MEN 1

MEN1 or multiple endocrine neoplasia type 1 also known as Wermer syndrome, is a rare endocrine tumor syndrome with high penetrance ¹. Multiple endocrine neoplasia type 1 (MEN1) primarily causes hyperplasia and/or neoplasia of parathyroid glands, anterior pituitary gland usually prolactinomas and the neuroendocrine tissue of gastro-entero-pancreatic tissue ².

Hyperparathyroidism is most common and occurs in 90% of cases; pancreatic neuroendocrine tumors (pNETs) occurs in 60% and pituitary adenoma in 40% of patients ³. The most common pancreatic neuroendocrine tumor is a gastrinoma frequently found in the duodenum but others include non-functioning tumors, vipomas, glucagonomas, somatostatinomas and Ppomas ². Tumors may function synchronously or meta-synchronously. More than one syndrome may occur in the same patient and metastases may secrete different hormones. In women with MEN-1 breast carcinoma is increased 2.8 fold. MEN-1 is a tumor suppressor gene on (11q13), and there are more than 300 different MEN-1 germ line mutations and about 20 % of MEN kindred have no mutation. Tumors have loss of zygousity and the allelic loss is from the unaffected parent. The protein encoded is menin that binds to double stranded DNA and is a tumor suppressor. MEN-1 gene mutations are also found in non-syndromic tumors.

MEN1 patient may also develop other endocrine and non-endocrine tumors like carcinoid tumors of the thymus, bronchus, or stomach, adrenocortical tumor, cutaneous tumors, central nervous system (CNS) tumors, leiomyoma, lipoma, collagenoma, and angiofibroma. As you can gather from all of the above, management of these patients is not straightforward. These complex and challenging patients should be seen, evaluated, and treated by an experienced multidisciplinary team.

Multiple endocrine neoplasia type 1 is quite rare affecting about 1 in 30,000 people ⁴. MEN-1 syndrome has an incidence of 0.25% determined from postmortem studies, and an estimated prevalence of between 0.02 and 0.2 per thousand ⁵. Multiple endocrine neoplasia type 1 affects all age groups and has been reported in children as young as 5 years. Multiple endocrine neoplasia type 1 is inherited in an autosomal dominant pattern, with a high degree of penetrance.

Clinical and biochemical manifestations develop in over 94% of the patients by the fifth decade. MEN1 has been shown to affect men and women equally, in the study by Gaudet et al ⁶ of 734 MEN1 patients there was a slight female preponderance (57.8%). The prevalence of pancreatic tumors was higher in men because of gastrinomas. The prevalence of pituitary tumors was slightly higher in women, and thymic tumors were exclusively found in men ⁶.

Cushing disease may be the first presentation in children with MEN1 as reported by Makri et al. in their retrospective chart review of 238 patients admitted at National Institute of Health (NIH) for evaluation of hypercortisolemia. Out of these, 6 patients had MEN1; 5 cases were familial; one case was sporadic ⁷.

MEN1 gene testing in an index case can confirm the diagnosis and allow early detection of asymptomatic mutation carriers, years before an MEN1-associated tumor can be detected. Diagnosis of MEN requires presence of the MEN1 gene mutation without signs or symptoms, an individual with the disease and the same disease in a 1st degree relative, or an individual who has two or more of the clinical syndromes. Diagnosis of MEN1 is established if the index case has at least 2 of the primary manifestations of MEN1 (tumor of parathyroid glands, anterior pituitary gland and neuroendocrine tissue of gastro-entero-pancreatic tissue) or at least one MEN1-related tumor and a first-degree relative with confirmed MEN1 (positive MEN1 gene mutation) or the index case has the pathologic mutation in the MEN1 gene. However, around 20% of MEN1 kindred have no mutation in the MEN1 gene ². Unfortunately, there is no genotypic-phenotypic correlation in MEN1, leading to different manifestations, even among family members, but nonsense and splicing mutations are associated with more aggressive neuroendocrine tumors.

Biochemical testing should include PTH, prolactin, fasting gastrin and a secretin/calcium provocative test. Tumor localization requires endoscopic ultrasound, Octreoscan and PET/CT using Ga-68-Dota(-D-)-Phe(1)-Tyr(3)-octreotide (Ga-68-DOTATOC) to image neuroendocrine tumors with a reported sensitivity and specificity of 91.7% and 93.5%, respectively have altered management in 47.6% of MEN1 patients. However this has not been found uniformly. Surgical management of the parathyroid usually involves total parathyroidectomy with implant of parathyroid in the forearm, allowing local excision in the case of recurrence. Localizing the pancreatic tumors requires transhepatic portal venous sampling and only the producing tumor(s) should be removed. The larger the tumor the more likely are metastasis. In general prognosis is good and the 15 year survival is 93%. Symptoms and secretions can be controlled. Mortality has shifted to thymic and carcinoid tumors.

Multiple endocrine neoplasia

Multiple endocrine neoplasia is a group of disorders that affect the body’s network of hormone-producing glands called the endocrine system ⁴. Hormones are chemical messengers that travel through the bloodstream and regulate the function of cells and tissues throughout the body. Multiple endocrine neoplasia typically involves tumors (neoplasia) in at least two endocrine glands; tumors can also develop in other organs and tissues. These growths can be noncancerous (benign) or cancerous (malignant). If the tumors become cancerous, the condition can be life-threatening.

The major forms of multiple endocrine neoplasia are called type 1, type 2, and type 4. These types are distinguished by the genes involved, the types of hormones made, and the characteristic signs and symptoms.

Many different types of tumors are associated with multiple endocrine neoplasia. Type 1 frequently involves tumors of the parathyroid glands, the pituitary gland, and the pancreas. Tumors in these glands can lead to the overproduction of hormones. The most common sign of multiple endocrine neoplasia type 1 is overactivity of the parathyroid glands (hyperparathyroidism). Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of bones, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue.

