K17、7、10/13、8及Ki-67在宫颈鳞状上皮内病变及未成熟鳞化中的表达及意义
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摘要
目的：
宫颈癌是世界范围内女性第二高发的肿瘤,其中又以宫颈鳞状细胞癌居多。宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)是宫颈鳞状细胞癌的癌前病变,其中高危险性病变和低危险性病变,肿瘤性病变和反应性病变有时不易鉴别。角蛋白(keratin, K)是细胞最复杂的一种中丝蛋白,是上皮分化的特征性标志物,角蛋白的表达因细胞的分化状态、生理环境和病理环境等的不同而不同,用于宫颈病变的辅助诊断一直受关注,但研究结果还在初步阶段。本实验采用免疫组织化学方法(Immunohistochemistry, IHC),检测角蛋白和核增殖抗原(Ki-67)在宫颈良性反应性病变和肿瘤性病变中的表达情况及进行相关性分析,研究宫颈上皮良恶性病变中细胞增殖和分化的不同,继而探讨角蛋白和Ki-67在宫颈鳞状上皮病变病理诊断中的价值。
方法：
收集2006年至2009年在天津医科大学总医院因宫颈活检、锥切及子宫全切的患者的存档病理蜡块及其相关的病例资料。包括正常宫颈鳞状上皮10例,宫颈未成熟鳞化上皮30例,宫颈低级别鳞状上皮内病变(CINⅠ)30例,宫颈高级别鳞状上皮内病变(CINⅡ和Ⅲ)共30例,其中CINⅡ11例,CINⅢ19例。选取组织蜡块做厚度4μm的连续切片,运用免疫组织化学的方法分别检测各实验组中鼠抗人细胞角蛋白17单克隆抗体、鼠抗人细胞角蛋白7单克隆抗体、鼠抗人细胞角蛋白8单克隆抗体、鼠抗人细胞角蛋白10/13,鼠抗人Ki-67单克隆抗的表达水平。采用非参数Kruskal-Wallis H检验,多组间的两两比较采用Mann-Whitney U检验。Ki-67采用Games-Howell检验。各组间的相关性采用Spearman秩相关分析。
结果：
1.K17在宫颈未成熟鳞化中高表达,而在正常宫颈鳞状上皮、低级别鳞状上皮内病变和高级别鳞状上皮内病变中低表达,在宫颈未成熟鳞化和高级别鳞状上皮内病变中的表达有显著性差异(P均小于0.01)。
2.K7在各组中的表达有统计学意义,其中高级别鳞状上皮内病变组的表达高于未成熟鳞化组、低级别鳞状上皮内病变组和正常宫颈鳞状上皮组,宫颈未成熟鳞化组的表达又高于低级别鳞状上皮内病变组和正常宫颈鳞状上皮组,低级别鳞状上皮内病变组高于正常宫颈鳞状上皮组(P均小于0.01)。
3.K10/13在各组中的表达有统计学意义,其中高级别鳞状上皮内病变组的表达低于宫颈未成熟鳞化组、低级别鳞状上皮内病变组和正常宫颈上皮组(P均小于0.01),低级别鳞状上皮内病变组和正常宫颈鳞状上皮组之间的表达无统计学意义(P>0.05)。
4.K8在各组之间的表达无明显统计学意义(P>0.05)。
5.Ki-67在高级别鳞状上皮内病变组的表达明显高于其他各组(P<0.01)。
6.K7与K10/13在宫颈正常鳞状上皮组、低级别鳞状上皮组和高级别鳞状上皮内病变组中的表达呈负相关(r=-0.427,P<0.001)
结论：
1.宫颈未成熟鳞化上皮中K17表达增加,明显高于其他各组,K17可能是宫颈炎症损伤状态下组织表达的“应激”蛋白,而在肿瘤性病变中表达未见明显增加,它可以作为鉴别二者的一个有用指标。
2.K7在宫颈鳞状上皮内病变中随病变级别的增加,表达增加,而K10/13在鳞状上皮内病变中随病变级别的增加表达减少,分化相关角蛋白亚型的表达发生改变,提示宫颈肿瘤性病变中出现细胞分化紊乱和分化异常。角蛋白亚型的表达改变可能是相关基因突变的结果。
3.宫颈未成熟鳞化上皮中K7、K10/13的表达未发生明显改变,细胞有分化成熟的趋势。
4.Ki-67是判断宫颈上皮病变增殖状态的有用指标,有助于宫颈良恶性病变的鉴别。
5.宫颈非典型性不成熟鳞状上皮化生是一组异质性病变,通过对比分析未成熟鳞化和高级别鳞状上皮内病变的分化相关角蛋白和增殖状态,认为联合检测K17、K7、K10/13和Ki-67,有助于对这一描述性诊断进行良恶性鉴别。
Objective:
Cervical cancer is the second most common cancer among women worldwide.Among them, the squamous cancer is more happened, cervical intraepithelial neoplasia is precancerous change of Cervical cancer.The difference between high risk chanciness and low risk chanciness is hard to distinguish. Keratins are a highly diverse family of intermediate filament and important markers of epithelial cell differentiation.. The composition of keratin pairs varies depending on cell type, differentiation status and environment,and a lot of researcher pay close attention to it for the auxiliary diagnosis of pathological changes. Our target was to explore the expression of keratins and Ki-67 in Cervical epithelial nonmalignant changes and tumorous changes, investigating the different of cell differentiation among Cervical epithelial changes and the function of keratins and Ki-67 as auxiliary diagnosis of pathologic diagnosis.
