1.
Epidemiology of Cervical
Cancer and the Role of
Human Papillomavirus

2.
Snapshot of Cervical Cancer
ò Each year, 500,000 incident cases and at least
200,000 deaths
ò 2nd most common cancer in women
ò United States:
ò American Cancer Society estimates 12,340 new
cases and 4,030 deaths in 2013
ò Major global and national disparities

3.
Age-Adjusted Incidence Rates
(per 100,000, by race, USA)
0
5
10
15
20
25
30
35
1973 1978 1983 1988 1993 1998
Year of Diagnosis
Black
White

4.
Age-Adjusted Mortality Rates
(per 100,000, by race, USA)
0
2
4
6
8
10
12
14
1973 1978 1983 1988 1993 1998
Black
White

5.
Annual Estimated Incidence and Mortality
Rates (per 100,000)
0 1 0 2 0 3 0 4 0 5 0
Western Asia
Northern America
Western Europe
Eastern Europe
South-Eastern Asia
South Central Asia
Southern Africa
South America
Eastern Africa
Mortality Incidence
International Agency for Research on Cancer

6.
Cause of Cervical Cancer
What we knew in 1980
ò Rigoni-Stern (1842): Cervical cancer is uncommon
in nuns and virgins
ò Cervical cancer precursor lesions can be detected
early and treated
ò Studies suggest earlier age of first intercourse and
greater number of partners associated with
increased risk
ò Variety of infections suspected

7.
Cause of Cervical Cancer
What we knew in 1990
ò Zur Hausen (1983): identification of HPV DNA
sequences in cervical biopsy specimens
ò Early studies utilize assays that are insensitive
and HPV infection is not adequately assessed
ò Conclude that various factors are the “cause”
of cervical cancer, e.g., smoking, HSV-2
ò HPV does not appear to be a risk factor in early
studies

8.
HPV and Cervical Cancer
Early Case-Control Studies
using PCR, 1994
Country Invasive
Cancer
Controls Odds
Ratio
No. %
HPV+
No. % HPV
+
Spain 142 69% 130 5% 46.2
Colombia 87 72% 98 13% 15.6

9.
Multi-National
Case-Control Studies
ò 2288 consecutive cases in 13 countries
ò HPV DNA prevalence
ò 91% in cases
ò 14% in controls
ò Cases were 83.3 times (95% CI: 54.9, 105.3) more
likely to have HPV compared to controls, adjusted for
age and country
ò Further analyses restricted to HPV+ in order to study
additional risk factors
ò Oral contraceptives
ò Parity
ò Smoking

10.
Causal Link Between HPV
and Cervical Cancer
ò Has been confirmed by additional case-control
studies as well as prospective studies
ò Strong and consistent
ò Association of HPV and cervical cancer holds all
over the world
ò HPV also associated with precursors of cervical
cancer (“cervical neoplasia”)
ò Fulfills all epidemiologic guidelines for causality

11.
Epidemiology of HPV
Key Features
ò Common infection, particularly in young,
sexually active individuals (Ho, 1998)
ò Cumulative 36-month incidence = 45%
ò Median duration new infections = 8 months
ò 100+ HPV types (40 infect the genital tract)
ò Categorized according to risk for cervical cancer
ò Responsible for nearly all squamous cell
abnormalities in the cervix, other anogenital
cancers, and subset of head/neck cancers

12.
Epidemiology of HPV
HPV Types by Risk
ò High-Risk
ò 16, 18, 31, 45
ò Intermediate-Risk
ò 33, 35, 39, 51, 52, 56, 58, 59, 68
ò Low Risk
ò 6, 11
ò 26, 40, 42, 53, 54, 55, 57, 66, 73, 82, 83, 84

13.
Worldwide Prevalence of HPV
ò International study of 1000 consecutive cervical
carcinomas from 22 countries
ò HPV prevalence of 93%
ò HPV 16 in 50% of specimens
ò Four HPV types (16, 18, 31, 45) found in 80%
cancers
Bosch, JNCI, 1995

14.
Prevalence of Individual HPV Types
International Study, 1995
0
10
20
30
40
50
60
70
%
Europe North
America
C/S
America
Africa SE Asia
16 18 45 31, 33 Other Bosch, JNCI, 1995

15.
Selected Case-Control Studies
ò Chichareon, JNCI, 1998: HPV infection strongly
associated with squamous cell carcinoma and
adenocarcinoma (OR=119 and 53)
ò Liaw, JNCI, 1999: Women who are HPV DNA+ at
enrollment are more likely to have LGSIL (OR=3.8)
and HGSIL (OR=2.7), compared with women who
are HPV DNA-
ò Wallin, NEJM, 1999: Baseline HPV DNA status is
associated with cervical cancer (33% of cases were
HPV DNA+, compared to 3% of controls, OR=16.4)

16.
Prospective Studies
of HPV Infection
ò Several prospective studies with ongoing follow-
up established in 1990s
ò Diverse populations (age, region, etc.)
ò Well-suited to study question of temporality
ò Studies confirm that HPV is common and the
dominant risk factor for cervical neoplasia and
cancer
ò Investigation of related co-factors