The most common sign of multiple endocrine neoplasia type 2 is a form of thyroid cancer called medullary thyroid carcinoma. Some people with this disorder also develop a pheochromocytoma, which is an adrenal gland tumor that can cause dangerously high blood pressure. Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B (formerly called type 3), and familial medullary thyroid carcinoma. These subtypes differ in their characteristic signs and symptoms and risk of specific tumors; for example, hyperparathyroidism occurs only in type 2A, and medullary thyroid carcinoma is the only feature of familial medullary thyroid carcinoma. The signs and symptoms of multiple endocrine neoplasia type 2 are relatively consistent within any one family.

Multiple endocrine neoplasia type 4 appears to have signs and symptoms similar to those of type 1, although it is caused by mutations in a different gene. Hyperparathyroidism is the most common feature, followed by tumors of the pituitary gland, additional endocrine glands, and other organs.

Multiple endocrine neoplasia type 1 causes

Germline inactivating mutations of the MEN1 gene on chromosome 11 cause MEN1 syndrome ¹. MEN1 syndrome is an autosomal dominant syndrome that occurs in around 90% of cases usually inherited from the affected parent or because of a de novo mutation in about 10% of cases.

Marini et al. ⁸ published an analysis of germline MEN1 mutations in 410 patients and found 99 different mutations, 41 frameshift, 26 missense, 13 nonsense, 11 splicing site mutations, 4 in-frame small deletions, and 4 large intragenic deletions spanning over 1 exon. They also found that gastro-entero-pancreatic tumors were more common in patients with nonsense mutations and thoracic neuroendocrine tumors were more common in individuals bearing a splice mutation ⁸.

About 20% of MEN1 kindreds lack any detectable mutation in the MEN1 gene; thus, clinical diagnostic criteria remain essential in the diagnosis of this syndrome.

Germline mutation of CDKN1B has been found to cause pituitary adenomas, parathyroid adenomas, and pancreatic neuroendocrine tumors. Therefore, it is possible that mutations in this gene could account for MEN1 syndromes without MEN1 gene mutation.

MEN-1 genetics

The MEN-1 gene locus was first mapped to the long arm of chromosome 11 (11q13), by Larsson et al ⁹. The MEN-1 gene is a tumor suppressor gene which has been identified and cloned ¹⁰. The gene contains 10 exons and spans 10kb of genomic DNA. More than 300 different MEN-1 germ line mutations have been identified thus far ¹¹. The mutations are spread over the entire genome including the intronic and promoter regions without significant clustering ¹². There are no true “hot spots”. As up to 20% of mutations involve intron sequences, it is important that these regions be searched for germline mutations ¹³. About 70% of the mutations are nonsense and frame shift mutations, resulting in truncation of the protein product. About 20% of MEN-1 kindreds lack an identified mutation in the MEN-1 gene. Thus, despite advances in the understanding of the genetics of MEN1, clinical diagnostic criteria remain important in making the diagnosis ¹².

Despite detailed study, no clinically relevant correlation between the genetic mutation and the phenotypic expression has been identified ¹². However, data about genetic mutations and disease modification are slowly emerging. The likelihood of finding a mutation appears to correlate with the number of MEN-1 associated tumors, and the presence of a family history ¹⁴. A recent study ¹⁵ suggests that the p27 tumor suppressor gene may act as a disease modifier in patients with MEN1 germline mutations, with patients possessing the p27 rs2066827 variant more likely to have tumors in 3 or 4 glands vs one or 2 glands. Patients with MEN1 mutations leading to CHES1 loss of interaction (LOI) have higher rates of functional pNETs (70% vs 34%), malignant pNETs (37% vs 9%), and increased pNET-related mortality (20% vs 4.5%) ¹⁶. It has also been shown that MEN1 patients with mutations in the JunD interacting domain have a higher risk of disease-associated death ¹⁷.

Endocrine tumors from MEN-1 patients have loss of heterozygosity (LOH). The allelic loss is always from the normal chromosome belonging to the unaffected parent, analogous to the second hit in retinoblastoma. A mouse model of MEN-1 has been generated through homologous recombination ¹⁸. Tumors in these mice show loss of the wild-type MEN-1 allele, as would be expected in a tumor suppressor gene.

The gene product has been identified and is a 610 amino acid protein called menin ¹⁰. Menin is a nuclear protein, the function of which is unknown. It has no homology to known proteins. There are different patterns of expression in pancreatic exocrine and islet cells ¹⁹. Menin interacts with the transcription factor Jun-D ²⁰, suggesting a potential role in transcriptional regulation. Menin has been shown to bind directly to double stranded DNA, with regulatory effects on cell proliferation ²¹. Menin interacts with activator S-phase kinase (ASK) with regulatory effects on cell proliferation ²². It appears that regulation of cyclin-dependant kinase inhibitor transcription by cooperative interaction between menin and mixed lineage leukemia (MLL) proteins plays a major role in menin-related tumor suppression ²³. Menin has been shown to interact with numerous proteins including JunD, and nuclear factor – KappaB, Smad3, Pem, Nm23H1, glial fibrillary acidic protein, vimentin, and probably p53 ²⁴. About 25 protein partners for menin have been identified, but the importance of many of these interactions remains unknown ²⁵. Thus, the effects of menin on transcriptional regulation and cellular proliferation appear to be complex due to its effects on multiple pathways.

