HPV-Associated Cancers and Precancers

Persistent infection with oncogenic types of HPV has a causal role in nearly all cervical cancers and in many vulvar, vaginal, penile, anal, and oropharyngeal cancers (789). However, the only HPV-associated cancer for which routine screening is recommended is cervical cancer.

Cervical Cancer

Screening Recommendations

Recommendations for cervical cancer screening in the United States are based on systematic evidence reviews and are largely consistent across the major medical organizations, including ACS, ACOG, and USPSTF (124-126) (https://www.cdc.gov/cancer/cervical/index.htm). Routine cervical screening should be performed starting at age 21 years and continue through age 65 years to prevent invasive cervical cancer. Testing can be performed using either conventional or liquid-based cytologic tests (i.e., Pap tests). For women aged ≥30 years, screening can include several FDA-approved oncogenic or high risk HPV (HR-HPV) tests. For cytopathologic and HR-HPV testing, clinics should use CLIA-certified laboratories using acceptable terminology (Bethesda 2001 or LAST terminology) (790,791). Annual cervical cancer screening is no longer recommended for all women. Instead, Pap testing is recommended every 3 years from ages 21–29 years. During age 30–65 years, women should either receive a Pap test every 3 years or a Pap test plus HPV test (co-test) every 5 years; co-testing can be done by either collecting one swab for the Pap test and another for the HPV test or by using the remaining liquid cytology material for the HPV test. Because of the high negative predictive value of two tests, women who test negative for both HPV and Pap test should not be screened again for 5 years. Cervical screening programs should screen women who have received HPV vaccination in the same manner as unvaccinated women. All major medical organizations concur that no Pap testing is recommended before age 21 years.

Women should be given a copy of their test results (Pap and HPV, if applicable); those with normal results should also be provided with general recommendations regarding when to schedule follow-up visits and the importance of cervical cancer screening. Women with abnormal screening tests should be referred to providers who are experienced in managing these cases (see Follow-Up). Women should be reassured and counseled about abnormal cervical cancer screening test results and informed about any implications for sex partner(s). (See counseling messages for HPV infection and for women receiving cervical cancer screening.)

The following additional management considerations are associated with performing Pap tests:

• The Pap test should not be considered a screening test for STDs.
• All women should receive cervical cancer screening, regardless of sexual orientation (i.e., women who identify as lesbian, bisexual, or heterosexual).
• Ideally, women should be advised to have a Pap test 10–20 days after the first day of menses. However, this test can be performed during menstruation depending on menstrual flow and type of cytology used (liquid-based cytology can differentiate cells from blood and mucus; conventional Pap test might not).
• If specific infections other than HPV (e.g., chlamydia or gonorrhea) are identified at the visit, the woman might need to have a repeat Pap test after appropriate treatment for those infections. However, in most instances (even in the presence of some severe infections), Pap tests will be reported as satisfactory for evaluation, and reliable final reports can be produced without the need to repeat the Pap test after treatment is received.
• The presence of a mucopurulent discharge should not postpone Pap testing. The test can be performed after removal of the discharge with a saline-soaked cotton swab.
• In the presence of cervical friability (see Cervicitis), liquid-based cytology should be used; conventional pap testing might need to be deferred in the presence of heavy bleeding until cervicitis is treated.
• In the absence of other indications, women who have external genital warts do not need Pap tests more frequently than women who do not have warts.
• The sequence of Pap testing in relation to collection of other endocervical specimens does not influence Pap test results or their interpretation (792). In general, vaginal specimens are preferred for chlamydia and gonorrhea screening in women, but in the setting of a pelvic exam, endocervical specimens for STD testing can be collected first.
• Women who have had a total hysterectomy do not require a routine Pap test unless the hysterectomy was performed because of cervical cancer or its precursor lesions. In women whose cervix remains intact after a hysterectomy, regularly scheduled Pap tests should be performed as indicated (793-795).
• Health-care facilities that train providers on Pap test collection and employ simple quality assurance measures are more likely to obtain satisfactory test results (as determined by the laboratory).
• The use of instruments designed to sample to the cervical transformation zone (e.g., cytobrushes) improves the accuracy of Pap tests (796).
• Liquid-based cytology is an acceptable alternative to conventional Pap tests, as it has similar test-performance characteristics.
• At an initial visit, providers should ask women about their most recent Pap test and results and history of evaluation and treatment (e.g., loop electrosurgical excision procedure and colposcopy) to assist with management; every effort should be made to obtain copies of recent results. The importance and frequency of Pap testing or co-testing (Pap and HPV testing) should be reinforced.

HPV Tests for Cervical Cancer Screening

Clinical tests for oncogenic types of HPV are used for 1) cervical cancer screening in conjunction with a Pap test, 2) triage of abnormal cervical cytology results, and 3) follow-up after treatment of cervical precancers. These tests are only approved for use with cervical specimens, not oral or anal specimens. The role of testing for non-oncogenic HPV types (e.g., 6 and 11) is unclear and is not recommended.