We investigated the 2006 to 2009 formalin-fixed paraffinembedded cervical specimens:cervical punch biopsies, knife cone and loop electrosurgical excision procedure (LEEP) excision specimens with varying proportions of normal cervical squamous epithelium(n=10), immature squamous metaplasia(n=30), low-grade squamous Intraepithelial lesion(CINⅠ,n=30) and high-grade squamous intraepithelial lesion (CINⅡ=11,CINⅢ= 19) from the department of Pathology in the General Hospital in Tianj in Medical University. The expression of keratin 17、7、8、10/13 and Ki-67 were examined by immunohistochemical technique. The data was analyzed by SPSS software.
Results:
1.K17 was high expressed in cervical immature squamous metaplasia and low in normal cervical squamous epithelium、low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion.There was a significant difference between immature squamous metaplasia and high-grade squamous intraepithelial lesion P＜0.01)
2. There was a significant difference of the expression of K7 among each group, K7 expression in high-grade squamous intraepithelial lesion was higher than immature squamous metaplasia、low-grade squamous intraepithelial and normal cervical squamous epithelium,in the immature squamous metaplasia was higher than low-grade squamous intraepithelial, in the low-grade squamous intraepithelial was higher than normal cervical squamous epithelium (P<0.01)
3.There was a significant difference of the expression of K10/13 among each group, K10/13 expression in high-grade squamous intraepithelial lesion was lower than immature squamous metaplasia、low-grade squamous intraepithelial and normal cervical squamous epithelium (P< 0.01), there was no statistic difference of K10/13 between low-grade squamous intraepithelial and normal cervical squamous epithelium (P＞0.05);
4. There was no statistic difference of K8 among every group (P＞0.05);
5. The expression of Ki-67 in high-grade squamous intraepithelial was higher than in others (P＜0.01)
6. In normal cervical squamous epithelium、low-grade squamous intraepithelial and high-grade squamous intraepithelial, there were positive correlation between the expression of K7 and K10/13 (r=-0.427,P＜0.001)
Conclusions:
1.K17 was high expressed in immature squamous metaplasia,that means it maybe the "stress" protein when cervical inflammation,while had no significantly changed in malignant disease,so K17 was useful to distinguish them;
2.K7 was up-regulated with the grade of disease,while K10/13 was converse.The change of them may means the cell differentiation disordered and may be the consequence of genetype mutation;
3.There had no changed of K7、10/13 expression in cervical immature squamous metaplasia,the cell was well differentiated;
4. Ki-67 was helpful to diagnose hyproliferation disease;
5. Atypical immature metaplasia is a group of heterogenicity disease,with the correlation between immature squamous metaplasia and high-grade squamous Intraepithelial lesion,coexpression of K17、7、10/13 and Ki-67 can distinction the innocent change from malignant disease.