Deletions of chromosome 11q13 have also been found in a significant portion of sporadic adenomas of the parathyroid gland, pancreas, and pituitary gland. Among sporadic tumors, MEN1 mutations are described as occurring in 10-20% of parathyroid adenomas, 10-50% of pNETs depending on the histologic type, and 25-35% of bronchial carcinoids ²⁵. In one study, mutations of the MEN-1 gene have been identified in 31% of sporadic gastrinomas. However, the mutations are clustered between amino acids 66-166, unlike MEN-1, where mutations are scattered through the gene ²⁶. MEN-1 mutations are identified less often in sporadic insulinoma, 17% in one series ²⁷. Mutations in the MEN-1 gene are believed to be an early event, since mutations have been identified in both benign and malignant pNETs ²⁸. MEN1 mutations were identified in 7 of 55(13%) of patients with sporadic pulmonary carcinoids, and those patients with mutations had a worse prognosis ²⁹. Thus, the MEN-1 gene appears to play an important role in both sporadic and familial endocrine tumorigenesis. A variety of other chromosomes and genetic changes may also be involved, such as PRAD1 in parathyroid adenoma, and Gs L-chain gene in pituitary adenoma. A recent study identified 3 new miRNA’s which appear to be involved in MEN1 parathyroid neoplasia ³⁰. The MEN1 gene may also play a role in the development of other tumor types . A study of human melanomas and melanoma cell lines showed that MEN1 acts as a melanoma tumor suppressor by stimulating transcription of genes involved in homologous recombination-directed DNA repair ³¹.

Several variants of MEN1 syndrome have been described. MEN1 Burin is characterized by a high incidence of prolactinomas (40%) and a low incidence of gastrinomas (10%) ³². No characteristic gene mutation has been identified in affected individuals. Familial isolated hyperparathyroidism is another MEN1 variant characterized by the development of hyperparathyroidism without other endocrinopathies in affected individuals ³³. This autosomal dominant variant is notable for mild missense or in-frame deletions in the MEN1 gene as opposed to nonsense mutations seen in approximately 80% of MEN1 patients. A syndrome named MEN4 is notable for a predisposition to parathyroid adenomas, pituitary adenomas, and pNETS, is associated with germline CDKN1B mutations, but appears clinically indistinguishable from MEN1 ³⁴.

Multiple endocrine neoplasia type 1 symptoms

MEN-1 is characterized by hyperplasia and/or neoplasm of the parathyroid glands, pancreatic islet cells, and pituitary glands. Hyperparathyroidism occurs in about 90% of patients, pancreatic neuroendocrine tumors (pNETs) in 60% of patients, and pituitary adenomas in 40% of patients ³. Hyperparathyroidism is usually the first manifestation of the multiple endocrine neoplasia type 1 syndrome. However, the presence of hyperparathyroidism may not be detected until clinical disease of the pancreas or pituitary has brought the patient to medical attention. The presence of hyperparathyroidism may also be detected when screening immediate family members of those with proven MEN-1. MEN-1 patients with hyperparathyroidism typically have multiple gland nodular hyperplasia. The disease usually takes a slow but progressive course. The individual gland involvement is often variable and asymmetric, resulting in enlargement of only one or two glands. Hyperparathyroidism is commonly diagnosed during the second decade of life.

The most frequent islet cell neoplasm in patients with MEN-1 is gastrinoma. This is usually identified during the third or fourth decade of life. However, with the advent of biochemical screening, it is now typically detected earlier ³⁵. Approximately one third of patients with gastrinomas are associated with MEN-1 ³⁶. However, fewer than 5% of insulinomas are found in MEN-1 patients ³⁷. Gastrinomas in MEN-1 syndrome are usually small, multiple adenomas in the pancreas or duodenum ³⁸. The malignant potential of MEN-1 associated gastrinomas is probably less than sporadic tumors. Other types of pancreatic neuroendocrine tumors (pNETs) identified in MEN-1 patients include non-functioning tumors, vipomas, glucagonomas, somatostatinomas, and Ppomas ³⁹. More than one clinical syndrome may develop in the same patient either synchronously, or more often meta-synchronously. Some patients may have lymph node or liver metastases with no clinical manifestations.

It has become apparent that gastrinomas in MEN-1 patients are most often located in the duodenum. These tumors are small, usually multiple, and may be associated with pancreatic gastrinomas as well (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients. World J Surg 2010; 34(2):249-255.)). Immunohistochemical studies of the pancreas from MEN-1 patients demonstrate that most tumors that stain positively for gastrin are in the duodenum, or in the head or uncinate process of the pancreas ³⁶. It has been shown that proliferative gastrin cell changes in the duodenal mucosa precede the development of duodenal gastrinomas in MEN-1, but not sporadic duodenal gastrinomas ⁴⁰. Patients with clinical syndromes usually have discrete tumors rather than diffuse islet cell disease as the cause of the syndrome ⁴¹. Even though diffuse islet cell dysplasia is found in most patients, these cells do not stain for either gastrin or insulin. At least 50% of patients with elevated serum gastrin have metastases already ³⁵.

Pituitary tumors are common in patients with MEN-1, and may be micro or macro adenomas ⁴². The tumors are generally functionally active and often secrete prolactin ⁴³. Less commonly, the pituitary tumors may secrete ACTH leading to Cushing’s syndrome, or growth hormone leading to acromegaly. It is especially important to establish that Cushing’s syndrome in the MEN-1 patient is pituitary dependent (i.e., Cushing disease) rather than pituitary independent caused by an adrenal adenoma, an islet cell tumor, or a bronchial carcinoid tumor secreting ACTH or corticotrophin-releasing factor.

There is an increased frequency of adrenal lesions in patients with MEN-1 syndrome occurring in approximately 18% of MEN1 patients ³⁹. The patients may have functional or non-functional adrenal cortical hyperplasia or adenomas. There is some evidence to suggest that the frequency of adrenal cortical carcinoma is increased in MEN-1 patients.

Carcinoid tumors also occur more frequently in MEN-1 patients ⁴⁴. Although they have been reported in a variety of locations, bronchial carcinoids occur more commonly in women, and thymic carcinoids occur more commonly in men. Patients with MEN-1 and gastrinoma who are on long term H2 blockers or proton pump inhibitors may develop gastric carcinoids ⁴⁵.

