Pediatric Multiple Endocrine Neoplasia 

Updated: Oct 11, 2017
Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Robert P Hoffman, MD 

Overview

Background

First reported in 1963 by Wermer, multiple endocrine neoplasia (MEN) syndromes, found in pediatric and adult patients, consist of rare, autosomal dominant mutations in genes that regulate cell growth.[1] Current classification recognizes type 1 and type 2 MEN, with the latter being divided into the subcategories type 2A MEN (Sipple syndrome) and type 2B MEN. (See Etiology.)

Menin protein, produced by the MENIN gene, is a tumor suppressor. Loss of this protein allows tumors to arise. Alternatively, Ret protein, produced by the RET gene, a proto-oncogene, can be constitutively activated, causing abnormal cell proliferation. (See Pathophysiology, Etiology, and Workup.)[2, 3]

Type 1 MEN

Type 1 MEN is defined by hyperfunctioning tumors in the following:

  • All 4 parathyroid glands

  • Pancreatic islets - Eg, gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor (VIPoma), pancreatic polypeptide–producing tumor (PPoma)

  • Anterior pituitary - Eg, prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning tumors

Other associated tumors include lipomas, angiofibromas, and those located in the adrenal gland cortex (rarely, in the adrenal medulla).

Type 2A MEN

Type 2A MEN is defined by medullary thyroid carcinoma (MTC), pheochromocytoma (about 50% of cases), and hyperparathyroidism caused by parathyroid gland hyperplasia (about 20% of cases). (See Pathophysiology, Presentation, Workup, and Treatment.

Type 2B MEN

Type 2B MEN is defined by MTC and pheochromocytoma. Associated abnormalities include mucosal neuromas, medullated corneal nerve fibers, and marfanoid habitus. (See Pathophysiology, Presentation, Workup, and Treatment.)

Familial MTC

Familial MTC is hereditary MTC without other associated endocrinopathies, although adrenomedullary hyperplasia secondary to a germline RET mutation may still be present but undiagnosed.

Epidemiology

The prevalence of MEN in adults is about 0.02-0.2 cases per 1000 population in the United States. Data for children are not available.

The male-to-female ratio for MEN is 2:1. Patients with hyperparathyroidism in type 1 MEN most often present at age 20-40 years, but the disease may appear in children younger than 10 years. However, all MEN syndromes are rare in children.

Patient education

For patient education information, see Anatomy of the Endocrine System.

Families can locate an endocrinologist and access helpful information through the Hormone Foundation and the Endocrine and Metabolic Diseases Information Service, which is a service of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Pathophysiology

Type 1 MEN

Hyperparathyroidism is the most common manifestation of type 1 MEN (80% of presentations); it results from hyperplasia of all 4 parathyroid glands. Abnormalities of parathyroid hormone (PTH) secretion may affect children younger than 10 years.

Islet-cell tumors that secrete predominantly gastrin are called gastrinomas; these tumors frequently metastasize. Children rarely have gastrinomas. Pituitary tumors (eg, as prolactinoma) can affect children as young as 5 years. Adrenal involvement includes silent adenomas, adrenocortical hyperplasia, cortisol-secreting adenomas, and, rarely, carcinomas.

In addition, pheochromocytomas have been reported in patients with type 1 MEN. Thymic and bronchial carcinoid tumors can also be associated with type 1 MEN.[4] Lipomas and angiofibromas may often lead to the diagnosis of type 1 MEN before the endocrine manifestations.

Type 2A MEN (Sipple syndrome)

Type 2A MEN accounts for most cases of type 2 MEN. In general, type 2 MEN affects about 1 in 40,000 individuals, and fewer than 1000 kindreds are known worldwide. C-cell hyperplasia develops early in life and can be viewed as the precursor lesion for MTC, which often arises multifocally and bilaterally.

