BMRT-HPV用于子宫颈癌筛查的有效性评价

Evaluation of the effectiveness of BMRT-HPV for cervical cancer screening

目的评价核酸分型定量法HPV检测(BMRT-HPV)用于子宫颈癌筛查的临床价值。方法采用巢式抽样法,在2016年9月—2018年1月中国子宫颈癌筛查多中心研究(CHIMUST)项目5个筛查点的8856例妇女中,选取其中医生取样或自取样标本中任一检测方法HPV阳性或HPV阴性但细胞学结果≥低级别鳞状上皮内病变(LSIL)者共1495例行BMRT-HPV检测,同时按照1∶2比例抽取年龄和参加筛查时间相匹配的HPV与细胞学结果均为阴性的2990例为对照。CHIMUST项目中对任一HPV阳性妇女回叫行阴道镜下子宫颈病灶四象限定点活检^+随机活检^+子宫颈管搔刮术方案子宫颈活检,以医生取样标本的基于实时PCR技术的Cobas 4800 HPV检测(Cobas-HPV)、基于第2代基因测序技术的HPV分型检测(SEQ-HPV)为对照,以子宫颈活检病理诊断为“金标准”,分析BMRT-HPV检测的高危型HPV(HR-HPV)亚型与Cobas-HPV、SEQ-HPV检测的一致性,并比较3种HPV检测方法对子宫颈上皮内瘤变(CIN)Ⅱ及以上级别病变(CINⅡ^+)、CINⅢ及以上级别病变(CINⅢ^+)的筛查效率。结果(1)BMRT-HPV检测方法分别与Cobas-HPV、SEQ-HPV检测方法比较,检测HR-HPV亚型整体的一致性分别为94.8%、94.4%,Kappa值分别为0.827、0.814。(2)BMRT-HPV、Cobas-HPV、SEQ-HPV 3种方法对CINⅡ^+筛查的敏感度分别为92.62%、94.26%、93.44%,两两比较,差异均无统计学意义(P>0.05);特异度分别为84.67%、83.25%、82.76%,BMRT-HPV检测对CINⅡ^+筛查的特异度显著高于Cobas-HPV、SEQ-HPV检测(P<0.01)。3种HPV检测方法对CINⅢ^+筛查的敏感度均达到100.00%,BMRT-HPV检测对CINⅢ^+筛查的特异度也显著高于Cobas-HPV、SEQ-HPV检测(分别为83.40%、81.95%、81.50%,P<0.01)。检出1例CINⅡ^+或CINⅢ^+所需要行阴道镜下子宫颈活检病理检查的患者数,BMRT-HPV检测显著少于Cobas-HPV和SEQ-HPV检测(P<0.01)。Cobas-HPV、SEQ-HPV、BMRT-HPV检测初筛阳性者分别以HPV 16和(或)18型(HPV 16/18型)阳性联合细胞学结果≥未明确诊断意义的不典型鳞状上皮细胞(ASCUS;即为方案一、二、三)进行二次分流,3种筛查方案对CINⅡ^+、CINⅢ^+筛查的敏感度分别比较均无显著差异(P>0.05),但方案三(即BMRT-HPV初筛阳性者)筛查CINⅡ^+、CINⅢ^+的特异度显著高于方案一(即Cobas-HPV初筛阳性者)和方案二(即SEQ-HPV初筛阳性者;P<0.05),而且阴道镜转诊率方案三也显著低于方案一、二(P<0.05)。结论BMRT-HPV检测筛查子宫颈癌具有与Cobas-HPV、SEQ-HPV检测相似的敏感度,但特异度更高,可作为子宫颈癌的初筛方法,值得临床推广使用。

Objective Evaluation of the clinical value of the BioPerfectus multiplex real time(BMRT)-HPV for cervical cancer screening.Methods Physician-collected specimens of 1495 women who were positive of Cobas 4800 HPV(Cobas-HPV),HPV genotyping based on SEQ uencing(SEQ-HPV),and(or)cytology≥low grade squamous intraepithelial lesion(LSIL)in the primary screening of Chinese Multiple-center Screening Trial(CHIMUST),and 2990 women selected from those who were negative of primary screening in the same project through nested control randomization with age-matching were tested for BMRT-HPV,which reported type-specific viral loads/10000 cells in each specimen.With comparing to Cobas-HPV results and taking cervical histopathological diagnosis as the endpoint,the concordance of high-risk(HR)-HPV subtypes among the three assays was explored,and the sensitivity and specificity of BMRT-HPV for cervical cancer screening were evaluated.Results(1)The overall agreenment of HR-HPV subtypes between BMRT-HPV and Cobas-HPV,or SEQ-HPV test sample was 94.8%,94.4%,with Kappa values 0.827,0.814.(2)The sensitivity and specificity for cervical intraepithelial neoplasia(CIN)Ⅱ^+of BMRT-HPV,Cobas-HPV and SEQ-HPV were 92.62%,94.26%,93.44%and 84.67%,83.25%,82.76%,respectively.There were no significant difference in sensitivity among the three HPV assays(all P>0.05),but the specificity of BMRT-HPV for CINⅡ^+was higher than those of Cobas-HPV and SEQ-HPV(P<0.01).The sensitivity for CINⅢ^+of three HPV assays were all 100.00%,and the specificity for CINⅢ^+of BMRT-HPV was higher than those of Cobas-HPV and SEQ-HPV(83.40%vs 81.95%,83.40%vs 81.50%;P<0.01).The number of pathological examinations of colposcopy for cervical biopsy detected in 1 case of CINⅡ^+or CINⅢ^+in BMRT-HPV was less than those in Cobas-HPV and SEQ-HPV(P<0.01).When using HPV 16/18^+cytology≥atypical squamous cell of undetermined signification(ASCUS)to triage HPV positive women among three assays,there was no different in the sensitivities of detecting CINⅡ^+and CINⅢ^+(P>0.05).The specificity BMRT-HPV was slightly higher than those in Cobas-HPV or SEQ-HPV(all P<0.05),and the colposcopy referral rate was lower than those in Cobas-HPV and SEQ-HPV(all P<0.05).Conclusions BMRT-HPV is as sensitive as Cobas-HPV or SEQ-HPV for primary cervical cancer screening,and has higher specificity.Therefore it could be used as a primary screening method for cervical cancer,which is worthy of clinical application.