Female MEN1 patients are at increased risk of invasive breast cancer, with a relative risk of 2.83, and occurring at a mean age of 48 years, compared to 60-65 years in the general population ⁴⁶. This risk is not related to other known breast cancer risk factors ⁴⁷. Thus, earlier breast cancer screening must be considered an integral part of the management of these patients.

Multiple endocrine neoplasia type 1 complications

The complications in MEN1 can occur because of the disease itself or due to surgery.

Pituitary tumors can cause complications like pituitary insufficiency and visual field defects.

Parathyroid tumors can cause metabolic bone disease and kidney stones. Tumors of gastro-entero-pancreatic tissue can cause complication by excessive secretion of gastrin, insulin, glucagon, or vasoactive intestinal peptide or by metastatic disease.

Multiple endocrine neoplasia type 1 diagnosis

A comprehensive history should be obtained during an initial visit as MEN1 can affect multiple organs. Complete family history can lead to early diagnosis as MEN1 may affect members of the same family. Patients in the same family may have different manifestations due to heterogeneous phenotypic expression.

A complete physical examination during initial and follow-up visits should be done to detect any visual field changes or a mass in the neck or abdomen area. Physicians identify MEN1 in many patients after incidental, abnormal lab or imaging studies. Symptoms may differ depending upon which organs are affected. The physical examination may be normal in many of these patients as the tumor size may be small.

Multiple endocrine neoplasia type 1 investigations

Evaluation of hyperparathyroidism involves measurement of serum calcium and PTH. The PTH level may be minimally elevated or in a high-normal range which can lead to a delay in making the diagnosis.

Imaging modalities like parathyroid USG and sestamibi scan are of limited value due to diffuse hyperplasia involving many glands in MEN1 patients.

Evaluation of gastro-entero-pancreatic tumors involves measurement of gastrin, glucagon, insulin, proinsulin, C-peptide, chromogranin A, pancreatic polypeptide, and vasoactive intestinal peptide (VIP).

Different modalities like transabdominal ultrasound, CT, MRI, octreoscan, and 68Ga-DOTATOC PET imaging are used for evaluation of gastro-entero-pancreatic tumors.

Endoscopic ultrasound has been found to be the most sensitive single modality to detect pancreatico-duodenal tumors. Multiple studies have reported significant superiority of EUS as compare to CT scan and somatostatin-receptor scintigraphy ⁴⁸.

Evaluation of pituitary gland tumors includes measurement of pituitary hormones including prolactin, growth hormone, insulin-like growth factor 1 (IGF-1 or somatomedin C), follicle-stimulating hormone (FSH), luteinizing hormone, adrenocorticotropic hormone (ACTH), TSH, T4, and cortisol ⁴⁹. These tumors most commonly secrete the hormone prolactin, followed by growth hormone. Serial basal PRL levels greater than 200 ng/ml confirm a prolactinoma and elevated IFG-1 levels with the failure of growth hormone (GH) to suppress during an oral glucose tolerance test (OGTT) confirm a growth hormone (GH) secreting adenoma. Non-secreting pituitary tumors can cause hypopituitarism by compression of the pituitary gland. MRI of the pituitary gland with contrast is the best diagnostic imaging. Thin cuts through pituitary gland should be done to avoid missing small tumors. Pituitary MRI is also used to evaluate the effectiveness of treatment during follow up of pituitary tumors.

Multiple endocrine neoplasia type 1 treatment

Because of the rarity of the MEN1 syndrome and the complexity of the disease, it is difficult to manage these patients.

Majority of recommendation regarding management of MEN1 patients lack a high level of evidence suggesting the need for more research in this field. Al-Salameh et al. ⁵⁰ reported that only 11 out of the 47 recommendations for MEN1 are considered having a high level of evidence.

Average life expectancy is shorter in patients with non-functioning pancreatic NET (pNET) compared to MEN1 patients without pancreatic NET tumors.

Parathyroid disease

Primary hyperparathyroidism is the most common and the first clinical manifestation of MEN1. It affects around 90% of MEN1 patients and is commonly diagnosed during the second decade of life.

Multi-gland, nodular hyperplasia is typical in MEN1 hyperparathyroidism, and it presents as hypercalcemia or its complications.

MEN1-related primary hyperparathyroidism is associated with more severe bone disease despite a milder biochemical presentation (PTH value in the normal range) when compared with sporadic primary hyperparathyroidism ⁵¹.

Parathyroid cancer is sporadic in MEN1. Di Meo et al. ⁵² reported 17 cases of parathyroid cancer of which 59% were seen in men, and the median age of diagnosis was 50.

Treatment of primary hyperparathyroidism in MEN1 with subtotal parathyroidectomy versus total parathyroidectomy is controversial. Total parathyroidectomy with forearm transplantation has been shown to be associated with the lesser chance of persistent hyperparathyroidism, but there is a significant risk of hypoparathyroidism with total parathyroidectomy (22% to 36%) compared to 10% with subtotal parathyroidectomy ².

Gastro-entero-pancreatic tumors

The neuroendocrine tumor (NET) of gastro-entero-pancreatic tissue occurs in around 30% to 75% of cases, but post-mortem studies have shown a prevalence of up to 80% to 100% ⁵³. A nonfunctioning NET is more common than a functioning tumor.

Pancreaticoduodenal NET in MEN1 presents early in life, is almost always multiple, and have uncertain behavior with a risk of malignancy.

Functioning NET secreting gastrin can cause peptic ulcer disease because of increased gastric acid secretion, known as Zollinger-Ellison Syndrome. Functioning NET can also cause hypoglycemia by secreting an excessive amount of insulin, but tumors secreting pancreatic polypeptide may not cause any clinical manifestations ⁵⁴.

