人附睾蛋白4和细胞角蛋白19片段联合检测在非小细胞肺癌辅助诊断中的意义

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张平, 周洪兴, 白阳, 胡玉静, 孙颖昕, 张红. 人附睾蛋白4和细胞角蛋白19片段联合检测在非小细胞肺癌辅助诊断中的意义. 29(12): 1215-1217
ZHANG Ping, ZHOU Hongxing, BAI Yang, HU Yujing, SUN Yingxin, ZHANG Hong. Significance on the combined detection of human epididymis protein 4 and CYFRA21-1 in the diagnosis of non-small cell lung cancer. Labratory Medicine, 29(12): 1215-1217 复制到剪切板

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人附睾蛋白4和细胞角蛋白19片段联合检测在非小细胞肺癌辅助诊断中的意义

张平¹, 周洪兴¹, 白阳¹, 胡玉静¹, 孙颖昕¹, 张红²

1.南京医科大学附属常州第二人民医院检验科,江苏常州 213003

2.南京中医药大学附属常州中医医院检验科,江苏常州 213003

通讯作者：张红,联系电话：051989896750。

作者简介：张平,男,1972年生,硕士,副主任技师,主要从事临床检验诊断学研究。

摘要

目的

探讨人附睾蛋白4(HE4)和细胞角蛋白19片段(CYFRA21-1)联合检测在非小细胞肺癌(NSCLC)辅助诊断中的意义。

方法

采用电化学发光法分别检测50例NSCLC患者、40例肺炎患者和50名健康体检者血清HE4、CYFRA21-1水平,通过受试者工作特征(ROC)曲线评价2项指标联合检测对NSCLC辅助诊断的价值。

结果

肺癌患者整体CYFRA21-1、HE4水平及Ⅰ~Ⅱ期肺癌患者HE4水平显著高于肺炎患者及健康体检者( P<0.05)。Ⅲ~Ⅳ期NSCLC患者HE4及CYFRA21-1水平高于Ⅰ~Ⅱ期NSCLC患者( P<0.05)。经ROC曲线分析,HE4和CYFRA21-1联合检测的敏感性显著高于任一单项检测的敏感性。

结论

血清HE4检测比CYFRA21-1对于NSCLC有更高的早期诊断价值。联合检测HE4和CYFRA21-1对诊断NSCLC有较高的敏感性,适用于临床的肺癌普查。

关键词: 人附睾蛋白4; 细胞角蛋白19片段; 非小细胞肺癌

中图分类号:R446.62 文献标志码:A 文章编号:1673-8640(2014)12-1215-03

Significance on the combined detection of human epididymis protein 4 and CYFRA21-1 in the diagnosis of non-small cell lung cancer

ZHANG Ping¹, ZHOU Hongxing¹, BAI Yang¹, HU Yujing¹, SUN Yingxin¹, ZHANG Hong²

1.Department of Clinical Laboratory, Changzhou Second People's Hospital, Nanjing Medical University, Jiangsu Changzhou 213003, China

2. Department of Clinical Laboratory, Changzhou Traditional Chinese Medicine Hospital, Nanjing Traditional Chinese Medicine University, Jiangsu Changzhou 213003, China

Abstract

Objective

To investigate the significance on the combined detection of human epididymis protein 4 (HE4) and cytokeratin 19 fragment (CYFRA21-1) in the diagnosis of non-small cell lung cancer (NSCLC).

Methods

The levels of serum HE4 and CYFRA21-1 were detected in 50 NSCLC patients, 40 patients with pneumonia and 50 healthy subjects. The diagnosis significance of the combined detection of serum HE4 and CYFRA21-1 for NSCLC was analyzed by receiver operating characteristic (ROC) curve.

Results

The levels of serum CYFRA21-1 and HE4 in all the NSCLC patients and the level of HE4 in patients with Ⅰ-Ⅱ stages of NSCLC were significantly higher than those in pneumonia patients and healthy subjects ( P<0.05). The levels of serum HE4 and CYFRA21-1 in patients with Ⅲ-Ⅳ stages of NSCLC were significantly higher than those in patients with Ⅰ-Ⅱ stages of NSCLC ( P<0.05). The sensitivity of the combined detection was high than that of any single detection.

