Multiple Endocrine Neoplasia Type 1 (MEN1) 

Updated: Oct 31, 2017
Author: Catherine Anastasopoulou, MD, PhD, FACE; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by inactivating mutations of the MEN1 tumor suppressor gene at the 11q13 locus. Although usually inherited as an autosomal dominant disorder, MEN1 can also occur sporadically (without a family history) as a result of new mutations.

MEN1 predisposes to the development of tumors in target neuroendocrine tissues. Type 2 MEN (MEN2), in contrast, is caused by mutations in the RET proto-oncogene and typically presents as medullary thyroid carcinoma, hyperparathyroidism, or pheochromocytoma.

MEN1 is characterized by the combination of parathyroid tumors, pancreatic islet cell tumors, and anterior pituitary tumors (see the images below).  Most MEN1 tumors are not aggressive, and many of them (particularly nonfunctioning tumors) follow a long-term indolent course, remaining asymptomatic for years. Nevertheless, patients with untreated MEN1 have a decreased life expectancy, with a 50% probability of death by age 50 years.[1]

Sagittal (left image) and coronal (right image), T Sagittal (left image) and coronal (right image), T1-weighted magnetic resonance images of the brain in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1). These images show a pituitary macroadenoma (arrows).
Indium-111 (111In) octreotide scan in a patient wi Indium-111 (111In) octreotide scan in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1). These nuclear images demonstrate abnormal activity in the pituitary macroadenoma (curved arrow), parathyroid adenoma (straight arrow), and gastrinoma metastases throughout the abdomen (arrowheads).

In 1954, Wermer was the first to describe the syndrome as a distinct clinical entity. The disorder was initially known as Wermer syndrome. 

Pathophysiology

Parathyroid tumors

Primary hyperparathyroidism, due to hyperplasia and/or adenoma of parathyroid glands, is the most common manifestation of multiple endocrine neoplasia type 1 (MEN1) and occurs in approximately 90% of all patients.[2]

Primary hyperparathyroidism in MEN1 can have a long-term asymptomatic course and is usually diagnosed by the incidental finding of elevated serum parathyroid hormone level in a patient with hypercalcemia or, in some cases, with normocalcemia. Clinical manifestations can include hypercalcemia, nephrolithiasis, and bone abnormalities (osteitis fibrosa cystica). Common symptoms associated with hypercalcemia include polydipsia, polyuria, constipation, and generalized malaise.

Primary hyperparathyroidism in MEN1 differs from non-MEN1 primary hyperparathyroidism in the following ways[3] :

  • Earlier age at onset (20-25 years)
  • Involvement of multiple parathyroid glands
  • High recurrence rate of hypercalcemia after parathyroidectomy (50% by 8-12 years after surgery)

Pancreatic islet cell tumors (neuroendocrine tumors)

Pancreatic islet cell tumors represent the second most common manifestation of MEN1, occurring in 30-80% of patients. Islet cell tumors encompass the following[1] :

  • Gastrinomas
  • Insulinomas
  • Glucagonomas
  • Vasoactive intestinal polypeptidomas (VIPomas)
  • Pancreatic polypeptidomas (PPomas).

Tumors are often multicentric and may undergo malignant transformation. These tumors can produce peptides and biogenic amines.

However, nonfunctioning pancreatic endocrine tumors are the most common enteropancreatic neuroendocrine tumor. Nonfunctioning tumors do not secrete hormone, or they may release hormonally inactive peptides such as pancreatic polypeptide (PP), chromogranin A, neurotensin, neuro-specific enolase, or ghrelin.

Especially small (< 2 cm) nonfunctional pNETs pose a challenge to treating physicians. The relatively recent availability and further increased use of sensitive radiological screening methods has allowed the diagnosis of these nonfunctional pancreatic tumors.  These tumors are important to diagnose, since by the age of 80 the penetrance of pNETs is over 80% and metastatic disease is the most important cause of MEN1-related mortality.[4, 5]  

Gastrinomas, seen in the image below, are the most common functional pancreatic neuroendocrine tumors and occur in 40-55% of patients.[6]  The development of gastrinomas is preceded by multifocal hyperplasia of the gastrin-producing cells.

Computed tomography (CT) scan of the pancreas in a Computed tomography (CT) scan of the pancreas in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1) and a gastrinoma. This image shows a pancreatic head mass (large, white arrow), as well as a low-attenuating lesion in the liver (small, black arrowhead) that indicates metastases. Note the calcifications of the right renal medullary pyramids (medullary nephrocalcinosis; black arrows) in this nonenhanced CT scan.

