p21, p27
& p57, inhibit all CDKs.
4. AVOID CELLULAR AGING:
After each mitosis (cell doubling) there is progressive shortening of telomeres
which are the terminal tips of chromosomes. Telomerase is the RNA enzyme that
helps in repair of such damage to DNA and maintains normal telomere length in
successive cell divisions. However, it has been seen that after repetitive mitosis for
a maximum of 60 to 70 times, telomeres are lost in normal cells and the cells cease
to undergo mitosis. Cancer cells in most malignancies have markedly upregulated
telomerase enzyme, and hence telomere length is maintained. Thus, cancer cells
avoid aging, mitosis does not slow down or cease, thereby immortalising the
cancer cells.
5. CONTINUED PERFUSION OF CANCER: TUMOUR ANGIOGENESIS :
Cancers survive only when they are adequately nourished. Neovascularisation in
the cancers not only supplies the tumour with oxygen and nutrients, but the newly
formed endothelial cells also elaborate a few growth factors for progression of
primary as well as metastatic cancer. Stimulus for angiogenesis is provided by:
i) Promoters of tumour angiogenesis: vascular endothelial growth factor (VEGF)
and basic fibroblast growth factor (bFGF).
ii) Anti-angiogenesis factors inhibiting angiogenesis include thrombospondin-1,
angiostatin, endostatin and vasculostatin. Mutated form of p53 gene in both
alleles in various cancers results in removal of anti-angiogenic role of
thrombospondin- 1, thus favouring continued angiogenesis.
6. INVASION AND DISTANT METASTASIS: most important characteristic
feature of cancers are invasiveness and metastasis. The mechanisms involved in
the biology of invasion and metastasis will be discussed later in the following
chapter.
7. MUTATOR GENES AND CANCER:
o Patients inherit mutant TP53 & the disease called Li-Fraumeni syndrome.
o Lynch syndrome: characterised by hereditary predisposition to develop
colorectal cancer. It is due to defect in genes involved in DNA mismatch repair
resulting in accumulation of errors in the form of mutations in many genes.
o Ataxia telangiectasia mutated gene (ATM ): These patients have multiple
cancers besides other features such as cerebellar degeneration, immunologic
derangements etc.
o Xeroderma pigmentosum: an inherited disorder in which there is defect in
DNA repair mechanism upon exposure to the UV radiation and such patients
are more prone to various forms of skin cancers.
o Bloom syndrome: a disorder caused by ionising radiation which cannot be
repaired due to inherited defect and the patients have increased risk to develop
cancers, particularly leukaemia.
o Hereditary breast cancer patients having mutated BRCA1 and BRCA2 genes
carry inherited defect in DNA repair mechanism. These patients are not only
predisposed to develop breast cancer but also cancers of various other organs.
8. CANCER PROGRESSION AND HETEROGENEITY: CLONAL
AGGRESSIVENESS:
In terms of molecular biology, cancer is due to the fact that with passage of time
cancer cells acquire more and more heterogeneity. This means that though cancer
cells remain monoclonal in origin, they acquire more and more mutations which,
in turn, produce multiple-mutated subpopulations of more aggressive clones of
cancer cells (i.e. heterogeneous cells) in the growth which have tendency to invade
and metastasise.
9. CANCER—A MULTISTEP THEORY: Cancer occurs in several sequential
steps of abnormalities in the target cell e.g. initiation, promotion & progression in
sequence. Similarly, multiple steps are involved at genetic levels: by activation of
growth promoters, loss of growth suppressors, escaping cellular aging etc.
10. MICRORNAs IN CANCER: ONCOMIRS:
An endogenous, noncoding single stranded RNA molecules. More than 500
