Infection and Cancer Group, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Universidad de Antioquia, Medellín, Colombia.
Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
Int J Cancer. 2021 Mar 15;148(6):1383-1393. doi: 10.1002/ijc.33314. Epub 2020 Oct 24.
The S5-methylation test, an alternative to cytology and HPV16/18 genotyping to triage high-risk HPV-positive (hrHPV+) women, has not been widely validated in low-middle-income countries (LMICs). We compared S5 to HPV16/18 and cytology to detect cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) and CIN3+ in hrHPV+ women selected from a randomized pragmatic trial of 2661 Colombian women with an earlier-borderline abnormal cytology. We included all hrHPV+ CIN2 and CIN3+ cases (n = 183) age matched to 183 <CIN2 hrHPV+. Baseline specimens were HPV-genotyped and tested by S5-methylation, blinded to cytology, histology and initial HPV results. We evaluated the test performance of predefined S5-classifier (cut-point 0.8) and a post hoc classifier at a different cut-point (3.1). S5 sensitivity for CIN2+ was 82% (95% confidence interval [CI] 76.4-87.5) and for CIN3+ 77.08% (95% CI 65.19-88.97). S5 sensitivity was higher than HPV16/18 sensitivity (48.1%, 95% CI 40.85-55.33) or cytology (31.21%, 95% CI 24.50-37.93) but with lower specificity (35%, 95% CI 28.1-42). At cut-point 3.1, S5 sensitivity for CIN2+ (55.2%, 95% CI 48-62.4) or CIN3+ (64.6%, 95% CI 51.0-78.1) was also superior to HPV16/18 (P < .05) or cytology (P < .0001). At this cut-point S5 specificity (76%, 95% CI 69.8-82.1 for <CIN2) was higher than HPV16/18 (67.21%, 95% CI 60.41-74.01, P = .0062) and similar to cytology (75.57%, 95% CI 69.34-81.79, P = 1). HPV16/18 plus cytology sensitivity was similar to S5 for CIN3+, however, false-positive rate was higher (50.27% vs. 24.04%). High sensitivity is crucial in LMICs, S5-methylation exceeded HPV16/18 or cytology sensitivity with comparable specificity for CIN2+ and CIN3+ in hrHPV-positive Colombian women. Furthermore, S5 triage had comparable sensitivity and significantly fewer false positives than cytology and HPV16/18 combination.
S5 甲基化检测是细胞学和 HPV16/18 基因分型的替代方法，用于对高危型 HPV 阳性（hrHPV+）女性进行分层，尚未在中低收入国家（LMICs）得到广泛验证。我们比较了 S5 与 HPV16/18 和细胞学检测，以检测来自 2661 例哥伦比亚早期边界异常细胞学的随机实用试验中选择的 hrHPV+女性的宫颈上皮内瘤变 2 级或更高级别（CIN2+）和 CIN3+。我们纳入了所有 hrHPV+CIN2 和 CIN3+病例（n=183），年龄与 183 例<CIN2 且 hrHPV+相匹配。基线标本进行 HPV 基因分型，并通过 S5 甲基化检测进行盲法检测，不考虑细胞学、组织学和初始 HPV 结果。我们评估了预定义 S5 分类器（截断值 0.8）和不同截断值（3.1）的 S5 分类器的测试性能。S5 对 CIN2+的灵敏度为 82%（95%置信区间[CI] 76.4-87.5），对 CIN3+的灵敏度为 77.08%（95%CI 65.19-88.97）。S5 敏感性高于 HPV16/18 敏感性（48.1%，95%CI 40.85-55.33）或细胞学敏感性（31.21%，95%CI 24.50-37.93），但特异性较低（35%，95%CI 28.1-42）。在截断值 3.1 时，S5 对 CIN2+（55.2%，95%CI 48-62.4）或 CIN3+（64.6%，95%CI 51.0-78.1）的敏感性也优于 HPV16/18（P<0.05）或细胞学（P<0.0001）。在该截断值时，S5 的特异性（76%，95%CI 69.8-82.1，用于<CIN2）高于 HPV16/18（67.21%，95%CI 60.41-74.01，P=0.0062）和细胞学（75.57%，95%CI 69.34-81.79，P=1）。HPV16/18 联合细胞学的敏感性与 S5 对 CIN3+相似，但假阳性率更高（50.27%比 24.04%）。在 LMICs 中，高敏感性至关重要，S5 甲基化检测对 CIN2+和 CIN3+的敏感性高于 HPV16/18 或细胞学，特异性相当。此外，S5 分诊的敏感性与细胞学和 HPV16/18 联合检测相当，但假阳性率显著更低。
