Characteristics Of Benign & Malignant Neoplasms

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Neoplasia IDefinitions, Terminology, andMorphologyTissue TypeCell omaChondrosarcomaBoneOsteomaOsteosarcomaVessels, etcMusclePatrice Spitalnik, lial cells ningiomaSmooth muscleLeiomyomaLeiomyosarcomaSkeletal sSquamouspapillomaSquamous cellcarcinomaDucts or aCharacteristics of Benign &Malignant NeoplasmsCancer - second leading cause ofdeaths in the US after CV disease Tissue Architecture – histologic features Cytologic features Terminology–––––Nomenclature Neoplasia “new growth” Neoplasms arise from genetic changes thatallow excessive, unregulated cellproliferation Cell type of parenchyma OMADifferentiation/anaplasiaDysplasiaRate of growthLocal InvasionMetastasisCharacteristics of Benign &Malignant Neoplasms Tissue architecture– Benign - well circumscribed, usuallyencapsulated– Malignant – poorly circumscribed, lack of cellpolarity and epithelial cell connections1

Characteristics, con’t. Cytologic features– Benign – small, uniform cells, no visiblenucleoli– Malignant – large, pleomorphic cells withlarge hyperchromatic nuclei, N:C ratio 1:1 (nl.1:4), large nucleoli, irregular nuclear outlinesAnaplasia Neoplasm without apparent differentiation,undifferentiated cellsDifferentiation Refers to original parenchymal cell, tissueappearance and function– Benign - well differentiated, resembles cell oforigin with few mitoses, secretion of products,hormones, mucins, etc.– Malignant - well to poorly differentiated withnumerous, bizarre mitosesAbnormal mitosis2

Dysplasia Disorderly cellular maturation If, full epithelial involvement –carcinoma insitu, pre-invasive stage HPV – cervix Smoking- respiratory tract GERD – esophagusLocal Invasion Benign – most encapsulated and cannotinvade or spread to other sites Malignant – not encapsulated and caninvadeBenign Neoplasia Remains localized Cannot spread to other sites Most patients survive, but some tumorlocations can cause serious problems (brainstem, spinal cord, pituitary)Rate of Growth Benign – slower growth, some dependenton hormones, leiomyoma Malignant – more rapid growth, areas ofnecrosis3

Malignant Neoplasia Can invade and destroy adjacent tissue Can spread to distant sites, metastasis4

Metastasis Dissemination to other organs:– Seeding of body cavities (ovary)– Lymphatic spread (carcinoma)– Hematogenous dissemination (sarcoma)Steps of Successful Metastasis Detachment of tumor cells (E-cadherin loss) Degradation of ECM (MMP’s - overexpressedand TIMP’s - reduced) Attachment to new ECM proteins (cleavageproducts of collagen and laminin bind to receptorson tumor cells - stimulate migration Migration of tumor cells (cytokines from tumorcells direct movement, autocrine, and stromal cellsproduce paracrine effectors, HGF/SCF, formotility that bind to tumor cells)5

Homing of Tumor CellsHoming of Tumor Cells Most metastases predicted by vascular andlymphatic drainage Some homing related to expression of endothelialadhesion molecules Chemokines and chemokine receptors are alsoinvolved in homing. (breast ca cells-chemokinereceptors: CXCR-4 and -7 bind to the chemokinesCXCL12 and CCL21 on distant organs) After extravasation, tumor cells survive only inreceptive ECM and stroma6

