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

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.

Should we use risk selection tests for HPV 16 and/or 18 positive cases: Comparison of p16/Ki67 and cytology

“…A retrospective analysis of cytologic‐virologic‐immunocytochemical‐histologic test results was conducted, and the PPV of cytology and DS as triage tests for specific major cervical cancer screening abnormalities was evaluated. The study data were retrieved from the Center's registry, with a detailed methodology previously described in a series of related studies 33–36 …”

“…According to a manufacturer's manual, a DS‐positive test result was defined as at least one observed epithelial cell with simultaneous red nuclear stain for Ki67 and brown cytoplasmatic stain for p16 in the same epithelial cell 37 . A detailed protocol for an evaluation of immunoexpression was presented previously 33–36 …”

“…The requirements of minimal colposcopy protocol included endocervical sampling (curettage and brushing), direct biopsies for all abnormal colposcopic findings or those suggestive for invasion, or additional random biopsies as per Polish protocols. All histologic diagnoses of cervical biopsies and endocervical sampling were reviewed by a gynecological pathologist according to the LAST 2012/WHO 2014 terminology 42,43 with more details available in a series of related studies 33–36 …”

“…37 A detailed protocol for an evaluation of immunoexpression was presented previously. [33][34][35][36]…”

“…The study data were retrieved from the Center's registry, with a detailed methodology previously described in a series of related studies. [33][34][35][36] Major screening abnormalities were defined in this study as screening abnormalities with potentially higher HSIL/CIN2+ risk that justifies a direct referral to colposcopy of HPV 16/18+ patients without prior triage testing, identified through primary HPV-based screening with limited genotyping. Management in these cases was according to ASCCP 2019 Risk-Based Management Consensus Guidelines.…”