卵巢癌肿瘤标志物的研究进展

卵巢癌(ovarian cancer，OC)是我国女性病死率最高的妇科肿瘤，而大部分卵巢癌患者在发病中晚期才能得到诊断，因此早期诊断卵巢癌对于疾病的治疗具有极其重要的价值。目前最常用早期诊断方式包括经阴道彩色多普勒超声、血清癌抗原125（cancer antigen，CA125）等检查方法，然而以上方法都尚存在局限性。近年来，许多研究者致力于寻找高敏感性、高特异性的肿瘤标志物，如:人附睾上皮分泌蛋白4（human epididymis，HE4）、共刺激分子B7同源体4（B7 homologous body 4，B7-H4）、人溶血磷脂酸（lysophosphatidic acid，LPA）等，以提高卵巢癌诊断率。本文就卵巢癌相关的肿瘤标志物作一综述。     

HE4在卵巢癌诊治中的临床应用评价

背景与目的:人附睾上皮分泌蛋白4(human epididymis protein,HE4)是近年来研究较热门的一种新型肿瘤标志物,并拟在中国临床上推广应用,但目前国内HE4在卵巢癌应用研究中报道的例数还很少,特别是在随访监测中的价值尚待探究.本研究扩大了样本量,进一步探讨HE4在中国人群上皮性卵巢癌(epithelial ovarian cancer,EOC)的早期诊断、疗效监测以及预后判断中的应用价值.方法:应用酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)法检测116例EOC患者、40例卵巢良性疾病患者、61例其他肿瘤患者及100名健康对照者血清的HE4浓度水平,同时对其中28例EOC患者进行随访测定HE4水平.结果:未绝经组和绝经组中,EOC患者血清的HE4水平均明显高于健康对照和卵巢良性疾病患者(chi-square值分别为32.2和64.4,P均<0.01);根据健康对照组的P95(percent 95)值,未绝经者HE4检测卵巢癌的Cut-off值为58.2 pmol/L,敏感度为57.5%,特异度为93.9%;绝经者HE4检测卵巢癌的Cut-off值为67.6 pmol/L,敏感度为80.3%,特异度为86.4%.卵巢癌患者血清HE4水平随着肿瘤分级、分期的升高而升高,淋巴结转移患者HE4水平显著高于未转移者(U值为665.5,P均<0.01).此外,随访检测了28例EOC患者的血清样本,HE4浓度的变化能很好地反映疾病发展趋势(chi-square值为26.6,P<0.01);结果分析表明,HE4浓度变化与病情发展间的符合率为82.2%(23/28).手术治疗后,病情好转者,HE4水平有所下降(21/25).结论:HE4检测在EOC诊断和疗效监测、预后判断等方面具有较好的应用价值.     

肿瘤标志物在卵巢癌诊断中的研究进展

肿瘤标志物检测是早期卵巢癌诊断常用的手段,传统肿瘤标志物如血清糖类抗原125(carbohydrate antigen125,CA125)、人类附睾蛋白4(human epididymis protein,HE4)等单一检测或联合检测均在卵巢癌诊断中发挥了重要作用,但是也存在一定局限性.近年来,液体活检技术的不断发展为...     

上皮性卵巢癌生物学标志物的研究进展

卵巢癌是女性生殖系统中死亡率最高的肿瘤,早发现、早诊断和早治疗是提高卵巢癌患者存活率和生存质量的重要且有效途径.除目前应用于临床的CA125之外,人附睾蛋白4（HE4）、配对盒基因8抗原（paired boxgene 8,PAX8）等生物学标志物有希望成为卵巢癌诊断和鉴别诊断的辅助或补充手段,以提高卵巢癌的早期检出率和诊断准确性.     

血清肿瘤标志物人附睾蛋白4在卵巢癌诊断中的研究进展

卵巢癌发病隐匿,且缺少有效的早期诊断方法, 是世界性的健康难题.目前,卵巢癌早期诊断的血清标志物最常用的是糖类抗原125(carbohydrate antigen 125,CA125),但其对卵巢癌的诊断并不特异,有时还会导致不必要的手术.因此,迫切需要寻找一种敏感度和特异度均较高的标志物来提高卵巢癌的诊断水平.新型肿瘤标志物人附睾蛋白4(human epididymis protein 4,HE 4)被认为是一个对卵巢癌早期诊断和卵巢良、恶性肿瘤鉴别诊断具有重要价值的血清标志物.本文就HE4在卵巢恶性肿瘤中的诊断和评估等方面的研究进展进行综述.     

