Neoplasia Mar 14 2005 Robbins and Cotran Chapter 7 pp 269 339 Definitions Neoplasia new growth Abnormal mass of tissue with growth that exceeds and is uncoordinated with that of the surrounding normal tissues autonomous Tumor synonymous with neoplasm Cancer common term for malignant neoplasm Neoplasms have parenchyma and stroma Benign and malignant tumors each have their own nomenclature Benign tumors Based on parenchymal component Mesenchymal tumors add oma to cell of origin Fibroblasts fibroma Cartilage chondroma Osteoblasts osteoma Epithelial tumors can be named for cell of origin microscopic architecture or macroscopic appearance Adenoma glandular appearance OR from glandular tissue Malignant tumors Mesenchymal tumors usually called sarcomas Fibrosarcoma liposarcoma leiomyosarcoma rhabdomyosarcoma Epithelial tumors usually called carcinomas Adenocarcinoma glandular growth pattern Squamous cell carcinoma squamous pattern Can either be named for organ of origin or poorly differentiated or undifferentiated Many exceptions Liver tumors Focal nodular hyperplasia spontaneous Nodular regenerative hyperplasia portal hypertension Hemangiomas benign blood vessel tumors Liver cell adenomas rarely become malignant Hepatocellular carcinoma HCC common Cholangiocarcinoma much less common Biology of tumor growth 1 Malignant change in target cell transformation 2 Growth of the transformed cells 3 Local invasion 4 Distant metastases Generally morphologic criteria can be used to distinguish benign and malignant tumors but not always Differentiation and anaplasia Differentiation extent to which neoplastic cells resemble normal cells Anaplasia lack of differentiation Hallmark of transformation But cancer is not reverse differentiation In general benign tumors are well differentiated Malignant tumors range from well differentiated to undifferentiated Features of anaplasia Pleomorphism Abnormal cell morphology atypia Abundant and or atypical mitoses Loss of polarity Dysplasia disordered growth In epithelia represents a state between hyperplasia and carcinoma in situ preinvasive neoplasia Does not necessarily progress to cancer Rates of tumor cell growth From 1 transformed cell to smallest clinically detectable mass 1 gm of 109 cells 30 doublings To reach 1012 cells 1 kg requires only 10 additional doublings Doubling time of tumor cells Fraction of tumor cells replicating Rate at which cells are shed lost Total cell cell cycle time is typically normal Figure removed for copyright reasons Source Figure 7 12 in RC Kumar V A K Abbas and N Fausto Robbins and Cotran Pathologic Basis of Disease 7th ed Philadelphia PA Elsevier 2005 ISBN 0721601871 Local invasion and metastasis Growth of cancer is usually accompanied by progressive infiltration invasion and destruction of surrounding tissue Next to metastasis invasiveness is the most reliable feature that distinguishes malignant tumors from benign tumors Metastasis tumor mass discontinuous with the primary tumor unequivocally marks a tumor as malignant Figure removed for copyright reasons Source Figure 7 22 in RC Molecular basis of cancer Acquired environmental DNA damaging agents Normal Cell Nonlethal genetic damage Clonal expansion of a precursor cell Main classes of genes involved 1 Oncogenes 2 Tumor suppressor genes 3 Genes regulating apoptosis 4 DNA repair genes Carcinogenesis is a multistep process 1 Chemicals 2 Radiation 3 Viruses Successful DNA repair DNA Damage Activation of growth promoting oncogenes Failure of DNA repair Inherited mutation in Mutations in the genome of somatic cells 1 Genes affecting DNA repair 2 Genes affecting cell growth or apoptosis Inactivation of tumor suppressor genes Unregulated cell proliferation Alterations in genes that regulate apoptosis Decreased apoptosis Clone Expansion Angiogenesis Additional mutations Escape from immunity Tumor progression Malignant neoplasm Figure by MIT OCW Invasion metastasis Figure removed for copyright reasons Source Figure 7 31 in RC Oncogenes First recognized in acute transforming retroviruses v onc Most known oncogenes do not have viral counterparts Function as growth factors receptors signal transducers transcription factors and cell cycle components Have similar functions as protooncogenes but lack regulation are constitutive Figure removed for copyright reasons Source Figure 7 32 in RC RAS oncogene 15 20 of all human cancers have a RAS mutation Normally RAS is activated by receptors to exchange GDP for GTP Activated RAS returns to ground state by its intrinsic GTPase activity GTPase activating proteins GAPs augment this process Mutant forms of RAS bind GAP but their GTPase activity is not augmented Tumor suppressor genes Normally serve to inhibit cell proliferation First recognized in retinoblastoma rare pediatric tumor of the eye RB tumor suppressor gene is a nuclear phosphoprotein that regulates cell cycle Active hypophosphorylated state in nondividing cells Inactive hyperphosphorylated in G1 S transition Many cancers have mutations in the RB pathway i e INK4a Cyclin D CDK4 OF RETINOBLASTOMA Figure by MIT OCW Retinoblastoma Retinal Cells Somatic cells of child Zygote Normal gene Germ cells Somatic cells of parents PAT H O G E N E S I S FAMILIAL FORM Mutation Mutant Rb gene Mutation Mutation SPORADIC FORM Metastasis Invasion of ECM Detachment from cells Attachment to ECM Degradation of ECM Migration of tumor cells Vascular dissemination Adhesion molecules Chemokines Figure removed for copyright reasons Source Figure 7 42 in RC Tumor immunity Immune surveillance Cancer immunoediting Tumor specific antigens Tumor associated antigens Anti tumor effector mechanisms CTL NK cell Macrophages Antibodies Normal host cell displaying multiple MHC associated self antigens Normal self proteins No T cell response MHC Class I Tumor cells expressing different types of tumor antigens Product of oncogene or mutated tumor suppressor gene Mutated self protein Overexpressed or aberrantly expressed self protein T cell T cell CD8 CTL T cell T cell CD8 CTL Various mutant proteins in carcinogen or radiation induced animal tumors various Tumor suppressor gene mutated proteins in products mutated p53 melanomas protein Oncogene products mutated RAS Bcr Abl fusion proteins Examples Oncogenic virus Figure by MIT OCW Overexpressed tyrosinase gp100 MART in melanomas Aberrantly expressed cancer testis antigens MAGE BAGE T cell Virus antigen specific CD8 CTL Human papilloma virus E6 E7 proteins in cervical carcinoma