Compared with non-MEN1 gastrinomas in Zollinger-Ellison syndrome (ZES), the gastrinomas in MEN1 are more often small (< 0.5 cm), multicentric, and located in the duodenum, thus diminishing the probability of surgical cure. The features predictive of poor prognosis include pancreatic location of lesions, metastases, ectopic Cushing syndrome, and height of gastrin levels. 

About 20-30% of patients with ZES have MEN1. In MEN1 patients, ZES appears to develop only in those with primary hyperparathyroidism.[1] Longstanding MEN1 and ZES may lead to the development of gastric carcinoid tumors that may be aggressive.[7]  

Insulinomas are the second most common functioning pancreatic neuroendocrine tumor in MEN1, developing at young age (< 35 years) in approximately 10-30% of patients. Insulinomas in MEN1 can manifest as single pancreatic macroadenoma (>2 cm) or, more commonly, as multiple microadenomas (< 2 cm) scattered along the entire pancreas.[8]  Insulinomas (see the images below) can be multicentric and can metastasize either to regional lymph nodes or to the liver.[1]

Endoscopic ultrasonogram in a patient with an insu Endoscopic ultrasonogram in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV). (From: Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. Jun 25 1992;326(26):1721-6.)
Computed tomography (CT) scan image with oral and Computed tomography (CT) scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (From: Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St. Louis, Mo: Mosby-Year Book; 1993: 272.)

Glucagonomas occur rarely (< 3%) in patients with MEN1 and can present silently or with hyperglycemia. Few patients show the typical skin lesions, known as necrolytic migratory erythema. Other presenting symptoms can be anemia, stomatitis, and weight loss, but these are often absent.

VIPomas occur in less than 1% of MEN1 patients. Presenting symptoms can include watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). Tumors secreting pancreatic polypeptide (PPomas) may not produce clinical manifestations; alternatively, PPomas may be nonsecretory.

Growth hormone–releasing hormone tumors (GHRHomas) have been reported in patients with MEN1. GHRHomas most commonly arise in the lungs, followed by the pancreas and small intestine.[1]

Pituitary tumors

MEN1-associated anterior pituitary tumors most commonly secrete prolactin (60%), followed by tumors that secrete growth hormone (25%). Less than 5% secrete corticotropin and others are nonfunctional.[1] Compared with non-MEN1 pituitary tumors, MEN1 pituitary tumors tend to be larger (macroadenomas) and more aggressive, with a higher rate of infiltration of tumor cells into normal pituitary tissue. MEN1-associated pituitary tumors are less responsive to therapy. However, there is no distinct histological difference between MEN1 and non-MEN1 pituitary tumors.[9]

Other tumors associated with MEN1

Carcinoid tumors can occur in patients with MEN1 and may be located in the bronchi, gastrointestinal tract, pancreas, and thymus. Thymic carcinoids associated with MEN1 are often nonfunctional and aggressive.[10] In women, bronchial carcinoids are most common. Carcinoids can actively secrete hormones such as serotonin, somatostatin, corticotropin, and growth hormone.

Cutaneous expression of MEN1 is common. Subcutaneous lipomas are found in one third of MEN1 patients. These lesions have loss of heterozygosity for band 11q12-12 and are associated with defective globular (G) protein function. Lipomas in MEN1 can also be retroperitoneal, visceral, or pleural. The presence of facial angiofibromas and collagenomas may allow presymptomatic diagnosis of MEN1 in relatives of diagnosed patients.[1]

Adrenal tumors occur in 20-40% of patients with MEN1. These tumors are most often benign and consist of nonfunctional cortical adenomas or diffuse or nodular hyperplasia. Adrenal cortical carcinomas are rare in MEN1 patients, but larger adrenal tumors (>1 cm) are more likely to undergo malignant transformation, so annual adrenal imaging in patients with known adrenal tumors is recommended.[1]

Thyroid adenomas occur in 5-30% of patients and have no specific MEN1-reported clinical significance. Meningiomas and other central nervous system tumors have been reported.

