Glucagonoma

Definition

The multiple endocrine neoplasia (MEN) syndromes are three related disorders in which two or more of the hormone-secreting (endocrine) glands of the body develop tumors. Commonly affected glands are the thyroid, parathyroids, pituitary, adrenals, and pancreas. Two common cancers are medullary thyroid cancer and gastrinomas. MEN is sometimes called familial multiple endocrine neoplasia (FMEN) and previously has been known as familial endocrine adenomatosis.

Description

The three forms of MEN are MEN1 (Wermer's syndrome), MEN2A (Sipple syndrome), and MEN2B (previously known as MEN3). Each form leads to excessive growth of normal cells (hyperplasia) and overactivity of a number of endocrine glands. Excessive growth can result in the formation of tumors (neoplasia) that are either benign (noncancerous) or malignant (cancerous). Overactive endocrine glands increase the secretion of hormones into the bloodstream. Hormones are important chemicals that control and instruct the functions of different organs. Their levels in the body are carefully balanced to maintain normal functioning of many vital processes, including metabolism, growth, timing of reproduction, and the composition of blood and other body fluids.

All three forms are genetic disorders. They result when an abnormal form of a gene is inherited from one parent. The gene causing MEN1, named the MEN1 gene, was isolated in 1997. Both types of MEN2 are caused by mutations of the RET (REarranged during Transfection) gene. MEN1 and MEN2 are both autosomal dominant genetic conditions, meaning that an individual needs only one defective copy of the MEN1 gene or the RET gene to develop the associated disorder. In all forms, the children of an affected individual have a 50% chance of inheriting the defective gene.

The three forms of MEN are further distinguished by the endocrine glands affected. MEN1 is characterized by conditions of the parathyroid glands, pancreas, and pituitary gland. Patients with MEN2 commonly experience a form of thyroid cancer and adrenal tumors.

MEN1

Enlarged and overactive parathyroid glands, a condition called hyperparathyroidism, is present in 90% to 97% of MEN1 gene carriers and is usually the first condition to develop. The four parathyroid glands are located in the neck region, with a pair of the glands on either side of the thyroid. They produce parathyroid hormone, which regulates calcium and phosphorus levels. Hyperparathyroidism leads to elevated levels of the hormone, resulting in high blood calcium levels (hypercalcemia), which can cause kidney stones and weakened bones. All four parathyroid glands tend to develop tumors, but most tumors are benign and parathyroid cancer is rare. Hyperparathyroidism may be present during the teenage years, but most individuals are affected by age 40.

Pancreatic tumors occur in 40% to 75% of individuals with the MEN1 gene. The pancreas, which sits behind the stomach, has two parts, an endocrine part and an exocrine part. Tumors in MEN1 occur only in the endocrine pancreas. Among the hormones secreted are ones that lower and raise blood sugar levels-insulin and glucagons-and the hormone gastrin, which is secreted into the stomach to aid in digestion. Thirty to 35% of pancreatic tumors are malignant, and they are the tumors most likely to cause cancer in MEN1 patients. Gastrin-producing tumors (gastrinomas) are the most common tumors that form, representing about 50% of the MEN1 pancreatic tumors. Other tumors that form are insulin-producing tumors (insulinomas), representing 25% to 30%, and glucagon-producing tumors (glucagonomas), representing 5% to 10%.

Gastrinomas can cause recurring upper gastrointestinal ulcers, a condition called Zollinger-Ellison syndrome. About half of MEN1 patients with a pancreatic condition develop this syndrome. Insulinomas raise the insulin level in the blood and can lead to hypoglycemia, or low blood sugar (glucose), resulting in glucose levels that are too low to fuel the body's activity. Glucagonomas can cause high blood sugar levels, or hyperglycemia.

Pituitary tumors are the third most common condition in MEN1, occurring in about 50% of MEN1 patients. Fewer than 5% of these tumors are malignant. The pituitary gland, located at the base of the brain, secretes many hormones that regulate the function of other endocrine glands. The most common tumors forming in MEN1 patients are prolactin-producing tumors (prolactinomas) and growth hormone-secreting tumors, which lead to a condition known as acromegaly.

