HPV E6/E7 mRNA检测对ASCUS患者分流管理的随访研究
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摘要
目的:通过对细胞学检测结果为意义不明确的不典型鳞状细胞(ASCUS)患者进行随访,探讨高危型人乳头瘤病毒(HPV)E6/E7 mRNA检测对其分流管理价值。方法:2015年12月至2017年8月在郑州大学第三附属医院行宫颈液基细胞学检查(TCT)的患者共40013例,对其中符合纳入标准的297例ASCUS患者,同时行HPV E6/E7 mRNA和HPV DNA检测及阴道镜下活检,并对活检病理阴性且符合纳入标准的119例患者随访至少1年,分析HPV E6/E7 mRNA检测对ASCUS患者的分流管理价值。结果:40013例患者经TCT诊断结果为阳性者共1191例,其中ASCUS 734例,其检出率为1.83%。297例ASCUS患者阴道镜下活检病理结果为正常者136例,LSIL 108例,HSIL 50例,宫颈癌3例。HPV E6/E7 mRNA检测ASCUS中HSIL及宫颈癌的敏感性(88.68%)与HPV DNA检测(98.11%)比较,差异无统计学意义(P>0.05),而特异性(42.21%)高于HPV DNA检测(17.21%),差异有统计学意义(P<0.001)。1年后随访结果:TCT结果正常且高危型HPV阴性者82例,高危型HPV阳性和(或)TCT结果≥正常但经阴道镜检查评估并行子宫颈活检组织病理检查诊断为正常者17例、LSIL 14例、HSIL 6例。HPV E6/E7 mRNA检测与HPV DNA检测相比较,预测1年后HSIL的敏感性均为100%,而特异性分别41.59%、12.39%,差异有统计学意义(χ~2=24.45,P<0.001)。HPV E6/E7 mRNA检测诊断病变进展的ROC曲线下面积(AUC)为0.712,高于HPV DNA检测(AUC=0.563)。结论:ASCUS的病理活检结果分布于宫颈炎至宫颈癌的各个阶段,HPV E6/E7 mRNA检测不仅能检出其中的HSIL,而且可预测宫颈病变的进展。
Objective:To explore the shunt management value in ASCUS(atypical squamous cells undefined significance) and the clinical significance in follow-up of women negative cervical biopsy with high-risk HPV E6/E7 mRNA detection.Methods:Between Dec.2015 to Aug.2017,40013 patients with cervical liquid-based cytology were collected in the Third Affiliated Hospital of Zhengzhou University.There were 297 ASCUS patients received HPV E6/E7 mRNA test、HPV DNA test and cervical biopsy under colposcopy.At least 1 year of follow-up was conducted in 119 patients with negative biopsy pathology who met the inclusion criteria,and analyze the value of HPV E6/E7 mRNA test for triage management in ASCUS patients.Results:Among the 40013 patients,there were 1191 patients with positive TCT diagnosis results,including 734 patients with ASCUS,whose detection rate was 1.83%.The pathological results of 297 ASCUS patients under vaginoscopy including 136 cases NILM,108 cases LSIL,50 cases LSIL,3 cases cervical cancer.There was no significant difference on the sensitivity for detecting HSIL+ between HPV E6/E7 mRNA(88.68%) and HPV DNA(98.11%)(P>0.05).The specificity of HPV E6/E7 mRNA(42.21%) was significantly higher than that of HPV DNA(17.21%)(P<0.001).In the first years of follow-up,among 119 patients,82 cases of them were NILM and HR HPV negative,17 cases were negative for intraepithelial lesion,14 cases were LSIL,6 cases were HSIL.The HPV E6/E7 mRNA test was compared with the HPV DNA test,and the sensitivity of the HSIL was predicted to be 100% after one year,while the specificity was 41.59%,12.39%(P<0.001).The area under the ROC curve of HPV E6/E7 mRNA test in diagnosing disease progression was 0.712,higher than that of HPV DNA test.Conclusion:The biopsy results of ASCUS contained cervicitis,LSIL,HSIL and cervical cancer,HPV E6/E7 mRNA detection can detect most HSIL+,and can predict the progression of cervical lesions.
Objective:To explore the shunt management value in ASCUS(atypical squamous cells undefined significance) and the clinical significance in follow-up of women negative cervical biopsy with high-risk HPV E6/E7 mRNA detection.Methods:Between Dec.2015 to Aug.2017,40013 patients with cervical liquid-based cytology were collected in the Third Affiliated Hospital of Zhengzhou University.There were 297 ASCUS patients received HPV E6/E7 mRNA test、HPV DNA test and cervical biopsy under colposcopy.At least 1 year of follow-up was conducted in 119 patients with negative biopsy pathology who met the inclusion criteria,and analyze the value of HPV E6/E7 mRNA test for triage management in ASCUS patients.Results:Among the 40013 patients,there were 1191 patients with positive TCT diagnosis results,including 734 patients with ASCUS,whose detection rate was 1.83%.The pathological results of 297 ASCUS patients under vaginoscopy including 136 cases NILM,108 cases LSIL,50 cases LSIL,3 cases cervical cancer.There was no significant difference on the sensitivity for detecting HSIL+ between HPV E6/E7 mRNA(88.68%) and HPV DNA(98.11%)(P>0.05).The specificity of HPV E6/E7 mRNA(42.21%) was significantly higher than that of HPV DNA(17.21%)(P<0.001).In the first years of follow-up,among 119 patients,82 cases of them were NILM and HR HPV negative,17 cases were negative for intraepithelial lesion,14 cases were LSIL,6 cases were HSIL.The HPV E6/E7 mRNA test was compared with the HPV DNA test,and the sensitivity of the HSIL was predicted to be 100% after one year,while the specificity was 41.59%,12.39%(P<0.001).The area under the ROC curve of HPV E6/E7 mRNA test in diagnosing disease progression was 0.712,higher than that of HPV DNA test.Conclusion:The biopsy results of ASCUS contained cervicitis,LSIL,HSIL and cervical cancer,HPV E6/E7 mRNA detection can detect most HSIL+,and can predict the progression of cervical lesions.
