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NEOPLASIA REVIEW PLUS 9-16-2014 T. Davis 1. A new test for prostate cancer (PC) is developed. 90% of men with PC test positive. 80% of men without PC test negative. 2. In a population of 1000 men, 30% (300 men) have the disease (the prevalence is 30%). Calculate sensitivity, specificity and PPV. Sensitivity and specificity • 90% sensitivity • 90% of 1000 or 900 would be the true positives • 10% of 1000 or 100 would be the false negatives • 80% specificity • 80% of 1000 or 800 would be the true negatives • 20% of 1000 or 200 would be the false positives PPV (predictive value) of a + with a prevalence of 30% • 410 men have a positive test: 270 TP (90%x300) and 140 FP (20%x700) • PPV= TP/FP+TP • PPV= 270 / 270 + 140 270/410 or about 66% A 68 y.o. male farmer has an ulcerated, pearly nodule on his upper lip. Dx? • • • • • A. B. C. D. E. Malignant melanoma Dermatofibtoma Actinic keratosis Nevocellular nevus Basal cell carcinoma E, BCC • • • • • Ulcerated Pearly Peripheral palisading Chronic solar damage Malignant but rare to metastasize 45 y.o. i.v dug user has huge scalp lesion. Diagnosis? • • • • • A. B. C. D. E. Basal cell carcinoma Melanoma Systemic lupus erythematosis Squamous cell carcinoma Ulcer D, Squamous cell carcinoma • Aids patient (drug abuse) • Immune supression • Deep invasion Cancer Precursor Lesions • • • • • Actinic keratosis Atyp. Hyp. Breast Ulcerative Colitis Endom. Hyperplasia Esoph. Metaplasia (Barrett’s) • Gastric metaplasia and lymphocytosis (Helicobacter) • Cirrhosis • Sq. Cell CA • Ductal CA • Adeno CA colon • Adeno CA endom. • Esoph. Adeno CA • Gastric Adeno CA (and low grade or MALT Lymphoma) • Adeno CA liver Precursors (2) • Scar in lung • Adeno CA • Sq. Dysplasia/cervix, lung/larynx • Sq. Cell CA • Adenomatous polyp • Adeno CA colon Malignant Tumors and Endocrinopathies • • • • • • Cushings;SIADH HCG/gynecomastia PTH/hyperCa++ Calcitonin/hypoCa++ Insulin/hypoglycemia Erythropoetin/polycy themia or HiHct • • • • • • Small Cell ChorioCA/testis SC CA/lung Med CA/thyroid Islet cell Renal Cell CA Hepatocellular CA The following image is most c/w which malignancy • • • • • A. B. C. D. E. Medullary Carcinoma of Thyroid Small cell carcinoma of Lung Sq. Cell Carcinoma of Lung Metastatic melanoma Renal Cell Adenocarcinoma Ans. C, SCC of Lung • These tumors frequently make a parathormone-like substance resulting in hypercalcemia and metastatic calcifications in lung and kidney. Anaplasia = Lack of differentiation • Anaplasia is considered a hallmark of malignant transformation. • Anaplastic features include: - Cellular/nuclear pleomorphism - Increased nuclear-cytoplasmic ratio - Nuclear hyperchromasia (increased DNA content) - Large nucleoli - Also called: Undifferentiated, poorly differentiated, high grade Anaplastic rhabdomyosarcoma GRADING TUMORS • Malignant tumors only • Differentiation and mitotic rate • Grades I-III/IV (higher grades are more anaplastic) • Important for some tumors: breast, prostate, endometrium, astocytomas • Dysplasias of the cervix are “graded” • Based on microscopic features SP SP Squamous cell carcinoma with “squamous pearls” (SP) * * Intercellular bridges (*) STAGING TUMORS • How far has the tumor spread • Malignant tumors only • Tumor size (T), lymph node (LN) involvement, distant metastases (M) • Staging often involves: the Pathologist, radiology or other imaging, lab tests (tumor markers) • CIS is referred to as Stage Zero METASTASIS • LIVER: (portal circulation) GI tract and pancreas; lung, breast, melanomas • LUNG: breast, stomach, sarcomas • BONE: 3rd most frequent site for metastases; lung, breast, prostate, kidney, thyroid; PROSTATE