Information on the following diseases can be found in the Related Disorders section of this report:

• pancreatic cholera, VIPoma syndrome
• Zollinger-Ellison syndrome
• Cushing syndrome
• mastocytosis
• hyperthyroidism
• pheochromocytoma
• pancreatic islet cell tumor

The symptoms of carcinoid tumors depend on where the tumor arises. They may include abdominal pain, anemia, pneumonia, a cough, and spitting of blood. Carcinoid tumors also can be present without producing any symptoms. These tumors may go undetected for a long 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 a decrease or hypotension); 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 dehydration and electrolyte imbalance. The syndrome may also be accompanied by stomach pain, blockage of 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 may become life-threatening. Not all of these features need be present in a carcinoid crisis or in the carcinoid syndrome.

The exact cause is not clear but in approximately 4% of cases the condition is inherited as a familial disease, sometimes as part of multiple endocrine neoplasia syndrome (also known as MEN 1 or Werner’s syndrome). The carcinoid tumors are slow-growing and can produce hormonal chemical substances such as serotonin, bradykinin, and other peptides. If the original carcinoid cells spread (metastasize) to the liver, larger than normal amounts of these substances are released into circulation, causing the signs and symptoms of carcinoid syndrome to appear. In rare cases, the syndrome may occur without the tumor having metastasized to the liver.

Carcinoid tumors are rare, with only 27 new cases per million diagnosed in the U.S. per year. Of these, only about 10% will exhibit the carcinoid syndrome. The syndrome affects males and females in equal numbers. All races can be affected though there is a slightly increased prevalence in blacks. All ages can be affected but most of the cases diagnosed occur in middle-aged individuals. The syndrome may be more prevalent than suspected because diagnosis is difficult and sometimes overlooked, and 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:

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
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 blood tests that can be done, the most common and useful being chromogranin-A, often in combination with an imaging technique known as octreoscan, that may confirm the diagnosis of carcinoid syndrome, even when 5-HIAA is normal. This technique may also be helpful in indicating the presence of carcinoid tumors when the full syndrome is not apparent. Other imaging techniques that may be helpful include CT scan, ultrasound or MRI of the abdomen and chest. Sometimes, the diagnosis is first established at the time of surgery for some other suspected condition such as intestinal obstruction or appendicitis.

The tumors most commonly occur in the small intestine and appendix, but 10% originate in the lung and they may also occur in 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.

Treatment
Standard treatment is surgical to remove (total resection) the tumor when possible and reduce (debulk) metasticized tissues. Debulking of liver metastases can be done by surgical excision or by the newer approved techniques of 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 usual drugs injected in this treatment are cisplatin, mitomycin, and doxorubicin. Systemic chemotherapy is also used with an overall beneficial response in approximately 1/3 of the patients. Drugs used for this purpose include dacarbazine, VP-16 (etoposide), cisplatin, doxorubicin, 5-fluorouracil, streptozotocin and cyclophosphamide. Some of the newer chemotherapeutic agents are currently being investigated. Once tumors have been removed, periodic long-term surveillance is needed.

Octreotide (Sandostatin) injections are the mainstay of carcinoid syndrome treatments. 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-q pump. Sometimes, it is combined with injection of low-dose alpha interferon, which enhances the body’s response to malignant disease.

Various nutritional products are available and may be useful, as may various anti-diarrheal and anti-cholinergic medications. Adrenaline and adrenaline-like drugs are to be avoided because of their provocative effect on the disorder.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Information on Cancer Clinical trials is also available through the Internet at www.cancer.gov or by calling 1-800-4CANCER.

Experimental treatments involving the radioisotope yttrium-90 have been studied. The drug thalidomide has also been studied as a possible treatment for carcinoid syndrome because of its ability to inhibit the formation of new blood vessels, which are necessary for tumor growth. Further studies are needed to determine the long-term safety and effectiveness of these experimental therapies.

