p16和Ki-67表达水平与宫颈上皮内瘤变(CIN)程度的相关性分析
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摘要
目的:分析免疫组化检测p16和Ki-67与宫颈上皮内瘤变(CIN)严重程度的关系,以及p16联合Ki-67在高级别CIN鉴别中的效能。方法:采用回顾性研究,纳入2016年1月至2018年3月期间粤北人民医院经HE染色病理确诊的宫颈病变患者160例,其中慢性宫颈炎者共38例归为对照组,CINⅠ级、Ⅱ级、Ⅲ级分别为41例、46例、35例;再将CIN患者分为低级别鳞状上皮内病变(LSIL)和高级别鳞状上皮内病变(HSIL)组。对比对照组与CINⅠ级、Ⅱ级、Ⅲ级组、ISIL组、HSIL组p16及Ki-67阳性表达情况;采用Spearman相关性分析观察p16阳性表达、Ki-67阳性表达与CIN严重程度的关系。联合使用p16、Ki-67半定量评分,评估联合p16、Ki-67半定量评分诊断结果与病理结果一致性,评估效能。结果:CINⅠ-Ⅲ级组p16阳性率较对照组高,CINⅡ、Ⅲ级p16阳性率较CINⅠ级高; HSIL组阳性率较LSIL组高,差异均有统计学意义,P <0. 05。Ki-67在对照组中阳性率为0. 00%,在LSIL组、HSIL组中分别为68. 29%、100. 00%。p16与宫颈病变程度呈正相关,r=0. 692,P=0. 021 0; Ki-67与宫颈病变程度呈正相关,r=0. 612,P=0. 001 8。p16联合Ki-67诊断炎症结果与病理完全一致,CINⅠ级共36例(87. 80%)符合,CINⅡ级共43例(93. 48%)符合,CINⅢ级共34例(97. 14%)符合; LSIL符合率为87. 80%(36/41),HSIL符合率为95. 06%(77/81)。p16联合Ki-67诊断LSIL敏感性、特异性为94. 74%和97. 58%,诊断HSIL敏感性、特异性分别为96. 25%、98. 81%,诊断CIN敏感性、特异性分别为92. 62%、96. 48%,其中LSIL敏感性高于单用,CIN诊断特异性较单用p16高,P <0. 05。结论:p16和Ki-67表达与宫颈上皮内瘤样病变严重程度密切相关,可以通过观察二者表达情况辅助CIN病情严重程度判断,联合p16和Ki-67免疫组化检测能提高诊断高级别鳞状上皮内病变诊断特异性、敏感性。
Objective:To analyze the relationship between p16 and Ki-67 and the severity of cervical intraepithelial neoplasia(CIN) by immunohistochemistry,and the efficacy of p16 combined with Ki-67 in high-grade CIN.Methods:A retrospective study was conducted to enroll 160 patients with cervical lesions diagnosed by HE staining in Yuebei people' hospital from January 2016 to March 2018.Among them,38 patients with chronic cervicitis were classified as control group,including CIN I,II and III with 41,46,and 35.The patients with CIN were divided into low-grade squamous intraepithelial lesion(LSIL) and high-grade squamous intraepithelial lesion(HSIL).The control group and CIN I grade,II grade,III grade group,ISIL group,HSIL group p16 and Ki-67 positive expression were compared.Spearman correlation analysis to observe the relationship between p16 positive expression,Ki-67 positive expression and CIN severity.Combined with p16 and Ki-67 semi-quantitative scores,the results of combined semi-quantitative scores of p16 and Ki-67 were compared with pathological results to evaluate the efficacy.Results:The positive rate of p16 in CIN I-III group was higher than that in control group,the positive rate of p16 in CIN II and III group was higher than that in CIN I group,and the positive rate of HSIL group was higher than that in LSIL group.The difference was statistically significant,P<0.05.The positive rate of Ki-67 in the control group was 0.00%,and it was 68.29% and 100.00% in the LSIL group and the HSIL group,respectively. p16 was positively correlated with cervical lesions,r=0.692,P=0.021 0.Ki-67 was positively correlated with cervical lesions,r=0.612,P=0.001 8.The diagnosis of p16 combined with Ki-67 was consistent with pathology.36 cases of CIN I were consistent(87.80%),43 cases of CIN II(93.48%) were consistent,and 34 cases of CIN III(97.14%) were consistent.LSIL coincidence rate was 87.80%(36/41).HSIL compliance rate was 95.06%(77/81).The sensitivity and specificity of p16 combined with Ki-67 diagnosis of LSIL was 94.74% and 97.58%.The sensitivity and specificity of diagnosis of HSIL were 96.25% and 98.81%,respectively.The sensitivity and specificity of diagnosis of CIN were 92.62% and 96.48%,respectively.Above the single use,the diagnostic specificity of CIN was higher than that of p16 alone,P<0.05.Conclusion:The expression of p16 and Ki-67 is closely related to the severity of cervical intraepithelial neoplasia.The expression of p16 and Ki-67 can be used to help determine the severity of CIN disease by observing their expression.Combined with immunohistochemical detection of p16 and Ki-67,diagnostic specificity and sensitivity of high-grade squamous intraepithelial lesions can be improved.
