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Multiple endocrine neoplasia type 1: Management

Multiple endocrine neoplasia type 1: Management
Literature review current through: Jan 2024.
This topic last updated: Sep 20, 2022.

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, islet cell, 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. Patients with classical MEN1 are at high risk of recurrent hyperparathyroidism 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 (see "Primary hyperparathyroidism: Management"). Whether early treatment of hyperparathyroidism reduces mortality or morbidity in patients with MEN1 is not known, but many clinicians lean toward surgery in young patients because of their long life expectancy (and years at risk for developing bone disease). In addition, kidney function has been reported to improve after parathyroidectomy in MEN1 patients with hyperparathyroidism and reduced glomerular filtration rate [9]. 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.

The clinician's threshold for recommending surgery for patients with asymptomatic hyperparathyroidism bears importantly on the decision to screen asymptomatic persons at risk (see "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Family members in MEN1 kindreds'). Such decisions must also take into account the level of surgical expertise available at one's institution, an important consideration because of the likelihood of recurrent hyperparathyroidism and need for another operation in the future.

We tend to defer surgery in young MEN1 patients with 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 renal 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'.)

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.

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 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].

Some centers have advocated lesser surgical approaches, particularly in young patients. The rationale for less than subtotal approaches (eg, unilateral clearance of ipsilateral glands) 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.

A more aggressive initial surgical approach involves complete parathyroidectomy and placement of a small parathyroid autograft in the muscles of the forearm or neck [21-24]. 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.

There are no randomized trials comparing 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.

When performed by a surgeon who has extensive experience in either subtotal parathyroidectomy or complete parathyroidectomy, as surgery for MEN1 patients should be, results should be good and complication rates low [25]. 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].

Thymectomy – Cervically accessible thymectomy during initial parathyroidectomy in MEN1 is generally recommended, acknowledging that high-quality evidence from randomized trials is lacking [12,26-28]. The rationales for thymectomy relate to the substantial frequency with which intrathymic parathyroid tissue is found as a present or future source of pathologic parathyroid hormone (PTH) production [26], and to the risk in MEN1 for developing thymic carcinoid, a rare but often aggressive tumor [27]. Since only part of the thymus is accessible cervically, this measure will not completely neutralize these risks. Still, we think the expected benefit of preventing some thymic carcinoids 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 [25,29].

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 [30], 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 [31]. 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 [32]. 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 [33]. 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 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 pancreatic islet cell and gastrointestinal tumors (enteropancreatic tumors) are the primary life-threatening components of the disorder. Endocrine cell tumors at these sites become clinically apparent in approximately one-third of patients with MEN1. However, subclinical involvement is more common; anatomic or intensive biochemical studies reveal evidence of enteropancreatic tumors in up to 80 percent of patients with MEN1 (figure 1).

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 fairly 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 MEN1 patients.

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 [34,35]. There are a wide range of treatment options available for patients with metastatic disease including systemic therapies and/or localized treatment approaches as employed for patients with sporadic NETs, although their optimal use has not been established in MEN1 patients. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)

Zollinger-Ellison syndrome — Active Zollinger-Ellison syndrome as part of the MEN1 syndrome should be treated primarily by proton pump therapy to limit the clinical manifestations and complications of peptic ulcer disease. The role of duodenal-pancreatic surgery to prevent metastatic disease is uncertain and controversial but could prove beneficial and requires further study.

General therapeutic considerations — Early attempts to treat the Zollinger-Ellison syndrome surgically in patients with MEN1 involved resection of palpable tumors or partial pancreatectomy, but historically, this approach typically failed to cure the hypersecretion of gastrin [36,37]. The recognition that patients with MEN1 often have small, multifocal tumors in the duodenum, not infrequently accompanied by lymph node metastases [38,39], is consistent with these failures and led to reexamination of the role of surgery. In a controversial area with a dearth of prospective studies to provide guidance, some surgeons are less inclined to operate, while some now regularly operate on MEN1 patients with the Zollinger-Ellison syndrome that persists after correction of hyperparathyroidism or if imaged tumors in the pancreaticoduodenal region exceed a certain size threshold (eg, 2 cm) [39-43].

If surgery is undertaken, one recommended approach includes duodenotomy and resection of detectable duodenal wall tumors, often preceded by endoscopic ultrasound (EUS) or accompanied by intraoperative ultrasonography, combined with subtotal/distal pancreatectomy and enucleation of tumors in the pancreatic head [44-46]. Even more aggressive resections, with increased risk of short- and long-term complications, are sometimes performed, subject to modification based upon the individual situation, including complete pancreatoduodenectomy (eg, in the setting of large pancreatic head tumors) [2,12,41,47].

Given the impressive efficacy of proton pump blockers in controlling symptoms and the fact that surgery for primary gastrinoma in MEN1 is unlikely to result in cure [48], the primary benefit to be sought from surgery is a decrease in mortality from metastatic gastrinoma. While results of modern surgical approaches seem promising [43,44,46,49-51], longer follow-up studies are needed because the likelihood of developing hepatic metastases and death may be low even in unoperated patients [39,46]. Currently, no definitive evidence exists that surgery decreases the mortality of the disease in MEN1 or the likelihood that clinically important metastases will develop, although nonrandomized evidence suggests that it may [40].

