Home > Treating GEP NETs  > Disease Background

Disease Background - Neuroendocrine Tumours (NETs)

Neuroendocrine tumours (NETs) arise from cells throughout the nervous and endocrine systems, such as cells of the pancreas, parathyroid, adrenal, and pituitary glands, and the calcitonin-producing cells of the thyroid glands and argentaffin cells of the gut.¹

NETs belong to a superclass of heterogenous neoplasms which includes¹:

• Multiple endocrine neoplasia, type 1 and type 2
• Medullary thyroid carcinoma
• Carcinoid tumour
• Islet cell tumours
• Pheochromocytoma/paraganglioma
• Poorly differentiated/small cell/atypical lung carcinoid
• Small cell carcinoma of the lung
• Merkel cell carcinoma

Although most NETs are malignant and metastatic, they are relatively slow growing. As they grow, these tumours produce and secrete excessive amounts of hormones and other substances that are normally regulated in the body in smaller amounts. The excessive secretions of these hormones lead to a constellation of debilitating symptoms.¹

The estimated incidence of NETs is 5.25 people per 100,000 each year. This number is on the rise and is projected to increase to approximately 7 people per 100,000 by the year 2013.^2,3

The most common type of NETs are gastroenteropancreatic neuroendocrine tumours (GEP NETs), which occur in the digestive tract, primarily in the stomach, intestines, or pancreas. GEP NETs comprise of 2% of all gastrointestinal (GI) malignancies. The majority of GEP NETs originate from the small intestine, with an estimated yearly incidence of 2.4 people per 100,000. NETs that originate from areas outside of the GI tract, such as the pancreas, are estimated to occur in 0.4 to 1.5 per 100,000 of the population per year.^4-6

The most common GEP NETs are listed below in order of prevalence^6-11:

• Carcinoid tumours arise from neuroendocrine cells in the appendix, ileum, rectum, and bronchus
• Insulinomas are a type of pancreatic islet cell tumour that secretes excess insulin, and may occasionally secrete other hormones, including gastrin, ACTH, and glucagons
• Gastrinomas are gastrin-releasing tumours of the pancreatic islet cell or duodenum associated with Zollinger-Ellison syndrome
• Vasoactive intestinal peptide (VIP) tumours (VIPomas; Verner-Morrison syndrome) primarily occur in pancreatic islet cells, although they may also occur in the lung, liver, adrenal glands, or sympathetic ganglia. These tumours secrete an excess of VIP, a 28-amino acid peptide hormone
• Glucagonomas are another type of pancreatic islet cell tumour that secretes an excess of glucagon, a 29-amino acid peptide hormone
• Somatostatinomas are a rare type of tumour that occur in the pancreas and small intestine, and which are characterised by diabetes mellitus, gallbladder disease, diarrhea, weight loss, steatorrhea, and hypochlorhydria
• GRFomas involve excessive secretion of growth hormone releasing factor (GRF). These tumours are of unknown frequency and their clinical syndrome is acromegaly

Genes Involved in NETs

Research indicates that the development of NETs is associated with the following genes^12-15:

• Menin (associated with multiple endocrine neoplasia type I)
• RET proto-oncogene (associated with multiple endocrine neoplasia type II, and medullary thyroid carcinoma)
• PRAD

Biology of NETs

The underlying biology of NETs is not fully understood, but several cellular components have been identified to play roles in the growth and activities of NETs^12,16-21:

• Growth factors/receptors, including insulin-like growth factor-1 (IGF-1), transforming growth factor-alpha (TGF-α), the transforming growth factor-beta (TGF-β) family, and the platelet-derived growth factor (PDGF) family
• Cell-surface adhesion molecules, such as CD44
• Angiogenic factors, such as basic fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF)
• Transmembrane receptors, including G protein-coupled receptors, tyrosine-kinase receptors, and ion-gated receptors

Read more details about neuroendocrine tumours (NETs).

References: 1. National Comprehensive Cancer Network. Neuroendocrine tumors. In: Practice Guidelines in Oncology—v.1. Fort Washington, PA: National Comprehensive Cancer Network; 2008. 2. Fazio N, de Braud F, Delle Fave GD, Oberg K. Interferon-α and somatostatin analog in patients with gastroenteropancreatic neuroendocrine carcinoma: single agent or combination? Ann Oncol. 2006:1-7. 3. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063-3072. 4. Oberg K. Neuroendocrine gastroenteropancreatic tumours—current views on diagnosis and treatment. Eur Oncol Rev. 2005:1-6. 5. Oberg K, Jelic S; on behalf of the ESMO Guidelines Working Group. Neuroendocrine gastroenteropancreatic tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008;19(suppl 2):ii104-ii105. 6. Warner RRP. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668-1684. 7. O'Grady HL, Conlon KC. Pancreatic neuroendocrine tumours. Eur J Surg Oncol. 2008;34:324-332. 8. Mansour JC, Chen H. Pancreatic endocrine tumors. J Surg Res. 2004;120:139-161. 9. Ghaferi AA, Chojnacki KA, Long WD, Cameron JL, Yeo CJ. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg. 2008;12:382-393. 10. Redlich PN, Ahrendt SA, Pitt HA. Tumors of the pancreas, gallbladder, and bile ducts. In: Lenhard RE, Osteen RT, Gansler T, eds. Clinical Oncology. Malden, MA: Blackwell Science, Inc; 2001:383-394. 11. Jensen RT. Endocrine tumors of the gastrointestinal tract and pancreas. In: Kasper DL, Fauci AS, Braunwald E, et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. Vol. II. New York, NY: McGraw-Hill, Medical Publishing Division. 2005:2220-2231. 12. Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9:61-72. 13. Hrascan R, Pecina-Slaus N, Martic TN, et al. Analysis of selected genes in neuroendocrine tumours: insulinomas and phaeochromocytomas. J Neuroendocrinol. 2008;20:1015-1022. 14. Rodriguez JM, Balsalobre M, Ponce JL. Pheochromocytoma in MEN 2A syndrome: study of 54 patients. World J Surg. 2008;32:2520-2526. 15. Chung DC. Cyclin D1 in human neuroendocrine: tumorigenesis. Ann N Y Acad Sci. 2004;1014:209-217. 16. von Wichert G, Jehle PM, Hoeflich A, et al. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res. 2000;60:4573-4581. 17. Celikel C, Eren F, Gulluoglu B, Bekiroglu N, Turhal S. Relation of neuroendocrine cells to transforming growth factor-alpha and epidermal growth factor receptor expression in gastric adenocarcinomas: prognostic implications. Pathol Oncol Res. 2007;13:215-226. 18. Blicharz-Dorniak J, Kos-Kudla B, Kudla M, et al. Polypeptide growth factors in gastroenteropancreatic neuroendocrine tumours. Pol J Endocrinol. 2007;58:42-50. 19. Oberg K. Biochemical diagnosis of neuroendocrine GEP tumor. Yale J Biol Med. 1997;70:501-508. 20. Turner HE, Harris AL, Melmed S, Wass JA. Angiogenesis in endocrine tumors. Endocr Rev. 2003;24:600-632. 21. Zhang J, Jia Z, Li Q, et al. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer. 2007;109:1478-1486.