(Published May 2013)
Cervical cancer is highly preventable with screening and early intervention. Despite this fact, in 2013 there will be about 12,340 new cases of cervical cancer in the United States.1
Cervical cancer is the long-term sequela of a sexually transmitted and persistent infection with human papillomavirus (HPV). Persistent infection with a high-risk type of HPV is necessary for progression to a cancer precursor lesion and to invasive cervical cancer. Oncogenic HPV also has a causal role in other lower genital tract cancers, including penile, vaginal, vulvar, and anal, as well as non-genital cancers of the oropharynx.
For a patient with cervical cytology abnormalities and a positive HPV test result, ideal management must balance (1) the need to identify and treat abnormalities that are likely to progress to invasive cancer with (2) the need to avoid unnecessary treatment of abnormalities related to transient HPV infection that is unlikely to lead to invasive cancer. Testing for HPV infection, screening for HPV-related disease, and managing HPV-associated conditions can be challenging topics for health care providers to master, especially with the shifts in recommendations about management that have occurred in response to the introduction of HPV testing.
This Quick Reference Guide for Clinicians offers concise guidance on the HPV-related issues that tend to be the most perplexing for front-line providers: the realities of HPV transmission and natural history, current recommendations for cervical cancer screening, efficacy and safety of the HPV vaccine, and key counseling messages for HPV and HPV-related diseases. For information about related topics that are covered thoroughly elsewhere, such as diagnosis and management of external genital warts and management of abnormal screening results for cervical cancer, please refer to Appendix B
Only a well-informed health care professional can effectively communicate with patients about HPV-related risks, dispel myths, and supply accurate information about the virus, associated conditions, and appropriate medical care. This Quick Reference Guide will highlight important areas of concern, clarify the optimal screening for and management of HPV-related disease, and provide useful tips for counseling patients about HPV, ultimately helping providers close the gap between ideal and delivered care.
Abbreviations and Acronyms used in this Guide:
- ACIP Advisory Committee on Immunization Practices
- ACS American Cancer Society
- AGC atypical glandular cells
- ACOG American College of Obstetricians and Gynecologists
- AIN anal intraepithelial neoplasia
- AIS adenocarcinoma in situ
- ASCCP American Society for Colposcopy and Cervical Pathology
- ASC-H atypical squamous cells; cannot exclude HSIL
- ASCP American Society for Clinical Pathology
- ASC-US atypical squamous cells of undetermined significance
- CDC Centers for Disease Control and Prevention
- CIN cervical intraepithelial neoplasia
- DES diethylstilbestrol
- FDA Food and Drug Administration
- HIV human immunodeficiency virus
- HPV human papillomavirus
- HSIL high -grade squamous intraepithelial lesion
- LSIL low-grade squamous intraepithelial lesion
- NOS not otherwise specified
- OC oral contraceptive
- SCC squamous cell carcinoma
- STIs sexually transmitted infections
- USPSTF United States Preventive Services Task Force
Introduction to HPV-Related Diseases
- Genital human papillomavirus (HPV) infection is the most commonly diagnosed sexually transmitted infection in the United States, based on estimates from HPV DNA testing.2
- HPV infection is necessary for the development of cervical cancer.3
- Virtually all cervical cancers are associated with persistent infection with high-risk types of HPV.4
- High-risk HPV is also associated with cancer of the penis, vagina, vulva, anus, and oropharynx.5
- Approximately half of all cases of invasive cervical cancer in the United States occur in women who were never screened; an additional 10% of cervical cancers occur among women not screened within the past 5 years.6,7
- In 2013, an estimated 12,340 cases of invasive cervical cancer will be diagnosed and an estimated 4,030 women will die from cervical cancer the United States.1
- Each year, almost 900,000 women in the United States have an abnormal Pap test result associated with HPV 16, one of the high-risk types of HPV.8,9
Incidence and Prevalence
- Approximately 6.2 million new HPV infections occur in the United States each year among people ages 14 to 44.10
- Approximately 20 million people in the United States currently are infected with HPV.11
- HPV prevalence varies by age and is highest for young women.12
- New HPV infection is common for young women with a new sex partner.13
- In one study of female college students, 39% of those who initially had a negative result for HPV DNA tested positive two years later. 13
- By age 50, 80% of sexually active women will have acquired genital HPV infection.11
- HPV is transmitted through sexual intercourse and genital skin-to-skin contact.14
- Genital HPV infections are acquired through direct genital contact rather than body fluids, like most sexually transmitted infections (STIs).13
- Sexual intercourse is not necessary for infection; however, HPV is most easily transmitted to the cervix through male-to-female penetrative intercourse.
