Intraductal Papillary Squamous Neoplasm (IPSN) of the Pancreas: Histologic and Molecular Characterization of a Novel and Distinct Intraductal Cancer Precursor

: We report six intraductal papillary squamous neoplasms (IPSNs) of the pancreas, a rare but distinctive tumor whose biological features remain largely unknown. Five cases were investigated using an integrated approach combining histomorphological evaluation, immunohistochemistry, and multi-regional molecular profiling through whole-exome DNA sequencing and whole-transcriptome RNA sequencing. Only targeted DNA sequencing was available on a sixth recently diagnosed case. Histologically, the intraductal lesions were characterized by large, confluent papillae with fibrovascular cores lined by multilayered epithelial cells with diffuse squamous differentiation. All cases harbored a concomitant invasive carcinoma. The associated invasive carcinomas consistently included a tubular/ductal adenocarcinoma (PDAC); in five cases, a poorly differentiated squamous cell carcinoma (SCC) was also present, the proportion/features of which met the diagnostic criteria of adenosquamous carcinoma in two of them. Genomic analyses revealed that IPSNs and their matched invasive carcinomas shared the vast majority of somatic alterations, supporting a shared clonal origin for the two components. Activating KRAS mutations and biallelic inactivation of CDKN2A were detected in all cases. Recurrent mutations involved members of the SWI/SNF chromatin-remodeling complex and KMT2D. Additionally, FGFR1 and MYC amplifications were identified in two distinct cases (one case each). Molecular alterations restricted to the invasive component involved mediators of the TGF-β signaling pathway. Transcriptomic profiling demonstrated a basal-like expression pattern in all IPSNs and SCCs, while in two cases the matched PDAC shifted toward a classical transcriptomic subtype. In conclusion, through integrated histological assessment and multi-regional molecular sequencing, we demonstrate that IPSN represents a bona fide precursor of invasive pancreatic cancer, a new addition to the intraductal neoplasms category. This study challenges the current paradigm that pancreatic squamous epithelium plays no role in the initiation of pancreatic carcinogenesis, providing the first evidence of its involvement in early tumorigenic processes and yielding immediate implications for pancreatic tumor classification and biological understanding.