Rare Disease Database
NORD gratefully acknowledges Henrietta Wilson, MBBS, BSc, Department of Oncology, Royal Surrey County Hospital, Guildford, Surrey, UK, for assistance in the preparation of this report.
Synonyms of Carcinoid Syndrome
- carcinoid apudoma
- carcinoid cancer
- carcinoid disease
- functioning argentaffinoma
- functioning carcinoid
- malignant carcinoid syndrome
- neuroendocrine tumor carcinoid type
Signs & Symptoms
Symptoms may be non-hormonal, secondary to tumor bulk and therefore depend on location; or hormonal as a result of carcinoid syndrome. Those caused by the tumour may include abdominal pain, anemia, pneumonia, cough and haemoptysis (cough productive of blood). Carcinoid tumors can also be present without producing any symptoms and may often go undetected for a long period of time.
The symptoms of carcinoid syndrome include episodes of warmth and redness of the face, head and upper chest; diarrhea; marked changes in blood pressure (usually hypotension, a decrease in blood pressure); asthmatic-like wheezing; weight loss or gain; malnutrition; dehydration; weakness; muscle and joint aching; and peptic ulcer.
In later stages, carcinoid syndrome may damage the heart valves, resulting in symptoms of congestive heart failure. The diarrhea may be so severe that vital nutrients of the body, such as potassium and water, are depleted creating life-threatening electrolyte imbalance. The syndrome may also be accompanied by stomach pain, blockage of the arteries in the liver, heart palpitations and excessive peptide excretion in the urine. In extremely rare cases, the acute occurrence of flushing, blood pressure changes, weakness, palpitations, faintness and wheezing constitutes a carcinoid crisis that can be life-threatening. Not all of these features need be present in a carcinoid crisis or for a diagnosis of carcinoid syndrome.
The underlying cause of carcinoid tumors remains unclear. Some studies have suggested risk factors such as smoking and dietary intake, however, further research is needed to confirm these findings. In the majority of cases tumors are slow-growing and can produce hormonal chemical substances such as serotonin, bradykinins, tachykinins and prostaglandins. If the original carcinoid cells spread (metastasize) to the liver, these substances are no longer broken down to their inactive form and are released into the systemic (main) circulation, causing the signs and symptoms of carcinoid syndrome. When tumors affect organs other than the gastrointestinal tract, such as the ovaries, carcinoid syndrome can occur in the absence of liver metastases.
Carcinoid tumors are rare, with only 27 new cases per million diagnosed in the U.S. per year. Of these, only about 10% will develop carcinoid syndrome. The syndrome affects males and females in equal numbers. All races can be affected though there is a slightly increased prevalence in black African males. All ages can be affected but most gastrointestinal cases occur in middle-age. Bronchial (airway) tumors are most often seen in the fifth decade but can affect people at any age. Carcinoid syndrome may be more prevalent than suspected because diagnosis is difficult and sometimes overlooked; some patients may not exhibit all three of the hallmark symptoms of flushing, wheezing, and diarrhea.
Symptoms of the following disorders can be similar to those of carcinoid syndrome. Comparisons may be useful for a differential diagnosis:
Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder in which benign (noncancerous) tumors arise from the cells of various glands of the endocrine system. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. In individuals with MEN type 1, benign tumors develop in multiple endocrine glands, most often the parathyroid, pancreas and pituitary glands. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms. Some benign tumors associated with MEN type 1 can become malignant (cancerous). MEN type 1 can run in families or can occur as the result of a spontaneous new gene mutation in the affected person.
Pancreatic cholera or VIPoma is characterized by watery diarrhea, the loss of potassium through the urine (hypokalemia) and acidosis. In most cases this disorder is due to a non-B-islet-cell tumor of the pancreas that secretes vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine. The episodes of diarrhea in association with profound loss of potassium, hypochlorhydria, and metabolic acidosis can be a life-threatening situation due to the excessive fluid and electrolyte loss.
Zollinger-Ellison syndrome is an unusual condition characterized by small tumors (usually of the pancreas) that secrete a hormone that produces excess amounts of stomach (gastric) juices and resultant peptic ulcers (gastrinoma). These tumors can also appear in the lower stomach wall, spleen or lymph nodes close to the stomach. Large amounts of gastric acid can be found in lower stomach areas where ulcers can form. Pain from these persistent ulcers may be severe. Diarrhea and excretion of fat in the feces (steatorrhea) commonly occurs. This can result in a decrease of potassium levels in the blood. (For more information on this disorder, choose “Zollinger” as your search term in the Rare Disease Database.)
Cushing syndrome consists of a group of symptoms attributable to an excess of cortisol and other hormones from the cortex of the adrenal gland. Cushing syndrome patients may have a chronically flushed face, high blood pressure (hypertension), edema, kidney stones, and severe metabolic disturbances. This syndrome is characterized by significant weight gain with fat deposits in particular parts of the body, such as the trunk, while other parts of the body, such as the arms and legs, remain slender. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)
Hyperthyroidism is a condition resulting from overproduction of thyroid hormones. Symptoms may include anxiety, fatigue, marked protrusion of the eyeballs (exophthalmos), sweating, heart palpitations, diarrhea, weight loss, and/or heat intolerance. Hyperthyroidism may result from any of a number of different underlying causes.
