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Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)

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Last Modified: 11/06/2014

Multiple Endocrine Neoplasia Type 1

Clinical Description
Parathyroid Tumors and PHPT
Duodenopancreatic NETs
Pituitary Tumors
Other MEN1-associated Tumors
Making the Diagnosis of MEN1
Molecular Genetics of MEN1
Genetic Testing and Differential Diagnosis
Surveillance
Interventions
        Parathyroid tumors
        Duodenopancreatic NETs
        Insulinomas
        Gastrinomas
        Nonfunctioning NETs
        Other pancreatic NETs
        Pituitary tumors



Clinical Description

Multiple endocrine neoplasia type 1 (MEN1) (OMIM) is an autosomal dominant syndrome, with an estimated incidence in the general population of 1 to 2 cases per 100,000.[1] The major endocrine features of MEN1 include the following:

A diagnosis of MEN1 is made when an individual has two of these three major endocrine tumors. Familial MEN1 is defined as at least one MEN1 case plus at least one first-degree relative with one of these three tumors.[2-4] The age-related penetrance of MEN1 is 45% at age 30 years, 82% at age 50 years, and 96% at age 70 years.[2,5]

Parathyroid Tumors and PHPT

The most common features and often the first presenting signs of MEN1 are parathyroid tumors, which result in PHPT. These tumors occur in 80% to 100% of patients by age 50 years.[2,6-8] Unlike the solitary adenoma seen in sporadic cases, MEN1-associated parathyroid tumors are typically multiglandular and often hyperplastic.[1] The average age at onset of PHPT in MEN1 is 20 to 25 years, in contrast to that in the general population, which is typically age 50 to 59 years. Parathyroid carcinoma in MEN1 is rare but has been described.[9-12]

Individuals with MEN1-associated PHPT will have elevated parathyroid hormone (PTH) and calcium levels in the blood. The clinical manifestations of PHPT are mainly the result of hypercalcemia. Mild hypercalcemia may go undetected and have few or no symptoms. More severe hypercalcemia can result in the following:

  • Constipation.
  • Nausea and vomiting.
  • Dehydration
  • Decreased appetite and abdominal pain.
  • Anorexia.
  • Diuresis.
  • Kidney stones.
  • Increased bone resorption with resultant increased risk of bone fracture.
  • Lethargy.
  • Depression.
  • Confusion.
  • Hypertension.
  • Shortened QT interval.

Since MEN1-associated hypercalcemia is directly related to the presence of parathyroid tumors, surgical removal of these tumors may result in normalization of calcium and PTH levels and relief of symptoms; however, high recurrence rates following surgery have been reported in some series.[13-15] (Refer to the Interventions section of this summary for more information.)

Duodenopancreatic NETs

Duodenopancreatic NETs are the second most common endocrine manifestation in MEN1, occurring in 30% to 80% of patients by age 40 years.[2,8] Gastrinomas represent 50% of the gastrointestinal NETs in MEN1 and are the major cause of morbidity and mortality in MEN1 patients.[2,13] Gastrinomas are usually multicentric, with small (<0.5 cm) foci throughout the duodenum.[16] Most result in peptic ulcer disease (Zollinger-Ellison syndrome), and half are malignant at the time of diagnosis.[13,16,17]

Other functioning pancreatic NETs seen in MEN1 include the following:

  • Insulinomas (10%–20% penetrance).
  • Vasoactive intestinal peptide tumors (VIPomas) (~1% penetrance).
  • Glucagonomas (1%–5% penetrance).
  • Somatostatinomas (~1% penetrance).

Nonfunctioning pancreatic NETs were originally thought to be relatively uncommon tumors in individuals with MEN1, with early penetrance estimates of 20%.[18,19] With the advent of genetic testing and improved imaging techniques, however, their prevalence in MEN1 has increased, with one study showing a frequency as high as 55% by age 39 years in MEN1 mutation carriers undergoing prospective endoscopic ultrasound of the pancreas.[20,21] These tumors can be metastatic. One study of 108 MEN1 mutation carriers with nonfunctioning pancreatic NETs showed a positive correlation between tumor size and rate of metastasis and death, with tumors larger than 2 cm having significantly higher rates of metastasis than those smaller than 2 cm.[22] (Refer to the Molecular Genetics of MEN1 section of this summary for more information about MEN1 gene mutations.)