Pheochromocytomas are bilateral in 70% of cases and develop on the background of adrenomedullary hyperplasia secondary to an RET germline mutation. Biochemical manifestations, imaging manifestations, or both occur in about 50% of patients. The peak age at onset is approximately 40 years, but children as young as 10 years are reported.

Less than 25% of patients with type 2A MEN develop frank hyperparathyroidism; this condition is rare in childhood. Reasons for this low prevalence and discrepancy in type 2A MEN are unknown. Although various RET mutations can cause type 2A MEN, those mutations within exon 16 are most often reported in association with hyperparathyroidism.

Type 2B MEN

Type 2B MEN represents about 5% of all cases of type 2 MEN. Patients have some aspects of a distinctive marfanoid phenotype and mucosal neuromas. MTC is relatively aggressive and frequently occurs in childhood; children as young as 12 months may develop MTC. Therefore, prophylactic thyroidectomy with lymph node dissection is recommended in children younger than 5 years who have a RET germline mutation in exon 16.

Pheochromocytomas also occur earlier than in patients with type 2A MEN, and patients have the same features arising in the context of adrenomedullary hyperplasia, multifocality, and, often, bilateral involvement. In contrast to MTC, which frequently metastasizes, metastatic pheochromocytomas rarely occur in patients with type 2 MEN (0-25%). An important parameter in this setting is the follow-up period and the time of first occurrence or diagnosis.

 

Content.

Etiology

Type 1 MEN

The MENIN gene responsible for type 1 MEN has been localized to chromosome band 11q13; it produces a nuclear protein called menin, a tumor suppressor. The MENIN gene is ubiquitously expressed and is localized to the nucleus of cells; there is increasing evidence that menin may act in DNA repair or synthesis.

Patients with type 1 MEN possess a germline mutation in the MENIN gene and develop tumors when inactivation of the wild-type allele occurs, resulting in unsuppressed growth. Mutations are distributed over the entire coding region without showing any significant hot spot region.[5]

In type 1 MEN, neuroendocrine tumors can derive from various tissues, including the so-called APUD cells, as well as from pluripotent stem cells of these respective tissue (eg, pituitary tissue).[6] Most tumors arise in the pituitary gland and pancreatic islet cells. There is a lower incidence of parathyroid involvement in type 1 MEN compared with tumor rates in other tissues. However, patients with type 1 MEN–associated hyperparathyroidism tend to be younger than patients with sporadic primary hyperparathyroidism.

Type 2 MEN

The genetic mutation in type 2 MEN occurs in a proto-oncogene called RET, located on band 10q11.2. RET encodes the tyrosine kinase RET protein subunit of a cell surface receptor. Activation of RET leads to hyperplasia of target cells in vivo. Subsequent secondary events then lead to tumor formation. RET is specifically expressed in neural crest–derived cells, such as the C cells in the thyroid gland and the chromaffin cells in the adrenal gland. The presence or absence of RET expression in parathyroid tissue is unknown.

There are typical genetic signatures for most cases of type 2 MEN. In type 2A MEN, 95% of RET mutations occur in exons 10, 11, and 14. Of patients with type 2B MEN, 95% have a point mutation in exon 16 (M918T). A second point mutation at codon 883 has been found in 2-3% of type 2B MEN cases. Interestingly, risk stratification strategies, targeting the age of development of medullary thyroid cancer, have been developed. These are based on the genomic signature of the RET mutation. Consensus guidelines for children with the highest risk mutations (eg, c.918,c.883) recommend total thyroidectomy and central lymph node dissection as early as 6 months after birth.[7] Mechanisms of tumorigenesis that have been elucidated show allelic imbalance between mutant and wild type RET alleles.

Most cases of MTC and/or pheochromocytoma are sporadic. Only about 10% of cases are hereditary and related to type 2 MEN.

So-called inactivating mutations due to deletions of RET are associated with congenital neurologic defects, such as aganglionic colon (ie, Hirschsprung disease).[8] Of interest, these mutations also occur on exons 10 and 11 (associated with type 2A MEN).

