P16/Ki-67双染检测技术在宫颈癌及癌前病变筛查中的价值

摘要/Abstract

摘要：

目的探讨P16/Ki-67双染检测技术在宫颈癌及癌前病变筛查中的价值和临床意义。方法选取2018年9月至2019年5月山东省潍坊市人民医院妇科收治的110例宫颈上皮内瘤变(CIN)2级以下的患者、31例CIN2级患者、27例CIN3级患者和12例宫颈癌患者,分别评估人乳头瘤病毒(HPV)DNA、液基细胞学技术(TCT)和P16/Ki-67双染检测作为宫颈癌及癌前病变初筛方法的敏感性、特异性、阳性预测值和阴性预测值,并探讨P16/Ki-67双染检测技术用作高危型HPV阳性患者分流的可行性。结果HPV DNA、TCT和P16/Ki-67双染检测诊断χ²=1.593,P=0.042;χ²=4.736,P=0.034;χ²=4.667,P=0.037;χ²=1.564,P=0.048),P16/Ki-67双染检测的特异性高于HPV DNA及TCT,敏感性及阳性预测值均高于TCT(均P<0.012 5)。3种方法诊断CIN2级的敏感性分别为90.32%、83.87%、96.77%,差异具有统计学意义(χ²=2.952,P=0.029);特异性分别为80.91%、75.45%、81.82%,差异无统计学意义(χ²=2.505,P=0.066);阳性预测值分别为57.10%、49.10%、60.00%,差异无统计学意义(χ²=1.939,P=0.079);阴性预测值分别为96.70%、94.30%、98.90%,差异具有统计学意义(χ²=3.175,P=0.013);P16/Ki-67双染检测的敏感性、阴性预测值均高于TCT(均P<0.012 5)。3种方法诊断CIN3级的敏感性分别为92.59%、96.30%、96.30%,差异无统计学意义(χ²=0.497,P=0.780);特异性分别为80.91%、75.45%、81.82%,差异具有统计学意义(χ²=4.677,P=0.036);阳性预测值分别为54.30%、49.10%、56.50%,差异具有统计学意义(χ²=1.760,P=0.045);阴性预测值分别为97.80%、98.80%、98.90%,差异无统计学意义(χ²=0.441,P=0.802);P16/Ki-67双染检测的特异性、阳性预测值均高于TCT(均P<0.012 5)。3种方法诊断宫颈癌的敏感性分别为91.67%、75.00%、100.00%,差异具有统计学意义(χ²=3.293,P=0.034);特异性分别为80.91%、75.45%、81.82%,阳性预测值分别为34.40%、25.00%、37.50%,阴性预测值分别为98.90%、96.50%、100.00%,差异均无统计学意义(χ²=2.736,P=0.255;χ²=1.834,P=0.400;χ²=3.075,P=0.081);P16/Ki-67双染检测的敏感性高于TCT(P<0.012 5)。针对高危型HPV阳性患者的分流,P16/Ki-67双染检测及TCT诊断的敏感性分别为98.44%、89.06%,特异性分别为85.71%、61.90%,阴性预测值分别为94.70%、65.00%,差异均具有统计学意义(χ²=4.800,P=0.028;χ²=3.079,P=0.039;χ²=5.284,P=0.022);阳性预测值分别为95.50%、87.70%,差异无统计学意义(χ²=2.565,P=0.109)。结论细胞学P16/Ki-67双染检测诊断

关键词:宫颈肿瘤,人乳头状瘤病毒DNA检测,基因,p16,Ki-67抗原

Abstract:

