Multiple endocrine neoplasia type 1: Management

INTRODUCTION — 

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder classically characterized by predisposition to tumors of the parathyroid glands (which occur in the large majority of patients by age 50 years), anterior pituitary, and pancreatic islet cells (figure 1). MEN1 also includes a predisposition to gastrinomas in the duodenum, thymic and bronchopulmonary neuroendocrine tumors (NETs), adrenal tumors, angiofibromas, lipomas, and other tumors (figure 2). The most common types of tumors in MEN1 are generally benign, but malignancy of some thymic, pancreatic, and gastrointestinal tract NETs are important causes of mortality in MEN1. Treatment of MEN1 can differ markedly from that of more common sporadic forms of the relevant endocrine tumors, and referral to centers with major experience and multidisciplinary expertise in MEN1 is strongly recommended.

This topic will review the treatment of MEN1. The classification, genetics, clinical manifestations, and diagnosis are reviewed separately. (See "Multiple endocrine neoplasia type 1: Genetics" and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

PARATHYROID TUMORS — 

Multiple parathyroid tumors causing primary hyperparathyroidism are the most common manifestation of MEN1, with over 90 percent penetrance by age 50 to 70 years (figure 1) [1-3]. Pathologic hypercellularity of multiple glands is common in these patients and, given sufficient time, perhaps universal. Thus, any parathyroid tissue remaining in situ after surgery can give rise to primary hyperparathyroidism; as a result, patients with classical MEN1 are at high risk of recurrent hyperparathyroidism even after apparently successful subtotal parathyroidectomy.

Symptomatic disease — Once the biochemical diagnosis of primary hyperparathyroidism is confirmed in a patient with known or presumed MEN1, the indications for surgical intervention are similar to those in patients with sporadic primary hyperparathyroidism. These include symptomatic or marked hypercalcemia, nephrolithiasis, and evidence of bone disease, such as diminished bone density or fracture [4]. Bone density of the lumbar spine and hip can improve after parathyroidectomy in patients with hyperparathyroidism associated with MEN1, as it does in patients with sporadic hyperparathyroidism [5] or perhaps to a lesser degree [6]. (See "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

An additional indication for parathyroidectomy in patients with MEN1 is the presence of severe peptic ulcer disease or other symptoms caused by a gastrinoma (the Zollinger-Ellison syndrome) that are difficult to control with medications. Hypercalcemia typically worsens hypergastrinemia, and parathyroidectomy may markedly reduce gastrin secretion in patients with a gastrinoma [7,8]. The typical high success of pharmacologic therapy for hypergastrinemia makes this a rare indication for operation.

The surgical approach is discussed below. (See 'Surgical management' below.)

Asymptomatic disease — Surgery or no therapy can be acceptable alternatives for patients with MEN1 who have asymptomatic or minimally symptomatic hyperparathyroidism, as they are for patients with sporadic hyperparathyroidism. Many clinicians lean toward surgery in young patients (including children and adolescents) because of their long life expectancy (and years at risk for developing bone disease). On the other hand, other clinicians defer surgery as long as possible, in the hope that fewer operations for recurrent hyperparathyroidism (which may be more difficult than the initial surgery) will be needed during the patient's lifetime, and acknowledging that hypoparathyroidism (ie, potentially resulting from extensive parathyroid surgery) may also be associated with considerable morbidity. Thus, no clear consensus exists for the treatment of hyperparathyroidism in those with asymptomatic mild disease. Such decisions must also consider the level of surgical expertise available at one's institution, an important consideration because of the likelihood of recurrent hyperparathyroidism and need for repeat surgery. (See "Primary hyperparathyroidism: Management".)

We tend to defer surgery in young patients with MEN1 and asymptomatic hyperparathyroidism who lack any specific indications for surgery, such as nephrolithiasis. In such patients, periodic monitoring should be performed for disease progression and development of indications for surgery. (See "Primary hyperparathyroidism: Management", section on 'Monitoring'.)

We do, however, tend to recommend surgery for asymptomatic patients with reduced bone density or declining kidney function for the reasons mentioned above and, therefore, find it reasonable to regularly screen individuals with MEN1 for biochemical hyperparathyroidism. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)

Whether early treatment of hyperparathyroidism reduces mortality or morbidity in patients with MEN1 is not known, but kidney function has been reported to improve after parathyroidectomy in patients with MEN1 and hyperparathyroidism and reduced glomerular filtration rate [9].

