[摘 要] 目的：探讨胃肝样腺癌（HAS）的临床病理特征与免疫微环境异质性，筛选预后标志物，阐释其高侵袭性与疗效差的 机制，为精准诊疗策略提供理论依据。方法: 回顾性收集2013年1月至2025年5月期间海军军医大学第一附属医院与第二附属 医院收治的65例HAS患者的临床信息及病理资料。采用免疫组织化学技术检测HAS 肝样分化标志物、神经内分泌标志物 等分 子表达情况，通过Kaplan-Meier生存分析法明确与预后相关的靶点。利用多色免疫荧光技术鉴定肿瘤区域内免疫细胞亚群分布 情况，以阐明其免疫微环境特征。结果：65例患者中，男性54例（83.1%），女性11例（16.9%），中位年龄68岁。肿瘤好发于贲门 （40%），其次为胃窦（32.3%）和胃体（27.7%）。中位随访时间23.18个月，15例患者死亡，46例生存，4例失访。HAS的胃镜及手术 标本大体观呈灰白色实性质硬肿物，镜下可见中低分化胃腺癌与肝细胞癌（HCC）样分化区交错分布。表达神经内分泌相关分子 的HAS患者呈现出更多的淋巴结转移数量及更短的总生存期。免疫微环境解析显示，HAS总体缺乏免疫细胞浸润，呈现“冷肿 瘤”特征；免疫细胞主要聚集于胃癌腺体周围区域，而在HCC样分化区域罕见淋巴细胞浸润。结论：HAS侵袭性强，根治性手术 是主要治疗手段；神经内分泌转化提示不良预后，是个体化治疗的关键标志；免疫细胞浸润缺乏，可能是其免疫治疗响应不佳的 原因。

[Abstract] Objective: To investigate the clinicopathological characteristics and heterogeneity of the tumor immune microenvironment in hepatoid adenocarcinoma of the stomach (HAS), identify prognostic biomarkers, and elucidate the mechanisms underlying its aggressive phenotype and poor therapeutic response in order to provide a rationale for developing improved diagnostic and therapeutic strategies. Methods: A retrospective analysis was conducted on clinical information and pathological specimens from 65 HAS patients treated at the First Affiliated Hospital of Naval Medical University and the Second Affiliated Hospital of Naval Medical University between January 2013 and May 2025. Immunohistochemistry was employed to detect the expression patterns of molecules, such as hepatoid differentiation markers and neuroendocrine markers. Prognosis-related targets were identified using Kaplan-Meier survival analysis. Multispectral immunohistochemistry was utilized to characterize the spatial distribution of immune cell subsets within tumor regions, thereby elucidating the distinctive features of HAS immune microenvironment. Results: Among the 65 patients (male: 54 [83.1%]; female: 11 [16.9%]; median age: 68 years), tumors predominantly occurred in the gastric cardia (40%), followed by the antrum (32.3%) and the gastric body (27.7%). The median follow-up time was 23.18 months. Fifteen patients died; 46 survived and 4 were lost to follow-up. On pathological examination, the tumor specimens collected in gastric endoscopy and surgery presented mainly as firm, grayish-white masses which, under microscope, appeared to have intertwining distribution of moderately-to-poorly differentiated gastric adenocarcinoma and hepatocellular carcinoma (HCC)-like differentiation regions. Patients with neuroendocrine differentiation demonstrated higher lymph node involvement and shorter overall survival. Immune microenvironment analysis demonstrated that HAS, with sparse immune infiltration, presented a "cold tumor" phenotype. Immune cells were primarily localized at the periphery of gastric adenocarcinoma glands and lymphocyte infiltration was rarely seen within HCC-like differentiation regions. Conclusion: HAS exhibits highly aggressive biological behavior. Radical resection is the main therapy. Neuroendocrine differentiation suggests poor prognosis and is a key biomarker for personalized therapy. Deficient immune cell infiltration may correlate with its poor response to immunotherapy.

[基金项目] 国家自然科学基金优秀青年科学基金（82222054）