Abstract:

Hepatoid adenocarcinoma of the stomach (HAS) is a rare and highly malignant variant of gastric cancer, distinguished by histological features resembling hepatocellular carcinoma and frequent elevation of serum alpha-fetoprotein (AFP). It demonstrates aggressive biological behavior, early metasta-tic potential, and intrinsic resistance to conventional platinum-based chemotherapy, resulting in poor outcomes. No standard systemic therapy exists for initially unresectable HAS, making conversion strategies a critical therapeutic goal. We present a 56-year-old male with biopsy-proven locally advanced HAS and markedly elevated AFP (1 729.53 μg/L). Imaging revealed bulky lymphadenopathy (largest node: 39 mm×27 mm), rendering the tumor unresectable. Molecular profiling confirmed human epidermal growth factor receptor 2 (HER2) amplification. First-line conversion therapy with oxaliplatin, fluoropyrimidine, sintilimab (a programmed death-1 inhibitor), and later trastuzumab yielded only transient stabilization followed by clear progression: After six cycles, AFP rose to 1 546.07 μg/L and target lymph nodes enlarged to 46 mm×31 mm on CT. Given treatment failure and persistent HER2 positivity, a second-line, biology-informed regimen was initiated: Disitamab vedotin (an HER2-targeted antibody-drug conjugate delivering monomethyl auristatin E), lenvatinib (a multi-targeted tyrosine kinase inhibitor blocking vascular endothelial growth factor receptor and other pro-angiogenic pathways), tislelizumab (a programmed death-1 inhibitor), and short-course capecitabine (discontinued after 7 days due to grade 3 thrombocytopenia). This combination produced rapid and sustained antitumor activity. Serum AFP declined drama-tically to 102.3 μg/L after two cycles. Radiological reassessment showed progressive shrinkage of metastatic lymph nodes (from 46 mm to 25 mm after cycle two, and further to 14 mm after cycle three) consistent with partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET-CT) confirmed reduced metabolic activity in residual lesions. These results enabled successful R0 radical distal gastrectomy in June 2024. Final pathology revealed minimal residual disease (ypT1bN1) with hepatoid morphology and positive immunostaining for AFP, glypican-3, Sal-like protein 4, and HER2 (2 +). The patient received two adjuvant cycles of the same targeted-immunotherapy backbone before transitioning to observation due to cumulative toxicity. Eighteen months postoperatively, he remained free of recurrence. This case underscores that in HER2-positive, chemotherapy-refractory HAS, a rationally designed, multimodal regimen integrating an HER2-directed antibody-drug conjugate, antiangiogenic agent, and immune checkpoint blockade can overcome therapeutic resistance, achieve meaningful downstaging, and enable long-term disease control. Early molecular characterization and aggressive, persona-lized intervention are essential for improving outcomes in this rare malignancy.

Key words: Adenocarcinoma, Stomach neoplasms, Neoadjuvant therapy, Precision medicine, Hepatoid adenocarcinoma of the stomach, Conversion therapy