Gastrinoma

The most frequent islet cell neoplasm is gastrinoma. Gastrinomas in MEN1 can be pancreatic or duodenal and are mostly diagnosed in the third or fourth decade of life. Detailed history and physical examination and biochemical evaluation should be done in patients with gastrinoma because around one-third of patients with gastrinoma have MEN1. These patients have hypergastrinemia and increased gastric acid output.

Duodenal gastrinomas in MEN1 syndrome are usually small (smaller than 1 cm), multifocal, and occur mainly in the proximal duodenum. Lymph node metastasis occurs in 45% to 95% of both pancreatic and duodenal gastrinoma, but liver metastasis is less common in duodenal NET ⁵³.

Insulinoma

Insulinoma is the second most common functional pancreatic NET; they represent around 10% to 30% patients of pancreatic NET in MEN1. These tumors secrete a significant amount of insulin which can cause the clinical manifestation of hypoglycemia including neuroglycopenic symptoms and sometimes severe hypoglycemia causing seizure or loss of consciousness. Patients with insulinoma due to MEN1 are mostly young (younger than 40 years old) when compared with insulinoma patients without MEN1 (older than 40 years old) ⁵⁴.

Fasting hypoglycemia with a glucose level of less than 45 mg/dl with concomitant hyperinsulinemia with an insulin level greater than 6 uU/mL is diagnostic of insulinoma ⁵⁵. An elevated level of proinsulin and C-peptide can confirm the diagnosis of insulinoma.

Surgical treatment is necessary for insulinoma patients. Preoperative tumor localization with different modalities including transhepatic portal venous sampling can improve the success rate of surgery. Surgical treatment can vary from enucleation of a single lesion to partial pancreatectomy. These patients can be managed medically with diazoxide or octreotide; frequent carbohydrate meals also help to lower risk of hypoglycemia.

Tonelli et al. reported 12 MEN1 insulinoma patients who underwent surgery; distal pancreatic resection was performed in 8 patients, 4 patients had pancreatoduodenectomy and enucleation of other macroadenoma present in the remnant pancreas was done in 9 out of 12 patients. There were no clinical recurrences at a mean follow-up of 85 months, but recurrence of nonfunctioning pancreatic macroadenoma occurred in 1 out of 12 patients ⁵⁶.

Chemotherapy can be used in patients with metastatic insulinoma.

Glucagonoma

Glucagonoma occurs in less than 3% of MEN1 patients. The typical manifestations include necrolytic migratory erythema, weight loss, anemia, and stomatitis. Glucagon levels are significantly elevated in these patients, usually greater than 500 pg/ml ⁵⁷. The most common site of occurrence is the tail of the pancreas, and surgical removal is the treatment of choice. Metastatic disease is present in up to 50% to 80% patient at the time of diagnosis. Medical management includes somatostatin analogs or chemotherapy.

VIPomas are not common in MEN1. These patients present with watery diarrhea, hypokalemia, and achlorhydria, known as Verner-Morrison-syndrome. Stool volume more than 0.5 to 1 L per day during a fast is typical. Use of laxatives and diuretics should be ruled out before confirming the diagnosis of VIPoma. Similar to glucagonoma, the most common site of involvement is the tail of the pancreas. Surgical resection can be curative in the absence of metastatic disease. Medical treatment includes somatostatin analogs, metoclopramide or chemotherapy agents like 5-fluorouracil or streptozotocin.

Nonfunctioning pancreatic NET is the most common gastro-entero-pancreatic tumor ⁵⁸. These lesions cause no clinical syndrome and may secrete a small amount of pancreatic polypeptide and gastrin. These are the most frequent cause of death in MEN1 patients. There can be a delay in diagnosis of nonfunctioning pancreatic NET due to lack of any specific clinical syndrome.

Radiological screening for diagnosis of pancreatic NET in MEN1 is recommended at the age of 10 years.

Treatment of nonfunctioning pancreatic NET is challenging and controversial because of the lack of consensus on the surgical indications. Triponez et al. reported that tumor size in nonfunctioning pancreatic NET correlates with the risk of metastasis and death ⁵⁸, but other studies did not confirm similar findings. Clinical practice guidelines for MEN1 recommend surgery if the size of the tumor is over 1 cm, but other studies do not recommend surgery until the size is 20 mm or more. Surgery can be considered for tumors less than 1 cm if there is rapid growth. So far tumor size has remained the deciding factor, but aggressive surgical management can cause significant complications like diabetes mellitus, steatorrhea, and early dumping syndrome.

Pituitary tumors

Prevalence of anterior pituitary tumors in MEN1 syndrome is around 20% to 60%, and the anterior pituitary tumor can be an initial presentation in around 25% of MEN1.

Anterior pituitary tumors in MEN1 are more common in women and are predominantly macroadenomas ⁵⁹.

Medical management includes the use of cabergoline or bromocriptine in patients with prolactinoma. Octreotide or lanreotide are used in GH producing tumors.

Studies have shown that anterior pituitary tumors in MEN1 patients are more aggressive and less likely to respond to medical management; thus requiring surgical management more often. Radiation treatment is used for patients with the residual unresectable tumor.

Surgical management is done in patients with large pituitary tumors with compression of optic nerve or tumors more than 1 cm or tumors which do not improve with medical management.

Carcinoid

Carcinoid tumors affect 3% of MEN1 patients. Common sites of involvement are the gastrointestinal (GI) tract, bronchi, pancreas, and thymus. Somatostatin analogs such as octreotide or lanreotide have been shown to cause regression of gastric carcinoid ⁶⁰.

Bronchial carcinoids causing MEN1 are more common in woman, but thymic carcinoids in European patients occur predominantly in men.

Thymic carcinoids are aggressive in MEN1 patients. Goudet et al. ⁶ reported a survival rate of only 9.5 years after diagnosis of a thymic tumor with 70% mortality linked directly to the tumor.