Objective:To analyze the relationship between p16 and Ki-67 and the severity of cervical intraepithelial neoplasia(CIN) by immunohistochemistry,and the efficacy of p16 combined with Ki-67 in high-grade CIN.Methods:A retrospective study was conducted to enroll 160 patients with cervical lesions diagnosed by HE staining in Yuebei people' hospital from January 2016 to March 2018.Among them,38 patients with chronic cervicitis were classified as control group,including CIN I,II and III with 41,46,and 35.The patients with CIN were divided into low-grade squamous intraepithelial lesion(LSIL) and high-grade squamous intraepithelial lesion(HSIL).The control group and CIN I grade,II grade,III grade group,ISIL group,HSIL group p16 and Ki-67 positive expression were compared.Spearman correlation analysis to observe the relationship between p16 positive expression,Ki-67 positive expression and CIN severity.Combined with p16 and Ki-67 semi-quantitative scores,the results of combined semi-quantitative scores of p16 and Ki-67 were compared with pathological results to evaluate the efficacy.Results:The positive rate of p16 in CIN I-III group was higher than that in control group,the positive rate of p16 in CIN II and III group was higher than that in CIN I group,and the positive rate of HSIL group was higher than that in LSIL group.The difference was statistically significant,P<0.05.The positive rate of Ki-67 in the control group was 0.00%,and it was 68.29% and 100.00% in the LSIL group and the HSIL group,respectively. p16 was positively correlated with cervical lesions,r=0.692,P=0.021 0.Ki-67 was positively correlated with cervical lesions,r=0.612,P=0.001 8.The diagnosis of p16 combined with Ki-67 was consistent with pathology.36 cases of CIN I were consistent(87.80%),43 cases of CIN II(93.48%) were consistent,and 34 cases of CIN III(97.14%) were consistent.LSIL coincidence rate was 87.80%(36/41).HSIL compliance rate was 95.06%(77/81).The sensitivity and specificity of p16 combined with Ki-67 diagnosis of LSIL was 94.74% and 97.58%.The sensitivity and specificity of diagnosis of HSIL were 96.25% and 98.81%,respectively.The sensitivity and specificity of diagnosis of CIN were 92.62% and 96.48%,respectively.Above the single use,the diagnostic specificity of CIN was higher than that of p16 alone,P<0.05.Conclusion:The expression of p16 and Ki-67 is closely related to the severity of cervical intraepithelial neoplasia.The expression of p16 and Ki-67 can be used to help determine the severity of CIN disease by observing their expression.Combined with immunohistochemical detection of p16 and Ki-67,diagnostic specificity and sensitivity of high-grade squamous intraepithelial lesions can be improved.
引文
[1] Guo Yanmin,Zhou Meixiang.Expression and significance of p16 and Ki-67 in cervical intraepithelial lesions [J].Journal of Diagnostic Pathology,2017,24(2):105-107.[郭艳敏,周梅香.p16、Ki-67在宫颈上皮内病变中的表达及意义[J].诊断病理学杂志,2017,24(2):105-107.]
[2] Tong Tingting,Ma Jie,Dong Lijie,et al.Expression of P16,P53 protein and HPV E6/E7 mRNA in cervical fluid-based exfoliated cells of patients with cervical squamous cell carcinoma [J].Journal of Zhengzhou University (Medical Edition),2017,52(5):637-640.[童婷婷,马杰,董丽杰,等.宫颈鳞癌患者宫颈液基脱落细胞中P16、P53蛋白及HPV E6/E7 mRNA的表达[J].郑州大学学报(医学版),2017,52(5):637-640.]
