Neoplasia

In these lectures you will understand the

following:
Etiology (causes) of neoplasia. What evidence is
there that neoplasia is a genetic disorder? What is
the role of the environment in carcinogenesis?
Molecular Basis of neoplasia.Oncogenes and
tumour suppressor genes. Multistep
carcinogenesis or tumour progression
environmental carcinogens and process of
carcingenesis
Mechanism of cancer spread. Types of cancer
spread
Tumour grading and staging
Effects of tumours on host: local effects, cancer
cachexia, paraneoplastic syndromes.

Neoplasia
Etiology genetic
Neoplasia is defined as: " an abnormal mass of tissue, the
growth of which exceeds and is uncoordinated with that of the
normal tissues and persists in the same excessive manner after
cessation of the stimuli that evoked the change."
Neoplasia has genetic and environmental causes. It is important
to note that both play parts in causing neoplasia.

Genetic evidence of tumourigenesis

1. Introduction of genes (activated oncogenes) in normal
Cells in culture make them transformed (they lose contact
Inhibition Grow in suspension and divide uncontrollably)
2. Transgenic mice/knock-out mice (mice with new oncoGenes Introduced in cells at early embryological stages or
Removing genes from them) have a higher incidence of cancer
3. Patients with familial cancers have siblings with relatively
Higher risk of developing cancer. For example, mutation of
BRCA-1 and BRCA-2 (Breast cancer )genes are linked to
Familial breast and ovarian cancer.
4. Patients with well known inherited cancer syndromes
In which inheritance of a single mutated gene have increased
Risk of developing tumours. A well known example is Familial
Polyposis coli. Patients who inherit mutations in the AdenomaPolyposis coli gene have innumerable polypoid adenomas of
The colon and in 85% of cases are fated to develop colorectal
Carcinoma by age 50 or so.

Neoplasia
Etiology environmental

The environment we live in is filled with cancer causing agents (See Table 1).
Rremarkable difference in the incidence and death rates of specific forms of
Cancer can be found around the world. This can either be explained by differences in the
Genetic make up of different races or more likely that the environment different people live in
Has different carcinogens.
We know that Death from skin cancer (Melanoma) are 6 times more frequent in Australia and
New Zealand (white settlers exposed to the sun) than in Iceland, which is probably attributed
to exposure to the sun. Also, The death rates from stomach cancer in both men and women
In Japan is seven to eight times more common than in Europe or the U.S.A. Why is that? Well
It could be that the Japanese have some small different genetic make up that makes them more
Susceptible to stomach cancer than the Americans but it is more likely that the Japanese are
Exposed to some carcinogens that the Americans are not. So if one studies the incidence of
Cancer in the Japanese Immigrants to the USA and their offspring's one can see that gastric
cancer mortality rates of Japanese immigrants and their offsprings dropped dramatically and
That these immigrants and their offsprings had increased rates of cancers common in the USA
(FIGURE 1). This strongly suggests that environmental factors have a strong role in the
neoplastic process

Neoplasia
Etiology environmental
Table 1: Carcinogenic agents and occupational cancer
Agent

Occupation

Cancer Site

Ionizing radiations
radon

certain underground
miners

bronchus

X-rays, radium

radiologists, radiographers

skin

Radium

luminous dial painters

bone

Ultraviolet radiation

farmers, sailors, etc.

skin

Polycyclic
hydrocarbons in soot

chimney sweepers,oil
workers

scrotum, skin,
bronchus

2-Naphthylamine; 1naph-thylamine

rubber workers

bladder

Benzidine; 4aminobiphenyl

chemical workers

bladder

Asbestos

shipyard and insulation

workers

Mesothelioma lung

Arsenic

sheep dip manufacturers,

gold miners

skin and bronchus

Benzene

workers with glues,

varnishes, etc.

marrow (leukemia

Vinyl chloride

PVC manufacturers

liver (angiosarcoma)

Aflatoxin B1

Food storage. Due to

growth of Aspergillus
flavus (fungi)