- Genital HPV infection by other routes is less common than infection through intercourse.14
- The virus can be transmitted through oral-genital contact.14,15
- Receptive anal intercourse is strongly associated with HPV infection.14
- Anal intercourse is not a requirement for the development of anal HPV infection, anal intraepithelial neoplasia (AIN), or anal cancer.
- Men who have sex with men (MSM) and women who have sex with women are at risk for HPV infection.
- HPV is not thought to survive for long on inanimate objects; however, it is possible that transmission could occur through objects shared in the short term, such as insertive sex toys.16
- The primary risk factor for cervical cancer is persistent infection with high-risk HPV.17
- Persistent infection has been defined as detection of the same high-risk HPV genotype two or more times within a given interval of time; however, the duration of time that defines ¡°persistence¡± is not yet agreed upon.18
- The average episode of HPV infection lasts 4 to 20 months.2
- Within 2 years, about 90% of HPV infections are cleared by the immune system. The remaining 10% of infections that persist are strongly linked to a high risk of a pre-cancer diagnosis.19,20
- Women with persistent high-risk HPV infection have a 300 times greater risk of developing high -grade squamous intraepithelial lesion (HSIL) than women who are negative for HPV.21
- HPV type 16 persists longer than other types and also is especially carcinogenic; the risk of cervical intraepithelial neoplasia-3 (CIN3) is 40% at 5 years.18
- Studies on the natural history of high-risk HPV infection in men are ongoing.15, 22
- A large, prospective, multi-national study of men, undertaken by Dr. Anna Giuliano and colleagues in 2005, is currently studying men living in Brazil, Mexico, and the United States who are HIV-negative and who have no history of cancer.
- The aims of the study are to establish a cohort of at least 3,000 men to determine the incidence and persistence of specific HPV types in men, study the immune response of men to HPV infection, and identify factors related to the acquisition, persistence, and clearance of various HPV types.
- The results of the study are ongoing and new data emerges daily.22
|Table 1: HPV Types Associated with Cancer and External Genital Warts23,24|
|Most Common High-Risk Types||12 Low-Risk Types|
|Selected types||16, 18, 31, 33, 35, 45, 52, 58||6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP6108 (89)|
|Associated abnormalities||Low-grade cervical lesions||Low-grade cervical lesions|
|High-grade cervical and other anogenital lesions||External genital warts|
|Cervical and other anogenital cancers|
- More than 120 types of HPV have been identified.25,26
- About 40 types can infect the genital tract.3
- Approximately 13 to 18 types are considered high risk, meaning that persistent infection with these types is associated with an increased risk of cervical, anogenital, and other cancers. (The number of types considered high risk has varied in different studies).25-27
- The International Agency for Research on Cancer (IARC) has classified 12 carcinogenic HPV types (including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), one type that is probably carcinogenic (HPV type 68), and several possibly carcinogenic types.28,29
- The most important high-risk types are 16 and 18. Type 16 alone causes 50% to 60% of all cases of cervical cancer. Type 18 causes another 10% to 12% of all cases.30
- In one large international retrospective study, HPV types 16 and 18 were detected in 71% of cases of invasive cervical cancer; HPV types 16, 18, and 45 accounted for 75% of squamous cell carcinomas and 94% of cervical adenocarcinomas.24
- Another study showed that women with normal cytology who were HPV 16+ and HPV 18+ were at the highest risk of developing ¡ÝCIN3.31
- Low-risk HPV types, the most important of which are 6 and 11, are associated with external genital warts, or condylomata acuminata, and with low-grade cervical lesions.32
