液基细胞学联合人乳头状瘤病毒核酸检测对宫颈癌筛查的效果评价

Performance of combined liquid based cytology and HPV nucleic acid test for detecting cervical precancer among women attending screening

目的评价人乳头状瘤病毒（HPV）分型检测联合细胞学在宫颈癌筛查人群中的应用效果。方法于2016年在内蒙古自治区入组的2 883例参加宫颈癌筛查的女性行液基细胞学和14种高危型HPV（HR－HPV）检测，HPV分型检测应用线性反向探针杂交技术。于2017年对HPV或细胞学任一异常者进行随访，以宫颈上皮内瘤样病变2级及以上（CIN2＋）为临床研究终点，计算不同型别HR－HPV的阳性率，以细胞学联合HR－HPV检测为筛查手段计算联合筛查不同转诊模式下的灵敏度、特异度、阳性预测值、阴性预测值、转诊率和漏诊例数。结果14种HR－HPV的检出率为18.87%（544/2 883），检出率最高的型别为HPV16（4.06%），其次为HPV52（3.61%）、HPV51（2.50%）、HPV58（1.98%）和HPV18（1.56%）。以HPV16、58、33、39、52、18、31、35、51、59、68、66、56、45的顺序依次累积计算临床应用相关指标，随着型别增加，灵敏度升高，特异度降低，当HPV16、58、33、39、52、18、31纳入分析时，受试者工作特征曲线下面积达到最大值（0.913，95% CI为0.882～0.944）。与传统以细胞学为主的筛查方法（8.99%）比较，联合筛查可降低漏诊例数，其中细胞学正常的女性应用HPV16、18进行分流、细胞学低度病变的女性应用HPV58、33、39、52、31等型别进行分流、细胞学高度病变的女性直接转诊阴道镜的方法在降低漏诊例数的同时，不会提高阴道镜转诊率（8.71%，P＝0.525），其灵敏度为92.1%，特异度为93.2%，漏诊5例。结论在联合筛查中，细胞学正常的女性应用HPV16、18进行分流，细胞学低度病变的女性应用HPV58、33、39、52、31等型别进行分流、细胞学高度病变的女性直接转诊阴道镜，可达到较好的临床应用效果。

ObjectiveTo evaluate the clinical performance of HPV genotyping with cytology for detecting cervical precancer among women attending co-testing.MethodsA total of 2 883 females who participated in cervical cancer screening program were recruited from Erdos in 2016. All the participants were tested by cytology and HPV genotyping. In 2017, women with abnormal cytology results or HPV positive were followed up. Pathological cervical intraepithelial neoplasia （CIN） 2＋ was the study end-point. Clinical performance indexes were calculated, including sensitivity, specificity, positive predictive value, negative predictive value, referral rate and missed cases.ResultsINNO-LiPA resulted in a detection rate of 18.87%（544/2 883） for the 14-type high risk HPV. HPV16 was the most common infectious genotype （4.06%）, followed by HPV52 （3.61%）, HPV51 （2.50%）, HPV58 （1.98%）, and HPV18 （1.56%）. With more HPV genotypes added into the group, sensitivity increased and the specificity decreased. Addition of HPV16, 58, 33, 39, 52, 18, 31 for detection lead to the maximun value of area under the curve （AUC）=0.913 （95%CI： 0.882-0.944）. Compared with traditional screening method by cytology, cotesting decreased the number of missed diagnosis. Meanwhile, the fifth method （co-testing： triage of women with HPV16/18＋ , cytological minor abnormalities and HPV58, 33, 39, 52, 31＋ or cytological high grade abnormalities） did not increase referral rate （8.99% vs. 8.71%, P=0.525）, with five cases of missed diagnosis （sensitivity of 92.1% and specificity of 93.2%）.ConclusionsCo-testing with triage of women with HPV16/18＋ , cytological minor abnormalities and HPV58, 33, 39, 52, 31＋ or cytological high grade abnormalities would provide better clinical performance. In co-testing, triage of HPV16/18 was used in women with normal cytology; triage of HPV58, 33, 39, 52 and 31 was used in women with low-grade abnormal cytology; referral colposcopy was used in women with high-grade abnormal cytology, which would provide better clinical performance.