Multiple Endocrine Neoplasia Type 2 (MEN 2)

• • Family of syndromes including:

  • -MEN 2A (Sipple syndrome)

    -MEN 2B

    -Familial medullary thyroid carcinoma (FMTC)

  • MEN 2A is characterized by:

  • -Medullary thyroid carcinoma (MTC)

    -Pheochromocytomas

    -Parathyroid hyperplasia

  • MEN 2B consist of MTC, pheochromocytoma, mucosal neuromas, gangliomatosis of the GI tract, and a distinctive marfinoid habitus

  • -Also have high incidence of skeletal abnormalities, such as congenital dislocation of the hip, pes planus or cavus, kyphosis, and pectus excavatum

  • Transmitted as mendelian autosomal trait, but can occur de novo (especially MEN 2B)

  • Common mutation is in the Ret proto-oncogone (tyrosine kinase), which maps to the centromeric region of chromosome 10

  • Families with hereditary MTC need to be identified with an aggressive screening program because early diagnosis and thyroidectomy renders MTC curable in a large percentage of patients

Epidemiology

• • MEN 2A and 2B are transmitted with 100% penetrance but variable expressivity

  • Nearly every affected person with MEN 2A and 2B develop bilateral, multicentric MTC

  • Pheochromocytomas are present in 50% of MEN 2A patients

  • Parathyroid hyperplasia is present in 25% of MEN 2A patients

  • MTC occurs earlier and is more aggressive in patients with MEN 2B than those with MEN 2A

  • 20% of MTC occurs in a familial setting

  • Peak incidence of MTC in setting of FMTC, MEN 2A, or MEN 2B is second or third decade of life

  • Pheochromocytomas appear in second or third decade of life; 60% are bilateral

Symptoms and Signs

• • Diarrhea

  • Palpable thyroid nodule, or multinodular thyroid gland

  • Enlarged, firm cervical nodes (if metastatic disease)

  • Hoarseness, dysphagia

Laboratory Findings

• • Calcitonin level is elevated (either basally, or after stimulation with calcium and pentagastrin)

  • Elevated plasma metanephrines; elevated urinary catecholamines

  • Elevated serum calcium and intact parathyroid hormone

Imaging Findings

• • Neck x-rays: May show irregular, dense calcifications

  • Chest film: May show calcified metastatic hilar and mediastinal nodes

  • Abdominal CT scan: Can demonstrate adrenal masses

  • MIBG scan: Can localize pheochromocytomas

• • MTC is usually the first abnormality expressed in MEN 2A and 2B

  • Pheochromocytomas are nearly always limited to the adrenal medulla and are nearly always benign

  • Most patients are asymptomatic with respect to parathyroid disease

  • Pheochromocytoma should be excluded prior to operative neck exploration

  • Genetic testing is available for Ret mutations

• • Complete history (including family) and physical exam

  • Serum calcitonin, calcium, parathyroid hormone, metanephrine levels

  • Genetic screening for all patients with MTC

Surgery

Indications

• • Elevation of calcitonin level or as soon as diagnosis of FMTC, MEN 2A, or MEN 2B is made

  • Presence of pheochromocytoma

  • Hypercalcemia

Treatment Monitoring

• • Calcitonin level

  • Routine radiologic and ...