Thymic neuroendocrine tumor (TH-NET) is a rare but fatal component of MEN1 that accounts for almost 20% of MEN1-associated mortality. In a single-center study plus systematic review and meta-analysis, the pool estimate of TH-NET prevalence was 3.7%, with a male predominance of almost 4:1; male predominance and history of smoking were more common in American and European series compared with Asian reports. Median age at diagnosis was 43 years.[11]

Compared with the general population, females with MEN1 were found to have a 2-3 times higher risk for breast cancer at younger age and showed to have loss of heterozygosity (LOH) at the MEN1 locus [12]

Epidemiology

Random postmortem studies report a prevalence of multiple endocrine neoplasia type 1 (MEN1) of 0.25%.[1] However, in patients with clinical manifestations associated with MEN1, such as primary hyperparathyroidism, the reported prevalence is 1-18%. From 16-38% of patients harboring one or more gastrinomas have MEN1, and 3% of patients with pituitary tumors have MEN1.[13, 14]

The MEN1 gene has a high penetrance. By age 20 years, the gene is 50% penetrant and by age 40 years, 95% penetrant. Patients younger than 5 years have not been identified as manifesting the typical features associated with the MEN1 gene carrier status, and, thus, the gene is likely nonpenetrant before this age.[1, 2]

Mortality/Morbidity

Patients with multiple endocrine neoplasia type 1 (MEN1) have a decreased life expectancy, with a 50% probability of death by age 50 years. Half the deaths result directly from a malignant process or the sequela of an endocrine disorder.

Malignant pancreatic neuroendocrine tumors and thymic carcinoid tumors have been associated with a marked increase in the risk of death in MEN1 patients.[6] In a Dutch study, median survival in patients with an identified mutation in the MEN1 gene was estimated at 73 years, versus 87 years in mutation-negative patients diagnosed on the basis of having two of the three main MEN1 manifestations (primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, and pituitary tumors).[15]

The rationale for an aggressive surveillance approach in MEN1 patients and asymptomatic carriers is based on the presumption that the early pre-symptomatic detection of MEN1 neoplasias may reduce the assoicated mortality.[1]

Individuals with MEN1 report a high degree of financial burden, negative financial events, and unemployment. All these factors were associated with worse health-related quality of life. Persistent hypercalcemia after parathyroid surgery was associated with higher levels of anxiety, depression, fatigue, and decreased social functioning. Patients diagnosed at a younger age (< 45 years) reported worse physical and social functioning.[16]

Race-, sex-, and age-related demographics

No racial differences have been found. The female-to-male incidence is approximately equal.

Age-related aspects of multiple endocrine neoplasia type 1 (MEN1) include the following:

  • The peak incidence of symptoms in MEN1 is during the third decade of life in women and during the fourth decade of life in men. The reported age range is 5-81 years.
  • Hyperparathyroidism, the most common feature in MEN1, occurs at an earlier age (20-25 years) than in non-MEN1 patients (55 years).
  • MEN1-associated gastrinomas usually develop after age 30 years.
  • MEN1-associated insulinomas typicaly occur in those younger than 40 years but many have appeared in patients younger than 20 years.
  • Pituitary tumors and neuroendocrine tumors can occur as early as age 5 years.
  • In the study by de Laat et al, the median age for developing the first main MEN1 manifestation was 10 years later in mutation-negative than mutation-positive patients. [15]
 

Presentation

History and Physical Examination

The presentation in multiple endocrine neoplasia type 1 (MEN1) varies from patient to patient. Patients may be asymptomatic, or may present with signs and symptoms related to the endocrine organs involved and the hormones secreted, as follows:

  • Hyperparathyroidism is usually the initial clinical manifestation of MEN1
  • Some patients initially present with Zollinger-Ellison syndrome (ZES). [17] Gastrinoma symptoms caused by ZES include diarrhea and upper abdominal pain due to peptic ulcers and esophagitis; complications include ulcer perforation or bleeding.
  • Insulinomas also may be identified prior to primary hyperparathyroidism-associated hypercalcemia. Hypoglycemia after a fast or exertion, with improvement in symptoms after sugar intake, is the classic presentation. [18]
  • Glucagonoma syndrome consists of a rash (necrolytic migratory erythema), weight loss, anorexia, anemia, diarrhea, venous thrombosis, and stomatitis. The full syndrome is rarely expressed.
  • Carcinoid tumor presenting features can include flushing, diarrhea, and bronchospasm.
  • Anterior pituitary tumors may produce signs and symptoms from hormonal secretion and/or mass effect.

MEN1 patients with hyperparathyroidism usually present with mild hypercalcemia, and rarely develop nephrolithiasis. Other manifestations include bone abnormalities and musculoskeletal complaints. Patients may report increased thirst and urination and/or constipation. In more severe hypercalcemia, generalized weakness and alterations of mental status may develop. These features are similar to presentations of other forms of hypercalcemia.

Clinical manifestations of anterior pituitary tumors are similar to those of sporadic pituitary adenomas and depend on hormone secretion and tumor size. Mass effects from tumor growth include headache and visual-field defects. Hormonal effects may include the following:

  • Prolactinomas may cause erectile dysfunction or decreased libido in men, while women may develop amenorrhea and galactorrhea.
  • Growth hormone–secreting tumors can cause acromegaly and result in enlargement of the hands, feet, and jaw; this last can manifest with increased drooling and larger spaces between teeth.
  • Corticotropin-producing tumors cause excess cortisol secretion; patients can present with large, purplish abdominal stretch marks; increased bruising; and proximal muscle weakness.

