自取样本高危型HPV分型检测的子宫颈癌初筛及其联合细胞学或病毒载量的二次筛查方案的评价

Performance of vaginal self-sampling high-risk HPV genotyping as primary and combining cytology or viral load as secondary in cervical cancer screening

目的评价阴道自取样本高危型HPV(HR-HPV)分型检测用于子宫颈癌初筛的筛查效率,并探讨以不同HR-HPV亚型组合联合医生取样本的细胞学检查或HR-HPV病毒载量检测对自取样本HR-HPV阳性者进行二次筛查的筛查效率。方法本研究的数据来自2009年4月至2010年4月深圳市子宫颈癌筛查项目Ⅱ(SHENCCAST-Ⅱ)数据库,收集其中有自取样本的基质辅助激光解吸电离-飞行时间质谱分析(MALDI-TOF-MS)技术进行的HR-HPV分型检测结果以及医生取样本的第2代杂交捕获技术(HC-Ⅱ)检测的HR-HPV病毒载量结果、子宫颈细胞学检查结果的妇女共8556例,转诊阴道镜检查者均有活检组织病理检查结果。分析自取样本HR-HPV分型检测作为子宫颈癌初筛方案(即方案1)时,基于其不同HR-HPV亚型组合[包括5个亚方案,即1a:HPV 16和(或)18型(HPV 16/18型)阳性;1b:HPV 16/18/58型阳性;1c:HPV 16/18/58/31/33型阳性;1d:HPV 16/18/58/31/33/52型阳性;1e:所有14种HR-HPV亚型中任一亚型阳性]的阴道镜转诊方案检出子宫颈上皮内瘤变(CIN)Ⅱ及以上病变(CINⅡ+)、CINⅢ及以上病变(CINⅢ+)的敏感度与特异度;并以自取样本HR-HPV初筛阳性者即以方案1中的各亚方案为基础,对比分析其联合医生取样本的细胞学检查(即方案2,包括2a、2b、2c、2d、2e共5个亚方案)或HR-HPV病毒载量检测(即方案3,包括3a、3b、3c、3d共4个亚方案)作为分流指标的二次筛查方案的筛查效率。结果(1)本研究纳入的8556例妇女的年龄为(38.9±7.9)岁,自取样本检测的HR-HPV阳性率为13.77%(1178/8556),其中HPV 16/18型、HPV 16/18/58型、HPV 16/18/58/31/33型和HPV 16/18/58/31/33/52型组合的阳性率分别为3.16%(270/8556)、5.14%(440/8556)、6.66%(570/8556)和9.81%(839/8556)。医生取样本的HR-HPV病毒载量≥10相对光单位/临床阈值(RLU/CO)者占8.87%(759/8556),细胞学结果≥未明确诊断意义的不典型鳞状上皮细胞(ASCUS)者占12.05%(1031/8556)。(2)方案1中,所有14种HR-HPV亚型中任一亚型阳性者(即方案1e)行阴道镜检查对检出CINⅡ+、CINⅢ+的敏感度在所有方案(包括3个方案共14个亚方案)中最高(分别为92.70%、94.33%),但是特异度和阳性预测值(PPV)在所有方案中最低(特异度分别为88.44%、87.58%,PPV分别为18.34%、11.29%),且阴道镜检查率在所有方案中最高(为13.77%)。方案1的其他亚方案(即方案1a、1b、1c、1d)中,检出CINⅡ+、CINⅢ+的特异度方案1a最高,分别为97.92%、97.69%,其他亚方案也较高,均达90%以上;但敏感度方案1d最高(分别为88.41%、92.20%)。(3)HPV 16/18型阳性者直接行阴道镜检查(即方案1a),非HPV 16/18型阳性者行医生取样本细胞学检查或HR-HPV病毒载量检测,细胞学结果达到阈值(≥ASCUS,即方案2a)或病毒载量达到阈值(≥10 RUL/CO,即方案3a)者行阴道镜检查,其阴道镜转诊率低,而筛查CINⅡ+、CINⅢ+的敏感度和特异度则较高。若在此两个二次筛查方案基础上,首先根据自取样本HR-HPV分型检测结果,依次增加另外4种HR-HPV亚型(即HPV 58、31、33和52型)阳性者行阴道镜检查,再以细胞学检查或病毒载量检测结果进行二次分流,筛查CINⅡ+、CINⅢ+的敏感度也相应提高。结论以自取样本HR-HPV分型检测为子宫颈癌初筛方案,以及其联合细胞学检查或病毒载量检测进行二次筛查的方案,可以在筛查CINⅡ+、CINⅢ+的敏感度、特异度以及阴道镜检查率之间获得较好的平衡;将HPV 58、31、33、52型纳入HPV 16/18型阳性的初筛分流指标,并联合细胞学检查或病毒载量检测的序贯二次筛查,可进一步提高筛查效率。

