ST2联合CEA、CYFRA211在早期非小细胞肺癌辅助诊断中的应用价值

doi:10.16150/j.1671-2870.2023.05.004

摘要/Abstract

摘要：

目的：探索3种生物标志物可溶性生长刺激表达基因2蛋白（soluble growth stimulation expressed gene 2 protein, ST2）、癌胚抗原（carcinoembryonic antigen，CEA）和CYFRA211（细胞角蛋白质19片段中的21和1表位）辅助诊断早期非小细胞肺癌（non-small cell lung cancer，NSCLC）价值。方法：收集2023年1月至8月期间上海交通大学医学院附属瑞金医院收治的91例早期NSCLC患者（TNM分期Ⅰ期）、21例中晚期NSCLC患者（TNM分期Ⅱ期16例、Ⅲ期5例），另选取同期的50例肺部良性病变患者及50例健康体检人群作为正常对照。用荧光免疫层析法检测所有研究对象的血浆ST2水平，用化学微粒子发光法检测其血清CEA、CYFRA211水平，比较组间差异，并分析单个或联合指标诊断NSCLC的价值。结果：检测ST2水平后发现，NSCLC早期组要高于肺部良性病变组和健康对照组（P<0.001)，肺部良性病变组要高于健康对照组（P<0.001)。NSCLC早期组的CEA浓度水平要高于健康对照组（P<0.05)、肺部良性病变组要高于健康对照组（P<0.05)。NSCLC早期组的CYFRA211浓度水平要高于健康对照组（P<0.05)。受试者操作特征（receiver operator characteristic, ROC）曲线分析显示，ST2、CEA、CYFRA211的临界值分别为≥25.0 ng/L、≥1.8 ng/mL、≥2.0 ng/mL时，其单独检测诊断早期NSCLC的曲线下面积分别为0.957、0.660、0.570；其中ST2的灵敏度和特异度分别为89.0%和98.0%，CEA和CYFRA211的灵敏度和特异度分别46.2%和80.0%、17.6%和96.0%；而三者联合检测诊断早期NSCLC的曲线下面积为0.973，灵敏度为92.3%、特异度为98.0%，均优于各项指标单独检测的结果。在临床病理特征中，肿瘤直径越大，NSCLC患者血浆ST2水平相对较高，差异具有统计学意义（P<0.05)；患者CEA水平在不同的肿瘤分化程度的组别间、是否存在区域淋巴结转移的组别间、有无气道播散的组别间、是否浸润胸膜的组别间及TMN分期Ⅰ期组与Ⅱ、Ⅲ、Ⅳ期组间差异均有统计学意义；而CYFRA211水平则在患者的不同性别、不同年龄组别和不同肺癌类型组别（腺癌与鳞癌）中有统计学差异（P<0.05)。结论：相对于CEA和CYFRA211，单独检测ST2水平在区分NSCLC早期患者与肺部良性病变患者、健康对照人群中更有优势；而将三者联合检测，具有较高的诊断价值，可用于辅助诊断早期NSCLC。

关键词: 可溶性生长刺激表达基因2蛋白, 非小细胞肺癌, 癌胚抗原, 细胞角蛋白19片段

Abstract:

