epidemology of cancer

1. CHARACTERISTIC FEATURES OF TUMOR
&
EPIDEMIOLOGY OF CANCERS
LEARNING OBJECTIVES
By the end of the lecture, the student should be able to know:
•Growth phases of malignant cancer
•Dysplasia and carcinoma-in-situ
•Functional capabilities of benign and malignant tumours
•Growth factors and rate and clinical implications
•Local invasion of benign and malignant tumours
•Pathways of spread, seeding, lymphatic and haematogenous spread
•Invasion of extracellular matrix
•Cancer incidence in males and females of different cancers in
Pakistan
•Commonest tumors in different ages
•Epidemiological factors namely environment factors, age, genetic
predisposition, chronic disease
•Precancerous conditions and non-hereditary predisposing
conditions leading to cancers.
BIOLOGY OF TUMOUR GROWTH
Natural history of malignant tumours divided in 4 phases:
•Malignant change in target cells (transformation)
•Growth of the transformed cells
•Local invasion
•Distant metastasis
DIFFERENTIATION AND ANAPLASIA
•‘Differentiation’ refers to the extent to which neoplastic cells
resemble comparable normal cells, both morphological and
functionally
•Lack of differentiation is called ‘Anaplasia’
•Well-differentiated tumour closely resembles normal cell – poorly
differentiated least
•Benign tumours, well-differentiated, example leiomyoma, a nodule
composed of normal looking SMC

2. DIFFERENTIATION AND ANAPLASIA
MALIGNANT NEOPLASMS:
• Range from well to poorly differentiated
•Mostly composed of undifferentiated cells (Anaplastic)
•Derived from proliferation with complete maturation of transformed
cells
•Lack of differentiation marked by morphologic changes –
pleomorphism, abnormal cell morphology, mitosis, loss of polarity,
other changes
PLEOMORPHISM
•Both cells and nuclei display variation in size & shape
•Anisocytosis – variation in size
•Poikilocytosis – variation in shape
ABNORMAL NUCLEAR MORPHOLOGY
•Nuclei contain abundant DNA, hyperploidy or polyploidy,
hyperchromasia (dark staining)
•Nuclei disproportionately large
•Variable nuclear shapes
•Nucleoli – prominent, multiple
MITOSIS
•As compared to benign tumours, malignant neoplasms have large
number of mitosis
•High mitosis – not necessarily a sign of malignancy
•In malignancy – atypical, bizarre mitosis; tripolar, quadripolar or
multipolar spindle
LOSS OF POLARITY
•Loss of normal orientation of cells to each other
•Cells grow in anarchic, disorganised fashion, sheets, groups, cords
•Eg. – dysplasia in epithelia, carcinoma – in – situ
DYSPLASIA
•Disorganised growth, loss of uniformity of individual cells as well as
their architectural orientation

3. •Dysplastic cells show considerable pleomorphism, hyperchromasia
and mitosis
•May be a pre-neoplastic condition, mild, moderate, severe
CARCINOMA IN SITU
•Dysplastic changes involving the full thickness of epithelium
•Lesion confined to normal tissue / epithelium, BM not breached
•A pre-invasive neoplasm: when BM breached, tumour invasive
OTHER CHANGES
•Tumour giant cells, may contain single large nuclear or multiple
nuclei, different from benign giant cells
•Areas of ischaemic, coagulative necrosis
FUNCTIONAL CAPABILITIES
•Benign and well-differentiated malignant tumours retain functional
capabilities, poorly differentiated do not
•Benign / well-differentiated tumours of endocrine glands may
produce hormones, well-differentiated SCC keratin, HCC – bile
•Poorly differentiated lose morphological as well as functional
resemblance to cells, elaboration of foetal proteins (&FP, CEA),
ectopic hormones
RATE OF GROWTH
•Understanding of factors influencing rate of growth of fundamental
importance in clinical outcome and therapeutic response
•Influenced by many factors
•Depends upon cells in proliferative pools, and those lost to non-
proliferative pool
•Variable, may depend upon hormones, some may become dormant,
slow growth, sudden spurts and spread widely
GROWTH RATE
Determined by 3 factors:
•Doubling time of tumour cells
•Fraction of cells in replicative pool

4. •Rate at which cells are shed / lost in growing lesion
GROWTH FRACTION
•Proportion of cells in proliferative pool referred as growth fraction
•In early phase, vast majority in proliferative pool due to shedding,
lack of nutrients, apoptosis, differentiation, enter GO phase
•Even in rapidly growing, growth fraction may be only 20%
ESTIMATION
•Study of histological sections
•Incorporation of tritrated thymidine
•Calculation by Brdu
•Immunohistochemistry – K67, MIBI, PNCA
•Flow cytometry
GROWTH RATE – CLINICAL IMPLICATIONS
•Fast growing tumors have high cell turnover, however the rate of
proliferation higher than loss
•Profound effect on cancer chemotherapy, most chemotherapeutic
agents act on cells during mitosis
•Some previously aggressive tumors (lymphomas) virtually melt away
•Well-differentiated, slow growing may not respond as well
LOCAL INVASION BENIGN TUMOURS
•Most grow as cohesive masses, remain localised
•Slow growth and expansion, rim of compressed CT around – capsule
•Benign tumours remain discrete, readily palpable and movable due
to capsule, cleavage plane, easily removed by surgery
•Exceptions – haemangioma, neurofibromas, pleomorphic adenoma
LOCAL INVASION MALIGNANAT TUMOURS
•Growth accompanied by progressive infiltration, invasion and
destruction of surrounding tissue
•Poorly demarcated, no capsule, no cleavage plane
•Slowly growing may develop pseudocapsule, micro invasion
•Invasive, penetrate wall of organs to project in a cavity or surface,
resection only with wide margin
•Metastasis and invasion – most reliable features of malignancy

