What are the management and treatment options for Multiple Endocrine Neoplasia type 2 (MEN 2)?

Management and Treatment Options for Multiple Endocrine Neoplasia Type 2 (MEN 2)

Prophylactic total thyroidectomy based on RET mutation analysis is the cornerstone of MEN 2 management, with timing determined by specific mutation risk level to prevent medullary thyroid carcinoma development and improve survival. 1

Overview of MEN 2

MEN 2 is a hereditary cancer syndrome characterized by medullary thyroid carcinoma (MTC) and variable expression of other endocrine tumors. There are three clinical subtypes:

• MEN 2A: MTC, pheochromocytoma, and primary hyperparathyroidism
• MEN 2B: MTC, pheochromocytoma, mucosal neuromas, and marfanoid habitus
• Familial MTC (FMTC): MTC without other endocrine manifestations

Genetic Testing and Risk Stratification

All patients with suspected MEN 2 should undergo genetic testing for RET proto-oncogene mutations. The specific mutation determines the risk level and guides management:

Risk Classification Based on RET Mutations:

1. Highest Risk (Level D):

   • Codons 883,918, and compound heterozygous mutations (V804M + E805K, V804M + Y806C, or V804M + S904C)
   • Associated with MEN 2B and most aggressive MTC

2. High Risk (Level B):

   • Codons 609,611,618,620,630,634
   • C634 mutations are most common in MEN 2A

3. Moderate Risk (Level A):

   • Codons 768,790,791,804, and 891
   • Associated with later onset and less aggressive MTC

Management Algorithm

1. Thyroid Management

Prophylactic Thyroidectomy Timing:

• Highest Risk (Level D) Mutations:

  • Total thyroidectomy during the first year of life or at diagnosis 1
  • Consider bilateral central neck dissection (level VI)

• High Risk (Level B) Mutations:

  • Total thyroidectomy by age 5 years or when mutation is identified (if identified at older age) 1
  • Therapeutic ipsilateral or bilateral central neck dissection if elevated calcitonin/CEA or abnormal ultrasound

• Moderate Risk (Level A) Mutations:

  • Annual basal calcitonin testing and ultrasound
  • Total thyroidectomy may be deferred if tests are normal, no family history of aggressive MTC, and family agrees 1
  • Consider prophylactic thyroidectomy around age 6 for codon 804 mutations, as MTC has been reported at this age 2

Surgical Considerations:

• Refer to surgeons experienced in pediatric thyroid surgery, especially for young children 1
• Consider more extensive lymph node dissection (levels II-V) for:
  • Tumors >1.0 cm (>0.5 cm for MEN 2B)
  • Positive central compartment lymph nodes 1
• Postoperative levothyroxine to normalize TSH (not for TSH suppression) 1

2. Pheochromocytoma Management

• Annual screening for pheochromocytoma in MEN 2A and MEN 2B
• If pheochromocytoma is detected:
  • Remove pheochromocytoma before thyroid surgery
  • Use α-adrenergic blockade (phenoxybenzamine) or α-methyltyrosine preoperatively
  • Implement forced hydration and α-blockade to prevent post-tumor-removal hypotension
  • Consider β-adrenergic blockade for tachyarrhythmias after α-blockade 1

3. Hyperparathyroidism Management (MEN 2A)

• Annual serum calcium and intact parathyroid hormone measurements
• For patients with concurrent hyperparathyroidism and MTC:
  • During thyroidectomy, leave or autotransplant the equivalent mass of one normal parathyroid gland if multiglandular hyperplasia is present
  • Consider cryopreservation of resected parathyroid tissue for potential future implantation 1

Surveillance After Treatment

Post-Thyroidectomy Surveillance:

• 2-3 months postoperative:

  • Serum calcitonin and CEA
  • Neck imaging

• If calcitonin undetectable or CEA within normal range:

  • Continue observation with calcitonin and CEA every 6-12 months
  • No additional imaging required if calcitonin and CEA remain stable 1

• If detectable calcitonin or elevated CEA:

  • Consider additional imaging if calcitonin >150 pg/mL
  • Contrast-enhanced CT or MRI of neck, chest, abdomen with liver protocol
  • Consider cervical reoperation if primary surgery was incomplete 1

Ongoing Surveillance:

• For MEN 2A: Annual screening for pheochromocytoma and hyperparathyroidism
• For MEN 2B: Annual screening for pheochromocytoma 1

Management of Recurrent or Persistent Disease

• Locoregional disease:

  • Surgical resection ± postoperative radiation therapy
  • Consider radiation therapy if symptomatic, progressive, or unresectable

• Distant metastases:

  • Clinical trials (preferred)
  • Consider palliative resection or ablation (radiofrequency, embolization)
  • For progressive metastatic MTC, FDA-approved targeted therapies include vandetanib and cabozantinib (in adults) 1, 3

Important Considerations and Pitfalls

1. Surgical Complications: Hypoparathyroidism and recurrent laryngeal nerve injury are the most common complications of thyroidectomy. Rates are lower when performed by experienced surgeons 1.

2. Timing of Surgery: Balancing the risk of MTC development against surgical complications in very young children is crucial. The specific RET mutation guides this decision 1.

3. Pheochromocytoma Screening: Failure to identify and treat pheochromocytoma before thyroid surgery can lead to potentially fatal hypertensive crisis during surgery 1.

4. Genotype-Phenotype Correlation: The specific RET mutation strongly correlates with disease aggressiveness and should guide management decisions. Surgical cure rates for MTC are significantly higher in presymptomatic carriers (89%) compared to symptomatic patients (25%) 1.

5. Family Testing: Once a RET mutation is identified in an index case, all first-degree relatives should undergo genetic testing to identify asymptomatic carriers who would benefit from prophylactic interventions 4.