Systemic mast cell disease (mastocytosis) is a rare disorder characterized by abnormal accumulations of specific cells (mast cells) normally found in connective tissue. The liver, spleen, lungs, bone, skin, and sometimes the membrane surrounding the brain and spine (meninges) may be affected. Cases beginning during adulthood tend to involve the inner organs more than the skin, whereas during childhood, the condition is often marked by skin manifestations with minimal organ involvement. Mastocytosis is initially characterized by a vague feeling of discomfort or ill health, weakness, nausea, vomiting, heart beat irregularities, weight loss, and/or diarrhea. (For more information on this disorder, choose “mastocytosis” as your search term in the Rare Disease Database.)
Pheochromocytoma is a rare type of tumor that arises from certain cells known as chromaffin cells, which produce hormones necessary for the body to function properly. Most pheochromocytomas originate in one of the two adrenal glands located above the kidneys in the back of the upper abdomen. (For more information on this disorder, choose “pheochromocytoma” as your search term in the Rare Disease Database.)
Pancreatic islet cell tumors may be nonfunctioning or functioning tumors. Nonfunctioning tumors may cause obstruction in the shortest part of the small intestine (duodenum) or in the biliary tract, which connects the liver to the duodenum and includes the gall bladder. These nonfunctioning tumors may erode and bleed into the stomach and/or the intestines, or they may cause an abdominal mass. Functioning tumors secrete excessive amounts of hormones, which may lead to various syndromes including low blood sugar (hypoglycemia), multiple bleeding ulcers (Zollinger-Ellison Syndrome), pancreatic cholera (Verner-Morrison Syndrome), carcinoid syndrome or diabetes. (For more information on this condition, choose “pancreatic islet cell tumor” as your search term in the Rare Disease Database.)
Frequently, carcinoid syndrome may be misdiagnosed as Crohn’s disease, irritable bowel syndrome, or in women, menopause.
Diagnosis is best achieved with a multimodality approach including biochemical investigation, radiological and nuclear imaging, and finally histological (tissue biopsy) confirmation where possible. The occurrence of episodic facial flushing and/or chronic diarrhea not diagnosed by standard tests as being a result of more common causes should lead to suspicion of carcinoid syndrome. In the past, measurement of 24-hour urinary excretion of 5-hydroxyendolacetic acid (5-HIAA), a product of the breakdown (metabolism) of serotonin, in a patient on a low serotonin diet was the main lab test used. It is still useful and the level of 5-HIAA will be clearly elevated in 50% of the cases. However, there are also blood tests available, the most useful being chromogranin-A, often in combination with an imaging technique known as octreoscan, that may confirm the diagnosis of carcinoid syndrome even when urinary 5-HIAA is normal. This technique may also be helpful in indicating the presence of carcinoid tumors when the full spectrum of symptoms is not apparent. Other investigations that may be helpful, depending on the location of the primary tumor, include CT scan, ultrasound, MRI and endoscopy. Sometimes the diagnosis is established incidentally at the time of surgery for another suspected condition such as intestinal obstruction or appendicitis.
Standard treatment is surgery to remove the entire tumor where possible and reduce (debulk) any metastases. In gastrointestinal tumors this will involve resection of the affected area. For bronchial (airway) lesions, procedures such as lobectomy, sleeve resection or pneumonectomy may be required depending on the location of the mass. Debulking of liver metastases can be done by surgical excision or by newer techniques such as cryoablation and radiofrequency ablation. Hepatic artery catheterization with injection of embolic inert particles alone or mixed with chemotherapy has been very effective in many patients with liver metastases. The chemotherapeutic drugs injected in this treatment are cisplatin, mitomycin, and doxorubicin. Systemic chemotherapy is also used with an overall beneficial response in approximately one third of the patients. Drugs used for this purpose include dacarbazine, VP-16 (etoposide), cisplatin, doxorubicin, 5-fluorouracil, streptozotocin and cyclophosphamide. Some newer agents are currently being investigated. Once the tumors have been removed, periodic long-term surveillance is required.
Octreotide (Sandostatin) injections are the mainstay for symptomatic management of carcinoid syndrome. Octreotide is a synthetic form of the pancreatic hormone, somatostatin, and it may be administered in three to four subcutaneous injections per day, one long-acting intramuscular injection every three or four weeks, or by continuous infusion with a sub-cutaneous pump. Sometimes, it is combined with injection of low-dose alpha interferon, which enhances the body’s response.
In 2017, Xermelo (telotriastat ethyl) tablets in combination with somatostatin analog (SSA) therapy was FDA approved for the treatment of adults with carcinoid syndrome diarrhea that SSA therapy alone inadequately controls. Xermelo is manufactured by Lexicon Pharmaceuticals, Inc.
Various nutritional products are available and may be useful, as may anti-diarrheal and anti-cholinergic medications. Patients are often advised to avoid certain substances such as alcohol and foods with a high concentration of tyramine, as these may make symptoms worse.
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For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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