Multiple Endocrine Neoplasia Type 2 (MEN2) 

Updated: Jun 11, 2021
Author: Melanie L Richards, MD, MPHE; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumors, and pheochromocytoma. MEN2 results from germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. There are two MEN2 syndromes: MEN2A and MEN2B. 

The MEN2A syndrome is further classified on the basis of the presence of associated conditions. Classical MEN2A is characterized by MTC, pheochromocytoma, and primary hyperparathyroidism. Three additional variants are MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HSCR), and familial medullary thyroid cancer (FMTC), which is diagnosed when the patient has a RET germline pathogenic variant and MTC but no family history of pheochromocytoma or hyperparathyroidism.[1]  

MEN2B is less common than MEN2A, accounting for 5% of MEN2 cases. It is characterized by more aggressive MTC (occurring in 100% of cases), pheochromocytoma (50%), mucosal neuromas (95%-98%) and intestinal ganglion neuromas (40%). Hyperparathyroidism is absent. In addition, nearly all patients have have a distinct marfanoid habitus.[2]

Substantiation of the genotype-phenotype correlation of inherited MTC may lead to the development of an individual approach to risk management in childhood genotype carriers, and research into potential modifying factors should take place. Early total thyroidectomy remains effective in preventing the development of MTC in the long term.[3, 4, 5]

 

 

Pathophysiology

Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2. Although its function is still unknown, the protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain.[6, 7]

The extracellular domain interacts with one of four ligands identified to date. These ligands—glial cell line–derived neurotrophic factor (GDNF), neurturin, persephin, and artemin—also interact with one of four coreceptors in the GDNF-family receptor–alpha family. GDNF appears to play a critical role in the normal function of pathways involved in enteric nervous system neurogenesis and renal organogenesis. The tyrosine kinase catalytic core is located in the intracellular domain and causes downstream signaling events through a variety of second-messenger molecules.[8]

Medullary thyroid carcinoma

MTC is a calcitonin-secreting tumor of the parafollicular or C cells of the thyroid. MTC develops in virtually all patients with MEN2A; it is is often the first expressed abnormality, with onset usually in the first to third decade of life. In patients with MEN2A, MTC is typically bilateral and multicentric and preceded by C-cell hyperplasia, in contrast to sporadic MTC, which is unilateral.[9]

Pheochromocytoma

Pheochromocytomas are present in approximately half of MEN2A patients. They are bilateral in 60-80% of cases, compared with 10% of sporadic pheochromocytomas. Pheochromocytomas tend to be diagnosed at the same time as MTC or several years later (with both occurring primarily in the second or third decade). The pheochromocytomas of MEN2A patients are nearly all benign. Even so, these lesions can cause life-threatening episodes of hypertension or arrhythmia.

Parathyroid hyperplasia

Parathyroid hyperplasias are present in nearly half of patients with MEN2A but are less common than pheochromocytomas. In many patients, such hyperplasias can be clinically silent. However, as in other cases of hyperparathyroidism, comprehensive questioning will often elicit a history of symptoms.

Etiology

Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Classical MEN2A is associated with germline missense mutations in RET codons 609, 611, 618, or 620 of exon 10 or codon 634 of exon 11, which map to the receptor’s extracellular cysteine-rich domain. MEN2A with cutaneous lichen amyloidosis is nearly always associated with mutation of codon 634, while patients with MEN2A and Hirschsprung disease typically harbor mutations involving RET exon 10.[10]  

Approximately 75% of MEN2B cases are sporadic and affected patients have de novo RET mutations, while 25% of cases occur in families with previous or current manifestations of MEN2B. Approximately 95% of patients with MEN2B have RET germline mutations in exon 16 (codon M918T) and fewer than 5% have RET germline mutations in exon 15 (codon A883F).[1]  

Epidemiology

The overall frequency of MEN2 in the United States is 1 case per 30,000-50,000 population. In decreasing order of frequency, MEN occurs as follows: MEN2A, MEN2A with FMTC only, and MEN 2B.

In MEN2A patients, 50% of those with RET gene mutations develop disease by age 50 years, and 70% develop the disease by age 70 years. MTC has been detected shortly after birth in MEN2B. (See Workup and Treatment.)

Prognosis

Early treatment of medullary thyroid carcinoma (MTC) can prevent death, and careful monitoring for pheochromocytomas can decrease the chance of hypertensive episodes.

MTC, the characteristic tumor of MEN2, is present in all subtypes. Pheochromocytomas appear in MEN2A and MEN2B patients. Primary hyperparathyroidism frequently develops in patients with MEN2A but rarely in those with MEN2B. Gastrointestinal, skeletal, and dermatologic abnormalities occur only in patients with MEN2B.

Almost all published reports on MEN2B concern patients with the RET codon M918T mutation, which is present in approximately 95% of MEN2B cases.[8] Little is known about the clinical behavior of patients with the RET codon A883F mutation. Recent reports, however, suggest that patients with the A883F codon mutation have a more indolent natural course compared with that of M918T carriers and that pheochromocytomas manifests later in A883F carriers than in M918T carriers.[11]

Medullary thyroid carcinoma

The prognosis in patients with MTC varies in part with the disease stage at the time of diagnosis. In addition, MTC associated with MEN2B is the most aggressive, whereas FMTC in the absence of other endocrine malignancies is the least aggressive.[9]   

Because the penetrance of MTC is nearly 100%, prophylactic thyroidectomy in infancy is indicated for patients with high-risk RET mutations or by age 5 years in children with an identifiable RET mutation.[12, 13] Patients who are at risk but who have not had genetic screening should undergo annual biochemical screening.