肿瘤标志物在卵巢癌早期诊断中的应用进展

卵巢癌（ovarian carcinoma）是女性生殖道常见的恶性肿瘤之一,尽管其发病率在女性生殖系统肿瘤中居第3位,死亡率却居第1位[1]。不同期别卵巢癌预后差异很大,早期卵巢癌患者通过手术和化疗其5年生存率可在90%以上,但目前能在早期获得诊断的患者不足25%。因此,早期诊断对提高卵巢癌患者生存率尤为重要。CA125是目前公认的卵巢癌术前诊断、疗效观察、术后复发和预后评估最具价值的观测指标,但CA125的合成受许多因素影响,如子宫内膜异位症,盆腔炎症等均可见CA125不同程度地升高,有研究发现40%～50%的Ⅰ～Ⅱ期卵巢癌患者的血清CA125检测值并不升高[2],     

新型肿瘤标志物HE4检测早期诊断卵巢癌

(2012年5月18日无锡新闻发布会讯)近日,罗氏诊断产品(上海)有限公司宣布,用于卵巢癌诊断的E1ecsys HE4定量检测已于今年2月正式在中国获批上市。人附睾蛋白4(HE4)是一种新的肿瘤标志物,有助于卵巢癌的早期诊断、鉴别诊断、治疗监测和预后评估。上海交通大学医学院附属仁济医院副院长、妇产科主任、上海交通大学医学院妇产科学系主任、上海市妇科肿瘤重点实验     

新型肿瘤标志物HE4检测早期诊断卵巢癌

(2012年5月18日无锡新闻发布会讯)近日,罗氏诊断产品(上海)有限公司宣布,用于卵巢癌诊断的Elecsys HE4定量检测已于今年2月正式在中国获批上市。人附睾蛋白4(HE4)是一种新的肿瘤标志物,有助于卵巢癌的早期诊断、鉴别诊断、治疗监测和预后评估。上海文通大学医学院附属仁济医院副院长、妇产科主任、上海交通大学医学院妇产科学系主任、上海市妇科肿瘤重点实验室主任狄文教授认为:"Elecsys HE4定量检测的上市,对于卵巢癌的管理具有非常重要的临床意义。HE4与CA125联合检测,不但能为临床诊断卵巢癌提供更准确的检测结果,还能帮助临床医生更好地判断盆腔肿块良性或恶性,早期卵巢癌患者的存活率     

新型肿瘤标志物HE4检测早期诊断卵巢癌

(2012年5月18日无锡新闻发布会讯)近日,罗氏诊断产品(上海)有限公司宣布,用于卵巢癌诊断的Elecsys。HE4定量检测已于今年2月正式在中国获批上市。人附睾蛋白4(HE4)是一种新的肿瘤标志物,有助于卵巢癌的早期诊断、鉴别诊断、治疗监测和预后评估。上海交通大学医学院附属仁济医院副院长、妇产科主任、上海交通大学医学院妇产科学系主任、上海市妇科肿瘤重点实验室主任狄文教授认为:"Elecsys HE4定量检测的上市,对于卵巢癌的管理具有非常重要的临床意义。HE4与CA125联合检测,不     

血清肿瘤标志物诊断早期卵巢癌的相关研究进展

卵巢癌是女性生殖道常见的恶性肿瘤之一。近年来,卵巢癌的诊疗技术得到了明显的提高,但卵巢癌的5年生存率未见明显改善。究其原因,主要与卵巢癌难以在早期发现有关。因此,寻找有效的卵巢癌早期检测手段,尤其是血清肿瘤标志物,对改善卵巢癌预后具有重要的意义。早期卵巢癌血清肿瘤标志物的研究一直是卵巢癌研究的热点之一,并取得了一定进展。     

