Neoplasm

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Neoplasia

NEOPLASIA (TUMORS):

NEOPLASIA (TUMORS) Definitions Nomenclature Biology of Tumor Growth Epidemiology Molecular Basis of Cancer Molecular Basis of Carcinogenesis Agents (The Usual Suspects) Host Defense (Tumor Immunity) Clinical Features of Tumors

Defnition of Neoplasia:

Defnition of Neoplasia “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change ” - Willis Genetic changes Autonomous Clonal

Nomenclature – Benign Tumors:

Nomenclature – Benign Tumors -oma = benign neoplasm Mesenchymal tumors chrondroma: cartilaginous tumor fibroma: fibrous tumor osteoma: bone tumor Epithelial tumor adenoma: tumor forming glands papilloma: tumor with finger like projections papillary cystadenoma: papillalry and cystic tumor forming glands polyp: a tumor that projects above a mucosal surface

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Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM) © 2005 Elsevier

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Colonic Polyp: Tubular Adenoma Stalk Tumor

Nomenclature – Malignant Tumors:

Nomenclature – Malignant Tumors Sarcomas: mesenchymal tumor chrondrosarcoma: cartilaginous tumor fibrosarcomama: fibrous tumor osteosarcoma: bone tumor Carcinomas: epithelial tumors adenocarcinoma: gland forming tumor squamous cell carcinoma: squamous differentiation undifferentiated carcinoma: no differentiation note: carcinomas can arise from ectoderm, mesoderm, or endoderm

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Tumors with mixed differentiation mixed tumors: e.g. pleomorphic adenoma of salivary gland carcinosarcoma Teratoma tumor comprised of cells from more than one germ layer arise from totipotent cells (usually gonads) benign cystic teratoma of ovary is the most common teratoma Aberrant differentiation (not true neoplasms ) Hamartoma : disorganized mass of tissue whose cell types are indiginous to the site of the lesion, e.g., lung Choriostoma : ectopic focus of normal tissue (heterotopia), e.g., pancreas, perhaps endometriosis too Misnomers hepatoma : malignant liver tumor melanoma: malignant skin tumor seminoma : malignant testicular tumor lymphoma: malignant tumor of lymphocytes

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Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM) © 2005 Elsevier

Natural History Of Malignant Tumors:

Natural History Of Malignant Tumors Malignant change in the target cell, referred to as transformation Growth of the transformed cells Local invasion Distant metastases.

Differentiation:

Differentiation Well differentiated neoplasm Resembles mature cells of tissue of origin Poorly diffentiated neoplasm Composed of primitive cells with little diffrerentiation Undifferentiated or “ anaplastic ” tumor Correlation with biologic behavior Benign tumors are well differentiated Poorly differentiated malignant tumors usually have worse prognosis

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If cells LOOK BAD , they are probably going to BEHAVE BAD Looking “bad” means NOT looking like the cells they supposedly arose from!

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If cells LOOK GOOD , they are probably going to BEHAVE GOOD Looking “good” means looking like the cells they supposedly arose from!

“ANAPLASIA” = CANCER:

Pleomorphism Size shape Abnormal nuclear morphology Hyperchromasia High nuclear cytoplasmic ratio Chromatin clumping Prominent nucleoli Mitoses Mitotic rate Location of mitoses Loss of polarity “ANAPLASIA” = CANCER

Dysplasia:

Dysplasia Literally means abnormal growth Malignant transformation is a multistep process In dysplasia some but not all of the features of malignancy are present, microscopically Dysplasia may develop into malignancy Uterine cervix Colon polyps Graded as low-grade or high-grade, often prompting different clinical decisions Dysplasia may NOT develop into malignancy HIGH grade dysplasia often classified with CIS

Tumor Growth Rate:

Tumor Growth Rate Doubling time of tumor cells Lengthens as tumor grows 30 doublings (10 9 cells) = 1 g (months to years) 10 more doublings (1 kg) = lethal burden (“) Fraction of tumor cells in replicative pool May be only 20% even in rapidly growing tumors Tumor stem cells Rate at which tumor cells are shed or lost Apoptosis Maturation Implications for therapy

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“clonal”

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Schematic Representation Of Tumor Growth

