Key Terms: Apudoma, Bronchi, Diffuse neuroendocrine system, Epithelial cells, Gastrointestinal tract, Gland, Hormone, Ileum, Metastasis, Nervous system, Neurohormone, Neuron.

Definition

Neuroendocrine tumors are tumors that develop from the cells of the diffuse neuroendocrine system, such as the enterochromaffin (EC) cells. These tumors are characterized by the presence of cells that possess secretory granules and have the ability to secrete neurohormones.

Description

The endocrine system is a network of glands consisting of endocrine cells that produce hormones in the body. The neuroendocrine system cells are specialized endocrine cells of the nervous system and produce neurohormones. Neuroendocrine cells do not form a specific gland; instead, they are found distributed in a wide variety of body organs where they help regulate body function.

Neuroendocrine tumors therefore represent a large class of cancers that can occur wherever neuroendocrine cells are found throughout the body. They are sometimes called carcinoid tumors, but it would be more accurate to consider these tumors as a sub-category of the larger family of neuroendocrine tumors. Neuroendocrine tumors are most often found in the digestive system and the lung. Statistically, 38% occur in the appendix, 23% in the ileum, 13% in the rectum, and 11.5% in the bronchi. Neuroendocrine pancreatic tumors are rather rare cancers with an incidence of 1-2 cases per 100,000 people. They occur with the same frequency in men and women and the average age at diagnosis is 53 years. Neuroendocrine tumors are also known as apudomas, or tumors that contain apud cells. These cells release excessive amounts of a variety of neurohormones in the bloodstream with chemical composition that varies with location, as does their effect on the body. Neuroendocrine tumors therefore have symptoms that vary with location. Unlike other cancers that are located in a specific organ, the hormone-releasing action of these tumors causes other symptoms to appear in many other organs of the body as well. The majority of neuroendocrine tumors can give rise to metastases with time if they are left untreated.

The total incidence of neuroendocrine tumors is thought to be between five and nine million people in the United States. It is possible that these tumors are under-reported because they grow slowly and do not always produce dramatic symptoms.

Types of Cancers

Because they can occur wherever neuroendocrine cells are found, neuroendocrine tumors come in a wide variety of types and have been classified according to their site of origin, usually either as digestive system, pancreatic or lung neuroendocrine tumors.

Neuroendocrine Tumors of the Digestive System

The types of neuroendocrine tumors found in the digestive system are also indicative of their general location:

• Foregut neuroendocrine tumors. Foregut tumors arise in the stomach or duodenum (first part of the small intestine) and represent approximately 15% to 25% of neuroendocrine tumors.
• Midgut neuroendocrine tumors. Midgut tumors are the most common variety and they include small and large intestine tumors.
• Hindgut neuroendocrine tumors. Hindgut tumors occur less frequently and are found in parts of the colon and in the rectum.

Pancreatic Neuroendocrine Tumors

Most neuroendocrine pancreatic tumors produce multiple hormones but usually there is excessive production of only one hormone. This is why neuroendocrine pancreatic tumors are often classified according to the predominant hormone secreted or resulting symptoms observed. For example, insulinomas produce excessive amounts of insulin, and gastrinomas produce excessive amounts of the peptide gastrin. Glucagonomas are associated with skin lesions and irritation around the eyes, and somatostatinomas are associated with gallstones, slight diabetes and diarrhea or constipation.

Lung Neuroendocrine Tumors

There are four main types of neuroendocrine lung tumors:

• Small-cell lung cancer (SCLC). SCLC represents one of the most rapidly growing types of cancer.
• Large-cell neuroendocrine carcinoma. A rare form of cancer, similar to SCLC in prognosis and treatment, except that the cancer cells are unusually large.
• Typical carcinoid tumors. These types of neuroendocrine lung tumors grow slowly and do not often spread beyond the lungs.
• Atypical carcinoid tumors. Atypical lung carcinoids tumors grow faster than the typical tumors and are more likely to metastasize to other organs.

Other Classifications for Neuroendocrine Tumors

Additionally, neuroendocrine tumors are subclassified into "functionally active" and "functionally inactive" tumors. Functionally active neuroendocrine tumors display specific symptoms, such as the excessive release of specific neurohormones from the tumor cell, as described above for pancreatic neuroendocrine tumors.

A recent classification groups neuroendocrine tumors into two types, depending on the kind of cells they develop from:

• Group I (epithelial). This group includes neuroendocrine carcinomas, graded 1, 2, and 3. Grade 1 neuroendocrine carcinomas are also known as carcinoid tumors. Grade 2 include tumors such as atypical carcinoid tumors, medullary thyroid carcinomas, and some pancreatic endocrine tumors. Grade 3 includes small-cell as well as large-cell neuroendocrine carcinomas.
• Group II (neural). Group II neuroendocrine tumors include paragangliomas, neuroblastomas, primitive neuroectodermal tumors, medulloblastomas, retinoblastomas, pineoblastomas and peripheral neuroepitheliomas.