宫颈癌是世界范围内女性第二高发的肿瘤,其中又以宫颈鳞状细胞癌居多。宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)是宫颈鳞状细胞癌的癌前病变,其中高危险性病变和低危险性病变,肿瘤性病变和反应性病变有时不易鉴别。角蛋白(keratin, K)是细胞最复杂的一种中丝蛋白,是上皮分化的特征性标志物,角蛋白的表达因细胞的分化状态、生理环境和病理环境等的不同而不同,用于宫颈病变的辅助诊断一直受关注,但研究结果还在初步阶段。本实验采用免疫组织化学方法(Immunohistochemistry, IHC),检测角蛋白和核增殖抗原(Ki-67)在宫颈良性反应性病变和肿瘤性病变中的表达情况及进行相关性分析,研究宫颈上皮良恶性病变中细胞增殖和分化的不同,继而探讨角蛋白和Ki-67在宫颈鳞状上皮病变病理诊断中的价值。
方法：
收集2006年至2009年在天津医科大学总医院因宫颈活检、锥切及子宫全切的患者的存档病理蜡块及其相关的病例资料。包括正常宫颈鳞状上皮10例,宫颈未成熟鳞化上皮30例,宫颈低级别鳞状上皮内病变(CINⅠ)30例,宫颈高级别鳞状上皮内病变(CINⅡ和Ⅲ)共30例,其中CINⅡ11例,CINⅢ19例。选取组织蜡块做厚度4μm的连续切片,运用免疫组织化学的方法分别检测各实验组中鼠抗人细胞角蛋白17单克隆抗体、鼠抗人细胞角蛋白7单克隆抗体、鼠抗人细胞角蛋白8单克隆抗体、鼠抗人细胞角蛋白10/13,鼠抗人Ki-67单克隆抗的表达水平。采用非参数Kruskal-Wallis H检验,多组间的两两比较采用Mann-Whitney U检验。Ki-67采用Games-Howell检验。各组间的相关性采用Spearman秩相关分析。
结果：
1.K17在宫颈未成熟鳞化中高表达,而在正常宫颈鳞状上皮、低级别鳞状上皮内病变和高级别鳞状上皮内病变中低表达,在宫颈未成熟鳞化和高级别鳞状上皮内病变中的表达有显著性差异(P均小于0.01)。
2.K7在各组中的表达有统计学意义,其中高级别鳞状上皮内病变组的表达高于未成熟鳞化组、低级别鳞状上皮内病变组和正常宫颈鳞状上皮组,宫颈未成熟鳞化组的表达又高于低级别鳞状上皮内病变组和正常宫颈鳞状上皮组,低级别鳞状上皮内病变组高于正常宫颈鳞状上皮组(P均小于0.01)。
3.K10/13在各组中的表达有统计学意义,其中高级别鳞状上皮内病变组的表达低于宫颈未成熟鳞化组、低级别鳞状上皮内病变组和正常宫颈上皮组(P均小于0.01),低级别鳞状上皮内病变组和正常宫颈鳞状上皮组之间的表达无统计学意义(P>0.05)。
4.K8在各组之间的表达无明显统计学意义(P>0.05)。
5.Ki-67在高级别鳞状上皮内病变组的表达明显高于其他各组(P<0.01)。
6.K7与K10/13在宫颈正常鳞状上皮组、低级别鳞状上皮组和高级别鳞状上皮内病变组中的表达呈负相关(r=-0.427,P<0.001)
结论：
1.宫颈未成熟鳞化上皮中K17表达增加,明显高于其他各组,K17可能是宫颈炎症损伤状态下组织表达的“应激”蛋白,而在肿瘤性病变中表达未见明显增加,它可以作为鉴别二者的一个有用指标。
2.K7在宫颈鳞状上皮内病变中随病变级别的增加,表达增加,而K10/13在鳞状上皮内病变中随病变级别的增加表达减少,分化相关角蛋白亚型的表达发生改变,提示宫颈肿瘤性病变中出现细胞分化紊乱和分化异常。角蛋白亚型的表达改变可能是相关基因突变的结果。
3.宫颈未成熟鳞化上皮中K7、K10/13的表达未发生明显改变,细胞有分化成熟的趋势。
4.Ki-67是判断宫颈上皮病变增殖状态的有用指标,有助于宫颈良恶性病变的鉴别。
5.宫颈非典型性不成熟鳞状上皮化生是一组异质性病变,通过对比分析未成熟鳞化和高级别鳞状上皮内病变的分化相关角蛋白和增殖状态,认为联合检测K17、K7、K10/13和Ki-67,有助于对这一描述性诊断进行良恶性鉴别。
Objective:
Cervical cancer is the second most common cancer among women worldwide.Among them, the squamous cancer is more happened, cervical intraepithelial neoplasia is precancerous change of Cervical cancer.The difference between high risk chanciness and low risk chanciness is hard to distinguish. Keratins are a highly diverse family of intermediate filament and important markers of epithelial cell differentiation.. The composition of keratin pairs varies depending on cell type, differentiation status and environment,and a lot of researcher pay close attention to it for the auxiliary diagnosis of pathological changes. Our target was to explore the expression of keratins and Ki-67 in Cervical epithelial nonmalignant changes and tumorous changes, investigating the different of cell differentiation among Cervical epithelial changes and the function of keratins and Ki-67 as auxiliary diagnosis of pathologic diagnosis.
