Pancreatic acinar cell carcinoma demonstrates marked clinical heterogeneity and recurrent actionable genomic alterations

Abstract

Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic malignancy with a molecular profile distinct from pancreatic ductal adenocarcinoma (PDAC) but is commonly treated using extrapolated paradigms. We retrospectively identified patients with histologically confirmed PACC at a tertiary academic center and abstracted clinical, pathologic, treatment, and outcome data. Next-generation sequencing (NGS) was reviewed for microsatellite status, tumor mutational burden, and actionable genomic alterations. Seven patients were identified (median age, 64 years; 57% male). Most presented with metastatic disease (71%), yet outcomes were heterogeneous, including prolonged progression-free survival exceeding 7 years and 16 years in select patients. Carbohydrate antigen 19–9 (CA 19–9) was normal in all cases, and jaundice was absent despite frequent pancreatic head involvement. All tumors were KRAS wild-type. NGS revealed recurrent alterations including CDKN2A/B and MTAP co-deletion, BRAF fusion, IKZF1 loss, and BAP1 mutation. Tumors were microsatellite stable with low-to-intermediate tumor mutational burden. One patient received matched targeted therapy through a precision oncology trial. PACC demonstrates substantial clinical heterogeneity with a subset of patients exhibiting prolonged survival despite metastatic disease. Recurrent actionable genomic alterations support routine molecular profiling and prioritization for biomarker-driven trials. These findings challenge extrapolation from PDAC and support a precision oncology framework for this ultra-rare malignancy.