1

What are carcinoid tumors?

Carcinoid tumors are slow-growing neoplasms of neuroendocrine tissue originating from enterochromaffin or Kulchitsky cells, with a reported incidence of 1 to 2 cases per 100,000 individuals. The term “carcinoid” originally was used to describe a small bowel tumor that was slow-growing but capable of metastatic spread. Carcinoid tumors can secrete an array of bioactive substances, including serotonin, histamine, prostaglandins, vasoactive intestinal peptide, adrenocorticotropic hormone, motilin, kallikreins, bradykinins, and tachykinins (e.g., substance P, neuropeptide K, neurokinin A). Carcinoid tumors arising from the ileum or jejunum appear as dense nests of cells with uniform size and nuclear appearance. Bronchogenic carcinoids may have a typical carcinoid appearance or may resemble oat cell carcinoma of the lung.

Diagnosis of carcinoid tumors can be made by urine and plasma assays of serotonin and its metabolite 5-HIAA; however, 20% of patients with carcinoid syndrome may have normal urinary 5-HIAA levels. Imaging techniques such as computed tomography scan, magnetic resonance imaging, endoscopy, endoscopic ultrasound, abdominal ultrasound, selective mesenteric angiography, and barium small bowel radiography can help identify the primary tumor and, if possible, any metastases. Bronchoscopy can be useful for locating a tumor in the bronchial tree. Localization studies such as radiolabeled somatostatin analogue scintigraphy, bone scintigraphy, and positron emission tomography can be used to identify primary and metastatic tumors. In the absence of carcinoid syndrome, carcinoid tumor may be diagnosed incidentally on chest or abdominal x-ray. Carcinoid syndrome may also be diagnosed in patients undergoing unrelated surgery who present with carcinoid crisis in the perioperative period.

2

Where do carcinoid tumors occur?

Most carcinoid tumors occur in the gastrointestinal tract, most commonly in the appendix, ileum, and rectum. They may also occur in the bronchial tree, genitourinary tract, thyroid, breast, pancreas, thymus, and liver. Because they are slow-growing tumors, carcinoid tumors are usually asymptomatic or produce vague, nonspecific symptoms such as abdominal pain. Over time, these tumors may cause intestinal obstruction or hemoptysis.

Metastatic disease occurs most commonly in the liver, but carcinoid can spread to bone, mesenteric lymph nodes, myocardium, breasts, orbits of the eyes, adrenal glands, ovaries, spleen, pancreas, and lungs. Mesenteric metastases can cause intermittent bowel obstruction and abdominal pain.

Traditional classification of carcinoid tumors is based on the embryonic site of origin because it affects the clinical presentation, the vasoactive substances that are secreted, and overall survival. Foregut carcinoid tumors are located in the thymus, esophagus, stomach, duodenum, pancreas, gallbladder, bronchus, lung, and trachea. Foregut carcinoid tumors may secrete adrenocorticotropic hormone and produce Cushing syndrome. Histamine release is more often associated with foregut carcinoid tumors, particularly tumors arising in the stomach. This histamine release may be due to the presence of histidine decarboxylase in normal gastric mucosa. Midgut carcinoid tumors are found in the jejunum, ileum, Meckel diverticulum, appendix, and colon. These tumors are more often associated with serotonin release and classic carcinoid syndrome. Hindgut carcinoid tumors are located in the rectum and are more likely to manifest with gastrointestinal bleeding. An alternative classification system assigns the term “carcinoid tumor” only to midgut carcinoid tumors. Tumors arising from any other site are referred to as neuroendocrine tumors of the site of origin.

3

Describe the pathophysiology of carcinoid syndrome.

Although about 25% of carcinoid tumors actively secrete bioactive substances, less than 10% of patients develop classic carcinoid syndrome. Because the liver is very efficient at metabolizing these bioactive substances, the syndrome occurs with primary tumors that are located in areas that do not drain into the portal system or with hepatic, bone, gonadal, or pulmonary metastases that bypass hepatic metabolism. Although tumor size may not correlate with the clinical course of the patient, large liver tumors may secrete so much of these bioactive substances that the liver’s ability to inactivate them may be overwhelmed. Carcinoid syndrome may result when the active forms of neuropeptides and amine substances are released into the systemic circulation.

Signs and symptoms of classic carcinoid syndrome include hypotension, hypertension, wheezing, diarrhea, and episodic cutaneous flushing of the head, neck, trunk, and upper extremities. Other possible manifestations include abdominal pain, nausea, vomiting, telangiectasia, right-sided valvular disease, arrhythmias, pericardial effusion, and pellagra (dermatitis, diarrhea, and dementia) ( Box 31-1 ). Dizziness and wheezing may occur with these episodes, which can be triggered by stress, exercise, or ingestion of alcohol, coffee, or serotonin-rich foods such as bananas, avocados, plums, tomatoes, pineapples, kiwis, eggplant, plantains, or walnuts.

Serotonin can cause vasoconstriction or vasodilation, which may manifest as hypertension or hypotension. Elevated serotonin levels can cause inotropic and chronotropic responses in cardiac function; increased gut motility, vomiting, bronchospasm, hyperglycemia, and secretion of water, sodium, chloride, and potassium by the small intestine. Because serotonin is synthesized from tryptophan via hydroxylation and decarboxylation, producing large amounts of serotonin may deplete the body’s tryptophan stores. Tryptophan is an essential amino acid necessary for the synthesis of proteins and nicotinic acid. Hypoproteinemia, hypoalbuminemia, decreased protein synthesis, decreased nicotinic acid production, and the symptoms of pellagra may result.

Histamine release may cause bronchospasm and possibly produce flushing, although this remains unclear. Kallikreins are protease enzymes that generate kinins from kininogens on release into the bloodstream. Bradykinin release may cause profound vasomotor relaxation resulting in severe hypotension. Bradykinins can also cause bronchospasm, particularly in asthmatics and in the presence of cardiac disease, and flushing, likely via increased nitric oxide synthesis. Tachykinins, including neuropeptide K, neurokinin A, vasoactive intestinal peptide, and substance P, may cause flushing and longer term cardiac manifestations. Although the etiology is unclear, elevated levels of serotonin and tachykinins are likely involved in the development of right-sided valvulitis and fibroblast proliferation. Tricuspid regurgitation is a common finding, but tricuspid stenosis, pulmonary insufficiency, and pulmonary stenosis may also develop. These valvular lesions may lead to right-sided heart failure, with edema, hepatomegaly, and fatigue on exertion. Left-sided valvular lesions, including aortic and mitral insufficiency, although less common, may occur. Fibrous tissue growth can interfere with electrical pathways, causing arrhythmias. Pericardial effusions, carcinoid plaques, and myocardial metastases are additional possible complications. Bronchial tumors may be associated with left-sided lesions, pulmonary hypertension, and bronchospasm.