Multiple endocrine neoplasia is a term that encompasses several genetic disorders characterized by a concomitant development of more than one tumor of primarily endocrine origin. Parathyroid, pituitary, and pancreatic tumors are hallmarks of MEN-1, whereas medullary thyroid carcinoma and pheochromocytoma are constitutive features of MEN-2. Clinical, laboratory, and imaging studies are needed to establish the diagnosis and treatment, most commonly involving some form of surgery, depending on the extent of the disease.
The clinical presentation of MEN is complex and numerous tumors may be seen       :
If a clinical suspicion toward MEN is made based on a positive family history and findings from a meticulously performed physical examination, the diagnostic workup should be extensive and the following procedures should be performed    :
If laboratory findings are strongly indicative of MEN, molecular analysis of DNA and identification of genetic mutations is used to confirm the diagnosis .
Although malignant transformation of parathyroid tumors is quite rare, either total or subtotal parathyroidectomy involving 3 and 1/2 of the total parathyroid tissue, together with cervical thymectomy, should be performed , primarily because almost all parathyroid glands have proliferated abnormally and caused major symptoms, but also because there is a high chance of recurrence with insufficient gland removal  . The main role of concomitant thymectomy is to prevent the potential development of thymic carcinoma . There are disputes regarding the timing of surgery in MEN-1, however, as early surgery is more beneficial for the patient, whereas delaying the procedure may reduce the number of complications that occur during the operation as glands become larger and easier to remove . Until recently, resection of parathyroid tissue and its transplantation to the non-dominant forearm was performed, but because of a high incidence of graft failure and consequent hypoparathyroidism, the procedure is not recommended anymore . A conservative approach including calcimimetic agents, such as cinacalcet, has recently been implemented on a subset of HPT patients and good initial results were observed .
Because prolactinomas are most common hypophyseal tumors in MEN, bromocriptine and cabergoline, two dopamine-2 (D2) receptor agonists, are the mainstay of therapy, while GH-secreting tumors are managed with somatostatin analogs lanreotide and octreotide . Transsphenoidal surgery is performed when a curative effect can be achieved, but the development of permanent diabetes insipidus is a potential complication of this approach , which is why a careful preoperative assessment is necessary.
Insulinomas, VIPomas, glucagonomas and other rare functional NETs are almost always treated by surgical resection, but the role of invasive treatment in the setting of gastrinomas or non-functional NETs is still not solidified, as curative rates are much lower . An additional reason is that the efficacy of pharmacologic therapy in managing excessive gastric acid secretion, diarrhea, and other associated symptoms with proton-pump inhibitors (PPIs) and histamine-2 receptor antagonists is very good and the risks of morbidity and mortality from surgery may outweigh its potential benefit .
When it comes to management of phaeochromocytoma in MEN-2 patients, the initial recommendations suggested bilateral adrenalectomies with consequent Addisonian-like complications and life-long use of steroids, but adrenal-sparing surgery is now becoming the mainstay of therapy, primarily to reduce these complications and provide a better quality of life .
Medullary thyroid carcinoma must be treated aggressively through surgical removal of the thyroid gland, but the presence of a pheochromocytoma must be excluded prior to any invasive procedure due to a very high risk of sudden preoperative death due to abrupt changes in catecholamine secretion . Management of metastatic MTC relies on symptomatic measures. Loperamide, codeine, and other anti-diarrheal agents are used, but the recent introduction of tyrosine kinase inhibitors vandetanib and cabozantinib have shown good results in clinical trials .
The prognosis of MEN of any type and subtype correlates with the time of diagnosis. Approximately 60% of duodenal gastrinomas or other neuroendocrine tumors have already metastasized at the time of diagnosis, which significantly reduces overall survival rates . The presence of liver metastases, regardless of the origin of the primary tumor, is particularly associated with a poor prognosis in MEN-1 patients . Additionally, the stage of MTC in MEN-2 patients is the single most important predictor of prognosis, as early recognition of this tumor markedly increases survival rates , ranging from 90% in localized disease to 40% in the presence of distant metastases, when observing a 10-year period from the diagnosis . MEN-2b is a particularly dangerous clinical subtype characterized by an aggressive form of MTC that often develops in the first year of life and a 100% mortality rate before 30 years of age if untreated .