引文
[1] 周红娣,金福明,沈铿.2016年美国妇产科医师学会推荐的宫颈癌筛查及预防指南的解读[J].现代妇产科进展,2016,25(6):401-405+410
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[3] 梅平,李旻,邝丽娟,等.不能明确意义的非典型鳞状上皮细胞形态学进一步分类及临床意义[J].临床与实验病理学杂志,2012,28(11):1239-1242
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[7] 潘嫱微,陈育梅,潘嘉佳,等.HPV E6/E7 mRNA检测用于ASCUS患者诊断分流的临床研究[J].中国计划生育学杂志,2015,23(7):471-473
[8] Verhoef VMJ,Bosgraaf RP,Kemenade FJV,et al.Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3):a randomised controlled non-inferiority trial[J].Lancet Oncol,2014,15(3):315-322
[9] Howie HL,Katzenellenbogen RA,Galloway DA.Papillomavirus E6 proteins[J].Virology,2009,384(2):324-334
[10] Mclaughlin-Drubin ME,Münger K.The human papillomavirus E7 oncoprotein[J].Virol,2009,384(2):335-344
[11] Sotirija D,Katerina PJ,Zorica Sarafinovska A,et al.HPV E6/E7 mRNA versus HPV DNA biomarker in cervical cancer screening of a group of Macedonian women[J].J Med Virol,2015,87(9):1578-1586
[12] Li Y,Rong S,Zhi Y,et al.Detection of cervical intraepithelial neoplasia with HPVE6/E7 mRNA among women with atypical squamous cells of unknown significance[J].Int J Gynecol Obstet,2017,137(2):145-149
[13] Bruno MT,Ferrara M,Fava V,et al.A prospective study of women with ASCUS or LSIL pap smears at baseline and HPV E6/E7 mRNA positive:a 3-year follow-up[J].Epidemiol Infect,2018,146(5):612-618
[14] Hanna J,Kaj B,Lotten D,et al.Presence of high-risk HPV mRNA in relation to future high-grade lesions among high-Risk HPV DNA positive women with minor cytological abnormalities[J].Plos One,2015,10(4):e124460
[2] 纪巧云,邓巧玲,郑朝晖.液基细胞学检查在宫颈癌筛查中的临床应用价值[J].中国妇幼保健,2018,43(7):1495-1498
[3] 梅平,李旻,邝丽娟,等.不能明确意义的非典型鳞状上皮细胞形态学进一步分类及临床意义[J].临床与实验病理学杂志,2012,28(11):1239-1242
[4] Desteli GA,Demiralay E,Gürsu T,et al.Detection of HPV positivity by immunohistochemistry in colposcopic cervical biopsies with a cytological diagnosis of ASCUS[J].Türk Patoloji Dergisi,2014,30(3):166-170
[5] Budal EB,Haugland HK,Skar R,et al.HPV DNA testing improves CIN2+ risk stratification and detection of CIN2+ in delayed triage of ASCUS and LSIL.A population-based follow-up study from Western Norway[J].Cancer Med,2014,3(1):182-189
[6] 金红,袁韦娜.高危型HPV检测在ASCUS分流监测中的应用效果[J].安徽医学,2016,37(10):1245-1247
[7] 潘嫱微,陈育梅,潘嘉佳,等.HPV E6/E7 mRNA检测用于ASCUS患者诊断分流的临床研究[J].中国计划生育学杂志,2015,23(7):471-473
[8] Verhoef VMJ,Bosgraaf RP,Kemenade FJV,et al.Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3):a randomised controlled non-inferiority trial[J].Lancet Oncol,2014,15(3):315-322
[9] Howie HL,Katzenellenbogen RA,Galloway DA.Papillomavirus E6 proteins[J].Virology,2009,384(2):324-334
[10] Mclaughlin-Drubin ME,Münger K.The human papillomavirus E7 oncoprotein[J].Virol,2009,384(2):335-344
[11] Sotirija D,Katerina PJ,Zorica Sarafinovska A,et al.HPV E6/E7 mRNA versus HPV DNA biomarker in cervical cancer screening of a group of Macedonian women[J].J Med Virol,2015,87(9):1578-1586
[12] Li Y,Rong S,Zhi Y,et al.Detection of cervical intraepithelial neoplasia with HPVE6/E7 mRNA among women with atypical squamous cells of unknown significance[J].Int J Gynecol Obstet,2017,137(2):145-149
[13] Bruno MT,Ferrara M,Fava V,et al.A prospective study of women with ASCUS or LSIL pap smears at baseline and HPV E6/E7 mRNA positive:a 3-year follow-up[J].Epidemiol Infect,2018,146(5):612-618
[14] Hanna J,Kaj B,Lotten D,et al.Presence of high-risk HPV mRNA in relation to future high-grade lesions among high-Risk HPV DNA positive women with minor cytological abnormalities[J].Plos One,2015,10(4):e124460