Features of Malignant Tumors:

Features of Malignant Tumors Cellular features Local invasion Capsule Basement membrane Metastasis Unequivocal sign of malignancy Seeding of body cavities Lymphatic Hematogenous

Significance of Nodal Mets:

Significance of Nodal Mets Example of breast cancer Halsted radical mastectomy Sentinel node biopsy Prognostic Number of involved nodes is an important component of TNM staging system Therapeutic Overall risk of recurrence Extent of nodal involvement Histologic grade and other considerations “Adjuvant” chemotherapy

Benign vs Malignant Features:

Benign vs Malignant Features Feature Benign Malignant Rate of growth Progressive but slow. Mitoses few and normal Variable. Mitoses more frequent and may be abnormal Differentiation Well differentiated Some degree of anaplasia LOCAL INVASION Cohesive growth. Capsule & BM not breached Poorly cohesive and infiltrative! Metastasis Absent May occur

Geographic & Environmental :

Geographic & Environmental Sun exposure Melanomas 6x incidence New Zealand vs Iceland Blacks have low incidence of melanoma, so do normally pigmented areas like areolae on white people Smoking and alcohol abuse Body mass Overweight = 50% increase in cancer Environmental vs racial factors Japanese immigrants to USA Viral exposure Human papilloma virus (HPV) and cervical cancer Hepatitis B virus (HBV) and liver cancer (Africa, Asia) Epstein-Barr Virus (EBV) and lymphoma

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Change In Incidence Of Various Cancers With Migration From Japan To The United States

Predisposing Factors for Cancer:

Predisposing Factors for Cancer Age Most cancers occur in persons ≥ 55 years Childhood cancers Leukemias & CNS neoplasms Bone tumors Genetic predispostion Familial cancer syndromes Early age at onset Two or more primary relatives with the cancer Multiple or bilateral tumors Polymorphisms that metabolize procarcinogens , e.g., nitrites Nonhereditary predisposing conditions Chronic inflammation? Precancerous conditions Chronic ulcerative colitis Atrophic gastritis of pernicious anemia Leukoplakia of mucous membranes Immune collapse?

MOLECULAR BASIS of CANCER:

MOLECULAR BASIS of CANCER NON-lethal genetic damage A tumor is formed by the clonal expansion of a single precursor cell ( monoclonal ) Four classes of normal regulatory genes PROTO-oncogenes Oncogenes  Oncoproteins DNA repair genes Apoptosis genes Carcinogenesis is a multistep process

TRANSFORMATION & PROGRESSION:

TRANSFORMATION & PROGRESSION Self-sufficiency in growth signals Insensitivity to growth-inhibiting signals Evasion of apoptosis Defects in DNA repair: “Spell checker” Limitless replicative potential: Telomerase Angiogenesis Invasive ability Metastatic ability

Normal CELL CYCLE Phases:

Normal CELL CYCLE Phases INHIBITORS: Cip/Kip, INK4/ARF Tumor (really growth) suppressor genes: p53

ONCOGENES:

ONCOGENES Are MUTATIONS of NORMAL genes (PROTO- oncogenes ) Growth Factors Growth Factor Receptors Signal Transduction Proteins (RAS) Nuclear Regulatory Proteins Cell Cycle Regulators Oncogenes code for  Oncoproteins

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Category PROTO- Oncogene Mode of Activation Associated Human Tumor GFs PDGF- β chain SIS Overexpression Astrocytoma Osteosarcoma Fibroblast growth factors HST-1 Overexpression Stomach cancer INT-2 Amplification Bladder cancer Breast cancer Melanoma TGF α TGF α Overexpression Astrocytomas Hepatocellular carcinomas HGF HGF Overexpression Thyroid cancer

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Category PROTO- Oncogene Mode of Activation Associated Human Tumor GF Receptors EGF-receptor family ERB-B1 (ECFR) Overexpression Squamous cell carcinomas of lung, gliomas ERB-B2 Amplification Breast and ovarian cancers CSF-1 receptor FMS Point mutation Leukemia Receptor for neurotrophic factors RET Point mutation Multiple endocrine neoplasia 2A and B, familial medullary thyroid carcinomas PDGF receptor PDGF-R Overexpression Gliomas Receptor for stem cell (steel) factor KIT Point mutation Gastrointestinal stromal tumors and other soft tissue tumors