Prognosis

Type 1 MEN

The prognosis is generally good in the presence of discrete parathyroid and pancreatic islet disease or pituitary adenoma. Pancreatic islet cell carcinoma and carcinoids are slowly progressive.

Patients with gastrinoma in type 1 MEN may have a prognosis better than that of patients with the sporadic form of the disease.

Type 2A MEN

The prognosis depends on the stage of medullary thyroid cancer and is generally good after prophylactic thyroidectomy.

Type 2B MEN

The prognosis for patients with type 2B MEN is worse than for patients with type 2A MEN because tumors, such as MTCs, are relatively aggressive, resulting in a 10-year survival rate of 50%.

Therefore, individuals with an RET germline mutation in exon 16 should undergo early prophylactic thyroidectomy and screening for pheochromocytomas. MTC may appear within the first year of life.

Morbidity and mortality

Death related to MEN can be caused by the following:

  • Complicated peptic ulcer disease

  • Metastases of endocrine pancreatic tumors

  • Severe hypercalcemia with arrhythmias

  • Metastatic MTC

  • Catecholamine release–related arrhythmias

  • Coronary heart disease

  • Stroke

  • Heart failure

  • Arrhythmias from cardiac myxomas

Zollinger-Ellison syndrome (ZES) is the major cause of morbidity and mortality in type 1 MEN. Mortality in type 2B MEN is mainly due to the aggressive nature of MTCs.

In a report on 103 patients with type 1 MEN, Doherty et al found that 46% of these individuals died from causes related to their endocrine tumors after a median of 47 years.[9]

 

Presentation

History

Type 1 MEN

Hyperparathyroidism is most common initial clinical manifestation of type 1 multiple endocrine neoplasia (MEN).[10] Some patients may manifest findings of ZES before they have hyperparathyroidism.

Symptoms of gastrinoma may become clinically apparent either with abdominal pain and diarrhea or with complications such as ulcer perforation or bleeding.

Type 2A MEN

All patients develop MTC on the basis of C-cell hyperplasia. About 50% of patients with MTC manifest pheochromocytomas (usually late in life), and 20% of patients have hyperparathyroidism.

Type 2B MEN

Pheochromocytomas occur earlier than in patients with type 2A MEN.

Physical Examination

The clinical picture depends on the glands involved and the hormones secreted.

Type 1 MEN

Hyperparathyroidism occurs with mild hypercalcemia and bone abnormalities. Musculoskeletal symptoms have also been observed in adults but rarely in adolescents.

Gastrinoma causes diarrhea, abdominal pain due to peptic ulcer disease, and esophagitis. Insulinoma causes hypoglycemia.

Glucagonoma can cause hyperglycemia. Rare cases of type 1 MEN are associated with erythema, anemia, diarrhea, or venous thrombosis.

Pituitary tumors may cause headaches, visual field defects, and other effects (depending on hormone production).

Malignancy may be increased in other tissues. In one series, female patients with MEN1 were found to be at increased risk for breast cancer. Loss of menin expression and loss of heterozygosity at the MEN1 locus could provide clues to a mammary cell–menin interaction, possibly mediated through menin's local action on estrogen receptor beta.[11]

Type 2A MEN

MTC causes one or more firm nodules, which are often associated with enlarged cervical lymph nodes. Pheochromocytomas cause hypertension, sweating, palpitations and tachycardia, headache, emotional lability, nausea, vomiting, polyuria, and polydipsia.

Type 2B MEN

Marfanoid phenotype develops in all patients. Phenotypic characteristics include a slender body build; long and thin extremities; abnormal laxity of joints; and, in many cases, a high-arched palate, pectus excavatum, or pes cavus. The facies is characterized by thick, enlarged lips as a result of embedded mucosal neuromas.

Neuromas may be found on the surface of the lips, tongue, eyelids, and cornea. Ganglioneuromas may occur at any level of the GI tract, causing constipation or diarrhea due to abnormal control of intestinal motility. MTC may appear within the first year of life.

