What is the management approach for multiple endocrine neoplasia type 2 (MEN2)?

Management of Multiple Endocrine Neoplasia Type 2 (MEN2)

The cornerstone of MEN2 management is 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. 1, 2

Genetic Testing and Diagnosis

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. 1 This allows identification of previously undiagnosed kindreds and enables cascade testing of at-risk family members. 3, 4

• 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. 1
• Testing should focus initially on exons 10,11,13,14,15, and 16, as these contain the vast majority of disease-causing mutations. 1

Risk Stratification Based on RET Mutation

The specific RET codon mutation dictates the aggressiveness of MTC and timing of prophylactic surgery. 1 Mutations are classified into three risk categories:

Highest Risk (Grade 1)

• Codons 883,918,922 (particularly p.M918T associated with MEN2B)
• Thyroidectomy is mandatory within the first year of life 1
• These mutations are associated with the most aggressive MTC, often presenting with metastatic disease if diagnosis occurs after age 5 years 1
• The p.M918T variant disrupts the tyrosine kinase domain and is the most common somatic mutation in sporadic MTC 1

High Risk (Grade 2)

• Codons 609,611,620,630,634,804,891
• Thyroidectomy should be performed before age 5-6 years 1
• Annual ultrasound and calcitonin screening should begin at age 3 years 1
• Surgery may be performed earlier if calcitonin levels become elevated (>40 pg/mL suggests low risk of metastatic disease) 1
• Codon 634 mutations carry higher risk of pheochromocytoma (50%) and hyperparathyroidism (20-30%) than other mutations 1, 2

Moderate Risk (Grade 3)

• Codons 768,790,791
• Thyroidectomy is performed when calcitonin levels become elevated or C-cell stimulation test becomes abnormal 1
• This approach allows delayed surgery but requires vigilant biochemical monitoring 1

Preoperative Evaluation

Before any thyroid surgery in MEN2, pheochromocytoma must be excluded and treated first to avoid hypertensive crisis during surgery. 1, 4

The preoperative workup includes:

• Biochemical screening: Basal calcitonin and carcinoembryonic antigen (CEA) levels 1
• Pheochromocytoma screening: Plasma or urine metanephrines in all patients with germline RET mutations (MEN2A and MEN2B) 1
• Hyperparathyroidism screening: Serum calcium and intact PTH (MEN2A only) 1
• Neck ultrasound: Essential for identifying regional lymphadenopathy and surgical planning 1
• Cross-sectional imaging: Contrast-enhanced CT or MRI of chest/mediastinum if N1 disease present or calcitonin >400 pg/mL 1
• Vocal cord assessment: Evaluation of vocal cord mobility 1

Surgical Management

Total thyroidectomy is the definitive preventive strategy for MTC in RET mutation carriers. 1, 2

• Surgery should be performed by surgeons experienced in MEN2 to minimize complications and maximize cure rates 1
• The surgical cure rate for MTC is 89% in asymptomatic converters versus only 25% in symptomatic patients presenting with a palpable nodule 1
• Level VI (central compartment) lymph node dissection depends on ability to identify and preserve parathyroid glands, preoperative imaging findings, and calcitonin levels 1
• Metastatic disease is rare if serum calcitonin <40 pg/mL, and neck dissection can often be avoided if cervical adenopathy is not detected 1

Critical pitfall: Physiological calcitonin levels in infancy may be as high as 50 pg/mL with a decreasing trend over the first three years of life, limiting utility of this marker in very young children. 1

Postoperative Surveillance

After prophylactic thyroidectomy, surveillance depends on postoperative calcitonin levels:

• Undetectable calcitonin: Annual calcitonin measurement only 1
• Elevated calcitonin postoperatively: At least stage III disease (T1-4N1M0) is present, requiring extensive localization studies for metastases 1
• If only lymph node metastases in the neck are visualized, reoperation may be considered, though cure rates are low 1

Management of Pheochromocytoma

• Pheochromocytomas occur in approximately 50% of MEN2A and MEN2B patients 2
• Codon 634 mutations carry the highest risk 1, 2
• Pheochromocytoma must be treated before any thyroid surgery 1, 4
• Laparoscopic adrenalectomy is the preferred surgical approach 1
• Screening should begin at age 16 years in mutation carriers 1

Management of Hyperparathyroidism

• Primary hyperparathyroidism occurs in 20-30% of MEN2A patients, particularly with codon 634 mutations 1, 2
• Hyperparathyroidism does not occur in MEN2B 2
• Surgical options include subtotal or total parathyroidectomy with consideration of parathyroid cryopreservation 4

Management of Metastatic MTC

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 1
• These agents are reserved for progressive or symptomatic disease, not biochemical disease alone 1

Critical pitfall: Biopsy of suspicious neck lesions should be avoided in patients with known or suspected MTC due to risk of seeding carcinomatous cells through the biopsy tract. 1

Family Screening and Genetic Counseling

• All first-degree relatives of MEN2 patients should be offered genetic testing and counseling 3, 4
• Early identification of mutation carriers allows preventive interventions that significantly reduce morbidity and mortality 2
• Patient support groups provide valuable assistance with emotional distress, disease information, and ethical/social issues regarding DNA analysis in children 1