1. Epidemiology, Predispositions and Clinical Course of Cancer Darrell Davidson, MD, PhD Department of Pathology and Laboratory Medicine

2. For the MD, PhD Candidates

3. Learning Objectives 1.US risk and importance of cancer. 2.3 most common cancer sites in men and women, mortality trends. 3.3 patterns genetic risk and examples. 4.4 categories of paraneoplastic syndrome. 5.Tumor stage and grade, and explain which is more important clinically.

4. 1 in 4 chance of cancer death (23%) –1.67x10 6 cases; 585,000 + deaths (2014est) –1600 deaths per day –males have 1 in 2 chance of getting CA (45%) –females have 1 in 3 chance of getting CA (38%) –survival rates improved significantly since 1974 for all body sites (SEER P<.05 1975-77 vs 1999-2005) New cases (incidence rate) decreasing –Men0.6 %/yr(2005-2009) –Women stable(2005-2009) Cancer death rate decreasing –Men1.8 %/yr(2005-2009) –Women1.5 %/yr(2005-2009) US Cancer Overall p271

5. 1.Heart Diseases599,41324.6 2.Cancer567,58823.3 3.Chronic lower respiratory diseases137,3535.6 4.Cerebrovascular diseases128,8425.3 5.Accidents (Unintentional injuries)118,0214.8 6.Alzheimer disease 79,0033.2 7.Diabetes mellitus 68,7052.8 8.Influenza & pneumonia53,6922.2 Cause of Death No. of deaths % of all deaths US Mortality Causes 2009 National Center for Health Statistics, Center for Disease Control and Prevention

6. Relative Importance of Cancer 2 nd overall cause of death –after Heart Disease –before COPD, CVA, Accidents 4 th cause of death before age 19 –after Accidents, Homicide and Suicide –before Congenital Anomalies and Heart Disease –2 nd cause before age 14 Exclusions –Non-melanoma skin cancers (~3,500,000) –CIS except bladder (125,940 breast & melanoma)

7. * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2004 Mortality Data: US Mortality Public Use Data Tape, 2004, NCHS, Centers for Disease Control and Prevention, 2006 Heart Diseases Cerebrovascular Diseases Pneumonia/ Influenza Cancer 1950 2004 Rate Per 10 5 Change in US Death Rates* 1950 & 2004

8. Cancer Incidence Trends in Men and Women (1975-2009) Decreasing prostate, lung, colon Increasing liver, renal, melanoma, pancreas Decreasing breast, colon Increasing thyroid, renal, melanoma, pancreas

9. Learning Objectives 1.US risk and relative rank of cancer. 2.3 most common cancer sites in men and women, mortality trends. 3.3 patterns genetic risk and examples. 4.4 categories of paraneoplastic syndrome. 5.Tumor stage and grade, and explain which is more important clinically.

10. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2010. Men 822,300 Women 774,370 29%Breast 14%Lung & bronchus 9%Colon & rectum 7%Leuk/Lymphoma 6%Uterine corpus 6%Thyroid 4%Melanoma (skin) Prostate28% Lung & bronchus14% Colon & rectum9% Leuk/Lymphoma8% Urinary bladder6% Melanoma (skin)5% Kidney5% 2010 Estimated US Cancer Cases* P272

11. Source: American Cancer Society, 2010. Men 300,430 Women 271,520 26%Lung & bronchus 14%Breast 9%Colon & rectum 7%Leuk/Lymphoma 7%Pancreas 5%Ovary 3%Uterine corpus Lung & bronchus28% Prostate10% Colon & rectum 9% Leuk/Lymphoma8% Pancreas6% Liver & 5% bile duct Esophagus4% 2013 Estimated US Cancer Deaths* p272

12. Cancer Mortality Trends (1975-2006) Deaths Avoided (1991-2006) 1990 1991 1999 A B C

13. Five-year Survival Rates 30-yr Increase by Site Melanoma Breast (F) Prostate Rectum Leukemia All Sites Lung Pancreas 45 19 12 40 35 32 23 150 % Incr.

14. *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2003, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006. Lung & bronchus Colon & rectum Stomach Rate Per 10 5 Prostate Pancreas Liver Leukemia Cancer Death Rates* 1930-2007 Men Lung & bronchus Colon & rectum Stomach Breast Ovary Women Leukemia Uterus&Cx p273

15. Lifetime Probability of Cancer * 2005-2007 For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2001 to 2003. † All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder. ‡ Includes invasive and in situ cancer cases SiteRisk All sites † 1 in 2 Prostate1 in 6 Lung and bronchus1 in 13 Colon and rectum1 in 19 Urinary bladder ‡ 1 in 26 Lymphoma1 in 43 All sites † 1 in 3 Breast1 in 8 Lung & bronchus1 in 16 Colon & rectum1 in 20 Uterine corpus1 in 38 - Cervix1 in 147 Lymphoma1 in 51 SiteRisk MenWomen

16. All Sites6959 10 Breast (female)9177 14* Prostate (male)10098 2 Uterine cervix7061 9* Colon 6755 12* Kidney & Renal Pelvis6966 3 Liver & Bile Duct1510 5* * Increased from 2011 *SEER Cancer Statistics Review, 1975-2995. Bethesda, MD; NCI; 2008. available at http://seer.cancer.gov/csr/1975_2005/ Cancer 5-Yr Survival by Site and Race, 1999-2005 Site White % Difference African American