- Approximately 12 HPV types have been classified as low-risk types.3
Risk Factors for HPV Infection
- The most consistent predictors of HPV infection are measures of sexual activity, such as:14
- Lifetime number of partners
- Younger age at sexual debut
- Lack of condom use
- Partner with a history of multiple partners
- In a study of female college students, nearly 30% of the cohort tested positive for HPV within 1 year of first intercourse with a male sex partner. The risk increased when the partner was sexually experienced. These results indicate that women are at high risk of acquiring an HPV infection from just one male sex partner.33
- Because the virus is transmitted by skin-to-skin contact, condoms do not completely prevent infection. According to one study, however, women whose partners used condoms consistently were 70% less likely to acquire an HPV infection than women whose partners did not use condoms consistently.13
Role of Persistent Infection in Progression to Invasive Cervical Cancer
- The current etiologic model for the development of invasive cervical cancer highlights persistent infection with high-risk HPV types as a necessary, but not sufficient, cause of cervical cancer. This model also incorporates the role of co-factors, such as:
- History of smoking
- Smoking is clearly associated with neoplastic progression.3,14
- However, it is still unclear at what stage or stages smoking influences the development of cancer (i.e., HPV persistence, progression to precancer, or development of invasive cancer) and by what molecular mechanisms.34
- Nutritional deficiencies
- Women with human immunodeficiency virus (HIV) are at higher risk of HPV infection, HPV persistence, and HPV-related CIN and cancer.35,36
- Long-term oral contraceptive (OC) use
- Some studies have suggested that OC use and the presence of other STIs may act as co-factors in neoplastic progression, persistence of HPV infection, or both.2
- However, OC use may be a proxy for measures of sexual activity that are associated with increased risk of HPV infection (listed previously).
- There is insufficient evidence to recommend that women who have infection with a high-risk HPV type should discontinue OC use.
- History of smoking
- Infection with HPV type 16 tends to persist longer than infection with other HPV types.2
- Certain HPV types (e.g., type 16) are more likely to induce progression toward malignancy.3
- Studies suggest that condom use reduces the risk of high-grade cervical lesions, increases HPV clearance, and promotes regression of HPV-related disease.37
When counseling a patient about HPV prevalence, transmission, and risk factors, explain these points:
Patient Education Fact Sheet: Making Sense of Cervical Cancer
- American Cancer Society. Cervical Cancer. Available at: http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-key-statistics. Accessed March 19, 2013.
- Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine. 2006;24(Suppl 1):S4-15.
- Munoz N, Castellsague X, de Gonzalez AB, Gissmann L. HPV in the etiology of human cancer. Vaccine. 2006;24(Suppl 3):S1-10.
- Walboomers, JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12-19.
- Parkin DM, Bray F. Chapter 2: the burden of HPV-related cancers. Vaccine. 2006;24(Suppl 3):S11-25.
- Freeman H, Wingrove B. Excess cervical cancer mortality: A marker for low access to health care in poor communities. Rockville, MD: National Cancer Institute, 2005.
- Spence, AR, Goggin P, Franco EL. Process of care failures in invasive cervical cancer: systematic review and meta-analysis. Prev Med. 2007;45:93-106.
- Davey DD, Neal MH, Wilbur DC, Colgan TJ, Styer PE, Mody DR. Bethesda 2001 implementation and reporting rates: 2003 practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med. 2004;128(11):1224-9.
- Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention; Advisory Committee on Immunization Practices. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices. MMWR. 2007;56(RR-2):1-24.
- Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004;36:6-10.
