Epidemiology, Predispositions and Clinical Course of

Cancer

Darrell Davidson, MD, PhDDepartment of Pathology and

Laboratory Medicine

For the MD, PhD Candidates

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.

• 1 in 4 chance of cancer death (23%)– 1.67x106 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– Men 0.6 %/yr (2005-2009)– Women stable (2005-2009)

• Cancer death rate decreasing– Men 1.8 %/yr (2005-2009)– Women 1.5 %/yr (2005-2009)

US Cancer Overall

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1. Heart Diseases 599,413 24.6

2. Cancer 567,588 23.3

3. Chronic lower respiratory diseases 137,353

5.6

4. Cerebrovascular diseases 128,842 5.3

5. Accidents (Unintentional injuries) 118,021

4.8

6. Alzheimer disease 79,003 3.2

7. Diabetes mellitus 68,705

2.8

8. Influenza & pneumonia 53,692

2.2

Cause of DeathNo. of deaths

% of all deaths

US Mortality Causes 2009

National Center for Health Statistics, Center for Disease Control and Prevention

Relative Importance of Cancer

• 2nd overall cause of death– after Heart Disease – before COPD, CVA, Accidents

• 4th cause of death before age 19– after Accidents, Homicide and Suicide– before Congenital Anomalies and Heart Disease – 2nd cause before age 14

• Exclusions– Non-melanoma skin cancers (~3,500,000)– CIS except bladder (125,940 breast & melanoma)

* 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

19.8

193.9

586.8

48.1

180.7217.0

185.8

50.0

0

100

200

300

400

500

600

HeartDiseases

CerebrovascularDiseases

Pneumonia/Influenza Cancer

1950

2004

Rate Per 105

Change in US Death Rates* 1950 & 2004

Cancer Incidence Trends inMen and Women (1975-2009)

Decreasingprostate,lung, colon

Increasingliver, renal, melanoma, pancreas

Decreasingbreast,colon

Increasingthyroid, renal, melanoma, pancreas

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.

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2010.

Men822,300

Women774,370

29% Breast

14% Lung & bronchus

9% Colon & rectum

7% Leuk/Lymphoma

6% Uterine corpus

6% Thyroid

4% Melanoma (skin)

Prostate 28%

Lung & bronchus 14%

Colon & rectum 9%

Leuk/Lymphoma 8%

Urinary bladder 6%

Melanoma (skin) 5%

Kidney 5%

2010 Estimated US Cancer Cases*

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Source: American Cancer Society, 2010.

Men300,430

Women271,520

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%

Pancreas 6%

Liver & 5%bile duct

Esophagus 4%

2013 Estimated US Cancer Deaths*

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Cancer Mortality Trends (1975-2006)

Deaths Avoided (1991-2006)

1990

1991

1999

A

B

C

*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.

0

20

40

60

80

1001930

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

Lung & bronchus

Colon & rectumStomach

Rate Per 105

Prostate

Pancreas

Liver

Leukemia

Cancer Death Rates* 1930-2007Men

0

20

40

60

80

100

1930

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

Lung & bronchus

Colon & rectum

Stomach

Breast

Ovary

Women

Leukemia

Uterus&Cx

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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

Site Risk

All sites† 1 in 2

Prostate 1 in 6

Lung and bronchus 1 in 13

Colon and rectum 1 in 19

Urinary bladder‡ 1 in 26

Lymphoma 1 in 43

All sites† 1 in 3

Breast 1 in 8

Lung & bronchus 1 in 16

Colon & rectum 1 in 20Uterine corpus 1 in 38 - Cervix 1 in 147

Lymphoma 1 in 51

Site Risk

Men Women

All Sites 69 59 10

Breast (female) 91 77 14*

Prostate (male) 100 98 2

Uterine cervix 70 61 9*

Colon 67 55 12*

Kidney & Renal Pelvis 69 66 3

Liver & Bile Duct 15 10 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%

DifferenceAfrican

American

Lung & Bronchus Pancreas Esophagus Stomach

Cancer Survival by Site, Stage and Race

4 Most Prevalent

Sites

48% of Cancer Deaths

50% of Cancer Deaths

52% of Cancer Cases

52% of Cancer Cases

Cancer Mortality by Age and Type

0

5

10

15

20

25

30

35

40

45

all ages under 15 15 - 34 35 - 54 55 - 74 age 75+

% C

A d

eath

s in

ag

e g

rou

p

lung

br/prost

colon

pancreas

leuk/NHL

CNS

sarcomas

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 3rd 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)

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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.

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

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Retinoblastoma• 40% familial, 60%

sporadic• Mutant Rb gene 10,000

fold risk• Bilateral tumors in

infancy• Increased risk of

osteosarcoma in childhood

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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

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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

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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)

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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.

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

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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.

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

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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

WD Squamous carcinoma pearls versus PD Gastric adenocarcinoma

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

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.

Answers to Learning Objectives

1. 1,665,540 new cases, 585,720 deaths23% all deaths2nd after cardiovascular

2. Lung, Breast/Prostate, Colorectal

3. Dominant–Rb, NF-1DNA Repair–XPFamilial–BRCA-1,2

4. Unexpected: Endocrinopathy, Neuromuscular, Dermatologic, Coagulopathy

5. Stage – invasion & metastasis,Grade – microscopic appearance