MEN2

Patients with MEN2A and MEN2B experience two main symptoms, medullary thyroid cancer (MTC) and a medullary adrenal tumor known as pheochromocytoma. Additional symptoms distinguish the two forms of MEN2. Twenty percent of MEN2A patients develop parathyroid tumors, which have not been reported for MEN2B. As in MEN1, parathyroid tumors in MEN2A affect all four glands and are usually benign. MEN2B is further characterized by the occurrence of benign tumors of the tongue, nasal cavities, and other facial surfaces (mucosal neuromas) and by a condition known as marfanoid habitus. Marfanoid habitus features a characteristic appearance resulting from severe wasting of the proximal muscles. A distinct facial appearance-an elongated face with a thick forehead, wide-eyed look, and broad nose-is often noted at birth. Gastrointestinal, skeletal, and pigmentation abnormalities may also occur. Mucosal neuromas occur in all MEN2B patients, and marfanoid habitus occurs in 65%. About 5% of MEN2 cases are MEN2B.

Ninety-five percent of MEN2A patients and 90% of MEN2B patients develop medullary thyroid carcinoma (MTC). Medullary thyroid carcinoma forms from the C-cells of the thyroid. C-cells make the hormone calcitonin, which is involved in regulating the calcium levels in the blood and calcium absorption by the bones. The thyroid, which is located in the front of the neck between the Adam's apple and the collarbone, also secretes hormones that are essential for the regulation of body temperature, heart rate, and metabolism.

Medullary thyroid carcinoma causes high blood levels of calcitonin. In MEN2B, MTC develops earlier and is more aggressive than in MEN2A. It has been described in MEN2B patients younger than one year, whereas in MEN2A patients it is likely to occur between the ages of 20 and 40.

Pheochromocytoma is found in 50% of MEN2A patients and 45% of MEN2B patients. A tumor of the medulla portion of the adrenal gland, it is usually a slow-growing and benign adrenal tumor. The two flat adrenal glands, one situated above each kidney, secrete the hormones epinephrine and norepinephrine to increase heart rate and blood pressure, along with other effects. Excessive secretion of these adrenal hormones can cause life-threatening hypertension and cardiac arrhythmia. Tumors form on both adrenal glands in 50% of MEN2 patients diagnosed with a pheochromocytoma. Tumor malignancy is very rare.

Demographics

MEN syndromes are rare. MEN1 occurs in about three to twenty persons out of 100,000, and MEN2 occurs in about three out of 100,000 people. Both MEN1 and MEN2 show no geographic, racial, or ethnic trend, and men and women have an equal chance of acquiring the MEN syndromes.

Ninety-eight percent of MEN1 gene carriers will develop varying combinations of tumors by age 30, but cancer has not been reported in patients younger than 18. Seventy percent of MEN2A gene carriers will have symptoms by age 70, with most diagnoses occurring between the ages of 30 and 50. MEN2B can occur before one year of age, but most symptoms appear anytime between the ages of 20 and 70.

Causes and symptoms

MEN1

MEN1 is caused by mutations of the MEN1 gene. The MEN1 gene encodes for a previously unknown protein named menin. The role of menin in tumor formation in endocrine glands is not known. But the MEN1 gene is thought to be one of a group of genes known as a tumor suppressor gene. A patient who inherits one defective copy of a tumor suppressor gene from either parent has a strong predisposition to the disease because of the high probability of incurring a second mutation in at least one dividing cell. That cell no longer possesses even one normal copy of the gene. When both copies are defective, tumor suppression fails and tumors develop.

As of 2001, a number of different mutations have been discovered in the MEN1 gene, but people having the same mutation do not always develop the same endocrine conditions. Members within a single family can show different sets of conditions. The symptoms of MEN1 depend on the endocrine condition present:

• Hyperparathyroidism: weakness, fatigue, constipation, kidney stones, loss of appetite (anorexia), and bone and joint pain.

• Gastrinoma: peptic ulcers of the stomach and small intestine, diarrhea, and weight loss.

