Performance of p16^INK4a/Ki-67 immunocytochemistry for identifying CIN2+ in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion specimens: a Japanese Gynecologic Oncology Group study

Background: p16^INK4a immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16^INK4a immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16^INK4a and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16^INK4a/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system. Methods: From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16^INK4a/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared. Results: p16^INK4a/Ki-67 immunocytochemistry was positive in 33.5 % (63/188) of ASCUS, and 36.8 % (88/239) of LSIL specimens. The sensitivity and specificity of p16^INK4a/Ki-67 immunocytochemistry was 87.3 % (95 % confidence interval 78.0–93.8 %) and 76.4 % (71.6–80.8 %), respectively. The positive and negative predictive values were 45.7 % (37.6–54.0 %) and 96.4 % (93.4–98.3 %), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16^INK4a/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test Conclusions: Compared with high-risk HPV genotyping, p16^INK4a/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.