Abstract / Summary
Abstract Alpha‑fetoprotein‑producing gastric cancer (AFPGC) represents a rare, highly aggressive subtype of gastric adenocarcinoma, with its hepatoid variant conferring dismal clinical outcomes. Despite accumulating genomic data for AFPGC, the hepatoid subtype concurrently bearing Epstein‑Barr virus (EBV) infection, ERBB2 amplification and multiple driver molecular alterations remains poorly characterized, and its pathological mechanisms are incompletely elucidated. We performed integrated molecular‑pathological profiling on one hepatoid AFPGC case using immunohistochemistry, in‑situ hybridization, FISH, and a 425‑gene NGS panel. A 79‑year‑old male presented with severe anemia and elevated serum AFP (431 ng/mL), alongside locally advanced gastric carcinoma and regional lymph‑node metastasis. Histopathological evaluation identified moderately‑to‑poorly differentiated adenocarcinoma featuring typical hepatoid differentiation and prominent intratumoral lymphoid stroma. Immunophenotypic assessment revealed focal AFP positivity, diffuse HepPar‑1 reactivity, strong HER2 overexpression (3+, 90% tumor cells), PD‑L1 CPS of 15, and positive EBER signals. Tumor cells displayed reduced membranous β‑catenin expression without nuclear or cytoplasmic translocation. FISH confirmed ERBB2 amplification. NGS uncovered three pathogenic somatic events: ERBB2 amplification, ARID1A nonsense mutation (p.R1276*), and activating PIK3CA mutation (p.P449L), together with microsatellite stability and a TMB of 6.2 mutations/Mb. Following short‑course induction therapy and subsequent S‑1 maintenance, the patient achieved a partial response accompanied by normalized AFP and negative EBV serology, maintaining remission at 4‑month follow‑up. Our findings characterize this rare composite molecular phenotype of EBV‑associated hepatoid AFPGC. Altered β‑catenin expression may correlate with hepatoid transdifferentiation, EBV‑mediated pathway perturbation and ARID1A deficiency, supporting precise pathological subtyping; this case broadens the molecular spectrum of hepatoid AFPGC and informs clinical diagnosis and individualized treatment.