Anal Cancer Screening Study

BACKGROUND: Human immunodeficiency virus (HIV) positive men who have sex with men (MSM) are at risk of anal cancer that approaches the risk of cervical cancer for unscreened women living in developing countries. There is currently no accepted method for screening HIV positive MSM for anal precancer to reduce the morbidity and mortality due to anal cancer ; in the absence of a standard and effective screening modality, clinics often resort to anoscopy, a diagnostic procedure akin to colposcopy, and directed biopsies on all HIV positive MSM. OBJECTIVE: Evaluate the clinical performance of detecting carcinogenic human papillomavirus (HPV) DNA and RNA, individual carcinogenic HPV genotypes, cytogenetic markers, p16(INK4a) and Ki-67 immunocytochemistry staining, anal cytology, and combinations of these biomarkers for identifying HIV positive MSM with prevalent, 1 year cumulative, and 2 year cumulative anal precancer and cancer (histologically-confirmed greater than or equal to AIN3) using clinician-collected anal specimens at baseline. ELIGIBILITY: HIV positive MSM seeking anal cancer screening. Inclusion: 1) KPNC member; 2) documented HIV-positive status; 3) able and mentally competent to provide written, informed consent. Exclusion:A current diagnosis of anal cancer at enrollment. DESIGN: To address this need and to improve detection of anal precancer and cancer, we propose a screening cohort study of 1,000 HIV positive MSM participating in the Kaiser Permanente Northern California (KPNC) health maintenance program. Under written, informed consent, participating KPNC members will respond to a self-administered risk factor questionnaire and will undergo two anal specimen collections into liquid-based cytology (LBC) medium prior to a digital exam and high resolution anoscopy. Subjects will be asked to self-collect at home into the same LBC buffer and return their specimen in a prepared return envelope to evaluate the utility of self-collection for anal cancer screening. Subjects will be followed annually for two years to collect follow-up clinical data related to outcomes. Baseline clinician-collected specimens will be tested in a masked fashion for the following clinical biomarkers: 1) carcinogenic HPV DNA in aggregate and individual carcinogenic HPV genotypes; 2) carcinogenetic HPV RNA and HPV16/18 RNA; 3) cytogentic changes (3q, 5p, and 20q amplification); and 4) p16(INK4a) and Ki-67 immunocytochemical staining. For reference, clinician-collected specimens will be used to make LBC slides and evaluated by an expert cytopathology laboratory. We will estimate the clinical performance (sensitivity, specificity, positive and negative predictive values, and referral rates) for detection of prevalently-detected, one-year cumulative, and two-year cumulative histologically-confirmed anal precancer (anal intraepithelial neoplasia grade 3) or worse (greater than or equal to AIN3). We will test the self-collected anal specimens by the best molecular test(s) or combination of tests for detection of prevalently-detected greater than or equal to AIN3 as determined from testing the clinician-collected specimens. All MSM will undergo diagnostic procedures at all visits and independent of testing results, which will result in unbiased disease ascertainment.