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.
Carcinoid syndrome is a disease consisting of a combination of symptoms, physical manifestations, and abnormal laboratory findings. Carcinoid syndrome is seen in individuals who have an underlying carcinoid tumour with spread to the liver. Carcinoid tumors are well-differentiated neuroendocrine tumours with secretory properties, releasing serotonin, along with a number of other active peptides. These tumors can arise anywhere along the primitive gut and are therefore found in the bronchial tree (airways) and along the gastrointestinal tract. The tumor cells can also migrate (metastasize) to the liver.
Carcinoid tumors most commonly occur in the small intestine and appendix, but 10% originate in the lung. Other affected areas include the rectum, colon, pancreas, stomach, ovary, thymus, kidney, prostate, breast and elsewhere. These slow-growing malignancies tend to spread to lymph nodes and the liver but can also metastasize to lung, bone, brain, and skin.
Only about 10% of the people with a carcinoid tumor will develop carcinoid syndrome. Major symptoms of this syndrome include hot, red facial flushing, diarrhea and wheezing. Carcinoid syndrome occurs when the tumor produces excessive amounts of serotonin in an individual with liver metastases. In patients who have no spread to the liver, the serotonin released by an intestinal tumor will be broken down to an inactive substance; thus, carcinoid syndrome does not occur.
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.
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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