Liver

Benzo(a)pyrene

Smokers

Lung

Dont forget the role of viruses and bacteria in Cancer

Neoplasia
Molecular basis of neoplasia
Basic principles
Basic Principles:
Cancer arises from nonlethal genetic damage which can be transmitted to
cell progeny. Most tumors initially develop as monoclonal, arising from a
single mutated cell.
Three kinds of genes are targets for carcinogenic transformation:
1) proto-oncogenes promote cell growth and require the alteration of
only one allele ?to create out of control cellular growth (dominant gene)
2) tumor suppressor genes inhibit cell growth and require the alteration
of both alleles to affect cell growth (recessive oncogenes), DNA repair
genes are similar
3) genes that regulate apoptosis may be dominant or recessive but
influence the ability of the cell to target itself for destruction following cell
damage
Tumor progression refers to the ability of transformed cells to acquire
further abnormal characteristics over time, independent of tumor size.
These include ability to invade, metastatic spread, further anaplasia. It is
believed that these characteristics are acquired through mutations within
the tumor leading to subgroups of cells with varying characteristics. At the
time of diagnosis, most tumors are heterogenous and have multiple cell
lines present. The absence of p53 in many human tumors may contribute
to the increased instability of DNA in tumorus.

Neoplasia
Molecular basis of neoplasia
Oncogenes
ONCOGENES
Proto-oncogenes are normal cellular genes that regulate cell growth, division, and
differentiation. Oncogenes are cancer-causing genes derived from proto-oncogenes
by mutation, retroviral transduction, gene amplification, or dislocations. Oncogenes
occur as transformations of genes that normally regulate expression of growth
factors and receptors, signal transducing proteins, nuclear transcriptions factors, and
cyclins and their associated proteins.
Classes of Oncogenes:
Growth Factors: Genes that encode growth factors may become oncogenic. For
example, cells that produce PDGF may also develop receptors for it and become
permanently turned on via autocrine stimulation. Usually, the PDGF gene (sis) is
normal, but oncogenes such as ras cause PDGF to be overexpressed. Excess growth
factor itself cannot completely transform a cell, but in conditions of excessive growth
and cell division, other mutations become more likely.
Growth Factor Receptors: most are transmembrane proteins that cause
phosphorylation of proteins on the cytoplasmic side when activated. Normally, the
cytoplasmic side gets transiently turned "on" and then rapidly deactivated.
Oncogenic receptors exist in a prolonged "on" state, even in the absence of bound
growth factor. Point mutations in the ret protooncogene (codes for receptor
associated with glial cells) are associated with MEN and familial medullary thyroid
carcinoma. Growth factor receptors may also be overexpressed. c-erb1 codes for an
EGF receptor overexpressed in many squamous cell cas, and HER-2in the adenoca of
the breast, ovary and others.
Signal Transducing Proteins: these proteins exist on the inner plasma membrane
and following activation work to phosphorylate cytoplasmic proteins. Ras, a GTP
cleaving protein receptor associated transducing protein, is the prototype and
mutated versions of the ras proteins are present in 10-20% of human cancers. The
normal GTPase activity of ras protein is accelerated when in association with GAPs
(GTPase-activating proteins). Ras normally works to activate MAP (mitogen activated
protein) kinase that increase nuclear transcription factors. Mutated forms of ras bind
GAP normally, but the GTPase activity of GAP fails to occur.
Translocation of the signal transducing protein (non-receptor associated) c-abl on
chromosome 9 to the bcr region of chromosome 22 activates it to increase cell
growth. This translocation is associated with CML.
Nuclear Transcription Proteins: these proteins influence DNA synthesis in the
nucleus. C-myc, forms a heterodimer with max protein, and the myc-max
combination activates transcription. Mad, a similar protein to myc, may also combine

Neoplasia
Molecular basis of neoplasia
Oncogenes
Methods of Activation of Oncogenes:
1.Point mutations: typical of ras proteins
2. Chromosomal rearrangements: translocation may associate a
growth factor or receptor with an actively transcribed area, or result in
the formation of an active hybrid protein. For example Philadelphia
chromosome c-abl-bcr has hybrid activity
3. Gene Amplification: duplication, multiplication of DNA sequences in
the genome. Associated with N-myc In neuroblastoma and c-erb 2 in
breast cancer.

