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Five-Year Risks of CIN 3+ and Cervical Cancer Among WomenWho Test Pap-Negative But Are HPV-Positive

Katki, Hormuzd A. PhD1; Schiffman, Mark MD, MPH1; Castle, Philip E. PhD, MPH2; Fetterman, Barbara SCT (ASCP)3; Poitras, Nancy E. PMP3; Lorey, Thomas MD3; Cheung, Li C. MS4; Raine-Bennett, Tina MD, MPH5; Gage, Julia C. PhD, MPH1; Kinney, Walter K. MD6

Journal of Lower Genital Tract Disease: April 2013 - Volume 17 - Issue - p S56–S63
doi: 10.1097/LGT.0b013e318285437b
Original Article

Objective Current US guidelines for cotesting recommend that the large numbers of women who test Pap-negative, but human papillomavirus (HPV)–positive, return in 1 year, and those who remain HPV-positive or have low-grade squamous intraepithelial lesion (LSIL) or worse Pap results be referred for colposcopy. However, the performance of these guidelines in routine clinical practice has not been evaluated.

Methods We estimated cumulative 5-year risks of cervical intraepithelial neoplasia grade 3 or worse (CIN 3+) among 32,374 women aged 30 to 64 years with HPV-positive/Pap-negative cotest results at Kaiser Permanente Northern California during 2003 to 2010.

Results The 5-year CIN 3+ risk after an HPV-positive/Pap-negative cotest result, which was found in 3.6% of women, was 4.5% (95% confidence interval [CI] = 4.2%–4.8%). The 5-year cancer risk was 0.34% (95% CI = 0.26%–0.45%), and half of the cases were adenocarcinoma. Overall, 48% of the women remained HPV-positive on return (median = 418 days after baseline), a percentage that varied little over ages 30 to 64 years. At the return after a baseline HPV-positive/Pap-negative result, almost every repeat cotest result predicted greater subsequent 5-year CIN 3+ risk than the same cotest result had at baseline (HPV-positive/LSIL, 9.2% vs 6.1%, p = .01; HPV-positive/atypical squamous cells of undetermined significance [ASC-US], 7.9% vs 6.8%, p = .2; HPV-positive/Pap-negative, 7.4% vs 4.5%, p < .0001; HPV-negative/LSIL,1.7% vs 2.0%, p = .8; HPV-negative/ASC-US, 2.9% vs 0.43%, p = .0005; HPV-negative/Pap-negative, 0.93% vs 0.08%, p < .0001).

Conclusions Using the principle of “equal management of equal risks,” women testing HPV-positive/Pap-negative had a subsequent CIN 3+ risk consistent with risk thresholds for a 1-year return. However, on returning in approximately 1 year, about one-half of women will be referred for colposcopy because of continued HPV positivity or Pap abnormality. Clinicians should keep in mind that cotest results at the return after a baseline HPV-positive/Pap-negative finding are riskier than the same baseline cotest results in the general population, supporting intensified clinical management at return testing.

Women with negative cytology who tested HPV-positive had low enough CIN 3+ risk to return in 1 year for cotesting, when half of women remained HPV-positive and would be referred for colposcopy.

1Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD; 2Albert Einstein College of Medicine, Bronx, NY; 3Regional Laboratory, Kaiser Permanente Northern California, Berkeley, CA; 4Information Management Services, Inc, Calverton, MD; 5Women’s Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland, CA; and 6Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA

Reprint requests to: Hormuzd A. Katki, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd Room 8014, EPS MSC 7244, Bethesda, MD 20882. E-mail:; Walter K. Kinney, MD, Kaiser Permanente Northern California, Sacramento Medical Center, 1650 Response Rd, Sacramento, CA 95815. E-mail:

Drs Schiffman and Gage report working with Qiagen, Inc. on independent evaluations of noncommercial uses of CareHPV (a low-cost human papillomavirus [HPV] test for low-resource regions) for which they have received research reagents and technical aid from Qiagen for free. They have received HPV testing for research at no cost from Roche. Dr Castle has received compensation for serving as a member of a Data and Safety Monitoring Board for HPV vaccines for Merck and also received HPV tests and testing for research at a reduced or no cost from Qiagen, Roche, MTM, and Norchip. Dr Castle is a paid consultant for BD, GE Healthcare, and Cepheid and has received a speaker honorarium from Roche. The other authors have declared they have no conflicts of interest.

The Intramural Research Program of the US National Institutes of Health/National Cancer Institute reviewed the final article for publication. The Kaiser Permanente Northern California Institutional Review Board (IRB) approved use of the data, and the National Institutes of Health Office of Human Subjects Research deemed this study exempt from IRB review.

©2013The American Society for Colposcopy and Cervical Pathology