The 5- and 10-year survival rates in patients with MTC and MEN 2A are approximately 90% and 75%, respectively.

Pheochromocytoma

These benign tumors of the adrenal medulla occur in 50% of patients with MEN2 by the time they are in their late 30s; however, prevalence varies in different families. Pheochromocytomas develop in more than 50% of patients with MEN2B and can appear during early childhood. The earliest possible detection of these tumors can prevent a hypertensive crisis. The risk of malignancy is low (< 5%).[14]

Adrenalectomy should be considered when patients have biochemical confirmation and an adrenal mass or enlargement on imaging. Bilateral adrenalectomy is reserved for bilateral adrenal masses. Patients become adrenal insufficient following bilateral adrenalectomy. Even patients who receive appropriate information on the management of their chronic adrenal insufficiency are at risk of addisonian crisis, which is a life-threatening emergency that may occur when the patient does not increase the replacement dosage when a major stress occurs. On the other hand, excessive steroid replacement is associated with premature osteoporosis, hypertension, and diabetes.[14]

 

Patient Education

Adhering to a surveillance program lessens disease complications. Order genetic counseling for the patient so that gene testing and reproductive options can be discussed. For patient education information, see Thyroid Problems.

 

Presentation

History

The presentation in patients with multiple endocrine neoplasia type 2 (MEN2) varies with the specific MEN2 syndrome (see Overview/Practice Essentials) and the presence and severity of associated conditions, as well as the patient's age. The most important questions to ask relate to a family history of multiple endocrine neoplasms.

Patients may present with symptoms related to medullary thyroid carcinoma (MTC), hyperparathyroidism, or pheochromocytoma. However, a young patient with an identified RET proto-oncogene mutation is likely to be asymptomatic. These patients generally have thyroid C-cell hyperplasia without progression to MTC.

Virtually all index patients have MTC at the time of diagnosis, although their clinical presentation may be consistent with pheochromocytoma or hyperparathyroidism.

Clinical manifestations of MEN2 can include hypertension, episodic sweating, diarrhea, pruritic skin lesions, or compressive symptoms from a neck mass. Patients with hypercalcemia may present with constipation, polyuria, polydipsia, memory problems, depression, nephrolithiasis, glucose intolerance, gastroesophageal reflux, and fatigue, or they may have no symptoms. They may also lose bone density.

If pheochromocytomas develop, an increase in blood pressure and heart rate may be the only signs. These increases can be chronic or episodic. Some patients have episodes of sweating and headaches.

Patients with extensive MTC may have a history of diarrhea as a result of elevated prostaglandin or calcitonin levels. Chronic constipation is a consistent finding in MEN2B patients and results from hyperplasia of the intrinsic autonomic ganglia in the intestinal wall. Infants may fail to thrive.

Cutaneous lichen amyloidosis in MEN2A patients manifests as multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back.[15] These lesions are associated with the deposition of altered cytokeratins rather than of calcitoninlike peptides. Dermal hyperneury (the presence of increased, hypertrophic myelinated and nonmyelinated nerve fibers in the dermis) and multiple sclerotic fibromas have been reported in a family with familial medullary thyroid carcinoma (FMTC).[16]

 

Physical Examination

The physical signs of MEN2 are extremely variable and often subtle. A neck mass or a dominant thyroid nodule may be palpable. Anterior neck lymph nodes are nontender; lymphadenopathy develops insidiously, and its presence may signify regional metastasis. Blood pressure and heart rate may be elevated if a pheochromocytoma is present.

Almost all MEN2B patients have the marfanoid habitus of high-arched palate, pectus excavatum, bilateral pes cavus, and scoliosis. Neuromas on the eyelids, conjunctiva, nasal and laryngeal mucosa, tongue, and lips are frequent findings. Patients also have prominent, hypertrophied lips, resulting in a characteristic facies. Localized pruritus appears over the upper back in MEN2B patients. These patients may have ectopic lenses in the eye or very flexible joints.[9]

 

DDx

Diagnostic Considerations

Hereditary pheochromocytomas may occur with the following conditions:

Hereditary hyperparathyroidism may occur with the following conditions:

 

Workup

Approach Considerations

Genetic testing is the mainstay in the diagnosis of multiple endocrine neoplasia type 2 (MEN2) syndromes. Perform genetic screening for RET mutations in all index patients. If a mutation is identified, also screen family members who are at risk.[8]

For individuals identified with a mutation or for persons who are at risk, biochemical screening consists of ascertainment of baseline calcitonin levels and of serum calcium and parathyroid hormone (PTH) levels, along with urine collection for catecholamines and metanephrine concentrations. (However, a plasma metanephrine level can be used for screening.) Note that one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations characteristic of syndromes associated with pheochromocytomas.