 

 

DDx

Diagnostic Considerations

DDX of MEN syndromes requires the identification of the typical pattern of endocrine and other organ involvement. Insofar as these patterns may emerge over time, initial presentations may take into account other conditions that could be associated with the presenting syndrome. For example, in the patient who presents with pheochromocytoma, other conditions that would present with pheochromocytoma such as Von Hippel Lindau syndrome, hereditary paraganglioma-pheochromocytoma syndrome, or even neurofibromatosis 1 may be considered. For patients presenting with acromegaly, familial AIP mutations or carney complex may appear in the differential diagnosis. The same would be true of each of the presentations of the MEN syndromes. 

Note that for patients presenting with MTC and no other endocrine manifestations, familial MTC should be considered as there can be a variable penetrance. 

Differential Diagnoses

 

Workup

Approach Considerations

With testing, type 1 multiple endocrine neoplasia (MEN) can be detected in individuals from kindreds before age 18 years (or even younger, if desired). MENIN mutations occur throughout the gene, and new mutations continue to emerge. Mutation screening helps in identifying as many as 85% of patients with type 1 MEN. The degree of penetrance of type 1 MEN at age 20 years is about 43%.

MEN type 2 is highly penetrant and should be diagnosed by RET mutation testing before age 5 years. If mutation tests are positive, subsequent prophylactic thyroidectomy with lymph node dissection is recommended. If a parent has type 2B MEN, earlier diagnosis is recommended for the affected adult's child because the disease is relatively aggressive.

Screening

Because early therapy substantially improves the patient's prognosis, screening is of paramount importance in all forms of MEN. Clinical practice guidelines for MEN1 were released in 2012 to address some of the concerns in screening and evaluation of this condition.[12]

Risk factors include known MEN, a positive family history of MEN, ZES, ganglioneuromas, cutaneous neuromas, a marfanoid somatic phenotype, parathyroid hyperplasia, multicentric medullary carcinoma of the thyroid, and multicentric or bilateral pheochromocytomas.

Screening tests include the following measurements based on the type of MEN:

  • Type 1 MEN - Serum calcium and intact PTH, prolactin, plasma chromogranin A, fasting gastrin, fasting glucose and insulin, and free IGF-I determinations

  • Type 2A MEN -RET germline mutation testing and determinations of plasma calcitonin, plasma free and total metanephrines and 24-hour urinary catecholamines (including fractionated metanephrines), and serum calcium levels

  • Type 2B MEN -RET germline mutation testing and determinations of serum calcitonin, plasma free metanephrines, and 24-hour urinary catecholamines, including fractionated metanephrines

If test results are in the reference range on 3 occasions and if the patient is older than 35 years, he or she can be declared a noncarrier. Offspring of noncarriers do not require testing. Mutation analysis of the MENIN gene permits the identification of people carrying a germline mutation.

For patients with family kindreds of type 1 MEN with known mutations, a separate series of routine screening recommendations has been established. These are available in guidelines from Brandi et al.[13]

Imaging Studies

Gastrinomas

Somatostatin-receptor scintigraphy (SRS) has a sensitivity of 70-90%, which is more than that of any other imaging procedure. SRS depends on the SSR receptor profile (types 2 and 5, rarely type 3) and tumor size (>5 mm). Endoscopic ultrasonography can depict tumors in the pancreatic head but rarely in the duodenal wall.

Insulinomas

Perform high-resolution computed tomography (CT) scanning and magnetic resonance imaging (MRI) first. SRS findings are positive in about 50% of patients. Intraoperative ultrasonography of the pancreas is highly recommended to detect additional tumors.

Pituitary tumors

Perform MRI, CT scanning, or both after biochemical evaluation.

