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Incidence: 1/100,000

~85% sporadic

~15% hereditary, for example, multiple endocrine neoplasia (MEN1), von Hippel-Lindau disease

Median age: 53–57 years
Male to female ratio: 0.8–1.3:1

Ekeblad SB et al. Clin Cancer Res 2008;14:7798–7803

Fischer L et al. Br J Surg 2008;95:627–635

Hochwald SN et al. J Clin Oncol 2002;20:2633–2642

Öberg K, Eriksson B. Best Pract Res Clin Gastroenterol 2005;19:753–781

Tomassetti PD et al. Ann Oncol 2005;16:1806–1810


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2017 WHO Classification: Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NEN)

Morphology Grade Ki–67 Index (%) Mitotic Count (2 mm2)
Well-differentiated neuroendocrine tumor Grade 1 <3% of cells Ki67+ Mitotic index <2
Well-differentiated neuroendocrine tumor Grade 2 2–20% of cells Ki67+ Mitotic index 2–20
Well-differentiated neuroendocrine tumor Grade 3 >20% of cells Ki67+ Mitotic index >20
Poorly differentiated neuroendocrine carcinoma      
 Small cell type Grade 3 >20% of cells Ki67+ Mitotic index >20
 Large cell type Grade 3 >20% of cells Ki67+ Mitotic index >20
Mixed neuroendocrine-non-neuroendocrine neoplasm      
Tumor-like lesions      

Note: Final grading is assigned based on whichever index (Ki67 or mitotic) places the tumor in the higher grade category

Lloyd RV et al (editors). WHO Classification of Tumors of Endocrine Organs, 4th ed, Volume 10. Lyon: IARC Press; 2017:211

Functional status:

Intestinal NETs

  • Presenting with carcinoid syndrome: 20%

  • Presenting without carcinoid syndrome: 80%

Notes: Carcinoid syndrome—symptoms and (secreted products):

− Flushing (prostaglandin, kinins, substance P)

− Diarrhea (serotonin)

− Wheezing (histamine, kinins)

− Endocardial fibrosis (serotonin)

Pancreatic NETs

Nonfunctioning: 59–76%

Functioning: 24–41%

Insulinoma: 8–17%

Gastrinoma: 10–14%

Glucagonoma: 1–6%

VIPoma: 2–5%

Notes: Functioning tumors—symptoms and (secreted products):

− Zollinger-Ellison syndrome (gastrin)

− Hypoglycemia (insulin)

− Necrolytic erythema (glucagon)

− Hyperglycemia

− WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome (vasoactive intestinal polypeptide [VIP])

− Diabetes, gallstones, diarrhea (somatostatin)

− Cushing syndrome (corticotropin-releasing hormone [CRH], adrenocorticotropic hormone [ACTH])

− Acromegaly (growth hormone releasing hormone [GHRH], growth hormone [GH])

− Hypercalcemia (parathyroid hormone related protein [PTHrP])

− Flushing (calcitonin)

− Diarrhea (serotonin)


Ekeblad SB et al. Clin Cancer Res 2008;14:7798–7803

Fischer L et al. Br J Surg 2008;95:627–635

Pape U-F et al. Cancer 2008;113:256–265

Rindi G, Klöppel G. Neuroendocrinology 2004;80(Suppl 1):12–15



  1. Body CT or MRI

  2. Positron emission tomography (PET) scan—as part of the staging and preoperative imaging and in selected cases at restaging

    • 68Ga/64Cu-labeled somatostatin analog PET/CT

    • (11C)5-hydroxy-l-tryptophan (5-HTP) PET/CT for well-differentiated tumors

    • Fluorodeoxyglucose (FDG) PET/CT for poorly differentiated tumors

  3. If the above not available, then use somatostatin receptor scintigraphy (SRS): Uses radioactive octreotide, a drug similar to somatostatin that attaches to tumor cells that have somatostatin receptors. It is less sensitive

  4. Serum chromogranin levels may be helpful in following patient

  5. Endoscopic ultrasound

  6. Intraoperative ultrasound

    • To localize small tumors not visualized by other modalities but suspected because of biochemical findings

    • To localize multiple tumors in MEN1 patients


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