Causes

 

The putative gene for multiple endocrine neoplasia type 1 (MEN1) has been localized to band 11q13 and codes for the menin protein. Menin is involved with regulation of transcription and genome stability. Loss of heterozygosity for this region is associated with MEN1, suggesting that the gene has tumor suppression function. Patients inherit one mutated copy of the gene and require a somatic mutation of the second copy for tumor development. MEN1 is an autosomal dominant disorder, but sporadic mutations also occur.

 

 

DDx

Diagnostic Considerations

Hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN1) must be separated from other familial forms of hypercalcemia, including familial parathyroid hyperplasia and familial adenomatous hyperparathyroidism. Familial hypocalciuric hypercalcemia may also have a similar presentation. These latter 2 syndromes have no pancreatic or pituitary manifestations.

Conditions other than Zollinger-Ellison syndrome (ZES) that are associated with elevated serum gastrin levels include the following:

  • Retained gastric antrum
  • Gastric outlet obstruction
  • Hypercalcemia
  • Massive small bowel resection
  • Atrophic gastritis
  • Proton pump inhibitor therapy

Patients with MEN1-associated ZES are on average 10 years younger than those with sporadic ZES at the time of diagnosis. ZES should be considered in MEN1 patients with new digestive symptoms, including loose stools, especially when diarrhea promptly disappears when using proton pump inhibitor (PPI) therapy, epigastric pain and signs of GERD without severe esophagitis or tiny duodenal erosions on gastroscopy.

Differential Diagnoses

 

Workup

Approach Considerations

The recognition, localization, staging and follow-up of MEN1 NETs are performed by tumor marker measurements in serum and urine, and by imaging, such as computed tomography (CT) scan of chest, abdomen and pelvis, magnetic resonance imaging (MRI) of chest, abdomen and liver, endoscopic ultrasounds (EUS) of stomach and abdomen, contrast-enhanced abdominal CT and non-contrast MRI of the head.

Laboratory Studies

Laboratory studies in patients known to have multiple endocrine neoplasia type 1 (MEN1) screen for different hormones associated with potential MEN1 tumors.

Gastrinomas

Fasting gastrin 10 times over the gastrin normal upper limit of 100 pg/mL, in presence of hyperchloryhydia or pH < 2. If fasting gastrin levels are below the diagnostic level of 1000 pg/mL, gastrin stimulation test by 12h- fasting intravenous injection of secretin is useful in establishing the diagnosis of gastrinoma. A gastrin increase of 120-500 pg/mL with respect to baseline value and a gastrin rise of 110 pg/mL immediately after secretin infusion strongly suggest gastrinoma; approximately 90% of patients with gastrinoma have a positive secretin test.[8]

Insulinomas

A supervised 72-hour fast is used most often to confirm this diagnosis. Increased plasma insulin occurs with hypoglycemia. Elevated C-peptide and proinsulin levels occur. Screening should start by age 5 years. Exclude the presence of oral hypoglycemic agents.

Glucagonomas

Elevated serum glucagon levels and hyperglycemia are present. Diagnosis may occur incidentally with imaging studies. Screening should start in children younger than 10 years.

Vasoactive intestinal polypeptidomas (VIPomas)

Watery diarrhea with hypokalemia and achlorhydria can occur. Elevated serum levels of vasoactive intestinal polypeptide with excess stool volume of 0.5-1L per day during fasting can establish the diagnosis. Screening should start in children younger than 10 years.

Pancreatic polypeptidomas (PPomas)

PPomas are not associated with a clinical syndrome. Pancreatic polypeptide levels are elevated. Chromogranin A levels can be elevated in any pancreatic neuroendocrine tumor. Screening should begin by age 10 years.

Carcinoid tumors

Elevated levels of chromogranin A, calcitonin, corticotropin, or urinary 5-hydroxyindoleacetic acid (5-HIAA) can occur. However, screening depends on radiological imaging, as no biochemical abnormality has been consistently observed.[1]

Pituitary tumors

Assess growth hormone levels (insulinlike growth factor-1 [IGF-1]) and prolactin. Screening should begin by age 5 years.

Hyperparathyroidism

The serum calcium is elevated, while the parathyroid hormone level is elevated or inappropriately normal. Screening should start by age 8 years. Patients with hypercalcemia should undergo continuous surveillance, including annual 24-hour urine calcium measurement and imaging studies (see below).

