Etiology
Neuroendocrine tumors of the gut are thought to arise from cells of the diffuse endocrine system. These cells are characterized by the production of a wide variety of hormonal peptides and other bioactive substances.[6] Midgut tumors that lead to carcinoid syndrome vary from benign, well-differentiated endocrine tumors to low-grade malignant endocrine tumors.[7] Occasionally, some midgut tumors can be poorly differentiated endocrine carcinomas.
Approximately 40% of neuroendocrine tumors (NETs) are functional. Carcinoid syndrome occurs in 20% to 30% of patients with midgut carcinoid tumors and approximately 5% of bronchial carcinoids. Other foregut tumors (e.g., pancreatic NETs) can cause carcinoid syndrome, although this is uncommon (1%). Hindgut tumors are generally nonfunctional and only occasionally cause carcinoid syndrome. Carcinoid syndrome is usually seen in patients with liver metastases (95% of patients), but excess tachykinins, serotonin (5-hydroxytryptamine [5-HT]) production from retroperitoneal metastases, or ovarian tumors can bypass the liver and systemic circulation.
Pathophysiology
Neuroendocrine tumors normally secrete biogenic amines into the circulation. However, when the primary site is within the gut, the secreted amines are degraded by the liver and symptoms do not generally occur.[8] When liver metastases are present, these amines drain into the circulation prior to being broken down and, hence, cause carcinoid syndrome.[9] The most prominent secretory products of carcinoid tumors are amines, kallikrein, and prostaglandins. One of these amines is 5-HT or serotonin. Normally, serotonin is synthesized from tryptophan and is subsequently metabolized by monoamine oxidase to 5-hydroxyindoleacetic acid, which is subsequently secreted in the urine.[10] In healthy people, approximately 99% of tryptophan is used for the synthesis of nicotinic acid and <1% is converted to 5-HT. However, in patients with carcinoid tumors there is a shift toward the production of 5-HT. The increased production of 5-HT and other products and their direct release into the systemic circulation, due to liver metastases, leads to the development of carcinoid syndrome.[11]
Classification
Functional/nonfunctional
Tumors can be either nonfunctional or functional, depending on whether or not they secrete peptides leading to syndromes (e.g., serotonin and kinins released from neuroendocrine tumors [NETs] leading to carcinoid syndrome).
Foregut/midgut/hindgut
Tumors can be separated depending on embryologic origin:
Foregut: from mouth to duodenum
Midgut: from jejunum to ascending colon
Hindgut: the remaining colon and rectum.
Typical/atypical bronchial NETs
Typical carcinoid tumors generally are slower growing and less likely to metastasize than atypical tumors. Atypical carcinoid tumors are more aggressive than typical tumors, with a higher rate of metastases.
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