Pituitary Tumors

Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor.[2,8] Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting.[23] Other functioning pituitary tumors can include somatotropinomas and corticotropinomas.

Other MEN1-associated Tumors

Other manifestations of MEN1 include carcinoids of the foregut (5%–10% of MEN1 patients). These are typically bronchial or thymic and are sometimes gastric. Skin lesions are also common and can include facial angiofibromas (up to 80% of MEN1 patients) and collagenomas (~75% of MEN1 patients).[24] Lipomas (~30% of MEN1 patients) and adrenal cortical lesions (up to 50% of MEN1 patients), including cortical adenomas, diffuse or nodular hyperplasia, or rarely, carcinoma are also common.[25-27] The following manifestations have also been reported:[28-30]

  • Thyroid adenomas.
  • Pheochromocytoma.
  • Spinal ependymoma.
  • Meningioma.
  • Leiomyoma (e.g., esophageal, lung, and uterine).
Making the Diagnosis of MEN1

MEN1 is often difficult to diagnose in the absence of a significant family history or a positive genetic test for a mutation in the MEN1 gene. One study of 560 individuals with MEN1 showed a significant delay between the time of the first presenting symptom and the diagnosis of MEN1.[31] This may be because some presenting symptoms of MEN1-associated tumors, such as amenorrhea, peptic ulcers, hypoglycemia, and nephrolithiasis, are not specific to MEN1.

Furthermore, identification of an MEN1-associated tumor is not sufficient to make the clinical diagnosis of MEN1 and may not trigger a referral to an endocrinologist. Other studies have shown similar findings, with median time between the first presenting symptom and diagnosis of MEN1 ranging from 7.6 years to 12 years.[5,26] Genetic testing alleviates some of this delay. Several studies have shown statistically significant differences in the age at MEN1 diagnosis between probands and their family members. In one study, clinically symptomatic probands were diagnosed with MEN1 at a mean age of 47.5 years (standard deviation [SD] +/- 13.5 years), while family members were diagnosed at a mean age of 38.5 years (SD +/- 15.4 years; P < .001).[31] In another study of 154 individuals with MEN1, probands were diagnosed at a mean age of 39.5 years (range: 18–74 years), compared with a mean age 27 years (range: 14–56 years; P < .05) in family members diagnosed by predictive genetic testing.[32] These findings underscore the importance of increased awareness of the signs and symptoms of MEN1-related tumors and the constellation of findings necessary to suspect the diagnosis. It also highlights the importance of genetic counseling and testing and communication among family members once a diagnosis of MEN1 is made. Figure 1 illustrates some of the challenges in identifying MEN1 in a family.

Enlarge
Pedigree showing some of the features of a family with a deleterious MEN1 mutation across four generations, including transmission occurring through paternal lineage. The unaffected male proband is shown as having an affected sister (self-report of neck surgery confirmed upon review of medical records to be hyperparathyroidism diagnosed at age 18 y, parathyroidectomy, and pituitary adenoma), father (self-report of stomach cancer confirmed upon review of medical records to be gastrinoma diagnosed at age 45 y), and paternal grandmother (suspected hyperparathyroidism and/or pancreatic tumor).
Figure 1. MEN1 pedigree. MEN1 can be very difficult to identify in a pedigree. The pedigree on the left was constructed based on self-report, and the pedigree on the right depicts the same family following a review of available medical records. This pedigree shows some of the features of a family with a deleterious MEN1 mutation across four generations, including affected family members with hyperparathyroidism, a pituitary adenoma, gastrinoma, and a suspected pancreatic tumor. The tumors in MEN1 typically occur at an earlier age than their sporadic counterparts. MEN1 families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages, as depicted in the figure.

Since many of the tumors in MEN1 are underdiagnosed or misdiagnosed, identifying an MEN1 gene mutation in the proband early in the disease process can allow for early detection and treatment of tumors and earlier identification of at-risk family members. Many studies have been performed to determine the prevalence of MEN1 gene mutations among patients with apparently sporadic MEN1-related tumors. For example, approximately one-third of patients with Zollinger-Ellison syndrome will carry an MEN1 mutation.[33,34] In individuals with apparently isolated PHPT or pituitary adenomas, the mutation prevalence is lower, on the order of 2% to 5%,[23,35,36] but the prevalence is higher in individuals diagnosed with these tumors before age 30 years. Some authors suggest genetic testing for mutations in MEN1 if one of the following conditions is present:[37,38]

  • Gastrinoma at any age.