Imaging Studies

Primary hyperparathyroidism

Radiographs in patients with hyperparathyroidism may reveal bone abnormalities, as seen in the images below. Patients with hypercalcemia should undergo annual screening that includes imaging of the urinary tract and dual-energy x-ray absorptiometry (DXA) for evaluation of bone mineral density (BMD).

Anteroposterior radiographic view of the right han Anteroposterior radiographic view of the right hand in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1) and primary hyperparathyroidism. This image shows subperiosteal bone resorption along the radial aspects of the middle phalanges (arrows).
Bilateral, anteroposterior radiographic views of t Bilateral, anteroposterior radiographic views of the hands in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1) and primary hyperparathyroidism. These images show subperiosteal bone resorption along the radial aspects of the middle phalanges.

Pituitary tumors

Magnetic resonance imaging (MRI), with attention to the sella turcica region (pancreatic protocol), is the screening test of choice.[19] Patients should also be screened every 3 years starting at age 5 years.

Gastrinomas

Biochemical evidence should be present to justify pursuing radiological evaluation. The majority of multiple endocrine neoplasia type 1 (MEN1) gastrinomas are multiple tumors localized in the submucosa of the proximal duodenum, and most are missed by conventional imaging surveillance (CT scan, MRI, and endoscopic ultrasonography [EUS]).

Somatostatin receptor scintigraphy (SRS) has a sensitivity range for gastrinomas of 70-90%. SRS findings can be enhanced by selective arterial secretagogue testing with secretin or calcium infusion. (In 10% of cases of gastrinomas, secretin is not diagnostically useful.)

EUS helps detect tumors in the pancreatic head but rarely in the duodenal wall. It is more sensitive than CT scanning or transabdominal ultrasonography.

Insulinomas

Biochemical evidence should be present before pursuing radiological evaluation. Tumors are generally localized by CT scan, MRI, or EUS of the pancreas body and tail. MRI is the imaging tehcnique of choice for periodical surveillance. SRS findings may be positive in up to 50% of patients with insulinomas. SRS is best used in conjunction with single-photon emission CT (SPECT) scanning.

EUS (see image below) has a reported detection sensitivity of up to 94%. Selective arterial calcium stimulation with hepatic venous sampling is often required, as patients with MEN1 are likely to have multiple lesions. Intraoperative ultrasonography can be helpful.

Endoscopic ultrasonogram in a patient with an insu Endoscopic ultrasonogram in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV). (From: Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. Jun 25 1992;326(26):1721-6.)

Parathyroid tumors

Parathyroid gland imaging with a sestamibi scanning is of limited benefit, as all parathyroid glands may be affected and neck exploration is required regardless. An example of a positive scan is illustrated (see image below).

Technetium-99m sestamibi scan (99mTc MIBI) in a pa Technetium-99m sestamibi scan (99mTc MIBI) in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1). These images demonstrate persistent abnormal activity of the inferior right parathyroid gland that is consistent with an adenoma.

Pancreatic neuroendocrine tumors (pNETs)

The sensitity of EUS is much higher than that of MRI for the detection of pNETs; EUS can identify tumors in 55% of asymptomatic patients. Annual MRI, CT scanning, or EUS screening is recommended. Adrenal gland imaging should be undertaken at the same time. Radiological screening should start before age 10 years.

Nonfunctioning neuroendocrine tumors

A combination of MRI, CT scan, and EUS of the abdomen is suggested every year. Improving sensitivity and specificity of imaging techniques have resulted in increased identification of nonfunctioning tumors in MEN1.[8]

Thymic and bronchial carcinoid tumors

CT scanning or MRI of the chest is recommended every 1-2 years. CT scan is more sensitive (about 95%). Screening should begin by age 15 years.

Other Tests

Genetic testing

MEN1 syndrome is caused by inactivating mutations of the tumor suppressor gene MEN1, positionally cloned in 1997 at 11q13 locus. The identification and genetic characterization of the causative gene opened the possibility of genetic testing and early diagnosis of the disease.