HE4 联合 CA125 在卵巢癌早期诊断中的应用价值

目的：探讨人附睾蛋白4（HE4）联合癌抗原125（CA125）在卵巢癌早期诊断中的应用价值.方法：应用电化学发光法及酶联免疫法,测定20例卵巢癌患者、20例良性肿瘤患者（子宫肌瘤和卵巢肿瘤）及30例健康妇女血清CA125、HE4水平,比较各组血清CA125、HE4水平,分析两标记物联合在卵巢癌患者检测中的意义.结果：卵巢癌组CA125、HE4水平明显高于健康组及良性肿瘤组,差异有统计学意义（P＜0.05）,晚期卵巢癌组CA125、HE4水平明显高于早期卵巢癌组,差异有统计学意义（P＜0.05）.联合检测HE4及CA125敏感性高于二者中任一标志物,特异性与CA125检测一致,低于HE4检测.结论：HE4联合CA125测定有助于卵巢癌的诊断,可作为很好的卵巢癌标志物,提高早期卵巢癌的诊断率.     

血清人附睾分泌蛋白4(HE4)和CA125在卵巢癌患者围手术期的变化及临床意义

目的:监测卵巢癌手术前后血清人附睾分泌蛋白4 (human epididymis secretory protein 4,HE4)、CA125(即糖类抗原125)的变化,分析HE4和CA125在卵巢癌诊治中的价值.方法:选取180例卵巢癌患者,根据临床分期分为早期组90例和中晚期组90例,选取90例卵巢良性疾病者作为良性组、90例健康成年女性作为对照组,在手术前后分别监测各组血清HE4和CA125表达水平,统计分析不同检测方法的诊断价值,同时随访卵巢癌患者12个月,对卵巢癌复发患者与未复发患者在手术前后的血清HE4和CA125进行统计分析.结果:血清HE4联合CA125特异度(98.89％)、阳性预测价值(99.27％)显著高于HE4单独检测及CA125单独检测,P＜0.05,组间有统计差异;手术后,卵巢癌患者血清HE4、CA125显著下降(P＜0.05),但是,在相同监测点,卵巢癌者血清HE4和CA125显著高于对照组和良性组(P＜0.05),且中晚期组血清HE4显著高于早期组(P＜0.05),良性组血清HE4、CA125略高于对照组,组间无显著差异(P＞0.05);卵巢癌复发者血清HE4、CA125显著高于未复发组者,P＜0.05,有统计学差异.结论:卵巢癌患者血清CA125和HE4显著异常升高,联合检测血清HE4和CA125不仅对于提高卵巢癌诊断特异性、阳性准确率具有重要价值,而且能够为预后评估提供可靠信息.     

Reference ranges for HE4 and CA125 in a large Asian population by automated assays and diagnostic performances for ovarian cancer

Human epididymis protein 4 (HE4) is a new biomarker for the detection of ovarian cancer. We evaluated the analytical performance of a novel automated HE4 assay and established reference ranges of HE4 and CA125. We also compared the diagnostic performance of both biomarkers for ovarian cancer. Precision performances and linearity of the HE4 assay were assessed. Serum samples from 2,182 healthy and 72 pregnant women were also assayed for HE4 and CA125, and the 95%, 97.5% and 99% reference limits for both markers were calculated. Additionally, sera from 66 ovarian cancer and 257 benign gynecologic disease patients were tested to validate reference ranges and diagnostic performances. The total precision of the HE4 assay was <5% coefficient of variation for most of the levels evaluated. The linearity range of this assay was from 15.0 to 1100.0 pmol/L. The 97.5% upper reference limits for HE4 and CA125 were 33.2 pmol/L (95% confidence interval [CI], 32.2-34.0) and 38.3 U/mL (95% CI, 35.1-41.5), respectively. Using these values as cutoff points, the sensitivity and specificity of HE4 for differentiating ovarian cancer from benign gynecologic diseases and healthy individuals were 90.9% and 94.1%, and those of CA125 were 72.7% and 94.4%. The receiver operating characteristic-area under the curve values of HE4 and CA125 for discriminating ovarian cancer from age-matched control were 0.94 and 0.86, respectively, and they were statistically different (p = 0.0095). The new automated HE4 assay showed good analytical and diagnostic performances. The reference limits established in our study could be used as cutoff levels to facilitate more accurate diagnosis of ovarian cancer in Asian population.     

