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Carcinoid tumors are neuroendocrine tumors arising from enterochromaffin (EC) and related cells found in epithelial organs throughout the body. EC cells are the most common endocrine cells and are frequently identified in the mucosa of the intestine and bronchus. Carcinoid tumors synthesize and store a variety of vasoactive substances and hormones. The tumors are commonly classified based on their embryologic site of origin into carcinoids of the foregut, midgut, and hindgut. Tumors within each subgroup have distinct histologic features, metabolism, and secretory products. “Carcinoid syndrome” refers to the complex manifestations of the systemic release of vasoactive compounds and hormones harbored by these tumors. The presence of carcinoid syndrome usually indicates the presence of metastatic disease.

The overall incidence of carcinoid tumors is estimated to be 1 to 2 cases per 100,000 individuals in clinical and surgical series, which is likely an underestimate. Results from autopsy series suggest that the incidence is closer to 0.65% to 1.2%. Carcinoids are generally diagnosed in the fifth or sixth decade of life, have a higher incidence in African-Americans, and are slightly more frequent in women (55%). At presentation, 40% to 60% of patients are asymptomatic.

A recent analysis of 10,878 carcinoid tumors from the Surveillance, Epidemiology, and End Result (SEER) Program of the National Cancer Institute found that 64% of all carcinoid tumors originate in the gastrointestinal tract and 28% originate in the lungs or bronchi. Within the gastrointestinal tract, carcinoids of the small intestine were most common (29%), followed in incidence by tumors of the rectum (14%), stomach (5%), and appendix (5%). The overall incidence of carcinoids has increased over the past 30 years. However, the incidence of carcinoid tumors at various sites has changed when results from sequential tumor registries spanning 1950 to 1999 were reviewed. Incidence rates of gastric carcinoid tumors increased from 2% to 6% and small bowel carcinoid increased from 19% to 29%. In contrast, the incidence rates of appendiceal carcinoids decreased from 44% to just 3%. Differences in reporting and the decreasing incidence of incidental appendectomy may be responsible, in part, for some of these differences.

“Typical” carcinoids have a characteristic histologic appearance of monotonous sheets of small round cells with uniform nuclei and cytoplasm without pleomorphism or mitoses. “Atypical” carcinoids have features associated with more aggressive behavior, such as greater nuclear atypia, higher mitotic rates, and/or necrosis. Malignancy can only be confirmed by the presence of invasion or distant metastases. Carcinoids may be subclassified histologically based on their growth patterns as insular (22%), trabecular (18%), undifferentiated (4%), glandular (2%), or mixed (43%). The historical classification of carcinoids into histologic subtypes based on patterns of silver impregnation (argentaffin-positive, argyrophilic) has been largely replaced by identification of the secretory peptides chromogranin, synaptophysin, and neuron-specific enolase, which are more specific for neuroendocrine tumors. Studies have not confirmed consistent predictors of metastatic behavior, such as mitotic rate, cellular atypia, or necrosis.

Most individuals with carcinoid tumors have abnormal metabolism of tryptophan. Normally, dietary tryptophan is oxidized to nicotinic acid. In individuals with carcinoid tumors, up to 60% of tryptophan instead undergoes 5-hydroxylation into 5-hydroxytryptophan (5-HTP). The bulk of serotonin is metabolized in the liver or kidney to 5-hydroxyindoleacetic acid (5-HIAA), which is then excreted in the urine. Systemic signs or symptoms result from direct secretion of serotonin and other secretory products into the systemic circulation, usually in the presence of liver metastases or bulky retroperitoneal disease.

The molecular pathogenesis of carcinoid tumors is incompletely understood. Carcinoids, particularly gastric carcinoids, occur in 10% of individuals affected with multiple endocrine neoplasia type 1 (MEN 1), an autosomal dominant disorder associated with loss of the tumor suppressor gene MEN1 on chromosome 11q13. For midgut carcinoids, the major areas of chromosomal loss are 18q (54%), 9p (15%), 11q (13%), and 16q (12%). Pulmonary carcinoids are associated with mutations of the p53 tumor suppressor gene and abnormal expression of proteins involved in apoptosis, including bcl-2 and bax. The expression of various growth factors, including basic fibroblast growth factor, vascular endothelial growth factor, transforming growth factor-alpha and beta, trefoil peptides, and platelet-derived growth factor, and some of their receptors has also been reported in carcinoid tumors.