ObjectiveTo explore the value and clinical significance of double staining detection of P16/Ki-67 in the screening of cervical cancer and precancerous lesions.MethodsPatients admitted to Department of Gynecology of Weifang People's Hospital of Shandong Province from September 2018 to May 2019 were selected, including 110 patients with cervical intraepithelial neoplasia (CIN) below grade 2, 31 patients with CIN2, 27 patients with CIN3, and 12 patients with cervical cancer. The sensitivity, specificity, positive predictive value and negative predictive value of human papillomavirus (HPV) DNA, thinprep cytologic test (TCT) and P16/Ki-67 double staining detection as primary screening method for cervical cancer and precancerous lesions were evaluated, and the feasibility of P16/Ki-67 double staining detection as shunt for high-risk HPV positive patients was discussed.ResultsThe sensitivities of HPV DNA, TCT and P16/Ki-67 double staining detection in the diagnosis of χ²=1.593,P=0.042;χ²=4.736,P=0.034;χ²=4.667,P=0.037;χ²=1.564,P=0.048). The specificity of P16/Ki-67 double staining detection was higher than that of HPV DNA and TCT, and the sensitivity and positive predictive value were higher than those of TCT (allP<0.012 5). The sensitivities of HPV DNA, TCT and P16/Ki-67 double staining detection in the diagnosis of CIN2 grade were 90.32%, 83.87%, 96.77%, with a statistically significant difference (χ²=2.952,P=0.029); the specificities were 80.91%, 75.45%, 81.82%, with no significant difference (χ²=2.505,P=0.066); the positive predictive values were 57.10%, 49.10%, 60.00%, with no significant difference (χ²=1.939,P=0.079); and the negative predictive values were 96.70%, 94.30%, 98.90%, with a statistically significant difference (χ²=3.175,P=0.013). The sensitivity and negative predictive value of P16/Ki-67 double staining detection were higher than those of TCT (bothP<0.012 5). The sensitivities of HPV DNA, TCT and P16/Ki-67 double staining detection in the diagnosis of CIN3 grade were 92.59%, 96.30%, 96.30%, with no significant difference (χ²=0.497,P=0.780); the specificities were 80.91%, 75.45%, 81.82%, with a statistically significant difference (χ²=4.677,P=0.036); the positive predictive values were 54.30%, 49.10%, 56.50%, with a statistically significant difference (χ²=1.760,P=0.045); and the negative predictive values were 97.80%, 98.80%, 98.90%, with no significant difference (χ²=0.441,P=0.802). The specificity and positive predictive value of P16/Ki-67 double staining detection were higher than those of TCT (bothP<0.012 5). The sensitivities of HPV DNA, TCT and P16/Ki-67 double staining detection in the diagnosis of cervical cancer were 91.67%, 75.00%, 100.00%, with a statistically significant difference (χ²=3.293, P=0.034); the specificities were 80.91%, 75.45%, 81.82%, the positive predictive values were 34.40%, 25.00%, 37.50%, and the negative predictive values were 98.90%, 96.50%, 100.00% respectively, with no significant differences (χ²=2.736,P=0.255;χ²=1.834,P=0.400;χ²=3.075,P=0.081). The sensitivity of P16/Ki-67 double staining detection was higher than that of TCT (P<0.012 5). For the shunt of high-risk HPV positive patients, the sensitivities of P16/Ki-67 double stain detection and TCT were 98.44% and 89.06%, the specificities were 85.71% and 61.90%, and the negative predictive values were 94.70% and 65.00% respectively, with statistically significant differences (χ²=4.800,P=0.028;χ²=3.079,P=0.039;χ²=5.284,P=0.022); the positive predictive values were 95.50% and 87.70%, with no significant difference (χ²=2.565,P=0.109).ConclusionCytology P16/Ki-67 double staining detection is more specific than HPV DNA and TCT in the diagnosis of

Key words:Uterine cervical neoplasms,Human papillomavirus DNA tests,Genes,p16,Ki-67 antigen

宋明泽, 程一鸣, 李刚, 王振明, 李世荣. P16/Ki-67双染检测技术在宫颈癌及癌前病变筛查中的价值[J]. 国际肿瘤学杂志, 2020, 47(11): 675-681.

Song Mingze, Cheng Yiming, Li Gang, Wang Zhenming, Li Shirong. Value of P16/Ki-67 double staining detection in screening cervical cancer and precancerous lesions[J]. Journal of International Oncology, 2020, 47(11): 675-681.

图/表13

图1

组别	HPV DNA			P16/Ki-67
n=110)	89	21	83	27	90	20
CIN2组(n=31)	3	28	5	26	1	30
CIN3组(n=27)	2	25	1	26	1	26
宫颈癌组(n=12)	1	11	3	9	0	12

表1

检测方法	AUC值	敏感性(%)	特异性(%)	阳性预测值(%)	阴性预测值(%)	Kappa值
HPV DNA	0.862	80.91	91.43^a	93.68	75.29	0.696
TCT	0.813	75.45^a	87.14^a	90.22^a	69.32	0.598
P16/Ki-67	0.895	81.82	97.14	97.83	77.27	0.754
χ²值		1.593	4.736	4.667	1.564
P值		0.042	0.034	0.037	0.048

