宫颈细胞学联合HC-Ⅱ-HPV DNA检测对宫颈病变诊断价值
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摘要
目的人乳头瘤病毒(human papillomavirus,HPV)感染具有普遍性,但绝大部分感染是暂时性的,可被机体清除掉,只有极少数人持续性或反复性HPV感染导致细胞向恶性转化,发生宫颈癌前病变及宫颈癌的风险大大增加。本研究探讨高危型人乳头瘤病毒(high risk human papilloma virus,HR-HPV)检测在宫颈异常细胞学中的临床诊疗价值。方法收集2017-12-01-2018-12-31在深圳市龙岗中心医院妇产科门诊进行宫颈液基细胞学检查、TBS细胞分类诊断和第二代杂交捕获检测(hybrid caprureⅡ,HC-Ⅱ)HPV-DNA的结果,筛选出细胞学异常者2 734例,其中HPV阳性1 934例,阴道镜下宫颈活检1 676例。将宫颈上皮内瘤样病变Ⅰ(cervical intraepithelial neoplasiaⅠ,CINⅠ)及以上病变列为组织病理学诊断阳性病变,以组织病理学诊断为"金标准",通过对HC-ⅡHPV DNA检测结果分析,评价该筛检方法在宫颈细胞学异常中的临床诊疗价值。结果细胞学异常病例2 734例中,包括意义不明确的非典型鳞状细胞(atypical squamous cell of undetermined significance,ASCUS)1 006例、低级别鳞状上皮内病变(low-grade squamous intraepithelial lesion,LSIL)1 094例、不能排除高级别鳞状上皮内病变的非典型鳞状上皮细胞(atypical squamous cell,cannot exclude high-grade squamous intraepithelial lesion,ASC-H)156例、高级别鳞状上皮内病变(high-grade squamous intraepithelial lesion,HSIL)436例、鳞状细胞癌/腺癌(squamous cell carcinoma/adenocarcinoma,SCC/AC)19例和非典型腺上皮细胞(atypical glandular cells,AGC)23例,其中HPV阳性1 934例,HPV检出率依次为51.8%、82.3%、69.9%、86.5%、94.7%和39.1%,HPV检出率比较差异有统计学意义,χ~2=313.32,P<0.001。HPV检出率随宫颈病变程度加重呈趋势性升高,且HPV阳性组的病理诊断阳性率高达51.8%。阴道镜下宫颈活检病例1 676例,病理诊断为无上皮内病变或恶性病变(negative for intraepithelial lesion or malignancy,NILM)894例、LSIL 269例、HSIL 447例、SCC/AC66例,HPV阳性率依次为72.5%、88.5%、88.8%和92.4%,HPV阳性率的差异有统计学意义,χ~2=72.202,P<0.001,HPV阳性率也随宫颈病变程度加重呈趋势性升高,且病理诊断阳性组的HPV阳性率高(89.0%)。以组织病理诊断作为"金标准",评价HC-ⅡHPV-DNA诊断效能,新柏氏液基细胞学检测(thinprep cytologic test,TCT)诊断为ASCUS、LSIL、ASC-H、HSIL组的HC-ⅡHPV-DNA检测结果中,HPV阳性的病理阳性率与HPV阴性的病理阳性率比较差异均有统计学意义,P<0.001;TCT诊断为ASCUS、ASC-H、LSIL、HSIL、SCC/AC组HC-ⅡHPV-DNA检测灵敏度依次为:78.3%、87.5%、93.4%、87.5%、90.7%和94.7%;TCT诊断为ASCUS、ASC-H、LSIL和HSIL组的约登指数依次为0.168、0.109、0.282和0.182;Kappa值依次为0.14、0.08、0.29和0.21。结论宫颈细胞学联合HC-ⅡHPV-DNA检测对宫颈病变的诊断虽有一定的灵敏度,但特异度较差,与金标准诊断的一致性较差。
OBJECTIVE Human papillomavirus infection is universal,but most of the infection is temporary and can be removed by the body.Only a small number of persistent or repetitive HPV infections cause cells malignant transformation,so the risk of cervical precancerous lesions and cervical cancer is greatly increased.This study investigates the value of high-risk human papillomavirus(HR-HPV)detection in clinical diagnosis and treatment of cervical cytology abnormalities.METHODS The data of cervical liquid-based cytological examination,TBS(The Bethesda System)cell classification diagnosis and HPV-DNA of second-generation hybrid capture detection(Hybrid captureⅡ,HC-2)were collected at the Obstetrics and Gynecology Clinic of Longgang Central Hospital from December 1,2017 to December 31,2018.2 734 cases of cytological abnormalities were screened,including 1 934 cases of HPV positive,and 1 676 cases of pathological diagnosis by colposcopy cervical biopsy.Cervical intraepithelial neoplasia(CINⅠ)and above were classified as histopathologically positive lesions,and histopathological diagnosis was regarded as the"gold standard".Clinical diagnosis and treatment value in cervical cytology abnormalities of the screening method was evaluated by analyzing the results of HC-Ⅱ HPV-DNA detection.RESULTS Among the 2 734 cases of cytological abnormalities,there were 1 006 cases of atypical squamous cell of undetermined significance(ASCUS),1 094 cases of low-grade squamous intraepithelial lesion(LSIL),156 cases of atypical squamous cells,cannot exclude high-grade squamous intraepithelial lesion(ASC-H),436 cases of high-grade squamous intraepithelial lesion(HSIL),19 cases of squamous cell carcinoma/adenocarcinoma(SCC/AC)and 23 