可溶性E-钙粘蛋白、糖类抗原125、人附睾蛋白4联合检测在卵巢癌早期诊断中的临床价值

目的:探讨联合检测sE-CAD、CA125和HE4在卵巢癌早期诊断中的临床应用价值,以改善传统CA125和HE4检测在早期卵巢癌诊断中的不足。方法:检测40例健康体检者、64例卵巢良性肿瘤患者、112例卵巢癌患者（I期:14例,II期:23例,Ⅲ期:41例,IV期:34例）血清中sE-CAD、CA125和HE4的表达水平,结合临床资料,进行相关统计学分析。结果:不同临床分期卵巢癌组、卵巢良性疾病组和健康对照组sE-CAD、CA125和HE4的表达水平比较,差异均有统计学意义（P＜0.05）,卵巢良性疾病组与健康对照组比较,CA125表达水平明显升高,差异具有统计学意义（P＜0.05）,sE-CAD、HE4水平则无显著变化（P＞0.05）。sE-CAD、CA125和HE4联合检测用于早期卵巢癌（I-II期）的诊断时,其灵敏度、特异度、阳性预测值和阴性预测值分别达到90.8%、91.1%、83.4%、93.6%,ROC曲线下面积也升高至0.956 5,95%CI为0.916 9~0.996 1,比各指标单独检测均有所提升。结论:sE-CAD、CA125和HE4联合检测具有较高的灵敏度、特异度和ROC曲线下面积,是诊断早期卵巢癌（I-II期）较为理想的生物标志物组合。     

Evaluation of ovarian cancer biomarkers HE4 and CA-125 in women presenting with a suspicious cystic ovarian mass

Objective

Women presenting with a large or complex ovarian cyst are referred to extensive surgical staging to ensure the correct diagnosis and treatment of a possible epithelial ovarian cancer. We hypothesized that measurement of the biomarkers HE4 and CA-125 preoperatively would improve the assignment of these patients to the correct level of care.

Methods

Patients diagnosed with a cystic ovarian mass and scheduled for an operation at our center of excellence for ovarian cancer surgery from 2001 to 2010 were prospectively included (n=394) and plasma was collected consecutively. Cut-off for HE4 was calculated at 75% specificity (85 pM and 71.8 pM for post and premenopausal women). For CA-125, 35 U/mL cut-off was used. The study population included women with malignant (n=114), borderline (n=45), and benign (n=215) ovarian tumors.

Results

Receiver operator characteristic (ROC) area under the curve (AUC) in the benign versus malignant cohorts was 86.8% for CA-125 and 84.4% for HE4. Negative predictive value was 91.7% when at least one of the biomarkers was positive, with only early stage epithelial ovarian cancer showing false negative results. Sensitivity at set specificity (75%) was 87% for risk of ovarian malignancy algorithm (ROMA) in the postmenopausal cohort (cut-off point, 26.0%) and 81% in the premenopausal cohort (cut-off point, 17.3%). ROC AUC in the benign versus stage I epithelial ovarian cancer was only 72% for HE4 and 76% for CA-125.

Conclusion

In our study, population HE4 did not outperform CA-125. Based on our data a prospective trial with patients already diagnosed with an ovarian cyst may be conducted.     

