Integrated Histopathologic and Targeted Genomic Characterization of Gastric Adenocarcinomas with Yolk Sac Tumor Differentiation.

Gastric adenocarcinomas with yolk sac tumor (YST) differentiation represent an exceptionally rare and poorly understood phenotype, characterized by the emergence of extraembryonic features within an epithelial malignancy. Their histogenesis remains debated, with increasing evidence supporting somatic lineage plasticity rather than germ cell origin. Here, we performed an integrated histopathologic and genomic characterization of three gastric adenocarcinomas with YST differentiation surgically treated at a tertiary cancer center. Histologically, all tumors showed a predominant adenocarcinoma component associated with variable YST differentiation, displaying reticular/microcystic and papillary patterns and expression of oncofetal markers, including alpha-fetoprotein (AFP) and Glypican-3. Targeted next-generation sequencing using a 523-gene panel revealed microsatellite-stable profiles with intermediate tumor mutational burden and substantial intertumoral heterogeneity. Despite gene-level variability, the detected alterations involved signaling pathways commonly implicated in epithelial tumorigenesis, including PI3K-AKT and RTK/RAS-MAPK signaling. Several recurrent alterations were identified across cases, including CCND3 variants and MDM2 copy number gains; however, their biological significance requires validation in larger cohorts. Functional enrichment analysis identified alterations involving developmental and proliferative signaling programs. Overall, these findings suggest that YST differentiation may represent a phenotypic manifestation of epithelial tumor plasticity arising within gastric adenocarcinoma and is associated with epithelial-related oncogenic programs, although broader genomic and comparative studies are required to clarify its histogenesis. This study provides preliminary molecular and histopathologic insights into this rare entity and supports the integration of molecular profiling into its diagnostic and translational management.