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CHARACTERISTIC FEATURES OF TUMOR                              &                  EPIDEMIOLOGY OF CANCERS                  ...
DIFFERENTIATION AND ANAPLASIAMALIGNANT NEOPLASMS:• Range from well to poorly differentiated•Mostly composed of undifferent...
•Dysplastic cells show considerable pleomorphism, hyperchromasiaand mitosis•May be a pre-neoplastic condition, mild, moder...
•Rate at which cells are shed / lost in growing lesion                          GROWTH FRACTION•Proportion of cells in pro...
METASTASIS•Tumour implants discontinuous with primary tumour•Metastasis unequivocally marks a tumour as malignant•Invasion...
LYMPHATIC SPREAD•In breast cancer – assessment of nodal involvement important forstaging, management•Previously by surgica...
INVASION OF ECM•Interaction of cells and ECM vital to function and structuralorganization of tissues•ECM composed of colla...
mechanisms•In vessels tumors tend to clump, by homotypic adhesion andplatelets•Platelet tumor aggregate formation enhance ...
INCIDENCE OF CANCER IN MALES IN NORTHERN PAKISTAN                      (1992-2001)S.No           Site       Percentage 1. ...
INCIDENCE OF CANCER IN FEMALES IN NORTHERN PAKISTAN(1992-2001)S.No            Site       Percentage 1.    Breast          ...
ENVIRONMENTAL FACTORS•Carcinogenecity of UV rays•Asbestos, vinyl chloride etc as occupational hazards•Risks due to lifesty...
•Recognition had important impact on understanding of cancers                  GENETIC PREDISPOSITIONAutosomal Dominant In...
•Interaction between heredity and environmental factors complex•Multi contributory genes involved•Even in hereditary cance...
•8th edition•Ch. 7, Neoplasia•Pgs. # 262-276             -------------------------THE END------------------------
Tumors
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Tumors