If a patient's calcitonin level is within reference ranges, a pentagastrin and/or Ca++ stimulation test may be used as a guide to assess the necessity of a central compartment or modified neck dissection.

Patients who have been diagnosed with medullary thyroid carcinoma require serial calcitonin (with or without provocative testing) and carcinoembryonic antigen (CEA) testing to assess for persistent or recurrent disease.

Genetic Testing

Germline RET proto-oncogene mutations (on chromosome arm 10q) discovered in MEN2-related syndromes include the following:

  • MEN2A – The majority of cases show substitutions of conserved cysteine residues in exons 10 and 11
  • MEN2B – 95% of cases show threonine-for-methionine substitution in codon 918 of exon 16.
  • Familial medullary thyroid carcinoma (FMTC) - Most commonly seen with mutations in exons 10, 13, and 14

Initial testing for MEN2A is either a single or multi-tiered analysis to detect RET mutations in the following:

  • Exon 10 (codons 609, 611, 618, and 620)
  • Exon 11 (codons 630 and 634)
  • Exons 8, 13, 14, 15, and 16

Sequencing of the entire coding region should be reserved for situations in which no RET mutation is identified or the identified genotype is inconsistent with the MEN2 phenotype. 

Initial testing for MEN2B should be to detect the RET codon M918T mutation (exon 16), and if negative, then testing for the RET codon A883F mutation (exon 15) should be completed. If no mutations are identified in these two exons the entire RET coding region should be sequenced.[1]

 

Screening for Cancer and Hyperparathyroidism

Calcitonin is the principal biochemical marker in medullary thyroid carcinoma (MTC); measurement of calcitonin is used for detection, staging, postoperative management, and determining prognosis. The higher the calcitonin levels are above normal, the greater the likelihood of MTC; basal levels of >100 pg/mL have been found to have 100% positive predictive value for MTC.[1] Very rarely, patients with clinically apparent MTC may not have elevated calcitonin levels.

Traditionally, a pentagastrin-induced rise in calcitonin secretion has been used to diagnose MTC; however, pentagastrin is not available in the United States, and DNA testing for RET has replaced this diagnostic method in familial cases. In European countries, however, pentagastrim stimulation testing is used to further delineate extent of disease. 

Calcitonin and CEA determinations remain useful serologic tests to identify recurrent disease.

Urinary catecholamine and metanephrine levels screen for pheochromocytomas. If these are elevated, imaging studies of the adrenals are recommended.

Serum calcium and PTH levels screen for hyperparathyroidism. An inappropriately elevated PTH level in relation to the serum calcium is consistent with primary hyperparathyroidism. If the 24-hour urine calcium level is low, the presence of familial hypocalciuric hypercalcemic syndrome should be considered.

Imaging Studies

Perform computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the adrenals. A metaiodobenzylguanidine (MIBG) scan is useful for localizing pheochromocytomas.[17, 18, 19]

If calcitonin levels are elevated at either baseline or with provocative testing, evaluate the chest and abdomen for metastatic disease. Available modalities include CT scanning, MRI, octreotide scanning, and, in some instances, laparoscopy.

Radionuclide scanning may reveal the extent of metastasis. OctreoScan provides a whole-body examination and is used to examine the spread of medullary thyroid carcinoma. For this procedure the somatostatin analogue octreotide, which is used for the treatment of hormone-related symptoms, is labeled with the isotope indium-111 (111In) and injected intravenously. The next day, the patient is examined with a gamma camera, which can detect the accumulation of radioactivity.

Other Tests

Fine-needle aspiration

Avoid the removal of cells from thyroid masses for cytology in patients with MEN2 who have had their diagnosis previously confirmed by either genetic analysis or elevated calcitonin levels. These patients have an established diagnosis, and a biopsy increases the possibility of tumor spread. A fine-needle aspiration biopsy is primarily used in an index patient who presents with a thyroid nodule when the clinician considers the presence of medullary thyroid carcinoma to be unlikely.

Histologic Findings

The tumor in medullary thyroid carcinoma is well demarcated, firm, and grayish white. Polygonal cells are uniform, with finely granular eosinophilic cytoplasm with central nuclei. Amyloid formed from calcitonin molecules is often found. Other findings include the following:

  • C-cell hyperplasia - Frequently found; it is a precursor in the malignant transformation to medullary thyroid carcinoma.

  • Pheochromocytomas - Benign tumors, often bilateral and multifocal, that arise from diffuse hyperplasia of the adrenal medulla

  • Parathyroid hyperplasia - In this, overgrowth is the most common finding, although adenomatous changes occur in a small percentage of cases

Staging

TNM classification is used for postoperative staging. (T = the size of the primary lesion, N = the presence or absence of regional lymph node metastatic involvement, and M = the presence or absence of distant metastatic lesions.)