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Category PROTO- Oncogene Mode of Activation Associated Human Tumor Signal Transduction Proteins GTP-binding K-RAS Point mutation Colon, lung, and pancreatic tumors H-RAS Point mutation Bladder and kidney tumors N-RAS Point mutation Melanomas, hematologic malignancies Nonreceptor tyrosine kinase ABL Translocation Chronic myeloid leukemia Acute lymphoblastic leukemia RAS signal transduction BRAF Point mutation Melanomas WNT signal transduction β- catenin Point mutation Hepatoblastomas , hepatocellular carcinoma

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Category PROTO- Oncogene Mode of Activation Associated Human Tumor Nuclear Regulatory Proteins Transcrip.activators C-MYC Translocation Burkitt lymphoma N-MYC Amplification Neuroblastoma, small cell carcinoma of lung L-MYC Amplification Small cell carcinoma of lung

MYC:

MYC Encodes for transcription factors Also involved with apoptosis

P53 and RAS:

P53 and RAS p53 Activates DNA repair proteins Sentinel of G1/S transition Initiates apoptosis Mutated in more than 50% of all human cancers RAS H, N, K, etc., varieties Single most common abnormality of dominant oncogenes in human tumors Present in about 1/3 of all human cancers

Tumor (really “GROWTH”) suppressor genes:

Tumor (really “GROWTH”) suppressor genes TGF- β  COLON E-cadherin  STOMACH NF-1,2  NEURAL TUMORS APC/ β -cadherin  GI, MELANOMA SMADs  GI RB  RETINOBLASTOMA P53  EVERYTHING!! WT-1  WILMS TUMOR p16 (INK4a)  GI, BREAST (MM if inherited) BRCA-1,2  BREAST KLF6  PROSTATE

Evasion of APOPTOSIS:

Evasion of APOPTOSIS BCL-2 p53 MYC

DNA REPAIR GENE DEFECTS:

DNA REPAIR GENE DEFECTS DNA repair is like a spell checker HNPCC ( H ereditary N on- P olyposis C olon C ancer): TGF- β , β - catenin , BAX Xeroderma Pigmentosum : UV fixing gene Ataxia Telangiectasia : ATM gene Bloom Syndrome: defective helicase Fanconi anemia

LIMITLESS REPLICATIVE POTENTIAL:

LIMITLESS REPLICATIVE POTENTIAL TELOMERES determine the limited number of duplications a cell will have, like a cat with nine lives. TELOMERASE , present in >90% of human cancers, changes telomeres so they will have UNLIMITED replicative potential

TUMOR ANGIOGENESIS:

TUMOR ANGIOGENESIS Q : How close to a blood vessel must a cell be? A: 1-2 mm Activation of VEGF and FGF-b Tumor size is regulated (allowed) by angiogenesis/anti-angiogenesis balance

TRANSFORMATION GROWTH BM INVASION ANGIOGENESIS INTRAVASATION EMBOLIZATION ADHESION EXTRAVASATION METASTATIC GROWTH etc.:

TRANSFORMATION  GROWTH  BM INVASION  ANGIOGENESIS INTRAVASATION  EMBOLIZATION  ADHESION  EXTRAVASATION  METASTATIC GROWTH  etc.

Invasion Factors:

Invasion Factors Detachment ("loosening up") of the tumor cells from each other Attachment to matrix components Degradation of ECM, e.g., collagenase, etc. Migration of tumor cells

METASTATIC GENES?:

METASTATIC GENES? NM23 KAI-1 KiSS

CHROMOSOME CHANGES in CANCER:

CHROMOSOME CHANGES in CANCER TRANSLOCATIONS and INVERSIONS Occur in MOST Lymphomas/Leukemias Occur in MANY (and growing numbers) of NON-hematologic malignancies also

