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浙江大学学报（医学版）
浙江大学学报（医学版）  2018, Vol. 47 Issue (4): 344-350    DOI: 10.3785/j.issn.1008-9292.2018.08.03
专题报道     
密封蛋白4与高危型人乳头瘤病毒联合检测对于高级别鳞状上皮内病变及宫颈鳞癌的诊断价值
狄晨红1(),金帆2,*()
1. 邵逸夫国际医疗中心妇产科, 浙江 杭州 310020
2. 浙江大学医学院附属妇产科医院生殖遗传科 生殖遗传教育部重点实验室, 浙江 杭州 310006
Value of combined detection of claudin 4 and high-risk human papilloma virus in high-grade squamous intraepithelial lesion and cervix squamous cell carcinoma
DI Chenhong1(),JIN Fan2,*()
1. Department of Gynecology, Run Run Shaw International Medical Center, Hangzhou 310020, China
2. Department of Reproductive Genetics, Women's Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics, Ministry of Education, Hangzhou 310006, China
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摘要：

目的: 探讨密封蛋白4（CLDN4）在不同级别宫颈病变组织中的表达及其与高危型人乳头瘤病毒（HR-HPV）联合检测的意义。方法: 选取2015年6月至2016年12月在浙江大学医学院附属邵逸夫医院妇科门诊就诊且经病理组织学检查证实的低级别鳞状上皮内病变（LSIL）、高级别鳞状上皮内病变（HSIL）和宫颈鳞癌患者的子宫颈组织标本各30份，同时选取30例慢性宫颈炎患者的子宫颈组织标本作为对照组。采用免疫组织化学法检测子宫颈组织中CLDN4蛋白表达，实时定量PCR检测HR-HPV，液基细胞学检查（TCT）检测宫颈脱落细胞学改变。采用ROC曲线分析比较TCT联合HR-HPV与CLDN4联合HR-HPV检测对HSIL和宫颈鳞癌的诊断价值。结果: 随着宫颈病变程度加重，CLDN4表达阳性率上升（r=0.832，P < 0.05）。HR-HPV感染与CLDN4表达共阳性主要出现在HSIL和宫颈癌组。TCT联合HR-HPV和CLDN4联合HR-HPV检测诊断HSIL和宫颈鳞癌的AUC分别为0.683和0.633。TCT联合HR-HPV检测诊断HSIL和宫颈鳞癌的敏感度、特异度、阳性预测值、阴性预测值和准确度分别为100.0%、36.7%、61.2%、100.0%、46.7%；CLDN4联合HR-HPV检测诊断HSIL和宫颈鳞癌的敏感度、特异度、阳性预测值、阴性预测值和准确度分别为96.7%、30.0%、58.0%、90.0%、55.0%。结论: CLDN4表达与宫颈鳞癌及癌前病变的发生和发展相关，CLDN4联合HR-HPV检测可指导临床HSIL及宫颈鳞癌的诊断和治疗。
关键词： 宫颈肿瘤/病理学;  宫颈肿瘤/诊断;  癌前状态/病理学;  癌前状态/诊断;  癌, 鳞状细胞/诊断;  乳头状瘤病毒科;  连接蛋白类/生物合成;  免疫组织化学    
Abstract:

Objective: To investigate the expression of claudin 4 (CLDN4) in cervical tissues from patients with different cervical lesions, and to explore the value of combined detection of CLDN4 and high risk human papilloma virus (HR-HPV). Methods: The cervical tissue specimens of low-grade squamous intraepithelial lesion (LSIL, n=30), high-grade squamous intraepithelial lesion (HSIL, n=30), squamous cell carcinoma (SCC, n=30) as well as chronic cervicitis (control, n=30) were collected from the Sir Run Run Shaw Hospital of Zhejiang University during June 2015 and December 2016. The expression of CLDN4 protein in tissue specimens was detected by immunohistochemistry, HR-HPV was detected by real-time quantitative PCR, and the cervical exfoliated cells were examined by thinprep cytologic test (TCT). The ROC curve was applied to analyze the diagnostic value of TCT combined with HR-HPV and CLDN4 combined with HR-HPV tests for HSIL and SCC of the cervix. Results: With the increase of the severity of cervical lesions, the positive rate of CLDN4 expression rose (r=0.832, P < 0.05). Positivity of both HR-HPV infection and CLDN4 expression was found mainly in the HSIL and SCC groups. The areas under curve (AUC) of TCT combined with HR-HPV and CLDN4 combined with HR-HPV tests for diagnosis of HSIL and SCC were 0.683 and 0.633, respectively; the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of TCT combined with HR-HPV test for diagnosis of HSIL and SCC were 100.0%, 36.7%, 61.2%, 100.0% and 46.7% respectively; those of CLDN4 combined with HR-HPV test were 96.7%, 30.0%, 58.0%, 90.0% and 55.0%, respectively. Conclusions: CLDN4 expression may be related to the occurrence and development of cervical carcinoma and precancerous lesions. CLDN4 combined with HR-HPV test may be used for diagnosis of HSIL and SCC of the cervix clinically.
Key words: Uterine cervical neoplasms/pathology    Uterine cervical neoplasms/diagnosis    Precancerous conditions/pathology    Precancerous conditions/diagnosis    Carcinoma, squamous cell/diagnosis    Papillomaviridae    Connexins/biosynthesis    Immunohistochemistry
收稿日期: 2018-06-30 出版日期: 2018-12-04
:  R737.33  
通讯作者: 金帆     E-mail: 296696990@qq.com;jinfan@zju.edu.cn
作者简介: 狄晨红(1987-), 女, 学士, 住院医师, 主要从事妇科门诊和体检工作; E-mail:296696990@qq.com; https://orcid.org/0000-0003-1125-5562
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引用本文:

狄晨红,金帆. 密封蛋白4与高危型人乳头瘤病毒联合检测对于高级别鳞状上皮内病变及宫颈鳞癌的诊断价值[J]. 浙江大学学报（医学版）, 2018, 47(4): 344-350.

