Carcinoid syndrome develops in some people with carcinoid tumors and is characterized by cutaneous flushing, abdominal cramps, and diarrhea. Right-sided valvular heart disease may develop after several years. The syndrome results from vasoactive substances (including serotonin, bradykinin, histamine, prostaglandins, polypeptide hormones) secreted by the tumor, which is typically a metastatic intestinal carcinoid. Diagnosis is clinical and by demonstrating increased urinary 5-hydroxyindoleacetic acid. Tumor localization may require a radionuclide scan or laparotomy. Treatment of symptoms is with somatostatin or octreotide, but surgical removal is performed where possible; chemotherapy may be used for malignant tumors.

Etiology

Endocrinologically active tumors of the diffuse peripheral endocrine or paracrine system produce various amines and polypeptides with corresponding signs and symptoms, including carcinoid syndrome. Carcinoid syndrome is usually due to endocrinologically active malignant tumors that develop from neuroendocrine cells (mostly in the ileum) and produce serotonin. It can, however, occur from tumors elsewhere in the GI tract (particularly the appendix and rectum), pancreas, bronchi, or, rarely, the gonads. Rarely, certain highly malignant tumors (eg, oat cell carcinoma of the lung, pancreatic islet cell carcinoma, medullary thyroid carcinoma) are responsible.

An intestinal carcinoid does not usually produce the syndrome unless hepatic metastases have occurred, because metabolic products released by the tumor are rapidly destroyed by blood and liver enzymes in the portal circulation (eg, serotonin by hepatic monoamine oxidase). Hepatic metastases, however, release metabolic products via the hepatic veins directly into the systemic circulation. Metabolic products released by primary pulmonary and ovarian carcinoids bypass the portal route and may similarly induce symptoms. Rare intestinal carcinoids with only intra-abdominal spread can drain directly into the systemic circulation or the lymphatics and produce symptoms.

Pathophysiology

Serotonin acts on smooth muscle to produce diarrhea, colic, and malabsorption. Histamine and bradykinin, through their vasodilator effects, cause flushing. The role of prostaglandins and various polypeptide hormones, which may be produced by paracrine cells, awaits further investigation; elevated human chorionic gonadotropin and pancreatic polypeptide levels are occasionally present with carcinoids.

Many patients develop right-sided endocardial fibrosis, leading to pulmonary stenosis and tricuspid regurgitation. Left heart lesions, which have been reported with bronchial carcinoids, are rare because serotonin is destroyed during passage through the lungs.

Symptoms and Signs

The most common (and often earliest) sign is an uncomfortable flushing, typically of the head and neck, often precipitated by emotional stress or the ingestion of food, hot beverages, or alcohol. Striking skin color changes may occur, ranging from pallor or erythema to a violaceous hue. Abdominal cramps with recurrent diarrhea occur and are often the patient's major complaint. Malabsorption syndrome may occur. Patients with valvular lesions may have a heart murmur. A few patients have asthmatic wheezing, and some have decreased libido and erectile dysfunction; pellagra develops rarely.

Diagnosis

• Urinary 5-hydroxyindoleacetic acid

Serotonin-secreting carcinoids are suspected on the basis of their symptoms and signs. Diagnosis is confirmed by demonstrating increased urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). To avoid false-positive results, measurement is performed after the patient has abstained from serotonin-containing foods (eg, bananas, tomatoes, plums, avocados, pineapples, eggplant, walnuts) for 3 days. Certain drugs, including guaifenesin, methocarbamol, and phenothiazines, also interfere with the test and should be stopped temporarily before testing. On the 3rd day, a 24-h urine sample is collected for assay. Normal excretion of 5-HIAA is < 10 mg/day (< 52 μmol/day); in patients with carcinoid syndrome, excretion is usually > 50 mg/day (> 260 μmol/day).

Provocative tests with Ca gluconate, catecholamines, pentagastrin, or alcohol have been used to induce flushing. These tests may be helpful when the diagnosis is in doubt, but they must be done with care. Localization of the tumor involves the same techniques used to localize a nonfunctioning carcinoid (see Carcinoid Tumors: Introduction) but may require extensive evaluation, sometimes including laparotomy. A scan with radionuclide-labeled somatostatin receptor ligand indium-111 pentetreotide or with iodine-123 metaiodobenzylguanidine may demonstrate metastases.

Other conditions that present with flushing and that could, therefore, be confused with carcinoid syndrome should be excluded. In patients in whom 5-HIAA excretion is not increased, disorders that involve systemic activation of mastocytes (eg, systemic mastocytosis with increased urinary levels of histamine metabolites and increased serum tryptase level) and idiopathic anaphylaxis may be responsible. Additional causes of flushing include menopause, ethanol ingestion, drugs such as niacin, and certain tumors (eg, vipomas, renal cell carcinoma, medullary thyroid carcinoma).

Prognosis

Despite metastatic disease, these tumors are slow growing, and survival of 10 to 15 yr is not unusual.

Treatment

• Surgical resection
• Octreotide for symptoms

Resection of primary lung carcinoids is often curative. For patients with hepatic metastases, surgery is only diagnostic or palliative, and radiation therapy is unsuccessful, in part because of the poor tolerance of normal hepatic tissue to radiation. No effective chemotherapeutic regimen has been established, but streptozocin with 5-fluorouracil is most widely used, sometimes with doxorubicin.

Certain symptoms, including flushing, have been relieved by somatostatin (which inhibits release of most hormones) without lowering urinary 5-HIAA or gastrin. Numerous studies have suggested good results with octreotide, a long-acting analog of somatostatin. Octreotide is the drug of choice for controlling diarrhea and flushing. Case reports indicate that tamoxifen has been effective infrequently; leukocyte interferon (IFN-α) has temporarily relieved symptoms.

Flushing also can be treated with phenothiazines (eg, prochlorperazine 5 to 10 mg or chlorpromazine 25 to 50 mg po q 6 h). Histamine₂ blockers may also be used. Phentolamine (an α-blocker) 5 to 15 mg IV has prevented experimentally induced flushes. Corticosteroids (eg, prednisone 5 mg po q 6 h) may be useful for severe flushing caused by bronchial carcinoids.

Diarrhea may be controlled by codeine phosphate 15 mg po q 4 to 6 h, tincture of opium 0.6 mL po q 6 h, loperamide 4 mg po as a loading dose and 2 mg after each loose bowel to a maximum of 16 mg/day, diphenoxylate 5 mg po qid, or peripheral serotonin antagonists such as cyproheptadine 4 to 8 mg po q 6 h or methysergide 1 to 2 mg po qid.

Niacin and adequate protein intake are needed to prevent pellagra, because dietary tryptophan is diverted to serotonin by the tumor. Enzyme inhibitors that prevent the conversion of 5-hydroxytryptophan to serotonin include methyldopa 250 to 500 mg po q 6 h and phenoxybenzamine 10 mg/day.

Last full review/revision May 2008 by Courtney M. Townsend, Jr., MD