[3] Jia Wulin,Ding Ling,Ren Zhiying,et al.The role and interaction of folic acid and p16 protein in cervical carcinogenesis [J].Chinese Journal of Epidemiology,2016,37(12):1647-1652.[贾吴琳,丁玲,任志英,等.叶酸与p16蛋白在宫颈癌变中的作用及其相互效应[J].中华流行病学杂志,2016,37(12):1647-1652.]
[4] Gao Baolian,Qian Ping,Ma Zhenyi,et al.Expression and significance of human papillomavirus L1 protein,P16 and Ki-67 in cervical squamous epithelial lesions [J].China Maternal and Child Health,2015,30(7):1109-1111.[高宝莲,钱萍,马祯一,等.宫颈鳞状上皮病变中人乳头瘤病毒L1蛋白与P16、Ki-67的表达及意义[J].中国妇幼保健,2015,30(7):1109-1111.]
[5] White C,Bakhiet S,Bates M,et al.Triage of LSIL/ASC-US with p16/Ki-67 dual staining and human papillomavirus testing:a 2-year prospective study[J].Cytopathology,2016,27(4):269-276.
[6] Chen Guandi,Fan Geying,You Keli,et al.5-aza-2'-deoxycytidine regulates gene expression in cervical cancer cells [J].Journal of Practical Medicine,2016,32(18):2995-2999.[陈观娣,范格英,游可理,等.5-氮杂-2'-脱氧胞苷对宫颈癌细胞的基因表达调控[J].实用医学杂志,2016,32(18):2995-2999.]
[7] Wang Jiao,Shu Lisha,Chen Shuling,et al.Diagnostic significance of P16 and Ki67 combined with cytological examination in cervical exfoliated cells [J].China Maternal and Child Health,2016,31(10):2176-2179.[王娇,舒丽莎,陈书玲,等.P16、Ki67联合细胞学检查在宫颈脱落细胞中的诊断意义[J].中国妇幼保健,2016,31(10):2176-2179.]
[8] Ding Lili,Niu Haiyan,Yang Cheng,et al.Expression of P16 and Ki-67 in cervical squamous intraepithelial lesions [J].Chongqing Medical Science,2018,47(7):969-971.[丁莉利,牛海艳,杨丞,等.P16和Ki-67在宫颈鳞状上皮内病变中的表达[J].重庆医学,2018,47(7):969-971.]
[9] He Fangfang,Gao Ying,Wei Li,et al.The significance of p16 and Ki-67 in the grading diagnosis of cervical squamous epithelial lesions [J].Modern Oncology,2016,24(8):1271-1274.[赫芳芳,高英,魏力,等.p16、Ki-67在宫颈鳞状上皮病变分级诊断中的意义[J].现代肿瘤医学,2016,24(8):1271-1274.]
[10] Zhang Tao,Mao Shihua,Tang Liangxi,et al.Expression of P16,HPVL-1 chitin in cervical intraepithelial neoplasia and early cervical cancer tissues and its correlation with HR-HPV load [J].Journal of Practical Obstetrics and Gynecology,2016,32(7):536-539.[张涛,毛世华,唐良萏,等.宫颈上皮内瘤变及早期宫颈癌组织中P16、HPVL-1壳蛋白的表达及与HR-HPV载量相关性研究[J].实用妇产科杂志,2016,32(7):536-539.]
[11] Jayashree Vinay Joshi,Sujata S Jagtap,Prajakta Hemant Paradkar,et al.Cytologic follow up of low-grade squamous intraepithelial lesions in Pap smears after integrated treatment with antimicrobials followed by oral turmeric oil extract[J].Journal of Ayurveda and Integrative Medicine,2016,7(2):109-112.
[12] Allan Hildesheim,Paula Gonzalez,Aimee R Kreimer,et al.Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment[J].American Journal of Obstetrics and Gynecology,2016,215(2):212.e1-212.e15.
[13] Khemthongcharoen Numfon,Ruangpracha Athisake,Sarapukdee Pongsak,et al.Novel p16 binding peptide development for p16-overexpressing cancer cell detection using phage display[J].Journal of Peptide Science:An official Publication of the European Peptide Society,2015,21(4):265-273.
[14] Suzanne M Selvaggi.The utility of high-risk HPV testing in the management of women 30 to 64 years of age with low-grade squamous intraepithelial lesions on cervical cytology[J].Journal of the American Society of Cytopathology,2015,4(5):290-293.
