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Five-Year Risk of Recurrence After Treatment of CIN 2, CIN 3, or AIS: Performance of HPV and Pap Cotesting in Posttreatment Management

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 S78–S84
doi: 10.1097/LGT.0b013e31828543c5
Original Article

Objective After excisional treatment, cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) can recur. It is not clear how many negative posttreatment Pap or cotest results are needed to ensure adequate safety against CIN 2+ before returning to extended retesting intervals.

Methods We observed 5-year risks of CIN 2+ for 3 follow-up management strategies after treatment (Pap-alone, human papillomavirus [HPV]-alone, and HPV/Pap cotesting) for 3,273 women aged 25 years and older who were treated for CIN 2, CIN 3, or adenocarcinoma in situ (AIS) between 2003 and 2010 at Kaiser Permanente Northern California.

Results Five-year risks of recurrent CIN 2+ after treatment varied both by antecedent screening test result and the histology of the treated lesion. The risk ranged from 5% for CIN 2 preceded by HPV-positive/atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion to 16% for CIN 3/AIS preceded by atypical glandular cells (AGC)/atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion (ASC-H)/high-grade squamous intraepithelial lesion or worse (HSIL+) (p < .0001). However, after posttreatment negative tests, risks were lowered and similar regardless of antecedent screening test and histology of treated disease. The 5-year recurrent CIN 2+ risk after a negative posttreatment cotest (2.4%) was lower than that following a negative HPV test (3.7%, p = .3) or negative Pap result (4.2%, p = .1). Two negative posttreatment tests of each kind conferred slightly lower 5-year CIN 2+ risk than one (2 negative Pap tests vs. 1, 2.7% vs 4.2%, p = .2; 2 negative HPV tests vs. 1, 2.7% vs 3.7%, p = .7; 2 negative cotests vs. 1, 1.5% vs 2.4%, p = .8). The 5-year CIN 2+ risk after 2 negative cotests of 1.5% (95% confidence interval = 0.3%–7.2%) approached the 0.68% risk after a negative Pap test during routine screening.

Conclusions Women with antecedent AGC/ASC-H/HSIL+ Pap results or those treated for CIN 3/AIS had a substantial risk of developing CIN 2+ posttreatment. On the basis of the principle of “equal management of equal risks,” after negative test results posttreatment, no subgroup of women achieved risk sufficiently low to return to 5-year routine screening. However, negative cotests after treatment provided more reassurance against recurrent CIN 2+ than either negative Pap tests or HPV tests alone.

Negative cotests after treatment seemed to provide more reassurance against recurrent CIN 2+ than either negative Pap tests or HPV tests alone.

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

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 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.

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:

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