Managing HPV: A New Era in Patient Care – Screening for HPV-Related Diseases

(Published May 2013)

• As stated by Saslow et al., “The fundamental goal of cervical cancer screening is to prevent morbidity and mortality from cervical cancer. The optimal screening strategy will:
  • Identify those cervical cancer precursors likely to progress to invasive cancer (maximizing the benefits of screening).
  • Avoid the detection and unnecessary treatment of transient HPV infections and associated benign lesions (minimizing the potential harm of screening).” ¹

• Cytology showing low-grade squamous intraepithelial lesion (LSIL) identifies many women who have very little risk for cervical cancer.
• In contrast, cytology showing HSIL is considered a screening success because it has identified a woman who is at high risk of invasive cancer, and treatment of a cervical cancer precursor may prevent cancer from developing.
• Positive HPV test results allow for risk stratification and identification of women who may have disease that was missed by the Pap test and women who are at a higher risk of developing neoplasia and cancer. Women with positive HPV test results require additional follow-up.
• HPV genotyping tests that show positivity for HPV16 or HPV18 allow for even further risk stratification by identifying the women who are at highest risk of developing CIN3 or greater.
• Status of cervical cancer guidelines:
  • In March 2012, the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) released new screening guidelines for the prevention and early detection of cervical cancer.
  • In March 2012, the United States Preventive Services Task Force (USPSTF) released its current recommendation on screening for cervical cancer.
  • In November 2012, the American College of Obstetricians and Gynecologists (ACOG) updated their cervical cancer screening recommendations. The recommendations align with the guidelines released earlier in 2012 by ACS/ASCCP/ASCP.

Cervical Cancer Screening: Pap Test

• Both conventional Pap tests and liquid-based cytology are acceptable screening methods.
• Recent well-controlled clinical trials have found little difference in performance of the two methods for identifying high-grade disease.^2-4
• One benefit of liquid-based cytology is that it facilitates cotesting for HPV from the same sample at the time of the Pap test in age appropriate women or reflex HPV testing in which the original sample is used to determine HPV status, thus avoiding a second visit if the Pap test is ASC-US and cotesting was not done.

Cervical Cancer Screening: HPV Testing

The tests below are FDA approved and commercially available in the United States; however, none of these tests are approved for primary, stand-alone screening.

• Hybrid Capture^® 2 High-Risk HPV DNA TestTM (Digene/QIAGEN) is an assay that uses a pooled mixture of probes to detect 13 of the high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), but is not HPV type specific.
• Cervista^® HPV HR test (Hologic) detects 14 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68). This test cannot determine the specific HPV type present. The Cervista HPV 16/18 test, a genotyping assay, can be used for reflex testing of women with positive high-risk HPV test results to detect the presence or absence of HPV types 16 and 18.
• The cobas^® HPV Test (Roche) offers genotyping for HPV types 16 and 18 concurrently with testing for the presence of 12 other high-risk HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).
• The APTIMA^® HPV Assay (Gen-Probe/Hologic) detects 14 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) but is not HPV type specific. The APTIMA HPV 16 18/45 Genotype Assay can be used for reflex testing of women with positive high-risk HPV test results to detect the presence or absence of HPV types 16 and 18 and/or 45, but does not differentiate between HPV types 18 and 45.

Clinical Uses of HPV Testing

• In the clinical setting, HPV testing is performed to identify high-risk types only.
• There are no clinical applications for low-risk HPV testing.
• Some laboratories routinely test for both high- and low-risk types; health care providers should request that the test for low-risk types not be performed.5
• Well-established clinical uses of HPV testing include:⁵
  • As an adjunct to cytology (either liquid-based or conventional) for screening women ages 30 and older
  • Management of women with atypical squamous cells of undetermined significance (ASC-US) cervical cytology results starting at age 25 (preferred), although it is acceptable to use for ASC-US management of women ages 21-24
  • Post-colposcopy follow-up of women with abnormal cytology results
  • Post-treatment follow-up of women who have been treated for CIN2/3 [Note: This applies to follow-up after any treatment and should not be conducted until 6 months after the treatment.]
  • To triage post-menopausal women with LSIL
• Use of HPV testing allows for less frequent screening because a normal Pap test result and a negative HPV test result give a high assurance that cervical cancer is not present and will not likely occur in the next few years.⁶
• The addition of the HPV test increases disease detection and the length of screening intervals.
• The 5-year risks of CIN3+ and cancer with a negative cotest are 0.16% and 0.016%, respectively.⁷
• HPV testing also identifies women who need increased surveillance because a positive HPV test result and a normal Pap test result reflect increased risk for either missed disease or for the subsequent development of CIN2/3 and cancer.⁶

Situations in Which HPV Testing Is NOT Appropriate

• HPV testing should NOT be used:⁸
  • To triage women with Pap test results other than ASC-US (with the exception of post-menopausal women with LSIL)
  • As an adjunct to Pap testing in primary screening of women <30 years old (concurrent Pap and HPV testing in women <30 years old is not recommended because HPV is highly prevalent and the prevalence of cervical cancer is low in this age group)
  • As an adjunct to Pap testing in primary screening of women after a total hysterectomy for benign disease
  • As an STI screen
  • To determine HPV status before vaccination

Age to Start Cervical Cancer Screening: Considerations

• Adolescents (under 21 years of age) have a higher incidence of HPV infection than older females; however, cervical cancer is rare in adolescents and young women.^9,10
• Screening of adolescents does not appear to change the incidence of cervical cancer in this age group.¹¹
• The prevalence of HPV infection drops considerably with increasing age.
• Concurrently, the incidence of CIN3 and cancer increases with age.
• The positive predictive value of HPV testing increases as women age.
• The evaluation of minor cytological abnormalities in young women is expensive, can cause considerable anxiety, and can result in unnecessary exams and treatment for cervical lesions that have a high probability of regressing.

