HPV-Associated Cancers and Precancers

Cervical Cancer

Screening Recommendations

Recommendations for cervical cancer screening in the United States are based on systematic evidence reviews by major medical and advocacy organizations, including USPSTF (174), ACS (177), and ACOG (175). Over time, general alignment across these organizations has emerged as to when to start and end cervical cancer screening as well as the periodicity of screening. Although no single guideline universally guides screening practices in the United States, the Patient Protection and Affordable Care Act required Medicaid and new private health insurance plans to provide coverage for preventive services graded A or B by USPSTF, which includes cervical cancer screening. In addition, the National Center for Quality Assurance provides a set of measures (the Healthcare Effectiveness Data and Information Set [HEDIS]) for up-to-date cervical cancer screening that aligns with USPSTF recommendations (https://www.ncqa.org/hedis/measures/cervical-cancer-screening). The Center for Medicaid and Medicare Services uses the same measure as HEDIS to measure cervical cancer screening performance.

USPSTF screening recommendations apply to persons with a cervix at average risk, defined as those with no previous cervical cancer or high-grade precancer, not currently under close follow-up for a recent abnormal result, not immunocompromised (e.g., persons with HIV), and who had no exposure to diethylstilbestrol in utero. Among these persons, screening should be performed starting at age 21 years and continue through age 65 years. Testing can be performed using either conventional or liquid-based cytologic tests (i.e., Pap tests). For persons aged ≥30 years, screening can include FDA-cleared tests for high-risk, oncogenic types of HPV. For cytopathologic testing, clinics should use CLIA-certified laboratories using acceptable terminology (Bethesda 2001 or LAST terminology) (1239).

Annual cervical cancer screening is not recommended for persons at average risk. Instead, cytology testing is recommended every 3 years for persons aged 21–29 years. For persons aged 30–65 years, a cytology test every 3 years, an HPV test alone every 5 years, or a cytology test plus an HPV test (cotest) every 5 years is recommended. Cotesting can be done by either collecting one sample for the cytology test and another for the HPV test or by using the remaining liquid cytology material for the HPV test. Cervical screening programs should screen those who have received HPV vaccination in the same manner as those that are unvaccinated. Screening is not recommended before age 21 years among those at average risk. For those aged 30–65 years, cytology alone or primary HPV testing is preferred by USPSTF; however, cotesting can be used as an alternative approach. ACOG (1240), ACS (177), and USPSTF (174) each have screening recommendations (1241) (Table 1).

Clinics should weigh the benefits of each screening strategy as well as their resources, such as time and cost, in deciding on which of the three possible screening strategies to implement. Decision analytic models (1242) estimating the benefits, harms, and costs (1243) of several different strategies might be useful in making this determination (174,1244,1245). Adopting recommended screening and follow-up procedures, including screening methods, results provision, and follow-up, can lead to success in implementing cervical cancer screening in clinics (1246).

Patients should be provided a copy of their test results; those with normal results should be provided information on follow-up visits and the importance of continued cervical cancer screening, if applicable. Those with abnormal screening tests should be managed per published guidelines. National consensus guidelines are available for the management of abnormal cervical cancer screening tests (1247). HPV testing or cotesting is preferred to cytology alone for surveillance after an abnormal screening test result. These guidelines base management recommendations on case-by-case assessment of risk considering past screening history and current results (see Follow-Up). Patients with abnormal cervical cancer screening test results should be counseled about those results (see Counseling Messages).