[15] Ana Laura Cavatorta,Alejandra Di Gregorio,Marina Bugnon Valdano,et al.DLG1 polarity protein expression associates with the disease progress of low-grade cervical intraepithelial lesions[J].Experimental and Molecular Pathology,2017,102(1):65-69.
[16] Karin Sundstr?m,Donghao Lu,K Miriam Elfstr?m,et al.Follow-up of women with cervical cytological abnormalities showing atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion:A nationwide cohort study[J].American Journal of Obstetrics and Gynecology,2017,216(1):48.e1-48.e15.
[17] Prigge Elena-Sophie,Toth Csaba,Dyckhoff Gerhard,et al.p16(INK4a)/Ki-67 co-expression specifically identifies transformed cells in the head and neck region[J].International Journal of Cancer,2015,136(7):1589-1599.
[18] Nader Saki,Hamed Poostchi Bonab,Nastaran Ranjbari,et al.Correlation of KI-67/MIB-1 in the papillary macro and micro-carcinomas of the thyroid gland with the prognosis of the patients[J].Asian Journal of Cell Biology,2015,10(1):13-18.
[19] Su Li,Lin Jing,Zhou Huirong,et al.The expression and significance of KLF4,Ki-67 and E-cadherin in cervical squamous cell carcinoma[J].Journal of Diagnostic Pathology,2016,23(2):110-113.[苏莉,林静,周辉蓉,等.KLF4、Ki-67和E-cadherin在宫颈鳞状细胞癌中的表达及意义[J].诊断病理学杂志,2016,23(2):110-113.]
[20] Wei Cong,Liu Yuancheng,Wang Youqiang,et al.Expression of PCNA and Ki-67 in cervical lesions and their correlation with HPV infection [J].China Maternal and Child Health,2015,30(22):3873-3876.[魏聪,刘远程,王友强,等.宫颈病变中PCNA、Ki-67的表达及其与HPV感染的相关性分析[J].中国妇幼保健,2015,30(22):3873-3876.]
[2] Tong Tingting,Ma Jie,Dong Lijie,et al.Expression of P16,P53 protein and HPV E6/E7 mRNA in cervical fluid-based exfoliated cells of patients with cervical squamous cell carcinoma [J].Journal of Zhengzhou University (Medical Edition),2017,52(5):637-640.[童婷婷,马杰,董丽杰,等.宫颈鳞癌患者宫颈液基脱落细胞中P16、P53蛋白及HPV E6/E7 mRNA的表达[J].郑州大学学报(医学版),2017,52(5):637-640.]
[3] Jia Wulin,Ding Ling,Ren Zhiying,et al.The role and interaction of folic acid and p16 protein in cervical carcinogenesis [J].Chinese Journal of Epidemiology,2016,37(12):1647-1652.[贾吴琳,丁玲,任志英,等.叶酸与p16蛋白在宫颈癌变中的作用及其相互效应[J].中华流行病学杂志,2016,37(12):1647-1652.]
[4] Gao Baolian,Qian Ping,Ma Zhenyi,et al.Expression and significance of human papillomavirus L1 protein,P16 and Ki-67 in cervical squamous epithelial lesions [J].China Maternal and Child Health,2015,30(7):1109-1111.[高宝莲,钱萍,马祯一,等.宫颈鳞状上皮病变中人乳头瘤病毒L1蛋白与P16、Ki-67的表达及意义[J].中国妇幼保健,2015,30(7):1109-1111.]
[5] White C,Bakhiet S,Bates M,et al.Triage of LSIL/ASC-US with p16/Ki-67 dual staining and human papillomavirus testing:a 2-year prospective study[J].Cytopathology,2016,27(4):269-276.
[6] Chen Guandi,Fan Geying,You Keli,et al.5-aza-2'-deoxycytidine regulates gene expression in cervical cancer cells [J].Journal of Practical Medicine,2016,32(18):2995-2999.[陈观娣,范格英,游可理,等.5-氮杂-2'-脱氧胞苷对宫颈癌细胞的基因表达调控[J].实用医学杂志,2016,32(18):2995-2999.]
[7] Wang Jiao,Shu Lisha,Chen Shuling,et al.Diagnostic significance of P16 and Ki67 combined with cytological examination in cervical exfoliated cells [J].China Maternal and Child Health,2016,31(10):2176-2179.[王娇,舒丽莎,陈书玲,等.P16、Ki67联合细胞学检查在宫颈脱落细胞中的诊断意义[J].中国妇幼保健,2016,31(10):2176-2179.]
