Human Papillomavirus Testing Following Loop Electrosurgical Excision Procedure Identifies Women at Risk for Posttreatment Cervical Intraepithelial Neoplasia Grade 2 or 3 Disease Aime ´e R. Kreimer, 1,2 Richard S. Guido, 4 Diane Solomon, 2 Mark Schiffman, 3 Sholom Wacholder, 3 Jose ´ Jeronimo, 3 Cosette M. Wheeler, 5 and Philip E. Castle 3 for the ASCUS-LSIL Triage Study (ALTS) Group 1 Cancer Prevention Fellowship Program, 2 Division of Cancer Prevention, and 3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland; 4 Magee-Women’s Hospital of the University of Pittsburgh Health Care System, Pittsburgh, Pennsylvania; and 5 Departments of Molecular Genetics and Microbiology and Obstetrics and Gynecology, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico Abstract Background: Loop electrosurgical excision procedure (LEEP) is the predominant treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN2+) in the United States, yet following treatment f10% of women are diagnosed again with CIN2+, necessitating close follow-up of such patients. Methods: Surveillance strategies using cytology and/or human papillomavirus (HPV) testing were compared among women who underwent LEEP (n = 610) in the Atypical Squamous Cells of Undetermined Significance (ASCUS) Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. Cervical specimens, collected at 6-month visits for 2 years, were used for cytology, Hybrid Capture 2 (HC2) detection of carcinogenic HPVs, and PCR for genotyping of carcinogenic and noncarcinogenic HPV types. At exit, women had colposcopy for safety and disease ascertainment. Results: Atthevisitpost-LEEP(mediantime:4.5monthsafter LEEP), 36.9% [95% confidence interval (95% CI), 32.7-41.1%] of women were positive for carcinogenic HPV by PCR and 33.7% (95% CI, 29.7-37.9) had ASCUS or more severe (AS- CUS+) cytology. The overall 2-year cumulative incidence of histologically confirmed posttreatment CIN2+ was 7.0%; this could be further stratified by the HPV risk category detected at the 6-month visit after LEEP. The 2-year risk associated with HPV16 positivity was 37.0%, significantly higher than for other carcinogenic HPV types (10.8%, P < 0.001), noncarcinogenic types (1.5%, P < 0.001), or testing HPV negative (0%). Post-LEEP cytology (using a positive thresh- old of ASCUS+) was 78.1% (95% CI, 60.0-90.7%) sensitive for detection of posttreatment CIN2+. By comparison, PCR for carcinogenic HPV and combination testing (using a positive result from carcinogenic HPV testing or cytology as the test threshold with HPV-negative ASCUS not referred) were significantly more sensitive (96.9% for each, P = 0.03); HC2 alone was nonsignificantly more sensitive (90.6%, P = 0.3). Specificity was similar for ASCUS+ cytology (69.1%, 95% CI, 64.6-73.3%) and PCR for carcinogenic HPV (67.1%, P = 0.5), yet was lower for HC2 (63.8%, P = 0.048) and combination testing (62.9%, P = 0.02). Conclusion: Women who tested positive after LEEP for car- cinogenic HPV types, especially HPV16, had high risk of subsequent CIN2+. HPV-based detection methods, alone or in combination with cytology, may be useful to incorporate in post-LEEP management strategies. (Cancer Epidemiol Biomarkers Prev 2006;15(5):908–14) Introduction Since its introduction in 1989 (1), loop electrosurgical excision procedure (LEEP) has quickly become the most common cervical treatment modality in the United States for cervical intraepithelial neoplasia grade 2 or 3 (CIN2+). LEEP is highly effective and offers the following advantages: (a ) unlike ablative techniques, LEEP provides a tissue specimen for histologic evaluation, and (b ) compared with cold knife conization, LEEP removes less normal tissue (2, 3). However, following LEEP, f10% of women have CIN2+ due to either residual or recurrent disease (2, 3). In previous studies, risk of residual or recurrent disease has been consistently associated with large lesion size before LEEP, endocervical extension of disease, and incomplete excision of the lesion (4-7). However, even women with clear margins following excision are at risk for disease recurrence (8). Carcinogenic human papillomavirus (HPV), the causative agent of cervical cancer and its precursor lesions, is present in up to one third of women following LEEP and is associated with disease recurrence (5, 6, 9-11). Therefore, HPV testing may serve as a surveillance tool for identifying women at high risk of recurrence. Two meta-analyses that investigated the clinical utility of post-treatment carcinogenic HPV testing and cytology showed greater sensitivity of carcinogenic HPV testing compared with cytology for identifying recurrent/ residual disease (12, 13). However, combination carcinogenic HPV testing and cytology (with a positive result from either test triaging to colposcopy) increased sensitivity further and was proposed as a method for monitoring women after treatment for CIN3 (12). Due to the elevated risk of post-treatment CIN2+ in women who have had LEEP, maximizing test sensitivity is of greater importance than it would be in a screening population in which most subjects have relatively low risk of disease. In the 908 Cancer Epidemiol Biomarkers Prev 2006;15(5). May 2006 Received 10/31/05; revised 2/7/06; accepted 2/21/06. Grant support: National Cancer Institute, NIH, Department of Health and Human Services contract nos. CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105. Some of the equipment and supplies were donated or provided at reduced costs by Digene Corporation (Gaithersburg, MD), Cytyc Corporation, (Fenton, MO), Denvu (Tucson, AZ), Roche Molecular Systems (Alameda, CA), and TriPath Imaging, Inc. (Burlington, NC). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Aimee R. Kreimer, National Cancer Institute, NIH, 6130 Executive Boulevard, Bethesda, MD 20892-7333; Phone: 301-594-0839; Fax: 301-480-9939. E-mail: kreimera@mail.nih.gov. Copyright D 2006 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-05-0845 Downloaded from http://aacrjournals.org/cebp/article-pdf/15/5/908/1940267/908.pdf by guest on 06 December 2023