This is a 5 year prospective study designed to: 1) examine the natural history of CIN-2 (cervical intra-epithelial lesions) subset of high grade squamous intra-epithelial lesions (HSIL) among adolescents, and 2) identify immunologic and behavioral factors associated with regression of CIN 2 lesions. The study of immunologic and behavioral factors that may influence CIN 2 regression will include: sustained local (cervical) Th-1 like cytokine response, systemic cytotoxic T lymphocyte (CTL) responses to HPV (for HPV 16 positive women only), size of lesion at diagnosis, amount of cervical immaturity (ectopy) at diagnosis, and hormonal contraception. Other factors that will be monitored for possible effects include high risk sexual behavior and outcomes (multiple partners, substance use, pregnancy, sexually transmitted infections, and bacterial vaginosis). Last, this study proposes to compare local immunologic responses among women who at baseline visit are diagnosed with CIN-1, CIN-2 and normal histology on biopsy. Approximately 40,000 young women 19 years or younger are expected to undergo cervical cytology screening within the Northern California Kaiser Permanente clinics over a 24 month period. Adolescents aged 13-19 years with abnormal cytology (estimated N=2680) will be recruited. Baseline examination will include interview and cervical samples for HPV DNA testing and quantitative cytokine studies using reverse transcriptase polymerase chain reaction techniques. Colpophotographs will be obtained to determine lesion size. All samples will be obtained prior to biopsy. Those with biopsy-confirmed CIN 2 (N=416) will be followed every 3 months using interview, colposcopy, HPV DNA testing, and cytology and undergo immune studies (cervical cell cytokine analysis using real-time RT-PCR and peripheral blood CTL assays on women with HPV 16 infection) until the end of the study. Women with CIN-3 are exited for standard therapy. Those with biopsied confirmed low grade (L) SIL or less will exited. Understanding of the natural history of CIN 2 will be critical in efforts to construct cost-effective strategies for cancer screening in adolescents. In addition, defining immunologic factors associated with CIN 2 regression will have important implications for vaccine and therapeutic strategies and defining clinical (including repeated HPV DNA testing) and behavioral risks will have important implications for triage and counseling strategies.
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