Nonfunctioning pancreatic endocrine tumors

After type 1 MEN is confirmed, perform pancreatic endoscopic ultrasonography to monitor the progression of nonfunctioning pancreatic endocrine tumors. Their incidence is high (54.9%), although their clinical significance remains uncertain. Follow-up of lesions discovered should be coordinated with experienced subspecialists.[14, 15]

Pheochromocytomas

Radiologic imaging for pheochromocytomas includes CT scanning, MRI, metaiodobenzylguanidine (MIBG) scanning, OctreoScan imaging, and positron emission tomography (PET) scanning.

Histologic Findings

Histologic findings in MEN include the following:

  • Parathyroid glands - The glands show hyperplasia and diffuse or nodular proliferations of chief cells, mixed with some oncocytic cells; all glands are involved.

  • Pancreas - Numerous microadenomas (mostly in the pancreatic tail) are present; the tumors display a trabecular pattern; immunohistochemically, tumor cells stain with antibodies directed to pancreatic polypeptide, glucagon, insulin, and gastrin.[16]

  • Duodenum - Duodenal tumors are most often gastrinomas in the first part of the duodenum; they stain positive for gastrin and may metastasize to regional lymph nodes

  • Stomach - In the stomach, diffuse hyperplasia of enterochromaffinlike (ECL) cells is found and is associated with tumors of considerable size but rarely of metastatic potential

  • Pituitary - Most tumors are single, are found in the anterior part of the gland, and produce prolactin and/or GH, and, occasionally, corticotropin

Laboratory Studies

Laboratory studies for MEN include investigations of the different tumor-expression patterns. Such studies include the following:

  • Gastrinomas (ZES) - Serum gastrin levels exceed 115 ng/mL and increase more than 200 ng/mL from baseline after secretin challenge (ie, intravenous [IV] injection of 2 U/kg of secretin); approximately two thirds of patients have basal gastrin levels of 150-1000 ng/mL

  • Glucagonoma - Findings are hyperglycemia with elevated serum glucagon levels

  • Watery diarrhea syndrome - Serum levels of vasoactive intestinal peptide are elevated; serum K levels may be low

  • Carcinoids - levels of serotonin, urinary 5-hydroxyindoleacetic acid (5-HIAA), calcitonin, and 24-hour urinary free cortisol and corticotropin may be elevated

  • Pituitary tumors - Tests reveal persistent elevation of serum somatotropin (growth hormone [GH]) during oral glucose challenge; serum free or total insulinlike growth factor (IGF)-I level more than 2 standard deviations (for age, sex, and Tanner stage); or elevated serum prolactin levels.

Insulinoma

Results may reveal fasting hypoglycemia with inappropriately elevated serum insulin, C-peptide, or proinsulin concentrations.

When the serum glucose level is less than 60 mg/dL, the serum insulin level should be less than 2 µU/mL. A serum insulin level of less than 2 µU/mL during hypoglycemia is consistent with hyperinsulinism.

Additional diagnostic criteria include the following:

  • Decreased fasting tolerance (defined during a controlled inpatient fast)

  • Inappropriate glycemic response to glucagon challenge when the patient is hypoglycemic - ie, an increase in the serum glucose level by more than 30 mg/dL from a baseline of less than 60 mg/dL within 20 minutes after 1mg of glucagon is intravenously or subcutaneously administered

  • Suppressed lipolysis - Free fatty acid concentration below 20 mm

  • Suppressed ketogenesis (when the patient has hypoglycemia) - Undetectable plasma acetoacetate or beta hydroxybutyrate

  • Acute insulin response to peripheral venous or intra-arterial calcium challenge - Performed at centers that include the University of Texas Health Science Center at San Antonio and the Children's Hospital of Philadelphia

Type 2 MEN

Patients with MTC frequently have elevated calcitonin levels. In patients with pheochromocytoma, the total urine catecholamine excretion exceeds 100-300 μg daily (over 24 h). Serum levels of more than 2000 μg/mL are pathognomonic for pheochromocytoma. Measuring plasma free and urinary fractionated metanephrines with a 24-hour collection is best.

