ATP1B1::PRKACA fusion-defined intraductal oncocytic papillary neoplasm of the pancreas: a case report

Background: Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas was first described by Adsay and colleagues in 1996 as a distinct intraductal neoplasm characterized by complex arborizing papillae lined by stratified oncocytic cells. Subsequent World Health Organization (WHO) classification grouped IOPN under intraductal papillary mucinous neoplasm (IPMN), including as the oncocytic subtype in the 2010 classification. Molecular characterization later demonstrated that IOPNs lack the KRAS, GNAS, and RNF43 alterations typical of IPMN and instead harbor recurrent PRKACA/PRKACB fusions, supporting the 2019 WHO recognition of IOPN as a distinct entity. These fusions activate protein kinase A signaling, resulting in the characteristic oncocytic morphology. Here we report an ATP1B1::PRKACA fusion-defined IOPN with mixed pancreaticobiliary-type morphology in which the standard cyst fluid panel limited to KRAS, GNAS, and loss of heterozygosity (LOH) was negative, and identify a coexisting likely pathogenic SMAD4 variant in this setting.

Case Description: A 70-year-old woman with autoimmune cholangitis, cardiac sarcoidosis, and heart failure presented with rapid enlargement of a known pancreatic cystic lesion. The mass grew from 8.4 × 6.1 cm to 11 × 7.7 cm within 2 weeks. Computed tomography (CT) demonstrated a multiloculated cystic mass with solid components extending into the retroperitoneum. Cyst fluid molecular testing was interpreted as benign in risk stratification despite rare atypical epithelial cells and discordant imaging features. Despite significant cardiac comorbidities, she underwent pancreaticoduodenectomy with portal vein resection. Pathology revealed a 10.8 cm IOPN of the pancreas. Molecular analysis confirmed ATP1B1::PRKACA fusion. All 23 lymph nodes were negative. At the most recent follow-up on May 1, 2026 (approximately 12 months postoperatively), the patient remained disease-free.

Conclusions: IOPNs represent a molecularly distinct pancreatic neoplasm defined by PRKACA/PRKACB fusions. Our case demonstrates successful surgical management despite significant patient comorbidities. The identification of ATP1B1::PRKACA fusion confirmed the diagnosis in this challenging case. This case highlights the diagnostic limitation of KRAS/GNAS/LOH-based cyst-fluid panels and supports consideration of fusion-inclusive testing in selected discordant cystic lesions rather than routine universal testing.