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Home » 2015 Issues, May 2015, Past ArticlesNegative Pap, positive hrHPV: what we know so farRebecca Ocque, MDChengquan Zhao, MDMay 2015—Cervical cancer is the second most common cancer in women worldwide, and high-risk human papillomavirus (hrHPV) is considered the principal causative factor in the development of most cervical cancer and its precursor lesions. For this reason, screening algorithms that include testing for hrHPV are part of the new cervical cancer screening guidelines set forth by the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology. Within the new guidelines, women age 30 and older can be screened with cytology alone and rescreened in three years if they have a negative result, or screened alternatively with both cytology and hrHPV testing every five years if both tests are negative.1More than 150 HPV types have been fully characterized, with about 40 being transmitted through sexual contact and infecting the anogenital region. HPV types have been referred to as low risk or high risk, based on their associated risk for cervical cancer. Low-risk HPV (lrHPV) types (6, 11, 42, 43, 44, 54, 61, 62, 70, 72, 81) are virtually never found in cervical cancers, while hrHPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82) have been identified in cancers of the cervix, vagina, vulva, anus, and penis.Currently there are five Food and Drug Administration-approved hrHPV tests for clinical samples. Digene Hybrid Capture 2 High-Risk HPV DNA Test was the first approved test that identifies 13 hrHPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68). The Cervista HPV HR and Genfind DNA Extraction Kit identifies DNA from 14 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68). Positive tests can then have reflex subtyping performed with Cervista HPV 16/18. The Cobas HPV Test, made by Roche, specifically identifies types HPV 16 and HPV 18 while concurrently detecting 12 other hrHPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68). In 2014, the FDA approved the Cobas HPV Test as the first cervical cancer screening test to be used alone without cervical Pap cytology for women age 25 and older. The most recent test to enter the U.S. market, Aptima HPV Assay, identifies HPV RNA from viral oncogenes E6 and E7 from 14 hrHPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68).Based on data from consecutive National Health and Nutrition Examination Surveys (2003–2006), the overall HPV prevalence in the U.S. was 42.5 percent (prevalence of hrHPV types, 29 percent; lrHPV types, 28.5 percent) in females 14–59 years of age, with significant variation by age, race, ethnicity, poverty level, and number of sex partners. The most significant variation was with age. The lowest hrHPV positivity rates were among females ages 14 to 19 (32.9 percent), and the highest (53.8 percent) were among 20- to 24-year-old females. Of all 37 tested HPV types, the most common was lrHPV 62 (6.5 percent). Among hrHPV types, HPV 53 (5.8 percent) was the most common, followed by HPV 16 (4.7 percent), HPV 51 (4.1 percent), HPV 52 (3.6 percent), and HPV 66 (3.6 percent). hrHPV 18 was documented in only 1.8 percent.2 In a study of nearly 1 million U.S. women, approximately four percent of cotested women age 30 and older were hrHPV positive.3The prevalence of hrHPV DNA in women with normal cytology has been reported to vary greatly, owing in part to the variety of Pap test preparations (conventional versus liquid based), hrHPV testing methods, and the aforementioned patient variables, which are not always taken into account in epidemiologic studies. A meta-analysis of 194 worldwide studies, published between 1995 and 2009, estimated the crude and adjusted hrHPV prevalence among 1,016,719 cytologically normal women to be 7.2 percent and 11.7 percent, respectively.4 Eight percent of the Kaiser Permanente (Portland, Ore.) patients were positive for hrHPV and had negative conventional Pap smear results at enrollment.5Women age 30 and older are the population of greatest interest given that the new guidelines suggest either cotesting this group with Pap cytology and hrHPV testing or using more frequent Pap cytology screening. Using a computer-assisted screening method, hrHPV was detected in only 1.9 percent (490 of 25,259) of women age 30 and older with negative cytology.6 In the ATHENA (Addressing the Need for Advanced HPV Diagnostics) study, among the 32,260 women age 30 and older with normal cytology, the overall prevalence of hrHPV (14 types, Cobas HPV Test) was 6.7 percent, and the overall prevalence rates for HPV 16, HPV 18, and the 12 other hrHPV genotypes were one percent, 0.5 percent, and 5.2 percent, respectively.7Histopathologic follow-up demonstrates higher rates of high-grade cervical intraepithelial neoplasia or greater (collectively CIN2/3+) lesions in women identified as being positive for hrHPV despite negative cytology results. In a large outcome-based study with an average follow-up period of almost two years (23.2 months), CIN2/3+ lesions were identified in 21 of 849 (2.4 percent) hrHPV-positive/cytology-negative patients.8 In the large Kaiser Permanente Portland study, two percent of patients who were hrHPV positive at enrollment developed CIN3 or greater lesions over 10 years.Referral for colposcopy of all women who are cytology negative but hrHPV positive could lead to a significant increase in women undergoing procedures of potentially limited utility. However, long-term observational studies using non-FDA-cleared genotyping studies have indicated an elevated risk of CIN2/3 or higher in women infected with hrHPV 16 and/or 18 as compared with hrHPV-positive, HPV 16/18-negative women.3 The10-year cumulative incidence rates of CIN3 or greater were 17.2 percent (95 percent confidence interval = 11.5 percent to 22.9 percent) among HPV 16+ women and 13.6 percent (95 percent CI = 3.6 percent to 23.7 percent) among HPV 18+ (HPV16–) women, but only three