Objective: To explore soluble growth stimulation expressed gene 2 protein (ST2), carcinoembryonic antigen（CEA） and cytokeratin fragment 21-1 (CYFRA211) in diagnosing early non-small cell lung cancer (NSCLC). Methods: From January to August 2023, 91 patients with early NSCLC (TNM stage Ⅰ) and 21 patients with middle and advanced NSCLC [TNM stage Ⅱ (16 cases) and Ⅲ (5 cases)] admitted to Ruijin Hospital were collected, and 50 patients with benign lung lesions(BL) and 50 healthy people(HC) were served as controls. Plasma ST2 levels were detected by fluorescence immunochromatography, and serum CEA and CYFRA211 levels were detected by chemiluminescence. The differences between groups were compared, and the diagnostic value of index alone or in combination for NSCLC was analyzed. Results: ST2 level in the early NSCLC group was higher than that in the BL and HC group （P<0.001), and ST2 level in BL group was higher than HC group (P<0.001). The CEA level in the early NSCLC group were higher than that in the HC group (P<0.05), BL group was higher than HC group (P<0.05). The CYFRA211 level in the early NSCLC group was higher than that in the HC group (P<0.05). When the cutoff values of ST2, CEA and CYFRA211 were set as 25.0 ng/L, 1.8 ng/mL and 2.0 ng/mL, areas under receiver operator characteristic (ROC) curve for diagnosing early NSCLC were 0.957, 0.660 and 0.570, respectively. The sensitivity of ST2,CEA and CYFRA211 for diagnosing early NSCLC were 89.0%, 46.2% and, 17.6%,and specificity were 98.0%, 80.0%, 96.0%, respectively. The area under the curve of the combined detection were 0.973, with a sensitivity of 92.3% and the specificity of 98.0%,which were higher than that of any index. In terms of clinicopathological features, plasma ST2 level was higher in NSCLC patients with larger tumors than with smaller tumors（P<0.05）. There were statistical differences in CEA levels among groups with different degrees of tumor differentiation, between groups with and without regional lymph node metastasis, groups with and without airway spread, groups with and without pleural invasion, and groups with TMN stage Ⅰ and TMN Ⅱ/Ⅲ/Ⅳ（P<0.05）. CYFRA211 levels were significantly different between diffe-rent sex groups, age groups and lung cancer types (P<0.05). Conclusions: Compared with CEA and CYFRA211, ST2 alone is more advantageous in distinguishing early NSCLC patients from patients with benign lung lesions and healthy controls. However, combined detection of the three tests has higher diagnostic value and is recommended to assist the diagnosis of early NSCLC.

Key words: Soluble growth stimulation gene 2 protein, Non-small cell lung cancer, Carcinoembryonic antigen, Cytokeratin 19 fragment

中图分类号:

R734.2
R446

范臻佳, 赵珺涛, 周嘉宽, 李占权, 万颖蕾. ST2联合CEA、CYFRA211在早期非小细胞肺癌辅助诊断中的应用价值[J]. 诊断学理论与实践, 2023, 22(05): 441-447.

FAN Zhenjia, ZHAO Juntao, ZHOU Jiakuan, LI Zhanquan, WAN Yinglei. Application value of ST2 combined with CEA and CYFRA211 in diagnosis of early non-small cell lung cancer[J]. Journal of Diagnostics Concepts & Practice, 2023, 22(05): 441-447.