  • Multifocal duodenopancreatic NETs at any age.

  • Parathyroid hyperplasia/adenomas before age 30 or 40 years.

  • Multiglandular parathyroid adenomas/hyperplasia or recurrent PHPT.

  • Presence of one of the three main MEN1 tumors plus one of the less common tumors/findings.

  • Presence of two or more features (e.g., adrenal adenomas and carcinoid tumor).

Molecular Genetics of MEN1

The MEN1 gene is located on chromosome 11q13 and encodes the protein menin.[3,39,40] Over 1,300 mutations have been identified in the MEN1 gene to date, and these are scattered across the entire coding region.[41] The majority (~65%) of these are nonsense or frameshift mutations. The remainder are missense mutations (20%), which lead to expression of an altered protein, splice-site mutations (9%), or partial- or whole-gene deletions (1%–4%). There is currently no evidence of genotype-phenotype correlations, and inter- and intra-familial variability is common.[42,43]

Genetic Testing and Differential Diagnosis

Genetic testing for MEN1 mutations is recommended for individuals meeting clinical diagnostic criteria and may be considered in a subset of the less common tumors. (Refer to the bulleted list in the Making the diagnosis of MEN1 section of this summary for more information.) For individuals meeting diagnostic criteria, the mutation detection rate is approximately 75% to 90% [42,44] but may be lower in simplex cases.[45] Individuals with isolated parathyroid and/or pituitary tumors are less likely to have an identifiable mutation than those with pancreatic tumors.[45] The majority of commercial laboratories currently offering MEN1 testing use DNA sequencing as their primary method.[46] Several offer additional analysis for partial- or whole-gene deletion and/or duplication, although such mutations are rare and deletion/duplication testing is often reserved for individuals or families in which there is a very high clinical suspicion.

Genetic testing for MEN1 mutations can be used to distinguish between MEN1 and other forms of hereditary hyperparathyroidism, such as familial isolated hyperparathyroidism (FIHP) (OMIM), hyperparathyroidism–jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH).  [Note: The hyperparathyroidism in FHH is not primary hyperparathyroidism, which is seen in MEN1, HPT-JT and FIHP.] HPT-JT, which is caused by germline mutations in the HRPT2 gene, is associated with PHPT, ossifying lesions of the maxilla and mandible, and renal lesions, usually bilateral renal cysts, hamartomas, and in some cases, Wilms tumor.[47,48] Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma.[49] FIHP, as its name suggests, is characterized by isolated PHPT with no additional endocrine features; in some families, FIHP is the initial diagnosis of what later develops into MEN1, HPT-JT, or FHH.[50-52] Approximately 20% of families with a clinical diagnosis of FIHP carry germline MEN1 mutations.[51,53,54] Mutations in the calcium-sensing receptor (CaSR) gene cause FHH, which can closely mimic the hyperparathyroidism in MEN1. Distinguishing between MEN1 and FHH can be critical in terms of management, as removal of the parathyroid glands in FHH does not correct the patient’s hyperparathyroidism and results in unnecessary surgery without relief of symptoms.[55] Given the differential risks and management of these conditions and the increased risk of parathyroid carcinoma in HPT-JT, genetic diagnosis in a patient presenting with early-onset hyperparathyroidism may play an important role in the management of these patients and their families. Refer to Table 1 for a summary of the clinical features of MEN1 and other forms of hereditary hyperparathyroidism.

Table 1. Major Clinical Features of MEN1, FIHP, HPT-JT, and FHH
Condition Gene(s) Major Clinical Features  
CaSR = calcium-sensing receptor gene; FHH = familial hypocalciuric hypercalcemia; FIHP = familial isolated hyperparathyroidism; HPT-JT = hyperparathyroidism–jaw tumor syndrome; HRPT2 = hyperparathyroidism 2 gene; MEN1 = multiple endocrine neoplasia type 1 (gene is italicized); NETs = neuroendocrine tumors; PHPT = primary hyperparathyroidism.
MEN1MEN1 PHPT, pituitary adenomas, pancreatic NETs [1]
FIHPMEN1, HRPT2PHPT [50-54]
HPT-JTHRPT2 PHPT; osteomas of maxilla and mandible; renal cysts or hamartomas; and rarely, Wilms tumor and parathyroid carcinoma [47-49]
FHHCaSR Hyperparathyroidism (not primary) [55,56]

