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Five-Year Risks of CIN 3+ and Cervical Cancer Among Women With HPV-Positive and HPV-Negative High-Grade Pap Results

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 S50–S55
doi: 10.1097/LGT.0b013e3182854282
Original Article

Objective High-grade Pap results (e.g., atypical glandular cells [AGC], atypical squamous cells cannot rule out HSIL [ASC-H], and high-grade squamous intraepithelial lesion [HSIL]) predict high cancer risks, resulting in referral for colposcopy without HPV triage. However, new guidelines recommending cotesting for women 30 years and older imply that clinicians will often receive the HPV test result concurrently for high-grade Pap results. We examined whether HPV testing provides useful risk stratification in this context.

Methods From a cohort of 965,360 women aged 30 to 64 years undergoing cotesting at Kaiser Permanente Northern California, we estimated 5-year risks for cervical cancer and CIN 3+ after AGC (2,074 women), ASC-H (1,647 women), and HSIL (2,019 women) according to HPV test results.

Results HPV positivity of AGC Pap results was 25% and decreased with age (30 to 34 vs 60 to 64 years, 44% vs 17%, p < .0001), whereas HPV positivity of ASC-H and HSIL was much higher (71% and 94%) and decreased less with age. Even for these high-grade Pap results, 5-year CIN 3+ risks differed substantially between HPV-positive and HPV-negative women (AGC, 33% vs 0.93%, p < .0001; ASC-H, 25% vs 3.5%, p < .0001; HSIL, 49% vs 30%, p = .006). However, except for AGC, cervical cancer risks differed less between HPV-positive and HPV-negative women (AGC, 9.0% vs 0.37%, p < .0001; ASC-H, 2.5% vs 2.1%, p = .8; HSIL, 6.6% vs 6.8%, p = .7).

Conclusions The risks of CIN 3+ among women with HPV-negative high-grade Pap results were lower than those among women with HPV-positive high-grade Pap results, especially after AGC. However, by the principle of “equal management of equal risks,” all HPV-negative high-grade Pap results had cancer risks high enough to warrant colposcopy, confirming that there is no current role for HPV triage of high-grade Pap results.

All women with AGC, ASC-H, or HSIL had high risks for cancer, even women testing HPV-negative, supporting referring all of them for immediate 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; 5 Women’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 at no cost. They have received free testing of specimens for research 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