Primary lesions are designated as follows:

  • T1 - Tumor 2 cm or less in greatest dimension, limited to the thyroid

  • T2 - Tumor greater than 2 cm but no more than 4 cm; limited to the thyroid

  • T3 - Tumor greater than 4 cm; limited to the thyroid

  • T4a - Tumor of any size that extends extrathyroidally and invades subcutaneous soft tissues

  • T4b - Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels

Regional lymph node metastatic involvement is designated as follows:

  • N0 - No evidence of lymph node metastases

  • N1 - Regional lymph node metastasis

  • N1a - Metastasis to level VI (central compartment) cervical lymph node(s)

  • N1b - Metastasis to unilateral or bilateral cervical nodes or to superior mediastinal lymph node(s)

Occurrence of distant metastatic lesions is designated as follows:

  • M0 – No evidence of distant metastases exists

  • M1 – Distant metastatic lesions exist

Postoperative staging is as follows:

  • Stage 1 - T1,N0,M0

  • Stage II - T2,N0,M0

  • Stage III – (T3,N0,M0), (T1,N1a,M0), (T2,N1a,M0), (T3,N1a,M0)

  • Stage IVA - (T4a,N0,M0), (T4a,N1a,M0), (T1,N1b,M0), (T2,N1b,M0), (T3,N1b,M0), (T4a,N1b,M0)

  • Stage IVB - T4b, any N, M0

  • Stage IVC - Any T, any N, and M1

 

Treatment

Approach Considerations

Multiple endocrine neoplasia type 2 (MEN2) is treated with surgery. Preoperative medical treatment may consist of prostaglandin inhibitors to alleviate diarrhea that may be associated with medullary thyroid cancer.

Evaluation for pheochromocytomas is important because these should be removed before other surgical interventions. This evaluation can be performed before parathyroidectomy or thyroidectomy under a single general anesthetic if the patient is stable. 

Hypercalcemia

Patients presenting with severe hypercalcemia should first be hydrated, after which they should be treated with furosemide. If they remain severely hypercalcemic, consider treatment with calcitonin, glucocorticoids, or bisphosphonates (such as pamidronate). While bisphosphonates are most commonly used, cinacalcet, a calcimimetic, can also be effective at reducing serum calcium levels. These patients need urgent parathyroidectomy when calcium levels have been lowered, ideally below 14 mg/dL. Patients who are not surgical candidates may also benefit from cinacalcet.

Thyroid supplementation

Thyroid hormone supplementation is necessary following total thyroidectomy in carriers of RET mutations or following a diagnosis of medullary thyroid carcinoma.

Deterrence/prevention

Start annual 24-hour urine collections for catecholamine concentrations to detect pheochromocytoma at the earliest age possible. Begin annual testing of serum calcium and PTH levels at age 10 years.

Outpatient care

Monitor patients for recurrence of medullary thyroid carcinoma with calcitonin, and CEA, and consider provocative calcitonin testing.

Perform annual screening for hyperparathyroidism with serum calcium and PTH levels in MEN2A patients. Obtain urinary catecholamine levels on an annual basis to assess for pheochromocytoma. Carefully monitor medication dosage and adverse effects.

Consultations

Consultations with the following specialists may be necessary:

  • Geneticist
  • Endocrinologist
  • Oncologist

Medullary Thyroid Carcinoma Surgery

 With nearly 100% penetrance of medullary thyroid carcinoma in MEN 2A patients, surgical intervention is recommended in all patients who are identified to carry the MEN2A gene. With genetic analysis available, these patients are often found to have an earlier stage of disease, with many patients having only parafollicular C-cell hyperplasia.

Total thyroidectomy has been recommended for patients as young as 3 years for MEN2A if they contain the genetic mutation. In patients with the RET genetic mutation for MEN 2B, total thyroidectomy is recommended in infancy because medullary thyroid carcinoma behaves more aggressively in these patients.

In contrast to patients with sporadic cases of medullary thyroid carcinoma, who have solitary tumors, patients with MEN2A have bilateral and multifocal disease.

Surgical strategies

The extent of surgery is controversial. Total thyroidectomy with central neck dissection is recommended for all patients with proven or probable medullary thyroid carcinoma. The need for either a unilateral or a bilateral modified neck dissection is controversial.

The inclusion of a modified neck dissection has been recommended for patients with palpable jugular chain lymphadenopathy. Some surgeons advocate a routine modified neck dissection. Others sample the jugular chain intraoperatively and proceed with dissection only if histologic evidence of metastatic disease is found on frozen section.

Children often do not require a node dissection, because their disease is at the hyperplasia stage and has not reached metastatic potential. Moreover, patients undergoing prophylactic thyroidectomy do not require lymphadenectomy.

Patients who have late-stage medullary thyroid cancer with symptomatic or progressive disease who are not surgical candidates may benefit from treatment with vandetanib, a tyrosine-kinase inhibitor that inhibits vascular endothelial growth factor and epidermal growth factor.

Persistent or recurrent calcitonin elevation

The treatment of persistent or recurrent elevations of calcitonin with random testing or following pentagastrin stimulation has been a clinical dilemma. Some investigators have found calcitonin levels to remain stable for approximately 5 years and have recommended surgical excision only for clinically apparent disease. Others have found that 66% of patients with node-positive disease died secondary to medullary thyroid carcinoma and advocate a more aggressive approach to follow-up care and surgery.

