EWSR1::BEND2 gene fusions characterize a majority of ACTH-producing neuroendocrine neoplasms of the pancreas: A follow-up study and brief review of the recent literature.

ACTH-producing pancreatic neuroendocrine neoplasms (PanNENs) are a rare aggressive subset of panNETs associated with clinical symptoms of ectopic Cushing syndrome. Until recently, their molecular pathogenesis remained poorly understood. Following our prior study highlighting high frequency of gene fusions (mostly EWSR1::BEND2) in them, we herein document our experience with 5 new tumors occurring in 4 women (one of unspecified sex) aged 36 to 79 (median, 45). All presented with clinical and biochemical signs of ectopic Cushing syndrome. Histologically, the tumors corresponded to NET grade 2 (n = 3) and grade 3 (n = 2). At last follow-up, three patients were alive with metastatic disease at 36, 48 and 72 months from initial diagnosis, one died of disease at 50 months and one was disease-free at 15 months. Targeted RNA sequencing revealed an EWSR1::BEND2 fusion in two cases and a possible CSE1L::TAF15 fusion in one. Two tumors were negative for fusions. This small series and review of the recent literature further confirm the significant association between the EWSR1::BEND2 fusions and ectopic ACTH-production in PanNETs with an overall frequency of ectopic Cushing among EWSR1::BEND2 fusion tumors of 70%. Given their highly aggressive course, recognition of this molecular subtype of panNETs is mandatory. Emerging BEND2 IHC represents a promising screening tool for recognizing these tumors.