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近年来,宫颈癌的发病率和死亡率仍呈上升趋势,且发病年龄呈年轻化趋势[1]。为了尽早发现癌前病变,降低宫颈癌的发病率,有必要找出宫颈癌早期诊断的生物标志物。理想的筛查方法应该识别更多的癌前病变,并尽可能减少阴道镜的转诊率。目前宫颈癌筛查方法主要有细胞学检测、人乳头瘤病毒(HPV)检测及两者联合检测,但细胞学检测缺乏敏感性,且易受阅片医师的主观影响;HPV检测缺乏特异性,不能甄别“持续性”高危型HPV(HR-HPV)感染这一宫颈癌发生的必要因素,较高的阳性率可能导致不必要的转诊和治疗。p16INK4a蛋白作为诱导细胞周期阻滞的一种细胞周期调节蛋白,被认为是HR-HPV持续感染的一个生物标志物,能够预测宫颈高级别上皮内病变的存在[2]。本研究以医院门诊人群为基础,同时行液基薄层细胞学(TCT)、HPV及p16检测,比较并探讨p16、HPV、TCT单独及联合检测对宫颈高级别上皮内瘤变和宫颈癌的诊断价值。
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790例受检者中,HR-HPV阳性率为25.6%(202/790),TCT阳性率为16.3%(129/790),p16阳性率为14.6%(115/790),任一筛查阳性者共270例,三者均阴性但有明显临床症状者17例(均行阴道镜活检,其中16例病理诊断为慢性炎,1例为LSIL),共召回210例女性行阴道镜活检,组织病理诊断为慢性炎131例、LSIL 41例、HSIL30例及宫颈癌8例。在HSIL及以上病变中,HPV阳性34例(89.5%),TCT阳性29例(76.3%),p16阳性33例(86.8%)。其中HPV16/18阳性率(67.6%,23/34)与非HPV16/18阳性率(32.4%,11/34)比较,差异有统计学意义(χ2= 8.47,P < 0.05);在非HPV16/18阳性HSIL及以上病变中,HPV33(54.5%,6/11)和HPV52(36.4%,4/11)较多(见表 1)。
病理类型 HPV TCT p16 HPV16/18
阳性非HPV16/18
阳性阳性 阴性 阳性 阴性 阳性 阴性 慢性炎症 96(73.3) 35(26.7) 55(42.0) 76(58.0) 40(30.5) 91(69.5) 38(39.6) 58(60.4) LSIL 37(90.2) 4(9.8) 25(61.0) 16(39.0) 15(36.6) 26(63.4) 18(48.6) 19(51.4) HSIL 27(90.0) 3(10.0) 22(73.3) 8(26.7) 25(83.3) 5(16.7) 18(66.7) 9(33.3) 宫颈癌 7(87.5) 1(12.5) 7(87.5) 1(12.5) 8(100.0) 0(0.0) 5(71.4) 2(28.6) χ趋势2 6.11 15.86 34.57 7.70 P < 0.05 < 0.01 < 0.01 < 0.01 表 1 不同级别宫颈上皮内病变各指标阳性率比较[n;百分率(%)]
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随着宫颈病变程度的加重,HPV、TCT和p16阳性率呈趋势性增加(P < 0.05~P < 0.01)(见表 1)。通过配对样本McNemar检验可知,在宫颈慢性炎及LSIL中,p16阳性率分别低于HPV阳性率和TCT阳性率,差异均有统计学意义(P < 0.05)。在HSIL及以上病变中,三者阳性率差异均无统计学意义(P>0.05)。
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790例筛查女性中,去除筛查阳性但未行阴道镜检查者77例,最终纳入713例受检者进行宫颈癌筛查效能的比较。p16、HPV、TCT检测诊断HSIL及以上的灵敏度分别为86.8%、89.5%和76.3%,特异度分别为91.9%、80.3%和88.1%。p16+TCT、HPV+TCT、p16+HPV检测的灵敏度分别为92.1%、94.7%和97.4%,特异度分别为85.6%、77.5%和78.8%(见表 2)。
筛查方法 病理 灵敏度/% 特异度/% PPV/% NPV/% 准确率/% 假阳性率/% 约登指数 阳性 阴性 p16 阳性 33 55 86.8 91.9 37.5 99.2 91.6 8.1 0.79 阴性 5 620 TCT 阳性 29 80 76.3 88.1 26.6 98.5 87.5 11.9 0.65 阴性 9 595 HPV 阳性 34 133 89.5 80.3 20.4 99.3 80.8 19.7 0.70 阴性 4 452 p16+TCT 阳性 35 97 92.1 85.6 26.5 99.5 86.0 14.4 0.78 阴性 3 578 阳性 36 152 94.7 77.5 19.2 99.6 78.4 22.5 0.72 阴性 2 523 p16+HPV 阳性 37 143 97.4 78.8 20.6 99.8 79.8 21.2 0.76 阴性 1 532 表 2 以HSIL及以上为终点时,p16、HPV、TCT单独筛查以及两两联合筛查的临床效果评价
