1. Cancers Linked to HPV Presenter: Chuck Lynch
2014 Iowa Cancer Summit
Cancers Linked to HPV Presenter: Chuck Lynch

2. During this presentation I will mention Gardasil and Cervarix, the two HPV vaccines currently approved by the FDA; I have no commercially vested interest in either of vaccines

3. Overview Human papillomavirus (HPV) Cancer sites associated with HPV
Cervical cancer and HPV
Head and neck cancer and HPV
Prevention and control

4. Human Papillomaviruses (HPV)
ds DNA viruses- Papillomaviridae family
>130 known HPV genotypes
> 40 genital HPV genotypes
15 HPV genotypes associated with high cancer risk (high-risk HPV genotypes)
HPV-16 most common

5. HPV Infection
One of the most common sexually transmitted infections worldwide 1
Estimated 14 million newly infected annually in U.S. 2
Most people who become infected do not know they have it 1
About 79 million persons in U.S. are infected 2
HPV cleared from body in 90% of infected people within two years – no health-related problems 1
Remaining 10% have persistent infection 1
Within 30 years, about half develop cancer
1Zandberg DP et al. Ca Cancer J Clin 2013.
2http://

6. Human Papillomavirus (HPV)
HPV-related cancers are defined as cancers at specific anatomic sites with specific cellular types in which HPV DNA is frequently found and include the back of the oral cavity and tonsils, anus, penis, cervix, vagina, and vulva
Necessary, but not sufficient, cause of these cancers
HPV-16 infection is the single most common high-risk type in most regions of the world, including Iowa
Estimated 70% of cervical cancers caused by types 16 and 18
In Iowa between 2006 and 2011, there were 2100 cancers diagnosed at HPV-related sites; 75% of these were likely caused by HPV infection.
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7. Schiffman M et al. Lancet, 2007.
HPV Biology
Schiffman M et al. Lancet, 2007.

8. HPV-Attributable Cancer Cases per Year, U. S
HPV-Attributable Cancer Cases per Year, U.S., CDC HPV Study Site Definitions Annually, about 33,000 new cases of cancer are found in parts of the body where human papillomavirus (HPV) is often found. HPV causes about 26,700 (81%) of these cancers
HPV-related % % % % % % % %

9. Age and Year of Diagnosis
Age-adjusted incidence rates (number of cases) of HPV-related among females, year and age of diagnoses, Iowa (Rates are per 100,000 and age-adjusted to the 2000 U.S. standard population)
Age and Year of Diagnosis
Cervix
Vagina
Vulva
Anus
Oropharynx**
<60
9.3 (593)
0.1 (7)
0.8 (48)
0.3 (16)
0.5 (32)
6.4+ (448)
0.2 (13)
1.5+ (117)
1.3+ (105)
0.7 (59)
60+
15.0 (289)
1.9 (39)
7.9 (159)
3.4 (66)
4.3 (82)
7.8+ (154)
1.5 (31)
8.1 (176)
5.2 (105)
4.4 (88)
Probably caused by HPVŧ
91%
75%
 69%
91%^
72%^
@ Cases are invasive, microscopically-confirmed, squamous cell carcinomas except for cervical cancer where adenocarcinomas are also included.
**Oropharynx subsites include base of tongue, tonsil, lingual and palatine tonsils, oropharynx, pharynx, and Waldeyer ring.
+Rate is significantly different (p < 0.05) from corresponding rate.
ŧData source: ^Percent is for males and females combined.

10. Year and Age of Diagnosis
Age-adjusted incidence rates (number of cases) of HPV-related among males, year and age of diagnoses, Iowa (Rates are per 100,000 and age-adjusted to the 2000 U.S. standard population)
Year and Age of Diagnosis
Anus
Oropharynx*
Penis
<60
0.3 (15)
1.8 (103)
0.3 (19)
0.6+ (50)
4.2+ (367)
0.2 (19)
60+
1.0 (14)
11.4 (164)
4.2 (57)
2.0 (32)
16.7+ (274)
4.5 (69)
Probably caused by HPVŧ
91%^
72%^
63%
@ Cases are invasive, microscopically-confirmed, squamous cell carcinomas except for cervical cancer where adenocarcinomas are also included.
*Oropharynx subsites include base of tongue, tonsil, lingual and palatine tonsils, oropharynx, pharynx, and Waldeyer ring.
+Rate is significantly different (p < 0.05) from corresponding rate.
ŧData source:
^Percent is for males and females combined.

11. Percent Distribution of HPV-related HNSCC in Iowa, 2006-2011 CDC HPV Study Site Definitions
Males (n=811)
Females (n=1296)

12. Pap Screening Tests for Asymptomatic Female Patients
Cervical Cancer (
Pap Screening Tests for
Asymptomatic Female Patients
USPSTF
Recommends screening for cervical cancer in women age 21 to 65 years with cytology (Pap smear) every 3 years or, for women age 30 to 65 years who want to lengthen the screening interval, screening with a combination of cytology and human papillomavirus (HPV) testing every 5 years.
Recommends against screening
For women who have had a total hysterectomy for benign disease
For cervical cancer in women younger than age 21 years
For cervical cancer in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer.
For cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer
For cervical cancer with HPV testing, alone or in combination with cytology, in women younger than age 30 years
Current ACS guidelines very similar

13. Normal
Pap Smear
Normal Pap Smear

14. Abnormal Pap Test Findings Severe dysplasia / CIN III / HSIL
Mild dysplasia / CIN I / LSIL
Severe dysplasia / CIN III / HSIL
Moderate dysplasia / CIN II / HSIL
Squamous cell carcinoma

15. Malignant Cervical Cancer Rates, Iowa, (Rates are per 100,000 men and age-adjusted to the U.S population.)
15% decrease in incidence between 1994 and 2006
64% decline between 1973 and 2010
40% decrease in mortality between 1994 and 2008
58% decline between 1973 and 2010

16. Percent of Iowa Female Population Who have had a Pap Test within the Past Three Years by Age Group and Year (
Age Group

17. Percent of Iowa Female Population Who have had a Pap Test within the Past Three Years by Education and Year (

18. approved first vaccine (Gardasil) against HPV types 6, 11, 16 and 18.
On June 8, 2006, FDA
approved first vaccine
(Gardasil) against HPV
types 6, 11, 16 and 18.