The cause of MEN varies depending on the underlying type, with different genes and mechanisms involved  :
Prevalence rates of MEN-1 are estimated at around 2-3 per 100,000 individuals and studies have detected this disease post-mortem in around 0.25% of individuals . In more than 80% of cases, the clinical onset of MEN-1 does not start before the third decade of life . The most common manifestation, hyperparathyroidism, is most frequently recognized in individuals between 20-25 years of age . Due to the very high penetrance of HPT in MEN-1 patients, all patients suffering from this syndrome will develop HPT by the age of 50 . MEN-2, on the other hand, is less commonly encountered in clinical practice than MEN-1, with an incidence rate of 1 in 200,000 live births . Although prevalence rates of exact subtypes are unknown, the prevalence of MEN-2b is estimated to be between 1 in 600,000 to 1 in 4 million cases . MEN-2a comprises more than 50% of cases, whereas only 5-10% of patients are diagnosed with MEN-2b and the remaining 35% is attributed to FMTC .
In the setting of MEN-1, various aberrations of the MEN-1 tumor suppressor gene and consequent changes of the protein encoded by this gene, menin, are key steps in the pathogenesis . Cell division, cell cycle control, regulation of gene transcription and genomic stability are all processes in which menin plays a key role . An instability of the MEN-1 gene and hyperplasia of duodenal cells are thought to be the key events in a proliferation of duodenal gastrinomas , but the exact model is yet to be discovered. Studies have also confirmed that menin is a coregulator of estrogen receptors and it was suggested that it may play a role in the pathogenesis of breast cancer, as much higher rates of this malignancy are seen in MEN-1 patients compared to the general population . The pathogenesis of MEN-2 stems from different genetic mutations. The RET proto-oncogene, encoding a transmembrane tyrosine kinase receptor, is a vital constituent of various signaling pathways, most notably during renal and enteric organogenesis . Like in MEN-1, the exact mechanism remains unclear, but this genetic aberration invariably leads to malignancy of the parafollicular C cells in the thyroid gland, causing medullary thyroid carcinoma (MTC) . Its role in the occurrence of other tumors is still a topic of research and the answer remains unclear.
Screening of at-risk patients is the main strategy in preventing MEN from reaching more advanced stages. MEN-1 screening is highly recommended for patients with 2 or more MEN-1 related tumors, those who experience recurrent HPT at a young age and all individuals having a positive family history . In fact, approximately 80% of MEN-1 patients are identified through MEN-1 gene sequencing . For this reason, all first and second-degree relatives of the diagnosed patient should be tested for MEN-1 mutations, so that they are aware of the potential risk and to allow early treatment .
Prophylactic screening for RET proto-oncogene mutations in MEN-2 patients and subsequent thyroidectomy at an earlier age is one of the key steps in reducing mortality rates from this type of MEN (especially MEN-2b subtype) when thyroidectomy should be performed within the first few years of life . For FMTC-positive families, screening of children at age 21 and subsequent thyroidectomy is recommended, but post-operative follow-up evaluation of CEA and calcitonin levels, as well as regular CT scans, are mandatory to detect possible recurrence .
Multiple endocrine neoplasia is a clinical entity describing a group of genetic disorders in which development of two or more neoplasms occurs . Two main types exist - MEN-1, with tumor proliferation stemming from mutations in the MEN-1 gene on chromosome 11 and subsequent alterations in menin, a tumor suppressor protein; and MEN-2, distinguished by mutations of the RET proto-oncogene located on chromosome 10 ; Both forms are transferred from parents to their children through an autosomal dominant pattern of inheritance, but in 10% of cases, however, de novo mutations have been described and the underlying cause is yet to be determined . MEN is a rare syndrome, affecting 2-3 per 100,000 individuals in the case of MEN-1, whereas an even lower incidence rate of 1 in 200,000 live births is estimated for MEN-2 . The clinical presentation of patients is diverse and significant variations exist depending on the type. Primary hyperparathyroidism (HPT) is seen in 90-100% of all MEN-1 patients and the two most frequent neoplasias accompanying HPT are pituitary tumors (most commonly prolactinomas and growth-hormone secreting tumors) and pancreatic neuroendocrine tumors of various classes (most commonly gastrinomas that produce Zollinger-Ellison syndrome) . Consequently, symptoms related to hypercalcemia (lethargy, confusion, anorexia), pituitary changes (gynecomastia, amenorrhea/oligomenorrhea, or acromegaly) and the gastrointestinal tract (diarrhea, vomiting, bleeding, peptic ulcer disease) are most