Current FDA-cleared HPV tests detect viral nucleic acid (DNA) or messenger RNA (mRNA). Several FDA-cleared tests for HPV are available for use in the United States, but use of non-oncogenic (e.g., types 6 and 11) tests is not recommended (110). The Hybrid Capture 2 High-Risk HPV DNA test (Qiagen, Gaithersburg, Maryland) and the Cervista HPV High-Risk DNA test (Hologics, Beford, Massachusetts) detect presence of 13–14 oncogenic HPV types, whereas the Cervista HPV 16/18 DNA test only detects oncogenic HPV types 16 and 18. The Digene HC2 HPV DNA test (Qiagen, Gaithersburg, Maryland) detects 13 oncogenic or five non-oncogenic HPV types. The Cobas 4500 (Roche, Pleasanton California) test detects 14 oncogenic HPV DNA types and can detect individual types HPV 16 and 18, while the APTIMA HR HPV (Gen Probe, San Diego CA) test detects 14 oncogenic HPV types of HPV mRNA. Aptima HPV 16/18/45 test is also FDA-cleared to triage its pooled Aptima HR HPV test further, although there are no algorithms for HPV 16/18/45 testing in any clinical guidelines. HPV assays should be FDA-cleared and used only for the appropriate indications (110).

In the United States, HPV tests to detect oncogenic types of HPV infection are most commonly used to triage Pap test results indicating atypical squamous cells of undetermined significance (ASC-US) in women aged ≥25 years (110). HPV testing for oncogenic types are now being incorporated into cervical cancer screening recommendations with Pap tests (i.e., co-testing) to reduce follow-up visits in women aged >30 years (see Screening Recommendations). HPV testing can be performed on the same swab as used for the Pap test or a separate supplied swab; reflex testing of residual material of a liquid-based cytology specimen is another option. HPV testing for 16 and 18 is also used to triage discordant test results (i.e., in the case of a negative Pap test and positive HPV test). In the future, oncogenic (high-risk) HPV tests might be considered for primary cervical cancer screening, but no such recommendation has been made by any medical organization.

HPV testing (including oncogenic HPV and HPV 16/18 tests) should not be performed in the following situations:

• Deciding whether to vaccinate against HPV;
• Conducting STD screening in women or men at risk for STDs;
• Providing care to persons with genital warts or their partners;
• Conducting screening for cervical cancer as a stand-alone test (i.e., without a concurrent Pap test);
• Testing women aged <30 years as part of routine cervical cancer screening; or
• Testing oral or anal specimens.

Follow-Up

If the results of the Pap test are abnormal, follow-up care should be provided according to ASCCP 2012 Consensus Guidelines for Management of Abnormal Cervical Cytology (110). If clinic resources do not allow for follow-up of women with abnormal results, protocols for linkage to follow-up care and management should be in place. The following are highlights of the ASCCP guidelines.

• Women aged 21–24 years are managed more conservatively than other women because of potential harms of overtreatment and low risk for cancer. For women in this age group who have ASC-US or LSIL, cytology should be repeated in 12 months.
• For women with ASC-US cytology, either cytology can be repeated in 12 months (for women of all ages) or reflex HPV testing can be performed (for women aged ≥25 years).
• For women with ASC-US who are HPV negative, a repeat HPV and Pap test in 3 years is recommended.
• For women who have normal cytology but lack endocervical cells, a repeat Pap is not required. For women who have unsatisfactory cytology, regardless of negative HPV result, a repeat cytology is required in 2–4 months.
• HPV 16/18 testing is one follow-up option for women who have discordant results (normal Pap test accompanied by a positive HPV test). If the HPV 16/18 test is positive, women should immediately receive colposcopy. If negative, these women should repeat the HPV co-test in 1 year.
• For women with LSIL or HSIL, management should be provided by a specialist according to existing guidelines (http://www.asccp.org).

Clinics in settings serving women who might not adhere to follow-up recommendations for whom linkage to care is unlikely should consider offering in-house colposcopy and biopsy services. ASCCP has an app available for purchase and download for management of abnormal cytologic and histologic results. Although this app takes current results into consideration, clinicians are required to have knowledge of past abnormal Pap or cervical procedures to provide management guidance (http://www.asccp.org/store-detail2/asccp-mobile-app).

Counseling

Women might believe the Pap test screens for conditions other than cervical cancer or might be confused by abnormal results (797-799). Health-care providers, a trusted source of information about HPV and abnormal Pap test results, are critical in educating women about high-risk HPV and can moderate the psychosocial impact of abnormal results (1,735,800,801). Women should be counseled on the risks, uncertainties, and benefits of screening (126,802). Education, counseling, and follow-up reminders by phone, text, or email might increase screening and adherence to follow-up (803). Multiple forms of communication (e.g., in-person counseling and printed or online information) might be more effective than one form alone (804). Print materials and online resources are available at https://www.cdc.gov/cancer/cervical/basic_info/screening.htm; https://www.cdc.gov/std/hpv/common/; http://www.ashasexualhealth.org/stdsstis/hpv/hpv-materials/ .

