Triage Strategies for Non-16/Non-18 HPV-Positive Women in Primary HPV-Based Cervical Cancer Screening: p16/Ki67 Dual Stain vs. Cytology

SIMPLE SUMMARY: Cervical cancer is often caused by certain high-risk types of human papillomavirus (HPV), mainly types 16 and 18. However, there are 12 other high-risk HPV types that can also increase the risk of cancer. When these non-16/non-18 high-risk HPV types are detected (HPV HR12+), additional tests are needed to assess the risk of precancerous changes and cancer and avoid unnecessary treatments. Currently, two triage tests, cytology and p16/Ki67 dual-stain (DS), are being considered. In our study, we looked back at how well three different screening strategies worked: M1—using cytology, M1A—using cytology with DS in selected cases, and M2—using DS in all cases. We found that using DS as a triage test was more effective than cytology alone in selected HPV HR12+ cases. It allowed us to find more cases of high-grade precancerous changes (HSIL+) while reducing the need for unnecessary colposcopies. ABSTRACT: Background: In the context of primary HPV cervical cancer screening, the identification of minor screening abnormalities necessitates triage tests to optimize management and mitigate overtreatment. Currently, reflex cytology and reflex p16/Ki67 dual-stain (DS) are under scrutiny for their applicability in primary HPV-based screening. However, there remains a dearth of comprehensive data for comparing their performance. Methods: Among 30,066 results from liquid-based cervical cancer screening tests, a cohort of 332 cases was meticulously selected based on available high-risk human papillomavirus (HPV) test results, limited genotyping for HPV 16 and 18, liquid-based cytology, DS, and histology outcomes from standardized colposcopy with biopsy. For cases positive for 12 other high-risk HPV genotypes, three retrospective triage approaches were analyzed. We computed the positive predictive value (PPV) for the detection of high-grade squamous intraepithelial lesions or worse (HSIL+). Results: Both triage models employing DS (reflex cytology followed by DS and reflex DS alone in all cases) exhibited significantly higher PPV for HSIL+ compared to the strategy with reflex cytology alone (35.9%/33.3% vs. 18.8%; p < 0.0001). Additionally, these DS-based models showed higher negative predictive values (NPV) (100%/96.2% vs. 69.2%; p = 0.0024/0.0079). In the DS-inclusive models, fewer colposcopies were necessitated (103/102 vs. 154), and fewer cases of HSIL+ were overlooked (0/3 vs. 8). Conclusions: Our findings suggest that p16/Ki67 dual-stain, either as a standalone or combined triage test, holds promise for the effective detection of HSIL+ in patients with minor screening abnormalities in primary HPV-based cervical cancer screening.