• Insulinoma: hypoglycemia characterized by weakness, shakiness, fast heartbeat, and difficulty concentrating.

• Glucagonoma: hyperglycemia characterized by inflammation of the tongue or stomach, anemia, weight loss, diarrhea, and blood clots.

• Prolactinoma: secretion of milk in women who are not nursing, headaches, sweating, fatigue, weight gain, fertility problems in men and women, and visual problems.

• Acromegaly: enlarged hands and feet, enlarged face, thickened oily skin, fatigue, sweating, bone and joint pain, weight gain, and high blood sugar.

MEN2

Both types of MEN2 are caused by mutations of the RET gene. The RET gene is a cancer-causing gene, or an oncogene. A number of different mutations lead to MEN2A, but only one specific genetic alteration leads to MEN2B.

Unlike for MEN1, the likelihood of developing different conditions in MEN2A is associated with specific mutations of the RET gene. Family history can indicate which conditions current family members are likely to develop. The symptoms of MEN2 are those that accompany hyperparathyroidism, MTC, and pheochromocytoma:

• Medullary thyroid cancer: enlargement of thyroid or neck swelling; lumps or nodules in the neck, pain in the neck region going to the ears, persistent cough unrelated to a cold, cough with bleeding, diarrhea or constipation, hoarseness, and difficulty swallowing or breathing.

• Pheochromocytoma: headaches, sweating, chest pains, feelings of anxiety.

The conditions of MEN2B patients show a variety of additional symptoms, including the occurrence of mucosal neuromas and marfanoid habitus, which is characterized by an elongated face, a thick forehead, and poor muscle development.

Diagnosis

The occurrence of one endocrine condition does not immediately lead to a suspicion of MEN syndromes. Diagnoses is based on the occurrence of one or more endocrine conditions and a family history of MEN1 or MEN2.

Since 1994, genetic testing using DNA technology has been available for both MEN1 and MEN2. The identification of the MEN1 gene in 1997 has made genetic screening for this gene more accurate.

A blood sample is usually analyzed for DNA testing, although other tissue can be used. The sample is sent to a laboratory that specializes in DNA diagnosis. There a geneticist will perform several tests on the DNA collected from the cells in blood sample. The exact tests performed will depend on whether MEN1 or MEN2 is suspected. Because different regions of the RET gene are associated with different endocrine conditions in MEN2A, several regions of the gene are examined. A positive result means the defective gene is present, and a negative result means the defective gene is not present.

As of 2000, the test results for the RET gene mutations are more reliable than for the MEN1 gene because detection techniques for identifying MEN1 are still being developed. A clinical diagnosis of MEN2 is confirmed with genetic testing 90-95% of the time. Even when a genetic test is negative, family medical records will be carefully reviewed to confirm the presence of MEN2, and periodic screening of related conditions will likely continue until age 30 or 40. The time required to obtain the test results for MEN2 is about 2-4 weeks, but MEN1 results will likely take longer because there are fewer diagnostic labs set up for MEN1 analysis.

Those considered at risk for MEN1 or MEN2 based on genetic tests or family history are offered preventative surgery, regular screening for associated endocrine conditions, or a combination of these treatment options. Conditions are screened following the accepted procedure for each condition. Diagnosis is based on clinical features and on testing for elevated hormone levels.

MEN1

Hyperparathyroidism is diagnosed when high levels of calcium and intact parathyroid hormone are measured in a blood sample. Normal values of calcium for adults is 4.4-5.3 mg/dl (milligrams per deciliter), and normal values of parathyroid hormone are 10-55 pg/ml (picograms per milliliter). Prior to the parathyroid test, no food should be eaten for at least six hours. An x ray of bones may be taken and then examined by a radiologist for signs of low bone density. An x ray of the abdominal region can reveal kidney stones. Patients should be screened yearly.

