(See also Overview of Carcinoid Tumors Overview of Carcinoid Tumors Carcinoid tumors develop from neuroendocrine cells in the gastrointestinal tract (90%), pancreas, pulmonary bronchi, and rarely the genitourinary tract. More than 95% of all gastrointestinal... read more .)
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 Small-Bowel Tumors Small-bowel tumors account for 1 to 5% of gastrointestinal tumors. Small-bowel cancer accounts for an estimated 11,110 cases and about 1,700 deaths in the US annually ( 1). Diagnosis is by enteroclysis... read more ) 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 Bronchial Carcinoid Bronchial carcinoids are rare (1 to 2% of all lung cancers in adults), slow-growing neuroendocrine tumors arising from bronchial mucosa; they affect patients in their 40s to 60s. Carcinoid tumors... read more , or, rarely, the gonads. Rarely, certain highly malignant tumors (eg, oat cell carcinoma of the lung, pancreatic islet cell carcinoma Overview of Pancreatic Endocrine Tumors Pancreatic endocrine tumors arise from islet and gastrin-producing cells and often produce many hormones. Although these tumors develop most often in the pancreas, they may appear in other organs... read more , medullary thyroid carcinoma Medullary Thyroid Carcinoma There are 4 general types of thyroid cancer. Most thyroid cancers manifest as asymptomatic nodules. Rarely, lymph node, lung, or bone metastases cause the presenting symptoms of small thyroid... read more ) 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.
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 Pulmonic Stenosis Pulmonic stenosis (PS) is narrowing of the pulmonary outflow tract causing obstruction of blood flow from the right ventricle to the pulmonary artery during systole. Most cases are congenital... read more and tricuspid regurgitation Tricuspid Regurgitation Tricuspid regurgitation (TR) is insufficiency of the tricuspid valve causing blood flow from the right ventricle to the right atrium during systole. The most common cause is dilation of the... read more . Lesions of the left side of the heart, which have been reported with bronchial carcinoids Bronchial Carcinoid Bronchial carcinoids are rare (1 to 2% of all lung cancers in adults), slow-growing neuroendocrine tumors arising from bronchial mucosa; they affect patients in their 40s to 60s. Carcinoid tumors... read more , 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 Overview of Malabsorption Malabsorption is inadequate assimilation of dietary substances due to defects in digestion, absorption, or transport. Malabsorption can affect macronutrients (eg, proteins, carbohydrates, fats)... read more may occur.
Patients with valvular lesions may have a heart murmur Cardiac Auscultation Auscultation of the heart requires excellent hearing and the ability to distinguish subtle differences in pitch and timing. Hearing-impaired health care practitioners can use amplified stethoscopes... read more . A few patients have wheezing due to bronchospasm, and some have decreased libido and erectile dysfunction Erectile Dysfunction Erectile dysfunction is the inability to attain or sustain an erection satisfactory for sexual intercourse. Most erectile dysfunction is related to vascular, neurologic, psychologic, and hormonal... read more . Pellagra Niacin Deficiency Dietary niacin deficiency (causing pellagra) is uncommon in developed countries. Clinical manifestations include the three Ds: localized pigmented rash (dermatitis); gastroenteritis (diarrhea)... read more 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-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.
Localization of the tumor involves angiography, CT, or MRI. These are the same techniques used to localize a nonfunctioning carcinoid Overview of Carcinoid Tumors Carcinoid tumors develop from neuroendocrine cells in the gastrointestinal tract (90%), pancreas, pulmonary bronchi, and rarely the genitourinary tract. More than 95% of all gastrointestinal... read more . 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 Systemic mastocytosis Mastocytosis is mast cell infiltration of skin or other tissues and organs. Symptoms result mainly from mediator release and include pruritus, flushing, and dyspepsia due to gastric hypersecretion... read more with increased urinary levels of histamine metabolites and increased serum tryptase level) and idiopathic anaphylaxis Anaphylaxis Anaphylaxis is an acute, potentially life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing antigen. Symptoms... read more may be responsible.
Additional causes of flushing include menopause Menopause Menopause is physiologic or iatrogenic cessation of menses (amenorrhea) due to decreased ovarian function. Manifestations may include hot flushes, night sweats, sleep disruption, and genitourinary... read more , ethanol ingestion, drugs such as niacin, and certain tumors (eg, vipomas Vipoma A vipoma is a non-beta pancreatic islet cell tumor secreting vasoactive intestinal peptide (VIP), resulting in a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). Diagnosis... read more , renal cell carcinoma Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more , medullary thyroid carcinoma Medullary Thyroid Carcinoma There are 4 general types of thyroid cancer. Most thyroid cancers manifest as asymptomatic nodules. Rarely, lymph node, lung, or bone metastases cause the presenting symptoms of small thyroid... read more ).
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
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, or radiofrequency ablation. Other promising treatments for metastatic or recurrent 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 (intermediate grade) metastatic disease who are unresponsive to other therapies, or have high tumor proliferation rates. However, the response duration is short.
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 orally every 6 hours 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)
Telotristat, a tryptophan hydroxylase inhibitor, 250 mg orally 3 times a day
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.
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.
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