Neoplasia
Molecular basis of neoplasia
Tumour suppressor genes
Tumor Suppressor Genes
Tumor suppressor genes are normal cell genes that "brake" cell division and cycling at
various point in the cell cycle. They work through similar mechanisms to protooncogenes, through signal transduction, through cell surface receptors and nuclear
transcription regulators.
Suppressor genes are "recessive" and require loss of both copies of the normal before
cancer becomes likely, the "two-hit" model of carcinogenesis. Retinoblastoma models
this behavior and exists as 60% sporadic and 40% familial, but occurs much earlier if
familial. The theory is that both alleles of Rb must be ineffective before tumor
suppression is lost. In the familial forms, all somatic cells have inherited one defective
allele, and only one cell must lose its other allele to become predisposed to produce
tumors. pRb works to prevent cells in G1 from advancing to S phase. This is an
extremely sensitive transition since no further growth factors are required to complete
mitosis following progression into S phase. pRb normally exists in an active,
hypophosphorylated state and when phosphorylated, it releases the brakes and allows
cell division to progress. Most likely, Rb forms tumors in the retina and osteosarcoma
because deletion of both active alleles should trigger apoptosis. But, for reasons not
fully understood, retinoblasts fail to die following transformation.
p53, a protein exclusive to the nucleus, is the most common transformed gene in
human cancer, presenting in over 50% of human tumors. p53, designated "guardian of
the genome," acts in the nucleus to stop replication of damaged cells. Following
damage, p53 gets rapidly up regulated and its accumulation triggers increased
transcription of DNA repair proteins and those that stop the cell cycle. If repair occurs,
the cell cycle resumes. If not, p53 plays a role in triggering apoptosis. Loss of both
normal alleles of p53 causes the cell cycle to continue with the mistakes in DNA
transcription intact.
p73 has recently been discovered and appears to work by similar mechanisms.
Other tumor suppressor genes include NF-1, NF-2, VHL, and WT-1.
Suppressors of apoptosis involved in carcinomas include bcl-2 , which inhibits
apoptosis and is transformed in most B cell lymphomas. Growth arises from decreased
cell death rather than increased cell proliferation. The bax and bad gene accelerates
cell death and opposes bcl-2.
Defective DNA repair genes are implicated in the development of cancers as they
may allow cell division despite mutated DNA. HNPCC (hereditary nonpolyposis colon
cancer) illustrates a cancer associated with defects in DNA repair.

Neoplasia
Molecular basis of neoplasia
Tumour progression/Multistep process of
carcinogenesis
Tumour progression implies the gradual transition of a localised, slow growing
tumour to an invasive, metastatic cancer.
In the past epidemiologists suggested that the age related increase in cancer could be
best explained by postulating that several independent steps were required for
tumourigenesis. It was Vogelstein et al who put a firm a firm molecular footing for
the concept of multistep carcinogenesis. Since colorectal cancer arise in preneoplastic
lesions called adenomas (small polyps), they have used colorectal cancer as a model
to answer the question: Do tumours accumulate genetic mutations (aberrations) as
they progress to cancers? Thus Vogelstein et al (1988). analysed the patterns and
frequencies of four different genetic abnormalities (losses in 5q, 17p, 18q and
mutations of ras genes). In this study, adenomas with different sizes and forms (class
I-III) were compared with carcinomas from different patients in an attempt to
delineate genetic alterations associated with progression of adenomas to carcinomas.
Deletions involving 5q chromosome were found in 29% of class II adenomas and
35% of carcinomas, indicating early involvement of genes on this chromosome arm
in tumour progression. A specific region of chromosome 18q was found to be deleted
in 47% of late adenomas (class III) and 73% of carcinomas, indicating that this
genetic aberration occurred late in the progression sequence. In addition, deletions
involving 17p were most frequent in carcinomas (75%) and were rarely found in
early adenomas. Mutant ras genes were found in 12% of class I adenomas, 42%-57%
of class II-III adenomas respectively and in 47% of carcinomas, indicating that ras
mutation occurs early in the progression sequence. The authors concluded that the
four molecular alterations accumulated in a fashion that paralleled the clinical
progression of tumours and that there appears to be a preferred sequence of genetic
changes that leads to progression in colorectal cancer (Figure 2). The authors also
concluded that it is not the sequential genetic aberration of particular genes in any
given order that is of prime importance, rather it is the overall accumulation of
genetic aberrations (Fearon and Vogelstein, 1990). Thus, while only 9% of class I
adenomas accumulated more than two of the four genetic aberrations, 40% of
carcinomas have accumulated more than two genetic aberrations.
Therefore, as trumours progress to cancer they accumulate more genetic

abnormalities.

