A larger fraction of endocrine cells in the pancreas are insulin-producing B and glucagon-producing A cells. Relatively minor populations of cells produce somatostatin (D), and pancreatic polypeptide (PP). Rare cells also produce serotonin (EC) and ghrelin (P/D₁).5 These endocrine cells are believed to be the source of pNETs. It is a matter of debate if tumors arise from islets or ducts. Transgenic mice that express potent oncogenes in endocrine cells6 and multiple endocrine neoplasia-1 (MEN-1) knockout mice7,8 point to an islet origin of tumors consistent with the autorenewal properties of islet cells9 and observation in MEN-1 patients.10 Conversely, molecular evidence from islet microdissection in MEN-1 patients indicate a duct cell origin.11 No matter where the truth lies, endocrine tumor cells largely display the same phenotype as their normal endocrine counterpart.

Endocrine tumors are classified on the basis of tumor cell differentiation as well-differentiated tumors/carcinomas (WDET/C) and poorly differentiated carcinomas (PDEC).12 WDET/C are characterized by bland features: trabecular, glandular, acinar, or mixed structures; the stroma is generally fine and rich in well-developed blood vessels, sometimes with hyalinized deposits of amyloid; tumor cells are monomorph with abundant, variably eosinophilic cytoplasm, low cytological atypia, and low mitotic index. Necrosis is usually absent or may be seen as spotty, limited areas in histologically more aggressive neoplasms. On the contrary, PDECs are characterized by a ...