Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary disorder. Its prevalence in the general population is estimated to be around 1–10 cases per 100,000. The disease penetrance exceeds 80% in individuals carrying the MEN2 genetic mutation. MEN2 can be divided into two distinct syndromes: MEN2A (also referred to as Sipple syndrome) and MEN2B. The clinical manifestations of MEN2A include medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism. MEN2B is characterized by medullary thyroid carcinoma and pheochromocytoma, with primary hyperparathyroidism being rare.
Pathogenesis
The pathogenesis of MEN2 involves mutations in the RET proto-oncogene. RET encodes a single-chain transmembrane glycoprotein with tyrosine kinase activity, expressed in many cells derived from the neural crest, such as those of the thyroid, adrenal glands, and the enteric nervous system, playing a critical role in development. RET is structurally characterized by multiple cysteine residues clustered near the cell membrane in its extracellular domain and a tyrosine kinase domain in its intracellular region. Mutations in the RET gene in MEN2A patients often involve missense mutations or small deletions/insertions in the cysteine residues. Such mutations are commonly detected in individuals with familial medullary thyroid carcinoma (FMTC) associated with MEN2A.
In MEN2B, RET mutations do not involve the cysteine residues seen in MEN2A or FMTC. Approximately 95% of mutations in MEN2B cases occur at codon 918, where methionine (Met) is substituted by threonine (Thr).
Clinical Manifestations
Medullary Thyroid Carcinoma (MTC)
MTC is the most common and earliest developing manifestation of MEN2, as well as the most critical determinant of disease progression. Pathologically, MTC begins as hyperplasia of parafollicular C cells that produce calcitonin, evolving into carcinoma. These tumors are often multicentric and typically involve the upper third of the thyroid, consistent with the normal distribution of parafollicular cells. Approximately one-quarter of all cases of MTC are hereditary, with around 45% associated with MEN2A, 50% with isolated familial MTC, and 5% with MEN2B. MTC in MEN2B tends to develop earlier (often before the age of 5), progress more aggressively, and have the most severe course among familial cases.
MTC initially spreads within the thyroid, subsequently involving regional lymph nodes, and later metastasizing to the liver, lungs, and bones. Pathological diagnosis identifies it as a poorly differentiated thyroid tumor, with immunohistochemical staining for calcitonin providing confirmation. Extracellular amyloid deposits, which react with anti-calcitonin antibodies, may assist in the diagnosis.
Pheochromocytoma
Pheochromocytoma occurs in approximately 50% of MEN2 patients and is commonly located in the adrenal glands, often bilaterally. Malignancy is rare. Pathological progression involves adrenal medullary hyperplasia, which later develops into tumors. Diagnostic methods are the same as those used in sporadic cases of pheochromocytoma.
Primary Hyperparathyroidism
Primary hyperparathyroidism in MEN2, similar to MEN1, results from hyperplasia of the parathyroid glands. It occurs in approximately 25% of MEN2A patients and is rare in MEN2B. Surgery for primary hyperparathyroidism in MEN2 is generally effective and does not present the treatment challenges seen in MEN1.
MEN2B patients may exhibit additional clinical features absent in MEN2A, including mucosal neuromas in areas such as the tongue, lips, eyelids, and gastrointestinal tract. They may also display a Marfanoid habitus, characterized by features such as pectus excavatum and long extremities.
Treatment
Treatment of medullary thyroid carcinoma in MEN2 typically involves total thyroidectomy with central lymph node dissection, as the condition often involves multicentric disease. Partial thyroidectomy is associated with a high risk of disease recurrence. In cases where pheochromocytoma is also present, adrenalectomy is performed first to prevent complications such as hypertensive crises or heart failure during thyroid surgery. MRI and selective venous sampling for calcitonin can aid in detecting metastatic lesions. For metastatic disease, surgical treatment is palliative and not curative. Chemotherapy and radiotherapy have limited efficacy and are primarily used for advanced-stage patients.
Treatment for pheochromocytoma in MEN2 is similar to that for sporadic cases, but special attention is necessary due to the bilateral nature of MEN2-associated pheochromocytomas. Postoperative surveillance is critical for unilateral cases to detect contralateral tumors early and ensure timely intervention.
Screening
RET genetic testing is recommended for family members of MEN2 patients, as it is significantly more reliable than calcitonin screening used in the past.