Zhang Luxin, Gao Haifeng, Ma Shuang, Fan Xiaoming, Guo Huahang, Sun Man, Wen Shuang, Liu Tianqing, Yu Guanghai, Yuan Xiaoying, Sun Xiuhua, Fan Bo
Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
Department of Urology, Central Hospital of Dalian, Dalian, Liaoning, China.
Front Immunol. 2025 May 13;16:1566794. doi: 10.3389/fimmu.2025.1566794. eCollection 2025.
Extranodal natural killer/T-cell lymphoma (ENKTL) involving the adrenal glands is extremely rare, and only a few cases have been reported. However, the genetic alterations, clinicopathological features and prognosis of these patients have not yet been fully elucidated.
Profiling of tumor mutations in ENKTL patients with adrenal involvement was conducted by whole-genome sequencing, and the predisposing genes and driver mutation gene variants were verified through Sanger sequencing. Immunohistochemical analysis of markers for the diagnosis and tumor microenvironment competent were performed to identify histopathological features. In addition, we searched the Surveillance, Epidemiology, and End Results (SEER), PubMed, Embase, and Scopus databases to perform a population-based study to compare the prognosis between adrenocortical carcinoma (ACC) patients and adrenal ENKTL patients using Kaplan-Meier survival curves and log-rank tests and analyzed the prognostic factors affecting the overall survival (OS) of adrenal ENKTL patients via univariate and multivariate Cox regression analyses.
We screened 15892 somatic single-nucleotide variants (SNVs), 364 somatic insertions and deletions (INDELs), and four driver mutation genes, namely, TET2, STAT3, FAS, and TP53. In addition, immunohistochemical analysis revealed that tumor cells were positive for CD3, CD43, CD56, TIA1, granzyme B, CD2, CD4, and CD7. The immunohistochemistry for detecting components of the tumor microenvironment reveled the infiltration of tumor-associated macrophages (CD68, CD163) and tumor-associated fibroblasts (vimentin, SMA) in the tumor sample. According to our population-based analysis, Kaplan-Meier survival curves revealed that ENKTL patients with adrenal involvement had a significantly poorer prognosis than did patients with ACC (<0.001), and chemotherapy was a significant prognostic factor for OS in ENKTL patients with adrenal involvement according to Cox multivariate analysis (hazard ratio = 0.318; =0.027).
The metastasis of ENKTL to the adrenal gland may be due to gene mutations caused by genetic variations, which may provide new therapeutic targets for this disease. The prognosis of adrenal ENKTL patients is markedly worse than that of ACC patients, and chemotherapy may serve as an independent factor of OS in adrenal ENKTL patients. However, our findings still need to be validated in additional studies.
累及肾上腺的结外自然杀伤/T细胞淋巴瘤（ENKTL）极为罕见，仅有少数病例报道。然而，这些患者的基因改变、临床病理特征及预后尚未完全阐明。
通过全基因组测序对累及肾上腺的ENKTL患者进行肿瘤突变分析，并通过Sanger测序验证易感基因和驱动突变基因变异。进行免疫组化分析以检测诊断标志物和肿瘤微环境相关标志物，从而确定组织病理学特征。此外，我们检索了监测、流行病学和最终结果（SEER）、PubMed、Embase和Scopus数据库，进行基于人群的研究，使用Kaplan-Meier生存曲线和对数秩检验比较肾上腺皮质癌（ACC）患者和肾上腺ENKTL患者的预后，并通过单因素和多因素Cox回归分析肾上腺ENKTL患者总生存（OS）的预后因素。
我们筛选出15892个体细胞单核苷酸变异（SNV）、364个体细胞插入和缺失（INDEL）以及四个驱动突变基因，即TET2、STAT3、FAS和TP53。此外，免疫组化分析显示肿瘤细胞CD3、CD43、CD56、TIA1、颗粒酶B、CD2、CD4和CD7呈阳性。检测肿瘤微环境成分的免疫组化显示肿瘤样本中有肿瘤相关巨噬细胞（CD68、CD163）和肿瘤相关成纤维细胞（波形蛋白、平滑肌肌动蛋白）浸润。根据我们基于人群的分析，Kaplan-Meier生存曲线显示，累及肾上腺的ENKTL患者预后明显比ACC患者差（<0.001），并且根据Cox多因素分析，化疗是累及肾上腺的ENKTL患者OS的显著预后因素（风险比=0.318；=0.027）。
ENKTL转移至肾上腺可能是由于基因变异导致的基因突变，这可能为该疾病提供新的治疗靶点。肾上腺ENKTL患者的预后明显比ACC患者差，化疗可能是肾上腺ENKTL患者OS的独立因素。然而，我们的研究结果仍需在更多研究中得到验证。
