Management of Multiple Endocrine Neoplasia Type 2 (MEN2)

Introduction to MEN2 Management

The American College of Surgeons and other medical organizations recommend early genetic testing for RET proto-oncogene mutations followed by risk-stratified prophylactic thyroidectomy, with the timing of surgery determined by the specific RET codon mutation identified, as the cornerstone of MEN2 management 1, 2

The National Comprehensive Cancer Network recommends that all patients with newly diagnosed medullary thyroid carcinoma (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 3
The de novo mutation rate is 9% in MEN2A and as high as 50% in MEN2B, making genetic testing essential even without family history 1, 2
RET mutations are found in at least 95% of MEN2A kindreds and 88% of familial MTC cases 3

The specific RET codon mutation dictates the aggressiveness of MTC and timing of prophylactic surgery, with mutations classified into three risk categories: Highest Risk (Grade 1), High Risk (Grade 2), and Moderate Risk (Grade 3) 4, 5
For Highest Risk (Grade 1) mutations, such as codons 883, 918, 922, thyroidectomy is mandatory within the first year of life 4, 1, 5, 6
For High Risk (Grade 2) mutations, such as codons 609, 611, 620, 630, 634, 804, 891, thyroidectomy should be performed before age 5-6 years 4, 1, 5

Before any thyroid surgery in MEN2, pheochromocytoma must be excluded and treated first to avoid hypertensive crisis during surgery, according to the National Comprehensive Cancer Network 3
The preoperative workup includes biochemical screening, pheochromocytoma screening, hyperparathyroidism screening, neck ultrasound, cross-sectional imaging, and vocal cord assessment 3, 1

Total thyroidectomy is the definitive preventive strategy for MTC in RET mutation carriers, and surgery should be performed by surgeons experienced in MEN2 to minimize complications and maximize cure rates 1, 2
The surgical cure rate for MTC is 89% in asymptomatic converters versus only 25% in symptomatic patients presenting with a palpable nodule 4, 5

Pheochromocytomas occur in approximately 50% of MEN2A and MEN2B patients, and codon 634 mutations carry the highest risk 2
Pheochromocytoma must be treated before any thyroid surgery, and laparoscopic adrenalectomy is the preferred surgical approach 3

Primary hyperparathyroidism occurs in 20-30% of MEN2A patients, particularly with codon 634 mutations, and does not occur in MEN2B 1, 2

For progressive or symptomatic metastatic MTC that cannot be cured surgically, cabozantinib and vandetinib are FDA-approved tyrosine kinase inhibitors for adults with metastatic MTC 1
Neither drug has been demonstrated to impact survival, and these agents are reserved for progressive or symptomatic disease, not biochemical disease alone 1