Expanding the clinical tumor phenotype of the EPAS1 -asssociated tumor syndrome

CONTEXT: Since the original discovery of the Pacak-Zhuang syndrome (PZS) in 2012, defined by the clinical triad of pheochromocytoma/paraganglioma (PPGL) and/or duodenal ampullar somatostatinoma with erythrocytosis, multiple multisystemic phenotypes have been identified in patients with somatic mosaic pathogenic variants in EPAS1/HIF2A. Deep phenotyping of patients along with evaluation of a transgenic murine model has led to the understanding of the role of HIF-2α in developmental processes, including tumor development. Interestingly, pancreatic neuroendocrine tumors (NETs) occur in von Hippel-Lindau disease and the VHL gene product regulates HIF-2α expression. OBJECTIVE: Characterize pancreatic NETs in PZS. METHODS: We have reviewed the clinical records in the index patient at Addenbrooke's Hospital (UK) and a cohort of patients with PZS from the NIH were assessed for pancreatic NETs. RESULTS: Herein, we describe a novel series from two institutions of patients with EPAS1-associated pancreatic neuroendocrine tumors including a case of a nonfunctioning pancreatic NET in association with an EPAS1 somatic mosaic variant. CONCLUSION: This case study extends our current understanding of the phenotypic spectrum in PZS and links pancreatic NETs to an additional hypoxia-associated gene, namely EPAS1.