The diagnostic test of choice for suspected carcinoid tumor is the measurement of urinary levels of the major serotonin metabolite 5-HIAA in a 24-hour urine sample. Urinary 5-HIAA levels are elevated in 50% of patients with carcinoids and have a diagnostic sensitivity of 70% and a specificity of 88% to 100%. Another tumor marker, chromogranin A (CGA), contained in the neurosecretory vesicles of neuroendocrine tumor cells, is detectable in the plasma of patients with endocrine neoplasms. Because it does not rely on serotonin secretion, serum CGA is a more sensitive and broadly applicable marker than urinary 5-HIAA. For instance, serum CGA levels may be measured in patients with bronchial and rectal carcinoid tumors in whom urinary 5-HIAA levels are less likely to be elevated.

Carcinoids may be detected incidentally on standard diagnostic studies, including chest radiographs, computed tomography (CT), or endoscopy. Since more than 80% of carcinoid tumors express membrane-bound receptors for the peptide somatostatin, the radiolabeled somatostatin analogue octreotide may be used to detect these tumors. These OctreoScans have a sensitivity of 80% to 90% and may be the initial imaging modality in localizing lesions in carcinoid patients.

The clinical presentation of carcinoid tumors varies depending on the site of origin, physical characteristics, and the release of hormonally active compounds produced and stored by the tumor. Most carcinoids are small, asymptomatic indolent tumors. When present, typical symptoms include flushing and diarrhea. Foregut carcinoids have atypical presentations based on their secretion of hormones other than serotonin. Midgut carcinoids, which contain high levels of serotonin, are symptomatic only in the setting of metastatic or bulky retroperitoneal disease. Hindgut carcinoids are clinically silent unless advanced.

Gastrointestinal carcinoids may present with multiple synchronous primary tumors or with synchronous second malignancies. The presence of metastatic disease in symptomatic patients correlates with the size of the primary lesion and with the location of the tumor. The metastatic risk for carcinoids is least for appendiceal tumors and greatest for rectal primaries. The risk is lowest for subcentimeter-sized tumors and rises with increased size, regardless of the site. Common sites of metastasis are the liver, lung, and bone.

Bronchopulmonary carcinoid tumors account for approximately 28% of all carcinoid tumors. “Typical” carcinoids are well-differentiated pulmonary neuroendocrine tumors with a perihilar location that manifest with recurrent obstructive pneumonia, cough, chest pain, or hemoptysis. “Atypical” carcinoids are larger and located more peripherally, with greater histologic atypia and more numerous mitoses and a more aggressive behavior. Localized tumors may be treated with wedge or segmental resection or with pulmonary lobectomy. The 5-year overall survival rates for bronchopulmonary carcinoid tumors with localized disease, regional spread, and distant metastases are 81%, 77%, and 26%, respectively.

Gastric carcinoids are associated with chronic atrophic gastritis type A (75%) or Zollinger-Ellison syndrome (5% to 10%) or arise sporadically (15% to 20%). Tumors smaller than 1 cm in size may be treated with a limited or endoscopic resection with close endoscopic surveillance. Larger or recurrent tumors and the typically more aggressive sporadic gastric carcinoids usually require more extensive resection. The 5-year overall survival rates for gastric carcinoid tumors with localized disease, regional spread, and distant metastases are 69%, 38%, and 21%, respectively.

The small bowel is the most common site for carcinoid tumors. The incidence of carcinoid tumors increases distally along the length of the small bowel. The tumors are multicentric in 20% to 40% of cases and are associated with a second primary malignancy in 20% to 30% of cases. Advanced disease may induce mesenteric fibrosis, resulting in buckling of the bowel wall, which in turn may cause bowel obstruction or mesenteric ischemia. Treatment for the primary tumor is generally bowel resection with wide en bloc mesenteric resection, to remove any potentially involved regional nodes for better local control. Limited palliative resection may be necessary for obstruction or ischemia due to mesenteric fibrosis. The 5-year overall survival rates for small bowel carcinoid tumors with localized disease, regional spread, and distant metastases are 60%, 73%, and 50%, respectively.

