Epidemiology,
Predispositions and
Clinical Course of
Cancer
Darrell Davidson, MD, PhD
Department 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.
US Cancer Overall
• 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
– Women
0.6 %/yr
stable
(2005-2009)
(2005-2009)
• Cancer death rate decreasing
– Men
– Women
1.8 %/yr
1.5 %/yr
(2005-2009)
(2005-2009)
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US Mortality Causes 2009
1.
2.
3.
4.
5.
6.
7.
8.
Cause of Death
No. of
deaths
Heart Diseases
Cancer
Chronic lower respiratory diseases
Cerebrovascular diseases
Accidents (Unintentional injuries)
Alzheimer disease
Diabetes mellitus
Influenza & pneumonia
599,413
567,588
137,353
128,842
118,021
79,003
68,705
53,692
National Center for Health Statistics, Center for Disease Control and Prevention
% of all
deaths
24.6
23.3
5.6
5.3
4.8
3.2
2.8
2.2
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)
Change in US Death Rates*
1950 & 2004
600
586.8
1950
500
2004
400
Rate
Per
105
300
217.0
200
193.9
180.7
185.8
100
50.0
48.1
19.8
0
Heart
Cerebrovascular Pneumonia/
Diseases
Diseases
Influenza
Cancer
* 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
Cancer Incidence Trends in
Men and Women (1975-2009)
Decreasing
prostate,
lung, colon
Decreasing
breast,
colon
Increasing
liver, renal,
melanoma,
pancreas
Increasing
thyroid, 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.
2010 Estimated US Cancer Cases*
Men
822,300
Prostate 28%
Lung & bronchus 14%
Women
774,370
29% Breast
14% Lung & bronchus
Colon & rectum
9%
9% Colon & rectum
Leuk/Lymphoma
8%
7% Leuk/Lymphoma
Urinary bladder
6%
6% Uterine corpus
Melanoma (skin)
5%
6% Thyroid
Kidney
5%
4% Melanoma (skin)
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2010.
P272
2013 Estimated US Cancer Deaths*
Men
300,430
Women
271,520
Lung & bronchus 28%
26% Lung & bronchus
Prostate
14% Breast
10%
Colon & rectum
9%
9% Colon & rectum
Leuk/Lymphoma
8%
7% Leuk/Lymphoma
Pancreas
6%
7% Pancreas
Liver &
bile duct
5%
5% Ovary
Esophagus
Source: American Cancer Society, 2010.
4%
3% Uterine corpus
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Cancer Mortality Trends
(1975-2006)
1999
B
Deaths Avoided (1991-2006)
1990
1991
A
C
Cancer Death Rates* 1930-2007
Men
100
Women
100
Lung & bronchus
80
80
Rate 60
Per
105
40
60
Lung & bronchus
Prostate
Colon & rectum
Stomach
40
Breast
Colon & rectum
Stomach
20
20
Pancreas
Uterus&Cx
Leukemia
Ovary
*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.
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2000
1995
1990
1985
1980
1975
1970
1965
1960
1955
1950
1945
1940
1935
0
1930
2000
1995
1990
1985
1980
1975
Leukemia
1970
1965
1960
1955
1950
1945
1940
1935
0
1930
Liver
Lifetime Probability of Cancer
Men
Women
Site
Risk
Site
Risk
All sites†
Prostate
1 in 2
1 in 6
All sites†
Breast
1 in 3
1 in 8
Lung and bronchus 1 in 13
Lung & bronchus 1 in 16
Colon and rectum
1 in 19
Urinary bladder‡
1 in 26
Colon & rectum
Uterine corpus
- Cervix
Lymphoma
Lymphoma
1 in 43
1 in 20
1 in 38
1 in 147
1 in 51
† All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder.
* 2005-2007 For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2001 to 2003.
‡ Includes invasive and in situ cancer cases
Cancer 5-Yr Survival by
Site and Race, 1999-2005
Site
White
African
American
%
Difference
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
Liver & Bile Duct
69
15
66
10
3
5*
* Increased from 2011
*SEER Cancer Statistics Review, 1975-2995. Bethesda, MD; NCI; 2008. available at
http://seer.cancer.gov/csr/1975_2005/
Cancer Survival by
Site, Stage and Race
Lung & Bronchus
Pancreas
Esophagus
Stomach
52% of
Cancer
Cases
48% of
Cancer
Deaths
4 Most
Prevalent
Sites
52% of
Cancer
Cases
50% of
Cancer
Deaths
Cancer Mortality by
Age and Type
lung
br/prost
colon
pancreas
leuk/NHL
CNS
sarcomas
% CA deaths in age group
45
40
35
30
25
20
15
10
5
0
all ages under 15
15 - 34
35 - 54
55 - 74
age 75+
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
p274
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
p275
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
p321t
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
Gastric adenocarcinoma
PD
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 deaths
23% all deaths
2nd 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