Neoplasia
Molecular basis of neoplasia
Tumour progression/Multistep process of
carcinogenesis
Normal
epithelium

Hyperproliferative
epithelium

Early
adenoma

Intermediate
adenoma

Dysplastic
adenoma

Loss of 5q
Mutation and loss of
Adenomatous Polyposis Coli
(APC) gene.

DNA hypomethylation

Mutation of ras genes

Loss of 18q
Loss of Deleted in Colorectal Carcinoma
(DCC) gene

Loss of 17p
Mutation and loss ofTP53
gene

Carcinoma

Other alterations
Metastases

figure2

Neoplasia
Carcinogens/process of carcinogenesis

Carcinogens are agents that have the ability to initiate the formation of cancer. They are divided into 4 groups:

Chemical Carcinogens

Physical Agents

Ionizing Radiation

Oncogenic Viruses
It is useful to remember that 80 - 90% of all cancers may be related to environmental
agents including diets, lifestyles, and viruses.
Several environmental agents often act together (co-carcinogenesis).
Chemical carcinogenesis
It was Sir Percival Pott in 1775 who associated the increased incidence of scrotal skin cancer to chronic
exposure to soot in chimney sweepers. Over the succeeding 2 centures hundreds of chemicals have been
Shown to transform cells in culture and to cause tumours in experimental animals and in humans exposed to
them (Table 1). These chemicals are known as carcinogens and the process by which they cause tumours
Or cancer is called carcinogenesis. Nature has protected cells from these harmful agents (think of some of
these protectors). Therefore, if one Or a group of agents are to produce a neoplasm they have to damage
more than one gene. Thus, the Neoplastic transformation is a progressive process involving
multiple hitsor genetic changes.
Alterations in DNA cause changes in one or both of the following types of genes:

Proto-oncogenes

Tumor suppressor genes

Neoplasia
Carcinogens/process of carcinogenesis
Chemical carcinogenesis
The multistep process involves
1.
Initiation
2.
Promotion
These concepts have arisen from classical experiments performed on mouse skin.

The researchers have shown that initiation results from the exposure of cells to a certain doze of
a carcinogen (initiator). An initiated cell is altered making it more likely to give rise to a tumour
(if exposed to another agent; group 2 and 3 in figure 3). Initiation alone is not sufficient for
tumour formation (group 1). Initiation cause permanent DNA damage (Mutations). Thus it is
rapid irreversible and inheritable (group 3). In this group tumours were produced even if the
application of the promoting agent was delayed for a long period of time after a single
application of the initiator. Initiators can themselves bind and change DNA(direct acting) or
procarcinogens, which require metabolic conversion in vivo to produce ultimate carcinogen

Promoters can induce tumours in initiated cells, but they are non-tumourigenic by themselves
(group 5). Also, tumours do not result when the promoting agent is applied before the initiating
agent (group 4). This indicates that unlike initiating agents, promoting agents do not affect DNA
directly and are reversible (group 6).

Figure 3

Neoplasia
Carcinogens/process of carcinogenesis
Chemical carcinogenesis
IN SUNNARY
Initiation
Results from interaction of chemical with DNA to activate a proto-oncogene or
inactivate a tumor suppressor gene by formation of covalent adducts.
Chemicals that can form adducts (direct acting) are usually electrophiles.
Many chemical carcinogens require activation by metabolic pathways (procarcinogens or indirect acting carcinogens) an example of a metabolic pathway is
the p-450 cytochrome mono-oxygenase.
Initiation alone does not result in tumours.
Promotion
Promotors are usually irritants or substances that produce cell activation and
proliferation.
Effects of promotors are reversible.
Promotors cannot induce neoplasia: i) alone, ii) if applied before initiator, iii) if
applied in too small an amount for effect, or iv) if too much time elapses between
applications.

Neoplasia
Carcinogens/process of carcinogenesis
other carcinogenesis
Ultraviolet Light
Strong epidemiologic relationship to squamous cell, basal cell, and melanocarcinoma in fair skinned people.
Causes formation of pyrimidine dimers in the DNA leading to mutations.
Activation of T-suppressor cells facilitates emergence of tumor clones.
Individuals with defects in the enzymes that mediate DNA excision-repair are
especially susceptible.
Ionizing Radiation
Ionizing radiation includes: X-rays, gamma rays, as well as particulate radiation;
alpha, beta, positrons, protons, neutrons and primary cosmic radiation.
All forms are carcinogenic with special sensitivity in:
Bone Marrow: Acute leukemia occurs before other radiation-induced
neoplasia (Seven year mean latent period in atomic bomb survivors).
Thyroid: Carcinoma occurs in 9 % of those exposed during infancy or
childhood.
Lung: Increased frequency of lung cancer in miners exposed to Radon gas
(an alpha particle emitter).
Viral Carcinogenesis

A large number of RNA and DNA viruses have been implicated in the causation of a variety of
cancers in animals and humans some important ones are listed below.