to bone gives osteoblastic lesions on Xray and high serum alkaline phosphatatse • ADRENAL: most common endocrine site COLON CANCER • • • • Grading is not very helpful STAGING: predicts clinical outcome TNM Robbins Table 17-11 Tumor Size (T) • Tis- insitu; not through the muscularis mucosa • T1- invades submucosa • T2- into but not through the muscularis propria • T3- through muscularis propria • T4- invades adjacent organs TNM Staging System Lymph Nodes (N) • N0- no nodes involved • N1- 1-3 regional LNs • N2- 4+ regional LNs Distant Metastases (M) • M0- no distant metastasis • M1- distant mets present • *note • Tx, Nx, Mx- cannot be assessed Which of the following best describes colon cancer? • • • • • A. B. C. D. E. Grading is very important Staging is not important Inactivation of a supressor gene X-linked recessive inheritance pattern Autosomal recessive inheritance pattern Answer: C, inactivation of APC • This disorder is autosomal dominant with the APC supressor gene on chromosome 5. COLON CANCER • OTHER • 50% of colorectal carcinomas show “ras” mutations; 50% of adenomas > 1cm also show ras mutations • CEA (carcinoembryonic Ag) can be used to follow patients after surgery- tumor monitoring using a tumor marker (CEA also done with PSA, HCG etc. • Deeply infiltrating tumors cause desmoplasia and cause “apple core/ napkin-ring” appearance Name the most common human tumor supressor genes and protooncogene (RESPECTIVELY) • • • • • A. B. C. D. E. P53 and RB P53 and RAS RB and RAS APC and P53 APC and RB Answer: B, P53 and RAS • P53 is the tumor supressor gene mutated in over 50% of human tumors. The mutation prevents DNA repair and inhibits apoptosis. The point mutation in the proto-oncogene RAS allows cell proliferation (GTP signal transduction) and is seen 30+% of human tumors What tumor markers are useful in management of colon cancer? • A. CEA is used to monitor tumor recurrence • B. CEA is used as a screening test for colon cancer • C. CEA is used as a confirmation test if the test for occult blood is positive • D. High PSA in serum is diagnostic • E. High AFP in serum is diagnostic Answer: A, used to monitor tumor recurrence • CEA is not specific for colon cancer and not a sensitive test. CEA levels are determined preand post-surgery. The CEA level should fall to near zero. If the level falls and then increases, the patient may receive chemotherapy for the recurrence. Markers • CEA- colon, pancreas, stomach, lung, breast, (19% smokers, 3% gen. pop.) • AFP- hepatocellular, germ cell (>500ng/ml) • CA 125- 80% non-mucinous ovarian CA • CA 19-9- pancreatic CA (80%) Markers (2) • PSA- (0-4 ng/ml normal) (>10 ng/ml highly suspicious); also AlkPhos elevation in prostate CA assoc. with bone metastasis (osteoblastic) • HCG- gestational trophoblastic tumors, testicular tumors Fibroadenoma Fibroadenoma of breast C C CN Intraductal carcinoma with cribbiforming (C) and comedonecrosis (CN) Invasive CA Stellate tumor Mammogram shows a mass and Ca** BREAST CARCINOMA GRADING • • • • • • • Bloom and Richardson Tubules present (1-3) Nuclear atypia (1-3) Mitoses (1-3) Total score 3-5: Grade I Total score 6,7: Grade II Total score 8,9: Grade III Breast carcinoma- Grade I BREAST CARCINOMA STAGING • • • • • Stage 0 (in situ or CIS): 5-year 92% Stage I. (<2 cm & LN-): 5-year 87% Stage II. (2-5 cm & 1-3 LN+): 5-year 75% *Stage III. (5 cm & >4 LN+): 5-year 46% Stage IV. Distant mets: 5-year 13% Invasive (infiltrating) ductal carcinoma with lymphatic invasion BREAST CARCINOMA • OTHER • Estrogen receptor (+): tumor is stimulated by estrogen and can be treated with the “anti-estrogen” tamoxifen. This is palliation. • HER-2 