Sequence analysis of the MEN1 gene for mutations provides the best evidence of gene carrier status. This genetic test is performed in several commercial laboratories. Genetic testing for MEN1 mutations is recommended for the following individuals[1] :

  • Clinical index cases with 2 or more MEN1-associated endocrine tumors
  • Asymptomatic first-degree relatives of a known MEN1 mutation carrier
  • First-degree relatives of a MEN1 mutation carrier with symptoms, signs, and biochemical or radiological evidence of MEN1 associated tumor(s)

Asymptomatic members of a mutation-bearing family should undergo genetic screening as early as possible, preferably before the age of 5 years. All individuals offered MEN1 mutation testing should be provided with genetic counseling before testing. A positive MEN1 genetic test is an indication for periodic screening with biochemical and imaging studies for MEN1-associated tumors, and for the early initiation of surgical and/or pharmacological treatment.[1]

With the development of new techniques such as multiplex ligation-dependent probe amplification (MLPA), new mutations of the MEN1 gene are being discovered, which increases the sensitivity of genetic analysis. In the past, genetic testing has failed to identify MEN1 mutations in 10-30% of patients who meet the clinical criteria for the diagnosis of MEN1 (eg, presence of at least two MEN1-associated tumors: primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, pituitary tumors).[15] Such patients are termed phenocopies.

The presence of a phenocopy should be suspected in presence of a negative MEN1 genetic test, by sequencing, gene dosage, and 11q13 haplotype analyses. Phenocopies are estimated to account for up to 5% of MEN1-like cases, mainly associated with features of parathyroid and pituitary disease.[20]

Patients with mutations in the cyclin-dependent kinase inhibitor (CDKN1B) gene are found to have different clinical course from patients with MEN1 mutations. These patients develop parathyroid and anterior pituiary tumors but are at lower risk of developing pancreatic neuroendocrine tumors (pNET).[21]

Histologic Findings

The parathyroid glands show diffuse or nodular proliferations of chief cells, with some oncocytic cells. Usually, all 4 glands are involved and show signs of hyperplasia.

Neuroendocrine tumors of the pancreas manifest with numerous microadenomas, usually in the pancreatic tail. The tumors display a trabecular pattern and may show conspicuous connective-tissue stroma. Immunohistochemically, expression of multiple hormones is found. Pancreatic polypeptide and glucagon are expressed most often, followed by insulin and, rarely, gastrin. Nesidioblastosis and islet cell hyperplasia are not features of multiple endocrine neoplasia type 1 (MEN1), as previously thought.

Most duodenal tumors are located proximally. They stain for gastrin and can metastasize to regional lymph nodes.

The presence of diffuse hyperplasia of enterochromaffinlike (ECL) cells in the stomach is often associated with carcinoid tumors of considerable size (rarely metastases).

Pituitary tumors are found in the anterior part of the gland and are usually single. Most are macroadenomas, and one third show invasive features with infiltration of tumor cells through surrounding pituitary tissue.

 

Treatment

Approach Considerations

Hyperparathyroidism

Surgery is the definitive treatment for the control of hypercalcemia. Subtotal (3.5 glands)[22] or total parathyroidectomy with forearm autotransplantation is performed with an open bilateral neck exploration. The recommended timing and type of surgery is controversial. Recurrent hypercalcemia is common. Reimplantation after total parathyroidectomy has a high incidence of graft failure and subsequent permanent hypoparathyrodism.

Surgery is fundamental in patients with hypercalcemia due to primary hyperparathyroidism with Zollinger-Ellison syndrome (ZES), since restoring a normal calcium level contributes to reducing gastric acid output and the consequent risk of peptic ulcers. Transcervical thymectomy may need to be performed at the same time, owing to the mortality associated with malignant carcinoid tumors of the thymus. Minimally invasive parathyroidectomy is usually not recommended because multiple glands are typically affected.[1]

Re-operation to cure recurrent and/or persistent primary hyperparathyroidism is often difficult and associated with increased morbidity. Multiple percutaneous parathyroid ethanol ablation (PEA) treatment has been shown to safely and effectively control hyperparathyroidsim with a low rate of hypocalcemia and permanent complications, when performed by an experienced radiologist.[23]

PEA is not a definitive therapy and cannot replace primary surgical therapy. However, it can be considered as an alternative approach who requires re-operation.

Calcimimetics (eg, cinacalcet), a class of calcium-sensing receptor agonists, can be used to reduce parathyroid hormone release by parathyroid cells and to control cell growth. Cinacalcet normalizes serum calcium in 70-80% of patients with primary hyperparathyroidism and can maintain the effect over 5 years. Cinacalcet neither impacts bone mineral density nor lowers biochemical markers of bone turnover. Cinacalcet is not recommended as a first line therapy.

Gastrinoma

Inhibition of acid hypersecretion is achieved with proton pump inhibitors (eg, omeprazole, lansoprazole, pantoprazole). Histamine receptor antagonists (eg, cimetidine, ranitidine, famotidine) may be added.