Surgical management

Preoperative localization — Most patients with MEN1 have multiple parathyroid tumors, so bilateral exploration of previously unoperated patients should be planned, regardless of the outcome of preoperative localization studies, such as ultrasonography, sestamibi imaging, or four-dimensional (4D)-computed tomography (CT). Although such imaging studies may not alter the surgical approach or identify all affected glands, the surgeon may find them to be anatomically helpful and may therefore order them. We do routinely obtain localization studies before reoperation in patients with recurrent or persistent disease. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

Surgical approach — The optimum extent of the parathyroidectomy procedure remains controversial. Some favor a more extensive procedure to reduce the risk of persistent or recurrent disease, while others favor a less extensive procedure to decrease the risk of hypoparathyroidism. Thus, achieving a balance between risk of persistent/recurrent disease and that of permanent hypoparathyroidism may be challenging, and decisions about the timing and extent of surgery should be made in partnership with a fully informed patient.

For patients with MEN1 and indications for initial parathyroidectomy, we favor bilateral neck exploration in an attempt to find all glands. In most cases, we suggest subtotal parathyroidectomy. Subtotal parathyroidectomy involves removal of three and one-half parathyroid glands (or all but one-half gland, if supernumerary glands are found), together with transcervical thymectomy. We view subtotal parathyroidectomy as the preferred approach because it is likely to yield a more sustained duration of normocalcemia than removal of fewer glands, and less likely to cause long-term hypoparathyroidism than complete/total parathyroidectomy.

We do not generally advocate lesser surgical approaches, but if they are to be considered in selected patients (eg, averse to more comprehensive surgery), it is important that the potential for persistent or early recurrent disease is fully discussed with the patient. Surgery is repeated if hypercalcemia and specific indications persist or recur [2,10-12].

●Subtotal parathyroidectomy rather than removal of fewer glands – Previous studies have indicated that subtotal parathyroidectomy is likely to provide the optimal balance between likelihood of recurrent hyperparathyroidism and permanent hypoparathyroidism [13], and in most circumstances, this is also our favored approach.

Patients with classical MEN1 are at high risk of recurrent hyperparathyroidism even after initially successful subtotal parathyroidectomy; in one report, the recurrence rate was 67 percent after eight years [14]. This finding reflects the strong and seemingly inexorable proliferative drive in parathyroid cells in this disorder.

In observational studies, recurrent disease is more common among patients who were treated with less than subtotal parathyroidectomy [2,8,15-20]. One report from the National Institutes of Health, for example, found a recurrence rate of greater than 50 percent at 12 years; the rate for long-term remission of hypercalcemia after initial parathyroidectomy was higher after removal of three or more glands compared with removal of two and a half or less (70 versus 34 percent) [1]. A recent study of 209 patients with MEN1 from a single center reported significantly shorter disease-free survival in patients undergoing "less than subtotal parathyroidectomy" compared with those undergoing subtotal or total parathyroidectomy [21]. A further study of 517 patients with MEN1 who underwent surgery for primary hyperparathyroidism reported that disease persistence and recurrence rates as well as need for reoperation were lower following subtotal parathyroidectomy compared with "less than subtotal parathyroidectomy" [22]. A systematic review and meta-analysis comparing "less than subtotal parathyroidectomy" with subtotal parathyroidectomy in 947 patients with MEN1-associated hyperparathyroidism reported that while the risk of persistent hyperparathyroidism was markedly higher with the less than subtotal parathyroidectomy (odds ratio [OR] 4.6, 95% CI 2.66-7.97), the rates of recurrent disease were not significantly different between groups [23]. As expected, less than subtotal parathyroidectomy was associated with lower rates of permanent hypoparathyroidism.

