Imaging, Diagnosis, Prognosis Performanceof p16/Ki-67 Immunostaining toDetectCervical Cancer Precursors in a Colposcopy Referral Population

Purpose:Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. Human papilloma virus (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 slidewas stainedusing theCINtec plus cytology assay. Pap cytology andHPVgenotypingwere conducted from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with a low-grade squamous intraepithelial lesion (LSIL) Pap. Results: p16/Ki-67 positivity increased with histologic severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2 to 92.8% in CIN3. Amongwomenwith CIN3, p16/Ki-67 positivity increased from 77.8% for women younger than 30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detectCIN3þwere 93.2%and46.1%, respectively, and increased to 97.2% and 60.0% amongwomen 30 years and older. In womenwith high-risk (HR)-HPV–positive atypical squamous cells of undetermined significance (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 colposcopybyalmost halfwhile detecting themost severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared with HPV testingmakesp16/Ki-67 a viableoption for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies. Clin Cancer Res; 18(15); 1–9. 2012 AACR.