Diagnosis of a gastrinoma follows established procedures and includes measuring the levels of gastrin in the blood and the level of stomach gastic acid production. Hypoglycemia associated with insulinomas is diagnosed by measuring blood glucose levels. This test may be administered while a patient is experiencing symptoms related to low insulin levels or during a supervised period of fasting. Depending on the type of test given, no food should be eaten from 6-12 hours prior to the test. Normal glucose levels range between 64-128 mg/dl. Blood glucagon levels above the normal range of 50-100 pg/ml can indicate hyperglycemia, which is associated with glucagonomas. Large pancreatic tumors are identified using computed tomography (CT scans) or radionuclide imaging, but ultrasonography conducted during surgery is the best method for detecting small tumors. There is no accepted system for staging the pancreatic tumors associated with MEN1.

Prolactinomas, the pituitary tumors most often associated with MEN1, are diagnosed when prolactin levels are greater than 20 ng/l (nanograms per liter). A tumor is identified using magnetic resonance imaging (MRI). Tumors secreting excess growth hormone are diagnosed when hormone levels are above the upper normal range of 3 ng/l and from observable changes in physical appearance.

MEN2

Medullary thyroid carcinoma is diagnosed by measuring calcitonin levels in blood and urine samples and from a biopsy of any thyroid nodules. Levels of calcitonin above 50 pg/ml can indicate the presence of MTC. Patients showing normal calcitonin levels may require a different test, in which calcitonin is measured at regular intervals after an injection of pentagastrin, a synthetic hormone.

Fine needle aspiration is the biopsy procedure used to diagnose MTC and other forms of thyroid cancer. A sample of cells is removed from a nodule, and the cells are then examined under a microscope by a pathologist to determine if cancer cells are present. MTC has four stages, based on the size of the tumor and where the cancer has spread. Tumor staging follows the system established for other forms of thyroid cancer.

A high level of epinephrine relative to norepinephrine indicates a pheochromocytoma on one or both adrenal glands. A CT scan, an MRI, or radionuclide imaging will be performed to locate the tumor.

Diagnosis of hyperparathyroidism in MEN2A patients is identical to its diagnosis for MEN1 patients, but with screening recommended every two to three years.

Treatment team

Conditions of MEN syndromes are first diagnosed by a pathologist who interprets blood and urine samples collected at a doctor's office or a clinic. Depending on the specific condition, a doctor specializing in conditions of the endocrine gland (an endocrinologist) may be consulted. When MEN syndromes are suspected, a genetic counselor will help prepare a patient for the genetic testing procedures and results. A geneticist will perform and interpret genetic tests. Since MEN syndromes often require surgery, the surgical team will likely consist of a surgeon experienced in operating on endocrine glands.

Clinical staging, treatments, and prognosis

No comprehensive treatment is available for genetic disorders such as MEN, but the symptoms of many conditions are treatable. Surgical removal of tumors is the recommended treatment for most conditions, and most MEN patients will require more than one endocrine gland surgery during a lifetime.

An important distinction between an endocrine condition in MEN patients and the same condition in patients not diagnosed with MEN is that endocrine tumors for MEN patients are likely to arise in many locations of a single gland or on multiple glands. Treatment options that work for patients with a single endocrine condition may not be effective in MEN patients. Surgery is often more extensive for MEN patients.

Genetic testing can exclude family members who do not have mutations of the RET or MEN1 gene. The advantage of testing is the early treatment and improved outcomes for those who carry the defective gene and relief from unnecessary anxiety and clinical testing for those not having the defective gene.

MEN1

A common approach to treating MEN1 is with regular screening. Surgical procedures may be delayed until a patient has developed clinical symptoms caused by excess hormone or an easily identifiable tumor.

There are two surgical options for MEN1 patients showing multiple symptoms of hyperparathyroidism or for patients having high blood calcium levels (hypercalcemia), even when no symptoms of the condition are present. All parathyroid tissue is identified and removed and parathyroid tissue is implanted in the forearm, or the surgeon removes three parathyroids and one half of the fourth. After surgery, blood calcium levels are regularly tested to ensure that the remaining parathyroid tissue has not enlarged and caused the condition to return. If hyperparathyroidism recurs, a portion of the remaining tissue is removed until calcium levels return to normal or all the remaining tissue is removed. For MEN1 patients, recurrence is likely within 15 years of the first surgery. Patients with no parathyroid tissue must take daily calcium and vitamin D supplements to prevent hypercalcemia.

