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中华临床医师杂志(电子版)

中华临床医师杂志(电子版) ›› 2024, Vol. 18 ›› Issue (05) : 455 -461. doi: 10.3877/cma.j.issn.1674-0785.2024.05.004

临床研究

胃淋巴上皮瘤样癌三级淋巴结构特征及其与预后的相关性
闫战涛1, 王辉1, 周梓迪1, 史勇强1, 陈铜兵1,†()   
  1. 1. 213000　江苏常州，常州市第一人民医院病理科
  • 收稿日期:2024-03-07 出版日期:2024-05-15
  • 通信作者: 陈铜兵
  • 基金资助:
    常州市应用基础研究计划(CJ20220202); 常州市卫健委青年项目(QN202304)

Tertiary lymphatic structure characteristics and their correlation with prognosis in patients with lymphoepithelioma-like gastric carcinoma

Zhantao Yan1, Hui Wang1, Zidi Zhou1, Yongqiang Shi1, Tongbing Chen1,†()   

  1. 1. Department of Pathology, The First People's Hospital of Changzhou, Changzhou 213003, China
  • Received:2024-03-07 Published:2024-05-15
  • Corresponding author: Tongbing Chen
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引用本文：

闫战涛, 王辉, 周梓迪, 史勇强, 陈铜兵. 胃淋巴上皮瘤样癌三级淋巴结构特征及其与预后的相关性[J]. 中华临床医师杂志(电子版), 2024, 18(05): 455-461.

Zhantao Yan, Hui Wang, Zidi Zhou, Yongqiang Shi, Tongbing Chen. Tertiary lymphatic structure characteristics and their correlation with prognosis in patients with lymphoepithelioma-like gastric carcinoma[J]. Chinese Journal of Clinicians(Electronic Edition), 2024, 18(05): 455-461.

目的

分析胃淋巴上皮瘤样癌（lymphoepithelioma-like gastric carcinoma，LELGC）中三级淋巴结构（tertiary lymphoid structure，TLS）特征及其与临床病理参数和预后的相关性。

方法

收集常州市第一人民医院2009年2月~2020年12月经病理确诊为LELGC的114例手术标本资料；然后手术标本切片进行病理组织学复核、TLS成熟度和密度分析；使用免疫组织化学染色方法检测肿瘤组织中淋巴细胞的CD3、CD4、CD8、CD20、CD21、PD-L1表达情况；使用Kaplan-Meirer和COX回归分析TLS对患者预后的影响。

结果

TLS主要分布在肿瘤间质内，集中在肿瘤侵袭性边缘区域；具有mTLS的肿瘤组织内以T淋巴细胞分布为优势，具有非mTLS的肿瘤组织内以B淋巴细胞分布为优势。mTLS组肿瘤平均直径（t=2.727，P=0.007）、脉管及神经侵犯阳性率（χ2=4.672，P=0.031）、淋巴结转移率（χ2=8.920，P=0.003）、临床分期Ⅲ/Ⅳ期发生率（χ2=15.360，P<0.001）均显著低于非mTLS组。TLS高密度组病理T分期（浸润深度）T3/T4发生率为80.0%（44/55），显著高于TLS低密度组的53.3%（35/59），比较差异具有统计学意义（χ2=5.721，P=0.017）。单因素COX回归分析显示，肿瘤直径（HR=1.177，P=0.011）、淋巴结（HR=11.873，P=0.016）、脉管神经侵犯（HR=4.430，P=0.007）、病理T分期（浸润深度，HR=13.706，P=0.011）、临床分期（HR=6.387，P<0.001）、TLS成熟度（HR=0.225，P=0.001）均与患者的预后显著相关；多因素COX回归分析显示，T分期（浸润深度，HR=9.765，P=0.028）、临床分期（HR=3.523，P=0.014）和TLS成熟度（HR=0.228，P=0.001）与患者的预后显著相关。Kaplan-Meirer生存分析显示，mTLS组患者平均生存期为（72.0±4.7）个月，显著高于非mTLS组的（33.7±5.5）个月，mTLS对总生存期有积极影响（χ2=14.063，P<0.001）；TLS高密度组患者平均生存期为（65.4±5.0）个月，显著高于TLS低密度组的（51.8±6.5）个月，TLS高密度对总生存期有积极影响（χ2=5.482，P=0.019）。

结论

LELGC中TLS主要分布在肿瘤侵袭性边缘区域；具有mTLS的肿瘤组织以T淋巴细胞分布为优势，而具有非mTLS的肿瘤组织以B淋巴细胞分布为优势；LELGC中mTLS和高密度TLS可能会对患者的预后有积极影响，为患者的预后和治疗提供新的预测指标和靶点。

关键词: 胃淋巴上皮瘤样癌, 三级淋巴结构, 预后
Objective

To investigate the characteristics of tertiary lymphoid structure (TLS) and their correlation with clinicopathological parameters and prognosis in patients with lymphoepithelioma-like gastric carcinoma (LELGC).

Methods

A total of 114 patients with LELGC were selected from Changzhou First People's Hospital from February 2009 to December 2020. Histopathological review and TLS maturity and density analysis were performed on 114 surgical specimens. Then, the expression of CD3, CD4, CD8, CD20, CD21, and PD-L1 in lymphocytes in tumor tissues was detected by immunohistochemical staining. Finally, Kaplan-Meirer survival analysis and COX regression analysis were used to examine the impact of TLS on patient prognosis.