Human papiloma virus (HPV). There are more than 70 types of these DNA viruses. HPV types
16, 18
and 31 are associated with precancerous and invasive squamous cancer of the cervix.

Epstein-Barr Virus (EBV) is a member of the Herpes family. It is associated with 4 types of
human cancers:
1.
African Burkitt lymphoma
2.
B-cell Lymphoma (particularly in immunosuppressed individuals)
3.
Hodgkin lymphoma
4.
Nasopharyngeal carcinoma

Hepatitis B virus is associated with increased risk of developing hepatocellular carcinoma

RNA viruses like Human T-Cell Leukemia Virus Type 1 (HTLV) is associated with some forms
Of T-Cell leukemia/Lymphoma.

Neoplasia
Cancer Invasion
What really distinguishes benign tumours from malignant cancers is the ability of cancer to invade and
matastasise.

Malignant Neoplasms grow by progressive infiltration, invasion, destruction, and penetration of the
surrounding tissue
Do not develop capsules
This is why surgeons do Wide Excisions
For a cancer cell to invade it has to:
Detachment from other tumor cells.
Adhesion to the extracellular matrix.
Proteolytic degradation of the extracellular matrix.
Motility and migration into the extracellular matrix.
This process requires a number of genes to be activated. The extracellular matrix
is a thick environment rich in collagen, glycoproteins and proteiglycans. Cells have
to detach from the tumour mass and they can do that by reducing the cell-cell
adhesion molecules on their surface (like E-Cadherins and others). They then have
to adhere to proteins in the extracellular matrix by producing molecules on the
surface called Integrins. Cells then can move towards rich sources of growth
factors in a process called chemotaxis. But there are still a lot of tightly packed
molecules and polymers in the Extracellular matrix so the cancer cell also secret
proteolytic molecules called (matrix metallo-proteases, serine and cysteine
proteases to degrade the extracellular matrix). This process also release some
growth factors hidden in the extracellular matrix.
Cell-Extracellular matrix adhesion molecules
involved in invasion and metastasis
Integrins: A family comprising many heterodimeric
cell-surface molecules that mediate cell adhesion to
different extracellular matrix molecules.
Laminin receptors
CD44: Mediates tumor cell attachment to hyaluronate.

Neoplasia
Cancer Invasion
Cancer Invasion

Neoplasia
Cancer metastasis

Metastasisisdefinedasthedevelopmentofsecondaryimplantsdiscontinuouswiththe
primaryMalignantneoplasmandpossiblyinremotetissues.Oncemetastasesaredetecteda
curebecomesdifficultifnotimpossible.Also,patientssurvivaldramaticallydropsifmetastases
arepresent.
Cancersspreadbythreeways:
1.
Directspreadintonaturalcavities.Suchasperitoneum,pleura,etc
2.
Lymphaticspread(vialymphaticvessels)
3.
Haematogenousspread(viaveins)Whynotarteries??
Metastasis is a multi-step process (Figure 4). A selected clone of cells growing in the primary tumour has to
detach from the tumour mass and invade through a thick layer of connective tissue known as the basement
membrane (BM). This process involves the production of a collection of proteolytic enzymes capable of
destroying collagen type IV and other proteins and carbohydrate polymers, which are the main constituents of
the BM. This process was discussed in invasion section. The metastatic cells then reach blood or lymphatic
vessels by which they are transported to distant sites. The tumour cells then extravasate from the vessels to
colonize distant organs as micrometastases. Metastasis is therefore a complex process involving multiple
steps and requiring the expression of multiple unrelated genes. Metastasis is an inefficient process. Metastatic
tumour cells are typically cleared from the host biphasically. The initial phase (6-24 hours), represents an
exponential decline of cell numbers due to mechanical trauma, oxygen toxicity and clearance by the immune
system. The second more gradual decline phase represents cell death at colonized sites (Weiss, 1990).
However, recent evidence from intravital videomicroscopy, have strongly proposed that the major cause of
metastasis inefficiency is failure of cells to grow in distant sites post-extravasation (Chambers et al., 1995;
Koop et al., 1996). Metastasis is therefore a complex process involving multiple steps and requiring the
expression of multiple unrelated genes.
Metastasis is an inefficient process. Metastatic tumour cells are typically cleared from the host biphasically.
The initial phase (6-24 hours), represents an exponential decline of cell numbers due to mechanical trauma,
oxygen toxicity and clearance by the immune system. The second more gradual decline phase represents cell
death at colonized sites (Weiss, 1990).
The liver represents the major site for metastasis in gastrointestinal cancers. However, metastasis to the lung,
brain and bone is not uncommon. Haemodynamic considerations could explain the involvement of the liver
in the majority of metastases, since the liver represents the first capillary bed encountered by metastatic
gastrointestinal cancer cells. Similarly, tumours in the lower rectum are more likely to metastasize to the lung
since the lower rectum principally drains into the systemic circulation via the inferior vena cava. Although
haemodynamic distribution contributes to the formation of metastases by mechanical trapping, it fails to
account for liver, instead of the expected lung, colonization after intravenous injections of tumour cells in
mice. The preference to metastasize to specific organs is well documented. Indeed, this 'soil phenomenon'