Parathyroid Disease Surgery

Hyperparathyroidism is the least common manifestation of MEN2A. It usually manifests in patients older than 30 years. Histologically, the parathyroid glands in MEN2A patients consist of a chief-cell hyperplasia; this hyperplasia is asymmetrical in terms of parathyroid size.

To reduce the risk of postoperative hypocalcemia, remove only grossly abnormal parathyroid glands. If all parathyroid glands are enlarged, a subtotal parathyroidectomy is advocated, leaving an approximately 60-mg remnant. Perform a cervical thymectomy because of the increased risk of supernumerary parathyroid glands.[20]

Persistent or recurrent hyperparathyroidism is unusual and less likely to occur in MEN2A patients than in MEN1 patients.

Pheochromocytoma Surgery

While all MEN2A patients may have bilateral adrenal medullary hyperplasia, the tumors may or may not be present bilaterally at the time of initial operation. In this situation, a unilateral adrenalectomy avoids the risk of addisonian crisis and improves the quality of life by not requiring replacement therapy. The advent of laparoscopic adrenalectomy has substantially decreased the morbidity of adrenalectomy.  

Cortical sparing is a surgical technique in which the surgeon leaves a small amount of vascularized unilateral or bilateral adrenal tissue that will be sufficient to maintain the normal function of the adrenal cortex for a prolonged period of time. Cortical-sparing adrenal surgery is increasingly performed, based on the very low risk of malignancy and the high probability of maintaining normal adrenal cortical function. In a review by Castinetti et al, glucocorticoid function was normal in 57–100% of patients treated for bilateral pheochromocytoma with at least one adrenal-sparing surgery.[14]  

The overall risk of recurrence of pheochromocytoma following cortical-sparing adrenal surgery is estimated as 0–21%. A study of 533 patients with MEN2-associated pheochromocytoma did not find any significant difference in the rate of recurrence between patients treated by total or partial adrenalectomy. In the cortical-sparing group, recurrence developed in the operated gland in four of 153 (2.6%) patients after a mean follow-up of 10 years; in the adrenalectomy group, recurrence occurred in 11 of 717 (1.5%) patients after a mean follow-up of 13 years.[21]

Long-Term Monitoring

Patients should be monitored on a lifelong basis for evidence of recurrent disease. After an initial follow-up visit, patients may be evaluated at 6 months, then yearly if they are asymptomatic.

Evaluations should include the following:

  • Physical examination
  • 24-hour urine catecholamine, metanephrine and vanillylmandelic acid levels
  • CEA level
  • Calcitonin level
  • Serum calcium level.

If recurrent hypercalcemia is suggested, consider patients for repeat cervical exploration.

If pheochromocytoma is suggested, evaluate patients for surgical resection. This tumor is likely in the remaining contralateral adrenal, although workup should include a CT scan and an MIBG scan to evaluate for recurrence at the resected area or at an extra-adrenal site. Recurrences in the resected area are more common if a subtotal adrenalectomy had been performed initially.

The management of patients with calcitonin/CEA elevations has been controversial. Resect any palpable cervical disease. Some practitioners have advocated routine cervical ultrasonography with exploration for any evidence of recurrence. Many patients remain asymptomatic with elevated calcitonin levels for 20 years or longer.

 

Guidelines

Guidelines Summary

In 2015, the American Thyroid Association (ATA) published revised guidelines for the diagnosis and treatment of medullary thyroid carcinoma (MTC) that included recommendations for management of multiple endocrine neoplasia type 2 (MEN2).[1] The National Comprehensive Cancer Network (NCCN) includes recommendations for diagnosis and treatment of MEN2 in its guidelines for thyroid cancer and its guideline for neuroendocrine and adrenal tumors.[9, 22]

Diagnosis

According to NCCN guidelines, the criterion for a clinical diagnosis of MEN2A is two or more MEN2A-associated tumors (medullary thyroid carcinoma [MTC], adrenal pheochromocytoma) in an individual or in a first-degree relative. Other physical findings include lichen planus amyloidosis and Hirschsprung disease.[9]

The criteria for clinical diagnosis of MEN2B includes the presence of the following[9] :

  • MTC
  • Pheochromocytoma
  • Mucosal neuromas of the lips and tongue
  • Medullated corneal nerve fibers
  • Ectopic lenses
  • Distinctive faces with enlarged lips
  • Marfanoid body habitus
  • Inability to cry tears

Evaluation

NCCN guidelines recommend offering a MEN2 clinical evaluation to individuals with a clinical diagnosis or suspicion of MEN2, even those with a negative RET genetic test. At-risk relatives should also be offered evaluation even if RET mutation has not been identified or if RET genetic testing has not been performed in the affected family member. Clinical evaluation should include the following tests[9] :

  • Biochemical tests of hormone levels
  • Imaging tests to localize MEN2-associated tumors
  • Genetic counseling and testing

Genetic Testing

Predictive RET gene testing is the clinical standard of care for all individuals with a positive family history of MEN2 because of the very high risk of early-onset MTC in affected individuals, including children.[23]

The ATA guidelines recommend offering genetic counseling and genetic testing for RET germline mutations to the following individuals[1] :

