Tissue Type Cell Type Benign Malignant Conn.Tissue Fibroblast Fibroma Fibrosarcoma Adipocyte Lipoma Liposarcoma Cartilage Chondroma Chondrosarcoma Neoplasia I Bone Osteoma Osteosarcoma Definitions, Terminology, and Vessels, etc Endothelial cells Hemangioma Angiosarcoma Meninges Meningioma Invasive Morphology meningioma Muscle Smooth muscle Leiomyoma Leiomyosarcoma Skeletal muscle Rhabdomyoma Rhabdomyosarcoma Epithelium Stratified Squamous Squamous cell Patrice Spitalnik, MD Squamous papilloma carcinoma [email protected] Ducts or glands Adenoma Adenocarcinoma Melanocytes Melanocytes Nevus Melanoma Characteristics of Benign & Malignant Neoplasms • Tissue Architecture – histologic features Cancer - second leading cause of • Cytologic features deaths in the US after CV disease • Terminology – Differentiation/anaplasia – Dysplasia – Rate of growth – Local Invasion – Metastasis Characteristics of Benign & Nomenclature Malignant Neoplasms • Neoplasia “new growth” • Tissue architecture • Neoplasms arise from genetic changes that – Benign - well circumscribed, usually allow excessive, unregulated cell encapsulated proliferation – Malignant – poorly circumscribed, lack of cell polarity and epithelial cell connections • Cell type of parenchyma + OMA 1 Characteristics, con’t. Anaplasia • Cytologic features • Neoplasm without apparent differentiation, – Benign – small, uniform cells, no visible undifferentiated cells nucleoli – Malignant – large, pleomorphic cells with large hyperchromatic nuclei, N:C ratio 1:1 (nl. 1:4), large nucleoli, irregular nuclear outlines Differentiation • Refers to original parenchymal cell, tissue appearance and function – Benign - well differentiated, resembles cell of origin with few mitoses, secretion of products, hormones, mucins, etc. – Malignant - well to poorly differentiated with numerous, bizarre mitoses Abnormal mitosis 2 Dysplasia Local Invasion • Disorderly cellular maturation • Benign – most encapsulated and cannot • If, full epithelial involvement –carcinoma in invade or spread to other sites situ, pre-invasive stage • Malignant – not encapsulated and can • HPV – cervix invade • Smoking- respiratory tract • GERD – esophagus Benign Neoplasia • Remains localized • Cannot spread to other sites • Most patients survive, but some tumor locations can cause serious problems (brain stem, spinal cord, pituitary) Rate of Growth • Benign – slower growth, some dependent on hormones, leiomyoma • Malignant – more rapid growth, areas of necrosis 3 Malignant Neoplasia • Can invade and destroy adjacent tissue • Can spread to distant sites, metastasis 4 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 - overexpressed and TIMP’s - reduced) • Attachment to new ECM proteins (cleavage products of collagen and laminin bind to receptors on tumor cells - stimulate migration • Migration of tumor cells (cytokines from tumor cells direct movement, autocrine, and stromal cells produce paracrine effectors, HGF/SCF, for motility that bind to tumor cells) 5 Homing of Tumor Cells Homing of Tumor Cells • Most metastases predicted by vascular and lymphatic drainage • Some homing related to expression of endothelial adhesion molecules • Chemokines and chemokine receptors are also involved in homing. (breast ca cells-chemokine receptors: CXCR-4 and -7 bind to the chemokines CXCL12 and CCL21 on distant organs) • After extravasation, tumor cells survive only in receptive ECM and stroma 6 7 Cinical Aspects of Neoplasia 1. Epidemiology: 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 -exposures to a host of Geography: chem. & viral agents Breast Ca: US/Eur. 4-5x higher Japan -e.g. ASBESTOS: Gastric Ca: Japan 7x higher than U.S. mesothelioma Hepato. Ca: Most lethal Ca in Africa -e.g. BENZENE: (vs. 4% of deaths in US) leukemia, Hodgkin EmigrationÆassume Ca rates of region lymphoma Age Environment Heredity ? Cancer -cancer w/ age 1. Inherited Cancer Syndromes -cancer mortality -Autosomal dominant genes peak 55-75 2. Familial cancers (clusters) -under age 15, 3. Inherited syndromes of cancer causes Defective DNA Repair approx. 10% of -Autosomal rec. genes all deaths 8 Clinical Effects of Cancer 1. Cachexia -cytokinesÆ anorexia TNF: from macrophages/tumor cells -suppresses appetite -inhibits lipoprotein lipase (inhibits FFA release from lipoprot’s) Small cell Ca Proteolysis-inducing factor: -ACTH or -breaks down skeletal muscle ACTH-like subst.Æ 2. Paraneoplastic syndromes Cushing syndrome ---ADH-Æ SIADH -hormone production by tumor cells -present in 10% - 15% of pts. with cancer Squamous cell Ca 3. Venous thrombosis ÆPTH-related prot. Æhypercalcemia -mucins from Ca’s activate clotting e.g. Pancreas: Trousseau phenomenon Death in Cancer 1. Overwhelm organ function -liver: coagulation, other protein synthesis -lung: diffusion/oxygenation -pancreas: biliary obstruction/liver mets Æ anorexia 2. Pulmonary embolus (pro-thrombotic Ca’s) 3. Progressive somnolence: hypercalcemia, etc. 4. Systemic electrolyte imbalances: Æ cardiac arrhythmia Æ mentation 5. Tumor-related products: -depression/other CNS effects G /S Checkpoint: Aut. Breast Ca 1 Diagnosis of Cancer Dom. Ovarian Ca BRCA-1 -delays cell cycle to allow BRCA-2 for DNA repair by homologous recombination •History—physical—occupation—exposure Aut. Recessive •Radiology Bloom •Blood tests: tumor markers UV Syndrome •Morphologic Diagnosis light -helicase mutation -osteosarcoma -light microscopy: biopsy pyrim. Fanconi anemia -cytology (Fine Needle Aspiration—FNA) -marrow hypofunc. pyrim. -hypoplasias: -immunohistochemistry kidney/spleen/bone NER Ataxia-telangiectasia -fluorescence in situ hybridization (FISH) (nucleotide excision -mutation of ATM gene: -molecular probes, incl. gene microarray repair) pathway DNA dbl.strd. break repair Xeroderma (kinase/phosph. p53Æ -flow cytometry (lymphomas, leukemias) Pigmentosum G1 arrest or apoptosis)Æ repair -skin cancers -loss of Purkinje cells/ataxia/ immunodef./lymphoid malign. 9 Tumor Markers *Molecules in plasma produced by tumor cells Oncofetal antigens carcinoembryonic antigen gut (CEA) colon Ca; pancreas, lung,breast Ca yolk sac,liver alphafetoprotein (AFP) hepatocellular Ca, germ cell testis Ca Specific proteins PSA (prostatic specific antigen) Mucins & other glycoproteins: CA’s: carbohydrate antigens CA-125 CA-19-9 CA-15-3 ovary Bile ducts, panc. breast Hormones medullary Ca trophoblastic tumor testis HCG thyroid calcitonin (placenta) Immunohistochemistry: --monoclonal Ab to specific cell Ag’s CK7+ CK20- CK7- CK20- CK7- Cytokeratins in epith. cells: CK20+ CK7 and CK20 aneuploid adenocarcinoma normal cell with 3-8 gene small cells copies EGFR Fluorescence In Situ Hybridization (FISH) 10 Grading Staging Staging: TNM AJC (American Joint Committee) Ca AJC 11.