Neoplasia
Cancer metastasis

Figure 4

Adhesion to endothelial cells

Tumour cells express E-Selectins
Molecules that bind to
Sialyl-Lewis X on endothelial cells

Neoplasia
Cancer metastasis

Multiple Liver
Metastases

Facts about metastasis

Directspread
CanceroftheColoninvadesthepericolonicfatandbreaksfreeintotheperitonealcavity
CanceroftheOvaryisanotherbigperitonealspreader
Cancerinvolvementofcavitiestendstoproducehaemorrhagiceffusion,adhesions
LymphaticSpread
Moretypicalofcarcinomasratherthansarcomas(hematogenous)e.gBreast,stomach,
Papillarythyroidcarcinoma
Cancercellstravelinlymphaticsandreachregionallymphnodes.Theygetarrested,die
orgrowortraveltoothernodes
RegionalLymphnodesdrainingthecancerareaarefirstinvolved
ItistherationaleforlymphnodedissectioninmanyCarcinomas.Thelymphnodesinthe
specimenareenlargedandfirm.
HematogenousSpread

SarcomaspredominatebutCarcinomasalsousethisrout

Arteriesarerarelyinvaded

Veinsaretherouteofhematogenousspread

LiverandLungsaretheusualendpointsofhematogenousspread,butrememberthat
metastasescanalsometastasise.

Portalflowtoliverandvenacavalflowtolungs

RenalCellCahasapropensitytoinvadetherenalveinandhepatocellularcancerhasa
tendencytopenetrateportalandhepaticradicles.

Thedistributionofmetastasesfollowtheanatomicaldistribution.Thus,breastcancerinthe
upperouterquadrantislikelytometastasisetotheaxillarylymphnodes,whileaupper
innerbreastcancer(medial)tendstometastasisetosupraclavicularlymphnodes.Colon
cancertendstometastasisetoLiverwhilecancersofthelowerrectumtendstometastasise
tothelungasdescribedearlier.

Prostatecancerprefertometastasisetobone

Bronchogeniccancertendstoinvolveadrenalsandbrain

Neuroblastomaspreadtoliverandbones.

WhydosomecancersmetastasisetocertainorgansandotherorganssuchasSkeletal
muscleandspleenarerarelyinvolved???

Neoplasia
Cancer grading and staging

Grading and staging tumours are important because of their clinical relevance and so that different
clinicians know how to standardise, plan and organise patients treatment.
Grading is based on the degree of differentiation and the number of mitosis within a tumour.
Cancers are classified as grades I to IV with increasing metaplasia. In general, Higher-grade tumours
are more aggressive than lower grade tumours. It is important to note that within the same tumour
Some cells have different grades and this is because of tumour progression. Thus tumour grade
could change as the tumour grows.
Staging is based on the anatomic extent of the tumour.
In 1932 Cuthbert Dukes described a system for staging rectal cancer. The staging system associated the
clinical-pathological behaviour of rectal tumours with prognosis (Figure 5). When the tumour is
confined entirely within the wall of the bowel (Dukes A) more than 90 % of patients can be cured by
surgery alone. Penetration through the muscularis propria (Dukes B) worsens the prognosis, and
when there is metastasis to the lymph nodes (Dukes C) the outlook deteriorates further so that twothirds of the affected patients die of the disease within five years. When distant metastases to the liver
are present (Dukes' D) most patients will die by the end of the first year (Dukes, 1932).
Currently, two of staging are used: the TNM (Tumour, Node, Metastases) and the American Joint
Committee (AJC) systems. Both systems use the primary tumour size, extent of invasion and number
of Lymph nods involved with the tumour and the presence or absence of distant metastases as factors
relevant to prognosis.
5-Years survival %