Type 2A multiple endocrine neoplasia (Sipple syndrome)

RET germline mutation testing has replaced the pentagastrin and calcium stimulation tests for the diagnosis of C-cell hyperplasia and MTC. This advance is especially important for children, because the stimulation tests were unpleasant, and reference values for calcitonin were not established in children.

In addition, stimulation tests are inaccurate for the diagnosis of MTC, as demonstrated with prophylactic thyroidectomy based on positive results on RET germline mutation tests. In studies, about 50% of patients with a negative pentagastrin result but a positive RET mutation had already developed MTC. Optimal timing of prophylactic thyroidectomy is risk stratified and depends highly on the genetic signature. Most commercial RET mutation tests search for only part of the RET proto-oncogene (exons 10, 11, 13, 14, 15, 16) and typically help in identifying 97% of patients with type 2 MEN.

Pheochromocytomas are bilateral in 70% of cases and develop on the background of adrenomedullary hyperplasia secondary to an RET germline mutation. Biochemical manifestations, imaging manifestations, or both occur in about 50% of patients. The peak age at onset is approximately 40 years, but children as young as 10 years are reported. Therefore, annual surveillance for plasma free metanephrines and urinary catecholamines, including fractionated metanephrines, is recommended in children older than 6 years (although collecting 24-h urine samples in children is difficult).

In adults with an adrenal incidentaloma and hypertension, measuring plasma chromogranin A in addition to plasma free metanephrines may be helpful.

 

Treatment

Approach Considerations

Treatments for the various conditions associated with multiple endocrine neoplasia (MEN) include the following:

  • Hypercalcemia - For patients with type 1 MEN who have hypercalcemia, surgery is the treatment of choice, including removal of 3.5 parathyroid glands

  • Gastrinoma - The current treatment consists of PPIs to reduce acid hypersecretion

  • Insulinoma - Surgery is the therapy of choice; unresectable tumors are treated with diazoxide

  • Glucagonoma - Glucagonomas are surgically removed

  • VIPoma - Octreotide controls symptoms (diarrhea) in 80% of patients; however, surgical tumor removal should be attempted

  • Prolactinoma - Prolactinomas are treated with dopamine agonists, such as bromocriptine or cabergoline

  • GH-producing pituitary tumor - These tumors are treated by transsphenoidal surgery; in rare instances, medical therapy with a GH receptor antagonist is recommended

Chemotherapy with streptozocin and dacarbazine may reduce the size of nonoperable neuroendocrine tumors.

Surgery for Type 1 MEN

Type 1 MEN with hyperparathyroidism

In patients with type 1 MEN who have hyperparathyroidism, surgery is the treatment of choice if any of the following conditions are present:

  • Serum albumin–adjusted serum calcium level that is more than 1 mg/dL of the upper limit of the reference range

  • Kidney stones

  • PTH-induced bone disease with a T score of -2.5

  • 24-Hour urinary calcium excretion of more than 400mg

Type 1 MEN with ZES

In patients with type 1 MEN with ZES who have hypercalcemia, perform parathyroidectomy before abdominal tumor resection. In these patients, parathyroid surgery is indicated even in mild forms of hypercalcemia because serum calcium levels in the reference range are often associated with lower serum gastrin levels and consecutively lower gastric acid secretion (high calcium stimulates gastrin in these patients).

Removal of 3.5-4 parathyroid glands controls hypercalcemia. If 4 glands are removed, immediate autograft of parathyroid tissue into the musculature of the nondominant arm is indicated.

Some authors recommend taking careful operative notes and marking the residual parathyroid tissue with clips, because reoperation in patients with type 1 MEN is likely.

Gastrinoma

The role of surgery in ZES and type 1 MEN remains controversial because cure is only occasionally achieved. Most tumors are multicentric, raising the possibility of recurrence. Surgery may be indicated in patients with positive findings on imaging studies and no distant metastases. Gastrinomas are found in the duodenal wall, in the pancreas, or in lymph nodes.