图/表 4

表1

表2

图1

表3

参考文献 21

[1]	WANG Z Z, ZHENG Y. Lung cancer worldwide and in China from 1990 to 2020:prevalence and prevention measures[J]. J Diagn Concepts Pract, 2023, 22(1):1-7.
[2]	张捷, 常莉, 王丽, 等. 非小细胞肺癌放疗联合免疫治疗相关进展[J]. 肿瘤, 2022, 42(9):667-672.
	ZHANG J, CHANG L, WANG L, et al. Progress in radiotherapy combined with immunotherapy for non-small cell lung cancer[J]. Tumor, 2022, 42(9):667-672.
[3]	TSOI K K, HIRAI H W, CHAN F C, et al. Cancer burden with ageing population in urban regions in China: projection on cancer registry data from World Health Organization[J]. Br Med Bull, 2017, 121(1):83-94. doi: 10.1093/bmb/ldw050 URL
[4]	中华医学会呼吸病学分会. 早期肺癌诊断中国专家共识(2023年版)[J]. 中华结核和呼吸杂志, 2023, 46(01):1-18.
	Chinese Thoracic Society. Chinese expert consensus on diagnosis of early lung cancer (2023 Edition)[J]. Chin J Tuberc Respir Dis, 2023, 46(01):1-18.
[5]	韩群啸, 鲍国林, 刘义庆. 肺癌早期诊断研究进展[J]. 中国医药, 2023, 18(5):761-764.
	HAN Q X, BAO G L, LIU Y Q. Research progress on early diagnosis of lung cancer[J]. Chin Med, 2023, 18(5):761-764.
[6]	缪怡静, 姚叶林, 林志坚, 等. CEA、CA125、CYFRA211、NSE肿瘤标志物联合检测对肺癌的鉴别诊断效果[J]. 吉林医学, 2022, 43(11):3082-3084.
	MIAO Y J, YAO Y L, LIN Z J, et al. The combined detection of CEA, CA125, CYFRA211, and NSE tumor markers in the differential diagnosis of lung cancer[J]. Jilin Med J, 2022, 43(11):3082-3084.
[7]	LEI S, JIN J, ZHAO X, et al. The role of IL-33/ST2 signaling in the tumor microenvironment and Treg immunotherapy[J]. Exp Biol Med (Maywood), 2022, 247(20):1810-1818. doi: 10.1177/15353702221102094 URL
[8]	张颖, 陈芊, 石玉霞, 等. 新辅助免疫治疗在非小细胞肺癌中的应用进展[J]. 安徽医学, 2022, 43(2):240-243.
	ZHANG Y, CHENG Q, SHI Y X, et al. Progress in the application of neoadjuvant immunotherapy in non-small cell lung cancer[J]. Anhui Med, 2022, 43(2):240-243.
[9]	罗玲, 王江红. 支气管肺泡灌洗液SCCA、CYFRA21-1、CEA联合检测在肺癌诊断中的价值[J]. 重庆医科大学学报, 2010, 35(11):1716-1718.
	LUO L, WANG J H. Combined determination of SCCA,CYFRA21-1 and CEA in bronchoalveolar lavage fluid for lung cancer diagnosis[J]. J Chongqing Univ, 2010, 35(11):1716-1718.
[10]	CHEN F, WANG X Y, HAN X H, et al. Diagnostic value of Cyfra21-1, SCC and CEA for differentiation of early-stage NSCLC from benign lung disease[J]. Int J Clin Exp Med, 2015, 8(7):11295-11300. pmid: 26379938
[11]	赵珺涛, 陆炜, 刘锦燕, 等. 血清肿瘤标志物CKAP4在肺癌辅助诊断中的应用[J]. 标记免疫分析与临床, 2022, 29(11):1832-1837,1911.
	ZHAO J T, LU W, LIU J Y, et al. The application of cytoskeleton-associated protein 4 in the auxiliary diagnosis of lung cancer[J]. Labeled Immunoassays & Clin Med, 2022, 29(11):1832-1837,1911.
[12]	HOMSAK E, GRUSON D. Soluble ST2: a complex and diverse role in several diseases[J]. Clin Chim Acta, 2020, 507:75-87. doi: S0009-8981(20)30166-2 pmid: 32305537
[13]	司盼. IL-33/ST2L通路调节CD4+T细胞分化对缺血性神经元的保护性研究[D]. 河南: 郑州大学, 2018.
	SI P. IL-33／ST2L signal ameliorates neuron-apoptosis by modulating CD4+T lymphocytes differentiation[D]. Zhengzhou University, 2018.
[14]	闫心怡, 张岩, 孙家梅, 等. 肺癌患者手术前后ST2水平变化及临床意义[J]. 中国免疫学杂志, 2022, 38(23):2902-2905,2911.
[1]	王泽洲, 郑莹. 1990年至2020年间全球及我国肺癌的发病流行趋势及防控措施[J]. 诊断学理论与实践, 2023, 22(1):1-7.
[14]	YAN X Y, ZHANG Y, SUN J M, et al. ST2 changes and its clinical significance in lung cancer patients before and after surgery[J]. Chin J Immunol, 2022, 38(23):2902-2905,2911.
[15]	WANG C, CHEN Z, BU X, et al. IL-33 signaling fuels outgrowth and metastasis of human lung cancer[J]. Biochem Biophys Res Commun. 2016; 479(3):461-468. doi: 10.1016/j.bbrc.2016.09.081 URL
[16]	YANG Z, GAO X, WANG J, et al. Interleukin-33 enhanced the migration and invasiveness of human lung cancer cells[J]. Onco Targets Ther. 2018; 11:843-849. doi: 10.2147/OTT URL
[17]	VITALI E, PICCINI S, TRIVELLIN G, et al. The impact of SST2 trafficking and signaling in the treatment of pancreatic neuroendocrine tumors[J]. Mol Cell Endocrinol, 2021, 527:111226. doi: 10.1016/j.mce.2021.111226 URL
[18]	王维飞, 何广思, 胡加海. 非小细胞肺癌患者六种血清指标的变化及其检测价值[J]. 中国临床研究, 2023, 36(6):849-855.
	WANG W F, HE G S, HU J H. Detection value of six serum indicators in non-small cell lung cancer patients[J]. Chin J Clin Res, 2023, 36(6):849-855.
[19]	王继鹏, 李朋玲, 陈胜. Pokemon、miR-451、IFITM1在非小细胞肺癌组织中的表达及与病理特征的相关性[J]. 中国老年学杂志, 2023, 43(9):2079-2083.
	WANG J P, LI P L, CHEN S. The expression of Pokemon, miR-451, and IFITM1 in non-small cell lung cancer tissues and their correlation with pathological features[J]. Chin J Gerontol, 2023, 43(9):2079-2083.
[20]	ZHOU W, YANG Y, WANG Z, et al. Impact of HSP90α, CEA, NSE, SCC, and CYFRA21-1 on Lung Cancer Patients[J]. J Healthc Eng, 2021:6929971.
[21]	GEZELIUS E, BENDAHL P O, GALLO W, et al. Circulating levels of the cardiovascular biomarkers ST2 and adrenomedullin predict outcome within a randomized phase Ⅲ lung cancer trial (RASTEN)[J]. Cancers (Basel), 2022, 14(5):1307. doi: 10.3390/cancers14051307 URL