cases of atypical glandular cells(AGC).Among them,1 934 cases were positive for HPV.HPV detection rate was 51.8%,82.3%,69.9%,86.5%,94.7% and 39.1%,respectively.The difference in HPV detection rate was statistically significant(χ~2=313.32,P<0.001).And the HPV detection rate increased with the severity of cervical lesions.The positive rate of pathological diagnosis in the HPV positive group was high(51.8%).Among the 1 676 cases of cervical biopsy under colposcopy,the pathological diagnosis was 894 cases of NILM(negative for intraepithelial lesion or malignancy),269 cases of LSIL,447 cases of HSIL and 66 cases of SCC/AC.The positive rate of HPV was 72.5%,88.5%,88.8% and 92.4%,respectively.The positive rate of HPV was statistically different(χ~2=72.202,P<0.001).And the positive rate of HPV also increased with the severity of cervical lesions.The positive rate of HPV in the pathologically positive group was high(89.0%).The diagnostic efficacy of HC-Ⅱ HPV-DNA was evaluated by histopathological diagnosis as the"gold standard".By the HCV-Ⅱ HPV-DNA detection results in ASCUS,LSIL,ASC-H,and HSIL groups of the TCT results,the rate of HPV-positive pathological positive and the rate of HPV-negative pathological positive were all different.The differences were also statistically significant(P<0.001).The sensitivity of HC-Ⅱ HPV-DNA detection in ASCUS,ASC-H,LSIL,HSIL,SCC/AC groups of the TCT results were 78.3%,87.5%,93.4%,87.5%,90.7%,and 94.7%,respectively.The Youden,s indexes of ASCUS,ASC-H,LSIL,and HSIL groups of the TCT results were 0.168,0.109,0.282,and 0.182,respectively.Kappa value were 0.14,0.08,0.29 and 0.21,respectively.CONCLUSION Cervical cytology combined with HC-Ⅱ-HPV-DNA detection has certain sensitivity to the diagnosis of cervical lesions,but the specificity is poor,and the consistency with the gold standard diagnosis is poor.
OBJECTIVE Human papillomavirus infection is universal,but most of the infection is temporary and can be removed by the body.Only a small number of persistent or repetitive HPV infections cause cells malignant transformation,so the risk of cervical precancerous lesions and cervical cancer is greatly increased.This study investigates the value of high-risk human papillomavirus(HR-HPV)detection in clinical diagnosis and treatment of cervical cytology abnormalities.METHODS The data of cervical liquid-based cytological examination,TBS(The Bethesda System)cell classification diagnosis and HPV-DNA of second-generation hybrid capture detection(Hybrid captureⅡ,HC-2)were collected at the Obstetrics and Gynecology Clinic of Longgang Central Hospital from December 1,2017 to December 31,2018.2 734 cases of cytological abnormalities were screened,including 1 934 cases of HPV positive,and 1 676 cases of pathological diagnosis by colposcopy cervical biopsy.Cervical intraepithelial neoplasia(CINⅠ)and above were classified as histopathologically positive lesions,and histopathological diagnosis was regarded as the"gold standard".Clinical diagnosis and treatment value in cervical cytology abnormalities of the screening method was evaluated by analyzing the results of HC-Ⅱ HPV-DNA detection.RESULTS Among the 2 734 cases of cytological abnormalities,there were 1 006 cases of atypical squamous cell of undetermined significance(ASCUS),1 094 cases of low-grade squamous intraepithelial lesion(LSIL),156 cases of atypical squamous cells,cannot exclude high-grade squamous intraepithelial lesion(ASC-H),436 cases of high-grade squamous intraepithelial