Evaluating the Performance of p16(INK4a) Immunocytochemistry in Cervical Cancer Screening

PURPOSE: When used for cervical cancer primary screening, liquid-based cytology (LBC) has a high specificity but a low sensitivity. For histological diagnosis of high-grade lesions, p16(INK4a) immunostaining has proven to be useful. Therefore, our objective was to evaluate the use of p16(INK4a) immuno-cytology as a primary screen and a secondary screen after primary high-risk human papillomavirus (hrHPV) screening or LBC screening. METHODS: A total of 1197 cytology slides were immuno-stained using automatic p16(INK4a) staining system (PathCIN(®)p16(INK4a)) in two studies from cervical screening programs. In the primary screening study, 875 slides were randomly selected and analyzed for p16(INK4a). In the secondary screening study, 322 of the remaining slides were chosen by virtue of being HPV 16/18+, other hrHPV+/LBC≥ASC-US, or HPV-negative/LBC ≥LSIL. The sensitivity and specificity for detection of cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+) were compared based on p16(INK4a), LBC and HPV test results. RESULTS: In combining two studies, there were 431 cases with biopsy pathology. They included 83 cases with CIN2+ and 41 cases with CIN3+. The p16 positivity rate increased with pathologic and cytologic severity (P<0.0001). For primary screening: p16 immuno-cytology was more specific than HPV testing and was similar in sensitivity. Also, p16 immuno-cytology compared favorably with routine LBC (≥ASC-US or ≥LSIL) in sensitivity and specificity. For secondary screening: after LBC screening, “Triaging ASC-US with p16” gave a higher specificity and a similar sensitivity as compared to the “Triaging ASC-US with hrHPV” algorithm. After HPV primary screening, p16 immuno-cytology was more specific than LBC (≥ASC-US); the calculated colposcopy referral rate was also decreased by using p16 immuno-cytology as triage. Triage of “HPV16/18 and p16” had higher specificity and similar sensitivity as compared to triage of “HPV16/18 and LBC ≥ASC-US”. CONCLUSION: For primary screening, p16(INK4a) immuno-cytology compares favorably to routine LBC and HPV testing. p16(INK4a) immunostaining could be an efficient triage to reduce the colposcopy referral rate after primary hrHPV screening or LBC screening. Therefore, p16(INK4a) immuno-cytology may be applicable as a favorable technology for cervical cancer screening.