  • First-degree relatives of patients with confirmed hereditary MTC
  • Parents whose infants or young children have the classic phenotype of MEN2B
  • Patients with cutaneous lichen amyloidosis
  • Infants or young children with Hirschsprung disease (HD) and exon 10  RET germline mutations, and adults with MEN2A and exon 10 mutations who have symptoms suggestive of HD

The NCCN guidelines recommend genetic counseling and RET testing for the following individuals[9] :

  • Patients diagnosed with MTC or clinically diagnosed with MEN2 or primary C-cell hyperplasia
  • At-risk relatives of patients with known germline  RET mutation

Prevention of medullary thyroid cancer

Both ATA and NCCN guidelines recommend prophylactic thyroidectomy for individuals who have a documented RET mutation and are at risk for aggressive medullary thyroid carcinoma.[22, 1]  

Risk stratification

The 2009 ATA guidelines stratified risk level of RET carriers into four categories, A through D, based on the increasing aggressiveness of the particular mutations. Due to some confusion and lack of uniformity with other staging guidelines, the 2015 revised ATA guidelines transition category D to “highest risk” (HST), transition category C to “high risk” (H), and combine categories B and A into “moderate risk”. The risk stratification, screening schedules, and prophylactic thyroidectomy schedules are described in the table below.[1]

Table. Revised ATA MTC Risk Levels and Pediatric Recommendations (Open Table in a new window)

Risk Level

RET codon Mutation

Possible Diagnoses

Prophylactic Thyroidectomy

Recommendations

Follow-up

Highest Risk (HST)

M918T+All MEN2B

MEN2B

Within the first year of life or the first months of life based upon specialist and parental discussions. The ability to identify and preserve or transplant parathyroid glands determines level VI dissection.

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually; begin screening for pheochromocytoma at age 11 yr

High Risk (H)

C634, A883F

MEN2A

At or before age 5 yr, to be determined on the basis of serum Ctn

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually. Begin screening for pheochromocytoma at age 11.

Moderate Risk (MOD)

All other mutations

MEN2A

When serum Ctn becomes elevated or in childhood to avoid lengthy evaluation period.

Evaluate every 6 months for 1 year. Annual follow-ups thereafter if serum Ctn is normal or undetectable. Begin screening for pheochromocytoma at age 16 yr

CEA=carcinoembryonic antigen;  Ctn=calcitonin; MEN=multiple endocrine neoplasia; US=ultrasound

Surveillance

The American Society of Clinical Oncology (ASCO) recommends the following screening tests for individuals with MEN2:

  • Yearly blood tests for ionized calcium and parathyroid hormone levels, beginning in childhood (MEN2A)

  • Yearly blood tests for catecholamines and catecholamine metabolites (metanephrine and normetanephrine), beginning in childhood 

  • Magnetic resonance imaging (MRI) or computerized tomography (CT or CAT) scan of the abdomen to detect pheochromocytomas, every 4 to 5 years or when abnormal catecholamine or metanephrine levels are detected.

Pheochromocytoma

Screening

The ATA guidelines recommend screening for pheochromocytoma by measuring free plasma metanephrines and normetanephrines or 24-hour urinary metanephrines and normetanephrines. Adrenal imaging with CT or MRI is indicated in patients with positive biochemical results. The following patients should be screened[1] :

  • Children in the ATA-H and ATA-HST categories by age 11 years 
  • Children in the ATA-MOD category by age 16
  • Women with MEN2 who are planning a pregnancy or are pregnant; if detected, pheochromocytoma should be treated prior to the third trimester

Before surgery for MTC, both the ATA and NCCN guidelines recommend screening for coexisting pheochromocytoma.[22, 1]  

Treatment 

The ATA and NCCN guidelines recommend removal of pheochromocytoma prior to surgery for MTC or hyperparathyroidism to prevent a possible hypertensive crisis.[22, 1]

Pheochromocytoma should be resected by laparoscopic or retroperitoneoscopic adrenalectomy. Subtotal adrenalectomy to preserve adrenal cortical function should be considered as an alternative procedure. Patients with no adrenal glands require glucocorticoid and mineralocorticoid replacement therapy and should be carefully monitored to ensure that their steroid levels are adequate. Patients should be educated regarding the risk of adrenal crisis and wear a bracelet or a necklace indicating that they have no adrenal glands and are on corticosteroid replacement therapy. Glucocorticoid supplementation will be required if they become severely ill or are injured.[1]  

Surveillance

Surveillance intervals for patients with pheochromocytomas following a complete resection include the following[9] :

  • History, physical examination with blood pressure, and tumor markers measured after 3 to 12 months, then every 6 months for the first 3 years and annually for up to 10 years
  • Chest CT with or without contrast, abdominal/pelvic CT or MRI with contrast, or FDG-PET/CT can be considered

Parathyroid Disease

The ATA guidelines include the following recommendations for the management of hyperparathyroidism in patients with MEN2A[1] :

  • Patients in the ATA-H and ATA-MOD categories should be screened for hyperparathyroidism at the time of screening for pheochromocytoma 
  • Only visibly enlarged parathyroid glands should be resected. If all four glands are enlarged, surgical options include subtotal parathyroidectomy with a piece of one gland left in situ on a vascular pedicle or total parathyroidectomy with a heterotopic autograft. 
  • Patients who develop hyperparathyroidism subsequent to thyroidectomy for MTC should have localization studies performed prior to repeat neck surgery.
  • When repeat surgery is performed, all enlarged parathyroid glands should be removed, and parathyroids of normal size should be left in situ. If only one enlarged parathyroid gland is identified and there is histological documentation that three parathyroid glands have been removed previously, a portion of the enlarged gland should either be left in situ with an adequate blood supply or grafted to a heterotopic site. 