Local tumor excision is preferred, with larger tumors of the pancreatic body or tail removed by distal pancreatectomy. This approach may reduce the risk of subsequent metastatic disease to the liver.

Resection of liver metastases may be beneficial. Total pancreatectomy is not indicated, because of the deleterious effects of this procedure (eg, pancreatic exocrine insufficiency, diabetes mellitus).

Insulinoma

Insulinomas are large, single tumors that can be enucleated. Resection may result in cure, although insulinomas in type 1 MEN may be multicentric.

Some authors recommend subtotal pancreatectomy (≥80% of the pancreas) in patients with multiple tumors or when the tumor is not localized. Surgical debulking in metastatic disease may reduce hypoglycemia to a certain extent.

Intraoperative ultrasonography facilitates tumor identification. Other methods include intraoperative monitoring of plasma glucose and insulin levels.

VIPoma

In VIPoma, resection of single and multiple tumors is indicated, which may include a pancreatic tail resection.

Carcinoid tumors

Carcinoid tumors are removed surgically; half of the tumors, particularly thymic carcinoids, are locally invasive or metastatic.[4]

Pituitary tumors

Transsphenoidal pituitary surgery is aimed at resection of any pituitary mass, particularly in acromegaly. Patients with incomplete resection remain on treatment with dopamine agonists.

Prolactinoma

Prolactinomas may be large and multicentric. The recurrence rate after surgical removal is high, and medical treatment is now the therapy of choice. Transsphenoidal surgery with external radiation therapy (external beam or gamma knife) is indicated in patients in whom long-term bromocriptine therapy is ineffective.

Surgery or Type 2 MEN

Total thyroidectomy with radical lymph-node dissection is recommended in patients aged 5 years if a RET germline mutation is identified. All regional lymph nodes must be removed, even if they are not macroscopically suspected. Before any surgery, screening for pheochromocytomas must be performed. For patients with germline mutations in codons 790/791, the age at which total thyroidectomy should be performed is controversial.

Pheochromocytomas require surgical excision under alpha-adrenergic blockade, starting 7-10 days before surgery (target blood pressure is 120/80 mm Hg while seated and a systolic blood pressure of >90 mm Hg while standing/upright).

Pheochromocytomas in patients with type 2 MEN may be bilateral. Explore both adrenal glands during surgery.

Patients with a pheochromocytoma and MTC should receive appropriate preparation with alpha-blocker therapy. Then, the pheochromocytoma should be removed first to avoid life-threatening complications (eg, hypertensive crisis, arrhythmias) caused by the adrenal tumor. Laparoscopic adrenalectomy has now become a routine procedure and is most often the management of choice; however, it results in associated Addisonianlike complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centers, may be another option.[17]

Inpatient Care

After parathyroid surgery, monitor serum ionized calcium and magnesium levels. Transient hypoparathyroidism frequently develops and requires calcium and vitamin D supplementation. In rare cases, hungry-bone syndrome may ensue, with rapid declines in serum calcium and magnesium levels.

Somatostatin therapy is indicated particularly in patients with acromegaly in whom surgery did not achieve complete tumor removal. Tumor shrinkage can be expected in one third of patients, and normalization of IGF-1 levels can be expected in as many as two thirds.

Pregnancy may ensue with treatment that includes cabergoline or bromocriptine in patients with prolactinoma.

Outpatient Care

In MTC, measure serum calcitonin levels every 6-12 months after surgery. Elevated serum levels in the neck region indicate recurrence that possibly requires further surgery. However, micrometastases often cannot be visualized by using current imaging techniques.

The resection of one endocrine tumor does not exclude a second tumor, even after an interval of several years. Patients need lifelong surveillance, as do their offspring.

Pheochromocytomas are monitored with blood pressure and plasma free metanephrines as well as 24-hour urinary catecholamines, including fractionated metanephrine measurements, to exclude recurrence.