19. Estimated 85% of 270,000 annual cervical
cancer deaths occur in developing nations

20. 90-95% squamous cell carcinomas
Head and Neck Cancers
90-95% squamous cell carcinomas

21. Cancer involving tonsil
Causal Evidence
Strong and consistent for oropharynx
Base of tongue, tonsil, pharynx
Weak and inconsistent
for oral cavity
Cancer involving tonsil

22. HPV-related HNSCC Subset of HNSCCs (oropharynx)
Base of tongue
Lingual and palatine tonsils
Pharynx
Predominantly HPV-16 (95%)

23. Blue-shaded = HPV-related; Orange-shaded = non-HPV-related
Percent Distribution of HNSCC in Iowa by HPV-related Site Status, CDC HPV Study Site Definitions
Blue-shaded = HPV-related; Orange-shaded = non-HPV-related

24. Age Distribution of HNSCC in Iowa by HPV Status, 2006-2011 CDC HPV Study Site Definitions

25. Rising Incidence of Oropharynx Cancers in U.S.
Declining incidence for oral cavity cancers
Decrease in smoking
Increasing incidence for oropharyngeal cancers
Chaturvedi et al, JCO, 2008.

26. Increased Incidence of HPV-positive Oropharynx Cancers
HPV-positive: 225% increase
HPV-negative: 50% decline
Overall oropharynx: 28% increase
Reweighted prevalence: 70% HPV-positive in 2004
Chaturvedi et al, JCO, 2011.

27. Future Burden of HPV-positive OPC
More OPC than cervical cancers by 2010
More HPV-positive OPC than cervical cancers by the year 2020
8600 HPV+ OPC
7700 cervical cancers
Majority occurring among men (7400 cases)
Chaturvedi et al, JCO, 2011.

28. Summary HPV-positive vs. HPV-negative HNSCCs
Distinct Characteristics of
HPV-positive HNSCCs
Epidemiologic
Predominantly among
-Young individuals
-Men
-Never smokers?
-Never drinkers?
Molecular
Low TP53 mutations
P16 overexpression
Distinct gene expression profile
Clinical
Better prognosis
Better response to chemoradiation

29. Prevention and Control Screening for HPV-associated OPCs
Not currently feasible
Cervix / Oral Cavity
Oropharynx
Precursor lesions
Well-defined ?
Screening tests
Cytology/histology
Difficult to visualize/sample
Treatments
Available
Kreimer AR et al. Can Prev Res, 2011.

30. Primary Prevention: HPV Vaccination
High efficacy of prophylactic HPV vaccines at anogenital sites
Vaccination anticipated to have equivalent efficacy in prevention of oropharynx HPV persistence, but no clinical trial data on efficacy
Site
Efficacy against persistent infection/ precursors
Cervix
91% to 98%
Anus
78% to 95%
Penis
90%
Vagina
100%
Vulva
Oropharynx ?

31. Primary Prevention: HPV Vaccination
Vaccines licensed by FDA; cost-effective
Gardasil (HPV4) targets HPV types 6, 11, 16, and 18
Cervarix (HPV2) targets HPV types 16 and 18
Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of females at age 11 or 12 years and catch-up vaccination for females aged 13 through 26 years
ACIP guidance for males: HPV4 given aged through 21 years to reduce likelihood of acquiring genital warts
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32. Primary Prevention: HPV Vaccination
High-coverage HPV vaccination programs resulting in rapid reduction of:
Genital warts
Cervical cytologic abnormalities
Diagnostic and therapeutic procedures
Reduction in cancer rates should follow
Since HPV vaccination does not protect against all cancer-causing types of HPV, vaccinated and unvaccinated women should still be screened for cervical cancer via Pap test
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33. Primary Prevention: HPV Vaccination
In 2012, data collected in the CDC’s National Immunization Survey-Teen showed state-level HPV vaccination coverage levels for one or more doses varied widely from 39% of adolescent girls in Florida to 74% in Rhode Island
Iowa’s percent was 58%
Iowa’s percent for three doses was 36%
Same survey showed that 21% of adolescent boys ages 13 through 17 nationwide and 19% in Iowa had received one or more doses of HPV vaccine
Major medical societies recently released “Dear Colleague” letter that encourages providers to promote HPV vaccination (
Health care advocate recommendations key to increasing this vaccination
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34. Conclusions
HPV is a strong risk factor for a subset of HNSCCs– base of tongue, tonsil, and pharynx
Recent increases in oropharynx cancers in the U.S. are caused by HPV infection; not smoking/alcohol
Should recent incidence trends continue, there will be more HPV-positive oropharynx cancers than cervical cancers in the U.S. by 2020
HPV vaccines should be effective against HPV oropharyngeal cancers
Health care advocates need to promote HPV vaccination
Since HPV vaccination does not protect against all cancer-causing types of HPV, vaccinated and unvaccinated women should still be screened for cervical cancer via Pap test

35. ?? ?? Questions ?? ??