Introduction to Carcinoid Tumors

Multiple Endocrine Neoplasm Syndrome (MEN)

There are three major patterns of disease that comprise the MEN syndrome: type I and type II, which has been subdivided into MEN IIA and IIB. With the cloning of the genes for MEN we have a better understanding of the pattern of gene mutations occurring among affected families. Tumors involved in the MEN syndromes occur within endocrine, gastrointestinal, or neural (nervous system) tissues. MEN syndromes are inherited as autosomal dominant genes with varying degrees of penetrance. Therefore, the same mutation may manifest itself clinically in affected individuals at differing ages. There may also be variability in the malignant potential of neuroendocrine tumors within a given family.

MEN I Tumor Genetics

MEN-1 is an inherited syndrome characterized by the occurrence of neoplastic tumors involving the parathyroid, pancreas, gastrointestinal tract and lung. The MEN I gene locus (MENIN gene) is assigned to 11q13 and inactivating mutations of this gene result in the syndrome. Patients with this disorder have been demonstrated to have losses of heterozygosity (LOH) of this gene. Now that the gene locus has been discovered, it is possible to determine the patterns of inheritance observed in MEN I.

MEN I-Associated Tumors

The MEN-1 Syndrome is associated with the development of gastroenteropancreatic (GEP) tumors, including carcinoid tumors. This association appears to be genetically linked and hyperparathyroidism (a condition marked by over production of the hormone parathormone by the parathyroid glands) occurs in 60% of the affected patients by age 20 and virtually 100% of patients by age 30. Pancreatic endocrine tumors (gastrinomas, glucagonomas, VIPomas, Ppomas and somatostatinomas) occur in 50% of patients.

MEN I, or Wermer's syndrome, usually present with hypercalcemia (the presence of an abnormally high concentration of calcium in the blood) or complications of hypercalcemia such as kidney stones. The clinical findings that are generally seen in descending order of frequency include:

• nephrolithiasis - the presence of kidney stones (calculi) in the kidneys
• peptic ulcer disease
• hypoglycemia - low blood sugar
• headache
• visual-field loss
• hypopituitarism - underactive pituitary gland resulting in low levels of pituitary hormones
• acromegaly - excessive growth due to overproduction of growth hormone by the pituitary gland
• galactorrhea - excessive or spontaneous flow of breast milk usually in a woman who is not breastfeeding
• amenorrhea - absence of menstruation
• Cushing's syndrome - a disease caused by the overproduction of the hormone cortisol by the adrenal glands
• complications related to the development of islet cell tumors of the pancreas.
• nephrocalcinosis - a kidney disorder involving the deposition of calcium and oxalate in the renal tubules of the kidneys.

The Zollinger-Ellison Syndrome (ZES), a rare disorder that causes tumors in the pancreas and duodenum and ulcers in the stomach and duodenum, occurs in approximately one-third of patients with MEN I. As a corollary, approximately 25% of patients with the Zollinger-Ellison Syndrome also have MEN-1; therefore MEN I screening is recommended in all patients with ZES.

Carcinoid tumors particularly involving the duodenum are seen in a significant number of patients with MEN-1 and occur more frequently when both ZES and MEN I are present. Generally carcinoid tumors are identified in the gastric and duodenum. In general these carcinoids appear to be less metastatic than in sporadic carcinoid tumor (i.e., carcinoid tumors in patients who do not have the MEN I syndrome).

Specific skin abnormalities have been recently identified in MEN-1 patients. These skin abnormalities include multiple angiofibromas, collagenomas, and lipomas.

The prognosis of NETs associated with the MEN-I syndrome has been controversial. In one study approximately half of the patients died as a direct result of a MEN I-specific illness that included islet cell tumors, peptic ulcer disease, hypercalcemia/uremia and carcinoid syndrome.