Complications

A retrospective single-center study by Kluijfhout et al found that patients younger than 3 years had a longer average length of stay (6.9 days) versus the older patient groups (1.7 and 3.5 days) after prophylactic thyroidectomy for MEN 2.[18]

 

Guidelines

Guidelines Summary

Clinical Practice Guidelines for (MEN) type 1 by the Endocrine Society recommend that testing for MEN1 germline mutation should be offered to patients with MEN1 and their first-degree relatives and that patients with MEN1 and their families should be managed by a multidisciplinary team that includes physicians who specialize in managing endocrine tumors.[19]  

Other Guidelines include:

  • Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001 Dec;86(12):5658-71. [20]
  • Waguespack SG, Rich TA, Perrier ND, et al. Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol. 2011 Aug 23;7(10):596-607. doi: 10.1038/nrendo.2011.139. [21]
  • Wells SA Jr, Asa SL, Dralle H, et al. American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. doi: 10.1089/thy.2014.0335. Review. [22]
  • Chen H, Sippel RS, O'Dorisio MS, et al. North American Neuroendocrine Tumor Society (NANETS). The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010 Aug;39(6):775-83. doi: 10.1097/MPA.0b013e3181ebb4f0. [23]

 

 

Medication

Medication Summary

Pharmacologic therapy for multiple endocrine neoplasia (MEN) is directed toward specific endocrine syndromes associated with the disorder. Patients with type 1 MEN and ZES need lifelong acid inhibition with PPIs.

As previously mentioned, somatostatin therapy is indicated in patients with acromegaly in whom surgery did not achieve complete tumor removal. One third of patients should experience tumor shrinkage, and up to two thirds of patients should achieve normalization of IGF-1 levels.

Although surgery is the therapy of choice for insulinomas, unresectable tumors are treated with the hyperglycemic agent diazoxide. There are some recent studies investigating the use of long acing somatostatin ligands in the treatment of unresectable or refractory insulinoma.  

Somatostatin analogs

Class Summary

Octreotide acetate acts similarly to the natural hormone somatostatin by suppressing peptide secretion from gastroenteropancreatic tumors.

Octreotide acetate (Sandostatin)

Octreotide acetate acts primarily on somatostatin receptor subtypes II and V. It inhibits GH secretion and has other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and gastrointestinal (GI) peptides. Octreotide acetate controls diarrhea in 80% of patients. Progressive increases in dosage may be necessary.

Somatostatin Analogs

Lanreotide (Somatuline Depot)

Proton Pump Inhibitors

Class Summary

Gastric acid secretion with PPIs is mandatory to prevent complications of gastric acid hypersecretion. PPIs are safe and cause no adverse effects, even after long-term use. The goal of therapy with these agents is to reduce the basal acid output to less than 10mEq/h 1 hour before the next dose in patients without previous acid-reducing gastric surgery, and to less than 5mEq/h in patients with previous acid-reducing gastric surgery.

Omeprazole (Prilosec)

Omeprazole is a substituted benzimidazole that suppresses acid secretion by specifically inhibiting the H+/K+ adenosine triphosphatase (ATPase) at the secretory surface of the parietal cell.

Hypoglycemia Antidotes

Class Summary

These agents inhibit insulin release from the tumor.

Diazoxide (Proglycem)

Diazoxide binds to the sulfonylurea receptor (SUR1) of the pancreatic beta cell, inhibiting insulin secretion. The oral form opens K adenosine triphosphate (ATP) channels and inhibits insulin secretion. Diazoxide increases a patient's blood glucose level within 1 hour by inhibiting insulin release from the patient's insulinoma. Unlike rapid IV administration of diazoxide, oral administration of the drug is not antihypertensive.

Antineoplastics, Tyrosine Kinase Inhibitor

Cabozantinib (Cabometyx, Cometriq)

Can be used in refractory medullary thyroid cancer 

Vandetanib (Caprelsa)

Can be used in refractory medullary thyroid cancer