Results

TLS was mainly distributed in the tumor stroma and concentrated in the invasive edge area of the tumor. T lymphocyte distribution was dominant in tumor tissues with mature TLS (mTLS), and B lymphocyte distribution was dominant in tumor tissues with non-mTLS. The average tumor diameter (t=2.727, P=0.007), positive rate of vascular and nerve invasion (χ2=4.672, P=0.031), lymph node metastasis rate (χ2=8.920, P=0.003), and incidence of clinical stage Ⅲ/Ⅳ (χ2=15.360, P<0.001) in the mTLS group were significantly lower than those of the non-mTLS group. The incidence of pathological T3/T4 stage (depth of invasion) in the TLS high-density group was 80.0% (44/55), which was significantly higher than that of the TLS low-density group (53.3%, 35/59) (χ2=5.721, P=0.017). Univariate COX regression analysis showed that tumor diameter (hazard ratio [HR]=1.177, P=0.011), lymph node metastasis (HR=11.873, P=0.016), vascular nerve invasion (HR=4.430, P=0.007), pathological T-stage (depth of invasion, HR=13.706, P=0.011), clinical stage (HR=6.387, P<0.001), and TLS maturity (HR=0.225, P=0.001) were significantly correlated with the prognosis of patients. Multivariate COX regression analysis showed that T stage (depth of invasion, HR=9.765, P=0.028), clinical stage (HR=3.523, P=0.014), and TLS maturity (HR=0.228, P=0.001) were significantly correlated with the prognosis of patients. Kaplan-Meirer survival analysis showed that the average survival time of patients in the mTLS group was (72.0±4.7) months, which was significantly longer than that of the non-mTLS group (33.7±5.5 months) (χ2=14.063, P<0.001). The average survival time of patients in the TLS high-density group was (65.4±5.0) months, which was significantly longer than that of the non-mTLS group (51.8±6.5 months) (χ2=5.482, P=0.019). mTLS and high density TLS had a positive effect on overall survival.

Conclusion

TLS in LELGC is mainly distributed in the invasive edge region of tumors. Tumor tissues with mTLS are dominated by T lymphocyte distribution, whereas tumor tissues with non-mTLs are dominated by B lymphocyte distribution. High-density and mature TLS in LELGC may have a positive impact on the prognosis of patients, providing new predictors and targets for the prognosis and treatment of patients.

Key words: LELGC, Tertiary lymphoid structure, Prognosis
图1 LELGC中TLS分布特征（200×）。图a为mTLS组织结构，HE染色；图b为CD20+ B淋巴细胞，免疫组化染色；图c为CD3+T淋巴细胞，免疫组化染色；图d为非mTLS组织结构，HE染色；图e为CD20+ B淋巴细胞，免疫组化染色；图f为CD3+T淋巴细胞，免疫组化染色
表1 每400倍视野CD20+细胞数和CD3+细胞数比较（）
TLS CD20+B细胞 CD3+T细胞 t值 P值
mTLS（n=69） 171.6±89.9 283.5±98.1 6.989 <0.001
非mTLS（n=45） 152.7±89.0 97.7±29.1 3.938 <0.001
表2 2组TLS成熟度和密度与临床病理特征的相关性
临床病理特征 TLS成熟度 TLS密度
mTLS（n=69） 非mTLS（n=45） t/χ2 P值 高密度（n=55） 低密度（n=59） t/χ2 P值
性别
男（n=76） 43 33 1.487 0.223 37 39 0.018 0.895
女（n=38） 26 12 18 20
年龄（岁）
≤68（n=61） 39 22 0.638 0.424 28 33 0.289 0.591
>68（n=53） 30 23 27 26
吸烟史
有（n=72） 47 25 1.847 0.174 37 35 0.773 0.379
无（n=42） 22 20 18 24
肿瘤直径（cm） 5.0±2.6 6.4±2.9 2.727 0.007 5.7±2.7 5.5±2.8 0.519 0.605
脉管及神经侵犯
+（n=67） 35 32 4.672 0.031 34 33 0.407 0.524
-（n=47） 34 13 21 26
淋巴结转移
+（n=75） 38 37 8.920 0.003 36 39 0.005 0.942
-（n=39） 31 8 19 20
病理T分期
T1+T2（n=35） 25 10 2.513 0.113 11 24 5.721 0.017
T3+T4（n=79） 44 35 44 35
临床分期
Ⅰ+Ⅱ（n=73） 54 19 15.360 <0.001 34 39 0.227 0.634
Ⅲ+Ⅳ（n=41） 15 26 21 20
PD-L1（CPS评分）
高评分（n=53） 33 20 0.125 0.723 27 26 0.289 0.591
低评分（n=61） 36 25 28 33
表3 TLS与患者预后的关系
临床病理特征 单因素Cox回归 多因素Cox回归
HR P值 95%CI HR P值 95%CI
肿瘤直径 1.177 0.011 1.038~1.334
淋巴结 11.873 0.016 1.593~87.931
脉管神经侵犯 4.430 0.007 1.504~13.053
T分期（浸润深度） 13.706 0.011 1.839~102.157 9.765 0.028 1.275~74.783
临床分期 6.387 <0.001 2.364~17.255 3.523 0.014 1.288~9.638
TLS成熟度 0.225 0.001 0.096~0.527 0.228 0.001 0.096~0.546
CD3 0.994 0.015 0.989~0.999
图2 患者的Kaplan-Meier 生存曲线。图a为mTLS组和非mTLS组；图b为TLS高密度组和TLS组低密度组
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