●Some centers have advocated lesser surgical approaches, particularly in young patients. The rationale for less than subtotal approaches (eg, unilateral clearance of ipsilateral glands in patients with preoperative imaging studies that indicate parathyroid gland abnormalities limited to one side) is to achieve a period of eucalcemia, without the risk of hypoparathyroidism, accepting that further surgery will be required at a later stage. However, these lesser approaches are reported to be associated with very high rates of persistent and recurrent hypercalcemia. One study evaluating 99 patients with MEN1 reported persistent hyperparathyroidism in approximately 70 percent of those who had only one or two glands removed at surgery compared with 6 percent in those who had ≥3.5 glands removed (median follow-up approximately 23 months) [19]. Other groups have reported more favorable short- to medium-term outcomes with these lesser approaches (eg, removal of one or two glands) with lower rates of persistent (14 percent) and recurrent hyperparathyroidism (21 percent), although longer-term outcome data are not available [18,20]. Of additional concern regarding an approach that could increase the number of parathyroid operations needed during a patient's lifetime would be a potentially heightened longer-term risk for surgical complications (eg, hypoparathyroidism, recurrent laryngeal nerve damage).

●Subtotal parathyroidectomy rather than complete parathyroidectomy – Some experts favor a more extensive procedure than subtotal parathyroidectomy to reduce the risk of persistent or recurrent disease. When performed by a surgeon who has extensive experience in either subtotal parathyroidectomy or complete parathyroidectomy, as surgery for patients with MEN1 should be, results should be good and complication rates low [24]. Overall, however, we view subtotal parathyroidectomy as the generally preferable approach in large part because of its lesser likelihood of causing long-term hypoparathyroidism [2,12].

A more aggressive initial surgical approach involves complete parathyroidectomy and placement of a small parathyroid autograft in the muscles of the forearm or neck [25-28]. Recurrent hyperparathyroidism due to growth of the autograft can then be treated by graft removal under local anesthesia. If, however, the autograft does not function, the patient may have the extremely undesirable outcome of long-term or permanent hypoparathyroidism. Immediate autotransplantation and use of cryopreserved tissue has been used in patients with MEN1. Permanent hypoparathyroidism (ie, reflecting autograft failure) is typically observed in 15 to 35 percent of patients undergoing total parathyroidectomy with autotransplantation, although reported rates vary considerably across series [29-31].

No randomized trials have compared the two approaches. In a review of 18 reports of 2 to 73 patients with MEN1 followed for 4 to 12 years after subtotal parathyroidectomy (three and one-half glands resected) with or without cervical thymectomy, persistent hyperparathyroidism was reported in 0 to 33 percent, recurrent hyperparathyroidism in 0 to 36 percent, and persistent hypoparathyroidism in 0 to 35 percent [15]. In the same review, there were 10 reports of 4 to 36 patients with MEN1 who had complete parathyroidectomy with cervical thymectomy and autologous placement of a small parathyroid autograft. After a mean follow-up of 6 to 10 years, persistent hyperparathyroidism was reported in 0 to 3 percent, recurrent hyperparathyroidism in 0 to 55 percent, and hypoparathyroidism in 0 to 46 percent. In these observational studies, the more aggressive approach was associated with lower rates of persistent hyperparathyroidism but higher rates of hypoparathyroidism.

●Thymectomy – Cervically accessible thymectomy during initial parathyroidectomy in MEN1 is generally recommended, although high-quality evidence from randomized trials is lacking [12,32-34]. The rationale for thymectomy includes the substantial frequency with which intrathymic parathyroid tissue is found as a present or future source of pathologic parathyroid hormone (PTH) production [32], as well as the risk in MEN1 for developing thymic neuroendocrine tumors, rare but often aggressive tumors [33]. Since only part of the thymus is accessible cervically, this measure will not completely neutralize these risks. Indeed, thymic neuroendocrine tumors are reported in patients with MEN1 treated with transcervical thymectomy [35]. Still, we think the expected benefit of preventing some thymic neuroendocrine tumors and lessening the risk of recurrent hyperparathyroidism outweighs the potential risk of this procedure in the hands of an expert surgeon, so we generally favor thymectomy in this setting [24,36]. However, post-thymectomy patients should still be considered at potential risk of a thymic neuroendocrine tumor.

Medical management — Calcimimetic agents (eg, cinacalcet) activate the calcium-sensing receptor in the parathyroid gland, thereby inhibiting PTH secretion. Although not typically used in the United States for the treatment of sporadic benign primary hyperparathyroidism, cinacalcet reduces serum calcium in the majority of affected patients. (See "Primary hyperparathyroidism: Management", section on 'Severe hypercalcemia'.)