Conclusions

The detection of serum HE4 has a high significance for the early diagnosis of NSCLC compared with CYFRA21-1 detection. The combined detection of HE4 and CYFRA21-1 for the diagnosis of NSCLC has a high sensitivity, and is suitable for the clinical screening of lung cancer.

Keyword: Human epididymis protein 4; Cytokeratin 19 fragment; Non-small cell lung cancer

Show Figures

肿瘤标志物检测简便且无创, 在肿瘤的筛查、诊断、预后评估等方面应用广泛。目前与肺癌相关的肿瘤标志物如细胞角蛋白19片段(cytokeratin 19 fragment, CYFRA21-1)、神经元特异性烯醇化酶(neuron-specific enolase, NSE)敏感性均不高, 往往在肿瘤负荷较重时才显著增高^{[1, 2]}。人附睾蛋白4(human epididymis protein 4, HE4)属于乳清酸性4-二硫化中心蛋白家族, 国外的研究发现其在卵巢癌中表达阳性率很高, 可用于卵巢癌的辅助诊断^[3]。另一些研究发现HE4在多种正常组织(包括呼吸道)上皮内均有表达, 在肺癌患者的血清及组织中存在HE4高水平表达^{[4, 5, 6]}, 提示HE4可作为一项对肺癌有诊断意义的肿瘤标志物。本研究的目的是将HE4与目前临床开展的CYFRA21-1联合检验, 以期提高对非小细胞肺癌(non-small cell lung cancer, NSCLC)诊断的敏感性。

材料和方法

一、一般资料

选取2013年1至10月在常州第二人民医院门诊或住院被确诊为原发性NSCLC患者50例, 其中男37例, 女13例, 年龄(68.4± 7.8)岁。另选取40例肺炎患者作为良性对照组, 其中男26例, 女14例, 年龄(61.2± 4.2)岁。将同期来常州第二人民医院体检, 血常规、肝肾功能、胸部X光透视均正常者50名设为健康对照组, 其中男31名, 女19名, 年龄(58.4± 9.6)岁。

二、仪器与试剂

HE4、CYFRA21-1用罗氏e602电化学发光检测仪及其配套试剂测定。

三、统计学方法

运用SPSS 13.0软件对数据进行分析, 各组数据进行正态性检验, 正态分布资料采用 $\begin{matrix} \bar{x} \end{matrix}$ ± s表示, 两组间比较采用t检验, 多组间比较采用单因素方差分析, 绘制HE4及CYFRA21-1诊断NSCLC的受试者工作特征(receiver operating characteristic, ROC)曲线, 分别比较其敏感性和特异性, 率的比较采用χ ²检验, 以P< 0.05为差异有统计学意义。

结果

一、NSCLC、肺炎患者及健康体检者血清CYFRA21-1、HE4含量

NSCLC患者血清CYFRA21-1、HE4平均含量均高于肺炎患者及健康体检者(P< 0.05)。Ⅰ ~Ⅱ 期NSCLC患者血清HE4含量高于肺炎患者及健康体检者(P< 0.05), 而Ⅰ ~Ⅱ 期NSCLC患者CYFRA21-1含量与肺炎患者及健康体检者差异无统计学意义, Ⅲ ~Ⅳ 期NSCLC患者血清CYFRA21-1及HE4含量均显著高于Ⅰ ~Ⅱ 期NSCLC患者(P< 0.05), 而不同组织来源的NSCLC患者血清CYFRA21-1及HE4含量在各类型间差异无统计学意义(P> 0.05)。见表1。

表1 NSCLC组、肺炎组和健康对照组血清CYFRA21-1、HE4含量比较(

\begin{matrix} \bar{x} \end{matrix}

± s)

组别	例数	CYFRA21-1 (ng/mL)	HE4 (pmol/L)
NSCLC组	50	8.43± 3.68^{* #}	97.45± 47.61^{* #}
分期
Ⅰ ~Ⅱ 期组	18	4.05± 1.78	71.15± 41.24^{* #}
Ⅲ ~Ⅳ 期组	32	10.41± 6.92^Δ	107.44± 65.73^Δ
组织类型
鳞癌组	32	6.86± 3.71	89.57± 41.21
腺癌组	11	8.51± 6.94	99.79± 52.73
大细胞癌组	6	8.11± 5.54	92.41± 46.58
肺炎组	40	2.35± 1.01	25.64± 18.49
健康对照组	50	1.99± 0.96	21.73± 14.58