We investigated the 2006 to 2009 formalin-fixed paraffinembedded cervical specimens:cervical punch biopsies, knife cone and loop electrosurgical excision procedure (LEEP) excision specimens with varying proportions of normal cervical squamous epithelium(n=10), immature squamous metaplasia(n=30), low-grade squamous Intraepithelial lesion(CINⅠ,n=30) and high-grade squamous intraepithelial lesion (CINⅡ=11,CINⅢ= 19) from the department of Pathology in the General Hospital in Tianj in Medical University. The expression of keratin 17、7、8、10/13 and Ki-67 were examined by immunohistochemical technique. The data was analyzed by SPSS software.
Results:
1.K17 was high expressed in cervical immature squamous metaplasia and low in normal cervical squamous epithelium、low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion.There was a significant difference between immature squamous metaplasia and high-grade squamous intraepithelial lesion P＜0.01)
2. There was a significant difference of the expression of K7 among each group, K7 expression in high-grade squamous intraepithelial lesion was higher than immature squamous metaplasia、low-grade squamous intraepithelial and normal cervical squamous epithelium,in the immature squamous metaplasia was higher than low-grade squamous intraepithelial, in the low-grade squamous intraepithelial was higher than normal cervical squamous epithelium (P<0.01)
3.There was a significant difference of the expression of K10/13 among each group, K10/13 expression in high-grade squamous intraepithelial lesion was lower than immature squamous metaplasia、low-grade squamous intraepithelial and normal cervical squamous epithelium (P< 0.01), there was no statistic difference of K10/13 between low-grade squamous intraepithelial and normal cervical squamous epithelium (P＞0.05);
4. There was no statistic difference of K8 among every group (P＞0.05);
5. The expression of Ki-67 in high-grade squamous intraepithelial was higher than in others (P＜0.01)
6. In normal cervical squamous epithelium、low-grade squamous intraepithelial and high-grade squamous intraepithelial, there were positive correlation between the expression of K7 and K10/13 (r=-0.427,P＜0.001)
Conclusions:
1.K17 was high expressed in immature squamous metaplasia,that means it maybe the "stress" protein when cervical inflammation,while had no significantly changed in malignant disease,so K17 was useful to distinguish them;
2.K7 was up-regulated with the grade of disease,while K10/13 was converse.The change of them may means the cell differentiation disordered and may be the consequence of genetype mutation;
3.There had no changed of K7、10/13 expression in cervical immature squamous metaplasia,the cell was well differentiated;
4. Ki-67 was helpful to diagnose hyproliferation disease;
5. Atypical immature metaplasia is a group of heterogenicity disease,with the correlation between immature squamous metaplasia and high-grade squamous Intraepithelial lesion,coexpression of K17、7、10/13 and Ki-67 can distinction the innocent change from malignant disease.