miRNAs have been identified. Recent evidence indicates that miRNAs have an
oncogenic role in initiation and progression of cancer and are termed as oncogenic
microRNAs. In combination with other tumour associated genes, oncomiRs can
perform various functions: as tumour suppressor, as tumour promoter, and as
pro-apoptotic.
Direct-Acting Agents: require no metabolic conversion to become carcinogenic.
They are in general weak carcinogens but are important because some of them
are cancer chemotherapy drugs (e.g., alkylating agents) used in regimens that
may cure certain types of cancer (e.g., Hodgkin lymphoma), only to evoke a
subsequent, second form of cancer, usually leukemia.
Indirect-Acting Agents: refers to chemicals that require metabolic conversion to
an ultimate carcinogen. Some of the most potent indirect chemical carcinogens
are formed in the high-temperature combustion of tobacco in cigarette smoking.
These products are implicated in the causation of lung cancer in cigarette
smokers. Polycyclic hydrocarbons may be produced in smoked meats and fish.
Physical agents in carcinogenesis are divided into 2 groups:
1. Radiation, both ultraviolet light and ionising radiation, is the most important
physical agent implicated as carcinogenic agent.
i) UV light penetrates the skin for a few millimetres only so that its effect is
limited to epidermis. The efficiency of UV light as carcinogen depends upon
the extent of light absorbing protective melanin pigmentation of the skin. In
humans, excessive exposure to UV rays can cause various skin cancers:
squamous cell carcinoma, basal cell carcinoma & malignant melanoma.
ii) Ionising radiation of all kinds like X-rays, alpha, gamma and gamma rays,
radioactive isotopes, protons and neutrons can cause cancer in animals and
in man. Most frequently, radiation-induced cancers are all forms of
leukaemias, cancers of the thyroid, cancer of skin, breast, ovary, uterus etc.
2. Non-radiation physical agents are the various forms of injury and are less
important eg., stones in the gallbladder, stones in the urinary tract, and healed
scars following burns or trauma, has been suggested as the cause of increased risk
of carcinoma in these tissues but the evidence is not convincing.
LYMPHATIC SPREAD. In general, carcinomas metastasise by lymphatic route
while sarcomas favour haematogenous route. However, sarcomas may also spread
by lymphatic pathway. The involvement of lymph nodes by malignant cells may
be of two forms:
i) Lymphatic permeation. The walls of lymphatics are readily invaded by cancer
cells and may form a continuous growth in the lymphatic channels called
lymphatic permeation.
ii) Lymphatic emboli. Alternatively, the malignant cells may detach to form
tumour emboli so as to be carried along the lymph to the next draining lymph
node. The tumour emboli enter the lymph node at its convex surface and are
lodged in the subcapsular sinus where they start growing. Later, of course, the
whole lymph node may be replaced and enlarged by the metastatic tumour.
 HAEMATOGENOUS SPREAD. Blood-borne metastasis is the common
route for sarcomas but certain carcinomas also frequently metastasis by this
mode, especially those of the lung, breast, thyroid, kidney, liver, prostate
and ovary. The sites where blood-borne metastasis commonly occurs are:
the liver, lungs, brain, bones, kidney etc. all of which provide ‘good soil’ for
the growth of ‘good seeds’ (seed-soil theory). However, a few organs such as
spleen, heart, and skeletal muscle generally do not allow tumour metastasis
to grow. Spleen is unfavourable site due to open sinusoidal pattern which
does not permit tumour cells to stay there long enough to produce
metastasis.
 SPREAD ALONG BODY CAVITIES AND NATURAL PASSAGES:

i) Transcoelomic spread:

a) Carcinoma of the stomach seeding to both ovaries (Krukenberg tumour).

b) Carcinoma of the bronchus and breast seeding to the pleura and pericardium.

ii) Spread along epithelium-lined surfaces. It is unusual for a malignant tumour to spread along the

epithelium lined surfaces because they are quite resistant to penetration. However, exceptionally a

malignant tumour may spread through:

a) the fallopian tube from the endometrium to the ovaries or vice-versa;

b) through the bronchus into alveoli;

iii) Spread via cerebrospinal fluid. Malignant tumour of leptomeninges may spread by release of

tumour fragments into the CSF and produce metastases at other sites in the central nervous system.

iv) Implantation. Rarely, a tumour may spread by implantation by surgeon’s scalpel, needles, sutures,

or may be implanted by direct contact such as transfer of cancer of the lower lip to the apposing upper

lip.
 Aggressive clonal proliferation and angiogenesis: The first step in the spread of cancer

cells is the development of rapidly proliferating clone of cancer cells. Tumour

angiogenesis plays a very significant role in metastasis since the new vessels formed as

part of growing tumour are more vulnerable to invasion.

 Tumour cell loosening. Normal cells remain glued to each other due to presence of cell

adhesion molecules (CAMs) i.e. E (epithelial)-cadherin. In epithelial cancers, there is

either loss or inactivation of E-cadherin & results in loosening of cancer cells.

 Tumour cell-ECM interaction. Loosened cancer cells are now attached to ECM

proteins, mainly laminin and fibronectin. This attachment is facilitated due to

profoundness of receptors on the cancer cells for both these proteins.

 Degradation of ECM. Tumour cells overexpress ezymes called proteases
(cathepsin) and matrix-degrading enzymes, metalloproteinases, (collagenases
and gelatinase). These enzymes bring about dissolution of ECM, then make
way for tumour cells through the interstitial matrix, and finally dissolve the
basement membrane of the vessel wall.
 Entry of tumour cells into capillary lumen. The tumour cells after degrading
the basement membrane migrate into lumen of capillaries or venules.
 Thrombus formation. The tumour cells protruding in the lumen of the
capillary are now covered with constituents of the circulating blood and form
the thrombus
 Extravasation of tumour cells. Tumour cells in the circulation (capillaries,
venules, lymphatics) may mechanically block these vascular channels and
attach to vascular endothelium.
 Survival and growth of metastatic deposit. The extravasated malignant cells on
lodgement in the right environment grow further under the influence of
growth factors produced by host tissues, & tumour cells . The metastatic
deposits grow further and metastasise to the same organ or to other sites by
forming emboli.
 Cancer can be treated, when it is discovered at it’s early stage and remains
localized.
 Advanced cancer stages are not curable.
 Although the tumour is removed at it’s earliest stage metastasis could happen,
because some cancer cells would have entered the circulation without our
knowledge.
CHEMOTHERAPHY
 Use of Anti-neoplastic drugs
 Kills the cancer cells
 Also kills the normal cells due to poor recognition
 Side effects: weight loss, poor immunity, hair falling etc.
 Treatment is given in the hospital under a good care
RADIOTHERAPHY
 Killing of cancer cells using radiation
 Side effects: mutation of normal cells, suppress BM activity causing aplastic
anemia etc.
SURGERY
 Treatment used in early stages of cancer
 Tumour removed by surgical incision
 Prevents metastasis
 Surgery is done along with chemotheraphy or radiotheraphy, if there is a
doubt whether the cancer cells has entered the circulation.
IMMUNOTHERAPHY
 Expensive treatment
 Try to activate the immune system of the human body by drugs to produce
antibodies to kill the cancer cells
Grading system for malignancy: based on 2 important histologic features: degree of
anaplasia & rate of growth.
Grade I: Well-differentiated ( less than 25% anaplastic cells).
Grade II: Moderately-differentiated (25%-50%)
Grade II: Moderately-differentiated (50%-75%)
Grade III: Poorly-differentiated (>75%)
Staging system for malignancy: Two important staging systems are:
o TNM staging: T for primary tumour, N for nodal involvement and M for distant
metastases.
To to T4: In situ lesion to largest & extensive primary tumour.
No to N3: No nodal involvement to widespread lymphnode involvement.
Mo to M2: No metastasis to haematogenous involvement.
o AJC staging: Divides all cancers into stage 0 to IV.