Appendiceal carcinoids are generally incidental findings during appendectomy. Appendectomy is recommended for patients with appendiceal carcinoids smaller than 2 cm, although the management for tumors between 1 and 2 cm in size is controversial. Right colectomy is recommended for tumors larger than 2 cm in size. Although only 5% are larger than 2 cm in size, 33% of these have metastatic disease at presentation. The 5-year overall survival rates for patients with localized disease, regional metastases, and distant metastases are 81%, 88%, and 10%, respectively.

Colonic carcinoid tumors are usually located in the cecum or right colon. Regional or distant metastatic disease is common. Treatment is radical colectomy with en bloc mesenteric resection. The 5-year overall survival rates vary depending on the portion of the colon involved.

Rectal carcinoid tumors are usually asymptomatic and almost never manifest carcinoid syndrome. Tumors smaller than 1 cm may be managed with wide local excision. Management of rectal carcinoids between 1 and 2 cm in size is controversial. Those with involvement of the muscularis propria, symptoms at diagnosis, or ulceration generally have a worse prognosis and should undergo full thickness excision via low anterior resection (LAR) or abdominoperineal resection (APR). Patients with tumors larger than 2 cm in size have such a high risk of distant metastasis that radical local resection offers little if any survival benefit over local excision with sphincter preservation. The 5-year overall survival rates for patients with localized disease, regional metastases, and distant metastases are 90%, 49%, and 26%, respectively.

Metastatic disease is present in 90% of symptomatic patients. The clinical course of patients with metastatic carcinoid is variable. Limited metastatic liver disease may be resected, for both long-term symptomatic relief and prolonged survival. When resection is not possible, tumor ablation may be considered. Liver transplantation results in a 5-year overall survival rate of 69%, but is limited as a treatment modality by organ availability.

Hepatic artery occlusion is a rapidly evolving treatment modality. This treatment modality is based on the fact that the blood supply for liver metastases is primarily derived from the hepatic artery and for hepatocytes is derived primarily from the portal vein. Selective occlusion of the hepatic artery devascularizes tumor cells. Occlusion with embolization provides effective palliation, but is commonly associated with a “postembolization syndrome,” consisting of high fevers, severe pain, nausea, fatigue, and a transient transaminitis.

Carcinoid syndrome is the hormonal manifestation of carcinoid tumors and is associated with poor survival. Common symptoms include flushing, diarrhea, edema, telangiectasia, bronchospasm, and hypotension. Symptoms occur after secretory products from the tumors are released into the systemic circulation, bypassing metabolism in the liver. This usually occurs in the presence of liver metastases, bulky retroperitoneal disease, or primary sites of disease outside the gastrointestinal tract.

Two thirds of patients with carcinoid syndrome have carcinoid heart disease, characterized by fibrous thickening of the endocardium, commonly involving the right side of the heart. The resulting fixation of the valves commonly leads to tricuspid regurgitation, pulmonary stenosis, tricuspid stenosis, and pulmonary regurgitation.

Carcinoid crisis is a life-threatening form of carcinoid syndrome triggered by specific events such as anesthesia, surgery, or chemotherapy, presumably stimulating release of an overwhelming amount of biologically active compounds. Symptoms include flushing, diarrhea, tachycardia, arrhythmias, hypertension or hypotension, bronchospasm, and altered mental status. Subcutaneous or intramuscular administration of 50 mg of octreotide perioperatively reduces the incidence of carcinoid crisis precipitated by anesthesia.

The role for surgery in advanced disease is unclear. When resection is not possible, other treatments are available. The efficacy of various therapies may be evaluated by their biochemical response rate (≥50% reduction in an elevated biomarker, commonly urinary 5-HIAA) or tumor response rate (reduction in tumor size on cross-sectional imaging studies).

Octreotide administered subcutaneously every 8 hours is effective in controlling the symptoms of carcinoid syndrome. Longer acting somatostatin analogues lanreotide (administered every 10 to 14 days) and depot octreotide (administered monthly) are available. Biochemical response rates of 27% to 72% have been observed, but tumor response rates only range from 0% to 9%. Interferon has been evaluated in several trials. Pooled data show biochemical and tumor response rates of 40% and 12%, respectively.

Trials with cytotoxic chemotherapy, as single agents or in combination, have been reported. Response rates, measured by either tumor regression or decrease in urinary 5-HIAA, were 0% to 29%. Currently available biologic therapies and chemotherapy regimens have minimal efficacy in reducing tumor size. More specific targeted therapies employing agents such as thalidomide, bevacizumab, and sunitinib are under investigation.