• If an adolescent presents with a history of abnormal cervical cancer screening, those results should not be ignored.
• If an adolescent is screened inappropriately and has an abnormal Pap test, refer to guidelines for women ages 21 to 24.12

Recommendations on Age to Start Screening^{1,10,11,14,15}

ACOG, ACS/ASCCP/ASCP, and USPSTF recommend that:

• Cervical cancer screening starts at age 21 years, regardless of age of sexual initiation or other risk factors.
• Cotesting with HPV testing and cytology starts at age 30 (cotesting is preferred by ACS/ASCCP/ASCP and ACOG; USPSTF considers cotesting an option for women who want to lengthen the screening interval).

Recommendations on Age to Stop Cervical Cancer Screening^1,14,15

• ACOG and ACS/ASCCP/ASCP
  • Can stop cervical cancer screening in women older than 65 with no history of CIN2+ within the past 20 years and with three or more consecutive normal Pap tests or two consecutive negative cotests within preceding 10 years, with the most recent test occurring within the past 5 years.
  • Should continue routine screening for at least 20 years after a diagnosis of CIN2 or greater, regardless of age.
  • Does not apply to women with a history of exposure to diethylstilbestrol (DES), cervical cancer, or immunosuppression.
• USPSTF
  • Can stop screening in women older than 65 if there has been adequate prior screening and the woman is not otherwise at high risk based on the ACOG and ACS/ASCCP/ASCP guidelines outlined above.
• ASCCP12
  • Postmenopausal women with ASC-US should be managed in the same manner as women in the general population, except women 65 and older that are considering exiting from screening.
    • ASC-US /HPV-negative should be considered abnormal
    • Repeat cotesting in one year

Recommendations for Screening Frequency^1,14,15

• ACOG and ACS/ASCCP/ASC
  • Cytology screening every 3 years for women ages 21 to 29.
  • For women ages 30 to 65, screening every 5 years with a Pap test and HPV test (cotesting) is preferable. Another acceptable option is for women to have a Pap test alone every 3 years.
  • Does not apply to women with a history of exposure to DES, cervical cancer, or immunosuppression.
• USPSTF
  • Cytology screening every 3 years for women ages 21 to 65.
  • For women ages 30 to 65, screening every 5 years with a Pap test and HPV test (cotesting) is a reasonable alternative for women wanting to extend the screening interval.

Screening Post-Hysterectomy^1,14,15

• ACOG, ACS/ASCCP/ASCP, and USPSTF all recommend against routine screening of women who have had a hysterectomy, with removal of the cervix, for benign disease and no history of high-grade precancer or greater.

• Although the Bethesda System provides terminology for reporting cervical cytology findings, over the last few decades, the most widely used terminology for histologic findings from a cervical biopsy has been cervical intraepithelial neoplasia (CIN) (previously, the common terminology was dysplasia). The CIN terminology is a three-tiered system:
  • CIN1: mild dysplasia
  • CIN2: moderate dysplasia
  • CIN3: severe dysplasia
• This nomenclature has also been used to designate intraepithelial neoplasia in other locations, such as VaIN (vagina), VIN (vulva), AIN (anus), and PeIN (penis).
• Correlation of cervical cytology findings with histologic findings from a cervical biopsy is essential for the proper management and follow-up of a patient.
• In June 2012, a new reporting system was published to standardize reporting for all HPV-associated preinvasive squamous lesions of the lower anogenital tract (LAT).¹⁸
• The goals of the new system, referred to as Lower Anogenital Squamous Terminology Standardization (LAST), include:

• Aligning terminology with the current understanding of the similar biology and morphology of these lesions
• Improving communication between pathologists making diagnoses and clinicians using these diagnoses
• Creating optimal, consistent, and more effective management of patients
• LAST changes the three-tiered system of reporting the pathology of squamous neoplasia in the cervix and other anatomic sites to a two-tiered system of reporting: LSIL and HSIL.
  • LSIL represents biologically transient, productive HPV infections
  • HSIL represents persistent precancerous lesions
• This reporting change will allow for more reliable and reproducible results, ultimately leading to improved patient outcomes.
• Integrating the LAST recommendations into the standard practice of pathologists and clinicians is an ongoing task.¹⁸

