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Multiple Endocrine Neoplasia

Multiple endocrine neoplasia (MEN) syndromes received their name because they predispose people to develop tumors of the endocrine glands. The endocrine system is comprised of glands that secrete hormones into the bloodstream that control numerous processes within the body. The endocrine system is instrumental in regulating mood, growth and development, metabolism, as well as sexual function and reproductive processes.

The major glands of the endocrine system affected by the MEN syndromes are the pituitary, thyroid, parathyroids, adrenals and pancreas. Currently, there are two distinct MEN syndromes, MEN1 and MEN2. In some ways, the two syndromes are similar, but there are important differences.

MEN1
Multiple endocrine neoplasia type 1 (MEN1) is characterized by development of tumors in the parathyroid glands, pituitary and pancreas. Nearly 100% of MEN1 patients will develop parathyroid tumors; 30-75% will develop pancreatic tumors and between 10% and 60% will develop a pituitary tumor. MEN1 is diagnosed when two of these three tumors are present. MEN1 is also diagnosed when an individual has one of the major tumors and has a first degree relative with two of the three endocrine tumors. More rarely, individuals with MEN1 will develop tumors of the adrenal cortex and carcinoid tumors of the thymus gland, lung or stomach. Adrenal tumors are typically benign, while carcinoid tumors can be cancerous. Other features include lipomas, facial angiofibromas, collagenomas or benign thyroid adenomas.

Hyperparathyroidism is usually the first sign of MEN1 and typically occurs between the ages 20 and 25. Nearly 100% of people with MEN1 will develop hyperparathyroidism by the age of 50.  Hyperparathyroidism caused by MEN1 is typically treated with surgical removal of three-and-a-half of the four parathyroid glands, although sometimes all four glands are removed, with a portion of the parathyroid gland inserted into the forearm.

MEN1 also causes tumors in the islet cells of the pancreas and the lining of the duodenum (the first portion of the small intestine), which can secrete several hormones involved with endocrine function. Tumors that develop in the pancreas can be benign (non-cancerous) or malignant (cancerous). However, malignancy is rare before the age of 30.

Tumors that secrete hormones are named for the hormone they produce (i.e., gastrinoma, insulinoma, glucagonoma, VIPoma). Gastrinomas are the most common functional pancreatic tumor in individuals with MEN1 and can cause Zollinger-Ellison syndrome (ZES). Symptoms of ZES include elevated levels of gastrin, ulcers, inflammation of the esophagus, diarrhea and abdominal pain. The second most common functional pancreatic tumor in MEN1 is insulinoma. Surgery is the main treatment for hypoglycemia due to an insulinoma. 

Except for insulinoma, the effects of hormone-secreting pancreatic tumors are typically well-managed with medication. The role of surgery in the treatment of other pancreatic tumors is debatable and depends greatly on the clinical history of the individual.

MEN1 can also cause benign (non-cancerous) tumors to develop in the anterior portion of the pituitary gland. The most common pituitary tumor is a prolactinoma; however, people with MEN1 can develop other pituitary tumors that are non-functional or that secrete hormones such as growth hormone, adrenocorticotropin hormone and thyroid stimulating hormone. Symptoms of a pituitary tumor are usually due to the tumor pressing on other nearby structures and can include headaches and changes in vision. However, prolactinomas can interfere with sexual function and fertility, and tumors secreting growth hormone over time can cause acromegaly (enlargement of the bones). Adrenocorticotropin-producing tumors can cause Cushing’s syndrome. Pituitary tumors generally respond well to medication; however, in some instances surgical removal of the tumor or radiation will be necessary.

 

MEN2
Multiple endocrine neoplasia type 2 (MEN2) is characterized by a very high risk of developing medullary thyroid cancer (MTC). Individuals with MEN2 have a greater than 95% chance of developing MTC in their lifetime. MEN2 is divided into three clinical subtypes:
MEN2A is characterized by the presence of medullary thyroid cancer in early adulthood, pheochromocytoma and hyperparathyroidism. About 50% of people with MEN2A will develop a pheochromocytoma and 20-30% will develop hyperparathyroidism.

MEN2B is characterized by medullary thyroid carcinoma in early childhood, and pheochromocytomas (50% frequency). Hyperparathyroidism is almost never seen in people with MEN2B. People with MEN2B often have other physical characteristics, including being tall and slender, having small benign (non-cancerous) tumors on the lips and tongue and a condition where the large intestine becomes enlarged and irritated. 

Familial Medullary Thyroid Carcinoma (FMTC) is medullary thyroid cancer occurring in multiple members of the same family without the presence of pheochromocytoma and/or hyperparathyroidism.

