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
(See also Overview of Carcinoid Tumors.)
Etiology of Carcinoid Syndrome
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 of Carcinoid Syndrome
Serotonin, the primary hormone produced by carcinoid tumors, acts on smooth muscle to cause diarrhea, colic, and malabsorption. Histamine and bradykinin, which are produced in smaller amounts, cause flushing through their vasodilator effects.
Some patients develop right-sided endocardial fibrosis, leading to pulmonic stenosis and tricuspid regurgitation. Lesions of the left side of the heart, which have been reported with bronchial carcinoids, are rare because serotonin is destroyed during passage through the lungs.
Symptoms and Signs of Carcinoid Syndrome
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.
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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 of Carcinoid Syndrome
Test for urinary 5-hydroxyindoleacetic acid (5-HIAA)
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< 10 mg/day (< 52 micromol/day); in patients with carcinoid syndrome, excretion is usually > 50 mg/day (> 260 micromol/day).
Tumor localization
Localization of the tumor involves angiography, CT, or MRI. These are 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 menopausevipomas, renal cell carcinoma, medullary thyroid carcinoma).
Prognosis for Carcinoid Syndrome
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 of Carcinoid Syndrome
Surgical resection
Resection of primary gastrointestinal and lung carcinoids is often curative.
Radiation therapy is unsuccessful, in part because of the poor tolerance of normal hepatic tissue to radiation.
Symptom relief
Diarrhea may be controlled by
Tincture of opium 0.6 mL orally every 6 hours
Diphenoxylate 5 mg orally 4 times a day
Peripheral serotonin
serotonin by the tumor. Enzyme inhibitors that prevent the conversion of 5-hydroxytryptophan to serotonin
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.
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.
More Information
The following is an English-language resource that may be useful. Please note that The Manual is not responsible for the content of this resource.
Cancer Net: Neuroendocrine Tumor Grades: Describes the WHO's grading and staging of neuroendocrine tumors