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

• Cytology (Pap tests) and HPV tests should not be considered screening tests for STIs.
• All persons with a cervix should receive cervical cancer screening, regardless of sexual orientation or gender identity (i.e., those who identify as lesbian, bisexual, heterosexual, or transgender).
• A conventional cytology test (in which the sample is smeared onto a dry slide) should ideally be scheduled for 10–20 days after the first day of menses. Liquid-based cytology can be performed at any time during the menstrual cycle.
• If specific infections other than HPV (e.g., chlamydia or gonorrhea) are identified at the visit, a repeat cytology test after appropriate treatment for those infections might be indicated. However, in most instances (even in the presence of certain severe cervical infections), cytology tests will be reported as satisfactory for evaluation, and reliable final reports can be produced without the need to repeat the cytology test after treatment.
• The presence of a mucopurulent discharge should not postpone cytology testing. The test can be performed after removal of the discharge with a saline-soaked cotton swab.
• HPV testing can be performed either as a separate test or by using material from the liquid-based cytology specimen.
• In the absence of other indications, the presence of external genital warts does not warrant more frequent cervical cancer screening.
• The sequence of cytology testing in relation to collection of other endocervical specimens does not influence Pap test results or their interpretation (600). Typically, vaginal specimens are preferred for chlamydia and gonorrhea screening; however, during a pelvic examination, endocervical specimens for STI testing can be collected first.
• Persons who have had a total hysterectomy with removal of the cervix do not require screening unless cervical intraepithelial neoplasia (CIN) 2, CIN 3, or adenocarcinoma in situ was diagnosed within the previous 20 years (175,1247). If the cervix remains intact after a supracervical hysterectomy, regularly scheduled Pap tests should be performed as indicated (1248–1250).
• Health care facilities that train providers on cytology test collection and use simple quality assurance measures are more likely to obtain satisfactory test results (as determined by the laboratory).
• The use of instruments designed to sample the cervical transformation zone (e.g., cytobrushes) improves the accuracy of cytology tests (1251).
• Both liquid-based and conventional cytology are acceptable because they have similar test-performance characteristics.
• At an initial visit, providers should ask patients about their recent cytology test and HPV results and any history of evaluation and treatment (e.g., loop electrosurgical excision procedure and colposcopy) to assist with management; effort should be made to obtain copies of recent results. The importance and frequency of screening should be reinforced.

Counseling

Persons might believe the cytology (Pap test) or HPV test screens for conditions other than cervical cancer, or they might be confused by abnormal results (1252–1254). Health care providers, as trusted sources of information about HPV infections and abnormal cytology test results, have an important role in educating persons about HPV and can moderate the psychosocial impact of abnormal results (1255,1256). Persons should be counseled on the risks, uncertainties, and benefits of screening (174,1257).

An abnormal cytology test or a positive HPV test can cause short-term anxiety, stress, fear, and confusion, possibly decreasing the patient’s ability to absorb and retain information and acting as a barrier to follow-up care (1258–1261). A positive HPV test might elicit concerns about partners, worries about disclosure, and feelings of guilt, anger, and stigmatization (1260). Providers should frame HPV positivity in a neutral, nonstigmatizing context and emphasize its common, asymptomatic, and transient nature. Providers also should emphasize that HPV infections often are shared between partners but it is often not possible to know the origin of an HPV infection; HPV tests might become positive many years after initial exposure due to reactivation of latent infections in both male and female partners. Having an HPV infection should not raise concerns about a male partner’s health (1262). Providers should communicate the meaning of both the cytology and HPV test results to patients at screening.

Providers also should screen for tobacco use and perform cessation counseling (www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2011/09/tobacco-use-and-womens-health). Smoking contributes to the progression of CIN, with both active and passive smoking associated with squamous cell carcinoma of the cervix in women with HPV 16 or 18 infection (1263–1266).

Promoting Cervical Cancer Screening

Clinics can use the evidence-based interventions in the Community Preventive Services Task Force guidelines to promote cervical cancer screening in their communities (https://www.thecommunityguide.org/findings/cancer-screening-multicomponent-interventions-cervical-cancer). Implementing interventions that increase community demand for screening (1266) (e.g., client reminders, client incentives, media, group education, or one-on-one education) together with those that increase community access to screening (e.g., reducing structural barriers and reducing client out-of-pocket costs) is effective in increasing cervical cancer screening coverage. These interventions are more effective if they are implemented with interventions to increase provider delivery of screening services (e.g., provider assessment and feedback, provider incentives, and provider reminders). Print materials and online resources are available at https://www.cdc.gov/cancer/cervical/basic_info/screening.htm and https://www.cdc.gov/std/hpv/facts-brochures.htm. Patient navigators can be effective in improving both screening and follow-up after abnormal results (1267).

