Beyond Morphology: Molecular Evidence Supporting a Clonal Relationship Between Pancreatic Undifferentiated Carcinoma with Osteoclast-like Giant Cells (UCOGC) and Conventional Pancreatic Ductal Adenocarcinoma (PDAC)

Background: Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) is a rare pancreatic malignancy with striking morphology. Its prognosis appears more heterogeneous than its high-grade histology would suggest. Larger clinicopathologic and population-based studies suggest that UCOGC may behave more favorably than conventional PDAC. However, the prognostic impact of an associated PDAC component remains unresolved. Methods: Six cases of pancreatic UCOGC, diagnosed between 2019 and 2024, were retrospectively identified and selected for immunohistochemical and molecular analysis. We retrieved available clinical, radiologic, and follow-up data from electronic medical records. We performed targeted next-generation sequencing on individually macro-dissected UCOGC and PDAC components. Results: The cohort included four females and two males, with a median age of 68.5 years. All tumors were associated with conventional PDAC, and, in this series, only two cases were correctly diagnosed at biopsy; others were interpreted as PDAC or sarcomatoid carcinoma, with a definitive UCOGC diagnosis made only at resection. Immunoreactivity for cytokeratin was observed in the epithelial component, while the undifferentiated and giant cell components showed vimentin and CD68 immunoreactivity, respectively. NGS revealed co-mutations in TP53 and KRAS in 4 cases. Pathogenic mutations in APC, BRCA2, BRAF, GNAS, PIK3CA, RB1, SMAD4, and CDKN2A/B loss were also detected. concordant pathogenic variants Paired analysis of macro-dissected components from the same tumor (n = 4) demonstrated concordant pathogenic variants, providing supportive evidence of a shared clonal relationship. Two patients received neoadjuvant chemotherapy, and systemic therapy was administered in five patients. Three patients were alive during the last follow-up, including two long-term survivors. Conclusions: Pancreatic UCOGC shares key genetic alterations with PDAC, and paired molecular analysis provides supportive evidence of a shared clonal relationship between the UCOGC and ductal components. The variable clinical outcomes observed in this small series are descriptive and hypothesis-generating and require validation in larger cohorts.