Screening for HPV-Associated Anal Lesions

• HPV-associated anal lesions include high-grade precursor lesions (AIN) and anal cancer.
• These lesions are associated with infection with high-risk HPV types. As with cervical cancer, HPV type 16 is most common, followed by type 1^8.19
• Risk factors include 15 or more lifetime sexual partners, receptive anal intercourse, current smoking, HIV infection, and in women, a history of CIN.^20,21
• In one study, 95% of 357 gay males had anal HPV and 50% had high-grade AIN.²²
• Sensitivity of anal cytology ranges from 50% to 80%.  Sensitivity is higher in HIV-positive patients.²³
• The role of routine screening for AIN and anal cancer in high-risk individuals is controversial:
  • Advocates believe that cytology is as effective for detecting anal disease as for cervical disease and note that cost-effective studies suggest that anal screening is an attractive option.
  • Opponents point out that at present there are no data confirming that treatment of AIN prevents cancer.
• Currently, the Centers for Disease Control and Prevention (CDC), USPSTF, ACS, and the Infectious Diseases Society of America do not recommend routine anal cytology screening.
• The New York State Department of Health recommends anal cytology for individuals who are infected with HIV and meet at least one of the following criteria:²⁴
  • MSM
  • History of genital warts
  • History of CIN or VIN
• HPV vaccination can protect men and women from anal cancer. Gardasil is now approved to prevent anal cancers in both men and women. Although Cervarix is approved by the Food and Drug Administration (FDA) only to prevent cervical cancers and pre-cancers, a recent study has shown that it is also helpful in preventing anal cancers.^25,26

References

1. Saslow, D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62:147-72.
2. Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol. 2008;111:167-77.
3. Davey E, Barratt A, Irwig L, et al. Effect of study design and quality on unsatisfactory rates, cytology classifications, and accuracy in liquid-based versus conventional cervical cytology: a systematic review. Lancet. 2006;367:122-32.
4. Ronco G, Cuzick J, Perotti P, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening randomised controlled trial. BMJ. 2007;335(7609):28.
5. American Society for Colposcopy and Cervical Pathology. Adapted and printed with permission from ASCCP Educate the Educators: HPV and the HPV Vaccines © 2006, ASCCP. All rights reserved.
6. Wright T, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;2:304-9.
7. Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011;12:663-72.
8. American Society for Colposcopy and Cervical Pathology. Diagnosis of HPV-Induced Disease: Cervical Intraepithelial Neoplasia Grades 1, 2, 3 (CIN1, 2, and 3). Available at: http://www.asccp.org/practicemanagement/hpv/diagnosisofhpvinduceddisease/tabid/5825/default.aspx. Accessed June 27, 2012.
9. Sherman ME, Schiffman M, Cox JT. Effects of age and human papilloma viral load on colposcopy triage: data from the Randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J Natl Cancer Inst. 2002;94:102-7.
10. Moscicki AB, Cox JT. Practice improvement in cervical screening and management (PICSM): symposium on management of cervical abnormalities in adolescents and young women. J Low Genit Tract Dis. 2010;14:73-80.
11. ACOG Committee Opinion No. 463: Cervical cancer in adolescents: screening, evaluation, and management. Obstet Gynecol. 2010;116:469-72.
12. Massad LS, Einstein MH, Huh WK, Katki HA, Kinnery WK, Schiffman M, Solomon D, Wentzensen N, Lawson HW. 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Low Genit Tract Dis. 2013:S1-S27.
13. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 Consensus Guidelines for the Management of Women with Abnormal Cervical Cancer Screening Tests. Am J Obstet Gynecol. 2007;197(4):346-55.
14. ACOG Practice Bulletin No. 131: Screening for cervical cancer. ACOG Committee on Practice Bulletins—Gynecology. Obstet Gynecol. 2012;120(5):1222-38.
15. Moyer VA on behalf of the U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;156:880-91.
16. Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting cervical cytology. JAMA. 2002;287:2114-9.
17. 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.
18. Darragh TM, Colgan TJ, Cox JT, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis. 2012;6(3):205-42.
19. Munoz N, Castellsague X, de Gonzalez AB, Gissmann L. HPV in the etiology of human cancer. Vaccine. 2006;24(Suppl 3):1-10.
20. Daling JR, Madeleine MM, Johnson LG, et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer. 2004;101(2):270-80.
21. Frisch M, Smith E, Grulich A, Johansen C. Cancer in a population-based cohort of men and women in registered homosexual partnerships. Am J Epidemiol. 2003;157(11):966-72.
22. Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS. 2005;19(13):1407-14.
23. Uronis HE, Bendell JC. Anal cancer: an overview. The Oncologist. 2007;12(5):524-34.
24. New York State Department of Health AIDS Institute. Neoplastic complications of HIV disease. Available at: www.hivguidelines.org/clinical-guidelines/adults/neoplastic-complications-of-hiv-infection. Accessed June 15, 2012.
25. American Cancer Society. Anal cancer: can anal cancer be prevented? Available at: www.cancer.org/Cancer/AnalCancer/DetailedGuide/anal-cancer-prevention. Accessed June 15, 2012.
26. Kreimer AR, Gonzalez P, Katki HA, et al. Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial. Lancet Oncol. 2011;12(9):862-70.