Key Messages About Cervical Cancer Screening

When counseling persons about cervical cancer screening, the provider should discuss the following:

• Cervical cancer can be prevented with regular screening tests, like the Pap test (cytology) and HPV tests. Those at average risk should start getting cytology tests at age 21 years.
• The cytology test can find abnormal cervical cells, which could lead to cervical cancer over time, and an HPV test detects HPV infection of the cervix. The HPV test can be used alone for cervical cancer screening or at the same time as the cytology test (known as cotesting) for those aged ≥30 years to 65 years. The HPV test is also used after a cytology test result of atypical squamous cells of undetermined significance (ASC-US) among persons aged >25 years (known as reflex HPV testing).
• Positive cytology and HPV tests are markers of cervical precancerous lesions, which often do not cause symptoms until they become invasive. Appropriate follow-up is essential to ensure that cervical cancer does not develop.
• HPV is a common infection and is often controlled by the body without any medical interventions. A positive HPV test does not mean that a person has cancer.
• Providers should emphasize that HPV infections often are shared between partners, and it is often not possible to know the origin of an HPV infection; HPV tests might become positive many years after initial exposure due to reactivation of latent infections in both male and female partners.

Management of Sex Partners

The benefit of disclosing a positive 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. Sex partners of persons with HPV infection also are likely have an HPV infection.
• Female sex partners of men who disclose they had a previous female partner with HPV should be screened at the same intervals as women with average risk. No data are available to suggest that more frequent screening is of benefit.
• When used correctly and consistently, condoms might lower the risk for HPV infection and might decrease the time to clear in those with HPV infection. However, HPV can infect areas not covered by the condom, and condoms might not fully protect against HPV (24,25).

Additional messages for partners include the messages for persons with HPV (see Cervical Cancer Screening; Counseling Messages).

Screening Recommendations in Special Populations

Pregnancy

Persons who are pregnant should be screened at the same intervals as those who are not. A swab, Ayre’s spatula, or cytobrush can be used for obtaining cytology test samples during pregnancy (1268–1270).

HIV Infection

Several studies have documented an increased risk for cervical precancers and cancers in individuals with HIV infection (1271–1273). Adolescents with HIV should be screened 1 year after onset of sexual activity but no later than age 21 years. Sexually active persons should be screened at the time of the initial HIV diagnosis. Conventional or liquid-based cytology (Pap test) should be used as primary HPV testing and is not recommended in individuals with HIV. Cotesting (cytology and HPV test) can be done in individuals aged ≥30 years with HIV. Annual screening is recommended for persons with HIV infection; after 3 years of consecutive normal cytology results or normal cotest (normal cytology and negative HPV test), the screening interval can be increased to every 3 years. Lifelong screening is recommended among persons with HIV infection.

Providers should defer to existing Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV for guidance on cervical cancer screening and management of results in persons with HIV (98).

Adolescents

Prevalence of HPV infection is high among those aged <21 years (174); however, HPV infections and squamous intraepithelial lesions caused by HPV in adolescents are more likely to regress than those in older persons. For these reasons, cervical cancer screening and HPV testing are not recommended in immunocompetent adolescents. However, for adolescents with HIV infection, providers should screen 1 year after onset of sexual activity, regardless of age or mode of HIV acquisition (e.g., perinatally acquired or sexually acquired) (98); such screening is warranted because of the reported high rate of progression of abnormal cytology in adolescents with HIV.

Human Papillomavirus Tests for Cervical Cancer Screening

Clinical tests for HPV are used for the following: cervical cancer screening as a primary test, cervical cancer screening with a cytology test, triage of some abnormal cervical cytology results, follow-up after abnormal screening test results, follow-up after a colposcopy in which no CIN 2 or CIN 3 is found, and follow-up after treatment of cervical precancers. These tests are only FDA cleared for use with cervical specimens, not oral or anal specimens. Testing for nononcogenic HPV types (e.g., types 6 and 11) is not recommended (https://www.asccp.org/guidelines).

FDA-cleared HPV tests detect viral DNA or messenger RNA. Several FDA-cleared tests for HPV are available for use in the United States. The Cobas 4800 HPV test (Roche Molecular Diagnostics) and the Onclarity HPV test (Becton Dickinson) can detect the presence of 14 oncogenic HPV types (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), as well as individual types 16 and 18, and are cleared for primary cervical cancer screening.

Other HPV tests are cleared for use in conjunction with a cytology test or to triage some abnormal cervical cytology results; they should not be used for primary HPV testing because they are not cleared for this purpose. These tests include the Hybrid Capture 2 High-Risk HPV DNA test (Qiagen), the Cervista HPV High-Risk DNA and HPV 16/18 DNA tests (Hologics), and the APTIMA HR HPV (Gen Probe) test. All HPV assays should be FDA cleared and used only for the appropriate indications (https://www.fda.gov/media/122799/download) (158).