Screening for these patients is done with radiologic imaging like CT scan and MRI every 1 to 2 years. Biochemical evaluation is not done routinely due to lack of any specific biochemical abnormality or hormone production.

Surgical removal is the treatment of choice. Thymic carcinoid has been seen even in patients who underwent prophylactic thymectomy; therefore, surveillance with imaging is required. Radiotherapy and chemotherapy can be used in patients with an unresectable tumor or metastatic disease.

Adrenal tumors

Asymptomatic adrenal tumors occur in around 20% to 73% of MEN1 patients. Compared to adrenal incidentalomas, there is more likelihood of hyperaldosteronism and adrenocortical cancer but less likelihood of pheochromocytoma in MEN1 patients ⁶¹.

The incidence of adrenocortical cancer is around 1% in MEN1 patients, but this can increase up to 13% with an adrenal tumor larger than 1 cm.

Biochemical evaluation of adrenal tumors includes the evaluation of plasma free metanephrines, 1-mg overnight dexamethasone suppression test, urine-free cortisol, evening salivary cortisol, plasma renin, and aldosterone concentration with increased aldosterone: renin ratio greater than 20 and an increase in urinary aldosterone secretion.

There is no consensus about management of nonfunctioning adrenal tumors in MEN1 patients, but because of an increased risk of adrenocortical cancer, surgery is recommended if the tumor size is larger than 4 cm or tumor size 1 to 4 cm if there is a significant measurable growth over 6 months with suspicious radiological features.

LeBodic et al. reported an immunohistochemical study of 100 pancreatic tumors in 28 MEN1 patients and found that out of 100 tumors, 83 produced a predominant hormone, 10 were pluri-hormonal, and multiple tumors had a different predominant hormonal secretion in the same patient in 23 out of 28 patients ⁶².

Breast cancer

Breast cancer is more common in female MEN1 patients and occurs at an early age. Rachel et al. ⁶³ found that median age of breast cancer in women with MEN1 was 45 compared to 57.5 years in female relatives without MEN1 and 61.2 in the Dutch reference population.

The importance of breast cancer screening cannot be overstated in these patients.

Multiple endocrine neoplasia type 1 prognosis

The prognosis of the MEN1 patient is variable. Tumors associated with MEN1 are more aggressive and challenging to treat. Neuroendocrine tumors can metastasize quickly and can cause premature death. Studies have shown an increased risk of premature death and decreased average life expectancy in MEN1 patients, often related to metastatic islet cell tumor ⁶⁴, ⁶⁵. These patients can also develop significant morbidity because of surgical complications.

However, in another large series of gastrinoma patients ⁶⁶, patients with MEN-1 had a 15 year survival of 93%, compared to 68% in sporadic patients. A study of 220 pNET patients from the Dutch National MEN1 database revealed that 34 (15%) developed liver metastases, and 16 of these patients died after a median follow-up of 4 years ⁶⁷. Approximately 60-70% of MEN1 patients who die will die directly related to MEN1 ⁶⁸. With the advent of medical therapy to control the hypersecretory states of gastrinoma and other functional pNETs, and improved management of hyperparathyroidism and the pituitary tumors, the mortality associated with MEN1 has shifted to malignant pNETs and thymic carcinoids ⁶⁸. The development of thymic carcinoid tumors is associated with an increased risk of death ⁶⁹. Glucagonomas, Vipomas, somatostatinomas and non-functioning pancreatic endocrine tumors in MEN1 have also been reported to confer a 3-4 fold increase risk of death ⁶⁹. Thus better strategies are needed to identify those patients whose tumors will exhibit more aggressive behavior, and thus merit more aggressive surgical treatment and closer follow-up.

