The peak incidence of neuroendocrine tumors is in the sixth decade, but they may appear at any age. Symptoms are determined by the hormones produced. For example, the carcinoid syndrome is caused by vasoactive substances secreted by the tumor that cause cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea, and right-sided cardiac valvular fibrosis. When tumors are confined to the intestine, the vasoactive substances released are metabolized to inactive forms by the liver—a “firstpass” effect similar to that seen with oral drugs. Thus, carcinoid syndrome occurs in less than 10% of patients and is strongly associated with metastatic disease.
The most important prognostic factor for gastrointestinal neuroendocrine tumors is location: • Foregut neuroendocrine (carcinoid) tumors found within the stomach, duodenum proximal to the ligament of Treitz, and esophagus, rarely metastasize and are generally cured by resection. Rare duodenal gastrin-producing neuroendocrine tumors, also termed gastrinomas, may present with symptoms related to increased acid production, including pain and/or bleeding from gastroduodenal ulcers, refractory gastroesophageal reflux, and diarrhea due to inactivation of pancreatic enzymes by excessive gastric acid.
Midgut neuroendocrine (carcinoid) tumors arise in the jejunum and ileum, are often multiple and tend to be aggressive. In these tumors, depth of local invasion, size, and the presence of necrosis and mitoses are associated with poor outcome.
Hindgut neuroendocrine (carcinoid) tumors arising in the appendix and colorectum are typically discovered incidentally. Those in the appendix occur at any age and are almost uniformly pursue a benign course. Rectal tumors tend to produce polypeptide hormones and may manifest with abdominal pain and weight loss. Because they are usually discovered when small, metastasis of rectal neuroendocrine tumors is uncommon.
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the abdomen, and more than half of these tumors occur in the stomach. A wide variety of other mesenchymal neoplasms may arise in the stomach. Many are named according to the cell type they most resemble; for example, smooth muscle tumors are called leiomyomas or leiomyosarcomas, nerve sheath tumors are termed schwannomas, and those resembling glomus bodies in the nail beds and at other sites are termed glomus tumors. These tumors are all rare and are not discussed here.
The most common genetic change underlying the pathogenesis of GISTs is gain-of-function mutations of the gene encoding the tyrosine kinase KIT, the receptor for stem cell factor. These are present in 75% to 85% of all GISTs. An additional 8% of GISTs have mutations that activate a related tyrosine kinase, platelet-derived growth factor receptor A (PDGFRA). The term stromal reflects historical confusion about the origin of this tumor, which is now recognized to arise from the interstitial cells of Cajal, or pacemaker cells, of the gastrointestinal muscularis propria. For unknown reasons, GISTs bearing PDGFRA mutations are overrepresented in the stomach. KIT and PDGFRA gene mutations are mutually exclusive, reflecting their activities within the same signal transduction pathway. Germ line mutations in these same genes are present in rare familial GISTs, in which patients develop multiple GISTs and may also have diffuse hyperplasia of Cajal cells.