注:与健康对照组比较, * P< 0.05; 与肺炎组比较, #P< 0.05; 与Ⅰ ~Ⅱ 期组比较, Δ P< 0.05

表1 NSCLC组、肺炎组和健康对照组血清CYFRA21-1、HE4含量比较(

\begin{matrix} \bar{x} \end{matrix}

± s)

二、血清HE4与CYFRA21-1联合检测对NSCLC的诊断价值

分别绘制CYFRA21-1、HE4对NSCLC的ROC曲线, 见图1。当CYFRA21-1与HE4分别为5.21 ng/mL和84.56 pmol/L时对NSCLC有最大诊断价值, 此时曲线下面积(area under the curve, AUC)分别为0.764和0.820, 而2项指标联合检测的AUC为0.927, 高于前两者。2项指标单独与联合检测对NSCLC诊断的价值见表2。

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	图1 CYFRA21-1和HE4对NSCLC诊断的ROC曲线

表2 血清CYFRA21-1和HE4单独及联合检测对NSCLC的诊断价值

讨论

有研究显示, 约70%的NSCLC患者可见CYFRA21-1升高, 目前认为CYFRA21-1是检测肺鳞癌的首选肿瘤标志物^[7], 肺炎、肺结核、支气管炎、哮喘等肺部良性疾病一般不升高^[8]。同时CYFRA21-1在膀胱癌、头颈部肿瘤、乳腺癌等肿瘤中也存在一定的阳性率^{[9, 10, 11]}。本研究显示其在NSCLC患者中水平显著高于健康体检者及肺炎患者, 且与肿瘤分期相关, 这与文献报道相一致。

HE4是人附睾上皮细胞中克隆出的定位于人类染色体20q12-13、编码一段长13 ku的蛋白^[12], 是近年来发现的新的肿瘤标志物, 其在子宫内膜癌、肺腺癌、乳腺癌等肿瘤组织中均有较高的阳性率^[3]。Iwahori等^[13]对49例肺癌患者血清中HE4含量进行测定, 发现肺癌患者血清HE4含量高于健康对照组, 通过分析, 当设定恰当的临界值时, 90%的NSCLC患者血清HE4浓度升高。本研究显示肺癌患者血清HE4浓度显著高于健康体检者及肺炎患者, 提示其对肺癌有辅助诊断价值, 但其与组织类型无关而与临床分期有关, 早期患者(Ⅰ ~Ⅱ 期)HE4水平较健康体检者和肺炎患者明显升高, 而CYFRA21-1水平仍然与健康体检者与肺炎患者无明显差异, 说明HE4比CYFRA21-1更有早期诊断价值。同时晚期肺癌患者(Ⅲ ~Ⅳ 期)HE4水平高于早期患者(Ⅰ ~Ⅱ 期), 对肺癌患者的分期有意义。

通过ROC曲线分析, HE4对肺癌诊断的敏感性高于CYFRA21-1, 两者联合检测对肺癌诊断的敏感性显著高于任一单独检测, 说明2项指标联合后能有效降低漏诊率。然而虽然联合检测提高了敏感性, 却降低了特异性, 因此在临床应用中更适于肺癌的早期诊断, 尤其是对高危人群的筛查方面有较好的应用前景。同时为了弥补特异性降低的缺陷, 当筛查出阳性后, 应进一步结合临床症状、影像及病理方法作出判断。

近年来的研究发现, HE4除可作为辅助诊断标志物外, 在肺癌患者的预后判断方面也有良好的应用价值。Liu等^[14]发现在血清HE4高水平表达的肺癌患者3年生存率显著低于相应低水平表达患者。Yamashita等^[15]的研究也显示肺腺癌组织HE4的表达阳性率与疾病进展有关, 并可作为一项独立危险因子用于肺腺癌患者的预后判断。鉴于此, 本研究小组后续除了进一步完善HE4对肺癌的辅助诊断价值研究外, 还将逐步开展此指标对肺癌患者疗效监测、预后判断等方面的研究。

The authors have declared that no competing interests exist.