lesion(HSIL),19 cases of squamous cell carcinoma/adenocarcinoma(SCC/AC)and 23 cases of atypical glandular cells(AGC).Among them,1 934 cases were positive for HPV.HPV detection rate was 51.8%,82.3%,69.9%,86.5%,94.7% and 39.1%,respectively.The difference in HPV detection rate was statistically significant(χ~2=313.32,P<0.001).And the HPV detection rate increased with the severity of cervical lesions.The positive rate of pathological diagnosis in the HPV positive group was high(51.8%).Among the 1 676 cases of cervical biopsy under colposcopy,the pathological diagnosis was 894 cases of NILM(negative for intraepithelial lesion or malignancy),269 cases of LSIL,447 cases of HSIL and 66 cases of SCC/AC.The positive rate of HPV was 72.5%,88.5%,88.8% and 92.4%,respectively.The positive rate of HPV was statistically different(χ~2=72.202,P<0.001).And the positive rate of HPV also increased with the severity of cervical lesions.The positive rate of HPV in the pathologically positive group was high(89.0%).The diagnostic efficacy of HC-Ⅱ HPV-DNA was evaluated by histopathological diagnosis as the"gold standard".By the HCV-Ⅱ HPV-DNA detection results in ASCUS,LSIL,ASC-H,and HSIL groups of the TCT results,the rate of HPV-positive pathological positive and the rate of HPV-negative pathological positive were all different.The differences were also statistically significant(P<0.001).The sensitivity of HC-Ⅱ HPV-DNA detection in ASCUS,ASC-H,LSIL,HSIL,SCC/AC groups of the TCT results were 78.3%,87.5%,93.4%,87.5%,90.7%,and 94.7%,respectively.The Youden,s indexes of ASCUS,ASC-H,LSIL,and HSIL groups of the TCT results were 0.168,0.109,0.282,and 0.182,respectively.Kappa value were 0.14,0.08,0.29 and 0.21,respectively.CONCLUSION Cervical cytology combined with HC-Ⅱ-HPV-DNA detection has certain sensitivity to the diagnosis of cervical lesions,but the specificity is poor,and the consistency with the gold standard diagnosis is poor.
引文
[1]陈晓红.宫颈液基细胞学检查在宫颈病变中的诊断价值[J].中国妇幼保健,2012,27(18):2890-2891.
[2]Shukla S,Shishodia G,Mahata S,et al.Aberrant expression and constitutive activation of STAT3in cervical carcinogenesis:Implications in high-risk human papillomavirus infection[J].Mol Cancerr,2010,9:282.
[3]Saslow D,Solomon D,Lawson HW,et al.American Cancer Society,American Society for Colposcopy and Cervical Pathology,and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer[J].J Low Genit Tract Dis,2012,16(3):175-204.
[4]Renshaw AA,Young NA,Birdsong GG,et al.Comparison of performance of conventional and ThinPrep gynecologic preparations in the College of American Pathologists Gynecologic Cytology Program[J].Arch Pathol Lab Med,2004,128(1):17-22.
[5]Chengquan Zhao,毛瑛玉.美国最新子宫颈癌筛查异常女性的临床处理指南介绍[J].中华妇产科杂志,2014,49(1):73-77.
[6]Darragh TM,Colgan TJ,Thomas Cox J,et al.The Lower Anogenital Squamous Terminology Standardization project for HPVassociated lesions:background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology[J].Int J Gynecol Pathol,2013,32(1):76-115.
[7]Szentirmay Z,Veleczki Z.Human papillomavirus associated cervix uteri morbidity in Hungary:Epidemiology and correlation with the HPV types and the simultaneous cytological diagnosis[J].Orv Hetil,2017,158(31):1213-1221.
[8]Chetty R.70years of the JCP-highly cited papers:The causal relation between human papillomavirus and cervical cancer[J].J Clin Pathol,2017,70(12):997.
[9]牛庆玲,卢爱妮.高危型人乳头瘤病毒负荷量与早期宫颈癌预后的关系[J].广东医学,2014,35(2):243-245.
[10]宛利梅.第二代基因杂交捕获法检测高危型HPV-DNA在宫颈癌前病变筛查中的应用研究[J].中国医药导报,2013,10(18):101-102,105.
