PAP/NGC Program Review

HPV testing in cervicovaginal cytology: Where are we today and where do we go from here?

May 2004

Dina R. Mody, MD

ASC-US triage. High-risk HPV typing has more or less become the standard for atypical squamous cells-undetermined significance, or ASC-US, triage. Thanks to the ALTS trial and American Society for Colposcopy and Cervical Pathology guidelines,¹ most health care providers and insurance carriers now offer this test and reimburse for it.

Primary screening. In March 2003, the Food and Drug Administration approved high-risk HPV typing for women over 30 in conjunction with Pap tests for primary screening. Although this has been available for more than a year, many payers do not cover this test and many providers do not offer it. With the publication of the interim guidance document² and the HART study,³ some of the issues related to managing women with disparity between Pap and high-risk HPV typing should be clarified. The interim guidance document offers the following recommendations:

• Age to initiate: 30 years or more.
• Age to discontinue: 65 years as per U.S. Preventative Service recommendations for cervicovaginal screening or age 70 as per American Cancer Society recommendations.
• Who should not receive HPV DNA testing in screening mode? Women under 30, immunocompromised patients, and patients who have had a total hysterectomy for benign gynecologic disease.
• A combination of negative high-risk HPV typing and a negative cytology should result in longer screening intervals, that is, three years.
• For cytology-negative, HPV-positive patients, repeat both in six to 12 months. If either abnormal at six to 12 months, then colposcopy. If negative colpo, then repeat both at 12 months.
• If HPV-negative but abnormal cytology, follow up as per management for abnormal cytology/ASCCP guidelines.

Post-treatment followup. A third and less publicized potential use is in the followup of patients with high-grade squamous intraepithelial lesions after treatment with cone or LEEP. In recent years, many publications,^4-10 especially in the European literature, have addressed this topic. No large U.S. study is available. Table 1 is a compilation of the results from pertinent studies. Although the sensitivity of high-risk HPV for recurrent/residual HSIL is high, it is the negative predictive value of a negative HPV test in conjunction with a negative cytology that could be used to triage these patients to routine screening quickly. The patients with positive post-treatment HPV and/or cytology could be followed more closely or colposcoped if they continue to be positive.

Atypical endocervical cells. The guidelines of the ASCCP do not recommend high-risk HPV typing for atypical endocervical cells, citing limited data. As per the current ASCCP guidelines, cases with a diagnosis of atypical endocervical cells undergo colposcopy and biopsy. However, as more data emerge, it appears that a compelling case could be made for testing in cases of atypical endocervical cells. Based on limited studies,^11-14 most if not all endocervical adenocarcinoma in situs are high-risk HPV-positive. The usual mucin-producing endocervical adenocarcinomas have a high rate of positivity in the 90+ percent range. Followup studies on atypical endocervical cells show squamous dysplastic lesions to be the most common histologic diagnosis. Table 2 is a compilation of the data from recent studies on high-risk HPV typing in glandular lesions with histologic followup. Endometrial lesions are not HPV-related and HPV testing has no role other than distinguishing between an endocervical versus an endometrial primary. This is being used in surgical pathology practice.

Quality improvement. High-risk HPV testing could also be used for quality improvement in the laboratory. Monitoring percentage positivity in ASC-US cases (50 to 60 percent is the reported range) can help a laboratory determine if it is in range. Percentage positivity rates can also be monitored for individual pathologists. Other scenarios include testing of selected postmenopausal women and followup of adolescent patients with LSIL. The 12-month HPV test has been recommended in the ASCCP guidelines for followup of patients (ASC-US, ASC-H confirmed on review of cytology, LSIL) with negative colposcopy. The era of HPV testing is still in its adolescence. Stay tuned for more.

References

1. Wright TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. Consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120–2129.
2. Wright TC, 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; 103: 304–309.
3. Cuzick J, Szarewski A, Cubie H, et al. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet. 2003; 362:1871–1876.
4. Chua K-L, Hjerpe A. Human papillomavirus analysis as a prognostic marker following conization of the cervix uteri. Gynecol Oncol. 1997;66:108–113.
5. Bollen LJM, Tjong-A-Hung SP, van der Velden J, et al. Prediction of recurrent and residual cervical dysplasia by human papillomavirus detection among patients with abnormal cytology. Gynecol Oncol. 1999;72:199–201.
6. Debarge VH, Collinet P, Vinatier D, et al. Value of human papillomavirus testing after conization by loop electrosurgical excision for high-grade squamous intraepithelial lesions. Gynecol Oncol. 2003; 90: 587–592.
7. Jain S, Tseng C-J, Horng S-G, Soong Y-K, Pao CC. Negative predictive value of human papillomavirus test following conization of the cervix uteri. Gynecol Oncol. 2001;82:177–180.
8. Zielinski GD, Rozendaal L, Voorhorst FJ, et al. HPV testing can reduce the number of follow-up visits in women treated for cervical intraepithelial neoplasia grade 3. Gynecol Oncol. 2003;91: 67–73.
9. Dalstein V, Reithmuller D, Prétet J-L, et al. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study. Int J Cancer. 2003;106:396–403.
10. Nobbenhuis MAE, Meijer CJLM, van den Brule AJC, et al. Addition of high-risk HPV testing improves the current guidelines on follow-up after treatment for cervical intraepithelial neoplasia. Br J Cancer. 2001;84(6):796–801.
11. Ronnett BM, Manos MM, Ransley JE, et al. Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results, and human papillomavirus DNA detection. Hum Pathol. 1999;30(7): 816–825.
12. Krane JF, Lee KR, Sun D, Yuan L, Crum CP. Atypical glandular cells of undetermined significance. Am J Clin Pathol. 2004;121:87–92.
13. Pirog EC, Kleter B, Olgac S, Bobkiewicz P, et al. Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma. Am J Pathol. 2000;157(4):1055–1062.
14. Plunkett M, Brestovac B, Thompson J, et al. The value of HPV DNA typing in the distinction between adenocarcinoma of endocervical and endometrial origin. Pathology. 2003;35(5):397–401.