Pancreatic endocrine neoplasia: familial syndromes

Abstract

While the vast majority of pancreatic neuroendocrine tumours (pNETs) are sporadic, the recognition of an inherited pNET represents an evolving clinical responsibility of practising pathologists in the era of personalized medicine. The initially well-defined inherited pNET syndromes includes multiple endocrine neoplasia type 1 (MEN-1), von Hippel Lindau disease (VHL), neurofibromatosis type 1 (NF) and tuberous sclerosis (TS). Over the past decade, the spectrum of inherited pNETs has been expanded by the inclusion of new presentations such as multiple endocrine neoplasia type 4 (MEN-4), glucagon cell adenomatosis (Mahvash disease) along with germline mutations in DNA repair genes (MUTYH, BRCA2, and CHEK2) in a subset of seemingly sporadic looking pNETs as well as isolated case reports of succinate dehydrogenase deficient (SDH)- and mismatch repair deficient-pNETs occurring in the setting of SDH-related familial paraganglioma syndrome and Lynch syndrome, respectively. The findings have pointed out that the spectrum of inherited pNETs is indeed larger than what most physicians generally anticipate, likely reaching a rate greater than 15% of the overall presentations. From a morphological perspective, the identification of multifocal pNET should prompt the attention of pathologists to the possibility of an underlying genetic susceptibility. Since not all inherited pNETs manifest with multifocal disease, careful morphological assessment of the tumour and the non-tumorous pancreas, and application of immunohistochemical biomarkers are essential in the prediction of inherited pNETs. In order to facilitate the recognition of inherited pNETs, this review is aimed to provide a practical overview of pancreatic endocrine manifestations of MEN-1, MEN-4, VHL, NF-1, TS and glucagon cell adenomatosis.