DI Chenhong,JIN Fan. Value of combined detection of claudin 4 and high-risk human papilloma virus in high-grade squamous intraepithelial lesion and cervix squamous cell carcinoma. J Zhejiang Univ (Med Sci), 2018, 47(4): 344-350.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2018.08.03    或    http://www.zjujournals.com/med/CN/Y2018/V47/I4/344

[${\bar x}$±s或n(%)]
组别 n 年龄
(岁)		 吸烟史 既往肿
瘤史		 手术史 妊娠史
“—”无相关数据.LSIL：低级别鳞状上皮内病变；HSIL：高级别鳞状上皮内病变.
对照组 30 42±14 5(16.7) 0(0.0) 1(3.3) 22(73.3)
LSIL组 30 44±19 6(20.0) 0(0.0) 0(0.0) 21(70.0)
HSIL组 30 43±12 4(13.3) 0(0.0) 0(0.0) 25(83.3)
宫颈癌组 30 45±15 7(23.3) 0(0.0) 1(3.3) 26(86.7)
P值 — ＞0.05 ＞0.05 ＞0.05 ＞0.05 ＞0.05
表 1  各组患者基线资料比较
图 1  不同宫颈病变组织中密封蛋白4(CLDN4)免疫组织化学染色结果
[n(%)]
组别 n 阴性 阳性
+ ++ +++ 合计
*与对照组比较，P＜0.05;#与ISIL组比较，P＜0.05；△与HSIL组比较，P＜0.05.LSIL：低级别鳞状上皮内病变；HSIL：高级别鳞状上皮内病变.
对照组 30 26(86.7) 4(13.3) 0(0.0) 0(0.0) 4(13.3)
LSIL组 30 21(70.0) 8(26.7) 1(3.3) 0(0.0) 9(30.0)*
HSIL组 30 12(40.0) 4(13.3) 8(26.7) 6(20.0) 18(60.0)*#
宫颈癌组 30 1(3.3) 3(10.0) 12(40.0) 14(46.7) 29(96.7)*#△
表 2  不同宫颈病变组织中密封蛋白4半定量分析结果
[n(%)]
组别 n 阴性 阳性
弱阳性 阳性 强阳性 合计
HR-HPV:高危型人乳头瘤病毒；LSIL：低级别鳞状上皮内病变；HSIL：高级别鳞状上皮内病变.
对照组 30 16(53.3) 3(10.0) 9(30.0) 2(6.7) 14(46.7)
LSIL组 30 11(36.7) 3(10.0) 11(36.7) 5(16.7) 19(63.3)
HSIL组 30 2(6.7) 6(20.0) 14(46.7) 8(26.7) 28(93.3)
宫颈癌组 30 1(3.3) 2(6.7) 12(40.0) 15(50.0) 29(96.7)
表 3  不同宫颈病变组织HR-HPV检测结果比较
[n(%)]
组别 n ASC-H LSIL HSIL 宫颈鳞癌 准确度
ASC-H:非典型鳞状细胞；LSIL：低级别鳞状上皮内病变；HSIL：高级别鳞状上皮内病变.
对照组 30 9(30.0) 11(36.7) 10(33.0) 0(0.0) 9(30.0)
LSIL组 30 7(23.3) 15(50.0) 8(26.7) 0(0.0) 15(50.0)
HSIL组 30 7(23.3) 10(33.3) 13(43.3) 0(0.0) 13(43.3)
宫颈癌组 30 2(6.7) 3(10.0) 10(33.3) 15(50.0) 15(50.0)
表 4  不同宫颈病变组织液基细胞学检测效率比较
[n(%)]
组别 n HR-HPV阳性 准确度
ASC-H LSIL HSIL 宫颈鳞癌
HR-HPV:高危型人乳头瘤病毒；ASC-H：非典型鳞状细胞；LSIL：低级别鳞状上皮内病变；HSIL：高级别鳞状上皮内病变.
对照组 30 4(13.3) 4(13.3) 2(6.7) 0(0.0) 4(13.3)
LSIL组 30 3(10.0) 11(36.7) 5(16.7) 0(0.0) 11(36.7)
HSIL组 30 5(16.7) 10(33.3) 13(43.3) 0(0.0) 13(43.3)
宫颈癌组 30 1(3.3) 3(10.0) 10(33.3) 15(50.0) 15(50.0)
表 5  不同宫颈病变组织液基细胞学联合HR-HPV检测的诊断效率比较
[n(%)]
组别 n HR-HPV阳性 准确度
CLDN4
-		 CLDN4
+		 CLND4
++		 CLND4
+++
“—”无相关数据.HR-HPV:高危型人乳头瘤病毒；CLDN4:密封蛋白4；LSIL：低级别鳞状上皮内病变；HSIL：高级别鳞状上皮内病变.
对照组 30 0(0.0) 0(0.0) 0(0.0) 0(0.0) —
LSIL组 30 19(63.3) 0(0.0) 0(0.0) 0(0.0) —
HSIL组 30 10(33.3) 4(13.3) 8(26.7) 6(20.0) 18(60.0)
宫颈癌组 30 1(3.3) 3(10.0) 11(36.7) 14(46.7) 28(93.3)
表 6  不同宫颈病变组织CLDN4联合HR-HPV检测的诊断效率比较
图 2  TCT联合HR-HPV和CLDN4联合HR-HPV检测诊断HSIL和宫颈鳞癌的ROC曲线
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