percent (95 percent CI = 1.9 percent to 4.2 percent) among hrHPV-positive women negative for HPV 16 or HPV 18.5 In a similar, more recent study, hrHPV-positive women were genotyped using laboratory-developed testing. They demonstrated a 4.7 percent three-year cumulative risk of CIN3 or greater among all cytology-negative, hrHPV-positive patients. The risk of CIN3 or greater in HPV16-negative women was 2.4 percent, and HPV 16 positivity increased the risk to 10.6 percent. Positivity for HPV 33 and for HPV 18 was also associated with an increased CIN3 or greater risk (both 5.9 percent).9New cervical cancer screening guidelines recommend women with negative cytology and a positive cotest for hrHPV be monitored with either of the following options: repeat cotesting in 12 months or immediate HPV genotype-specific testing (for HPV 16 alone or for HPV 16/18). If immediate HPV genotype-specific testing is used, women who test positive for HPV 16 or HPV 16/18 should be referred directly to colposcopy, and women who test negative for HPV 16 or HPV 16/18 should be cotested in 12 months.1 FDA-approved genotype testing to detect HPV 16/18 first became available for routine gynecologic cervical samples in 2009. Current consensus guidelines support immediate colposcopy referral for women age 30 and older with negative cervical cytology and detection of HPV 16 or HPV 18 because of the perceived increased risk of developing significant cervical pathology.1 Although some studies exist that reviewlaboratory-developed genotype testing, even fewer studies are available in the literature that review the histologic follow-up in this setting. A subanalysis of the ATHENA trial reported an increase in the absolute risk (11.7 percent) and relative risk (42 percent) of CIN3 or greater in women with HPV 16 or HPV 18 detected by the Cobas HPV Test compared with women who were hrHPV negative.7 Retrospective analysis assessing the routine use of an FDA-approved HPV 16/18 genotyping test (Cervista) in patients age 30 and older with negative cytology and hrHPV-positive cervical screening tests identified 824 patients in which 101 (12.3 percent) tested positive for HPV 16 and/or HPV 18.10 HPV detection rates for HPV 16, HPV 18, and both HPV 16 and 18 were 9.1 percent, 2.4 percent, and 0.7 percent, respectively. Short-term histopathologic follow-up in this subset of patients documented no cervical cancers, but high-grade CIN (CIN2/3) was detected in four of 51 (7.8 percent) hrHPV-positive/cytology-negative/HPV 16/18-positive patients. Despite the shorter follow-up time in the current study (average 3.5 months), the histopathologic CIN2/3 diagnostic rate of 7.8 percent was more than three times higher for HPV-positive/cytology-negative/HPV 16/18-positive patients than the CIN2/3+ histopathologic diagnostic rate for HPV-positive/cytology-negative patients without genotype testing (2.4 percent).A similar retrospective but smaller series of 122 hrHPV-positive, Pap cytology-negative patients who had reflex HPV 16/18 genotype testing and subsequent biopsy found that women who tested positive for HPV 16/18 had a higher risk of CIN2/3+ (5.9 percent) thanwomen who tested negative (2.7 percent).11 However, this difference was not statistically significant (P=0.0676).Studies using FDA-approved HPV genotype tests with longer follow-up are needed to address the efficacy of the new screening guidelines and the usefulness of genotyping hrHPV in the clinical management of cytology-negative hrHPV-positive patients.1. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, AmericanSociety for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervicalcancer. Am J Clin Pathol. 2012;137:516–542.2. Hariri S, Unger ER, Sternberg M, et al. Prevalence of genital human papillomavirusamong females in the United States, the National Health and Nutrition Examination Survey, 2003–2006. J Infect Dis. 2011;204:566–573.3. Katki HA, Schiffman M, Castle PE, et al. Five-year risks of CIN3+ and cervical canceramong women with HPV testing of ASC-US Pap results. J Low Genit TractDis. 2013;17:S36–S42.4. Bruni L, Diaz M, Castellsagué X, Ferrer E, Bosch FX, de Sanjosé S. Cervical humanpapillomavirus prevalence in 5 continents: meta-analysis of 1 million women with normal cytological findings. J Infect Dis. 2010;202:1789–1799.5. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervicalprecancer 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 CancerInst. 2005;97:1072–1079.6. Bansal M, Austin RM, Zhao C. High-risk HPV DNA detected in less than 2% of over25,000 cytology negative imaged liquid-based Pap test samples from women 30 and older. Gynecol Oncol. 2009;115:257–261.7. Wright TC Jr, Stoler MH, Sharma A, et al.; ATHENA Study Group. Evaluation ofHPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+cytology-negative results. Am J Clin Pathol. 2011;136:578–586.8. Zhao C, Chen X, Onisko A, Kanbour A, Austin RM. Follow-up outcomes for a largecohort of US women with negative imaged liquid-based cytology findings and positive high risk human papillomavirus test results. Gynecol Oncol. 2011;122:291–296.9. Schiffman M, Burk RD, Boyle S, et al. A study of genotyping for management ofhuman papillomavirus-positive, cytology-negative cervical screening results. J Clin Microbiol. 2015;53:52–59.10. Woodard A, Austin RM, Li Z, Beere J, Zhao C. Prevalence of HPV 16/18 genotypesand histopathologic follow-up outcomes in women with negative cytology andpositive high-risk HPV test results. J Am Soc Cytopathol. Epub ahead of print March 6, 2015. /10.1016/j.jasc.2015.03.001.11. Khanna A, Patel S, Gong Y, Staerkel G, Guo M. The efficacy of HPV 16/18genotyping in predicting CIN2+ in women with HPV+/Pap- results. J Am SocCytopathol. 2014;3:S1–S2 (abstract PP03).Dr. Ocque is a cytopathology fellow and Dr. Zhao is a professor of pathology and associate director of cytopathology, Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center. Dr. Zhao is a member of the CAP Cytopathology Committee.。