Objective To evaluate the efficacy of high-risk HPV(HR-HPV)genotyping with vaginal self-sampling in primary screening and combining cytology or viral load for HR-HPV positive as secondary screening strategies.Methods The data referring to HR-HPV genotyping of self-collected sample with mass array matrix-assisted laser desorption-ionization time-of-flight mass spectrometry(MALDI-TOF-MS),HR-HPV viral load of physician-collected sample with hybrid captureⅡ(HC-Ⅱ),liquid-based cytology and histology of 8556 women were from Shenzhen cervical cancer screening trialⅡ(SHENCCAST-Ⅱ)conducted between April 2009 and April 2010.The data were reanalyzed to determine the sensitivity and specificity to cervical intraepithelial neoplasia(CIN)of grade 2 or worse(CINⅡ+),CIN of grade 3 or worse(CINⅢ+)when HR-HPV genotyping combining with colposcopy as primary screening strategy based on varied HR-HPV subtype(strategy 1,including 5 sub-strategies:1a:HPV 16/18 positive;1b:HPV 16/18/58 positive;1c:HPV 16/18/58/31/33 positive;1d:HPV 16/18/58/31/33/52 positive;1e:any HR-HPV positive).The data were also compared to determine the efficacy of cytology(strategy 2,including 5 sub-strategies:2a,2b,2c,2d,2e)or HR-HPV viral load(strategy 3,including 4 sub-strategies:3a,3b,3c,3d)of physician-collected sample as a triage with HR-HPV genotyping for self-sampling HR-HPV positives.Results(1)The HR-HPV positive rate was 13.77%(1178/8556)in the self-collected samples of 8556 pregnant women.Of them,the prevalences of HPV 16/18,HPV 16/18/58,HPV 16/18/58/31/33 and HPV 16/18/58/31/33/52 were 3.16%(270/8556),5.14%(440/8556),6.66%(570/8556)and 9.81%(839/8556),respectively.The HR-HPV viral load≥10 relative light units/control(RLU/CO)was 8.87%(759/8556),while cytological results≥atypical squamous cell of undetermined signification(ASCUS)were 12.05%(1031/8556).(2)The strategy 1e had the highest sensitivities for CINⅡ+,CINⅢ+which were 92.70%and 94.33%,respectively,among 14 sub-strategies,while the lowest specificity and positive predictive value(PPV).Meanwhile,the required colposcopy referral rates were much higher than other 13 sub-strategies(13.77%).The other 4 sub-strategies of strategy 1(1a,1b,1c,1d),strategy 1a had the highest specificities for CINⅡ+and CINⅢ+(97.92%,97.69%,respectively),while 1d had the highest sensitivities for CINⅡ+and CINⅢ+(88.41%,92.20%,respectively).(3)Both strategies of referring self-sampling HPV 16/18 positives for immediate colposcopy followed by triage physician-collected sample cytology(≥ASCUS)or viral load(≥10 RLU/CO)for non-HPV 16/18 positives had significantly higher sensitivity and specificity for CINⅡ,CINⅢ+,as well as lower referral rates(strategy 2a and 3a).Additionally,based on these two secondary screening strategies,cumulatively using the other four HR-HPV(HPV 58,31,33 and 52)positives as triage for immediate colposcopy showed an enhanced sensitivity.Conclusions Primary HR-HPV cervical cancer screening strategy based on self-sampling with triage of cytology(≥ASCUS)or viral load(≥10 RUL/CO)provides a good balance among sensitivity,specificity for CINⅡ+and CINⅢ+and the number of tests required,referral rates.The efficacy of HR-HPV genotyping combining cytology or viral load secondary screening strategies will have a spiral escalation when HPV 58,31,33,52 are included.