引文
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[50].周庚寅,翟启辉,张庆慧等译,诊断免疫组织化学.北京大学医学出版社,2008.
[1]. Rosai, J., Rosai&Ackerman外科病理学[M].1532-1535.
[2]. Crum, L.,妇产科诊断病理学[M].2006.
[3].汤钊酋,朱世能,曹世龙等.现代肿瘤学[M].2000：166-167.
[4]. Kurokawa, I.,Takahashi, K.,Moll, I., et al., Expression of keratins in cutaneous epithelial tumors and related disorders-distribution and clinical significance [J]. Exp Dermatol,2011.20(3):217-228.
[5]. Schweizer, J.,Bowden, p. E.,Coulombe, P. A.,.New consensus nomenclature for mammalian keratins[J]. J Cell Biol,2006.174(2):169-174.
[6].王为民,侯洪春,细胞角蛋白与宫颈癌及癌前病变[J].泰山医学院学报,2010(06)：479-482.
[7].Chu, P.G. and L.M. Weiss, Keratin expression in human tissues and neoplasms[J]. Histopathology,2002.40(5):403-439.
[8].Moll, R.,Divo, M.,Langbein, L. The human keratins:biology and pathology[J]. Histochem Cell Biol,2008.129(6):705-733.
[9].Bragulla, H.H. and D.G. Homberger, Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia[J]. J Anat,2009.214(4): 516-559.
[10].Feng, D.,Peng, C.,Li, C., et al., Identification and characterization of cancer stem-like cells from primary carcinoma of the cervix uteri[J]. Oncol Rep,2009. 22(5):1129-1134.
[11].Martens, J,Baars, J,Smedts, F,et al. Can keratin 8 and 17 immunohistochemistry be of diagnostic value in cervical cytology? A feasibility study [J]. Cancer Cytopathology,1999.87(2):87-92.
[12].Ikeda K.,Tate, G.,Suzuki, T., et al., Coordinate expression of cytokeratin 8 and cytokeratin 17 immunohistochemical staining in cervical intraepithelial neoplasia and cervical squamous cell carcinoma:an immunohistochemical analysis and review of the literature [J]. Gynecol Oncol,2008.108(3):598-602.
[13].Smedts, F., F.C.S. Ramaekers, and A.H.N. Hopman, CK17 and p16 expression patterns distinguish (atypical) immature squamous metaplasia from high-grade cervical intraepithelial neoplasia[J]. Histopathology,2008.52(4):515-516.
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[18].Faleiro-Rodrigues, C. and C. Lopes, E-cadherin, CD44 and CD44v6 in squamous intraepithelial lesions and invasive carcinomas of the uterine cervix: an immunohistochemical study [J]. Pathobiology,2004.71(6):329-336.
[19].Kaplanis, K. E-cadherin expression during progression of squamous intraepithelial lesions in the uterine cervix[J]. Eur J Gynaecol Oncol,2005.26(6): 608-610.
[20].Primakoff, P. and D.G. Myles, The ADAM gene family-surface proteins with adhesion and protease activity[J]. Trends in Genetics,2000.16(2):83-87.
[21].Black, R.A. and J.M. White, ADAMs:focus on the protease domain[J]. Current Opinion in Cell Biology,1998.10(5):654-659.
[22].Blobel, C.P., Metalloprotease-disintegrins:links to cell adhesion and cleavage of TNF alpha and Notch[J]. Cell,1997.90(4):589-592.
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[24].Grutzmann, R. ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma[J]. British Journal of Cancer,2004.90(5):1053-1058.
[25].Carl-McGrath, S. The disintegrin-metalloproteinases ADAM9, ADAM 12, and ADAM 15 are upregulated in gastric cancer[J]. International Journal of Oncology, 2005.26(1):17-24.
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[27].O'Shea, C. Expression of ADAM-9 mRNA and protein in human breast cancer[J]. International Journal of Cancer,2003.105(6):754-761.
[28].Zubel, A. Expression of ADAM9 in CIN3 lesions and squamous cell carcinomas of the cervix[J]. Gynecol Oncol,2009.114(2):332-336.