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Malignancy Translocation Affected Genes Chronic myeloid leukemia (9;22)(q34;q11) Ab1 9q34 bcr 22q11 Acute leukemias (AML and ALL) (4;11)(q21;q23) AF4 4q21 MLL 11q23 (6;11)(q27;q23) AF6 6q27 MLL 11q23 Burkitt lymphoma (8;14)(q24;q32) c- myc 8q24 IgH 14q32 Mantle cell lymphoma (11;14)(q13;q32) Cyclin D 11q13 IgH 14q32 Follicular lymphoma (14;18)(q32;q21) IgH 14q32 bcl -2 18q21 T-cell acute lymphoblastic leukemia (8;14)(q24;q11) c-myc 8q24 TCR-α 14q11 (10;14)(q24;q11) Hox 11 10q24 TCR-α 14q11 Ewing sarcoma (11;22)(q24;q12) Fl-1 11q24 EWS 22q12

Carcinogenesis is “MULTISTEP”:

Carcinogenesis is “MULTISTEP” NO single oncogene causes cancer BOTH several oncogenes AND several tumor suppressor genes must be involved Gatekeeper/Caretaker concept Gatekeepers: ONCOGENES and TUMOR SUPPRESSOR GENES Caretakers: DNA REPAIR GENES Tumor “PROGRESSION” ANGIOGENESIS HETEROGENEITY from original single cell

Carcinogenesis: The USUAL (3) Suspects:

Carcinogenesis: The USUAL (3) Suspects Initiation/Promotion concept: BOTH initiators AND promotors are needed NEITHER can cause cancer by itself INITIATORS (carcinogens) cause MUTATIONS PROMOTORS are NOT carcinogenic by themselves, and MUST take effect AFTER initiation, NOT before PROMOTORS enhance the proliferation of initiated cells

Q: WHO are the usual suspects?:

Q: WHO are the usual suspects? Inflammation? Teratogenesis? Immune Suppression? Neoplasia? Mutations?

A: The SAME 3 that are ALWAYS blamed!:

A: The SAME 3 that are ALWAYS blamed! 1) Chemicals 2) Radiation 3) Infectious Pathogens

CHEMICAL CARCINOGENS: INITIATORS:

CHEMICAL CARCINOGENS: INITIATORS DIRECT β-Propiolactone Dimeth. sulfate Diepoxybutane Anticancer drugs (cyclophosphamide, chlorambucil, nitrosoureas, and others) Acylating Agents 1-Acetyl-imidazole Dimethylcarbamyl chloride “PRO”CARCINOGENS Polycyclic and Heterocyclic Aromatic Hydrocarbons Aromatic Amines, Amides, Azo Dyes Natural Plant and Microbial Products Aflatoxin B1  Hepatomas Griseofulvin  Antifungal Cycasin  from cycads Safrole  from sassafras Betel nuts  Oral SCC

CHEMICAL CARCINOGENS: INITIATORS:

CHEMICAL CARCINOGENS: INITIATORS OTHERS Nitrosamine and amides (tar, nitrites) Vinyl chloride  angiosarcoma in Kentucky Nickel Chromium Insecticides Fungicides P oly C hlorinated B iphenyls (PCBs)

CHEMICAL CARCINOGENS: PROMOTORS:

CHEMICAL CARCINOGENS: PROMOTORS HORMONES PHORBOL ESTERS (TPA), activate kinase C PHENOLS DRUGS, many “Initiated” cells respond and proliferate FASTER to promotors than normal cells

RADIATION CARCINOGENS:

RADIATION CARCINOGENS UV: BCC, SCC, MM (i.e., all 3) IONIZING: photons and particulate Hematopoetic and Thyroid (90%/15yrs) tumors in fallout victims Solid tumors either less susceptible or require a longer latency period than LEUK/LYMPH BCCs in Therapeutic Radiation

VIRAL CARCINOGENESIS:

VIRAL CARCINOGENESIS HPV  SCC EBV Burkitt Lymphoma HBV Hepatocellular Carcinoma (Hepatoma) HTLV1 T-Cell Malignancies KSHV Kaposi Sarcoma

H. pylori CARCINOGENESIS:

H. pylori CARCINOGENESIS 100% of gastric lymphomas (i.e., M.A.L.T.-omas) Gastric CARCINOMAS also!

HOST DEFENSES:

HOST DEFENSES IMMUNE SURVEILLENCE CONCEPT CD8+ T-Cells NK cells MACROPHAGES ANTIBODIES

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CYTOTOXIC CD8+ T-CELLS are the main eliminators of tumor cells

How do tumor cells escape immune surveillance?:

How do tumor cells escape immune surveillance? Mutation, like microbes ↓ MHC molecules on tumor cell surface Lack of CO-stimulation molecules, e.g., (CD28, ICOS), not just Ag- Ab recognition Immunosuppressive agents Antigen masking Apoptosis of cytotoxic T-Cells (CD8), i.e., the damn tumor cell KILLS the T-cell!

Effects of TUMOR on the HOST:

Effects of TUMOR on the HOST Location  anatomic ENCROACHMENT HORMONE production Bleeding, Infection ACUTE symptoms, e.g., rupture, infarction METASTASES

CACHEXIA:

CACHEXIA Reduced diet: Fat loss>Muscle loss Cachexia: Fat loss AND Muscle loss TNF ( α by default) IL-1 PIF ( P roteolysis I nducing F actor)

PARA-Neoplastic Syndromes:

PARA-Neoplastic Syndromes Endocrine Nerve/Muscle, e.g., myasthenia w. lung ca. Skin: e.g., acanthosis nigricans, dermatomyositis Bone/Joint/Soft tissue: HPOA ( H ypertrophic P ulmonary O steo A rthropathy) Vascular: Trousseau, Endocarditis Hematologic: Anemias Renal: e.g., Nephrotic Syndrome

ENDOCRINE:

ENDOCRINE Cushing syndrome Small cell carcinoma of lung ACTH or ACTH-like substance Pancreatic carcinoma Neural tumors Syndrome of inappropriate antidiuretic hormone secretion Small cell carcinoma of lung; intracranial neoplasms Antidiuretic hormone or atrial natriuretic hormones Hypercalcemia Squamous cell carcinoma of lung Parathyroid hormone-related protein (PTHRP), TGF-α, TNF, IL-1 Breast carcinoma Renal carcinoma Adult T-cell leukemia/lymphoma Ovarian carcinoma Hypoglycemia Fibrosarcoma Insulin or insulin-like substance Other mesenchymal sarcomas Hepatocellular carcinoma Carcinoid syndrome Bronchial adenoma (carcinoid) Serotonin, bradykinin Pancreatic carcinoma Gastric carcinoma Polycythemia Renal carcinoma Erythropoietin Cerebellar hemangioma Hepatocellular carcinoma

GRADING/STAGING:

GRADING/STAGING GRADING : HOW “DIFFERENTIATED” ARE THE CELLS? STAGING : HOW MUCH ANATOMIC EXTENSION? TNM Which one of the above do you think is more important?

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WELL? (pearls) MODERATE? (intercellular bridges) POOR? (WTF!?!) GRADING for Squamous Cell Carcinoma

ADENOCARCINOMA GRADING Let’s have some FUN!:

ADENOCARCINOMA GRADING Let’s have some FUN!

LAB DIAGNOSIS:

LAB DIAGNOSIS BIOPSY CYTOLOGY: (exfoliative) CYTOLOGY: (FNA, F ine N eedle A spirate)

IMMUNOHISTOCHEMISTRY:

IMMUNOHISTOCHEMISTRY Categorization of undifferentiated tumors Leukemias/Lymphomas Site of origin Receptors, e.g., ERA, PRA

TUMOR MARKERS:

TUMOR MARKERS HORMONES: (Paraneoplastic Syndromes) “ONCO”FETAL: AFP, CEA ISOENZYMES: PAP, NSE PROTEINS: PSA, PSMA (“M” = “membrane”) GLYCOPROTEINS: CA-125, CA-19-5, CA-15-3 MOLECULAR: p53, RAS NOTE: These SAME substances which can be measured in the blood, also can be stained by immunochemical methods in tissue

MICRO-ARRAYS:

MICRO-ARRAYS THOUSANDS of genes identified from tumors give the cells their own identity and FINGERPRINT and may give important prognostic information as well as guidelines for therapy. Some say this may replace standard histopathologic identifications of tumors. What do you think?

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