Cinacalcet also appears to decrease the serum calcium concentration in patients with primary hyperparathyroidism due to MEN1 [37], although the data are limited. In a case report of a patient with MEN1 and recurrent hyperparathyroidism five years after parathyroidectomy, treatment with cinacalcet reduced serum calcium and PTH levels to normal [38]. During one year of treatment, levels remained normal. Similarly, in a one-year study of MEN1-associated hyperparathyroidism, cinacalcet reduced serum calcium levels (but not PTH) and was generally well tolerated; bone mineral density (BMD) at the spine and femur (no distal radius data) were unchanged, as was urinary calcium excretion [39]. Thus, cinacalcet may be beneficial for patients with MEN1 and recurrent symptomatic primary hyperparathyroidism who are not candidates for or refuse repeated surgical procedures. However, there are no long-term data evaluating the effect of cinacalcet on clinically important outcomes (eg, bone density, fracture, nephrolithiasis, mortality) in patients with MEN1.

PITUITARY ADENOMAS — 

Approximately 15 to 20 percent of patients with MEN1 have clinically apparent pituitary adenomas, or approximately 40 percent if one includes microadenomas detected via systematic screening of asymptomatic individuals [40]. The characteristics of these adenomas in terms of hormonal activity and other features are similar to those in patients with sporadic pituitary adenomas. The most common pituitary adenoma in MEN1 is a lactotroph adenoma, but all other types of adenomas can occur (figure 2). Multiple pituitary tumors are rarely present in MEN1. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

Individuals with MEN1 who have pituitary adenomas should generally be treated in the same way as patients with sporadic adenomas [2,12]. (See "Management of hyperprolactinemia" and "Treatment of gonadotroph and other clinically nonfunctioning pituitary adenomas" and "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation" and "Treatment of acromegaly".)

PANCREATIC ISLET CELL/GASTROINTESTINAL TUMORS — 

Because of the efficacy of therapy for hyperparathyroidism and pituitary tumors in patients in MEN1, malignant duodenopancreatic neuroendocrine tumors (as well as less frequent malignant tumors, eg, thymic neuroendocrine tumors) are the primary life-threatening components of the disorder. Clinically important duodenopancreatic neuroendocrine tumors are reported in 30 to 60 percent of patients with MEN1. Such tumors may be multiple and either synchronous or asynchronous in an individual. However, subclinical involvement is even more common; anatomic or intensive biochemical studies reveal evidence of enteropancreatic tumors in up to 80 percent of patients with MEN1 (figure 1), while microscopic pancreatic endocrine abnormalities are likely universal.

The most common cause of symptoms is the Zollinger-Ellison (gastrinoma) syndrome (table 1). Approximately 40 percent of patients with MEN1 have either the Zollinger-Ellison syndrome or asymptomatic elevation in serum gastrin concentrations. Symptomatic insulinomas are also common, but tumors that are symptomatic due to secretion of vasoactive intestinal polypeptide, glucagon, or pancreatic polypeptide are rare. Clinically nonfunctioning pancreatic neuroendocrine tumors (NETs) are now the leading cause of premature mortality in MEN1, and their management remains challenging. Given the complexity of decision-making and specialized skills needed for treating duodenopancreatic endocrine tumors in MEN1, it is strongly recommended that this be done in centers with established multidisciplinary teams experienced in the care of patients with MEN1.

Surgical treatments are typically recommended for functioning tumors located within the pancreas in the absence of metastatic disease (eg, insulinoma), while surgery for nonfunctioning pancreatic NETs is typically based on size thresholds. Although these vary among centers, all would advocate surgery for nonfunctioning tumors ≥2 cm [41,42]. (See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms".)

Zollinger-Ellison syndrome — Most patients with MEN1-associated gastrinoma(s) display a relatively indolent disease course and have generally favorable outcomes. However, approximately 20 to 25 percent of patients ultimately develop evidence of distant metastases (eg, hepatic metastases). In some patients, metastases are associated with reduced survival (10-year survival in those with distant metastases has been reported to be approximately 50 percent). (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)

All patients with ZES due to MEN1 are treated with pharmacologic therapy using a proton pump inhibitor (PPI) to limit the clinical manifestations, related symptoms, and complications of peptic ulcer disease. Further details on the use of PPIs and other management strategies for Zollinger-Ellison syndrome/gastrinomas associated with MEN1 are discussed in detail separately. (See "Management and prognosis of gastrinoma (Zollinger-Ellison syndrome)".)