[8] Ding Lili,Niu Haiyan,Yang Cheng,et al.Expression of P16 and Ki-67 in cervical squamous intraepithelial lesions [J].Chongqing Medical Science,2018,47(7):969-971.[丁莉利,牛海艳,杨丞,等.P16和Ki-67在宫颈鳞状上皮内病变中的表达[J].重庆医学,2018,47(7):969-971.]
[9] He Fangfang,Gao Ying,Wei Li,et al.The significance of p16 and Ki-67 in the grading diagnosis of cervical squamous epithelial lesions [J].Modern Oncology,2016,24(8):1271-1274.[赫芳芳,高英,魏力,等.p16、Ki-67在宫颈鳞状上皮病变分级诊断中的意义[J].现代肿瘤医学,2016,24(8):1271-1274.]
[10] Zhang Tao,Mao Shihua,Tang Liangxi,et al.Expression of P16,HPVL-1 chitin in cervical intraepithelial neoplasia and early cervical cancer tissues and its correlation with HR-HPV load [J].Journal of Practical Obstetrics and Gynecology,2016,32(7):536-539.[张涛,毛世华,唐良萏,等.宫颈上皮内瘤变及早期宫颈癌组织中P16、HPVL-1壳蛋白的表达及与HR-HPV载量相关性研究[J].实用妇产科杂志,2016,32(7):536-539.]
[11] Jayashree Vinay Joshi,Sujata S Jagtap,Prajakta Hemant Paradkar,et al.Cytologic follow up of low-grade squamous intraepithelial lesions in Pap smears after integrated treatment with antimicrobials followed by oral turmeric oil extract[J].Journal of Ayurveda and Integrative Medicine,2016,7(2):109-112.
[12] Allan Hildesheim,Paula Gonzalez,Aimee R Kreimer,et al.Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment[J].American Journal of Obstetrics and Gynecology,2016,215(2):212.e1-212.e15.
[13] Khemthongcharoen Numfon,Ruangpracha Athisake,Sarapukdee Pongsak,et al.Novel p16 binding peptide development for p16-overexpressing cancer cell detection using phage display[J].Journal of Peptide Science:An official Publication of the European Peptide Society,2015,21(4):265-273.
[14] Suzanne M Selvaggi.The utility of high-risk HPV testing in the management of women 30 to 64 years of age with low-grade squamous intraepithelial lesions on cervical cytology[J].Journal of the American Society of Cytopathology,2015,4(5):290-293.
[15] Ana Laura Cavatorta,Alejandra Di Gregorio,Marina Bugnon Valdano,et al.DLG1 polarity protein expression associates with the disease progress of low-grade cervical intraepithelial lesions[J].Experimental and Molecular Pathology,2017,102(1):65-69.
[16] Karin Sundstr?m,Donghao Lu,K Miriam Elfstr?m,et al.Follow-up of women with cervical cytological abnormalities showing atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion:A nationwide cohort study[J].American Journal of Obstetrics and Gynecology,2017,216(1):48.e1-48.e15.
[17] Prigge Elena-Sophie,Toth Csaba,Dyckhoff Gerhard,et al.p16(INK4a)/Ki-67 co-expression specifically identifies transformed cells in the head and neck region[J].International Journal of Cancer,2015,136(7):1589-1599.
[18] Nader Saki,Hamed Poostchi Bonab,Nastaran Ranjbari,et al.Correlation of KI-67/MIB-1 in the papillary macro and micro-carcinomas of the thyroid gland with the prognosis of the patients[J].Asian Journal of Cell Biology,2015,10(1):13-18.
[19] Su Li,Lin Jing,Zhou Huirong,et al.The expression and significance of KLF4,Ki-67 and E-cadherin in cervical squamous cell carcinoma[J].Journal of Diagnostic Pathology,2016,23(2):110-113.[苏莉,林静,周辉蓉,等.KLF4、Ki-67和E-cadherin在宫颈鳞状细胞癌中的表达及意义[J].诊断病理学杂志,2016,23(2):110-113.]
[20] Wei Cong,Liu Yuancheng,Wang Youqiang,et al.Expression of PCNA and Ki-67 in cervical lesions and their correlation with HPV infection [J].China Maternal and Child Health,2015,30(22):3873-3876.[魏聪,刘远程,王友强,等.宫颈病变中PCNA、Ki-67的表达及其与HPV感染的相关性分析[J].中国妇幼保健,2015,30(22):3873-3876.]