Nonmetastatic gastrinomas located in the pancreas are rare but can be surgically excised. Removal of tumors larger than 2 cm in diameter reduces the frequency of liver metastasis, which is an important prognostic factor.[1]

Surgical cure of multiple duodenal gastrinomas is difficult and is not associated with a high disease-free state.[24] More extensive gastrointestinal surgery, such as Whipple pancreaticoduodenectomy, can be associated with a higher cure rate at the expense of a higher operative mortality risk. Other novel approaches, such as chemotherapeutic agents or hormonal therapy with somatostatin analogs, can be considered for treatment of disseminated gastrinomas.

Insulinoma

No curative long-term medical treatment exists for insulinomas. Surgical removal of the tumor is the treatment of choice.[25] Unresectable tumors can be treated with diazoxide or octreotide. Chemotherapeutic agents or hepatic artery embolization has been used to treat metastatic disease.[2, 13]

Insulinomas are most often single, large tumors that can be enucleated. Resection may result in cure, although insulinomas in patients with multiple endocrine neoplasia type 1 (MEN1) may be multicentric and small. A problem in these familial cases is that the lesion detected radiologically may not be the one causing hypoglycemia. Insulin measurements in the portal or hepatic veins may be required to localize the source of excess insulin secretion.[25]

Some authors recommend subtotal pancreatectomy (80% or more of the pancreas) in patients with multiple tumors or when the tumor is not localized. Surgical debulking in metastatic disease may reduce hypoglycemia to a certain extent. Intraoperative ultrasonography facilitates tumor identification. Other methods include intraoperative monitoring of plasma glucose and insulin levels.

Glucagonomas

Surgical removal of the tumor is the treatment of choice. Usually, this involves excision of the tail of the pancreas. However, in many cases metastases have already occurred at the time of diagnosis. Somatostatin analogs (lanreotide or octreotide), chemotherapeutic agents, and hepatic artery embolization have also been used.[2, 13]

Vasoactive intestinal polypeptide tumor (VIPoma)

Somatostatin analogs control symptoms in 80% of cases. Nevertheless, surgical cure should be attempted.

Asymptomatic nonfunctioning pancreatic neuroendocrine tumors

A consensus regarding surgical indications has not been established. The goal is to reduce mortality and morbidity associated with metastatic disease while preserving pancreatic tissue. Conflicting expert opinion suggests surgical removal of tumors greater than 1 cm versus 2 cm.

Pituitary tumors

Treatment is similar to non-MEN1–associated pituitary tumors.  Prolactinomas are treated with dopamine agonists (bromocriptine or cabergoline); trans-sphenoidal surgery and radiotherapy are usually reserved for drug-resistant tumors and for macroadenomas that are compressing adjacent structures. 

Somatostatin analogs (octreotide or lanreotide) is used to control growth hormone over-secretion, and is reserved for second line therapy or for patients not eligible for surgery.

Carcinoid tumors

If resectable, surgery is the treatment of choice. For unresectable tumors, treatment with radiotherapy or chemotherapeutic agents can be used. Somatostatin analogs can help with symptoms and may shrink some tumors.

Cutaneous manifestations of MEN1

Management is conservative for lipomas, facial angiofibromas, and collagenomas. Local excision can be performed if desired.

Adrenal tumors

Surgery is indicated for functioning tumors (eg. primary hyperaldosteronism or hypercortisolism), and nonfunctioning tumors with atypical features, size greater than 4 cm, or significant growth over a 6-month interval.[1]

Consultations

Multiple endocrine neoplasia type 1 (MEN1) involves many organ systems, and significant difficulties in diagnosis and management are associated with each system. Centers with expertise in MEN1 diagnosis and treatment are recommended for patients. Multiple consultations are generally necessary, including evaluation by specialists in endocrinology, gastroenterology, neurosurgery, general surgery, and dermatology.

 

Medication

Medication Summary

Many hormonal abnormalities may be expressed in patients with multiple endocrine neoplasia type 1 (MEN1). Medications that may be used are outlined below.

Somatostatin analogues

Class Summary

These drugs suppress peptide secretion of gastroenteropancreatic tumors or growth hormone – producing tumors. They have also been reported to relieve pain from spinal metastasis.

Octreotide (Sandostatin)

Octreotide acts primarily on somatostatin receptor subtypes II and V. It inhibits growth hormone secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, vasoactive intestinal peptide, and GI peptides.

Proton pump inhibitors

Class Summary

Proton pump inhibitors inhibit gastric acid secretion by inhibition of the H+/K+ -ATP-ase enzyme system in the gastric parietal cells. Esomeprazole (Nexium), omeprazole (Prilosec), pantoprazole (Protonix), rabeprazole (AcipHex), and lansoprazole (Prevacid) are available.