There are two views on the best screening strategy for pancreatic tumors in MEN1 patients. One approach is yearly screening, particularly for gastrinomas. This strategy emphasizes the earliest possible detection and surgical removal of tumors. The other approach is screening every 2-3 years, with the reasoning that although tumors are detected at a later stage, they can be better managed with drugs and, if necessary, with surgery.

Surgical removal of insulinomas and glucagonomas, as well as of other less commonly occurring pancreatic tumors in MEN1 patients, is generally the recommended treatment because these tumors are difficult to treat with medication.

The best treatment option for gastrinomas is complex because in MEN1 patients there can be multiple gastrinomas of varying sizes on the pancreas and upper portion of the small intestine (duodenum), and they have a tendency to recur. Most doctors support the use of medication to control the condition and do not recommend surgical intervention. Common treatment of symptoms is the use of drugs that block acid production, called acid pump inhibitors. Others recommend surgery that includes removal of the duodenum and a section of the pancreas and cutting nerves to the section of the stomach involved in acid secretion. Surgery is supported as a way to reduce the risk for metastasis. In some cases, gastrin levels and gastric acid levels returned to normal, and MEN1 patients experienced no symptoms after the surgery. A treatment no longer recommended is removal of the entire stomach. Malignant gastrinomas cause death in 10% to 20% of MEN1 patients with this condition, and 30% to 50% will eventually spread to the liver.

Treatment of pituitary tumors in MEN1 patients rarely involves surgery. For prolactinomas, medications are effective in returning prolactin levels to normal and preventing tumor growth.

MEN2

Medullary thyroid carcinoma is the primary concern for those testing positive for the RET gene mutations. Since genetic testing became available for MEN2, two approaches have emerged to manage this cancer. Some recommend removing the entire thyroid gland (thyroidectomy) before any symptoms occur, although doctors disagree at what age to perform this surgery. This strategy emerged owing to a number of cases in which thyroids removed from identified MEN2 patients showing no clinical signs of MTC were found to be cancerous. Preventative thyroid surgery is offered to those with RET gene mutations beginning at age 5. Some recommend surgery after age 10, unless calcitonin tests are positive earlier. They contend that surgery before age 10 may increase the chance of damaging the larynx or the parathyroids.

The second approach is yearly blood calcitonin testing beginning in early childhood. A thyroidectomy is performed after the first abnormal calcitonin test. There is only a 10% chance of recurrence 15-20 years after surgery for those identified using this method. The advantage of this method is to delay surgery until it is necessary. The disadvantages are the cost and discomfort of yearly testing. Also, the first detection of elevated levels of calcitonin in the blood may occur after the cancer has already reached an advanced stage.

A thyroidectomy is the standard treatment for all stages of MTC. If MTC is diagnosed in an advanced stage, the spread of the cancer may have already occurred. Metastasis is very serious in MTC because chemotherapy and radiation therapy are not effective in controlling metastasis. Further tests are likely to include a CT scan and an MRI.

All MTC patients must take thyroid hormone medication for the rest of their lives in order to maintain normal body functions. Follow-up treatment to assure that the cancer has not recurred includes monitoring the levels of calcitonin in the blood. The survival rate 10 years after the initial diagnosis is 46%. If the cancer is detected using genetic screening before the patient shows signs of having the disease, surgical removal of the thyroid gland can cure MTC.

Pheochromocytoma may occur after the MTC diagnosis by as much as 20 years. Pheochromocytoma in MEN2 can be cured by surgical removal of the affected adrenal gland. If a pheochromocytoma occurs on only one gland, there is some debate on whether to remove both adrenal glands or only the affected gland. Fifty percent of MEN2 patients who underwent removal of one adrenal gland developed a pheochromocytoma in the other gland within 10 years. Because malignancy is rare, most doctors recommend removing the affected glands first and then monitoring hormone levels to see if a second tumor occurs. If both glands are removed, hormone replacement therapy is required.