groups	n	ST2	CEA	CYFRA211	Combination detection
Lung cancer stage Ⅰ	91	69.1(51.4，90.4)	1.60(1.09，2.41)	1.18(0.81，1.75)	16.8(12.3，22.1)
Benign diseases	50	42.7(29.5，62.4)a）	1.49(1.08，2.77)	1.23(0.80，1.79)	11.4(8.1，16.3)
Healthy people	50	10.7(8.3，16.5)a),b)	1.24(0.85，1.76)	1.07(0.78，1.54	4.2(3.3，5.2)
Healthy people vs Benign diseases		P<0.001	P=0.010	P=0.086	P<0.001
Benign diseases vs Lung cancer stage Ⅰ		P<0.001	P=0.995	P=0.368	P=0.001
Healthy people vs Lung cancer stage Ⅰ		P<0.001	P=0.002	P=0.006	P<0.001

Indice	N	ST2		CEA		CYFRA211
Indice	N	Mean	P value	Mean	P value	Mean	P value
Age			0.066		0.032		0.006
<60	35	63.3		1.85		1.26
≥60	77	77.3		4.69		1.66
Sex			0.177		0.065		0.022
Male	58	79.0		3.85		1.75
Female	54	66.5		3.76		1.29
Degree of tumor differentiation			0.820		0.032		0.358
Medium and high differentiation	53	70.42		1.99		1.42
Poorly differentiated	59	75.23		5.44		1.63
Lung cancer types			0.144		0.084		0.017
Adenocarcinoma	96	70.64		3.91		1.44
Squamous cell carcinoma	14	85.83		3.37		2.03
TNM classification			0.472		<0.001		0.124
Stage Ⅰ	91	72.87		2.36		1.51
Stage Ⅱ, stage Ⅲ, and stage Ⅳ	21	73.34		10.07		1.63
Tumor size (T)			0.025		0.005		0.052
<3 cm (T₁)	95	71.12		3.43		1.47
≥3 cm (T₂+T₃+T₄)	17	83.24		5.94		1.82
Involvement of lymph nodes (N)			0.161		0.002		0.976
Without lymph node metastasis (N₀)	102	74.81		2.52		1.55
With lymph node metastasis (N₁+N₂+N₃)	10	54.03		16.90		1.32
Spread through air spaces (STAS)			0.661		<0.001		0.157
Without	81	72.67		1.96		1.46
With	31	73.70		8.63		1.71
Tumor location type			0.483		0.549		0.108
Peripheral type	103	71.71		3.93		1.47
Central type	9	87.14		2.36		2.13
Single or multiple type			0.709		0.804		0.446
Single type	104	73.09		3.90		1.56
Multiple primary lung cancer	8	71.23		2.66		1.14
Pleural invasion			0.880		<0.001		0.174
Without	89	72.33		2.14		1.52
With	23	75.37		10.26		1.57

Indice	Sensitivity(%)	Specificity(%)	Positive predictive value(%)	Negative predictive value(%)	Yoden index	AUC	Cut-off value
ST2	89.0	98.0	98.7	83.1	0.871	0.957	25.0
CEA	46.2	80.0	80.8	44.9	0.267	0.660	1.8
CYFRA211	17.6	96.0	88.9	39.0	0.157	0.570	2.0
Joint detection	92.3	98.0	97.7	87.3%	0.904	0.973	6.4