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Clinical trials
Sym015(Anti-MET) en Pacientes con tumor solido avanzado.
Ensayo de fase 1a/2a, abierto y multicéntrico, para investigar la seguridad, tolerabilidad y actividad antitumoral de dosis repetidas de Sym015, una mezcla de anticuerpos monoclonales dirigida frente al receptor MET, en pacientes con tumores malignos sólidos en fase avanzada
DU176b-D-U311
Estudio fase IIIB, prospectivo, randomizado, abierto que evalúa la eficacia y seguridad de Heparina/Edoxaban versus Dalteparina en tromboembolismo venoso asociado con cáncer.
Estudio fase III, multicéntrico, aleatorizado, doble ciego, con control activo para evaluar la seguridad y eficacia de Rolapitant en la prevención de náuseas y vómitos por la quimioterapia (NVIQ) en pacientes que reciben quimioterapia altamente emética
Tumores sólidos. Antiemesis Estudio fase III, multicéntrico, aleatorizado, doble ciego, con control activo para evaluar la seguridad y eficacia de Rolapitant en la prevención de náuseas y vómitos por la quimioterapia (NVIQ) en pacientes que reciben quimioterapia altamente emética (QAE). A phase III, multicenter, randomized, double blind, placebo controlled study of the safety and efficacy of Rolapitant for the treatment of Chemotherapy-induced nausea and vomiting in subjects receiving highly Emetogenic Chemotherapy (HEC)
Ensayo clínico en fase I de determinación de dosis del antiangiogénico multidiana Dovitinib (TKI258) más paclitaxel en pacientes con tumores sólidos
Ensayo clínico en fase I de determinación de dosis del antiangiogénico multidiana Dovitinib (TKI258) más paclitaxel en pacientes con tumores sólidos.

MEN1
Risk Factors
MEN1 is caused by mutations in the MEN1 gene, which is a tumor suppressor gene. Mutations of the MEN1 gene "disable" tumor suppression, causing unregulated cell division that leads to tumor formation. All children of a parent with MEN1 have a 50% chance of developing the disease. 

Genetic testing of a blood sample can identify MEN1 gene mutations in about 75-90% of people with clinical symptoms. A positive test result can confirm a diagnosis in an affected individual, or identify family members at risk of developing MEN1. However, a negative test result cannot definitively rule out MEN1 in patients when a mutation has not been previously identified in another family member. Genetic testing is offered to adults. Children with symptoms are also tested on case-by-case basis, but testing is typically not done on children who don't have symptoms, because there are currently no preventive treatments. A genetic counselor will discuss testing with you and your family, answer any questions and help you make an informed decision regarding testing. 

Screening Guidelines
Screening guidelines may vary depending on the patient's age and clinical history, but some annual screening recommendations apply to all adults with MEN1 or who are at risk for MEN1. These include assessment of calcium, parathyroid hormone, gastrin and prolactin levels. Occasionally, individuals will need additional imaging tests such as ultrasound, CT or MRI to screen for carcinoid, pancreatic, pituitary and other tumors. Screening has been recommended as early as age five for children at risk for MEN1.

 

MEN2
Risk Factors
MEN2 is caused by mutations in the RET gene, which cause affected cells to divide uncontrollably, resulting in tumor formation. Genetic testing can identify RET mutations in approximately 95% of people with clinical symptoms of MEN2A and MEN2B, and in about 88% of families with FMTC. All children of a parent with MEN2 have a 50% chance of getting the disease.

Genetic testing of blood samples can both confirm a diagnosis of MEN2 in individual patients and identify family members who may be at risk of developing the disease. Depending on the specific RET mutation, predicting the severity and progression of the disease to some degree is possible. This is helpful in determining screening recommendations, as well as the appropriate age for performing a prophylactic thyroidectomy (surgery to remove the thyroid before disease strikes). General recommendations are to remove the thyroid gland:

Within the first six months of life for individuals with MEN2B
By five to 10 years of age for individuals with MEN2A and FMTC
However, these recommendations ultimately depend on the patient's personal and family history. A genetic counselor can discuss genetic testing with you and your family, answer any questions and help you make an informed decision. 

Adrenal Manifestations of MEN2
A pheochromocytoma is a tumor that occurs in the adrenal medulla that makes excess hormones called catecholamines (such as adrenaline). A pheochromocytoma is diagnosed in about 50% of people with MEN2A and MEN2B, although they do not occur in individuals with true FMTC. Pheochromocytomas may also occur in both adrenal glands in MEN2. Although a pheochromocytoma is a tumor, it is rarely malignant in MEN2.

If detected early, pheochromocytomas are easily treated. However, if not treated, they may be potentially fatal due to dangerously high blood pressures that can occur during accidents, surgery, childbirth or other physically stressful situations.

Regular screening for pheochromocytoma allows for early diagnosis and treatment, often before the tumorbecomes symptomatic. Screening should also be done prior to any elective surgery, pregnancy and childbirth. Screening involves either a 24-hour urine collection or a blood test, which measure levels of catecholamines. If screening indicates a pheochromocytoma, an imaging study will be ordered, which may include a CT scan, MRI and/or a special nuclear medicine test called an MIBG study.

All patients with MEN2 should be screened annually, or more often if symptoms develop. Individuals with FMTC should also undergo screening because some families classified as FMTC actually have MEN2A. Pheochromocytoma screening should also be done prior to any elective surgery, pregnancy and childbirth.