P16^INK4a is superior to high-risk human papillomavirus testing in cervical cytology for the prediction of underlying high-grade dysplasia

BACKGROUND The primary goal of this study was to compare the clinical performance of an optimized and rigorously controlled immunocytochemical (ICC) assay for p16^INK4a to high-risk (HR) human papillomavirus (HPV) detection by polymerase chain reaction (PCR) as diagnostic adjuncts for cytology specimens from colposcopy patients. METHODS: The study included 403 cervical cytology specimens collected within 3 months of colposcopy. The colposcopic impression and cervical biopsy diagnosis served as the standards for correlation with cytological, p16^INK4a, and HPV data. p16^INK4a was evaluated using an immunoperoxidase- based assay that was linear over 4 logs for the detection of HeLa-spiked positive control cytology specimens, using a threshold for positive test results that was based on receiver operating characteristic curve analysis. HR-HPV was detected by multiplex PCR using genotype-specific primers. RESULTS: In all combined diagnostic categories (negative for intraepithelial lesion and malignancy, atypical glandular cells, atypical squamous cells of undetermined significance, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion), the p16^INK4a ICC and HR-HPV assays, respectively, had sensitivity of 81.7% and 83.3% (P=.81) and specificity of 78.1% and 50.9% (P < .001) for the detection of underlying ≥grade 2 cervical intraepithelial neoplasia (CIN) lesions on biopsy. Furthermore, the positive predictive value of p16 ^INK4a ICC was greater than that of HR-HPV for patients with biopsies ≥CIN-2 (41.2% and 24.2%, respectively, P=.001). CONCLUSIONS: This p16 ^INK4a immunocytochemical assay has superior specificity but similar sensitivity to HR-HPV testing to predict underlying high-grade dysplastic lesions in patients who are referred for colposcopy. The determination of the overall performance characteristics of p16^INK4a immunocytochemistry, as an independent test or in combination with HPV testing in low-risk screening populations, however, will require subsequent large-scale prospective clinical trials.