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Signs and Symptoms

Neuroendocrine tumours (NETs) are a heterogeneous class of tumours originating from cells in the diffuse endocrine system. NETs most commonly occur in the gastroenteropancreatic (GEP) axis. These are often referred to as GEP NETs. GEP NETs can be grouped into 2 categories based on the location of the tumours^1-3:

• Gastrointestinal neuroendocrine tumours
• Pancreatic neuroendocrine tumours

Depending on whether or not they are associated with specific clinical syndromes, NETs can also be classified as functional or nonfunctional tumours, respectively.

Functional NETs are often detected when the tumours have metastasised to the liver. These metastases release a large concentration of peptide hormones and biogenic amines into circulation by the blood, causing an array of clinical symptoms associated with functional NETs.^4,5

Carcinoid syndrome, which occurs in approximately 10% of people with NETs, is a set of distinct symptoms caused by the secretions of functional GEP NETs. The probability of occurrence and the associated severity of carcinoid syndrome depend on several factors, including tumour size, location, and the degree of metastasis. The incidence of metastases is almost 100% in tumours larger than
2 cm and less than 2% in tumours smaller than 1 cm.^6-8

The excessive secretory activites of GEP NETs lead to carcinoid syndrome because the tumour is unable to:

• Store newly synthesised hormones within the cell
• Respond to a physiological feedback mechanism that regulates the production and release of the hormones

The most common symptoms of carcinoid syndrome are diarrhoea and flushing. Flushing is red or purple colouring that appears suddenly on the face or neck; it may be accompanied by a feeling of warmth or a rapid heartbeat. Additional symptoms may include abdominal pain, heart disease, bloating, and sweating.⁹

In the early stages of the disease, GEP NET patients may exhibit nonspecific symptoms. These patients are often misdiagnosed with other gastrointestinal disorders, such as irritable bowel syndrome. In addition, the age of onset of GEP NETs may vary anywhere from below 30 years to above 50 years old. Due to the vague symptoms and the wide age range of GEP NET patients, correct diagnosis is typically delayed anywhere from 2 to 20 years from the initial onset of symptoms. A surveillance, epidemiology, and end results (SEER) program analysis showed that 40% of patients diagnosed with GEP NETs are diagnosed after the tumours have metastasised.^2,7,9,10

Fig. 1. Adapted with permission from Vinik AI, et al. Dig Dis Sci. 1989;34
(suppl 3):14S-27S.⁷

References: 1. Warner RRP. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668-1684. 2. Modlin IM, Champaneria MC, Chan AKC, Kidd M. A three-decade analysis of 3,911 small intestinal neuroendocrine tumors: the rapid pace of no progress. Am J Gastroenterol. 2007;102:1-10. 3. Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9:61-72. 4. Oberg K. Carcinoid tumors, carcinoid syndrome, and related disorders. In: Larsen P, Kronenberg H, Melmed S, Polonsku K, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: The Curtis Center; 2003:1857-1876. 5. National Comprehensive Cancer Network. Neuroendocrine tumors. In: Practice Guidelines in Oncology—v.1. Fort Washington, PA: National Comprehensive Cancer Network; 2008. 6. Creutzfeldt W. Carcinoid tumors: development of our knowledge. World J Surg. 1996;20:126-131. 7. Vinik A, Moattari AR. Use of Somatostatin analog in management of carcinoid syndrome. Dig Dis Sci. 1989;34:14S-27S. 8. McCormick D. Carcinoid tumors and syndrome. Gastroenterol Nurs. 2001;25:105-111. 9. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:1559-1574. 10. Oberg K. Neuroendocrine gastroenteropancreatic tumours—current views on diagnosis and treatment. Eur Oncol Rev. 2005:1-6.