17.
Prospective Studies
ò Koutsky et al, 1992
ò 241 women with normal Pap smears in U.S.
ò Cumulative 2-year incidence of cervical disease = 28% if HPV+ and
3% if HPV-
ò Ho et al., 1998
ò 608 college women in U.S.
ò Cumulative 36-month HPV incidence = 45%
ò Median duration of new infections was 8 months
ò Franco et al, 1999
ò 1425 low-income women in Brazil
ò 1.3% new infections/month and 38% cumulative HPV positivity after
18 months

18.
Prospective Studies
ò Moscicki et al., 2001
ò 601 females aged 13-21 years in U.S.
ò HPV and smoking risk factors for cervical disease
ò Woodman et al, 2001
ò 1075 cytologically normal women in U.K.
ò Cumulative 3-year risk of HPV infection 44%
ò Risk of disease highest for HPV-16
ò Ahdieh et al, 2001
ò 862 HIV+ women & 422 high-risk HIV- women in U.S.
ò HIV/CD4 impact HPV prevalence, incidence and type-specific
persistence

19.
HPV is a Necessary Cause of
Invasive Cervical Cancer
Worldwide
Walboomers et al, Journal of Pathology, 1999
HPV prevalence in 1000+ cervical
carcinomas from 22 countries reexamined
with more comprehensive techniques.
HPV prevalence = 99.7%

20.
HPV and Cervical Cancer
Necessary? Sufficient?
ò Necessary?
ò Walboomers et al. conclude: HPV is necessary
ò Association of HPV and cervical cancer meets Hill’s
guidelines
ò Sufficient?
ò Although many women develop HPV, a relatively
small % develop cervical precursor lesion and of
these and even smaller % develop cervical cancer
ò The role of co-factors in HPV-associated progression
largely unknown

21.
Evidence for a Causal Link
Hill’s Guidelines
ò Strength of association
ò Consistency
ò Temporality
ò Dose-response relationship
ò Biological plausibility
ò Does reduction of exposure reduce disease
Hill, Proc R Soc Med, 1965

22.
Cervical Cancer
Factors of Interest
ò HPV
ò Risk factors for HPV acquisition
ò Co-factors for progression to cervical cancer

23.
Cervical Cancer
Factors of Interest
ò HPV
ò Type (high-risk, intermediate-risk, low-risk)
ò Variant
ò Viral load

24.
Cervical Cancer
Factors of Interest
ò HPV
ò Type, variant, viral load
ò Risk Factors for HPV Acquisition
ò Age at first intercourse
ò Lifetime # of sexual partners
ò Sexual practices of male partner

25.
Cervical Cancer:
Factors of Interest
ò HPV
ò Type, variant, viral load
ò Risk Factors for HPV Acquisition
ò Age at first intercourse, lifetime # of sexual partners, sexual practices
of male partner
ò Co-factors for Progression
ò Smoking
ò Parity, Oral contraceptives
ò Immunosuppression
ò Other infectious agents (HSV-2, chlamydia)
ò Dietary factors
ò Genetic factors

26.
Transient Infection
Etiological Model of Cervical Cancer
(Adapted from Franco, 2001)
Sexual Activity
Invasive Cervical Cancer
HPV Infection
Normal Cervical Epithelium
Low-grade Lesions
High-grade Lesions
Coexisting factors:
• Smoking
• Oral contraceptive use
• Parity
• HLA
• Other STDs
• Viral variants
• Viral load
• Immunosuppression
Persistent Infection

27.
Cause of Cervical Cancer
What we know now
ò (Nearly) all cervical cancers caused by HPV
ò Case-control studies illustrate central role of
HPV infection
ò Longitudinal studies describe duration, risk
factors for persistence, risk factors for cervical
neoplasia/cancer
ò Given that many individuals are infected with
HPV, but only a subset develop cancer, co-
factors are expected to play an important role

28.
Randomizied Clinical Trial of
HPV Vaccination
ò Future II
ò Random assignment of 12,167 women
ò Ages 15-26
ò Vaccine (Gardasil) or placebo
ò Among those who had not been exposed to HPV
16/18, vaccine prevented 98% of high-grade lesions

29.
HPV Vaccine
A Public Health Victory
ò In 2006, FDA approved first HPV vaccine
ò Types 16, 18, 6, and 11
ò 100% efficacy against infection
ò A bivalent vaccine is also available
ò ACIP: Vaccination of adolescent females 11-12
years old
ò Catch up for 13-26 years
ò In 2011, recommendation expanded to included
adolescent males
ò 3 doses (within 6 months)

30.
Summary
ò Strong and consistent association between HPV and
cervical cancer
ò Role of other factors in progression of disease following
initial HPV infection
ò Pap smear screening and subsequent treatment is a
public health success
ò Major disparities persist, however
ò Tools in hand to decrease cervical cancer burden
ò Development of vaccine within 15 years of identifying
HPV in etiology of cervical cancer is a major contribution
of epidemiologic methods to public health