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Cinical Aspects of Neoplasia1. Epidemiology:Cancer incidence—Cancer deaths2. Pathogenetic factors: a balance of risks3. Clinical effects of cancer4. Death in cancer5. Grading and Staging6. Diagnosis-exposures to a host ofchem. & viral agents-e.g. ASBESTOS:mesothelioma-e.g. BENZENE:leukemia, HodgkinlymphomaAgeGeography:Breast Ca: US/Eur. 4-5x higher JapanGastric Ca: Japan 7x higher than U.S.Hepato. Ca: Most lethal Ca in Africa(vs. 4% of deaths in US)EmigrationÆassume Ca rates of regionEnvironment Heredity? Cancer-cancer w/ age-cancer mortalitypeak 55-75-under age 15,cancer causesapprox. 10% ofall deaths1. Inherited Cancer Syndromes-Autosomal dominant genes2. Familial cancers (clusters)3. Inherited syndromes ofDefective DNA Repair-Autosomal rec. genes8

Clinical Effects of Cancer1. Cachexia-cytokinesÆ anorexiaTNF: from macrophages/tumor cells-suppresses appetite-inhibits lipoprotein lipase(inhibits FFA release from lipoprot’s)Proteolysis-inducing factor:-breaks down skeletal muscleSmall cell Ca-ACTH orACTH-likesubst.ÆCushing syndrome---ADH-Æ SIADH2. Paraneoplastic syndromes-hormone production by tumor cells-present in 10% - 15% of pts. with cancer3. Venous thrombosisSquamous cell CaÆPTH-related prot.Æhypercalcemia-mucins from Ca’s activate clottinge.g. Pancreas: Trousseau phenomenonDeath in Cancer1. Overwhelm organ function-liver: coagulation, other protein synthesis-lung: diffusion/oxygenation-pancreas: biliary obstruction/liver mets Æanorexia2. Pulmonary embolus (pro-thrombotic Ca’s)3. Progressive somnolence: hypercalcemia, etc.4. Systemic electrolyte imbalances:Æ cardiac arrhythmiaÆ mentation5. Tumor-related products:-depression/other CNS effectsAut.Dom.Breast CaOvarian CaBRCA-1BRCA-2G1/S Checkpoint:-delays cell cycle to allowfor DNA repair byhomologous recombinationAut. RecessiveBloomSyndromeUVlight-helicase mutation-osteosarcomapyrim.Fanconi anemiapyrim.-marrow tide excisionrepair) pathwayrepairAtaxia-telangiectasia-mutation of ATM gene:DNA dbl.strd. break repairXerodermaPigmentosum-skin cancers(kinase/phosph. p53ÆG1 arrest or apoptosis)Æ-loss of Purkinje cells/ataxia/immunodef./lymphoid malign.Diagnosis of Cancer History—physical—occupation—exposure Radiology Blood tests: tumor markers Morphologic Diagnosis-light microscopy: biopsy-cytology (Fine Needle e in situ hybridization (FISH)-molecular probes, incl. gene microarray-flow cytometry (lymphomas, leukemias)9

Tumor Markers*Molecules in plasma produced by tumor cellscarcinoembryonic antigen(CEA)Oncofetal antigensgutcolon Ca; pancreas, lung,breast Cayolk sac,liveralphafetoprotein (AFP)hepatocellular Ca, germ cell testis CaSpecific proteinsPSA (prostatic specific antigen)Mucins & other glycoproteins: CA’s: carbohydrate antigensCA-19-9CA-125Hormonestrophoblastic tumor(placenta)CA-15-3Bile ducts, panc.ovarytestisHCGbreastmedullary al Ab tospecific cell Ag’sCK7 CK20-CK7CK20-CK7CK20 Cytokeratins in epith. cells:CK7 and CK20normalsmall cellsaneuploidadenocarcinomacell with 3-8 genecopies EGFRFluorescence In Situ Hybridization (FISH)10

GradingStagingStaging: TNMAJC (American Joint Committee)CaAJC11

Cancer incidence—Cancer deaths 2. Pathogenetic factors: a balance of risks 3. Clinical effects of cancer 4. Death in cancer 5. Grading and Staging 6. Diagnosis? Cancer Age Environment Heredity-cancer mortality peak 55-75-under age 15, cancer causes approx. 10% of all deaths-cancer w/ ag

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