17. Lung & BronchusPancreasEsophagusStomach Cancer Survival by Site, Stage and Race

18. 4 Most Prevalent Sites 48% of Cancer Deaths 50% of Cancer Deaths 52% of Cancer Cases

19. Cancer Mortality by Age and Type

20. Stomach Carcinoma Geographic Variation 8x more common in Japan than US Incidence in Japanese immigrants to US decreases with each generation –Same as US by 3 rd generation –Iiver CA also decreases, colon and prostate increase after moving to US Possible environmental factors –Food (Sushi?) –Refrigeration (Why not South America?) –Helicobacter (Causes lymphoma, not CA) p273

21. Learning Objectives 1.US risk and relative rank of cancer. 2.3 most common cancer sites in men and women, mortality trends. 3.3 patterns genetic risk and examples. 4.4 categories of paraneoplastic syndrome. 5.Tumor stage and grade, and explain which is more important clinically.

22. Hereditary Predispositions Dominant Inheritance Pattern –Relative risk 100 – 10,000 –Marker phenotype in affected individuals –Multiple generations, many family members DNA Repair Defects –Relative risk 10 – 100 –Sensitive to environmental carcinogens –Fail to detect or repair mutations Familial Cancer Pattern –Relative risk 2 - 10 –No marker phenotype –2 or more close relatives, early onset P273-76

23. Retinoblastoma 40% familial, 60% sporadic Mutant Rb gene 10,000 fold risk Bilateral tumors in infancy Increased risk of osteosarcoma in childhood p274

24. Neurofibromatosis Café-au-lait spots and Lisch nodules –Hyperpigmented patches increase with age –Pigmented hamartomas of iris seen with slit lamp Plexiform neurofibromas Sarcomas, esp. neurogenic Two genetic types –NF1: gliomas and MPNST –NF2: early mortality of spinal astrocytomas and ependymomas p275

25. DNA Repair Defect High spontaneous mutation rate Chromosomal instability Environmental carcinogen sensitivity Four original clinical syndromes –Xeroderma pigmentosum –Ataxia-telangiectasia –Bloom’s syndrome –Fanconi’s anemia p275

26. Familial Pattern No marker phenotype Two or more close relatives Early occurrence of malignancy Multiple or bilateral tumors Examples –BRCA-1 and BRCA-2 –Lynch Syndrome (HNPCC Hereditary Non-Polyposis Colon Cancer) p275

27. Learning Objectives 1.US risk and relative rank of cancer. 2.3 most common cancer sites in men and women, mortality trends. 3.3 patterns genetic risk and examples. 4.4 categories of paraneoplastic syndrome. 5.Tumor stage and grade, and explain which is more important clinically.

28. Paraneoplastic Syndromes Symptoms unexpected for tumor type –10% of patients with advanced malignancy –may be first sign of occult malignancy –may be lethal or most debilitating of symptoms –may mimic metastatic disease, cause overstaging Endocrinopathies –Hypercalcemia in SCCA, breast –Cushing’s in oat cell Neuromuscular –Antineuronal antibodies in oat cell Dermatologic –Acanthosis nigricans 50% familial 50% paraneoplastic Coagulopathies –Trousseau’s syndrome in GI adenocarcinoma p321t

29. Learning Objectives 1.US risk and relative rank of cancer. 2.3 most common cancer sites in men and women, mortality trends. 3.3 patterns genetic risk and examples. 4.4 categories of paraneoplastic syndrome. 5.Tumor stage and grade, and explain which is more important clinically.

30. Tumor Prognosis Grading –degree of differentiation or proliferation Staging –degree of invasion and metastasis Prognostic markers –Gene expression array (Van de Vijver, MP, et al, NEJM 347:1999-2009, 12/19/02) –estrogen and progesterone receptor in breast CA –aneuploidy by flow cytometry or image analysis –cytogenetic –molecular, eg. p53, HER2-neu, N-myc P322-27

31. Tumor Grade Subjective –nuclear features, necrosis, mitotic index –many different systems of criteria for many organs –poor reproducibility Important for some tumor types –non-Hodgkin’s lymphomas (Working Formulation) –soft tissue sarcomas Useless for some tumor types –neuroendocrine neoplasms

32. WD Squamous carcinoma pearls versus PD Gastric adenocarcinoma

33. Tumor Stage Clinical or Pathologic –both correlate better with survival than grade –used for therapy selection Size of primary tumor –TX = don’t know or can’t tell –T0 or Tis = in situ (T0 no evidence of primary) –T1-T4 = increasing size or depth of invasion Lymph node metasteses –N0 = absent –N1-N3 = increasing number and range of nodes Hematogenous metasteses –M0 = no distant metasteses –M1 = distant organ metastasis

34. Learning Objectives 1.US risk and relative rank of cancer. 2.3 most common cancer sites in men and women, mortality trends. 3.3 patterns genetic risk and examples. 4.4 categories of paraneoplastic syndrome. 5.Tumor stage and grade, and explain which is more important clinically.

35. Answers to Learning Objectives 1.1,665,540 new cases, 585,720 deaths 23% all deaths 2 nd after cardiovascular 2.Lung, Breast/Prostate, Colorectal 3.Dominant–Rb, NF-1 DNA Repair–XP Familial–BRCA-1,2 4.Unexpected: Endocrinopathy, Neuromuscular, Dermatologic, Coagulopathy 5.Stage – invasion & metastasis, Grade – microscopic appearance