Management of Positive RET Mutation in MEN2
Patients with a positive RET mutation require risk-stratified prophylactic total thyroidectomy, with the timing determined by the specific codon mutation identified, and must undergo preoperative screening to exclude pheochromocytoma before any thyroid surgery. 1
Immediate Preoperative Requirements
Before proceeding with any surgical intervention, you must exclude pheochromocytoma, as it occurs in approximately 50% of MEN2A and MEN2B patients and must be treated first to avoid hypertensive crisis during thyroid surgery. 2, 1 If pheochromocytoma is present, perform laparoscopic adrenalectomy with α-adrenergic blockade (phenoxybenzamine) or α-methyltyrosine, followed by forced hydration and α-blockade to prevent hypotension after tumor removal. 2
Additionally, screen for hyperparathyroidism in MEN2A patients (occurs in 20-30% of cases, particularly with codon 634 mutations) by measuring serum intact parathyroid hormone and calcium levels. 2, 1
Risk-Stratified Surgical Timing Based on RET Codon
The specific RET mutation dictates both the aggressiveness of medullary thyroid carcinoma (MTC) and the timing of prophylactic surgery:
Highest Risk (Level D) Mutations
- Codons 883,918,922 (MEN2B or compound heterozygous mutations V804M + E805K, V804M + Y806C, or V804M + S904C): Perform total thyroidectomy within the first year of life or at diagnosis. 2, 1 These mutations carry 100% lifetime risk of MTC with early aggressive behavior and distant metastatic spread. 2, 3
High Risk (Level B) Mutations
- Codons 609,611,618,620,630,634: Perform prophylactic total thyroidectomy by age 5 years or when mutation is identified (if diagnosed at older age). 2 Codon 634 mutations are the most common RET mutations in MEN2A. 2, 1
Moderate Risk (Level A) Mutations
- Codons 768,790,791,804,891: These mutations have lower lethality and later onset of MTC development. 2 You may defer total thyroidectomy beyond age 5 if all of the following criteria are met:
- Annual basal calcitonin testing remains normal
- Annual neck ultrasound is unremarkable
- No family history of aggressive MTC
- Family agrees to surveillance approach 2
Surgical Approach
Perform total thyroidectomy with bilateral central neck dissection (level VI) as the standard procedure. 2, 4 The extent of lymph node dissection depends on preoperative findings:
For prophylactic surgery in MEN2A: Add therapeutic ipsilateral or bilateral central neck dissection (level VI) if elevated calcitonin/CEA or ultrasound shows thyroid or nodal abnormality. 2
For MEN2B: Consider bilateral central neck dissection (level VI) for all patients. 2
For established MTC ≥1 cm or central node metastases: Consider more extensive lymph node dissection (levels II-V). 2
Refer patients to surgeons experienced in pediatric thyroid surgery, as this minimizes complications including hypoparathyroidism (0.5-3% permanent rate) and recurrent laryngeal nerve injury (1.9-3% rate). 2, 4
Management of Concurrent Hyperparathyroidism
If multiglandular parathyroid hyperplasia is present during surgery, leave or autotransplant the equivalent mass of one normal parathyroid gland. 2 Consider cryopreservation of resected parathyroid tissue for potential future implantation if iatrogenic hypoparathyroidism develops. 2
Postoperative Management
Initiate levothyroxine therapy immediately after surgery to maintain TSH in the normal range (not suppressed, as C cells lack TSH receptors). 2
At 2-3 months postoperatively, measure basal calcitonin and CEA:
- Undetectable basal calcitonin: Continue observation with calcitonin/CEA every 6-12 months. 2 The likelihood of significant residual disease is very low. 2
- Detectable calcitonin or elevated CEA: Obtain contrast-enhanced CT or MRI of neck, chest, abdomen with liver protocol if calcitonin >150 pg/mL. 2
For MEN2A/2B patients, perform annual lifelong screening for pheochromocytoma and hyperparathyroidism (MEN2A only). 2, 1
Genetic Testing and Family Screening
All patients with newly diagnosed MTC, even those appearing to have sporadic disease, should undergo RET genetic testing, as approximately 6% of clinically sporadic MTC cases carry germline RET mutations. 2, 1 The de novo mutation rate is 9% in MEN2A and up to 50% in MEN2B, making genetic testing essential even without family history. 1
Critical Pitfalls to Avoid
- Never proceed with thyroid surgery before excluding and treating pheochromocytoma—this can cause fatal hypertensive crisis. 2
- Do not use TSH suppression therapy postoperatively, as MTC cells lack TSH receptors; maintain TSH in normal range. 2
- Do not delay surgery in highest-risk mutations (codons 883,918,922) beyond the first year of life. 2, 1
- Prophylactic thyroidectomy achieves 89% surgical cure rate in asymptomatic carriers versus only 25% in symptomatic patients with palpable nodules. 1