Alternative and complementary therapies

There are no alternative treatments specifically targeted for people with MEN syndromes, although cow and shark cartilage treatments are being investigated as a way to decrease tumor growth in some cancers. These treatments are administered orally, by injection, or as an enema, but studies of the effectiveness of this treatment for humans are inconclusive.

Coping with cancer treatment

The surgery that most MEN syndromes patients will face can cause anxiety and fear. Patients should discuss their concerns about an operation with their personal physician, the surgeon, nurses, and other medical personnel. Getting specific answers to questions can provide a clear idea of what to expect immediately after the surgery as well as any long-term changes in quality of life.

Clinical trials

Clinical studies of MEN syndromes focus on understanding the genes involved in the inheritance of MEN1 and MEN2 and on the unique treatment needs for the endocrine gland conditions occurring in MEN patients. One ongoing study investigates new imaging techniques for locating pheochromocytomas, particularly in MEN2 patients. Contact information:

National Institute of Child Health and Human Development (NICHD), 9000 Rockville Pike, Bethseda, MD 20892. (800) 411-1222

A second clinical trial is a genetic-analysis study of known and suspected individuals with MEN1. Participants are offered genetic counseling with an option for involvement in research designed to improve genetic counseling services. Contact information:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 9000 Rockville Pike, Bethseda, MD 20892. (800) 411-1222

Prevention

There is no preventive measure to block the occurrence of the genetic mutations that cause MEN syndromes. Medullary thyroid carcinoma, one of the most serious conditions of MEN2, can be prevented by thyroidectomy.

Special concerns

It is important to seek professional genetic counseling before proceeding with genetic testing, particularly for children. Adults may have to make treatment decisions for children.

Genetic tests are often expensive. Whether or not health insurance will cover the costs of counseling and testing will depend on individual policies. Some insurance companies cover the costs only when a patient shows symptoms of a condition. Genetic tests raise issues of privacy. Most states in the United States have legislation that restricts the use of genetic test results by insurance companies and employers.

FormAssociated diseases/conditionsMEN 1 (Wermer's syndrome)Parathyroid hyperplasia
Pancreatic islet cell carcinomas, Pituitary hyperplasia
Thymus, adrenal, carcinoid tumors (less common)MEN 2A (Sipple syndrome)Medullary thyroid carcinoma, Pheochromocytoma
Parathyroid hyperplasiaMEN 2BMedullary thyroid carcinoma, Pheochromocytoma
Parathyroid hyperplasia
Swollen lips
Tumors of mucous membranes (eyes, mouth, tongue, nasal cavities)
Enlarged colon
Skeletal problems such as spinal curvingFamilial medullary thyroid carcinomaMedullary thyroid carcinoma

KEY TERMS

Endocrine

A term used to describe the glands that produce hormones in the body.

Exocrine

A term used to describe organs that secrete substances outward through a duct.

Hyperplasia

An overgrowth of normal cells within an organ or tissue.

Medullary thyroid cancer (MTC)

A slow-growing tumor of which about 20% are associated with MEN2.

Neoplasm

An abnormal formation of tissue; for example, a tumor.

Oncogene

A gene with a mutation that causes cell growth and division, leading to the formation of cancerous tumors.

Pheochromocytoma

A tumor of the medullary of the adrenal gland.

RET (REarranged during Transfection) gene

Located on chromosome 10q11.2, mutations in this gene are associated with two very different disorders, the multiple endocrine neoplasia (MEN) syndromes and Hirschsprung disease.

Tumor suppressor gene

A type of gene that instructs cells on the appropriate time to die. A mutation can turn off the gene, resulting in cell growth and tumor formation.

QUESTIONS TO ASK THE DOCTOR
• Are the tumors associated with this condition cancerous?

• Can one endocrine tumor spread to other endocrine glands?

• What are the long-lasting effects of this disorder?

• What are the long-lasting effects of treatment?

• After treatment, what are the chances that a condition will recur?

• Are there alternative treatments to surgery?

• Will I need to take hormone supplements, if so, for how long?

• Will this disorder affect my ability to have children?

• What is the current status of predictive gene testing?

• Who in my family should be tested for this disorder?