Insulinoma — Approximately 10 percent of patients with MEN1 have an insulinoma (table 1). Approximately 4 to 10 percent of patients with insulinomas have MEN1, and in most, but not all, the MEN1 is known or suspected. Treatment is complicated by the possible presence of multiple insulinomas (in up to 30 percent of patients) and/or other pancreatic NETs, the likelihood that preoperative or intraoperative localization techniques may miss small tumors, and the continuing risk for pancreatic tumors after surgery. In most instances, MEN1-associated insulinoma displays clinically benign behavior without evidence of metastatic spread. Surgery is typically recommended for MEN1-associated insulinoma for symptomatic control. The surgical approach will depend on preoperative localization studies and is typically tailored to specific clinical setting based on the size and location of the tumor(s). Imaging and regionalization approaches are similar to that for sporadic insulinoma but must account for the potential presence of other pancreatic tumors. Functional techniques for preoperatively distinguishing an insulinoma from other pancreatic lesions are under investigation, notably use of 68-Ga-exendin 4 positron emission tomography (PET)/CT imaging, which exploits the high-density expression of the glucagon-like peptide 1 (GLP-1) receptor in benign insulinomas [12,43]. In the presence of a solitary dominant tumor (eg, >1 cm), enucleation or segmental resection can be considered to preserve pancreatic tissue. Tumors located in the body or tail or pancreas may be suitable for distal pancreatectomy with or without enucleation of additional pancreatic neuroendocrine tumors in the head of the pancreas. More extensive partial pancreaticoduodenal resections are avoided if possible and are typically reserved for larger tumors involving the head of pancreas [41]. Medical therapy for patients with insulinoma awaiting surgery is reviewed separately. (See "Insulinoma".)

Clinically nonfunctional pancreatic neuroendocrine tumors — In the absence of metastatic disease, the management of nonfunctional pancreatic NETs in MEN1 is controversial [2,12]. The majority of small nonfunctional pancreatic NETs demonstrate indolent growth rates, although occasionally more rapid disease progression occurs. The risk of metastatic disease and/or worse outcomes is reported to be related to increased tumor size, rate of tumor growth, and tumor grade/increased Ki-67 (World Health Organization [WHO] grade ≥2 tumors having a higher risk of metastases). Other potential adverse prognostic factors include reduced uptake on somatostatin receptor scintigraphy, increased avidity on fludeoxyglucose-positron emission tomography (FDG-PET), and specific pathologic features. Noninvasive biomarkers of tumor behavior are unavailable [42,44]. Studies have investigated the utility of a number of tumor or blood-based biomarkers to guide prognosis of MEN1-associated pancreatic neuroendocrine tumors, but these are yet to be translated into clinical decision-making [45-47].

The aims of treatment for nonfunctioning pancreatic endocrine tumors should endeavor to strike a balance between minimizing the risk of metastatic disease while preserving pancreatic tissue, as well as avoiding complications related to pancreatic surgery, acknowledging that patients with MEN1 may develop multiple pancreatic endocrine tumors over their lifetime [41]. Thus, determining the optimal timing of surgery is frequently difficult. Surgery for nonfunctioning pancreatic NETs is typically based on size thresholds:

●Tumor size ≥2 cm – In an emerging consensus (albeit not based on randomized, controlled approaches), many experienced clinicians have been using a tumor size threshold of 2 cm in the decision to surgically resect the lesions [44,48,49], and corresponding surveillance recommendations have been made [4,50-54].

●Tumor size 1 to <2 cm – Available data offer less guidance for tumors between 1 to <2 cm size, although resection of rapidly growing lesions in this size range is a reasonable approach.

●Tumor size <1 cm – Generally speaking, tumors under 1 cm appear to have a very low risk for substantial growth and metastasis, and avoiding surgery with continued surveillance seems reasonable, given the relative high morbidity associated with pancreatic surgery. We try to individualize surveillance protocols to minimize lifetime radiation exposure in younger individuals.

For tumors not selected for surgical management (eg, most tumors <2 cm), the optimal frequency and modality of surveillance imaging has not been established. Surveillance strategies should be tailored to the individual based on variables including current tumor size and previous growth trajectory.

