Screening for Cervical Cancer Precursors With p16/Ki-67 Dual-Stained Cytology: Results of the PALMS Study

Abstract

BackgroundPap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2+ in screening while maintaining high specificity. Results were compared with Pap cytology and HPV testing.MethodsA total of 27349 women 18 years or older attending routine cervical cancer screening were prospectively enrolled in five European countries. Pap cytology, p16/Ki-67 immunostaining, and HPV testing were performed on all women. Positive test results triggered colposcopy referral, except for women younger than 30 years with only positive HPV test results. Presence of CIN2+ on adjudicated histology was used as the reference standard. Two-sided bias-corrected McNemar P values were determined.ResultsThe p16/Ki-67 dual-stained cytology positivity rates were comparable with the prevalence of abnormal Pap cytology results and less than 50% of the positivity rates observed for HPV testing. In women of all ages, dual-stained cytology was more sensitive than Pap cytology (86.7% vs 68.5%; P < .001) for detecting CIN2+, with comparable specificity (95.2% vs 95.4%; P = .15). The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older. HPV testing in women 30 years or older was more sensitive than dual-stained cytology (93.3% vs 84.7%; P = .03) but less specific (93.0% vs 96.2%; P < .001).ConclusionsThe p16/Ki-67 dual-stained cytology combines superior sensitivity and noninferior specificity over Pap cytology for detecting CIN2+. It suggests a potential role of dual-stained cytology in screening, especially in younger women where HPV testing has its limitations.

mRNA biomarker detection in liquid-based cytology: a new approach in the prevention of cervical cancer

“…10,17 Recently, the combination of p16 and Ki67 detected by immunohistochemistry has been used in cytological samples to identify patients with high-grade cervical lesions. 18,19 In our study, the analysis of these biomarkers in biopsy material by immunohistochemistry showed that all were positive in a high proportion of the HSIL lesions, which is consistent with current evidence. 8,16,[20][21][22][23] Nevertheless, immunohistochemistry is not adequate for screening purposes.…”

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).…”

Metastatic Cervical Carcinoma with High-Risk Human Papillomavirus (HPV) Positive and P16/ Ki-67 Positive in a 28 Year-Old Female That Did Not Meet the Current Screening Guidelines

“…A study that looked at the dual stained cytology of p16/Ki-67 showed these markers have superior sensitivity with noninferior specificity with that of Pap cytology when screening for CIN2. 4 However, this testing currently is not FDA approved for routine screening.…”