Five-Year Risk of Cervical Precancer Following p16/Ki-67 Dual-Stain Triage of HPV-Positive Women

Abstract

Importance: As cervical cancer screening transitions to primary human papillomavirus (HPV) testing, effective triage and management of HPV-positive women is critical to avoid unnecessary colposcopy referral and associated harms while maintaining high sensitivity for cervical precancer. Triage with p16/Ki-67 dual-stain (DS) testing has shown high sensitivity and specificity for detection of cervical precancers; however, longitudinal studies are needed to determine the long-term risk of precancer following a negative DS result.

Objective: To evaluate the longitudinal performance of p16/Ki-67 DS triage for detection of cervical precancer in HPV-positive women over 5 years of follow-up in the context of clinical management thresholds.

Design, setting, and participants: Prospective cohort study of HPV-positive women 30 years or older undergoing routine cervical cancer screening in 2012 with HPV and Papanicolaou (hereinafter "cytology") co-testing within the Kaiser Permanente Northern California health care system. Follow-up of medical records was conducted through 2017.

Exposures: All p16/Ki-67 DS testing was performed on residual SurePath material, and slides were evaluated for p16/Ki-67 positivity.

Main outcomes and measures: Histological end points were ascertained from the clinical database through 2017. We estimated 5-year cumulative risks of cervical intraepithelial neoplasia grades of 2 or worse (≥CIN2) or grades 3 or worse (≥CIN3) by baseline DS and cytology at yearly intervals using Logistic Weibull models. Risks were compared with clinical management thresholds for colposcopy referral and a 1-year return interval.

Results: Among the 1549 HPV-positive women in this study, the mean age at enrollment was 42.2 years, and the median follow-up time was 3.7 years (range, 0.2-5.4 years). Positive DS results were associated with significantly higher cumulative 5-year risks of ≥CIN2 compared with abnormal cytology (31.0%; 95% CI, 27.2%-35.3% vs 25.0%; 95% CI, 21.7%-28.7%; P = .03). Women with DS-negative findings had significantly lower 5-year risks of ≥CIN2 compared with women with normal cytology (8.5%; 95% CI, 6.5%-11.1% vs 12.3%; 95% CI, 9.8%-15.4%; P = .04). In DS-negative women, the risks of both ≥CIN2 and ≥CIN3 remained below the colposcopy referral threshold for all 5 years, crossing the 1-year return threshold at 3 years.

Conclusions and relevance: Triage with p16/Ki-67 DS provides better long-term risk stratification than cytology over 5 years. The low risk of cervical precancer in p16/Ki-67 DS-negative women permits safe extension of follow-up intervals for 3 years.

Figure 1.. Study Population Enrollment Flow Diagram

Women missing follow-up data and those with baseline positive co-test results and/or other positive follow-up screening results without a colposcopy visit were considered indeterminate for the presence or absence of disease (n = 121). DS indicates p16/Ki-67 dual-stain testing; CIN2, cervical intraepithelial neoplasia grade of 2; CIN3, CIN grade of 3; Pap, Papanicolaou cytology testing.

Figure 2.. Cumulative Risk of ≥CIN2 and ≥CIN3 by p16/Ki-67 Dual-Stain Testing (DS) and Papanicolaou Cytology (Pap) Results

The 5-year cumulative risk curves were generated using the logistic Weibull model. The dashed line corresponds to the threshold for a 1-year return, and the dotted line corresponds to the threshold for immediate colposcopy referral in this study population. Plus sign indicates positive; minus sign, negative; ASC-US atypical squamous cells of undetermined significance; CIN2, cervical intraepithelial neoplasia grade of 2; CIN3, CIN grade of 3; NILM, negative for intraepithelial lesion or malignancy.

Figure 3.. Cumulative Risk of ≥CIN2 and ≥CIN3 by Combined Categories of p16/Ki-67 Dual-Stain Testing (DS) and Papanicolaou Cytology (Pap) Results

The 5-year cumulative risk curves were generated using the logistic Weibull model. The dashed line corresponds to the threshold for a 1-year return, and the dotted line corresponds to the threshold for immediate colposcopy referral in this study population. Plus sign indicates positive; minus sign, negative; ASC-US, atypical squamous cells of undetermined significance; CIN2, cervical intraepithelial neoplasia grade of 2; CIN3, CIN grade of 3; NILM, negative for intraepithelial lesion or malignancy.