Natural History of CIN2 in Adolescents

这是一项为期5年的前瞻性研究，旨在：1)检测青少年高级别鳞状上皮内病变(HSIL)的CIN-2(宫颈上皮内病变)亚型的自然病史，2)确定与CIN 2病变消退相关的免疫和行为因素。对可能影响CIN 2消退的免疫学和行为学因素的研究将包括：持续的局部(宫颈)Th-1样细胞因子反应，全身性细胞毒性T淋巴细胞(CTL)对HPV的反应(仅适用于HPV16阳性妇女)，确诊时病变的大小，确诊时宫颈未成熟(异位)的数量，以及激素避孕。其他将被监测的可能影响的因素包括高风险的性行为和结果(多性伴、药物使用、怀孕、性传播感染和细菌性阴道病)。最后，这项研究建议比较在基线检查时被诊断为CIN-1、CIN-2和活检组织学正常的妇女的局部免疫反应。大约40,000名19岁或以下的年轻女性预计将在24个月的时间里在北加州凯撒永久诊所接受宫颈细胞学筛查。13-19岁的细胞学异常青少年(估计N=2680)将被招募。基线检查将包括用于HPV DNA检测的面谈和宫颈样本，以及使用逆转录聚合酶链式反应技术进行的定量细胞因子研究。将获得摄像照片以确定病变大小。所有样本都将在活检前获得。经活检证实为CIN 2(N=416)的患者将每3个月接受一次访谈、阴道镜检查、HPVDNA检测和细胞学检查，并接受免疫检查(对感染HPV16的妇女进行宫颈细胞因子实时定量RT-PCR分析和外周血CTL检测)，直至研究结束。患有CIN-3的女性需要接受标准治疗。经活检证实为低级别(L)及以下的患者将退出。了解CIN2的自然历史对于构建具有成本效益的青少年癌症筛查策略至关重要。此外，明确与CIN 2回归相关的免疫学因素将对疫苗和治疗策略具有重要意义，确定临床风险(包括重复的HPV DNA检测)和行为风险将对分诊和咨询策略具有重要意义。

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.