Epidemiology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
ISPRO Oncological Network, Prevention and Research Institute, Regional Laboratory of Cancer Prevention Unit, Florence, Italy.
J Natl Cancer Inst. 2021 Mar 1;113(3):292-300. doi: 10.1093/jnci/djaa105.
The study presents cross-sectional accuracy of E6 and E7 (E6/E7) mRNA detection and p16/ki67 dual staining, alone or in combination with cytology and human papillomavirus (HPV)16/18 genotyping, as a triage test in HPV DNA-positive women and their impact on cervical intraepithelial neoplasia (CIN2+) overdiagnosis.
Women aged 25-64 years were recruited. HPV DNA-positive women were triaged with cytology and tested for E6/E7 mRNA and p16/ki67. Cytology positive women were referred to colposcopy, and negatives were randomly assigned to immediate colposcopy or to 1-year HPV retesting. Lesions found within 24 months since recruitment were included. All P values were 2-sided.
40 509 women were recruited, and 3147 (7.8%) tested HPV DNA positive; 174 CIN2+ were found: sensitivity was 61.0% (95% confidence interval [CI] = 53.6 to 68.0), 94.4% (95% CI = 89.1 to 97.3), and 75.2% (95% CI = 68.1 to 81.6) for cytology, E6/E7 mRNA, and p16/ki67, respectively. Immediate referral was 25.6%, 66.8%, and 28.3%, respectively. Overall referral was 65.3%, 78.3%, and 63.3%, respectively. Cytology or p16/ki67, when combined with HPV16/18 typing, reached higher sensitivity with a small impact on referral. Among the 2306 HPV DNA-positive and cytology-negative women, relative CIN2+ detection in those randomly assigned at 1-year retesting vs immediate colposcopy suggests a -28% CIN2+ regression (95% CI = -57% to +20%); regression was higher in E6/E7 mRNA-negatives (Pinteraction = .29). HPV clearance at 1 year in E6/E7 mRNA and in p16/ki67 negative women was about 2 times higher than in positive women (Pinteraction < .001 for both).
p16/ki67 showed good performance as a triage test. E6/E7 mRNA showed the highest sensitivity, at the price of too high a positivity rate to be efficient for triage. However, when negative, it showed a good prognostic value for clearance and CIN2+ regression.
本研究旨在评估 HPV E6/E7mRNA 检测和 p16/ki67 双染在 HPV DNA 阳性女性中的单独应用或联合细胞学及 HPV16/18 基因分型的应用作为分流试验的横断面准确性，并探讨其对宫颈癌前病变（CIN2+）过度诊断的影响。
招募年龄 25-64 岁的女性。对 HPV DNA 阳性的女性进行细胞学和 E6/E7mRNA 及 p16/ki67 检测。细胞学阳性的女性转诊行阴道镜检查，细胞学阴性的女性随机分为即刻阴道镜检查或 1 年 HPV 复查。所有 24 个月内发现的病变均纳入研究。所有 P 值均为双侧。
共招募 40509 名女性，其中 3147 名（7.8%）HPV DNA 阳性；发现 174 例 CIN2+：细胞学的敏感性为 61.0%（95%可信区间[CI] = 53.6 至 68.0）、94.4%（95%CI = 89.1 至 97.3）和 75.2%（95%CI = 68.1 至 81.6），E6/E7mRNA 和 p16/ki67 的敏感性分别为 61.0%、94.4%和 75.2%。即刻转诊率分别为 25.6%、66.8%和 28.3%。总转诊率分别为 65.3%、78.3%和 63.3%。细胞学或 p16/ki67 联合 HPV16/18 基因分型可提高敏感性，而转诊率影响较小。在 2306 名 HPV DNA 阳性且细胞学阴性的女性中，随机分配至 1 年复查组与即刻阴道镜检查组的相对 CIN2+检出率提示 CIN2+消退率为-28%（95%CI = -57%至 +20%）；E6/E7mRNA 阴性患者的 CIN2+消退率更高（P 交互值=0.29）。E6/E7mRNA 和 p16/ki67 阴性患者的 HPV 清除率在 1 年时约为阳性患者的 2 倍（两者 P 交互值均＜0.001）。
p16/ki67 作为分流试验具有良好的性能。E6/E7mRNA 的敏感性最高，但阳性率过高，用于分流效率不高。然而，当 E6/E7mRNA 阴性时，其对 HPV 清除和 CIN2+消退具有良好的预后价值。