Pharmacologic treatment — Medical therapy for patients with a MEN1-associated gastrinoma is administration of a proton pump inhibitor, such as omeprazole or lansoprazole (see "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)", section on 'Medical management'). When given once or twice daily, these drugs effectively inhibit acid secretion and relieve acid-peptic symptoms in these patients for prolonged periods [43,52]. A nine-year prospective study of the safety and efficacy of omeprazole revealed no tachyphylaxis or important toxicity [53].

Surgery — The question of whether or not to recommend duodenal-pancreatic surgery in patients with MEN1 who have pharmacologically controllable Zollinger-Ellison syndrome and no other clinically evident hormonal excess syndrome or imaged tumors is an especially difficult one. Because clinical outcome data are not definitive, we extensively discuss potential advantages and risks of both options with the patient. While we do not strongly advocate for surgery, we do not discourage a patient who wishes to have surgery for MEN1-associated Zollinger-Ellison syndrome, as long as the individual recognizes that solid proof of improved mortality is lacking and the surgeon is experienced and knowledgeable. Furthermore, if such a patient requires abdominal surgery for another reason (such as insulinoma), it seems appropriate to include duodenotomy in the procedure.

For patients with pharmacologically controlled Zollinger-Ellison who do not have surgery, we monitor symptoms and perform periodic imaging studies (CT/magnetic resonance imaging [MRI], EUS), with a preference toward minimizing radiation exposure in younger patients. As clinicians who favor pancreaticoduodenal surgery when a tumor exceeds the often used 2 cm size threshold, we generally use published guidance [4] for their timing, but it should be kept in mind that data favoring the use of such specific triggers in improving outcomes (eg, preventing metastases, mortality) are very limited [39,43]. It should also be borne in mind that patients with duodenal gastrinomas may have concomitant nonfunctioning pancreatic tumors, although irrespective of the functional status of the pancreatic lesion, surgery is likely to be beneficial for pancreatic tumors >2 cm [34]. (See 'Clinically nonfunctional pancreatic neuroendocrine tumors' below.)

The best course for patients with hepatic metastases is unclear, and multiple options exist. The considerations are very similar to those with non-MEN1 advanced gastroenteropancreatic endocrine tumors, discussed in detail elsewhere. (See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)", section on 'Therapy of metastatic disease' and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring".)

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 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. As a result, some experienced surgeons recommend excision of any tumors found in the head of the pancreas plus a distal subtotal pancreatectomy [54]. This approach differs from that in patients with sporadic insulinomas, who typically have a solitary tumor and in whom localization and local excision alone are usually successful. 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 [12,55]. (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 is reported to be related to increased tumor size, rate of tumor growth, and tumor grade (World Health Organization [WHO] grade ≥2 tumors having a higher risk of metastases). However, accurate noninvasive biomarkers of tumor behavior are currently not available [35].

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 [34]. 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 [56-58], and corresponding surveillance recommendations have been made [4,59-63].

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 high morbidity associated with pancreatic surgery. We try to individualize surveillance protocols to minimize lifetime radiation exposure in younger individuals.

Clearly, further study of risks, benefits, and alternative approaches would benefit the field [58,64,65]. 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 MEN1 patients with 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 [13,66].

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 MEN1 patients. Systemic therapies include somatostatin analogues, targeted molecular therapies (eg, the tyrosine kinase inhibitor sunitinib and mTOR inhibitor everolimus), chemotherapy, and peptide receptor radioligand therapy (eg, with 177-Lu-dotatate). (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)

THYMIC NEUROENDOCRINE TUMORS — Thymic neuroendocrine tumors (NETs, thymic carcinoids) occur in 2 to 8 percent of MEN1 patients 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 neuroendocrine tumors' 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 MEN1 patients 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 (carcinoid) tumors", 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 [67]. Larger tumors presenting with clinical symptoms are less frequent. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Thymic and bronchopulmonary neuroendocrine tumors'.)

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 [67].

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

ADRENAL TUMORS — The majority of adrenal tumors occurring in MEN1 are benign, although adrenocortical carcinoma is reported [68]. (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 [2,12,69]. In a retrospective review of 233 patients with MEN1 treated at the Mayo Clinic, the overall 20-year survival of MEN1 patients was significantly lower than that of an age-, sex-, and geographically matched population (64 versus 81 percent) [70]. 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 [71]. Compared with nonaffected patients, those with thymic tumors and duodenopancreatic neuroendocrine or nonfunctioning tumors had a higher risk of death [72]. Because effective treatment is available for hyperparathyroidism and pituitary disease in MEN1, the malignant potential of pancreatic endocrine tumors and carcinoids are the primary life-threatening manifestations of MEN1. These tumors are often present at initial assessment [27,73]. Whether earlier detection through radiographic screening improves mortality remains uncertain [43]. (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: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

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. (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 adenomas".)

Enteropancreatic NETs

Zollinger-Ellison syndrome – Active Zollinger-Ellison syndrome as part of the MEN1 syndrome should be treated primarily by proton pump therapy to limit the clinical manifestations and complications of peptic ulcer disease. The role of duodenal-pancreatic surgery to prevent metastatic disease is uncertain and controversial but could prove beneficial and requires further study. (See 'Zollinger-Ellison syndrome' above and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)", section on 'Medical management'.)

Insulinoma – Surgery is indicated for patients with MEN1 and insulinoma. Because patients with MEN1 often have additional pancreatic tumors that may include other insulinomas, local excision of any tumors in the head of the pancreas plus a distal subtotal pancreatectomy is frequently performed. (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 "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion" and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)

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