Clinical Performance of Triage Strategies for Hr-HPV–Positive Women; A Longitudinal Evaluation of Cytology, p16/K-67 Dual Stain Cytology, and HPV16/18 Genotyping

Abstract

Background: We evaluated the longitudinal performance of three options: HPV16/18 genotyping (HPV16/18), cytology (LBC) and p16/Ki-67 Dual Stain cytology (DS) for the triage of Hr-HPV positive (Hr-HPV+) women within the cervical screening programme in Scotland. Methods: Data were derived from a cohort of Hr-HPV+ women (n=385) who participated in PaVDaG (Papillomavirus Dumfries and Galloway) study. Performance of triage strategies for detecting high-grade disease was assessed at three years (in women <50 years) or five years (in women > 50 years). Sensitivity, specificity, PPV and cNPV of each triage test were calculated for CIN2+ and CIN3+ when used singly or sequentially. Results: The sensitivity of LBC (>= borderline), DS and HPV 16/18 genotyping for the detection of CIN2+ was 62.7% (50.7-73.3), 77.7% (63.1-83.7) and 62.7% (50.7-73.3) with corresponding cNPVs of 10.9%, 8.4% and 11.9%. The option with the highest sensitivity and lowest cNPV was HPV 16/18 genotyping followed by LBC of Hr-HPV other+ and then DS of the LBC negatives. This yielded sensitivity of 94.7% (86.2-98.3) and cNPV 2.7% for CIN2+. Triage performance was similar if women had tested Hr-HPV + positive by vaginal self-sampling. Conclusions: Two-step triage with HPV 16/18 genotyping prior to LBC (or DS) for Hr-HPV Other+ for Hr-HPV Other + women were associated with a lower risk of significant disease at follow up compared to single triage approaches. Impact: This study provides longitudinal performance data on triage strategies in Hr-HPV+ women and will be informative for the evolution of cervical screening programs that increasingly rely on molecular technologies.

Enhancing Cervical Cancer Screening: Review of p16/Ki-67 Dual Staining as a Promising Triage Strategy

“…However, the increased sensitivity of p16/Ki-67 dual staining was lower than that of cytology [55,64,69]. This reduced specificity may lead to more false-positive results, where the test indicates the absence of a potential lesion.…”

“…Recent advancements in cervical cancer screening have increased the efficacy of the p16/Ki-67 dual-staining technique, particularly for triaging human papillomavirus (HPV)positive women [64,65]. A growing body of research indicates that this dual-staining method outperforms traditional cytology in several key aspects, notably sensitivity and negative predictive value (NPV), albeit with a trade-off in specificity [14,56].…”

“…The most striking advantage of p16/Ki-67 dual staining is its heightened sensitivity for detecting CIN2+ or CIN3+ lesions, which are precursors of cervical cancer [61,64,67]. Studies have consistently indicated that the sensitivity of dual staining is markedly higher than that of traditional cytology.…”

“…However, this increased sensitivity results in a trade-off in specificity, potentially leading to more biopsies. Comparative studies indicate that the use of dual staining might result in more biopsies being performed because more women are classified as being at risk of developing CIN2+ lesions [56,61,64]. Although this increases the detection rate of significant cervical lesions, it also increases the potential for overtreatment in cases where the lesions might regress spontaneously.…”

Overview of Ancillary Techniques in Cervical Cytology

“…Their results demonstrated significantly higher sensitivity and specificity for the detection of CIN2 or worse in HPV-positive women, as compared with HPV 16/18 genotyping in combination with cytology triage, and higher sensitivity but lower specificity when compared to cytology alone [53]. Interestingly, a study evaluating the clinical performance of LBC, p16/Ki-67 dual staining, and HPV 16/18 genotyping as triage strategies in HPV-positive women, demonstrated that the triage modality with the highest sensitivity and lowest negative predictive value for the detection of ≥CIN2, was a twostep triage including HPV 16/18 genotyping followed by LBC of hr-HPV non-16/18 + women [54].…”