表2

检测方法	AUC值	敏感性(%)	特异性(%)	阳性预测值(%)	阴性预测值(%)	Kappa值
HPV DNA	0.856	90.32^b	80.91	57.10	96.70	0.589
TCT	0.797	83.87^a	75.45	49.10	94.30^a	0.473
P16/Ki-67	0.893	96.77	81.82	60.00	98.90	0.644
χ²值		2.952	2.505	1.939	3.175
P值		0.029	0.066	0.079	0.013

表3

检测方法	AUC值	敏感性(%)	特异性(%)	阳性预测值(%)	阴性预测值(%)	Kappa值
HPV DNA	0.868	92.59	80.91	54.30	97.80	0.581
TCT	0.859	96.30	75.45^a	49.10^a	98.80	0.526
P16/Ki-67	0.891	96.30	81.82	56.50	98.90	0.617
χ²值		0.497	4.677	1.760	0.441
P值		0.780	0.036	0.045	0.802

表4

检测方法	AUC值	敏感性(%)	特异性(%)	阳性预测值(%)	阴性预测值(%)	Kappa值
HPV DNA	0.863	91.67	80.91	34.40	98.90	0.417
TCT	0.752	75.00^a	75.45	25.00	96.50	0.267
P16/Ki-67	0.909	100.00	81.82	37.50	100.00	0.470
χ²值		3.293	2.736	1.834	3.075
P值		0.034	0.255	0.400	0.081

表5

图2

图3

图4

图5

表6

TCT与P16/Ki-67双染单项检测对≥CIN2级及≥CIN3级患者的诊断价值(%)"

诊断指标	≥CIN2级(n=70)		χ²值	P值	≥CIN3级(n=39)		χ²值	P值
诊断指标	TCT	P16/Ki-67	χ²值	P值	TCT	P16/Ki-67	χ²值	P值
敏感性	87.14	97.14	4.834	0.028	89.74	97.44	0.855	0.355
特异性	75.45	81.82	1.326	0.250	62.41	64.54	2.811	0.094
阳性预测值	69.32	77.27	1.422	0.233	39.77	43.18	1.906	0.167
阴性预测值	90.22	97.83	4.738	0.031	95.65	98.91	0.964	0.326
假阴性率	12.86	2.86	4.834	0.028	10.26	2.56	0.855	0.355
假阳性率	24.55	18.18	1.326	0.250	37.59	35.46	2.811	0.094

表6

检测方法	AUC值	敏感性 (%)	特异性 (%)	阳性预测值 (%)	阴性预测值 (%)
TCT	0.755	89.06	61.90	87.70	65.00
P16/Ki-67	0.921	98.44	85.71	95.50	94.70
χ²值		4.800	3.079	2.565	5.284
P值		0.028	0.039	0.109	0.022