frequently encountered . On the other hand, medullary thyroid carcinoma (MTC) is the principal finding of MEN-2, together with pheochromocytoma that is encountered in approximately 50% of cases. Three clinical subtypes of MEN-2 exist: MEN-2a (parathyroid disease develops in 20-30%), MEN-2b (early-onset of mucosal neuromas of the lips and tongue, a Marfanoid body habitus and distinctive facies with enlarged lips ) and familial MTC . A myriad of tumors of both endocrine and non-endocrine etiology have been described in these patients, which is why the diagnosis of MEN may be difficult to attain, particularly without obvious evidence of positive family history. A complete laboratory and imaging workup is necessary in order to support clinical suspicion, while genetic studies are needed to confirm the diagnosis . Treatment principles somewhat depend on the stage of the tumors at the diagnosis, but surgery is the most frequent modality. Subtotal or total parathyroidectomy, adrenal-sparing surgery in the setting of pheochromocytoma and thyroidectomy are frequently performed . If surgery is not able to provide a curative effect, which may be the case for neuroendocrine tumors, or if conservative treatment is possible (in the case of smaller prolactinomas), alleviation of symptoms through the use of drugs is recommended, but the therapeutic process is complex and long-term monitoring of patients is necessary . Several preventive strategies have been advised, such as screening of families with known RET proto-oncogene or MEN-1 gene mutations and prophylactic thyroidectomy of patients at risk for MEN-2b, but the main focus of prevention is early recognition of the disease, since almost all MEN types and subtypes carry a much poorer prognosis if diagnosed before reaching advanced stages of the disease .
Multiple endocrine neoplasia (MEN) is a term that encompasses a group of genetic disorders represented by the development of more than one tumor in the body. Two main forms exist: MEN-1, in which mutations of MEN-1 gene that codes for menin, a tumor suppressor protein, leads to tumors of the parathyroid glands, the pancreas, and the pituitary gland; and MEN-2, distinguished by mutations of the RET proto-oncogene, in whom malignant tumors of the thyroid gland (known as medullary thyroid carcinoma) are seen. Furthermore, MEN-2 is divided into MEN-2a, MEN-2b and familial medullary thyroid carcinoma (FMTC), each having some specific clinical features. Regardless of the type, MEN is a disease that is transmitted from parents to their children and due to the nature of the disease, a 50% chance of transfer exists if one parent is suffering from the disease. MEN is considered as a rare condition, as MEN-1 is seen in approximately 2-3 per 100,000 individuals and even lower rates are seen in the case of MEN-2. However, the diagnosis can be difficult to make, as numerous signs and symptoms may be seen, including gastrointestinal (diarrhea, abdominal pain, bleeding, vomiting, bloating, anorexia, esophageal reflux), musculoskeletal (weakness, increased risk of fractures, changes in the shape of extremities), constitutional (weight loss, confusion, altered mental state, dehydration, etc.) and various other. In addition to tumors that are regarded as essential features of MEN, a myriad of other neoplasias may be discovered in these patients, including those of the skin, central nervous system, muscles, kidneys and the breast. For this reason, it is necessary to perform a thorough clinical examination and obtain a detailed patient history to possibly find out about the presence of tumors within the family. Laboratory studies should include evaluation of serum electrolytes (calcium, sodium, potassium and chloride), pituitary hormones (prolactin and tests that indicate growth hormone levels), calcitonin (secreted by malignant cells of the thyroid gland) and parathyroid hormone, whereas invasive imaging studies such as endoscopic ultrasonography are considered to be the gold standard for discovering tumors confined to the gastrointestinal tract. For many tumors encountered in MEN, either partial or total surgical removal of the affected gland is recommended. Symptom management through the use of drugs is performed when the risks of surgery outweigh the benefits (in the case of pancreatic tumors), but an individualized approach is mandatory to ensure optimal outcomes. To prevent the risks and the harm these disorders may cause, screening of at-risk individuals for genetic mutations is highly advised, so that procedures including preventive removal of the thyroid gland may be performed in the setting of MEN-2b, a very aggressive form of the disease that carries a poor prognosis if not diagnosed early. It is imperative to obtain an early diagnosis of all MEN forms, in fact, as survival rates are significantly lower if the disease is recognized when tumor progression occurs. This may not be easy, however, as the clinical course of many tumors is insidious and often present with very few symptoms.