Type 2 Multiple Endocrine Neoplasia

Updated: Dec 11, 2015
  • Author: Melanie L Richards, MD, MPHE; Chief Editor: George T Griffing, MD  more...
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Overview

Background

Type 2 multiple endocrine neoplasia (MEN 2) is a rare familial cancer syndrome caused by mutations in the RET proto-oncogene. Sipple first described an association between thyroid cancer and pheochromocytoma (benign tumor of the adrenal medulla) in 1961. The thyroid cancer found with pheochromocytoma was discovered in 1965 to be a medullary carcinoma characterized by stromal amyloid. In 1968, this familial constellation of pathology in conjunction with parathyroid hyperplasia was recognized as MEN 2. (See Pathophysiology and Etiology.)

Although patients with mucosal neuromas were identified at this time, the distinction between MEN 2A and MEN 2B was not made until 1975. The differences between these variations of the disease are as follows (see Presentation and Workup):

  • Phenotype - MEN 2A patients do not have the phenotypic abnormalities of mucosal neuromas and marfanoid habitus found in MEN 2B patients
  • Medullary thyroid carcinoma - MEN 2A patients have a less virulent form of medullary thyroid carcinoma than do MEN 2B patients
  • Parathyroid hyperplasia - MEN 2A patients may have parathyroid hyperplasia, which is exceedingly rare in MEN 2B patients

A third subtype of MEN 2 is familial medullary thyroid carcinoma only (FMTC only).

Epidemiology

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

In MEN 2A patients, 50% of those with RET gene mutations develop the disease by age 50 years, and 70% develop the disease by age 70 years. Medullary thyroid carcinoma has been detected shortly after birth in MEN 2B. (See Workup and Treatment.)

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. (See Treatment.)

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Pathophysiology

As previously stated, MEN 2 is a rare familial cancer syndrome caused by mutations in the RET proto-oncogene. Inherited as an autosomal dominant disorder, MEN 2 has 3 distinct subtypes, including MEN 2A, MEN 2B, and FMTC only. The subtypes are defined by the combination of tissues affected. Developmental abnormalities may also be present.

By age 70 years, the penetrance rate is 70%. Genetic testing and clinical surveillance beginning in childhood provide the opportunity to treat the devastating and sometimes fatal complications of this disorder. [1]

The RET proto-oncogene is 80 kilobases (kb) long and encodes a putative tyrosine kinase receptor. Its endogenous ligand may be glial cell line–derived neurotrophic factor (GDNF), which appears to play a critical role in the normal function of pathways involved in enteric nervous system neurogenesis and renal organogenesis.

Data suggest that an overrepresentation of mutant RET as an undefined second hit event may trigger tumorigenesis. However, alterations in other genes may contribute to this overrepresentation of RET or may influence MEN 2-related tumor development through completely different mechanisms and pathways.

Glandular hyperplasia begins with an increase of C cells located in the thyroid gland follicles and can progress to malignancy.

Medullary thyroid carcinoma

Virtually all patients with MEN 2A develop medullary thyroid carcinoma. This is often the first expressed abnormality and usually occurs in the second or third decade of life. The medullary thyroid carcinoma in patients with MEN 2A is typically bilateral and multicentric, in contrast to sporadic medullary thyroid carcinoma, which is unilateral.

Pheochromocytoma

Pheochromocytomas are present in approximately half of MEN 2A patients. They are bilateral in 60-80% of patients, compared with 10% of patients with sporadic pheochromocytomas. Pheochromocytomas tend to be diagnosed at the same time as medullary thyroid carcinoma or several years later (with both occurring primarily in the second or third decade). The pheochromocytomas of MEN 2A patients are nearly all benign. Even so, these lesions can cause a life-threatening hypertensive episode or arrhythmia.

Parathyroid hyperplasia

Parathyroid hyperplasias are present in nearly half of patients with MEN 2A but are less common than pheochromocytomas. In many patients, such hyperplasias can be clinically silent. However, as in other cases of hyperparathyroidism, symptoms can often be elucidated following comprehensive questioning.

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Etiology

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. [2, 3]

Point mutations associated with MEN 2A and the FMTC-only subtype were identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Almost all individuals with MEN 2B have an identical mutation in codon 918 of exon 16. Inheritance is autosomal dominant, with variable penetrance and expressivity.

Substantiation of the genotype-phenotype correlation of inherited medullary thyroid carcinoma 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 medullary thyroid carcinoma in the long-term. [4, 5, 6]

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Prognosis

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

MEN 2A, MEN 2B, and the FMTC-only subtype elicit overlapping and distinct abnormalities. The characteristic tumor of MEN 2 medullary thyroid carcinoma is present in all subtypes. Pheochromocytomas appear in MEN 2A and MEN 2B patients. Primary hyperparathyroidism frequently develops in patients with MEN 2A but rarely in those with MEN 2B. Gastrointestinal, skeletal, and dermatologic abnormalities occur only in patients with MEN 2B.

Medullary thyroid carcinoma

The prognosis of medullary thyroid carcinoma is associated with the disease stage at the time of diagnosis. Because the penetrance of medullary thyroid carcinoma is nearly 100%, perform prophylactic thyroidectomy in infancy for patients with high-risk RET mutations or by age 5 years in children with an identifiable RET mutation. [7, 8] For patients who are at risk but who have not had genetic screening, perform annual biochemical screening.

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

Pheochromocytoma

These benign tumors of the adrenal medulla occur in 50% of patients with MEN 2 by the time they are in their late 30s; however, prevalence varies in different families. Pheochromocytomas develop in more than 50% of patients with MEN 2B and can appear during early childhood. The earliest possible detection of these tumors can prevent a hypertensive crisis.

Adrenalectomy should be considered when patients have biochemical confirmation and an adrenal mass or enlargement on imaging. A bilateral adrenalectomy is reserved for bilateral adrenal masses. Subtotal adrenalectomy remains controversial. [9, 10]

Hyperparathyroidism

Extremely uncommon in MEN 2B patients, parathyroid hyperplasia affects 20-30% of MEN 2A patients. Patients may present with hypercalcemia and other vague symptoms.

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