Differentiation Versus Grade for Pancreatic Neuroendocrine Neoplasms.

Context.—: Pancreatic neuroendocrine neoplasia (panNEN) is a tumor disease with distinctive morphology and often poses diagnostic challenges.

Objective.—: To present and discuss the current diagnostic criteria of PanNEN.

Data sources.—: PanNENs are classified by the World Health Organization (WHO) criteria into well-differentiated neuroendocrine tumor (panNET) and poorly differentiated neuroendocrine carcinoma (panNEC) of large or small cell type. panNETs are graded as G1-G3 on the basis of their proliferation capacity by mitotic count and/or Ki-67 proliferation index. Differentiation and grading are overlapping tools essentially directed to the definition of tumor cell resemblance to the normal cell counterpart (differentiation) and its proliferation capacity (grading). Both tools aim at defining the panNEN malignant potential, and ultimately the overall and event-free survival. The 2 panNEN families mirror different molecular backgrounds. The panNET genotype consistently displays mutation/copy number variation of DAXX (death domain associated protein), ATRX (ATRX chromatin remodeler), and MEN1 (menin 1) genes, while in panNEC the usual cancer drivers TP53 (tumor protein 53), RB1 (RB transcriptional corepressor 1), and KRAS (KRAS proto-oncogene, GTPase) genes are mutated/abnormal. The more subtle differences measured by grade in panNET G1-G3 reflect a progressive gene disorder, with G3 often involving TP53. This rare genetic setting is usually associated with a difficult differential diagnosis between panNET G3 and panNEC. Immunohistochemistry for the informative genes DAXX, ATRX, TP53, RB1, P16 (cyclin-dependent kinase inhibitor 2A), and SST2 (somatostatin receptor 2) are the key to separating panNETG3 and panNEC; however, molecular investigation is often required and decisive. Nonetheless, ambiguous cases may remain unresolved.

Conclusions.—: The WHO diagnostic criteria for panNEN are simple and effective tools for a clinically meaningful patient stratification. Areas of uncertainty remain and deserve further investigation.