Relevant Physiology and Pathophysiology
Carcinoid tumors are an interesting group of neoplasms that have their origin in the endocrine argentaffin cells in the small intestinal mucosa (argentaffinomas). They are found incidentally in 0.50% to 0.75% of autopsies. Carcinoid tumors occur frequently in the ileum, where argentaffin cells are more abundant, and 20% of these tumors are multifocal. Histologic criteria do not help the physician to distinguish benign from malignant carcinoid tumors. The tumors are invariably small. About 80% of tumors more than 2 cm in diameter metastasize; those less than 1 cm are almost always benign. Metastases are to local lymph nodes, liver, lung, and bone. Carcinoid tumors may induce a reactive fibrosis in the bowel mesentery, sometimes creating an angulated intestinal segment. Even malignant and metastatic carcinoid tumors are indolent. More than 50% of patients with unresectable local metastases survive 5 years, as do about 30% of those with liver metastases. About 10% of individuals with liver metastases survive more than 10 years.

Laboratory and Other Diagnostic Tests
The biochemical marker for the carcinoid syndrome is increased urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA). More than 30 mg of 5-HIAA is usually excreted in 24 hours by patients with carcinoid syndrome. Less striking increases in urinary 5-HIAA may be found in some patients with malabsorption such as occurs in celiac disease and bacterial overgrowth syndromes. Blood serotonin and 5-hydroxytryptophan levels can now be determined; the latter is helpful if gastric carcinoid is suspected. When urinary 5-HIAA excretion is being tested, patients should avoid drugs that may produce false-positive test results, most notably glyceryl guaiacolate, phenothiazines, and methenamine mandelate. Foods rich in serotonin should also be avoided. These include pineapples, bananas, avocados, and walnuts.

Carcinoid tumors may secrete a variety of other hormones, including insulin, adrenocorticotropic hormone, melanocyte-stimulating hormone, gastrin, and glucagon. The endocrine cells from which carcinoid tumors originate are part of the amine content, precursor uptake, and decarboxylation (APUD) family. Foregut carcinoid tumors have also been associated with pluriglandular adenomatoses (e.g., pituitary, adrenal, and parathyroid tumors) and with pancreatic gastrinomas.

Differential Diagnosis
Carcinoid tumors of the small bowel seldom ulcerate and bleed and are usually too small to cause obstruction. They may, however, produce transient intussusceptions and cause cramping abdominal pain and diarrhea. These symptoms may be long standing and intermittent, suggesting irritable bowel syndrome or Crohn’s disease.

In about one third of patients with liver metastases, carcinoid syndrome, which occurs rarely with only nodal metastases, develops. Carcinoid syndrome is characterized primarily by episodes of flushing and diarrhea. The flush may produce a cyanotic appearance, and if attacks are prolonged, facial edema and telangiectasis may develop. The mediator of the carcinoid flush is unknown. Kallikrein, bradykinin, other kinin peptides, substance P, prostaglandins, serotonin, and histamine have been implicated. The flush has been precipitated by ingestion of a meal and by administration of ethanol, calcium, epinephrine, isoproterenol, and pentagastrin. The diarrhea and cramps in this syndrome appear to be related to the production of serotonin (5-hydroxytryptamine).

Bronchial spasm is often part of carcinoid syndrome, and wheezing may become a prominent feature. Right-sided heart lesions, particularly pulmonary and tricuspid valvular fibrosis, may develop with associated murmurs of pulmonary stenosis and tricuspid insufficiency. Right-sided congestive heart failure may produce further hepatomegaly, ascites, pulmonary congestion, and edema.

Diarrhea in carcinoid syndrome is usually watery, episodic, and associated with abdominal cramping and loud borborygmi. Gastric carcinoids that tend to produce more 5-hydroxytryptophan than serotonin and that also may produce histamine usually are not associated with diarrhea.

Most patients with carcinoid syndrome have liver metastases, which are usually evident on physical examination and liver scans. Carcinoid tumors with nodal metastases that produce the syndrome may cause a palpable abdominal mass. Ovarian carcinoid tumors are usually detected by abdominal or pelvic examination, and bronchial carcinoid tumors by chest radiography.

Management
Carcinoid tumors of the small bowel should be surgically resected. If metastatic disease is present, the approach remains the same as in other bowel malignancies. In patients with the carcinoid syndrome all treatment must be carefully monitored and controlled to prevent precipitating a carcinoid crisis. Chemotherapy has had some benefit in unresectable disease, but treatment efforts, in general, should be tempered by the usually indolent growth of these tumors. A variety of antiserotonin agents, antihistamines, antiadrenergics, antiprostaglandins, and steroids have been helpful in the carcinoid syndrome, but benefits must be weighed against side effects. Intravenous somatostatin has been used to ameliorate acute symptoms, and subcutaneous somatostatin analogs have become important agents for successful long-term control.

Author: Charles J. Lightdale

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