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Tumors
This document discusses characteristic features of tumors and the epidemiology of cancers. It begins by outlining the learning objectives which are to understand the growth phases of cancer, dysplasia and carcinoma-in-situ, functional capabilities of benign and malignant tumors, and cancer incidence and epidemiological factors in Pakistan. It then describes the biology of tumor growth, differentiation, invasion, metastasis and spread. Specifics are provided on the incidence of cancers in males and females in northern Pakistan. Environmental, genetic and chronic disease factors that can predispose individuals to cancer are also outlined.
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Tumors
- 1. CHARACTERISTIC FEATURES OFTUMOR & 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 MALIGNANTNEOPLASMS: • 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 showconsiderable 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 whichcells 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 discontinuouswith 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 breastcancer – 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 •Interactionof 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 tumorstend 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 CANCERIN 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 CANCERIN 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 ofUV 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 importantimpact 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 heredityand 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 -------------------------THE END------------------------