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    Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Genetics - Health Professional Information [NCI] - Multiple Endocrine Neoplasia Type 2

    Clinical Description

    The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are medullary thyroid cancer (MTC); its precursor, C-cell hyperplasia (CCH); pheochromocytoma; and parathyroid adenomas and/or hyperplasia. MEN2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH. In contrast, sporadic MTC is typically unilateral and/or unifocal. Since approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of familial disease.[1] Metastatic spread of MTC to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites, such as the liver, is common in patients who present with a palpable thyroid mass or diarrhea.[2,3] Although pheochromocytomas rarely metastasize, they can be clinically significant in cases of intractable hypertension or anesthesia-induced hypertensive crises. Parathyroid abnormalities in MEN2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

    Historically, individuals and families with MEN2 were classified into one of the following three clinical subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

    1. MEN2A (OMIM).
    2. Familial medullary thyroid carcinoma (FMTC) (OMIM).
    3. MEN2B (OMIM).

    Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on genotype (i.e., the mutation) and phenotype.[4]

    Clinical findings in the three MEN2 subtypes are summarized in Table 3. All three subtypes confer a high risk of MTC; MEN2A and MEN2B confer an increased risk of pheochromocytoma, and MEN2A has an increased risk of parathyroid hyperplasia and/or adenoma. Classifying a patient or family by MEN2 subtype is useful in determining prognosis and management.

    Table 3. Percentage of Patients with Clinical Features of MEN2 by Subtype

    Subtype Medullary Thyroid Carcinoma (%)a Pheochromocytoma (%)a Parathyroid Disease (%)a
    FMTC = familial medullary thyroid carcinoma; MEN2 = multiple endocrine neoplasia type 2.
    a Percentages based on observations in referral populations.[5,6,7,8,9]
    MEN2A 95 50 15-30
    FMTC ~100 0 0
    MEN2B 100 50 Uncommon

    MTC and CCH

    MTC originates in calcitonin-producing cells (C-cells) of the thyroid gland. MTC is diagnosed when nests of C-cells extend beyond the basement membrane and infiltrate and destroy thyroid follicles. CCH is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C-cells.[10,11] Individuals with RET (REarranged during Transfection) mutations and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal.[12,13] MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration.

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