P16INK4a/ki67 Immunocytochemistry in Improving the Predictive Value for High Grade Cervical Intraepithelial (≥CIN2) Neoplasia in Pap Smear

Abstract

Introduction: Cervical cytology has limited sensitivity to detect cervical pre-cancerous lesions. High-risk human papillomavirus (hr-HPV) DNA testing has high sensitivity but its specificity is limited. This study was done to assess the utility of p16^INK4a/ki-67 dual stained cytology in improving the predictive value for high-grade cervical (CIN2+) lesions.

Aim/objective: To assess the significance of P16/Ki-67 immunocytochemistry in improving the predictive value for high-grade cervical intraepithelial (≥CIN 2+) lesions on Pap smear.

Material and methods: This was a prospective diagnostic study that included 93 patients with ASC-US/LSIL/ASC-H and HSIL on thin prep cervical smears and who also underwent hr-HPV DNA test and colposcopy-guided biopsy. Biopsy was the gold standard against which the performance of P16^INK4a/Ki-67 and hr-HPV results were compared.

Results: In women of all ages, sensitivity of (96.8%) hr-HPV test and p16/Ki-67 dual immunocytochemistry (≥1 positive cell) were similar and negative predictive value (NPV) was (97.1% vs. 97.9%) but the latter test showed better specificity (69.4% vs. 53.2%) and positive predictive value (PPV, 61.2% vs. 50.8%) for ≥CIN 2 lesions. A higher cut off of at least 10 positive cells gives a higher specificity and PPV, with slightly decreased sensitivity and NPV.

Conclusion: Because high-risk HPV test has a high sensitivity and NPV, whereas P16/Ki-67 dual immunocytochemistry (≥10 positive cells) has a high specificity and PPV, the latter can be recommended as an ancillary test in hr-HPV-positive women to reduce the number of women going for colposcopy and biopsies.

Keywords: ASC-H; ASC-US; HSIL; LSIL; P16INK4a/ki-67; cervical intraepithelial neoplasia – CIN 2+; hr-HPV DNA.

Figure 1

(a–f) p16/Ki-67 dual immunostaining. (a) Positive control-squamous cell carcinoma showing positivity for p16/Ki-67 (400×). (b) Negative control-negative for intraepithelial lesion showing negativity for p16/Ki-67 (400×). (c) HSIL showing positivity for p16/Ki-67 (400×). (d) ASC-H showing positivity for p16/Ki-67 (400×). (e) LSIL showing positivity for p16/Ki-67 (400×). (f) ASC-US showing positivity for p16/Ki-67 (400×)