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HPV、TCT、p16单独及联合诊断宫颈HSIL及以上病变的ROC曲线见图 3。由ROC曲线分析可知,HPV、TCT、p16、HPV+TCT、p16+HPV、p16+TCT诊断宫颈病变的曲线下面积分别为0.849、0.822、0.893、0.861、0.881、0.889,各指标对宫颈病变的诊断价值均有统计学意义(P < 0.01)(见表 3)。
指标 AUC SE P 95%CI HPV 0.849 0.030 < 0.01 0.789~0.908 TCT 0.822 0.041 < 0.01 0.742~0.902 p16 0.893 0.032 < 0.01 0.830~0.957 HPV+TCT 0.861 0.024 < 0.01 0.813~0.909 p16+HPV 0.881 0.020 < 0.01 0.842~0.920 p16+TCT 0.889 0.027 < 0.01 0.836~0.941 表 3 HPV、TCT、p16单独及联合筛查诊断宫颈HSIL及以上病变的ROC曲线分析
宫颈细胞学p16INK4a蛋白检测联合细胞学检测在宫颈癌筛查中的价值
Value of cervical cytological p16INK4a protein detection combined with cytological test in screening cervical cancer
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摘要:
目的探讨宫颈细胞学p16INK4a蛋白联合细胞学检测在宫颈癌筛查中对宫颈癌前病变和宫颈癌的诊断价值。 方法选取790例20~70岁自愿行宫颈癌筛查的女性,同时行高危型人乳头瘤病毒(HR-HPV)、液基薄层细胞学检查(TCT)以及细胞学p16INK4a蛋白检测。任一检测结果阳性以及检测均阴性但有明显临床症状高度怀疑宫颈病变者转诊阴道镜及活检,比较HPV、TCT及p16单独和两两联合筛查识别宫颈癌前病变及宫颈癌的检测效果。 结果所有筛查对象中,p16、TCT为不典型鳞状细胞以上(TCT≥ASCUS)和HR-HPV阳性率分别为14.6%、16.3%和25.6%。p16、HPV、TCT阳性率均随宫颈病变程度的加重呈趋势性增加(P < 0.05~P < 0.01)。p16+TCT、HPV+TCT、p16+HPV检测的灵敏度分别为92.1%、94.7%和97.4%,特异度分别为85.6%、77.5%和78.8%。HPV、TCT、p16、HPV+TCT、p16+HPV、p16+TCT诊断宫颈病变的曲线下面积分别为0.849、0.822、0.893、0.861、0.881、0.889,各指标对宫颈病变的诊断价值均有统计学意义(P < 0.01)。 结论与HPV联合TCT检测相比,p16联合TCT检测对宫颈高级别病变及宫颈癌的筛查效果具有相似的敏感性和更高的特异性,可作为一种新型宫颈癌初筛方法。 Abstract:ObjectiveTo explore the value of cervical cytological p16INK4a protein assay combined with cytological assay in screening precancerous lesions of uterine cervix and cervical cancer. MethodsA total of 790 women aged 20 to 70 who volunteered to undergo cervical cancer screening were selected, and the high-risk human papillomavirus(HR-HPV), thinprep cytologic test(TCT) and p16INK4a cytology detection in the subjects were implemented.The colposcopy and biopsy in patients with any positive test result or all negative test results complicated with obvious clinical symptoms with high suspicion of cervical lesions were examined.The detection effects of HPV, TCT and p16 alone, and combined screening for cervical precancerous lesions and cervical cancer were compared. ResultsAmong all screening subjects, the