HPV testing should not be performed in the following situations:

• Deciding whether to vaccinate against HPV
• Conducting HPV tests for low-risk (nononcogenic) HPV types (e.g., types 6 and 11)
• Providing care to persons with genital warts or their partners
• Testing persons aged <25 years as part of routine cervical cancer screening
• Testing oral or anal specimens

Unlike cytology, samples for HPV testing have the potential to be collected by the patient and mailed to health programs for analysis, thus self-collection might be one strategy for increasing screening rates among populations where screening rates are low. Self-collection for HPV testing is not cleared by FDA or recommended by U.S. medical organizations (174).

Follow-Up of Abnormal Cytology and Human Papillomavirus Test Results

If the result of the cytology (Pap test) is abnormal, follow-up care should be provided according to the 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors (158). Clinics that serve clients who might have difficulty adhering to follow-up recommendations and for whom linkage to care is unlikely should consider offering in-house colposcopy and biopsy services.

Consensus guidelines for management of abnormal cervical cancer screening tests combine patient-level risk data with clinical action thresholds to generate personalized management recommendations (Table 2). This framework allows management on the basis of risk for CIN 3, not specific test results. The guidelines were designed to identify persons at high risk who require colposcopy or expedited treatment and persons at low risk who might be able to safely defer invasive diagnostic procedures. The risk-based framework was designed to easily incorporate future revisions, such as the inclusion of new technologies for screening and management. Use of the guidelines can be facilitated by electronic technology that is continually updated, such as a smartphone application or the website (https://www.asccp.org/Default.aspx).

The following are highlights of the new management guidelines:

• Colposcopy can be deferred for patients at low risk.
  • If a patient has a minimally abnormal test result (i.e., negative for intraepithelial lesion or malignancy HPV positive, ASC-US HPV positive, LSIL, or HPV positive) that was preceded by a negative screening HPV test or cotest within the past 5 years, follow-up in 1 year instead of colposcopy is recommended (a negative HPV test or cotest performed during follow-up of abnormal results would not similarly reduce risk).
  • Referral to colposcopy is recommended if cytology test results are abnormal or the HPV test is positive at the 1-year follow-up visit.
• Treatment can be expedited for high-risk patients.
  • If a patient has a high-grade cytology (Pap test) result (i.e., HSIL) and an HPV test that is positive for HPV type 16, then treatment with a loop electrosurgical excision procedure (LEEP) is preferred. A colposcopy with biopsy is not necessary to confirm the diagnosis first.
  • If a patient who has not been screened in more than 5 years (i.e., rarely screened) has an HSIL cytology result and a positive HPV test (regardless of type), then treatment with LEEP is preferred. A colposcopy with biopsy is not necessary to confirm the diagnosis first.
  • When considering treatment without confirmatory biopsy, shared decision-making with the patient is important. Considerations include age, concern about cancer, ability to follow up, financial concerns, and concerns about the potential effect of treatment on a future pregnancy.
• When primary HPV testing is used for screening, cytology testing should be performed for all positive HPV test results to help determine the next steps in management.
  • Ideally, cytology testing should be performed by the laboratory as a reflex test from the same specimen so the patient does not need to return to the clinic. Colposcopy is recommended if HPV genotyping is positive for types 16 or 18, and it can be considered if it is infeasible for the patient to return for cytology alone (1274).
  • HPV 16 is the highest-risk HPV type. Expedited treatment should be considered for HSIL cytology results, and colposcopy is recommended in all other cases, even if the cytology test is normal.
  • HPV 18 has a relatively high association with cancer, and colposcopy is recommended in all cases, even if the cytology test is normal. Because of the association of HPV 18 with adenocarcinoma, endocervical sampling is acceptable at the time of colposcopy.
  • If the HPV type is not HPV 16 or 18, and the cytology test is normal, return in 1 year is recommended in most cases.
• HPV testing or cotesting is preferred to cytology testing alone for follow-up after an abnormal test result.
  • Negative HPV testing or cotesting is less likely to miss disease than normal cytology testing alone. Therefore, cytology testing is recommended more often than HPV testing or cotesting for follow-up of abnormal results. Specifically, cytology testing is recommended annually when HPV testing or cotesting is recommended at 3-year intervals, and cytology testing is recommended at 6-month intervals when HPV testing or cotesting is recommended annually.
• After treatment for a high-grade precancer (moderate or severe dysplasia), surveillance should continue for at least 25 years.
  • Initial testing includes an HPV test or cotest at 6, 18, and 30 months. If cytology alone is used, testing should occur at 6, 12, 18, 24, and 30 months.
  • After completing initial testing, long-term surveillance includes testing at 3-year intervals if using HPV testing or cotesting, or annual testing if using cytology testing alone.
  • Surveillance should continue for at least 25 years after the initial treatment, even if this extends beyond age 65 years. If a woman undergoes hysterectomy during the surveillance period, vaginal screening should continue.