表7

图6

参考文献19

[1]	王麟华, 吴玉梅, 于新平. DNA损伤修复在宫颈癌放疗敏感性中的研究进展[J]. 解放军预防医学杂志, 2019,37(8):193-194.
[2]	周焕娣, 黄小军, 夏燕卿, 等. 探讨P16/Ki67蛋白检测在宫颈上皮内瘤变诊断中的应用[J]. 中国实用医药, 2018,13(12):16-17. DOI: 10.14163/j.cnki.11-5547/r.2018.12.007.
[3]	颜丽, 周德平, 杨君. 人乳头瘤病毒L1壳蛋白在宫颈脱落细胞中的表达及其临床意义[J]. 重庆医科大学学报, 2016,41(10):1064-1068. DOI: 10.13406/j.cnki.cyxb.001031.
[4]	李博涵, 谭桂春. 高危型人乳头瘤病毒阳性患者宫颈病变风险预测方法及进展[J]. 国际妇产科学杂志, 2019,46(1):98-103. DOI: 10.3969/j.issn.1674-1870.2019.01.025.
[5]	王琳倩, 余辉, 高亮, 等. 液基细胞学联合DNA定量细胞学在筛查宫颈病变中的应用价值[J]. 中国优生与遗传杂志, 2014,22(5):14-17, 80.
[6]	叶延青. HPV检测在宫颈未明确诊断意义的不典型鳞状上皮细胞中临床意义[J]. 中国实用医药, 2010,5(19):61-62. DOI: 10.3969/j.issn.1673-7555.2010.19.038.
[7]	Liu G, Sharma M, Tan N, et al. HIV-positive women have higher risk of human papilloma virus infection, precancerous lesions, and cervical cancer[J]. AIDS, 2018,32(6):795-808. DOI: 10.1097/QAD.0000000000001765. doi:10.1097/QAD.0000000000001765pmid:29369827
[8]	Arbyn M, Ronco G, Anttila A, et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer[J]. Vaccine, 2012,30 Suppl 5: F88-F99. DOI: 10.1016/j.vaccine.2012.06.095. doi:10.1016/j.vaccine.2012.06.095
[9]	Stanczuk GA, Baxter GJ, Currie H, et al. Defining optimal triage strategies for hrHPV screen-positive women-an evaluation of HPV 16/18 genotyping, cytology, and p16/Ki-67 cytoimmunochemistry[J]. Cancer Epidemiol Biomarkers Prev, 2017,26(11):1629-1635. DOI: 10.1158/1055-9965.EPI-17-0534. doi:10.1158/1055-9965.EPI-17-0534pmid:28887297
[10]	Wentzensen N, Schiffman M, Palmer T, et al. Triage of HPV positive women in cervical cancer screening[J]. J Clin Virol, 2016,76 Suppl 1: S49-S55. DOI: 10.1016/j.jcv.2015.11.015. doi:10.1016/j.jcv.2015.11.015
[11]	Rijkaart DC, Berkhof J, van Kemenade FJ, et al. Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening[J]. Int J Cancer, 2012,130(3):602-610. DOI: 10.1002/ijc.26056. doi:10.1002/ijc.26056pmid:21400507
[12]	Wentzensen N, von Knebel Doeberitz M. Biomarkers in cervical cancer screening[J]. Dis Markers, 2007,23(4):315-30. DOI: 10.1155/2007/678793. doi:10.1155/2007/678793pmid:17627065
[13]	da Costa LBE, Triglia RM, Andrade L. p16INK4a, cytokeratin 7, and Ki-67 as potential markers for low-grade cervical intraepithelial neoplasia progression[J]. J Low Genit Tract Dis, 2017,21(3):171-176. DOI: 10.1097/LGT.0000000000000310. doi:10.1097/LGT.0000000000000310pmid:28403025
[14]	Ciavattini A, Sopracordevole F, Di Giuseppe J, et al. Cervical intraepithelial neoplasia in pregnancy: interference of pregnancy status with p16 and Ki-67 protein expression[J]. Oncol Lett, 2017,13(1):301-306. DOI: 10.3892/ol.2016.5441. doi:10.3892/ol.2016.5441pmid:28123559
[15]	Uijterwaal MH, Polman NJ, Witte BI, et al. Triaging HPV-positive women with normal cytology by p16/Ki-67 dual-stained cytology testing: baseline and longitudinal data[J]. Int J Cancer, 2015,136(10):2361-2368. DOI: 10.1002/ijc.29290. doi:10.1002/ijc.29290pmid:25345358
[16]	梁江红, 罗蕊丽. p16/Ki67细胞学双染检测对宫颈癌筛查患者的分流管理现状[J]. 湖北医药学院学报, 2016,35(2):228-230. DOI: 10.13819/j.issn.1006-9674.2016.02.029.
[17]	Celewicz A, Celewicz M, Wezowska M, et al. Clinical efficacy of p16/Ki-67 dual-stained cervical cytology in secondary prevention of cervical cancer [J]. Pol J Pathol, 2018,69(1):42-47. DOI: 10.5114/pjp.2018.75335. doi:10.5114/pjp.2018.75335pmid:29895125
[18]	Zhang R, Ge X, You K, et al. p16/Ki67 dual staining improves the detection specificity of high-grade cervical lesions[J]. J Obstet Gynaecol Res, 2018,44(11):2077-2084. DOI: 10.1111/jog.13760. doi:10.1111/jog.13760pmid:30094887
[19]	Areán-Cuns C, Mercado-Gutiérrez M, Paniello-Alastruey I, et al. Dual staining for p16/Ki67 is a more specific test than cytology for triage of HPV-positive women[J]. Virchows Arch, 2018,473(5):599-606. DOI: 10.1007/s00428-018-2432-z. doi:10.1007/s00428-018-2432-zpmid:30094492