Characterization of undifferentiated carcinomas of the pancreas with and without osteoclast-like giant cells.

Background: Undifferentiated carcinoma (UC) is a rare subtype of pancreatic cancer differentiated from UC with osteoclast-like giant cells (UC-OGC) in 2019, impacting interpretation of literature that does not distinguish these subtypes. We sought to identify translationally relevant differences between these two variants and as compared to pancreatic ductal adenocarcinoma (PDAC).

Methods: We characterized clinical and multiomic differences between UC (n = 32) and UC-OGC (n = 15) using DNA-sequencing (seq), RNA-seq, and multiplex immunofluorescence (mIF) and compared these findings to PDAC.

Results: Characteristics at diagnosis were similar between UC and UC-OGC, though UC-OGC was more resectable (p = .009). Across all stages, median overall survival (OS) was shorter for UC than UC-OGC (0.4 vs 10.8 years, respectively; p = .003). This shorter survival was retained after stratification by resection, albeit without statistical significance (1.8 vs 11.9 years, respectively; p = .08). In a subset of patients with available tissue, the genomic landscape was similar between UC (n = 9), UC-OGC (n = 5), and PDAC (n = 159). Bulk RNA-seq was deconvoluted and, along with mIF in UC (n = 13), UC-OGC (n = 5), and PDAC (n = 16), demonstrated statistically significantly increased antigen-presenting cells (APCs), including M2 macrophages and NK cells, and decreased cytotoxic and regulatory T cells (Tregs) in UC and UC-OGC vs PDAC. Findings were similar between UC and UC-OGC except decreased Tregs in UC-OGC (p = .04).

Conclusions: In this series, UC is more aggressive than UC-OGC with these variants having more APCs and fewer Tregs than PDAC, suggesting potential for immune-modulating therapies in treatment of these pancreatic cancer subtypes.