[11]钟奇志.第二代捕获杂交法(HC-Ⅱ)检测HPV-DNA在宫颈癌筛查中应用[J].中国妇幼保健,2008(7):974-975.
[12]陈勇霞,刘颖,梁爽爽.HR-HPV检测联合宫颈液基细胞学及经阴道镜活检诊断宫颈病变[J].热带医学杂志,2012,12(12):1473-1476.
[13]Egli-Gany D,Spaar Zographos A,Diebold J,et al.Human papillomavirus genotype distribution and socio-behavioural characteristics in women with cervical pre-cancer and cancer at the start of a human papillomavirus vaccination programme:The CIN3+plus study[J].BMC Cancer,2019,19(1):111.
[14]李婷媛,吴泽妮,姜明月,等.不同感染状态下高危型人乳头状瘤病毒载量与子宫颈病变发生的关系[J].中华肿瘤杂志,2018,40(6):475-480.
[15]许惠惠,朱海燕,章彤彤,等.高危型人乳头状瘤病毒感染在宫颈病变进展中的风险研究[J].中华实验和临床病毒学杂志,2017,31(4):302-306.
[16]邱峰,黄匡,唐虹,等.HPV分型及血清肿瘤标志物在宫颈癌诊断中的临床意义[J].检验医学与临床,2017,14(14):2011-2013,2016.
[2]Shukla S,Shishodia G,Mahata S,et al.Aberrant expression and constitutive activation of STAT3in cervical carcinogenesis:Implications in high-risk human papillomavirus infection[J].Mol Cancerr,2010,9:282.
[3]Saslow D,Solomon D,Lawson HW,et al.American Cancer Society,American Society for Colposcopy and Cervical Pathology,and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer[J].J Low Genit Tract Dis,2012,16(3):175-204.
[4]Renshaw AA,Young NA,Birdsong GG,et al.Comparison of performance of conventional and ThinPrep gynecologic preparations in the College of American Pathologists Gynecologic Cytology Program[J].Arch Pathol Lab Med,2004,128(1):17-22.
[5]Chengquan Zhao,毛瑛玉.美国最新子宫颈癌筛查异常女性的临床处理指南介绍[J].中华妇产科杂志,2014,49(1):73-77.
[6]Darragh TM,Colgan TJ,Thomas Cox J,et al.The Lower Anogenital Squamous Terminology Standardization project for HPVassociated lesions:background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology[J].Int J Gynecol Pathol,2013,32(1):76-115.
[7]Szentirmay Z,Veleczki Z.Human papillomavirus associated cervix uteri morbidity in Hungary:Epidemiology and correlation with the HPV types and the simultaneous cytological diagnosis[J].Orv Hetil,2017,158(31):1213-1221.
[8]Chetty R.70years of the JCP-highly cited papers:The causal relation between human papillomavirus and cervical cancer[J].J Clin Pathol,2017,70(12):997.
[9]牛庆玲,卢爱妮.高危型人乳头瘤病毒负荷量与早期宫颈癌预后的关系[J].广东医学,2014,35(2):243-245.
[10]宛利梅.第二代基因杂交捕获法检测高危型HPV-DNA在宫颈癌前病变筛查中的应用研究[J].中国医药导报,2013,10(18):101-102,105.
[11]钟奇志.第二代捕获杂交法(HC-Ⅱ)检测HPV-DNA在宫颈癌筛查中应用[J].中国妇幼保健,2008(7):974-975.
[12]陈勇霞,刘颖,梁爽爽.HR-HPV检测联合宫颈液基细胞学及经阴道镜活检诊断宫颈病变[J].热带医学杂志,2012,12(12):1473-1476.
[13]Egli-Gany D,Spaar Zographos A,Diebold J,et al.Human papillomavirus genotype distribution and socio-behavioural characteristics in women with cervical pre-cancer and cancer at the start of a human papillomavirus vaccination programme:The CIN3+plus study[J].BMC Cancer,2019,19(1):111.
[14]李婷媛,吴泽妮,姜明月,等.不同感染状态下高危型人乳头状瘤病毒载量与子宫颈病变发生的关系[J].中华肿瘤杂志,2018,40(6):475-480.
[15]许惠惠,朱海燕,章彤彤,等.高危型人乳头状瘤病毒感染在宫颈病变进展中的风险研究[J].中华实验和临床病毒学杂志,2017,31(4):302-306.
[16]邱峰,黄匡,唐虹,等.HPV分型及血清肿瘤标志物在宫颈癌诊断中的临床意义[J].检验医学与临床,2017,14(14):2011-2013,2016.