Misclassification Of Cervical Precancer: Impact Of A New Colposcopy Protocol On Disease Ascertainment And Biomarker Performance

Introduction: Cytology-based screening for and treatment of cervical precancers has led to substantial reduction of cervical cancer incidence and mortality worldwide. Current screening approaches have limited accuracy, however, and lead to misclassification of cervical precancer at the levels of primary screening, colposcopic evaluation, and histological evaluation. We designed the Biopsy Study to systematically evaluate the extent of misclassification of cervical precancer at colposcopy. Methods: Previously-untreated women referred to the University of Oklahoma colposcopy clinic for abnormal screening results were enrolled. Before colposcopy, a specimen was taken for liquid-based cytology, HPV genotyping, and biomarker studies. During colposcopy, a digital image of the cervix was taken and annotated for observed lesions and biopsy sites. Up to four colposcopically directed biopsies were taken from distinct lesions; if less than four targeted biopsies were obtained, a random biopsy was added. All biopsies were ranked by severity based on visual impression and evaluated individually in histology. Three cervical cancer screening tests, Pap cytology, HPV DNA testing, and p16/ki67 cytology, were evaluated against disease endpoints based on the most severely appearing biopsy (representing the current clinical standard) and based on the worst histology result from all four biopsies. Results: To date, more than 450 women have been enrolled in the study; 86% of women had at least three, and 64% had four biopsies taken. For 377 women, a histological diagnosis was available. Forty-one of 377 women (10.8%) had CIN3, 119 (31.6%) had CIN2, 82 (35.3%) had CIN1, and 84 (22.3%) had benign changes or normal results as worst histological result. In 70.7% of women, the precancer was detected in the first biopsy, in 22.0% it was found at the second biopsy and in 7.3% it was detected in the third or fourth biopsies. Cervical cancer screening tests were evaluated in a subset of 241 women. The specificity of HPV DNA, Pap cytology, and p16/ki67 for the detection of CIN2+ increased by 6%, 7.5%, and 11.8%, respectively when the improved gold standard was applied. Meanwhile, the sensitivity of all screening tests was not reduced. Discussion: Current colposcopy-biopsy protocols have limited sensitivity in detecting prevalent cervical precancer. In our study, we quantified the incremental benefit of taking multiple biopsies to detect cervical precancer. In the interim analysis, adding a second targeted biopsy improved disease detection by over 20%. The improved sensitivity of colposcopy resulted in decreased misclassification of cervical disease and a more accurate evaluation of cervical cancer screening tests. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3189. doi:10.1158/1538-7445.AM2011-3189