Hypoparathyroidism is a common complication of thyroidectomy. NCCN guidelines recommend 4-gland exploration and selective resection of abnormal parathyroid glands. Normal parathyroid glands should be left intact when possible. Subtotal parathyroidectomy is recommended when all glands appear abnormal. After subtotal or total parathyroidectomy, calcium levels should be evaluated to screen for parathyroid tumors.[9]  

 

Medication

Medication Summary

Patients require hormone replacement following total thyroidectomy and bilateral adrenalectomy or when they have postoperative hypoparathyroidism. In addition, patients who develop postoperative hypoparathyroidism need supplemental calcium and/or vitamin D.

The corticosteroid cortisone and the mineralocorticoid fludrocortisone acetate can be used in combination in patients suffering from adrenocortical insufficiency.

Preoperatively, prepare patients with pheochromocytomas by treating them with an alpha-blocker or a tyrosine hydroxylase inhibitor, such as metyrosine, for 1-2 weeks, after which administration of a beta-blocker can be considered. Many practitioners routinely treat patients with a beta-blocker, while others selectively treat patients based on blood pressure control and tachycardia.

Patients presenting with severe hypercalcemia should first be hydrated, after which they should be treated with furosemide. If they remain severely hypercalcemic, consider treatment with calcitonin, glucocorticoids, or bisphosphonates (such as pamidronate). These patients need urgent parathyroidectomy when calcium levels have been lowered, ideally below 14 mg/dL.

Alpha-Adrenergic Receptor Blockers

Class Summary

At low doses, alpha-adrenergic receptor blockers may be used as monotherapy in the treatment of hypertension. At higher doses, they may cause sodium and fluid to accumulate. As a result, concurrent diuretic therapy may be required to maintain the hypotensive effects of alpha-receptor blockers.

Phenoxybenzamine hydrochloride (Dibenzyline)

This is a long-acting adrenergic alpha-receptor blocker that can produce and maintain a chemical sympathectomy. Phenoxybenzamine hydrochloride lowers supine and upright blood pressure. It does not affect the parasympathetic nervous system.

Doxazosin mesylate (Cardura, Cardura XL)

Doxazosin mesylate is a quinazoline compound that is a selective alpha1-adrenergic antagonist. It inhibits postsynaptic alpha-adrenergic receptors, resulting in the vasodilation of veins and arterioles and a decrease in total peripheral resistance and blood pressure.

Phentolamine mesylate (Oraverse)

This is a nonselective alpha-adrenergic blocking agent. Its drug action is transient and alpha-adrenergic blockade incomplete. Phentolamine mesylate is often used immediately prior to or during adrenalectomy to prevent or control paroxysmal hypertension resulting from anesthesia, stress, or operative manipulation of the tumor. It is an alpha1- and alpha2-adrenergic blocking agent that blocks circulating epinephrine and norepinephrine action, reducing hypertension that results from catecholamine effects on alpha receptors.

Tyrosine Kinase Inhibitors

Class Summary

These agents are used to inhibit catecholamine synthesis in pheochromocytoma.

Metyrosine (Demser)

Metyrosine inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis. In patients with pheochromocytoma, administration of metyrosine reduces catecholamine biosynthesis by 35-80%, as measured by urinary catecholamine levels. It is indicated in patients with malignant pheochromocytoma or in cases of pheochromocytoma in which surgery is contraindicated. It can be useful in patients who are refractory to phenoxybenzamine therapy, or it can be administered as an adjunct to phenoxybenzamine therapy.

Beta-Adrenergic Receptor Blocking Agents

Class Summary

These agents compete with beta-adrenergic agonists for available beta-receptor sites.

Propranolol hydrochloride (Inderal LA, InnoPran XL)

This is a nonselective beta-adrenergic receptor blocker. After primary treatment with an alpha-receptor blocker, propranolol hydrochloride may be used as adjunctive therapy if control of tachycardia becomes necessary before or during surgery. It may be used to treat excessive beta-receptor stimulation in patients with inoperable metastatic pheochromocytoma. The drug has membrane-stabilizing activity and decreases the automaticity of contractions.

Propranolol hydrochloride is not suitable for the emergency treatment of hypertension; do not administer it intravenously in hypertensive emergencies.

Atenolol (Tenormin)

Atenolol selectively blocks beta1 receptors, with little or no affect on beta2 types.

Diuretics, Loop

Class Summary

Diuretics induce calciuresis. In patients with severe hypercalcemia, the individual typically is volume depleted, which means that volume should be replaced with saline prior to institution of diuretic therapy.

Furosemide (Lasix)

Furosemide inhibits the resorption of sodium and chloride in the loop of Henle and the proximal and distal tubules of the kidney. Its onset of action is rapid after an intravenous dose.

