Management and Treatment of Multiple Endocrine Neoplasia (MEN) 2 Syndromes
Management of MEN 2 syndromes requires prophylactic thyroidectomy based on specific RET mutation risk level, with highest risk mutations requiring surgery during the first year of life to prevent medullary thyroid carcinoma development and improve survival. 1
Genetic Testing and Classification
MEN 2 syndromes result from pathogenic germline variants in the RET proto-oncogene and include:
- MEN 2A (91% of cases): Characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT)
- MEN 2B (9% of cases): Features earlier and more aggressive MTC, PHEO, mucosal neuromas, intestinal ganglioneuromatosis, and marfanoid habitus 2
- Familial MTC: Now considered a variant of MEN 2A with decreased penetrance of PHEO and PHPT 2
RET genetic testing is essential for:
- All patients with MTC to identify hereditary cases
- All at-risk family members of MEN 2 patients
- Guiding timing of prophylactic surgery based on mutation risk level 1
Surgical Management
Thyroid Management
Prophylactic thyroidectomy timing is based on RET mutation risk level:
- Highest Risk (Level D mutations, e.g., M918T): Total thyroidectomy during first year of life or at diagnosis 1
- High Risk (Level B mutations): Total thyroidectomy by age 5 years 1
- Moderate Risk (Level A mutations): Annual calcitonin testing and ultrasound with surgery when abnormal 1
For established MTC:
- Total thyroidectomy with bilateral central neck dissection (level VI) for tumors ≥1 cm or bilateral disease
- Total thyroidectomy for tumors <1 cm with unilateral disease 1
Pheochromocytoma Management
- Annual screening for pheochromocytoma in all MEN 2A and MEN 2B patients
- Critical: Pheochromocytoma must be identified and treated before thyroid surgery to prevent potentially fatal hypertensive crisis
- Preoperative preparation with α-adrenergic blockade (phenoxybenzamine) 1
Hyperparathyroidism Management
- Subtotal or total parathyroidectomy with parathyroid cryopreservation for PHPT in MEN 2A 3
- Not required in MEN 2B as PHPT does not occur in this variant 2
Surveillance Recommendations
Post-Genetic Diagnosis
- MEN 2A/2B carriers require lifelong surveillance
- Annual screening for pheochromocytoma starting at age 8 (plasma/urine metanephrines)
- Serum calcium and PTH monitoring for hyperparathyroidism in MEN 2A 2
Post-Thyroidectomy
- Serum calcitonin and CEA at 2-3 months post-surgery
- Additional imaging if calcitonin >150 pg/mL or elevated CEA
- Levothyroxine therapy to maintain TSH in normal range (not suppressed) 1
Advanced/Metastatic Disease Management
For unresectable or metastatic MTC:
- Molecular testing to guide therapy selection
- RET-specific inhibitors (selpercatinib, pralsetinib) for RET-mutant MTC
- Vandetanib and cabozantinib as alternative targeted therapies
- Palliative procedures including radiofrequency ablation or embolization for symptomatic metastases 1
Special Considerations
- Early diagnosis of MEN 2B is crucial, with surgery within first year of life significantly improving outcomes (89% cure rate in presymptomatic carriers vs. 25% in symptomatic patients) 1
- Intestinal symptoms in infants (constipation, obstruction) may be early signs of MEN 2B due to intestinal ganglioneuromatosis 4
- Surgical complications (hypoparathyroidism, recurrent laryngeal nerve injury) must be balanced against MTC risk, especially in very young children 1
The specific RET mutation strongly correlates with disease aggressiveness and should guide all management decisions, making genetic testing the cornerstone of MEN 2 syndrome management 2, 1.