Langenbeck's Archives of Surgery

, Volume 396, Issue 8, pp 1145–1156 | Cite as

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

  • Irvin M. ModlinEmail author
  • Steven F. Moss
  • Bjorn I. Gustafsson
  • Ben Lawrence
  • Simon Schimmack
  • Mark Kidd
Review Article



Neuroendocrine neoplasms (NENs) are increasing in incidence and prevalence. This reflects greater clinical awareness, effective imaging, and increasing pathological diagnostic recognition. Although the identification and treatment of clinical neuroendocrine syndromes are established, there is confusion when a NEN has no discernible clinical symptoms.


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.


Carcinoid Functional Epidemiology Incidence Nonfunctional Pancreatic neuroendocrine tumor SEER Survival 



MK was supported in part by NIH: DK080871. BL was supported in part by a grant from the Genesis Oncology Trust, Auckland, New Zealand.

Conflicts of interest



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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Irvin M. Modlin
    • 1
    Email author
  • Steven F. Moss
    • 2
  • Bjorn I. Gustafsson
    • 3
    • 4
  • Ben Lawrence
    • 1
  • Simon Schimmack
    • 1
    • 5
  • Mark Kidd
    • 1
  1. 1.Gastrointestinal Pathobiology GroupYale University School of MedicineNew HavenUSA
  2. 2.Liver Research CenterBrown UniversityProvidenceUSA
  3. 3.Department of Gastroenterology, St Olavs HospitalNorwegian University of Science and TechnologyTrondheimNorway
  4. 4.Department of Cancer Research and Molecular MedicineNorwegian University of Science and TechnologyTrondheimNorway
  5. 5.Department of General, Visceral, and Transplantation Surgery, Heidelberg University HospitalHeidelbergGermany

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