Calcium Metabolism Modifiers

Class Summary

Bisphosphonates may be used if the patient remains severely hypercalcemic following the diuretic therapy. These agents are analogues of inorganic pyrophosphate and act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. They prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.

For maximum gut absorption, all oral bisphosphonates should be taken at least 2 hours before or after meals. The newer bisphosphonates are not completely free of the risk of causing a mineralization defect, but their safe therapeutic window is much wider. They clearly are more potent than etidronate in reducing disease activity and normalizing alkaline phosphatase levels.

Calcitonin analogues may also be used if the patient remains severely hypercalcemic following the diuretic therapy. These agents directly inhibit osteoclastic bone resorption and have a significant analgesic effect on bone. Human calcitonin is no longer available. Salmon calcitonin is more likely than human calcitonin to cause resistant antibodies. As many as 26% of patients treated with salmon calcitonin demonstrated loss of biochemical responsiveness after initial improvement. High titers of salmon calcitonin antibodies produce resistance. All patients resistant to salmon calcitonin responded to human calcitonin.

Pamidronate (Aredia)

The main action of pamidronate is to inhibit the resorption of bone. The mechanism by which this inhibition occurs is not fully known. The drug is adsorbed onto calcium pyrophosphate crystals and may block the dissolution of these crystals, also known as hydroxyapatite, which are an important mineral component of bone. There is also evidence that pamidronate directly inhibits osteoclasts.

Alendronate (Fosamax)

Alendronate is a potent third-generation bisphosphonate that principally acts by inhibiting osteoclastic bone resorption. It is recommended for treatment of Paget disease. Retreatment may be considered after 6-month posttreatment evaluation in patients whose serum alkaline phosphatase level did not normalize.

Risedronate (Actonel, Atelvia)

Risedronate is a potent aminobisphosphonate that principally acts by inhibiting osteoclastic bone resorption. It is recommended for the treatment of Paget disease.

Etidronate (Didronel)

Etidronate was the first bisphosphonate to be studied in humans and approved in the United States (1978) for the treatment of Paget disease. It is the least potent of currently available bisphosphonate drugs.

Tiludronate (Skelid)

Tiludronate is a sulfur-containing bisphosphonate of intermediate potency between etidronate and newer nitrogen-containing bisphosphonates. No food, indomethacin, or calcium should be ingested within 2 hours before and 2 hours after. A 3-month posttreatment evaluation follows.

Zoledronate (Reclast, Zometa)

Zoledronate inhibits bone resorption. It inhibits osteoclastic activity and induces osteoclastic apoptosis.

Salmon calcitonin (Miacalcin, Fortical)

This agent may be used if the patient remains severely hypercalcemic following the diuretic therapy. This agent is a peptide hormone that binds to calcitonin receptors on osteoclasts and rapidly inhibits bone resorption. Osteoclasts do not induce cytotoxic effects in bone cells.

Salmon calcitonin induces reductions in urinary hydroxyproline and serum alkaline phosphatase levels. Serum alkaline phosphatase begins to decline 4 weeks after initiation of treatment. Levels of urinary hydroxyproline may decrease quickly, indicating inhibition of bone resorption. These laboratory markers slowly increase back to pretreatment levels if treatment is stopped. If no response is noted by 3 months, treatment should be discontinued.

Restoration of more normal bone can be seen radiographically, especially after long-term calcitonin treatment. Bone biopsy samples also reflect reduced disease activity because decreased bone cells, marrow fibrosis, and woven bone are present. Reduction in bone pain, cardiac output, and skin temperature over lower limb bones can be observed. Improvement of neurologic deficits and stabilization of hearing have been noted.

Reduction of hemorrhage from orthopedic procedures has been demonstrated with preoperative calcitonin treatment. However, salmon calcitonin only partially suppresses disease while treatment continues.

Thyroid Hormones

Class Summary

These agents are used for supplemental therapy in hypothyroidism.

Levothyroxine sodium (Synthroid, Levoxyl, Levothroid, Tirosint)

The goal of therapy for primary hypothyroidism is to achieve and maintain a clinical and biochemical euthyroid state. In active form, thyroid hormones influence growth and maturation of tissues. These hormones are involved in normal growth, metabolism, and development.

Vitamins, Fat-Soluble

Class Summary

Vitamin D supplements may increase serum calcium levels by improving calcium absorption.

Calcitriol (Rocaltrol, Vectical, Calcijex)

Calcitriol may be required in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism. This supplement is important in maintaining calcium balance and in the regulation of PTH. Patients are advised to have a dietary intake of calcium of, at minimum, 1000mg daily.

Corticosteroids

Class Summary

Corticosteroids cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.

Cortisone

Cortisone is the drug of choice for patients with adrenocortical insufficiency. It is used in replacement doses for postsurgical adrenalectomy.

Fludrocortisone acetate (Florinef)

Mineralocorticoids provide a partial replacement therapy for primary and secondary adrenocortical insufficiency. The combination of fludrocortisone acetate tablets with a glucocorticoid, such as hydrocortisone or cortisone, provides substitution therapy approximating normal adrenal activity, with minimal risk of unwanted effects.