>90

T1N0M0

85-75

70

65-35

T2-3N0M0 T4N0M0 T2N1M0 T3-4N1M0

<5

TXNXM1

Mucosa
Submucosa
Muscularis Propria
Serosa
Lymph nodes

B1
B2

B3

C1
C2
Metastasis
Liver
Lung
Brain
Bone

Primary tumor (T)

T0
T1
T2

No evidence of primary tumor

Tumor <5 cm
Tumor >5 cm

Lymph nodes (N)

N0
N1

No regional metastasis
Regional node metastasis

Distant metastasis (M)

M0
M1

No distinct metastasis
Distant metastasis

Histopathalogic grading (G)

G1
G2
G3
G4

Well differentiated (low grade)

Moderately differentiated (intermediate grade)
Poorly differentiated (high grade)
Undifferentiated

American Joint
Committee on Cancer
AJCC of soft tissue
sarcomas classification
Stage
IA
IB
IIA
IIB
IIIA
IIIB
IVA
IVB

G1
G1
G2
G2
G3
G4
G3
G4
Any G
Any G

T1
T2
T1
T2
T1
T1
T2
T2
Any T
Any T

N0
N0
N0
N0
N0
N0
N0
N0
N1
Any N

M0
M0
M0
M0
M0
M0
M0
M0
M0
M1

Neoplasia
Tumour effects on Host

Tumours can effect the host in the following ways:

Local Effects

Finger
Clubbing

Cancer Cachexia
Paraneoplastic Syndromes
Endocrinopathies
Neuromyopathies
Osteochondral Disorders
Vascular Phenomena
Fever
Nephrotic Syndrome

Local Effects
Tumor Impingement on nearby structures
Pituitary adenoma on normal gland, Pancreatic carcinoma on bile duct, Esophageal
carcinoma on lumen
Ulceration/bleeding
Colon, Gastric, and Renal cell carcinomas. Patient presents with anaemia.
Infection (often due to obstruction)
Pulmonary infections due to blocked bronchi (lung carcinoma), Urinary infections
due to blocked ureters (cervical carcinoma)
Rupture or Infarction
Ovarian, Hepatocellular, and Adrenal cortical carcinomas; Melano-carcinoma
metastases

Neoplasia
Tumour effects on Host

Cachexia
Cachexia is seen in advanced ca and includes body wasting, weakness, anorexia, and
anemia. It is *not* caused by the tumor's nutritional needs, although the larger the
tumor, the worse it is. Both fat and protein are consumed equally. Cause unknown, but
some relation to Tumour necrosis factor alpha (TNF-alpha) and perhaps to a newly
isolated protein-mobilizing factor, which, when injected into healthy mice causes rapid
weight loss despite maintenance of caloric intake.

Paraneoplastic Syndromes
Cushings Syndrome

Adrenal carcinoma (cortisol) more common with benign adrenal processes.

Small cell undifferentiated lung cancer (ACTH) released through cleavage of pro-opiomelano-cortin
gene product.
Inappropriate ADH syndrome (Hyponatremia)
Small cell undifferentiated lung cancer (vassopressin-like hormone.
Hypothalamic tumors (vasopressin)
Hypercalcemia Hypercalcemia arises from either osteolysis by primary tumors or
production of PTHrP that may act as PTH at various sites. Hypercalcemia is especially
associated with carcinomas of breast, kidney, ovary, and squamous cell ca of the
lung.
-Squamous cell lung cancer (PTH-like peptide)
Renal cell carcinoma (prostaglandins)
Parathyroid carcinoma (PTH)
Multiple myeloma and T-cell lymphoma (IL-1 and perhaps TNF-a)
Breast carcinoma, usually by bone metastasis
Disseminated intravascular coagulation , migratory thrombophlebitis,
neuromyopathies are also associated with various forms of advanced cancer.