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Tumors

  1. 1. CHARACTERISTIC FEATURES OF TUMOR & EPIDEMIOLOGY OF CANCERS LEARNING OBJECTIVESBy 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 inPakistan•Commonest tumors in different ages•Epidemiological factors namely environment factors, age, geneticpredisposition, chronic disease•Precancerous conditions and non-hereditary predisposingconditions 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 cellsresemble comparable normal cells, both morphological andfunctionally•Lack of differentiation is called ‘Anaplasia’•Well-differentiated tumour closely resembles normal cell – poorlydifferentiated least•Benign tumours, well-differentiated, example leiomyoma, a nodulecomposed of normal looking SMC
  2. 2. DIFFERENTIATION AND ANAPLASIAMALIGNANT NEOPLASMS:• Range from well to poorly differentiated•Mostly composed of undifferentiated cells (Anaplastic)•Derived from proliferation with complete maturation of transformedcells•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 largenumber of mitosis•High mitosis – not necessarily a sign of malignancy•In malignancy – atypical, bizarre mitosis; tripolar, quadripolar ormultipolar 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 astheir architectural orientation
  3. 3. •Dysplastic cells show considerable pleomorphism, hyperchromasiaand 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 multiplenuclei, different from benign giant cells•Areas of ischaemic, coagulative necrosis FUNCTIONAL CAPABILITIES•Benign and well-differentiated malignant tumours retain functionalcapabilities, poorly differentiated do not•Benign / well-differentiated tumours of endocrine glands mayproduce hormones, well-differentiated SCC keratin, HCC – bile•Poorly differentiated lose morphological as well as functionalresemblance to cells, elaboration of foetal proteins (&FP, CEA),ectopic hormones RATE OF GROWTH•Understanding of factors influencing rate of growth of fundamentalimportance 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 RATEDetermined by 3 factors:•Doubling time of tumour cells•Fraction of cells in replicative pool
  4. 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 ofproliferation higher than loss•Profound effect on cancer chemotherapy, most chemotherapeuticagents 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 dueto capsule, cleavage plane, easily removed by surgery•Exceptions – haemangioma, neurofibromas, pleomorphic adenoma LOCAL INVASION MALIGNANAT TUMOURS•Growth accompanied by progressive infiltration, invasion anddestruction 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. 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 metastasiseearly, 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 throughthem•Peritoneal, pleural, pericardial, subarachnoid and joint spacesinvolved•CA stomach involving ovaries – Krukenberg tumors•Ovarian carcinomas involving peritoneal cavity, tumor implants,pseudomyxoma peritonei LYMPHATIC SPREAD•Common pathway for initial dissemination of carcinomas, sarcomasmay also employ this route•Through lymphatics at periphery of tumour mass, many connectionsbetween lymphatics and BV•Pattern of lymph node involvement follow natural route of drainage•Different quadrants of breast to various groups of nodes, from lungto perihilar, tracheobronchial and mediastinal, skip lesions
  6. 6. LYMPHATIC SPREAD•In breast cancer – assessment of nodal involvement important forstaging, management•Previously by surgical dissection of axilla, associated with morbidityand mortality•Sentinel lymph node assessment (1st LN in a regional lymphaticbasin that receives lymph from a primary tumours), mapping byinjection 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 byhistopathology HAEMATOGENOUS SPREAD•Disorganised growth, loss of uniformity of individual cells as well astheir architectural orientation•Dysplastic cells show considerable pleomorphism, hyperchromasiaand mitosis•May be a pre-neoplastic condition, mild, moderate, severe INVASION / METASTASIS - PATHOGENESIS•Hallmark of malignancy tumours, major cause of cancer relatedmorbidity and mortality•Many steps involved in process of invasion and metastasis•Millions of cells released from primary tumour, only a few producemetastatic deposits•Multiple views; subclones or metastatic signature, stromal response•Two major steps – invasion of ECM and vascular dissemination /homing of tumour cells
  7. 7. INVASION OF ECM•Interaction of cells and ECM vital to function and structuralorganization of tissues•ECM composed of collagens, glycoproteins and proteoglycans•Tumours cells to interact with various components of ECM duringprocess 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 ofcolon 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 andhost 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 andchemotactic factors•Inhibition of collagenase activity by TIMP by transfection with genereduces metastasis, could be of value in treatment of cancer VASCULAR DISSEMINATION•Once in circulation, vulnerable to destruction by immune
  8. 8. mechanisms•In vessels tumors tend to clump, by homotypic adhesion andplatelets•Platelet tumor aggregate formation enhance tumor cell survival andimplantibility EPIDEMIOLOGY•Study of cancer patterns in populations important•Patterns of various tumours differ substantially in various parts ofworld•May contribute substantially to find the origin of cancers•Epidemiological studies relating to environmental, hereditary orcultural influences•Certain diseases associated with increased risk of cancer CANCER INCIDENCE•An individuals likelihood of developing a cancer expressed bynational incidence and mortality rates•In USA 0.5 million deaths in 2003 – 23% of all mortality rate, in USAeveryone 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 ratetwice in USA than Japan•Skin cancer more frequent in New Zealand and Iceland•Environmental influences supreme•Cancer mortality rates immigrant Japanese to USA, 1st generationintermediate, second generation closer
  9. 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 3.2410. Liver 2.81
  10. 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
  11. 11. 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, morecommon neuroblastoma, wilm’s tumor, acute leukaemia,rhabdomyosarcoma•Main cause of death 50 – 80 years, more environmental, with ageingpopulations incidence likely to rise in these age groups GENETIC PREDISPOSITION•Environmental influence important, 10% cancer patients haveinherited mutations predisposing to cancer•For some specific tumour frequency low (0.1%)
  12. 12. •Recognition had important impact on understanding of cancers GENETIC PREDISPOSITIONAutosomal Dominant Inherited Cancer Syndromes :•Inherited mutation in tumour suppressor gene, point mutation•Examples; 40% retinoblastoma inherited, bilateral involvement, laterosteosarcoma• Familial adenomatous polyposis, inherit APC – tumour suppressorgene, 100% develop cancer by 50 years•Others; Li-Franmeni syndrome (p53 mutation), MEN-1 and MEN-2,hereditary nonpolyposis colon cancer (HNPCC) GENETIC PREDISPOSITIONDefective DNA Repair Syndromes :•Defects in DNA repair and resultant DNA instability•Autosomal recessive pattern•Examples; Xeroderma pigmentosum, ataxia telangiectasia, Bloomsyndrome, HNPCC GENETIC PREDISPOSITIONFamilial Cancer :•Certain families have high cancer susceptibility, mostly withoutdefined pattern of transmission•Virtually all sporadic cancer have also been reported in familial forms•Features of familial cancers – early age of onset, multiple or bilateraltumors, arising in two or more close relatives•BRAC 1 and BRAC 2 mutations have high incidence of breast,ovarian cancer, familial melanomas GENETIC PREDISPOSITIONInteraction between Genetic and non-geneticfactors :
  13. 13. •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 inducedcancers, cigarette smoking NONHEREDITARY PREDISPOSING CONDITIONS•Every one alive at risk, greater risk in certain conditions•Certain clinical conditions important, wherever cell replicationinvolved; regenerative, hyperplastic and dysplastic proliferationsprovide fertile soil and cancer•Examples; endometrial hyperplasias cervical dysplasias, bronchialmucosal 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 transformedcells, 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
  14. 14. •8th edition•Ch. 7, Neoplasia•Pgs. # 262-276 -------------------------THE END------------------------

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