Hepatoid adenocarcinoma of the biliary tract: Clinicopathologic analysis of 9 institutional cases with literature review.

Hepatoid adenocarcinoma (HAC) of the biliary tract is an exceptionally rare malignancy with substantial diagnostic challenges. We performed a descriptive clinicopathologic study of 9 institutional cases supplemented by a literature review of 34 previously reported cases. The institutional cohort underwent centralized histopathologic review, immunohistochemical analysis, and molecular profiling. Across the combined cohort (n = 43), tumors arose in the gallbladder (n = 27) and bile ducts (n = 16), with a female predominance (male-to-female ratio, 0.56), mean age of 68.4 years, and distant metastases in 39% of patients. Within the institutional cohort, Glypican-3 and SALL4 showed the highest sensitivity among tested markers, exceeding HepPar-1 and alpha-fetoprotein. Histologic heterogeneity was frequent, and two mixed hepatoid-enteroblastic tumors demonstrated shared mutational profiles supporting a common clonal origin. One longitudinally sampled case showed genomic and immunophenotypic changes during metastatic progression. These findings expand the limited literature on biliary HAC and support a morphologically heterogeneous disease spectrum, with Glypican-3 and SALL4 serving as useful adjunctive markers.