- Centers for Disease Control and Prevention. Self-Study STD Module ¨C Genital Human Papillomavirus (HPV) Infection. Available at: http://www2a.cdc.gov/stdtraining/self-study/hpv.asp. Accessed September 11, 2012.
- Hariri S, Unger ER, Sternberg M, et al. Prevalence of genital human papillomavirus among females in the United States: the National Health and Nutrition Examination Survey, 2003-2006. J Infect Dis. 2011;204(4):566-73.
- Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218-26.
- Burchell, AN, Winer RL, de Sanjose S, Franco EL. Epidemiology and transmission dynamics of genital HPV infection. Vaccine 2006:24(Suppl 3):52-61.
- Hernandez BY, Wilkens LR, Zhu X, Thompson P, McDuffie K, Shvetsov YB. Transmission of human papillomavirus in heterosexual couples. Emerg Infect Dis. 2008;14:888-92.
- Trottier H, Franco EL. Human papillomavirus and cervical cancer: burden of illness and basis for prevention. Am J Manag Care. 2006;12:S462-72.
- Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370:890-907.
- Moscicki A-B, Schiffman M, Kjaer S, Villa LL. Updating the natural history of HPV and anogenital cancer. Vaccine. 2006;24(Suppl 3):42-51.
- Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler, CM, ALTS Group. A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis. 2007:195(11):1582-9.
- Rodriguez AC, Schiffman M, Herrero R, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst. 2008; 100:513-7.
- Bory JP, Cucherousset J, Lorenzato M, et al. Recurrent human papillomavirus infection detected with the hybrid capture 2 assay selects women with normal cervical smears at risk for developing high grade cervical lesions: a longitudinal study of 3,091 women. Int J Cancer. 2002;102:519-25.
- Giuliano AR, Lee J-H, Fulp W, et al. Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study. Lancet. 2011;377(9769):932-40.
- Schiffman M, Clifford G, Buonaguro F. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer. 2009;4:8.
- de Sanjose S, Quint WG, Alemany L, et al. Retrospective International Survey and HPV Time Trends Study Group. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11:1048-56.
- de Villiers EM, Gunst K, Stein H, Scher¨¹bl H. Esophageal squamous cell cancer in patients with head and neck cancer: prevalence of human papillomavirus DNA sequences. Int J Cancer. 2004;109:253-8.
- zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst. 2000;92:690-8.
- Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518-27.
- Bouvard V, Baan R, Straif K, et al. A review of human carcinogens¡ªpart B: biological agents. Lancet Oncol. 2009;10(4):321-2.
- Schiffman M, Wentzensen N, Wacholder S, Kinney W, Gage J, Castle P. Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst. 2011;103:368-83.
- Bosch FX, de Sanjos¨¦ S. Chapter 1: human papillomavirus and cervical cancer¡ªburden and assessment of causality. J Natl Cancer Inst Monogr. 2003;31:3-13.
- Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072-9.
- Soper D. Reducing the health burden of HPV infection through vaccination. Infect Dis Obstet Gynecol. 2006;14:1-5.
- Winer RL, Feng Q, Hughes JP, O¡¯Reilly S, Kiviat NB, Koutsky LA. Risk of female human papillomavirus acquisition associated with first male sex partner. J Infect Dis. 2008;197(2):279-82.
- Castle PE. How does tobacco smoke contribute to cervical carcinogenesis? J Virol. 2008;82(12):6084-6.
- Moscicki AB, Ellenberg JH, Farhat S, Xu J. Persistence of human papillomavirus infection in HIV-infected and -uninfected adolescent girls: risk factors and differences, by phylogenetic type. J Infect Dis. 2004;190:37-45.
- Palefsky J. Biology of HPV in HIV infection. Adv Dent Res. 2006;19(1):99-105.
- Hogewoning CJ, Bleeker MC, van den Brule AJ, et al. Condom use promotes regression of cervical intraepithelial neoplasia and clearance of human papillomavirus: a randomized clinical trial. Int J Cancer. 2003;107:811-6.
About Audrey Kelly, PharmD