Pancreatic neuroendocrine neoplasms (PanNENs) represent a heterogeneous group of epithelial tumors of the pancreas showing neuroendocrine differentiation. These neoplasms are classified into well-differentiated pancreatic neuroendocrine tumors (PanNETs), which include G1, G2, and G3 tumors, and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs), which are G3 by definition. This classification mirrors clinical, histologic, and behavioral differences and is also supported by robust molecular evidence.


To summarize and discuss the state of the art regarding neoplastic progression of PanNENs. A better comprehension of the mechanisms underpinning neoplastic evolution and progression of these neoplasms may open new horizons for expanding the biologic knowledge and ultimately for addressing new therapeutic strategies for patients with PanNEN.

Data Sources.—

Literature review of published studies and the authors' own work.


PanNETs can be seen as a unique category, where G1-G2 tumors may progress to G3 tumors mainly driven by DAXX/ATRX mutations and alternative lengthening of telomeres. Conversely, PanNECs display totally different histomolecular features more closely related to pancreatic ductal adenocarcinoma, including TP53 and Rb alterations. They seem to derive from a nonneuroendocrine cell of origin. Even the study of PanNEN precursor lesions corroborates the rationale of considering PanNETs and PanNECs as separate and distinct entities. Improving the knowledge regarding this dichotomous distinction, which guides tumor evolution and progression, will represent a critical basis for PanNEN precision oncology.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.

This study has been supported by the Associazione Italiana Ricerca sul Cancro (AIRC IG n. 26343), the Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017), and the Fondazione Italiana Malattie Pancreas (FIMP-Ministero Salute J38D19000690001).

Presented in part at the Companion Meeting of the Pancreatobiliary Pathology Society at the 2022 United States and Canadian Academy of Pathology Annual Meeting; March 20, 2022; Los Angeles, California.