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Carcinoid Syndrome

By

B. Mark Evers

, MD, Markey Cancer Center, University of Kentucky

Last full review/revision May 2020| Content last modified May 2020
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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 the somatostatin analog, octreotide, but surgical removal is done where possible; chemotherapy may be used for malignant tumors.

Etiology

Endocrinologically active tumors of the diffuse peripheral endocrine or paracrine system (neuroendocrine tumors) produce various amines and polypeptides with corresponding symptoms and signs, including carcinoid syndrome. Carcinoid syndrome is usually due to endocrinologically active malignant tumors that develop from neuroendocrine cells (mostly in the ileum—see Small Bowel Tumors) and produce serotonin. It can, however, occur as a result of neuroendocrine tumors elsewhere in the gastrointestinal 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 cause carcinoid 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 cause symptoms.

Pathophysiology

Serotonin acts on smooth muscle to cause 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.

Some patients develop right-sided endocardial fibrosis, leading to pulmonic 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 of carcinoid syndrome is

  • Uncomfortable flushing, typically of the head and neck

Flushing is 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 wheezing due to bronchospasm, and some have decreased libido and erectile dysfunction. Pellagra develops rarely.

Diagnosis

  • Urinary 5-hydroxyindoleacetic acid (5-HIAA)

Serotonin-secreting carcinoids are suspected based on their symptoms and signs. Diagnosis is confirmed by demonstrating increased urinary excretion of the serotonin metabolite 5-HIAA. To avoid false-positive results, clinicians do the test 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-hour urine sample is collected for assay. Normal excretion of 5-HIAA is < 10 mg/day (< 52 micromol/day); in patients with carcinoid syndrome, excretion is usually > 50 mg/day (> 260 micromol/day).

In the past, provocative tests with calcium gluconate, catecholamines, pentagastrin, or alcohol have been used to induce flushing. Although these tests may be helpful when the diagnosis is in doubt, they are rarely used and must be done with care.

Tumor localization

Localization of the tumor involves angiography, CT, or MRI, the same techniques used to localize a nonfunctioning carcinoid. Localization may require extensive evaluation, sometimes including laparotomy. A scan with radionuclide-labeled somatostatin receptor ligand indium-111 pentetreotide, with iodine-123 metaiodobenzylguanidine, or, more recently, with gallium-68 DOTATATE may be useful in identifying metastases with a high degree of sensitivity.

Exclusion of other causes of flushing

Other conditions that manifest 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

Prognosis depends on primary site, grade, and stage. Despite metastatic disease, neuroendocrine tumors are slow growing, and survival of 10 to 15 years is not unusual.

Treatment

  • Surgical resection

  • Octreotide and other drugs for symptoms

Resection of primary gastrointestinal and lung carcinoids is often curative.

For patients with hepatic metastases, surgical debulking, while not curative, may relieve symptoms and, in certain instances, prolong survival. In addition, locoregional therapies for liver metastases could include transarterial chemoembolization (TACE), bland embolization, radioembolization with yttrium-90 microspheres, and radiofrequency ablation. Other promising treatments for progressive disease include everolimus, a mammalian target of rapamycin (mTOR) inhibitor, and newly developed peptide receptor radionuclides.

Radiation therapy is unsuccessful, in part because of the poor tolerance of normal hepatic tissue to radiation.

No effective chemotherapeutic regimen has been established. Combination treatment that includes streptozotocin, 5-fluorouracil, and cyclophosphamide is typically used only for symptomatic patients with grade 2 metastatic disease who are unresponsive to other therapies, or have high tumor proliferation rates. However, the response duration is short.

Symptom relief

Certain symptoms, including flushing, have been relieved by somatostatin analogs (which inhibit release of most hormones) without lowering urinary 5-HIAA or gastrin. Numerous studies have suggested good results with long-acting analogs of somatostatin including octreotide and lanreotide, which are the drugs of choice for controlling diarrhea and flushing. Octreotide is begun with about 50 mcg subcutaneously twice a day, increasing if needed up to 750 mcg total daily dose. After stabilizing for at least 2 weeks on the short-acting formulation, patients may be switched to a depot formulation of octreotide 20 mg intramuscularly every 4 weeks, increasing if needed to a maximum of 30 mg. Lanreotide is a depot formulation given as 120 mg subcutaneously every 4 weeks.

Flushing also can be treated with phenothiazines (eg, prochlorperazine 5 to 10 mg or chlorpromazine 25 to 50 mg orally every 6 hours). Histamine type 2 (H2) blockers may also be used. Phentolamine (an alpha-blocker) 5 to 15 mg IV has prevented experimentally induced flushes. Corticosteroids (eg, prednisone 5 mg orally every 6 hours) may be useful for severe flushing caused by bronchial carcinoids.

Diarrhea may be controlled by

  • Codeine 15 mg orally every 4 to 6 hours

  • Tincture of opium 0.6 mL orally every 6 hours

  • Loperamide 4 mg orally as a loading dose and 2 mg after each loose bowel to a maximum of 16 mg/day

  • Diphenoxylate 5 mg orally 4 times a day

  • Peripheral serotonin antagonists (eg, cyproheptadine 4 to 8 mg orally every 6 hours)

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 orally every 6 hours.

Key Points

  • Only some carcinoid tumors secrete the substances that cause carcinoid syndrome.

  • The main causative substances are serotonin, which causes abdominal cramps and diarrhea, and histamine, which causes flushing.

  • Diagnosis is made by detection of the serotonin metabolite 5-hydroxyindoleacetic acid.

  • Octreotide may help control symptoms.

  • Surgical resection may be curative in the absence of metastases.

  • Surgical debulking may help relieve symptoms and possibly prolong survival in patients with hepatic metastases.

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