The endocrine disorders observed in Multiple Endocrine Neoplasia type 2 (MEN 2) are medullary thyroid cancer (MTC), its precursor C-cell hyperplasia (CCH), pheochromocytoma, and parathyroid adenomas and/or hyperplasia. MEN 2-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. 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 because of intractable hypertension or anesthesia-induced hypertensive crises. Parathyroid abnormalities in MEN 2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident hyperparathyroidism with hypercalcemia and renal stones.
Clinical findings in the three MEN 2 subtypes are summarized in Table 1. All three subtypes confer a high risk of MTC; MEN 2A and MEN 2B confer an increased risk of pheochromocytoma, and MEN 2A has an increased risk of parathyroid hyperplasia and/or adenoma. Classifying a patient or family by MEN 2 subtype is useful in determining prognosis and management.
Historically, individuals and families were classified into one of three clinical subtypes, MEN 2A (OMIM), familial medullary thyroid carcinoma (FMTC) (OMIM), and MEN 2B (OMIM), based on the presence or absence of certain endocrine tumors in the individual or family. Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on genotype (i.e., the mutation) as well as phenotype.
Table 1. Percentage of Patients with Clinical Features of MEN 2 by Subtype
FMTC = familial medullary thyroid carcinoma; MEN 2 = multiple endocrine neoplasia type 2.
Percentages based on observations in referral populations.[5,6,7,8,9]
|Subtype ||Medullary Thyroid Carcinoma (%)||Pheochromocytoma (%)||Parathyroid Disease (%)|
|MEN 2A ||95||50 ||15-30|
|FMTC ||~100||0 ||0 |
|MEN 2B ||100||50 ||Uncommon|
Medullary Thyroid Cancer and C-Cell Hyperplasia
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.
A study of 10,864 patients with nodular thyroid disease found 44 (1 of every 250) cases of MTC after stimulation with calcitonin, none of which were clinically suspected. Consequently, half of these patients had no evidence of MTC on fine-needle biopsy and thus might not have undergone surgery without the positive calcitonin stimulation test. CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population; therefore, the plasma calcitonin responses to stimulation do not always distinguish CCH from small MTC and cannot always distinguish between carriers and noncarriers in an MEN 2 family.[12,13]