References

1. Singh G, Jialal I. Multiple Endocrine Neoplasia Type 1 (MEN I, Wermer Syndrome) [Updated 2019 Nov 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536980
2. Vinik A, Perry RR, Hughes MS, et al. Multiple Endocrine Neoplasia Type 1. [Updated 2017 Oct 7]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK481897
3. Oberg K, Skogseid B, Eriksson B. Multiple endocrine neoplasia type 1 (MEN-1). Clinical, biochemical and genetical investigations. Acta Oncol 1989; 28(3):383-387.
4. Multiple endocrine neoplasia. https://ghr.nlm.nih.gov/condition/multiple-endocrine-neoplasia
5. Thakker RV, Ponder BA. Multiple endocrine neoplasia. Baillieres Clin Endocrinol Metab 1988; 2(4):1031-1067.
6. Goudet P, Bonithon-Kopp C, Murat A, Ruszniewski P, Niccoli P, Ménégaux F, Chabrier G, Borson-Chazot F, Tabarin A, Bouchard P, Cadiot G, Beckers A, Guilhem I, Chabre O, Caron P, Du Boullay H, Verges B, Cardot-Bauters C. Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d’etude des Tumeurs Endocrines. Eur. J. Endocrinol. 2011 Jul;165(1):97-105.
7. Makri A, Bonella MB, Keil MF, Hernandez-Ramirez L, Paluch G, Tirosh A, Saldarriaga C, Chittiboina P, Marx SJ, Stratakis CA, Lodish M. Children with MEN1 gene mutations may present first (and at a young age) with Cushing disease. Clin. Endocrinol. (Oxf). 2018 Oct;89(4):437-443.
8. Marini F, Giusti F, Fossi C, Cioppi F, Cianferotti L, Masi L, Boaretto F, Zovato S, Cetani F, Colao A, Davì MV, Faggiano A, Fanciulli G, Ferolla P, Ferone D, Loli P, Mantero F, Marcocci C, Opocher G, Beck-Peccoz P, Persani L, Scillitani A, Guizzardi F, Spada A, Tomassetti P, Tonelli F, Brandi ML. Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database. Endocrine. 2018 Oct;62(1):215-233.
9. Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjold M. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 1988; 332(6159):85-87.
10. The European Consortium on MEN1. Linkage disequilibrium studies in multiple endocrine neoplasia type 1 (MEN1). Hum Genet 1997; 100(5-6):657-665.
11. Chandrasekharappa SC, Guru SC, Manickam P et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997; 276(5311):404-407.
12. Hyde SM, Cote GJ, Grubbs EG. Genetics of Multiple Endocrine Neoplasia Type 1/Multiple Endocrine Neoplasia Type 2 Syndromes. Endocrinol Metab Clin North Am 2017; 46(2):491-502.
13. Calender A. Molecular genetics of neuroendocrine tumors. Digestion 2000; 62 Suppl 1:3-18.
14. Agarwal SK, Lee BA, Sukhodolets KE et al. Molecular pathology of the MEN1 gene. Ann N Y Acad Sci 2004; 1014:189-198.
15. Longuini VC, Lourenco DM, Jr., Sekiya T et al. Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations. Eur J Endocrinol 2014; 171(3):335-342.
16. Bartsch DK, Slater EP, Albers M et al. Higher risk of aggressive pancreatic neuroendocrine tumors in MEN1 patients with MEN1 mutations affecting the CHES1 interacting MENIN domain. J Clin Endocrinol Metab 2014; 99(11):E2387-E2391.
17. Thevenon J, Bourredjem A, Faivre L et al. Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d’etude des Tumeurs Endocrines (GTE) cohort study. Hum Mol Genet 2013; 22(10):1940-1948.
18. Ellard S, Hattersley AT, Brewer CM, Vaidya B. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin Endocrinol (Oxf) 2005; 62(2):169-175.
19. Crabtree J, Scacheri P, Ward J et al. A mouse model of multiple endocrine neoplasia, type 1, develop multiple endocrine tumors. PNAS 2001; 98(3):1118-1123.
20. Cavallari I, D’Agostino DM, Ferro T et al. In situ analysis of human menin in normal and neoplastic pancreatic tissues: evidence for differential expression in exocrine and endocrine cells. J Clin Endocrinol Metab 2003; 88(8):3893-3901.
21. Agarwal SK, Guru SC, Heppner C et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 1999; 96(1):143-152.
22. La P, Silva AC, Hou Z et al. Direct binding of DNA by tumor suppressor menin. J Biol Chem 2004; 279(47):49045-49054.
23. Schnepp RW, Hou Z, Wang H et al. Functional interaction between tumor suppressor menin and activator of S-phase kinase. Cancer Res 2004; 64(18):6791-6796.
24. Milne TA, Hughes CM, Lloyd R et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci U S A 2005; 102(3):749-754.
25. Oberg K. The genetics of neuroendocrine tumors. Semin Oncol 2013; 40(1):37-44.
26. Poisson A, Zablewska B, Gaudray P. Menin interacting proteins as clues toward the understanding of multiple endocrine neoplasia type 1. Cancer Lett 2003; 189(1):1-10.
27. Goebel SU, Heppner C, Burns AL et al. Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas. J Clin Endocrinol Metab 2000; 85(1):116-123.
28. Zhuang Z, Vortmeyer AO, Pack S et al. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 1997; 57(21):4682-4686.
29. Swarts DR, Scarpa A, Corbo V et al. MEN1 gene mutation and reduced expression are associated with poor prognosis in pulmonary carcinoids. J Clin Endocrinol Metab 2014; 99(2):E374-E378.
30. Luzi E, Ciuffi S, Marini F, Mavilia C, Galli G, Brandi ML. Analysis of differentially expressed microRNAs in MEN1 parathyroid adenomas. Am J Transl Res 2017; 9(4):1743-1753.
31. Fang M, Xia F, Mahalingam M, Virbasius CM, Wajapeyee N, Green MR. MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair. Mol Cell Biol 2013; 33(13):2635-2647.
32. Hao W, Skarulis MC, Simonds WF et al. Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma. J Clin Endocrinol Metab 2004; 89(8):3776-3784.
33. Hannan FM, Nesbit MA, Christie PT et al. Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene. Nat Clin Pract Endocrinol Metab 2008; 4(1):53-58.
34. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol 2014; 386(1-2):2-15.
35. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore) 2004; 83(1):43-83.
36. Howard TJ, Passaro E Jr. Gastrinoma. New medical and surgical approaches. Surg Clin North Am 1989; 69(3):667-681.
37. Pipeleers-Marichal M, Somers G, Willems G et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med 1990; 322(11):723-727.
38. Wynick D, Williams SJ, Bloom SR. Symptomatic secondary hormone syndromes in patients with established malignant pancreatic endocrine tumors. N Engl J Med 1988; 319(10):605-607.
