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Five-Year Risks of CIN 3+ and Cervical Cancer Among Women With HPV Testing of ASC-US 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 S36–S42
doi: 10.1097/LGT.0b013e3182854253
Original Article

Objective New screening guidelines recommend that human papillomavirus (HPV)–negative/atypical squamous cells of undetermined significance (ASC-US) results be considered as equivalent to HPV-negative/Pap-negative results, leading to rescreening in 5 years. However, despite ample data, the routine clinical performance of HPV testing of women with ASC-US has not been adequately documented.

Methods We estimated 5-year risks of cervical intraepithelial neoplasia (CIN) 3+ and of cancer among 2 groups of women between 2003 and 2010 at Kaiser Permanente Northern California: 27,050 aged 30 to 64 years who underwent HPV and Pap cotesting and had an ASC-US Pap result and 12,209 aged 25 to 29 years who underwent HPV triage of ASC-US.

Results Five-year risks of CIN 3+ and of cancer among women aged 30 to 64 years testing HPV-negative/ASC-US and among 923,152 women testing Pap-negative alone were similar although statistically distinguishable (CIN 3+, 0.43% vs 0.26%, p = .001; cancer, 0.050% vs 0.025%, p = .1). The increased risk of cancer after HPV-negative/ASC-US versus Pap-negative alone was confined to women aged 60 to 64 years (0.26% vs 0.035%, p = .3). Five-year risks of CIN 3+ and cancer among women with HPV-negative/ASC-US results were substantially higher than those among women testing HPV-negative/Pap-negative (CIN 3+, 0.43% vs 0.08%, p < .0001; cancer, 0.050% vs 0.011%, p = .003). For women aged 30 to 64 years testing HPV-positive/ASC-US, 5-year risks of CIN 3+ and cancer were slightly higher than those among 9,374 women with low-grade squamous intraepithelial lesion (LSIL) (CIN 3+, 6.8% vs 5.2%, p = .0007; cancer, 0.41% vs 0.16%, p = .04). Similar patterns were seen for women aged 25 to 29 years.

Conclusions Women with HPV-negative/ASC-US had a similar risk as women testing Pap-negative alone but had a higher risk than women testing HPV-negative/Pap-negative. Based upon the principle of “equal management of equal risks,” our findings support the equal management of women with HPV-negative/ASC-US and those with Pap-negative alone, except for exiting women from screening because cancer risks at ages 60 to 64 years may be higher for women testing HPV-negative/ASC-US. Our findings also support managing HPV-positive/ASC-US and LSIL similarly.

Women testing HPV-negative/ASCUS have a similar risk for CIN 3+ or cancer as women testing Pap-negative alone but have a higher risk than women testing HPV-negative/Pap-negative.

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 an independent evaluation 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 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 also 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 and Kaiser Permanente Northern California 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