参考文献

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2008

0.0

... 目前与肺癌相关的肿瘤标志物如细胞角蛋白19片段(cytokeratin 19 fragment, CYFRA21-1)、神经元特异性烯醇化酶(neuron-specific enolase, NSE)敏感性均不高,往往在肿瘤负荷较重时才显著增高^[1,2] ...

2009

0.0

2012

0.0

... 人附睾蛋白4(human epididymis protein 4,HE4)属于乳清酸性4-二硫化中心蛋白家族,国外的研究发现其在卵巢癌中表达阳性率很高,可用于卵巢癌的辅助诊断^[3] ...

... HE4是人附睾上皮细胞中克隆出的定位于人类染色体20q12-13、编码一段长13 ku的蛋白^[12],是近年来发现的新的肿瘤标志物,其在子宫内膜癌、肺腺癌、乳腺癌等肿瘤组织中均有较高的阳性率^[3] ...

2014

0.0

... 另一些研究发现HE4在多种正常组织(包括呼吸道)上皮内均有表达,在肺癌患者的血清及组织中存在HE4高水平表达^[4,5,6],提示HE4可作为一项对肺癌有诊断意义的肿瘤标志物 ...

2012

3.009

0.0

2012

0.0

. 2012, 33(6):2365-2370 DOI:10.1007/s13277-012-0499-8

Serum level of HE4 is closely associated with pulmonary adenocarcinoma progression

1. Department of General Thoracic, Breast and Pediatric Surgery, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonanku, Fukuoka, 814-0180, Japan 3. Department of Surgery II, Faculty of Medicine, Oita University, Oita, Japan 2. Department of Histology and Cell Biology, Advanced Medical Research Center, Yokohama City University School of Medicine, Yokohama, Japan

Abstract The human epididymis 4 (HE4) protein is expressed in the epididymis and respiratory tract. We previously reported that HE4 is also expressed in pulmonary adenocarcinoma. The purpose of this study was to investigate serum levels of HE4 as a biological marker in pulmonary adenocarcinoma. As the trained set, 102 patients with pulmonary adenocarcinoma who underwent surgery in our institute from 2008 to 2011 were evaluated. They were compared with 58 healthy controls and 16 cases of benign lung disease. In the validation, we used 104 patients with pulmonary adenocarcinoma operated on between 2000 and 2007. Postoperative changes of serum HE4 levels were investigated in 35 patients. The level of HE4 was determined by enzyme immunometric assay and compared with clinicopathological factors. In the trained set, HE4 levels in sera in pulmonary adenocarcinoma were significantly higher than in healthy controls and benign lung disease. Receiver operating characteristic curve showed that HE4 was a good discriminator of pulmonary adenocarcinoma (cut-off point, 50.3 pM; area under curve, 0.825; 95 % confidence interval, 0.76–0.89, p p = 0.032). The 5-year overall survival rate was 52.6 % in the HE4-positive group compared with 97.1 % in the HE4-negative group ( p = 0.001). These data showed that HE4 expression in sera is associated with progression of pulmonary adenocarcinoma and a possible biomarker.

2000

0.0

... 讨论有研究显示,约70%的NSCLC患者可见CYFRA21-1升高,目前认为CYFRA21-1是检测肺鳞癌的首选肿瘤标志物^[7],肺炎、肺结核、支气管炎、哮喘等肺部良性疾病一般不升高^[8] ...

2013

0.0

2012

0.0

... 同时CYFRA21-1在膀胱癌、头颈部肿瘤、乳腺癌等肿瘤中也存在一定的阳性率^[9,10,11] ...

2008

0.0

... 同时CYFRA21-1在膀胱癌、头颈部肿瘤、乳腺癌等肿瘤中也存在一定的阳性率^[9,10,11] ...

2006

0.0

... 同时CYFRA21-1在膀胱癌、头颈部肿瘤、乳腺癌等肿瘤中也存在一定的阳性率^[9,10,11] ...

