Performance of p16/Ki-67 Immunostaining to Detect Cervical Cancer Precursors in a Colposcopy Referral Population

Abstract

Purpose Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. HPV DNA testing is highly sensitive and provides a high, long-term reassurance of low risk of cervical cancer. However, the specificity of HPV DNA testing is limited, requiring additional, more disease-specific markers for efficient screening approaches. Experimental Design Liquid based cytology samples were collected from 625 women referred to colposcopy. A slide was stained using the CINtec plus cytology assay. Pap cytology and HPV genotyping were performed from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with an LSIL Pap. Results p16/Ki-67-positivity increased with histological severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2, to 92.8% in CIN3. Among women with CIN3, p16/Ki-67-positivity increased from 77.8% for women <30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detect CIN3+ were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women 30 years and older. In women with HR-HPV-positive ASC-US and LSIL, sensitivity and specificity for detection of CIN3 were 90.6% and 48.6%, respectively. Conclusions p16/Ki-67 testing could reduce referral to colposcopy by almost half while detecting the most severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared to HPV testing makes p16/Ki-67 a viable option for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies.

CCNA1 Promoter Methylation: a Potential Marker for Grading Papanicolaou Smear Cervical Squamous Intraepithelial Lesions

“…Emerging from this is the question, "which test would be the best in triage for women who have positive HPV DNA test but negative cytological result for immediate referral for colposcopy?". HPV 16/18 genotyping, p16/Ki-67 dual immunocytochemistry staining, and HPV E6/E7 mRNA testing are currently available and acceptable markers for patient selection (Eide and Debaque, 2012;Wentzensen et al, 2012). Currently, better diagnostic biomarkers with higher specificity are being developed as additional tools for cervical cancer screening strategies.…”

Interobserver reproducibility and accuracy of p16/Ki‐67 dual‐stain cytology in cervical cancer screening

“…The p16/Ki-67 or dual-stain assay has been evaluated in several populations. [9][10][11][12] However, a formal reproducibility analysis of the dual-stain assay has not been reported to date. We conducted a systematic reproducibility analysis of 480 p16/Ki-67 dual-stain cytology specimens among 10 raters in a routine US cytology practice compared with an expert evaluation and assessed clinical performance between the evaluators for the detection of cervical intraepithelial neoplasia grade 2 or greater (CIN21).…”

HPV16 genotype, p16/Ki‐67 dual staining and koilocytic morphology as potential predictors of the clinical outcome for cervical low‐grade squamous intraepithelial lesions

“…It is considered to be even better than HPV DNA testing in triage and in the prediction of the clinical outcome of ASC-US and LSILs. [29][30][31][32][33][34][35] The aim of this study was to evaluate the HPV DNA test result, HPV genotype, p16/Ki-67 dual immunostaining and the presence of koilocytosis in LSIL, and their association with its clinical outcome.…”