The archaic distinction between functioning and nonfunctioning neuroendocrine neoplasms is no longer clinically relevant

Abstract

Nonfunctional tumors are usually diagnosed incidentally and at a later stage largely because either they do not secrete a bioactive product or do so, but in a form that is either inactive or in quantities that have no discernible effect. Nevertheless, the histopathology is indistinguishable from functional NENs, and tumors exhibit somatostatin receptor expression, and positive immunohistochemistry for neuroendocrine cell markers (CgA, NSE/synaptophysin). Similarly, their rates of growth and metastatic behavior are, like other NENs, predictably based on staging and grading (mitotic rate and Ki67 expression). Both types are diagnosed biochemically (CgA) and by imaging in an identical fashion with computed tomography, magnetic resonance imaging, somatostatin receptor scintigraphy, and endoscopic ultrasound. NENs, irrespective of function or bioactive secretory profile, respond with equal efficacy to the same regimen of surgery or antitumor drugs (e.g., somatostatin analogs with or without tyrosine kinase inhibitors/antiangiogenics or cytotoxics) depending on grade. Given the efficacy of somatostatin analogs in increasing progression free survival, nonfunctional NENs should be managed identically to symptomatic NENs. The consideration of NENs as functional or nonfunctional is an archaic clinical concept that should be discarded since the tumors are indistinguishable at a cellular, biological, and morphological level. All current evidences indicate that their diagnosis and treatment should follow the same common principles.

Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model

“…Neuroendocrine tumors (NETs) consist of a heterogeneous group of neoplasms originating from cells characterized by the synthesis and release of amines/peptides [1]. Since 1973, the incidence of NETs has been increasing, in which genetic factors might play a role [2] and in addition improved diagnostics contributed to a higher registered incidence of NETs [1].…”

Clinicopathological features of gastroenteropancreatic neuroendocrine tumors: A retrospective evaluation of 42 cases

“…Various typical symptoms can be seen related to carcinoid syndrome, Zollinger-Ellison syndrome, Whipple's triad, Verner-Morrison syndrome, insulinoma, and glucagonoma (11). However, Modlin et al (12) advocated that categorizing these tumors as functional or nonfunctional is an archaic clinical concept because they are indistinguishable at the cellular, biological, and morphological levels.…”

Cystic pancreatic neuroendocrine tumors: To date a diagnostic challenge

“…It would be expected to apply more practically the classifications listed above, but some controversial issues in the preoperative diagnoses of the pancreatic NETs still remain. The classification of PNETs is complex and generally subdivided into either functional or non-functional, although the clinical relevance of this distinction has recently been questioned as the treatment of these tumors follow the same general principles [20].…”