Omeprazole (Prilosec)

Proton pump inhibitors effectively block the H+, K+-ATPase of the parietal cell at the secretory surface and inhibit acid secretion, which is required in MEN1-associated gastrinomas. The goal is to reduce the basal acid output to less than 10 mEq/h 1 hour prior to the next dose in patients without previous acid-reducing gastric surgery and to less than 5 mEq/h in patients with previous acid-reducing gastric surgery.

Esomeprazole (Nexium)

Esomeprazole is an S-isomer of omeprazole. It inhibits gastric acid secretion by inhibiting H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Pantoprazole (Protonix)

Pantoprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells. Use of the intravenous preparation has only been studied for short-term use (ie, 7-10 d).

Rabeprazole sodium (AcipHex)

Rabeprazole sodium suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Lansoprazole (Prevacid)

Rabeprazole sodium suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Dopamine agonists

Class Summary

Dopamine agonists are the treatment of choice in prolactinomas. In growth hormone producing pituitary tumors, they are usually added to somatostatin analogues if complete remission has not been achieved. They have modest effects if used as a single agent for acromegaly. Bromocriptine (Parlodel) and cabergoline (Dostinex) are available.

Bromocriptine (Parlodel)

Bromocriptine is a dopamine agonist that reduces pituitary production of prolactin and may shrink prolactinomas. It may be an alternative for treatment of acromegaly, but adverse effects at high dose may limit applicability.

Cabergoline (Dostinex)

Cabergoline is a long-acting dopamine receptor agonist with high affinity for D2 receptors and low affinity for D1 receptors. It inhibits prolactin secretion. Prolactin secretion by the anterior pituitary predominates under hypothalamic inhibitory control exerted through dopamine.

Antihypoglycemic agents

Class Summary

These agents increase blood glucose by inhibiting pancreatic insulin release and possibly through an extrapancreatic effect.

Diazoxide (Hyperstat, Proglycem)

The inhibitory effect of diazoxide in insulinoma may be effective in 90% of patients. The remaining 10% may not respond or tolerate the drug. Treat adverse effects with hydrochlorothiazide. Hyperglycemic effects start within 1 hour and usually last a maximum of 8 hours with normal renal function. In patients not responsive to diazoxide, somatostatin may be indicated.

 

Follow-up

Further Outpatient Care

Current clinical guidelines suggest that patients with multiple endocrine neoplasia type 1 undergo annual screening for pancreatic neuroendocrine tumors (pNETs), using plasma hormonal measurements and imaging studies. Screening can permit timely interventions to prevent morbidity and mortality related to metastasis.[1] See the table below.

Table. Recommended screening schedules for patients with multiple endocrine neoplasia type 1 (Open Table in a new window)

Tumor

Age at which to begin screening (yr)

Blood tests (annual)

Imaging studies

Insulinoma

5

Fasting glucose, insulin

 –

Anterior pituitary

5

Prolactin, IGF-I

MRI (every 3 yr)

Parathyroid

8

Calcium, PTH

 –

Other pancreatic neuroendocrine tumors

< 10

Chromogranin-A; pancreatic polypeptide,

glucagon, VIP

MRI, CT, or EUS (annually)

Adrenal

< 10

Only in patients with symptoms or signs of a functioning tumor and/or tumor >1 cm identified

on an imaging study

MRI or CT (annually with pancreatic

imaging)

Thymic and bronchial carcinoid

15

None

CT or MRI (every 1-2 yr)

Gastrinoma

20

Gastrin (± gastric pH)

 –

CT = computed tomography; EUS = endoscopic ultrasound; IGF-1 = Insulin-like growth factor 1; ( MRI = magnetic resonance imaging; PTH = parathyroid hormone; VIP = vasoactive intestinal peptide

Adapted from Thakker RV, et al. Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep. 97(9):2990-3011.[1]

Current guidelines also suggest biochemical screening of pituitary tumors, with levels of plasma prolactin (PRL) and insulinlike growth factor–1 (IGF-1) measured annually and head magnetic resonance imaging (MRI) performed every 3-5 years.[1] A nonfunctioning pituitary adenoma can cause elevation of the PRL through compression of the pituitary stalk. These nonfunctioning adenomas are not detected by annual biochemical analysis but they can grow rapidly, compressing and damaging adjacent structures. Some authors have suggested that head MRI scans should be performed every 1-2 years in all MEN1 patients.[26]

 

Prognosis

Untreated multiple endocrine neoplasia type 1 (MEN1) patients have a decreased life expectancy, with a 50% probability of death by age 50 years. The cause of death is usually associated with a malignant tumor or sequelae of the disease.[1] One multicenter study suggests that 70% of patients with MEN1 die of causes directly related to MEN1.[6]