positive rates of p16, TCT diagnosed as ASCUS or higher grade and HR-HPV were 14.6%, 16.3% and 25.6%, respectively.The positive rates of p16, HPV and TCT gradually increased with the increasing of cervical lesions severity(P < 0.05 to P < 0.01).The sensitivities of p16+TCT, HPV+TCT and p16+HPV detection were 92.1%, 94.7% and 97.4%, respectively.The specificities of p16+TCT, HPV+TCT and p16+HPV detection were 85.6%, 77.5% and 78.8%, respectively.The area under the curve of HPV, TCT, p16, HPV+TCT, p16+HPV, and p16+TCT in the diagnosis of cervical lesions were 0.849, 0.822, 0.893, 0.861, 0.881, 0.889, respectively.The differences of the diagnostic value among each index to cervical lesions were statistically significant(P < 0.01). ConclusionsCompared with the results of HPV plus TCT, the p16 plus TCT has similar sensitivity and higher specificity for screening cervical precancerous lesions and cervical cance, and can be used as a new screening method for cervical cancer. -
表 1 不同级别宫颈上皮内病变各指标阳性率比较[n;百分率(%)]
病理类型 HPV TCT p16 HPV16/18
阳性非HPV16/18
阳性阳性 阴性 阳性 阴性 阳性 阴性 慢性炎症 96(73.3) 35(26.7) 55(42.0) 76(58.0) 40(30.5) 91(69.5) 38(39.6) 58(60.4) LSIL 37(90.2) 4(9.8) 25(61.0) 16(39.0) 15(36.6) 26(63.4) 18(48.6) 19(51.4) HSIL 27(90.0) 3(10.0) 22(73.3) 8(26.7) 25(83.3) 5(16.7) 18(66.7) 9(33.3) 宫颈癌 7(87.5) 1(12.5) 7(87.5) 1(12.5) 8(100.0) 0(0.0) 5(71.4) 2(28.6) χ趋势2 6.11 15.86 34.57 7.70 P < 0.05 < 0.01 < 0.01 < 0.01 表 2 以HSIL及以上为终点时,p16、HPV、TCT单独筛查以及两两联合筛查的临床效果评价
筛查方法 病理 灵敏度/% 特异度/% PPV/% NPV/% 准确率/% 假阳性率/% 约登指数 阳性 阴性 p16 阳性 33 55 86.8 91.9 37.5 99.2 91.6 8.1 0.79 阴性 5 620 TCT 阳性 29 80 76.3 88.1 26.6 98.5 87.5 11.9 0.65 阴性 9 595 HPV 阳性 34 133 89.5 80.3 20.4 99.3 80.8 19.7 0.70 阴性 4 452 p16+TCT 阳性 35 97 92.1 85.6 26.5 99.5 86.0 14.4 0.78 阴性 3 578 阳性 36 152 94.7 77.5 19.2 99.6 78.4 22.5 0.72 阴性 2 523 p16+HPV 阳性 37 143 97.4 78.8 20.6 99.8 79.8 21.2 0.76 阴性 1 532 表 3 HPV、TCT、p16单独及联合筛查诊断宫颈HSIL及以上病变的ROC曲线分析
指标 AUC SE P 95%CI HPV 0.849 0.030 < 0.01 0.789~0.908 TCT 0.822 0.041 < 0.01 0.742~0.902 p16 0.893 0.032 < 0.01 0.830~0.957 HPV+TCT 0.861 0.024 < 0.01 0.813~0.909 p16+HPV 0.881 0.020 < 0.01 0.842~0.920 p16+TCT 0.889 0.027 < 0.01 0.836~0.941 -
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