1995

8.65

0.0

2012

0.0

Tumor Biol.. 2012, 33(4):1141-1149

Serum HE4 as a diagnostic and prognostic marker for lung cancer

Kota Iwahori (1) (2) , Hidekazu Suzuki (3) , Yoshiro Kishi (4) , Yoshihiro Fujii (4) , Rie Uehara (4) , Norio Okamoto (3) , Masashi Kobayashi (3) , Tomonori Hirashima (3) , Ichiro Kawase (3) , Tetsuji Naka (1)

1. Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan 2. Department of Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan 3. Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, 3-7-1 Habikino, Habikino, Osaka, 583-8588, Japan 4. Medical & Biological Laboratories, Co., Ltd., 4-5-3, Sakae, Naka-ku, Nagoya, 460-0008, Japan

We evaluated the diagnostic and prognostic efficacy of human epididymis protein 4 (HE4) for lung cancer patients by using our novel enzyme-linked immunosorbent assay ( ELISA ) system. We measured serum HE4 levels of cancer patients including 49 lung cancer and 18 ovarian cancer patients. Furthermore, we evaluated the relationship between serum HE4 levels and overall survival after chemotherapy of 24 lung cancer patients. Serum HE4 levels were significantly higher for non-small, small cell lung cancer and ovarian cancer patients than for healthy controls. The area under the receiver operating characteristic curve (AUC) was calculated for differentiation of lung cancer patients and healthy controls. AUC for serum HE4 was 0.988 for differentiating lung cancer patients from healthy controls, with a cutoff value of 6.56 ng/ml (sensitivity = 89.8%, specificity = 100%). Serum HE4 levels were elevated in 36/40 (90.0%) non-small cell lung cancer patients, 8/9 (88.9%) small cell lung cancer patients and 8/18 (44.4%) ovarian cancer patients. High levels of serum HE4 (>15 ng/ml) after chemotherapy were significantly correlated with worse overall survival after the treatment. These findings suggest that serum HE4 is a potential diagnostic and prognostic marker for lung cancer patients.

... Iwahori等^[13]对49例肺癌患者血清中HE4含量进行测定,发现肺癌患者血清HE4含量高于健康对照组,通过分析,当设定恰当的临界值时,90%的NSCLC患者血清HE4浓度升高 ...

2013

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2.5

... Liu等^[14]发现在血清HE4高水平表达的肺癌患者3年生存率显著低于相应低水平表达患者 ...

2011

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Tumor Biol.. 2011, 32(2):265-271

Prognostic significance of HE4 expression in pulmonary adenocarcinoma

Shin-ichi Yamashita (1) , Keita Tokuishi (1) , Takafumi Hashimoto (1) , Toshihiko Moroga (1) , Mirei Kamei (1) , Kiyoshi Ono (1) , Michiyo Miyawaki (1) , Shinsuke Takeno (1) , Masao Chujo (1) , Satoshi Yamamoto (1) , Katsunobu Kawahara (1)

1. Department of Surgery II, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita, 879-5593, Japan

We investigated the possibility of human epididymis 4(HE4) to predict survival for patients with pulmonary adenocarcinoma. One hundred and thirty-seven patients with pulmonary adenocarcinoma underwent surgery in our institute from 2000 to 2008. We used immunohistochemical analysis to determine the expression of HE4 and compared with the clinicopathological factors and survival. Serum levels of HE4 in lung adenocarcinoma were investigated by enzyme immunometric assay. Fifty-seven of 137 cases (41.6%) were HE4 positive. It was found that there was no correlation between HE4 expression by immunohistochemistry and clinicopathological factors, however, adenocarcinoma subtype was significantly associated with HE4 expression. Sera in lung adenocarcinoma were significantly higher than in healthy control. Five-year disease-free survival in the HE4-positive group (44.6%) was significantly different from that in the negative group (82.3%, p = 0.001) by immunohistochemistry. The five-year overall survival rate was 60.1% in the HE4-positive group, as compared with 90.8% in the HE4-negative group ( p = 0.001). In multivariate Cox regression analysis, positive HE4 protein expression was a worse prognosis factor of disease-free and overall survival (HR = 3.7, 95%CI = [1.7–8.4], p = 0.001; HR = 5.5, 95%CI = [1.8–17.2], p = 0.003, respectively), in addition to nodal status as a powerful value. When HE4 expression in adenocarcinoma cases except the BAC were analyzed, nodal status and HE4 expression were independent prognostic factors in disease-free and overall survivals. These data showed that HE4 expression is associated with a worse prognosis and is a possible prognostic factor of lung adenocarcinoma.

... Yamashita等^[15]的研究也显示肺腺癌组织HE4的表达阳性率与疾病进展有关,并可作为一项独立危险因子用于肺腺癌患者的预后判断 ...