1. NEOPLASIA REVIEW PLUS 9-16-2014 T. Davis

2. 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.

3. 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

4. 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%

5. A 68 y.o. male farmer has an ulcerated, pearly nodule on his upper lip. Dx? A. Malignant melanoma B. Dermatofibtoma C. Actinic keratosis D. Nevocellular nevus E. Basal cell carcinoma

7. E, BCC Ulcerated Pearly Peripheral palisading Chronic solar damage Malignant but rare to metastasize

8. 45 y.o. i.v dug user has huge scalp lesion. Diagnosis? A. Basal cell carcinoma B. Melanoma C. Systemic lupus erythematosis D. Squamous cell carcinoma E. Ulcer

10. D, Squamous cell carcinoma Aids patient (drug abuse) Immune supression Deep invasion

11. 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

12. Precursors (2) Scar in lung Sq. Dysplasia/cervix, lung/larynx Adenomatous polyp Adeno CA Sq. Cell CA Adeno CA colon

13. 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

14. The following image is most c/w which malignancy A. Medullary Carcinoma of Thyroid B. Small cell carcinoma of Lung C. Sq. Cell Carcinoma of Lung D. Metastatic melanoma E. Renal Cell Adenocarcinoma

16. Ans. C, SCC of Lung These tumors frequently make a parathormone-like substance resulting in hypercalcemia and metastatic calcifications in lung and kidney.

17. 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

18. Anaplastic rhabdomyosarcoma

19. 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

20. Squamous cell carcinoma with “squamous pearls” (SP) SP

21. * * Intercellular bridges (*)

22. 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

23. METASTASIS LIVER: (portal circulation) GI tract and pancreas; lung, breast, melanomas LUNG: breast, stomach, sarcomas BONE: 3 rd 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

24. COLON CANCER Grading is not very helpful STAGING: predicts clinical outcome TNM Robbins Table 17-11

26. 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

27. TNM Staging System

28. Lymph Nodes (N) N0- no nodes involved N1- 1-3 regional LNs N2- 4+ regional LNs

29. Distant Metastases (M) M0- no distant metastasis M1- distant mets present *note Tx, Nx, Mx- cannot be assessed

30. Which of the following best describes colon cancer? A. Grading is very important B. Staging is not important C. Inactivation of a supressor gene D. X-linked recessive inheritance pattern E. Autosomal recessive inheritance pattern

31. Answer: C, inactivation of APC This disorder is autosomal dominant with the APC supressor gene on chromosome 5.

32. 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

35. Name the most common human tumor supressor genes and protooncogene (RESPECTIVELY) A. P53 and RB B. P53 and RAS C. RB and RAS D. APC and P53 E. APC and RB

36. 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

38. 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

39. Answer: A, used to monitor tumor recurrence CEA is not specific for colon cancer and not a sensitive test. CEA levels are determined pre- and 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.

40. 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%)

41. 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

42. Fibroadenoma

43. Fibroadenoma of breast

44. C C CN Intraductal carcinoma with cribbiforming (C) and comedonecrosis (CN)

45. Invasive CA

46. Mammogram shows a mass and Ca** Stellate tumor

47. 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

48. Breast carcinoma- Grade I

49. 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%

50. Invasive (infiltrating) ductal carcinoma with lymphatic invasion

51. 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.

52. ER (+)

53. HER-2 Neu (+)

54. 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%

55. 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

56. Carcinoma Insitu

57. Normal Low Grade ModerateSevere/CIS

58. Microinvasive Squamous Cell CA

59. What is the most sensitive test for high grade dysplasia of the cervix? A. Pap smear B. HPV DNA or RNA test for high risk types C. HPV culture for DNA type 16 D. HPV culture for DNA type 18 E. HPV serum antibodies to DNA type 16

60. 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

61. 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

62. Normal CIS Squamous CA

63. Adeno CA Small cell undifferentiated carcinoma Large cell CA

64. keratin Nuclear molding Squamous Cell Carcinoma Small Cell Carcinoma

65. 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

66. 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 syndrome- diarrhea, flushing, high output murmur)

67. Viruses and Cancer (RNA) HCV HTLV-1 Hepatocellular T-cell leukemia/ lymphoma

68. 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

69. Neoplasms Benign Non-invasive Non-metastatic Malignant Invasive Metastatic or non- metastatic

70. 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

71. Exceptions to the Rule Benign tumors that may kill the patient Meningioma Leiomyoma Malignant tumors without metastasis Glioblastoma multiforme Basal cell carcinoma

72. 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

73. Glioblastoma Multiforme (Astrocytoma III/IV

74. Metastatic melanoma

75. 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

76. Stage of tumors at diagnosis listed by organ/site

77. 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 1 st to axillary nodes Hematogenous spread: esp. sarcoma; also carcinoma; usually veins Other: eg. Perineural spread

78. Breast carcinoma with perineural invasion

79. 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

80. Liver with metastases

81. 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

82. 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

83. 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

84. 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!

85. 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

86. 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

87. Metastatic Cascade

92. Invasion of the Extracellular Matrix (ECM) Basement membrane Interstitial connective tissue Vessel basement membrane Interstitial connective tissue

93. Tumor Cells in Circulation They clump with each other, RBCs and platelets Adhesion to endothelium (integrins-laminin- proteinases)

94. Metastasis Oncogenes SNAIL and TWIST (breast cancer) E-cadherin is down-regulated and vimentin is up-regulated

95. 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

97. Metastases and Tropism Primary Site and Histology Organ Clear cell carcinoma (kidney)Thyroid Cutaneous melanomaSmall bowel/brain Ocular melanomaLiver Adenocarcinomas Ovary (Kruckenberg of the GI tract tumor) Follicular carcinoma, thyroidBone

99. 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

102. Target (2) Monoclonal Antibodies Herceptin- invasive breast carcinomas (that show overexpression of HER-2-neu)

103. Target (3) Anti-angiogenesis Angiostatin (from plasminogen) Endostatin (from collagen)