Surveillance

Screening and surveillance for MEN1 may employ a combination of biochemical tests and imaging. Available recommendations are summarized in Table 2.[4,37]

Table 2. Practice Guidelines for Surveillance of Multiple Endocrine Neoplasia Type 1 (MEN1)a
Biochemical Test or Procedure Condition Screened For Age Screening Initiated (y)  Frequency  
Serum prolactin and/or insulin-like growth factor 1Pituitary tumors5Every 1 y
Fasting total serum calcium and/or ionized calcium and PTHParathyroid tumors and PHPT8Every 1 y
Fasting serum gastrinDuodenopancreatic gastrinoma20Every 1 y
Chromogranin A, pancreatic polypeptide, glucagon, and vasointestinal polypeptidePancreatic NETs<10Every 1 y
Fasting glucose and insulinInsulinoma5Every 1 y
Brain MRIPituitary tumors5Every 3–5 y based on biochemical results
Abdominal CT or MRIb [4]Pancreatic NETs20Every 3–5 y based on biochemical results
Abdominal CT, MRI, or endoscopic USb [37]Pancreatic NETs<10Every 1 y

CT = computed tomography; MRI = magnetic resonance imaging; NETs = neuroendocrine tumors; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; US = ultrasound.
aAdapted from Brandi et al. [4] and Thakker et al. [37].
bThe recommendations for abdominal imaging differ between two published guidelines for the diagnosis and management of MEN1.[4,37] There is weak evidence at this time to support annual imaging before age 10 years. Imaging before age 10 years does identify disease in a high proportion of patients, but it is not clear whether this impacts prognosis.[20,57]

Interventions

Surgical management of MEN1 is complex and controversial, given the multifocal and multiglandular nature of the disease and the high risk of tumor recurrence even after surgery. Establishing the diagnosis of MEN1 prior to making surgical decisions and referring affected individuals to a surgeon with experience in treating MEN1 can be critical in preventing unnecessary surgeries or inappropriate surgical approaches.

Parathyroid tumors

Once evidence of parathyroid disease is established biochemically, the recommended course of action is surgical removal of the parathyroid glands. The timing and the extent of surgery, however, remain controversial.[58] Some groups reserve surgical intervention for symptomatic patients, with continued annual biochemical screening for those who are asymptomatic. Once surgery is necessary, subtotal parathyroidectomy (removal of 3–3.5 glands) is often suggested as the initial treatment. However, the rate of recurrence is quite high (55%–66%), and reoperation is often necessary.[13-15] Another study has shown that bilateral thymectomy reduces the likelihood of recurrence.[59] Total parathyroidectomy with autotransplantation of parathyroid tissue to the forearm is also an option. A benefit of this approach is the easier removal of recurrent disease from the forearm than from the neck. Although the likelihood of recurrence is lowered by more extensive surgery, this must be weighed against the risk of rendering the patient hypoparathyroid.[59] Management of persistent hypoparathyroidism with oral calcitriol is necessary.

Duodenopancreatic NETs

The role of surgery for pancreatic NETs in MEN1 is controversial, given postoperative morbidity, long-term complications, and low cure rates. The timing and extent of surgery depend on many factors, including severity of symptoms, extent of disease, type and location of tumor, risk of metastasis, and patient preference. The primary goal of surgery is to improve long-term survival by reducing symptoms associated with hormone excess and lowering the risk of distant metastasis.[17] While more extensive surgical approaches (e.g., pancreatoduodenectomy) have been associated with higher cure rates and improved overall survival,[60-62] they also have higher rates of postoperative complications and long-term morbidity.[63] Therefore, the risks and benefits should be carefully considered, and surgical decisions should be made on a case-by-case basis.