39. Goudet P, Murat A, Binquet C et al. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients. World J Surg 2010; 34(2):249-255.
40. Doherty GM. Multiple endocrine neoplasia type 1: duodenopancreatic tumors. Surg Oncol 2003; 12(2):135-143.
41. Anlauf M, Perren A, Meyer CL et al. Precursor lesions in patients with multiple endocrine neoplasia type 1-associated duodenal gastrinomas. Gastroenterology 2005; 128(5):1187-1198.
42. Brandi ML. Multiple endocrine neoplasia type I: general features and new insights into etiology. J Endocrinol Invest 1991; 14(1):61-72.
43. Norton JA, Doppman JL, Collen MJ et al. Prospective study of gastrinoma localization and resection in patients with Zollinger-Ellison syndrome. Ann Surg 1986; 204(4):468-479.
44. Schimke RN. Multiple endocrine neoplasia: how many syndromes? Am J Med Genet 1990; 37(3):375-383.
45. Farhangi M, Taylor J, Havey A, O’Dorisio TM. Neuroendocrine (carcinoid) tumor of the lung and type I multiple endocrine neoplasia. South Med J 1987; 80(11):1459-1462.
46. Dreijerink KM, Goudet P, Burgess JR, Valk GD. Breast-cancer predisposition in multiple endocrine neoplasia type 1. N Engl J Med 2014; 371(6):583-584.
47. van Leeuwaarde RS, Dreijerink KM, Ausems MG et al. MEN1-Dependent Breast Cancer: Indication for Early Screening? Results From the Dutch MEN1 Study Group. J Clin Endocrinol Metab 2017; 102(6):2083-2090.
48. van Asselt SJ, Brouwers AH, van Dullemen HM, van der Jagt EJ, Bongaerts AH, Kema IP, Koopmans KP, Valk GD, Timmers HJ, de Herder WW, Feelders RA, Fockens P, Sluiter WJ, de Vries EG, Links TP. EUS is superior for detection of pancreatic lesions compared with standard imaging in patients with multiple endocrine neoplasia type 1. Gastrointest. Endosc. 2015 Jan;81(1):159-167.e2.
49. Gounden V, Rampursat YD, Jialal I. Secretory tumors of the pituitary gland: a clinical biochemistry perspective. Clin. Chem. Lab. Med. 2018 Dec 19;57(2):150-164.
50. Al-Salameh A, Baudry C, Cohen R. Update on multiple endocrine neoplasia Type 1 and 2. Presse Med. 2018 Sep;47(9):722-731.
51. Eller-Vainicher C, Chiodini I, Battista C, Viti R, Mascia ML, Massironi S, Peracchi M, D’Agruma L, Minisola S, Corbetta S, Cole DE, Spada A, Scillitani A. Sporadic and MEN1-related primary hyperparathyroidism: differences in clinical expression and severity. J. Bone Miner. Res. 2009 Aug;24(8):1404-10.
52. Di Meo G, Sgaramella LI, Ferraro V, Prete FP, Gurrado A, Testini M. Parathyroid carcinoma in multiple endocrine neoplasm type 1 syndrome: case report and systematic literature review. Clin. Exp. Med. 2018 Nov;18(4):585-593.
53. Norton JA, Krampitz G, Jensen RT. Multiple Endocrine Neoplasia: Genetics and Clinical Management. Surg. Oncol. Clin. N. Am. 2015 Oct;24(4):795-832.
54. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML., Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 2012 Sep;97(9):2990-3011.
55. Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012 Dec;26(6):737-53.
56. Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML. Operation for insulinomas in multiple endocrine neoplasia type 1: When pancreatoduodenectomy is appropriate. Surgery. 2017 Mar;161(3):727-734.
57. Sandhu S, Jialal I. Glucagonoma Syndrome. [Updated 2019 Nov 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519500
58. Triponez F, Dosseh D, Goudet P, Cougard P, Bauters C, Murat A, Cadiot G, Niccoli-Sire P, Chayvialle JA, Calender A, Proye CA. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann. Surg. 2006 Feb;243(2):265-72.
59. Vergès B, Boureille F, Goudet P, Murat A, Beckers A, Sassolas G, Cougard P, Chambe B, Montvernay C, Calender A. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J. Clin. Endocrinol. Metab. 2002 Feb;87(2):457-65.
60. Tomassetti P, Migliori M, Caletti GC, Fusaroli P, Corinaldesi R, Gullo L. Treatment of type II gastric carcinoid tumors with somatostatin analogues. N. Engl. J. Med. 2000 Aug 24;343(8):551-4.
61. Gatta-Cherifi B, Chabre O, Murat A, Niccoli P, Cardot-Bauters C, Rohmer V, Young J, Delemer B, Du Boullay H, Verger MF, Kuhn JM, Sadoul JL, Ruszniewski P, Beckers A, Monsaingeon M, Baudin E, Goudet P, Tabarin A. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’etude des Tumeurs Endocrines database. Eur. J. Endocrinol. 2012 Feb;166(2):269-79.
62. Le Bodic MF, Heymann MF, Lecomte M, Berger N, Berger F, Louvel A, De Micco C, Patey M, De Mascarel A, Burtin F, Saint-Andre JP. Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. Am. J. Surg. Pathol. 1996 Nov;20(11):1378-84.
63. van Leeuwaarde RS, Dreijerink KM, Ausems MG, Beijers HJ, Dekkers OM, de Herder WW, van der Horst-Schrivers AN, Drent ML, Bisschop PH, Havekes B, Peeters PHM, Pijnappel RM, Vriens MR, Valk GD. MEN1-Dependent Breast Cancer: Indication for Early Screening? Results From the Dutch MEN1 Study Group. J. Clin. Endocrinol. Metab. 2017 Jun 01;102(6):2083-2090.
64. Norton JA, Fraker DL, Alexander HR et al. Surgery increases survival in patients with gastrinoma. Ann Surg 2006; 244(3):410-419.
65. Maton PN, Gardner JD, Jensen RT. Diagnosis and management of Zollinger-Ellison syndrome. Endocrinol Metab Clin North Am 1989; 18(2):519-543.
66. Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT. Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome. Ann Surg 2001; 234(4):495-505.
67. Conemans EB, Nell S, Pieterman CRC et al. Prognostic factors for survival of MEN1 patients with duodenopancreatic tumors metastatic to the liver: Results from the DMSG. Endocr Pract 2017; 23(6):641-648.
68. Jensen RT, Norton JA. Treatment of Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1: Some Clarity But Continued Controversy. Pancreas 2017; 46(5):589-594.
69. Horiuchi K, Okamoto T, Iihara M, Tsukada T. An analysis of genotype-phenotype correlations and survival outcomes in patients with primary hyperparathyroidism caused by multiple endocrine neoplasia type 1: the experience at a single institution. Surg Today 2013; 43:894.