Multiple Endocrine Neoplasia, Type 2 Treatment & Management

MEN 2A is treated with surgery. Preoperative medical treatment may consist of prostaglandin inhibitors to alleviate diarrhea that may be associated with medullary thyroid cancer.

Preoperatively, prepare patients with pheochromocytomas by treating them with an alpha blocker or a tyrosine hydroxylase inhibitor, such as metyrosine, for 1-2 weeks, after which consider administration of a beta blocker. Reports of successful management using a calcium channel blocker rather than an alpha blocker have been noted. Many practitioners routinely treat patients with a beta blocker, while others selectively treat patients based on blood pressure control and tachycardia.

Patients presenting with severe hypercalcemia should first be hydrated, after which they should be treated with furosemide. If they remain severely hypercalcemic, consider treatment with calcitonin, mithramycin, glucocorticoids, or bisphosphonates such as pamidronate.

These patients need urgent parathyroidectomy when calcium levels have been lowered, ideally below 14 mg/dL.

Evaluation for pheochromocytomas is important because these should be removed before other surgical interventions. This can be performed before parathyroidectomy or thyroidectomy under a single general anesthetic if the patient is stable.

• Evaluation includes screening for mutations in the RET gene.
• Thyroid hormone supplementation is necessary following total thyroidectomy in carriers of RET mutations or following a diagnosis of medullary thyroid carcinoma. Patients who have been diagnosed with medullary thyroid carcinoma require serial calcitonin (+/- provocative testing) and carcinoembryonic antigen (CEA) testing to assess for persistent or recurrent disease.
• Start annual 24-hour urine collections for catecholamine concentrations to detect pheochromocytoma at the earliest age possible.
• Begin annual testing of serum calcium and PTH levels at age 10 years.

• Medullary thyroid carcinoma

  • The advent of genetic analysis has negated the need for pentagastrin stimulation testing to identify patients with hereditary medullary thyroid carcinoma. Carefully screen patients without a family history for pheochromocytoma and hyperparathyroidism because almost 19% of sporadic cases of medullary thyroid carcinoma are index MEN 2A cases.
  • Calcitonin and CEA determinations remain useful serologic tests to identify recurrent disease. With nearly 100% penetrance of medullary thyroid carcinoma in MEN 2A patients, surgical intervention is recommended in all patients who are identified to carry the MEN2A gene. With genetic analysis available, these patients are often found to have an earlier stage of disease, with many patients having only parafollicular C-cell hyperplasia.
  • Total thyroidectomy has been recommended for patients as young as age 3 years for MEN 2A if they contain the genetic mutation. In patients with the RET genetic mutation for MEN 2B, total thyroidectomy is recommended in infancy because medullary thyroid carcinoma behaves more aggressively in these patients.
  • In contrast to patients who have sporadic cases of medullary thyroid carcinoma with solitary tumors, patients with MEN 2A have bilateral and multifocal disease.
  • The extent of surgery is controversial. Total thyroidectomy with central neck dissection is recommended for all patients with proven or probable medullary thyroid carcinoma. The need for either a unilateral or a bilateral modified neck dissection is controversial. The inclusion of a modified neck dissection has been recommended for patients with palpable jugular chain lymphadenopathy. Some surgeons advocate a routine modified neck dissection. Others sample the jugular chain at operation with frozen section, proceeding with dissection only with histologic evidence of metastatic disease.
  • Children often do not require a node dissection because their disease is at the hyperplasia stage and has not reached metastatic potential.
  • The treatment of persistent or recurrent elevations of calcitonin with random testing or following pentagastrin stimulation has been a clinical dilemma. Some investigators have found calcitonin levels to remain stable for approximately 5 years and have recommended surgical excision only for clinically apparent disease. Others have found that 66% of patients with node-positive disease died secondary to medullary thyroid carcinoma and advocate a more aggressive approach to follow-up care and surgery.
  • Patients undergoing prophylactic thyroidectomy do not require lymphadenectomy.
• Parathyroid disease

  • Hyperparathyroidism is the least common manifestation of MEN 2A. It usually manifests in patients older than 30 years. Histologically, the parathyroid glands in MEN 2A patients consist of a chief-cell hyperplasia. This hyperplasia is asymmetrical in terms of parathyroid size. To reduce the risk of postoperative hypocalcemia, remove only grossly abnormal parathyroid glands. If all parathyroid glands are enlarged, a subtotal parathyroidectomy is advocated, leaving an approximately 60-mg remnant. Perform a cervical thymectomy because of the increased risk of supernumerary parathyroid glands.^[11]
  • Persistent or recurrent hyperparathyroidism is unusual and less likely to occur in MEN 2A patients than in MEN 1 patients.
• Pheochromocytoma

  • Screen all MEN 2A patients for pheochromocytomas. This screening should consist of a 24-hour urine collection for catecholamines and metanephrine. Localization studies are not necessary unless biochemical evidence is consistent with pheochromocytoma.
  • While all MEN 2A patients may have bilateral adrenal medullary hyperplasia, the tumors may or may not be present bilaterally at the time of initial operation. In this situation, a unilateral adrenalectomy avoids the risk of Addisonian crisis and improves the quality of life by not requiring replacement therapy. Some investigators have advocated bilateral adrenalectomy in all patients. These proponents argue for the risk of malignancy (rare) and the operative complications from subsequent surgeries. The advent of laparoscopic adrenalectomy has substantially decreased the morbidity of adrenalectomy. A subtotal adrenalectomy can be performed to preserve adrenal cortical function, but the risk for recurrence may be increased.
  • Remember that one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations characteristic of syndromes associated with pheochromocytomas.

• Geneticists
• Endocrinologists
• Oncologists