Anal Cancer

Anal cancer is rare in the general population (1–2 cases per 100,000 person-years); however, incidence is substantially higher among specific populations, including MSM with HIV infection (80–131 cases per 100,000 person-years), men with HIV infection (40–60 cases per 100,000 person-years), women with HIV infection (20–30 cases per 100,000 person-years), and MSM without HIV infection (14 cases per 100,000 person-years) (1275–1279). Incidence is variable among women with previous HPV-related gynecologic dysplasia and cancer (6–63 cases per 100,000 person-years) (1280,1281). Persistent HPV infection might be a risk factor for preventable HPV-associated second primary cancers among survivors of HPV-associated cancers (1282).

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 (DARE) might be useful to detect masses on palpation in persons with HIV infection and possibly in MSM without HIV with a history of receptive anal intercourse (98). 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.

Populations at High Risk and Digital Anorectal Examination

Providers should discuss anal cancer risk with their patients among specific populations to guide management. According to the HIV Opportunistic Infection guidelines and the International Anal Neoplasia Society, a DARE should be performed to detect early anal cancer in persons with HIV infection and MSM without HIV with a history of receptive anal intercourse (98,1283). DARE is acceptable to patients and has a low risk for adverse outcomes (1284,1285).

Data are insufficient to guide initiation of DARE at a defined age or optimal intervals for examination. Whereas anal HSIL is observed among young adults, cancer incidence begins to increase after the early 30s and continues to increase as a function of age.

Populations at High Risk and Anal Cytology

Data are insufficient to recommend routine anal cancer screening with anal cytology among populations at risk for anal cancer. Certain clinical centers perform anal cytology to screen for anal cancer among populations at high risk (e.g., persons with HIV infection, MSM, and those having receptive anal intercourse), followed by high-resolution anoscopy (HRA) for those with abnormal cytologic results (e.g., ACS-US, LSIL, or HSIL). Sensitivity and specificity of anal cytology to detect HSIL are limited (sensitivity 55%–89% and specificity 40%–67%) (1286–1291). Health centers that initiate a cytology-based screening program should only do so if referrals to HRA and biopsy are available.

HRA can be used for diagnosis of HSIL, to monitor response to therapy, or to conduct surveillance of HSIL for evidence of progression. HRA is the primary method used for diagnosis of superficially invasive squamous carcinoma, a very early form of anal cancer that is not palpable on DARE. However, data are insufficient to conclude whether use of HRA leads to reductions in anal cancer incidence or improves anal cancer morbidity and mortality. An ongoing clinical trial is investigating whether treatment of HSIL is effective in reducing the incidence of anal cancer among persons with HIV infection (NCT02135419).

Human Papillomavirus Testing

HPV tests (using high-risk HPV types) are not clinically useful for anal cancer screening because of a high prevalence of anal HPV infection among populations at high risk, particularly MSM (1278,1289,1290). No standard HPV-based algorithms exist for anal cancer screening, due to the high prevalence of high-risk HPV infection among groups at risk.

Treatment of Anal High-Grade Squamous Intraepithelial Lesion

Multiple office-based treatments exist for anal HSIL, including ablative methods (e.g., laser, electrocautery, or infrared coagulation) and topical patient-applied therapies (e.g., imiquimod). Recurrence rates with both provider-applied and patient-applied treatments are high, ranging from approximately 50% at 1 year to 77% after 3 years (1289,1292,1293). In addition, evidence exists that HSIL might spontaneously regress without treatment (1294,1295). Shared decision-making about treatment for anal HSIL is recommended because of limited data on the natural history of anal HSIL, including factors related to progression or regression of lesions.

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