Diagnostic dilemmas in hepatoid adenocarcinoma of the stomach: Navigating clinical and pathological loopholes

Hepatoid adenocarcinoma of the stomach (HAS) is a rare and highly aggressive gastric cancer subtype characterized by hepatic morphological features and often elevated alpha-fetoprotein (AFP) levels. Despite its distinct biology HAS frequently eludes early diagnosis due to nonspecific gastrointestinal symptoms, radiological mimicry of hepatocellular carcinoma, and variable expression of diagnostic biomarkers. Imaging modalities like CT and magnetic resonance imaging offer limited specificity, often misinterpreting hepatic metastases as primary liver tumors. While elevated AFP is a supportive clue, it lacks sensitivity and specificity, particularly in AFP-negative HAS. Histologically, HAS poses challenges with subtle or focal hepatoid differentiation, especially in limited biopsy samples. Immunohistochemical variability, especially inconsistent staining of markers like SALL4, Glypican-3, and HepPar-1, further complicates accurate classification. Misdiagnosis can lead to inappropriate management and a worse prognosis. The lack of standardized diagnostic criteria globally exacerbates variability in reporting and treatment decisions. This review outlined the multidimensional diagnostic hurdles in HAS and underscored the necessity of an integrated, multidisciplinary approach. Enhanced tissue sampling, combined immunohistochemical panels, and emerging molecular tools may collectively improve diagnostic accuracy and clinical outcomes for this aggressive gastric malignancy.