Metatypic Carcinoma of the Pancreas

A distinct type of pancreatic carcinoma (n=31; 6% of adenocarcinomas) is described, distinguished from conventional pancreatic ductal adenocarcinoma (PDAC) by: (1) solid/undifferentiated (sheet-like, stroma-poor) carcinomas lacking features of other entities (no osteoclasts, microsatellite stable, INI-1 retained, nonkeratinizing squamous <30%), often admixed with ordinary PDAC; (2) radiology/gross showing central necrosis/demarcation mimicking nonductal neoplasms, not scirrhous like PDAC; (3) marked intratumoral heterogeneity with divergent patterns, including basal/squamoid (81%), solid sheets punctuated with megavacuoles (77%), clear cell (68%), mucoepidermoid-like (36%), sarcomatoid (36%), and occasional choriocarcinomatous or angiosarcomatous patterns, and some with carcinomatous vasculitis; (4) cellular anaplasia with pleomorphic giant cells (55%), multinucleated nonosteoclastic (32%), and rhabdoid-like (32%); (5) immunohistochemically (n=16) consistently showing a basal phenotype with common GATA6 loss/depletion and/or CK5/6, p40, or p63 expression; (6) molecular-genetic profile (n=13) showing altered frequencies: ARID1A (31% vs. 4%) and CDKN2A/p16 (92% vs. 30%) alterations, universal KRAS mutations with enrichment in KRAS G12D, frequent TP53, and lower SMAD4 loss (8% vs. 55%). Limited follow-up suggests comparable or more favorable outcomes. In conclusion, this is a distinct type of carcinoma in the pancreas that is prone to being misdiagnosed as nonductal/non-PDAC cancers. It is the first pancreatic carcinoma type in which a basal molecular phenotype can be indicated clinically by both imaging and histopathology, with major potential management implications (as it is also enriched in actionable targets like ARID1A). Recognition of this category is critical for cancer research, as it offers an invaluable group to study plasticity, stroma versatility, necrosis mechanisms, and the basal type in pancreatic cancer.