Clearly, further study of risks, benefits, and alternative approaches would benefit the field [44,55,56]. For example, the role of somatostatin analogues has been investigated in a small number of patients with MEN1 with nonfunctioning pancreatic tumors <2 cm. In an observational study evaluating the effect of the lanreotide in 42 patients with MEN1 and small nonfunctioning tumors, objective tumor response rates and disease stability improved when compared with an active surveillance group, although such results require caution, and larger controlled studies are required to assess impact of disease progression and survival [13,57].

●Advanced disease – The management of advanced disease is similar to that used for patients without MEN1 and includes a range of systemic and locoregional approaches. However, the optimal application (and sequencing) of treatment options have not been formally assessed in patients with MEN1. Systemic therapies include somatostatin analogues, targeted molecular therapies (eg, the tyrosine kinase inhibitor sunitinib and mTOR inhibitor everolimus), chemotherapy, and peptide receptor radionuclide therapy (eg, with 177-Lu-dotatate). (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

THYMIC NEUROENDOCRINE TUMORS — 

Thymic neuroendocrine tumors (NETs, thymic carcinoids) occur in 2 to 8 percent of patients with MEN1 and, in European populations, occur almost exclusively in males. Symptomatic presentations (eg, anterior chest pain) are typically associated with advanced disease. Surveillance thoracic imaging of asymptomatic individuals (eg, with MRI or CT) may identify earlier stage tumors, although the optimal frequency of such imaging or impact on overall survival has not been established. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Thymic and bronchopulmonary NETs' and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)

The treatment of thymic NETs depends on the stage of presentation. When feasible, complete surgical resection is the treatment of choice. For those with advanced disease, additional treatment options include chemotherapy, somatostatin analogs, radiotherapy, mTOR inhibitors, and peptide receptor radioligand therapy, although the evidence base to determine the optimal approach in patients with MEN1 is not established. Prophylactic thymectomy at the time of parathyroid surgery is usually recommended, which may reduce (but not entirely exclude) the risk of subsequent thymic NETs [13]. (See "Thymic neuroendocrine neoplasms", section on 'Prognosis and management'.)

BRONCHOPULMONARY NEUROENDOCRINE TUMORS — 

Imaging studies indicate that bronchopulmonary NETs occur in 20 to 30 percent of patients with MEN1, although the majority of these patients are asymptomatic with small tumors with indolent growth rates [58]. Larger tumors presenting with clinical symptoms are less frequent. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Thymic and bronchopulmonary NETs'.)

Risk stratification of lesions with imaging (CT for size, growth rates, fludeoxyglucose-positron emission tomography [FDG-PET] for FDG avidity) and/or histologic assessment may help identify lesions with malignant potential. Surgery has been recommended for bronchopulmonary NETs, although the increased detection of small, sometimes multiple and bilateral, slow-growing tumors suggests that surveillance may be appropriate in some settings [58].

GASTRIC NEUROENDOCRINE TUMORS — 

Multiple small enterochromaffin-like cell carcinoids (ECLomas; ie, type 2 gastric carcinoids) may occur in patients with MEN1 with concurrent hypergastrinemia. Although surgery and somatostatin analogues have been used to treat these tumors, the optimal approach in patients with MEN1 remains to be determined. (See "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors", section on 'Stomach'.)

ADRENAL TUMORS — 

The majority of adrenal tumors occurring in MEN1 are benign, although adrenocortical carcinoma is reported [59]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Adrenal tumors'.)

The treatment of functioning adrenal tumors (eg, aldosterone- or cortisol-secreting tumors) does not differ from that of their sporadic counterparts. Otherwise, surgery is reserved for adrenal tumors where malignancy cannot be excluded (eg, large or rapidly growing lesions, or those with indeterminate or concerning imaging characteristics). (See "Treatment of primary aldosteronism" and "Overview of the treatment of Cushing syndrome", section on 'Primary adrenal diseases'.)

