Evaluating the Performance of p16^INK4a Immunocytochemistry in Cervical Cancer Screening

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.

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.

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".

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.