Currently (2004), there are four clinical trials listed within the NIH information that explore and evaluate new treatments for carcinoid syndrome and conditions synonymous with carcinoid syndrome. They are as follows:

A phase II trial sponsored by the National Cancer Institute (NCI) is investigating the effectiveness of FR901228, a chemotherapy drug, in treating patients with locally advanced or metastatic neuroendocrine tumors. For information, visit the Clinical Trials web site or call Manisha H. Shaw, MD, at Ohio State University, at (614) 293-8629 or write to shah-2@medctr.osu.edu.

A phase I/II trial of the drug BB-10901 is being sponsored by British Biotech Pharmaceuticals. BB-10901 is a substance that combines a monoclonal antibody (huN901) with an anti-cancer drug (DM1). Monoclonal antibodies are laboratory-produced substances sometimes used to find cancer cells and deliver cancer-killing substances to them. The trials in the United States are located in Texas and Massachusetts, and examine the effectiveness of BB-10901 in gastrointestinal and pulmonary carcinoid tumors. For information, contact John McCann, MD, at Baystate Medical Center in Springfield, Massachusetts, at (413) 794-3316, John.McCann@bhs.org, or Frank Vito Fossella, MD, at MD Anderson Cancer Center at (713) 792-6363.

Novartis Pharmaceuticals is sponsoring an international phase II trial of the drug, SOM230 to determine its safety and effectiveness in treating patients with metastatic carcinoid tumors. Contact Allen Reha at (862) 778-2330 or allen.reha@pharma.novartis.com for location and contact information.

Patients are being recruited for a phase II study of a combination of the drugs Bevacizumab and PEG-Interferon alfa-2b. The purpose of this study is to investigate the effectiveness of this drug mixture as a treatment for recurrent, metastatic, and regional gastrointestinal carcinoid tumors. The study is sponsored by the National Cancer Institute. For information, contact James Yao, MD, the principal investigator, at MD Anderson Cancer Center in Houston (713 792-2828).

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REVIEW ARTICLES
Leong WL, Pasieka JL. Regression of metastatic carcinoid tumors with octreotide therapy: two case reports and a review of the literature. J Surg Oncol. 2002;79:180-87.

Tomassetti P, Migliori M, Lalli S, et al. Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumors. Ann Oncol. 2001;12 Suppl 2:S95-99.

Oberg K. Chemotherapy and biotherapy in the treatment of neuroendocrine tumours. Ann Oncol. 2001;12 Suppl 2:S111-14.

Pasieka JL, McKinnon JG, Kinnear S, et al. Carcinoid syndrome symposium on treatment modalities for gastrointestinal carcinoid tumours: symposium summary. Can J Surg. 2001;44:25-32.

Fehmann HC, Wulbrand U, Arnold R. Treatment of endocrine gastroenteropancreatic tumors with somatostatin analogues. Recent Results Cancer Res. 2000;153:15-22.

JOURNAL ARTICLES
Oberg K, Kvols M, Scaplin G, et al. Consensus report on the use of somatostatin analogs for the Management of neuroendocrine tumors of the gastroenteropancreatic system. Annals of Oncology. 2004;15:966-973.

Anthony LB, Woltering EA, Espenan GD, et al. Semin Nucl Med. 2002;32:123-32.

Simula DV, Edwards WD, Tazelaar HD, et al. Surgical pathology of carcinoid heart disease: a study of 139 valves from 75 patients spanning 20 years. Mayo Clin Proc. 2002;77:139-47.

Kulaksiz H, Eissele R, Rossler D, et al. Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies. Gut. 2002;50:52-60.

Quaedvlieg PF, Visser O, Lamers CB, et al. Epidemiology and survival inpatients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients. Ann Oncol. 2001;12:1295-300.

Waldherr C, Pless M, Maecke HR, et al. The clinical value of [90Y-DOTA]-D-Phe 1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol. 2001;12:941-45.

O’Toole D, et al. Treatment of carcinoid syndrome: A prospective crossover evaluation of lanreotide versus octreotide in terms of efficicacy, patient acceptability and tolerance. Cancer. 2000;88:770-76.
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