PROGNOSIS — 

The long-term mortality of patients with MEN1 is increased compared with the general population or unaffected members of their families [2,12,60]. In a retrospective review of 233 patients with MEN1 treated at the Mayo Clinic, the overall 20-year survival of patients with MEN1 was significantly lower than that of an age-, sex-, and geographically matched population (64 versus 81 percent) [61]. Among those in whom a cause of death could be reliably obtained (60 of 69 patients), 28 percent died of causes related to MEN1, most commonly metastatic islet cell tumors. Similarly, in European populations, the mean ages at death for patients with MEN1 was significantly lower than in the average population [62]. Compared with nonaffected patients, those with thymic tumors and duodenopancreatic neuroendocrine or nonfunctioning tumors had a higher risk of death [63]. Because effective treatment is available for hyperparathyroidism and pituitary disease in MEN1, the malignant potential of duodenopancreatic and thymic neuroendocrine tumors are the primary life-threatening manifestations of MEN1. These tumors are often present at initial assessment [33,64]. Whether earlier detection through radiographic screening improves mortality remains uncertain, although this appears likely as outcomes in patients with MEN1 have improved over time relative to the general population [65]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuroendocrine neoplasms".)

SUMMARY AND RECOMMENDATIONS

●Definition – Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder classically characterized by predisposition to tumors of the parathyroid glands (which occur in the large majority of patients by age 50 years), anterior pituitary, and pancreatic islet cells (figure 1). MEN1 also includes a predisposition to gastrinomas in the duodenum, thymic and bronchopulmonary neuroendocrine tumors (NETs), adrenal tumors, angiofibromas, lipomas, and other tumors (figure 2). (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Definition of MEN1'.)

●Parathyroid tumors – The indications for parathyroidectomy in patients with MEN1 are similar to those in patients with sporadic adenomas causing primary hyperparathyroidism and include symptomatic hypercalcemia, nephrolithiasis, and evidence of bone disease, such as diminished bone density or fracture. For asymptomatic or minimally symptomatic hyperparathyroidism, surgery or no therapy can be acceptable alternatives, as they are for patients with sporadic hyperparathyroidism. (See 'Symptomatic disease' above and 'Asymptomatic disease' above and "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

For most patients with MEN1 and indications for initial parathyroidectomy, we suggest subtotal (three and one-half gland) parathyroidectomy (Grade 2C). We view subtotal parathyroidectomy as the preferred approach because it is likely to yield a more-sustained duration of normocalcemia than removal of fewer glands, and less likely to cause long-term hypoparathyroidism than complete parathyroidectomy. We also suggest cervical thymectomy in this setting (Grade 2C). Surgery should only be performed by surgeons highly experienced in parathyroid surgery. Alternate approaches have been suggested by others, and all decisions with regard to surgery should be made in full discussion with the patient. (See 'Surgical approach' above.)

●Pituitary adenomas – Pituitary adenomas in patients with MEN1 should be treated in the same way as sporadic pituitary adenomas. (See "Management of hyperprolactinemia" and "Treatment of acromegaly" and "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation" and "Treatment of gonadotroph and other clinically nonfunctioning pituitary adenomas".)

●Enteropancreatic NETs

•Zollinger-Ellison syndrome – All patients with Zollinger-Ellison syndrome/gastrinomas due to MEN1 are treated with pharmacologic therapy using a proton pump inhibitor (PPI) to limit the clinical manifestations, related symptoms, and complications of peptic ulcer disease. Further details on the use of PPIs and other management strategies for Zollinger-Ellison syndrome/gastrinomas due to MEN1 are discussed in detail separately. (See 'Zollinger-Ellison syndrome' above and "Management and prognosis of gastrinoma (Zollinger-Ellison syndrome)".)

•Insulinoma – Surgery is typically indicated for patients with MEN1 and insulinoma. The surgical approach will depend on preoperative localization studies and should be determined by the size and location of the tumor(s). During evaluation and surgical treatment of insulinoma, the possible presence of other pancreatic neuroendocrine tumors (eg, coexistent nonfunctioning tumors) should also be considered. (See 'Insulinoma' above and "Insulinoma".)

•Nonfunctioning pancreatic NETs – Surgery is indicated for patients with MEN1 and nonfunctioning pancreatic NETs ≥2 cm or smaller tumors considered to be at higher risk of progression (eg, rapid growth on serial imaging or higher grade tumors). The majority of small nonfunctioning tumors (<2 cm) run an indolent course with low growth rates such that surveillance is often appropriate. (See 'Clinically nonfunctional pancreatic neuroendocrine tumors' above.)

•Metastatic disease – The management of metastatic gastroenteropancreatic NETs is reviewed separately. (See "Clinical presentation, imaging and biomarker monitoring, and prognosis of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion" and "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors" and "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors".)