Individuals with MEN1 who are diagnosed with NETs often have multiple tumors of various types throughout the pancreas and duodenum, some of which can be identified using magnetic resonance imaging or computed tomography. Many tumors, however, are too small to be detected using standard imaging techniques, and intra-arterial secretin stimulation testing and/or intraoperative ultrasound may be useful.[64,65] Preoperative assessment using various biochemical and imaging modalities, intraoperative assessment of tumor burden, and resolution of hormonal hyper-secretion are critical and, in some series, have been associated with higher cure rates and longer disease-free intervals.[64-66]

In the current era of effective treatment for hyperfunctional hormone excess states, most MEN1-related deaths are due to the malignant nature of pancreatic NETs. A less common but important risk of death is from malignant thymic carcinoid tumors. Indicators of a poor MEN1 prognosis include elevated fasting serum gastrin, the presence of functional hormonal syndromes, liver or distant metastases, aggressive pancreatic NET growth, large pancreatic NET size, or the need for multiple parathyroidectomies. The most common cause of non-MEN1–related death in this patient cohort is from cardiovascular disease.[67]

Insulinomas

Medical management of insulinoma using diet and medication is often unsuccessful; the mainstay of treatment for this tumor is surgery.[37] Insulinomas in MEN1 patients can be located throughout the pancreas, with a preponderance found in the distal gland,[68-70] and have a higher rate of metastasis than sporadic insulinoma.[71] Surgery can range from enucleation of single or multiple large tumors to partial pancreatic resection, or both,[69] to subtotal or total pancreatectomy.[68,69] More extensive surgical approaches are associated with a lower rate of recurrence [60,61,69] but a higher rate of postoperative morbidity. Because insulinoma often occurs in conjunction with nonfunctioning pancreatic tumors, the selective intra-arterial calcium-injection test (SAS test) may be necessary to determine the source of insulin excess.[72] Intraoperative monitoring of insulin/glucose can help determine whether insulin-secreting tumors have been successfully excised.[65,73]

Gastrinomas

The majority of MEN1-associated gastrinomas originate in the duodenum. These tumors are typically multifocal and cause hyper-secretion of gastrin, with resultant peptic ulcer disease (Zollinger-Ellison syndrome). The multifocal nature makes complete surgical resection difficult. It is critical to manage symptoms prior to considering any type of surgical intervention. Historically, some groups have recommended close observation of individuals with smaller tumors (<2.0 cm on imaging) who have relief of symptoms using medications (e.g., proton pump inhibitors or histamine-2 agonists);[74] however, this approach may not be optimal for all patients.

Several published series have shown a positive correlation between primary tumor size and rate of distant metastasis. One retrospective study showed that 61% of patients with tumors larger than 3 cm had liver metastases.[17] In another series, 40% of patients with tumors larger than 3 cm had liver metastases.[75] In contrast, both of these series showed significantly lower rates of liver metastases in individuals with tumors smaller than 3 cm (32% and 4.8%, respectively). On the basis of these and other data, many groups recommend surgery in individuals with nonmetastatic gastrinoma who have tumors larger than 2 cm.[37,62]

The type of surgery for gastrinoma depends on many factors. A Whipple procedure is typically discouraged as an initial surgery, given the high postoperative morbidity and long-term complications, such as diabetes mellitus and malabsorption. Less extensive surgeries have been described with varying results. At a minimum, duodenectomy with intraoperative palpation and/or ultrasound to locate and excise duodenal tumors and peri-pancreatic lymph node dissection are performed.[64,76] Because most patients with gastrinoma will have concomitant NETs throughout the pancreas, some of which may be nonfunctional, some groups recommend resection of the distal pancreas and enucleation of tumors in the pancreatic head in addition to duodenal tumor excision.[64,76,77]

Nonfunctioning NETs

Approximately 50% of individuals with MEN1 will develop nonfunctioning NETs.[20,22] These are often identified incidentally during assessment and exploration for functioning tumors. As with gastrinomas, the metastatic rate is correlated with larger tumor size;[22] the presence of metastatic disease has been associated with earlier age at death than in those without pancreatic NETs.[22,78]

Other pancreatic NETs

Glucagonomas, VIPomas, and somatostatinomas are rare but often have higher rates of malignancy than other pancreatic NETs.[79] These are often treated with aggressive surgery.[71]

Pituitary tumors

Medical therapy to suppress hypersecretion is often the first line of therapy for MEN1-associated pituitary tumors. In one series of 136 patients, medical therapy was successful in approximately one-half of patients with secreting tumors (49 of 116, 42%), and successful suppression was correlated with smaller tumor size.[80] Surgery is often necessary for patients who are resistant to this treatment. Radiation therapy is reserved for patients with incomplete surgical resection.[37,81]

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