Abnormal Pap test and/or HPV test results can cause short-term anxiety, stress, fear, and confusion, decreasing women’s ability to absorb and retain information and possibly acting as a barrier to follow-up care (798,805-807). A positive HPV test might exacerbate these feelings and elicit concerns about partner(s); worry about disclosure; and feelings of guilt, anger, and stigmatization (800,806). Providers should frame oncogenic HPV positivity in a neutral, nonstigmatizing context and emphasize its common, asymptomatic, and transient nature. Providers also should emphasize that HPV is often shared between partners. Therefore, having HPV does not imply infidelity, nor should it raise concerns about a partner’s health (800).

Key Messages for Women Regarding Cervical Cancer Screening

• Cervical cancer can be prevented with regular screening tests, like the Pap test and the HPV DNA test (HPV test). All women should start getting regular Pap tests at age 21 years.
• The Pap test can find abnormal cells on a woman’s cervix, which could lead to cervical cancer over time, and an HPV test detects HPV infection of the cervix. The HPV test can be used at the same time as the Pap test (known as “co-testing”) for women aged ≥30 years. The HPV test also can be used after an inconclusive Pap test among women aged ≥25 years; testing for this purpose is known as “reflex HPV testing.”
• Positive Pap and HPV tests are markers of early signs of cervical cancer, which often does not cause symptoms until it is advanced. Appropriate follow-up is essential to ensure that cervical cancer does not develop. All women, even those who feel healthy, should receive screening for cervical cancer.
• HPV is a common infection and is often cleared from the body without any medical interventions. A positive HPV test does not mean that a person has cancer.
• HPV is often shared between partners and can lie dormant for many years; having HPV does not imply infidelity, nor should it necessarily raise concerns about a partner’s health (https://www.cdc.gov/cancer/hpv/basic_info/screening).

Management of Sex Partners

The benefit of disclosing a positive oncogenic HPV test to current and future sex partners is unclear. The following counseling messages can be communicated to sex partners:

• Sex partners do not need to be tested for HPV.
• Sex partners tend to share HPV, even though signs of HPV such as an abnormal Pap-test result might occur in only one partner. Sex partners of persons with HPV infection also likely have HPV.
• When used correctly and consistently, condoms might lower the risk for HPV infection and might decrease the time to clear in women with HPV infection. However, HPV can infect areas not covered by the condom and might not fully protect against HPV.

Additional messages for partners include the messages for persons with HPV (see Counseling Messages for Persons with HPV).

Special Considerations

Pregnancy

Pregnant women should be screened at the same intervals as nonpregnant women. However, pregnant women with abnormal screening tests should be referred to a specialist (808-810), because treatment recommendations differ for this population. A swab, Ayre’s spatula, or cytobrush can be used for obtaining Pap tests in pregnant women (811-813).

HIV Infection

Several studies have documented an increased risk for cervical precancers and cancers in women with HIV infection (814,815). Women with HIV infection should be screened within 1 year of sexual activity or initial HIV diagnosis using conventional or liquid-based cytology (Pap test); testing should be repeated 6 months later. Management recommendations for women with HIV infection are detailed elsewhere (http://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/0) (247).

Adolescents

Prevalence of oncogenic HPV types are high among adolescents aged <21 years (816), and oncogenic HPV and squamous intraepithelial lesions caused by HPV in adolescent girls are more likely to regress than those in older women. For these reasons, cervical cancer screening and HPV testing are not recommended in adolescents. However, for adolescents with HIV infection, providers should screen 1 year after onset of sexual activity, regardless of age or mode of HIV infection (e.g., perinatally acquired or sexually acquired) (247); such screening is warranted because of the reported high rate of progression of abnormal cytology in adolescents with HIV infection.

Anal Cancer

Data are insufficient to recommend routine anal cancer screening with anal cytology in persons with HIV infection, MSM without HIV infection, and the general population. An annual digital anorectal examination may be useful to detect masses on palpation that could be anal cancer in persons with HIV infection and possibly HIV-negative MSM with a history of receptive anal intercourse (247). More evidence is needed concerning the natural history of anal intraepithelial neoplasia, the best screening methods and target populations, the safety and response to treatments, and other programmatic considerations before screening can be routinely recommended. However, some clinical centers perform anal cytology to screen for anal cancer among high-risk populations (e.g., persons with HIV infection, MSM, and history of receptive anal intercourse), followed by high-resolution anoscopy (HRA) for those with abnormal cytologic results (e.g., ASC-US or worse). Oncogenic HPV tests are not clinically useful for anal cancer screening among MSM because of a high prevalence of anal HPV infection (817,818).

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