The application of HE4 in diagnosis of gynecological pelvic malignant tumor

OBJECTIVE To investigate the value of human epididymis gene product 4 （HE4） in differential diagnosis of gynecological pelvic tumors. METHODS The level of serum HE4 in 132 women was determined. These women were divided into three groups, i.e., 46 women with good health being classified as the normal control （NC） group, and based on clinicopathological results, the other 86 with pelvic masses being classified into groups of benign （n = 56） and malignant lesions （n = 30）, respectively. RESULTS The range of serum HE4 in the NC group was （23.5-46.0） pmol/L, with an average value of （34.1± 5.6） pmol/L; the range of serum HE4 in the benign lesion group was （30.1-58.9） pmol/L, with an average value of （39.1 ± 7.2） pmol/L; the range of serum HE4 in the group of malignancy was （31.2-1430.0） pmol/L, and the average value was （248.7 ± 364.5） pmol/L. The level of HE4 in the malignant lesion group was significantly higher than that in the other 2 groups, with a statistical difference, P 〈 0.001. The diagnostic index reached maximum （0.847） when the serum HE4 was at 51.6 pmol/L, and the sensitivity and specificity of HE4 were 86.7% and 98.0%, respectively. The area under the receiver- operator characteristic curve （ROC） was 0.935 （95% CI 0.832-1.037, P = 0.000）. The consistency checking Kappa value of HE4 in the diagnosis of pelvic malignant tumors was 0.867, P = 0.000. CONCLUSION The determination of serum HE4 is a good indicator in differential diagnosis of benign and malignant ovarian tumors.     

血清中人附睾蛋白4、抑制素A及癌胚抗原125联合检测在卵巢癌诊断中的意义

目的：探讨人附睾蛋白4（HE4）、抑制素A（inhibinA）及癌胚抗原125（CA125）在卵巢癌患者中的诊断价值。方法：应用ELISA法检测卵巢癌组、卵巢良性肿瘤组及正常对照组患者血清中HE4、InhibinA、CA125水平。结果：血清HE4水平：卵巢癌组（133.86±127.94）pmol/L、卵巢良性肿瘤组（42.67±22.77）pmol/L、正常对照组（33.40±19.50）pmol/L;血清InhibinA水平：卵巢癌组（177.22±114.35）ng/L、卵巢良性肿瘤组（76.60±14.10）ng/L、正常对照组（70.70±21.66）ng/L;血清CA125水平：卵巢癌组（750.52±1230.34）U/L、卵巢良性肿瘤组（67.25±106.16）U/L、正常对照组（17.69±6.13）U/L。统计学分析血清HE4、InhibinA数值显示：卵巢癌组与卵巢良性肿瘤组、正常对照组比较,P〈0.05,差异有统计学意义;而卵巢良性肿瘤组与正常对照组比较,P〉0.05,差异无统计学意义。血清CA125卵巢癌组与卵巢良性肿瘤组、正常对照组比较,P〈0.05,差异有统计学意义;良性肿瘤组与正常对照组比较,P〈0.05,差异有统计学意义。卵巢癌诊断中的阳性率分别是：HE4 71.8%、InhibinA 66.7%、CA125 61.5%,三者联合阳性率为92.3%。结论：HE4、InhibinA、CA125在卵巢癌诊断中有重要意义,三者联合检测能明显提高卵巢癌的诊断率。     

The Application of HE4 in Diagnosis of Gynecological Pelvic Malignant Tumor

OBJECTIVE To investigate the value of human epididymis gene product 4 (HE4) in differential diagnosis of gynecological pelvic tumors.METHODS The level of serum HE4 in 132 women was determined. These women were divided into three groups, i.e.,46 women with good health being classified as the normal control(NC) group, and based on clinicopathological results, the other 86 with pelvic masses being classified into groups of benign (n = 56) and malignant lesions (n = 30), respectively.RESULTS The range of serum HE4 in the NC group was (23.5~46.0) pmol/L, with an average value of (34.1 ± 5.6) pmol/L;the range of serum HE4 in the benign lesion group was (30.1~58.9)pmol/L, with an average value of (39.1 ± 7.2) pmol/L; the range of serum HE4 in the group of malignancy was (31.2-1430.0) pmol/L, and the average value was (248.7 ± 364.5) pmol/L. The level of HE4 in the malignant lesion group was significantly higher than that in the other 2 groups, with a statistical difference, P < 0.001.The diagnostic index reached maximum (0.847) when the serum HE4 was at 51.6 pmol/L, and the sensitivity and specificity of HE4 were 86.7% and 98.0%, respectively. The area under the receiver- operator characteristic curve (ROC) was 0.935 (95% CI 0.832~1.037,P = 0.000). The consistency checking Kappa value of HE4 in the diagnosis of pelvic malignant tumors was 0.867, P = 0.000.CONCLUSION The determination of serum HE4 is a good indicator in differential diagnosis of benign and malignant ovarian tumors.