Role of p16INK4a Cytology Testing as an Adjunct to Enhance the Diagnostic Specificity and Accuracy in Human Papillomavirus-Positive Women within an Organized Cervical Cancer Screening Program

Abstract

Objective: We evaluated the performance of cytologic p16^INK4a (p16) immunostaining within a cervical cancer screening program for the categories of atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LS after triage with high-risk human papillomavirus (HR-HPV) testing and atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesion (ASC-H) and high-grade squamous intraepithelial lesion (HSIL). We also verified whether the routine introduction of p16 staining might enhance the specificity and positive predictive value (PPV) for cervical intraepithelial neoplasia grade 2 or higher (CIN2+) lesions predicted by a cytological screening test. Study Design: Performance of the p16 cytology test was estimated in 578 cytological samples, of which 213 were HR-HPV+ ASC-US, 186 were HR-HPV+ LSIL, 74 were ASC-H, 56 were HSIL-CIN2 and 49 were HSIL-CIN3. All samples had histological follow-up. Results: In the ASC-US category, p16 sensitivity was 91% for CIN2+ and 100% for CIN3, while specificity was 64 and 58%, respectively, negative predictive value (NPV) was 96 and 100%, respectively, and PPV was 39%. In the LSIL category, sensitivity was 77 and 75%, respectively, for CIN2+ and CIN3, while specificity was 64 and 57%, NPV was 93 and 98% and PPV was 30%. Sensitivity for ASC-H and HSIL-CIN3 was 100% for CIN2+ and CIN3, while for HSIL-CIN2 it was 91 and 95%, respectively; NPV for ASC-H was 100%, and for HSIL-CIN2 it was 43 and 86%, respectively. Follow-up examinations of 8 cases diagnosed as p16+ ASC-H and HSIL-CIN3, but histologically negative or CIN1 on the first biopsy, showed 4 CIN2 and 4 CIN3 lesions. Conclusions: Sensitivity, specificity, PPV and NPV confirm the importance of the utilization of p16 in the categories ASC-US and LSIL after triage with an HR-HPV test. In the ASC-H and HSIL-CIN3 lesions, p16 was shown to be an excellent marker for picking up CIN2+ lesions, especially in cases with cytohistological discordance.

The role of p16 as putative biomarker for cervical neoplasia: A controversial issue?

“…14 Several studies have shown increased sensitivity and specificity for cervical cancer screening using p16 staining in conjunction with other biomarkers, such as p16/Ki-67 15,16,[24][25][26] and Survivin, the inhibitor of apoptosis. 27 …”

Predictive Value of the Combined p16^INK4a and Ki-67 Immunocytochemistry in Low-Grade Squamous Intraepithelial Lesions

“…The detection of p16 INK4a overexpression indicates cellular transformation by high-risk HPV due to cell cycle deregulation. The diagnostic evaluation of p16 INK4a as an individual biomarker was shown to be unreliable in its practical application [23,24,25,26]. An immunocytochemical detection of both p16 INK4a and Ki-67 in the same cell, however, indicates neoplastic cellular transformation [1].…”

Human Papillomavirus Genotype Distribution in Cytologically Screened Women from Northwest Germany

“…A possible explanation for the large differences between CIN2 and CIN3 in the distribution of HPV type, as observed in our study, could be the additive use of immunohistochemistry to detect overexpression of the cell cycle protein p16 INK4a for histological grading of CIN lesions. This immunohistochemical method has been shown to improve the accuracy of grading CIN lesions significantly [20,21]. …”

“…Cervical neoplasia expresses high levels of p16 INK4a in contrast to other cervical epithelia. This overexpression is linked to oncogenic transformation mediated by persistent hrHPV infection and it has been shown to significantly improve the accuracy of grading CIN lesions [20,21]. …”