Verhoef Lisanne, Bleeker Maaike C G, Polman Nicole, Kroon Kelsi R, Steenbergen Renske D M, Ebisch Renée M F, Melchers Willem J G, Bekkers Ruud L M, Molijn Anco C, van Kemenade Folkert, Meijer Chris J L M, Heideman Daniëlle A M, Berkhof Johannes
Amsterdam UMC, location Vrije Universiteit Amsterdam, Pathology, Amsterdam, The Netherlands.
Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands.
Int J Cancer. 2025 Mar 1;156(5):1065-1073. doi: 10.1002/ijc.35289. Epub 2024 Dec 16.
High-risk HPV (hrHPV)-based screening has led to many unnecessary colposcopy referrals, mainly because of direct referral after low-grade cytology (ASC-US/LSIL). DNA methylation and genotyping tests on ASC-US/LSIL samples have the potential to significantly improve the efficiency of screening. In this study, 12 triage strategies were constructed from FAM19A4/miR124-2 or ASCL1/LHX8 methylation, HPV16/18 or HPV16/18/31/33/45 genotyping and 1-year repeat cytology. The performance was evaluated on 215 hrHPV-positive ASC-US/LSIL samples from the IMPROVE trial (NTR5078). Performance was measured by colposcopy referral rate, positive predictive value (PPV) for detecting precancer (CIN3), and negative predictive value (NPV). To evaluate efficiency, strategies were ordered by the cumulative colposcopy referral rate after 1-year cytology and compared by the marginal PPV to detect one additional CIN3 (mPPV). The most conservative strategy (referral when HPV16/18 and FAM19A4/miR124 methylation results are positive) had a direct referral rate of 5.2%, a cumulative referral rate after 1-year cytology of 54.1%, and mPPV of 19.3%. Replacing HPV16/18 by HPV16/18/31/33/45 increased the cumulative 1-year referral rate to 54.6%, and yielded an mPPV of 10.0%. Similar results were obtained for strategies with ASCL1/LHX8 methylation. Of all strategies, referral after an HPV16/18/31/33/45 positive, ASCL1/LHX8 methylation-positive, and/or 1-year cytology-positive result yielded the highest direct and cumulative 1-year colposcopy referral rates of 64.4% and 79.1%, respectively. The NPVs after 1-year cytology varied between 98.1% and 99.4%, warranting a return to routine screening. Altogether, DNA methylation-based triage strategies are recommended as they are discriminative for CIN3 and control the number of immediate colposcopy referrals.
基于高危型人乳头瘤病毒（hrHPV）的筛查导致了许多不必要的阴道镜检查转诊，主要原因是在低度细胞学检查（非典型鳞状细胞不能明确意义/低度鳞状上皮内病变，ASC-US/LSIL）后直接转诊。对ASC-US/LSIL样本进行DNA甲基化和基因分型检测有可能显著提高筛查效率。在本研究中，根据FAM19A4/miR124-2或ASCL1/LHX8甲基化、HPV16/18或HPV16/18/31/33/45基因分型以及1年重复细胞学检查构建了12种分流策略。在来自IMPROVE试验（NTR5078）的215份hrHPV阳性的ASC-US/LSIL样本上评估了这些策略的性能。通过阴道镜检查转诊率、检测癌前病变（CIN3）的阳性预测值（PPV）和阴性预测值（NPV）来衡量性能。为了评估效率，根据1年细胞学检查后的累积阴道镜检查转诊率对策略进行排序，并通过边际PPV来比较以检测另外一例CIN3（mPPV）。最保守的策略（当HPV16/18和FAM19A4/miR124甲基化结果为阳性时转诊）的直接转诊率为5.2%，1年细胞学检查后的累积转诊率为54.1%，mPPV为19.3%。用HPV16/18/31/33/45替代HPV16/18可使1年累积转诊率提高到54.6%，mPPV为10.0%。对于ASCL1/LHX8甲基化的策略也获得了类似结果。在所有策略中，HPV16/18/31/33/45阳性、ASCL1/LHX8甲基化阳性和/或1年细胞学检查阳性结果后转诊的直接和1年累积阴道镜检查转诊率最高，分别为64.4%和79.1%。1年细胞学检查后的NPV在98.1%至99.4%之间，值得恢复常规筛查。总之，推荐基于DNA甲基化的分流策略，因为它们对CIN3有鉴别力，并能控制立即进行阴道镜检查转诊的数量。
