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Clinicopathological characteristics and immune microenvironment analysis of hepatoid adenocarcinoma of the stomach: a study of 65 cases
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Abstract:
[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.
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