Diagnosis

The diagnosis of carcinoid syndrome is made by the measurement of 5–hydroxy indole acetic acid (5–HIAA) in the urine. 5–HIAA is a breakdown (waste) product of serotonin. If the syndrome is diagnosed, the presence of carcinoid tumor is a given. When the syndrome is not present, diagnosis may be delayed, due to the vague symptoms present. Diagnosis can sometimes take up to two years. It is made by performing a number of tests, and the specific test used depends on the tumor's suspected location. The tests that may be performed include gastrointestinal endoscopy, chest x ray, computed tomography scan (CT scan), magnetic resonance imaging, or ultra-sound. A biopsy of the tumor is performed for diagnosis. A variety of hormones can be measured in the blood as well to indicate the presence of a carcinoid.

Treatment

The only effective treatment for carcinoid tumor is surgical removal of the tumor. Although chemotherapy is sometimes used when metastasis has occurred, it is rarely effective. The treatment for carcinoid syndrome is typically meant to decrease the severity of symptoms. Patients should avoid stress as well as foods that bring on the syndrome. Some medications can be given for symptomatic relief; for example, tumors of the gastrointestinal tract may be treated with octreotide (Sandostatin) or lanreotide (Somatuline) to relieve such symptoms as diarrhea and flushing. These drugs are known as somatostatin analogs.

Liver transplantation is a treatment option for patients with neuroendocrine tumors that have metastasized only to the liver. As of 2004, this approach is reported to offer patients long disease-free periods and relief of symptoms.

Prognosis

The prognosis of carcinoid tumors is related to the specific growth patterns of that tumor, as well as its location. For example, a group of researchers at the University of Wisconsin reported in 2004 that patients with gastrointestinal tumors in the hindgut had longer periods of disease-free survival than those with foregut or midgut cancers. For localized disease the five-year survival rate can be 94%, whereas for patients where metastasis has occurred, the average five-year survival rate is 18%. It is not unusual for patients with carcinoid tumors to live ten or fifteen years after the initial diagnosis.

Prevention

Neuroendocrine tumors such as carcinoid tumors are rare, and no information consequently is yet available on cause or prevention.

Resources

Books

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Carcinoid Tumors." Section 2, Chapter 17 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Periodicals

Ahlman, H., S. Friman, C. Cahli, et al. "Liver Transplantation for Treatment of Metastatic Neuroendocrine Tumors." Annals of the New York Academy of Sciences 1014 (April 2004): 265–269.

Chatal, J. F., M. F. Le Bodic, F. Kraeber-Bodere, C. Rousseau, and I. Resche. "Nuclear medicine applications for neuroendocrine tumors." World Journal of Surgery 24 (November 2000): 1285–1289.

Jensen, R. T. "Carcinoid and pancreatic endocrine tumors:recent advances in molecular pathogenesis, localization, and treatment." Current Opinions in Oncology 12 (July 2000): 368–377.

Oberg, K., L. Kvols, M. Caplin, et al. "Consensus Report on the Use of Somatostatin Analogs for the Management of Neuroendocrine Tumors of the Gastroenteropancreatic System." Annals of Oncology 15 (June 2004): 966–973.

Rougier, P., and E. Mitry. "Chemotherapy in the treatment of neuroendocrine malignant tumors." Digestion 62, Supplement 1 (2000): 73–78.

Singhal, Hemant, MD, and Alan A. Saber, MD. "Carcinoid Tumor, Intestinal." eMedicine April 13, 2004. .

Van Gompel, J. J., R. S. Sippel, T. F. Warner, and H. Chen. "Gastrointestinal Carcinoid Tumors: Factors That Predict Outcome." World Journal of Surgery 28 (April 2004): 387–392.

Warner, R. R. P. "Exploring Carcinoid Tumors." Coping with Cancer Magazine January-February 2001: 49–50.

Warner, R. R. P., L. P. Angel, C. M. Divino, S. T. Brower, T. Damani. "Pancreatic Neuroendocrine Tumors: A Ten Year Experience." Regulatory Peptides 94 (October 2000): 51–56.

Organizations

The Carcinoid Cancer Foundation, Inc. 1751 York Avenue, New York, NY 10128. Phone: (888)722-3132 or (212)722–3132. Web site: .

Other

The Carcinoid Cancer Online Support Group. To subscribe: .

European Neuroendocrine Tumor Network. Web site: .

—Monique Laberge, Ph.D.; Rebecca J. Frey, Ph.D.

Gale Encyclopedia of Cancer. Copyright © 2006 by The Gale Group, Inc. All rights reserved.