Clinical validation of p16/Ki-67 dual-stained cytology triage of HPV-positive women: Results from the IMPACT trial

Abstract

Triage strategies are needed for primary human papillomavirus (HPV)-based cervical cancer screening to identify women requiring colposcopy/biopsy. We assessed the performance of p16/Ki-67 dual-stained (DS) immunocytochemistry to triage HPV-positive women and compared it to cytology, with or without HPV16/18 genotyping. A prospective observational screening study enrolled 35 263 women aged 25 to 65 years at 32 U.S. sites. Cervical samples had HPV and cytology testing, with colposcopy/biopsy for women with positive tests. Women without cervical intraepithelial neoplasia Grade 2 or worse (≥CIN2) at baseline (n = 3876) were retested after 1 year. In all, 4927 HPV-positive women with valid DS results were included in this analysis. DS sensitivity for ≥CIN2 and ≥CIN3 at baseline was 91.2% (95% confidence interval [CI]: 86.8%-94.2%) and 91.9% (95% CI: 86.1%-95.4%), respectively, in HPV16/18-positive women and 83.0% (95% CI: 78.4%-86.8%) and 86.0% (95% CI: 77.5%-91.6%) in women with 12 "other" genotypes. Using DS alone to triage HPV-positive women showed significantly higher sensitivity and specificity than HPV16/18 genotyping with cytology triage of 12 "other" genotypes, and substantially higher sensitivity but lower specificity than using cytology alone. The risk of ≥CIN2 was significantly lower in HPV-positive, DS-negative women (3.6%; 95% CI: 2.9%-4.4%), compared to triage-negative women using HPV16/18 genotyping with cytology for 12 "other" genotypes (7.4%; 95% CI: 6.4%-8.5%; P < .0001) or cytology alone (7.5%; 95% CI: 6.7%-8.4%; P < .0001). DS showed better risk stratification than cytology-based strategies and provided high reassurance against pre-cancers both at baseline and at 1-year follow-up, irrespective of the HPV genotype. DS allows for the safe triage of primary screening HPV-positive women.

Keywords: HPV testing; cervical cancer; p16/Ki-67 dual-stain.

FIGURE 1

CONSORT diagram. Triage of cobas 6800/8800 HPV‐positive women. There were 481 (DS positive), 535 (DS negative) and 77 (DS unsatisfactory) cases with no baseline CPR results, which made them eligible to be referred to the 1 year follow‐up phase. Among them, there were 20, 30 and 7 cases in the DS positive, DS negative and DS unsatisfactory categories, respectively, which had valid 1‐year CPR results. ACIS, adenocarcinoma in situ; CIN, cervical intraepithelial neoplasia; CPR, central pathology review; DS, dual stain; NILM, negative for intraepithelial lesion or malignancy

FIGURE 2

Risk of ≥CIN3 in cobas 6800/8800 HPV‐positive women dependent on HPV genotype group, cytology and dual‐stain results. Cumulative 1‐year risks of ≥CIN3 for HPV genotype groups (16/18+; 12 other+), cytology (NILM, ≥ASC‐US) and dual‐stain (DS+, DS−) test results are plotted on the y‐axis, with the number of subjects within the respective categories indicated