Neu amplification: by immunostaining or FISH. If HER-2 Neu is amplified (20%), the patient can be treated with Herceptin. This is very expensive and tends to be used in high grade/high stage lesions that are HER-2 Neu positive. ER (+) HER-2 Neu (+) Squamous Carcinoma of Cervix • • • • • • • • Squamous metaplasia Dysplasia CIS Microinvasive cancer (<5mm below BM) Invasive cancer (>5mm below BM Stage I: 5-year is 90% Stage II: 5-year is 70% Stage IV: 5-year is 10% HPV and Cervical Cancer • HPV DNA types 6 and 11: condyloma • HPV 16, 18, 13 others: carcinoma • Viral protein E7 acts via retinoblastoma gene protein • Viral protein E6 acts via to P53 (TP53). • Proliferation is stimulated and apoptosis is inhibited Carcinoma Insitu Normal Moderate Low Grade Severe/CIS Microinvasive Squamous Cell CA What is the most sensitive test for high grade dysplasia of the cervix? • • • • • A. B. C. D. E. Pap smear HPV DNA or RNA test for high risk types HPV culture for DNA type 16 HPV culture for DNA type 18 HPV serum antibodies to DNA type 16 HPV DNA or RNA test are more sensitive tests for High Grade dysplasia • Pap smear 55% • HPV DNA 95% • **RNA test more specific- requires integration into host DNA for expression LUNG CANCER • Large cell carcinomas, adenocarcinomas and squamous cell carcinomas: can be cured by surgery if caught early (<1/3); radiation may offer palliation; chemotherapy and targeted therapy improving for adenocarcinomas • SMALL CELL carcinoma: “always” metastatic at diagnosis, therefore, surgery usually not an option; remains poorly controlled by chemotherapy Normal Squamous CA CIS Squamous CA Small cell undifferentiated carcinoma Adeno CA Large cell CA keratin Nuclear molding Squamous Cell Carcinoma Small Cell Carcinoma Paraneoplastic Syndromes • • • • • Acanthosis nigricans Eaton-Lambert Osteoarthropathy Seborrheic keratosis Migratory thrombophlebitis (Trousseau’s) • • • • Adeno CA (gastric) Small Cell CA Bronchogenic CA Gastric CA • Pancreatic CA PARANEOPLASTIC SYNDROMES • Small Cell CA • Squamous cell CA hypercalcemia • Carcinoid tumor (invasive in lung or liver usually) • ACTH (Cushings); ADH (SIADH) • PTH-like (Hypercalcemia) • Serotonin, bradykinin (Carcinoid syndromediarrhea, flushing, high output murmur) Viruses and Cancer (RNA) • HCV • Hepatocellular • HTLV-1 • T-cell leukemia/ lymphoma Viruses and Cancer (DNA) • EBV t(8;14) • • • • HBV (<p53) HPV 16 (E6/p53) HPV 18 (E7/RB) HHSV-8 (HIV/cytokines) • Burkitt L., NP CA, MC Hodgkin • Hepatocellular CA • SC CA cervix, anus • Same as HPV 16 • Kaposi’s sarcoma in AIDS Neoplasms • Benign • Malignant • Non-invasive • Non-metastatic • Invasive • Metastatic or nonmetastatic Malignant Tumor Properties • Penetration of the basement membrane • Invasion and destruction of surrounding tissue • Penetrate organ walls or fungate through the surface • Local invasion, like metastasis is a marker for malignancy • See Robbins Table 7-2 for benign vs malignant features Exceptions to the Rule • Benign tumors that may kill the patient • Malignant tumors without metastasis • Meningioma • Leiomyoma • Glioblastoma multiforme • Basal cell carcinoma Metastasis • #1 marker of malignancy • Exceptions: gliomas (astrocytomas) of the brain and basal cell carcinomas of the skin RARELY metastasize; also, meningiomas LOCALLY invade skull bone, but do not metastasize and are considered benign. • ** On board exams they sometimes substitute invasiveness for metastasis Glioblastoma Multiforme (Astrocytoma III/IV Metastatic melanoma Cancer Statistics • 90 % of cancer deaths are due to metastases • 1/3 of breast and colon cancer patients have lymph node metastases at diagnosis • Frequency overall: liver, lung, bone • #1 endocrine site: adrenal glands Stage of tumors at diagnosis listed by organ/site Pathways of Spread • Direct seeding of body cavities: peritoneal #1; also pleural, pericardial, subarachnoid, joint • Lymphatic spread: carcinoma> sarcoma; follows natural drainage- breast cancer (Upper-Outer Quadrant) goes 1st to axillary nodes • Hematogenous spread: esp. sarcoma; also carcinoma; usually veins • Other: eg. Perineural spread Breast carcinoma with perineural invasion Venous Drainage • Portal: liver • Caval: lungs • Paravertebral plexus: thyroid and prostate carcinomas metastasize to the vertebrae • Renal Cell CA: invades renal vein and grows into the vena cava Liver with metastases Sentinel LN Biopsy • “The first node in a regional lymphatic basin that receives lymph flow from the primary tumor” • Dyes and radiolabeled tracers mark the node • Breast, colon and melanomas • In breast carcinomas it replaces a total dissection of the axillary lymph nodes and reduces morbidity ANGIOGENESIS • Tumors stimulate the growth of host blood vessels • Any tumor >2 mm in diameter must have a vascular supply • New vessels supply oxygen and nutrients and endothelial cells secrete growth factors Tumor-associated Angiogenic Factors • VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) are made mostly by tumor cells but also by macrophages and stromal cells ANGIOGENIC SWITCH • Angiogenesis is delayed; a minority of the cells become angiogenic • p53 inhibits angiogenesis by inducing production of thrombospondin-1 and down-regulating VEGF • Angiogenesis inhibitors made by tumor cells: thrombospondin-1; and angiostatin (from plasminogen), endostatin/tumstatin (collagen) • All are possible therapeutic targets! Invasion and Metastasis • Robbins Figure 7-42 • Cells break loose, enter and exit vessels and establish a secondary growth site • Rare malignant cells are successful at metastasis; Robbins Figure 7-43 Steps in Metastasis •Detachment of cells from the primary tumor •Invasion of the surrounding tissue •Penetration to blood and lymphatic vessels •Arrest at target sites •Egression (extravasation) •Proliferation •Establishment of a new blood supply Metastatic Cascade Invasion of the Extracellular Matrix (ECM) • • • • • Basement membrane Interstitial connective tissue Vessel basement membrane Vessel basement membrane Interstitial connective tissue Tumor Cells in Circulation • They clump with each other, RBCs and platelets • Adhesion to endothelium (integrins-lamininproteinases) Metastasis Oncogenes • SNAIL and TWIST (breast cancer) • E-cadherin is down-regulated and vimentin is up-regulated Tumor Tropism • Different endothelial receptors in different organs • Different chemokine receptors on the tumor cells- eg. breast cancers express CXCR4 and CCR7 receptors and “matching” chemokines are at high levels in lung and lymph nodes • “unfertile soil” like skeletal muscle without receptors Metastases and Tropism Primary Site and Histology Organ Clear cell carcinoma (kidney) Thyroid Cutaneous melanoma Small bowel/brain Ocular melanoma Liver Adenocarcinomas of the GI tract Follicular carcinoma, thyroid Ovary (Kruckenberg tumor) Bone Targeted Therapy • Signal-transduction Inhibitors • Block enzymes and Growth Factor Receptors • GLEEVEC (imatinib)- GIST and CML (abnormal tumor enzymes); • IRESSA (gefetinib)- non-small-cell lung cancer (EGFR) • Zelboraf (vemurafenib)- blocks B-raf/MEK if V600E BRAF mutation present with apoptosis Target (2) • Monoclonal Antibodies • Herceptin- invasive breast carcinomas (that show overexpression of HER-2-neu) Target (3) • Anti-angiogenesis • Angiostatin (from plasminogen) • Endostatin (from collagen)