5. METASTASIS
•Tumour implants discontinuous with primary tumour
•Metastasis unequivocally marks a tumour as malignant
•Invasion of local tissue, BV, lymphatics permit tumour to spread,
exception - glial tumour of CNS, BCC, locally invasion only
•More aggressive and rapidly growing tumours generally metastasise
early, unpredictable
•30% metastasised by diagnosis, make cure difficult
PATHWAYS OF SPREAD
3 Pathways:
• Seeding of body cavities and surface
• Lymphatic spread
• Haematogenous spread
SEEDING OF BODY CAVITIES & SURFACES
•Tumors which penetrate into natural open fields may spread through
them
•Peritoneal, pleural, pericardial, subarachnoid and joint spaces
involved
•CA stomach involving ovaries – Krukenberg tumors
•Ovarian carcinomas involving peritoneal cavity, tumor implants,
pseudomyxoma peritonei
LYMPHATIC SPREAD
•Common pathway for initial dissemination of carcinomas, sarcomas
may also employ this route
•Through lymphatics at periphery of tumour mass, many connections
between lymphatics and BV
•Pattern of lymph node involvement follow natural route of drainage
•Different quadrants of breast to various groups of nodes, from lung
to perihilar, tracheobronchial and mediastinal, skip lesions

6. LYMPHATIC SPREAD
•In breast cancer – assessment of nodal involvement important for
staging, management
•Previously by surgical dissection of axilla, associated with morbidity
and mortality
•Sentinel lymph node assessment (1st LN in a regional lymphatic
basin that receives lymph from a primary tumours), mapping by
injection of radiotracer or blue dye
•Sentinel LN assessment being done in other tumours also,
melanoma, colon cancer
LYMPHATIC SPREAD
•LN serve as effective barriers, eventually broken and further spread
•LN enlargement not necessary due to tumour spread
•May be due to reactive hyperplasia or metastasis, assessment by
histopathology
HAEMATOGENOUS SPREAD
•Disorganised growth, loss of uniformity of individual cells as well as
their architectural orientation
•Dysplastic cells show considerable pleomorphism, hyperchromasia
and mitosis
•May be a pre-neoplastic condition, mild, moderate, severe
INVASION / METASTASIS - PATHOGENESIS
•Hallmark of malignancy tumours, major cause of cancer related
morbidity and mortality
•Many steps involved in process of invasion and metastasis
•Millions of cells released from primary tumour, only a few produce
metastatic deposits
•Multiple views; subclones or metastatic signature, stromal response
•Two major steps – invasion of ECM and vascular dissemination /
homing of tumour cells

7. INVASION OF ECM
•Interaction of cells and ECM vital to function and structural
organization of tissues
•ECM composed of collagens, glycoproteins and proteoglycans
•Tumours cells to interact with various components of ECM during
process of invasion / metastasis
INVASION OF ECM - STEPS
•Detachment of tumour cells from each other
•Attachment to matrix components
•Degradation of ECM components
•Migration of tumour cells
INVASION OF ECM - MECHANISM
•Normal cells glued to each other by adhesion molecules – cadherins
•E-cadherin mediates homotypic adhesion between epithelial cells
•Downregulation of E-cadherin molecules in adenocarcinomas of
colon and breast results in loosening of tumour cells
•Attachment to BM by laminin and fibronectin receptors
•Enzymatic degradation of ECM by proteases, by tumour cells and
host cells
INVASION OF ECM - MECHANISM
•Proteases – serine, cysteine and matrix metaloproteases (MMP),
balance of MMP & TIMP
•Pathway created in ECU for passage of tumor cells
•Cleavage products of ECU act as growth promoting, angiogenic and
chemotactic factors
•Inhibition of collagenase activity by TIMP by transfection with gene
reduces metastasis, could be of value in treatment of cancer
VASCULAR DISSEMINATION
•Once in circulation, vulnerable to destruction by immune

8. mechanisms
•In vessels tumors tend to clump, by homotypic adhesion and
platelets
•Platelet tumor aggregate formation enhance tumor cell survival and
implantibility
EPIDEMIOLOGY
•Study of cancer patterns in populations important
•Patterns of various tumours differ substantially in various parts of
world
•May contribute substantially to find the origin of cancers
•Epidemiological studies relating to environmental, hereditary or
cultural influences
•Certain diseases associated with increased risk of cancer
CANCER INCIDENCE
•An individuals likelihood of developing a cancer expressed by
national incidence and mortality rates
•In USA 0.5 million deaths in 2003 – 23% of all mortality rate, in USA
everyone has 1 in 5 chance of dying of cancer
•In USA 1 million readily curable cancer of skin, 0.1 million in-situ
•Age – adjusted death rates in populations have changed over years
•7:23 - two half - Pakistan data
GEOGRAPHIC FACTORS
•Remarkable differences in incidence / death rates around world
•CA stomach 7-8 times higher in Japan than USA, CA lung death rate
twice in USA than Japan
•Skin cancer more frequent in New Zealand and Iceland
•Environmental influences supreme
•Cancer mortality rates immigrant Japanese to USA, 1st generation
intermediate, second generation closer

9. INCIDENCE OF CANCER IN MALES IN NORTHERN PAKISTAN
(1992-2001)
S.No Site Percentage
1. Prostrate 9.44
2. Skin 8.38
3. Lymph node 8.35
4. Leukemia 7.83
5. Urinary bladder 7.66
6. Colorectal 6.37
7. Bone 4.40
8. Lung 3.75
9. Stomach 3.24
10. Liver 2.81

10. INCIDENCE OF CANCER IN FEMALES IN NORTHERN PAKISTAN
(1992-2001)
S.No Site Percentage
1. Breast 26.04
2. Skin 8.50
3. Leukemia 4.91
4. Ovary 4.78
5. Colorectal 3.85
6. Lymph node 3.28
7. Bone 3.25
8. Liver 2.81
9. Cervix 2.69
10. Gall bladder 2.49

12. ENVIRONMENTAL FACTORS
•Carcinogenecity of UV rays
•Asbestos, vinyl chloride etc as occupational hazards
•Risks due to lifestyle, personal exposure (dietary)
•Overweight / obesity – 52 – 62% higher death rate due to cancer
•Alcohol abuse, cigarette smoke, hepatitis B/C and aflatoxins
AGE
•Important influence on likelihood of cancer
•Children, mostly due to genetic factors, 10% of all deaths, more
common neuroblastoma, wilm’s tumor, acute leukaemia,
rhabdomyosarcoma
•Main cause of death 50 – 80 years, more environmental, with ageing
populations incidence likely to rise in these age groups
GENETIC PREDISPOSITION
•Environmental influence important, 10% cancer patients have
inherited mutations predisposing to cancer
•For some specific tumour frequency low (0.1%)

13. •Recognition had important impact on understanding of cancers
GENETIC PREDISPOSITION
Autosomal Dominant Inherited Cancer Syndromes :
•Inherited mutation in tumour suppressor gene, point mutation
•Examples; 40% retinoblastoma inherited, bilateral involvement, later
osteosarcoma
• Familial adenomatous polyposis, inherit APC – tumour suppressor
gene, 100% develop cancer by 50 years
•Others; Li-Franmeni syndrome (p53 mutation), MEN-1 and MEN-2,
hereditary nonpolyposis colon cancer (HNPCC)
GENETIC PREDISPOSITION
Defective DNA Repair Syndromes :
•Defects in DNA repair and resultant DNA instability
•Autosomal recessive pattern
•Examples; Xeroderma pigmentosum, ataxia telangiectasia, Bloom
syndrome, HNPCC
GENETIC PREDISPOSITION
Familial Cancer :
•Certain families have high cancer susceptibility, mostly without
defined pattern of transmission
•Virtually all sporadic cancer have also been reported in familial forms
•Features of familial cancers – early age of onset, multiple or bilateral
tumors, arising in two or more close relatives
•BRAC 1 and BRAC 2 mutations have high incidence of breast,
ovarian cancer, familial melanomas
GENETIC PREDISPOSITION
Interaction between Genetic and non-genetic
factors :

14. •Interaction between heredity and environmental factors complex
•Multi contributory genes involved
•Even in hereditary cancers great influence of non-genetic factors
•Genotype can influence the development of environmentally induced
cancers, cigarette smoking
NONHEREDITARY PREDISPOSING CONDITIONS
•Every one alive at risk, greater risk in certain conditions
•Certain clinical conditions important, wherever cell replication
involved; regenerative, hyperplastic and dysplastic proliferations
provide fertile soil and cancer
•Examples; endometrial hyperplasias cervical dysplasias, bronchial
mucosal metaplasia, cirrhosis
CHRONIC INFLAMMATION AND CANCER
•Potential relationship between Ch inflammation long proposed (1863
– Virchow)
•IDB, H.pylori gastritis, viral hepatitis, Chronic pancreatitis
•Precise mechanism not established
•Proposed mechanism; cytokines stimulating growth of transformed
cells, increased pool of stem cells, genomic instability by ROS
PRECANCEROUS CONDITIONS
• Certain non-neoplastic conditions have well-defined with cancers
• Chronic atrophic gastritis, chronic ulcerative colitis; leukoplakia of oral
cavity, vulva, penis
• Villous adenoma of colon-50%
• Rarely in benign tumors, mostly cancer arise de-novo
REFERENCES
•Pathologic basis of disease
•Robbins & Cotran

15. •8th edition
•Ch. 7, Neoplasia
•Pgs. # 262-276
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