What are the components and management of Multiple Endocrine Neoplasia type 2 (MEN2)?

Multiple Endocrine Neoplasia Type 2 (MEN2): Components and Management

Multiple Endocrine Neoplasia Type 2 (MEN2) is characterized by a triad of medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT), with MTC being the most penetrant component and the primary cause of mortality. 1, 2

MEN2 Subtypes and Clinical Features

MEN2A (91% of cases)

• Classic triad:

  • Medullary thyroid carcinoma (MTC): >95% lifetime risk
  • Pheochromocytoma (PHEO): 50% risk
  • Primary hyperparathyroidism (PHPT): 20-30% risk in high-risk alleles 1

• Variants:

  • Classical MEN2A
  • MEN2A with cutaneous lichen amyloidosis (CLA)
  • MEN2A with Hirschsprung disease (HD)
  • Familial MTC (now considered a variant of MEN2A with decreased penetrance for PHEO and PHPT) 3, 4

MEN2B (9% of cases)

• Components:
  • Medullary thyroid carcinoma (100% risk, more aggressive, often presents in infancy)
  • Pheochromocytoma (50% risk)
  • No hyperparathyroidism
  • Distinctive features: mucosal neuromas, intestinal ganglioneuromatosis, marfanoid habitus, alacrima, constipation 1, 2
  • Approximately 50% of cases occur de novo 1

Genetics and Inheritance

• Inheritance pattern: Autosomal dominant 1, 4
• Genetic cause: Activating germline mutations in the RET proto-oncogene (10q11.21) 1, 3
• Genotype-phenotype correlation:
  • Specific mutations predict disease aggressiveness and timing of onset
  • MEN2B: Primarily associated with M918T mutation in exon 16 (highest risk)
  • MEN2A: Most commonly mutations in exons 10 and 11 (95% of cases) 1, 2

Diagnosis and Screening

• Genetic testing: Recommended for all patients with MTC and first-degree relatives of MEN2 patients 1, 2
• Screening protocols:
  • Annual screening for pheochromocytoma with plasma/urine metanephrines starting at age 8 2
  • Serum calcium and PTH monitoring for hyperparathyroidism in MEN2A 2
  • Calcitonin and CEA monitoring for MTC surveillance 2

Management Approach

1. Medullary Thyroid Carcinoma

• Prophylactic thyroidectomy based on RET mutation risk level:

  • Highest risk (Level D): Total thyroidectomy during first year of life
  • High risk (Level B): Total thyroidectomy by age 5
  • Moderate risk (Level A): Annual monitoring with thyroidectomy when indicated 2

• 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, 2

2. Pheochromocytoma Management

• Critical: Must be identified and treated before thyroid surgery to prevent potentially fatal hypertensive crisis 1, 2
• Preoperative preparation: α-adrenergic blockade (phenoxybenzamine) or α-methyltyrosine 1
• Surgical approach: Typically laparoscopic adrenalectomy 1
• Post-removal care: Forced hydration and continued α-blockade to prevent hypotension 1

3. Hyperparathyroidism Management (MEN2A only)

• Subtotal or total parathyroidectomy with parathyroid cryopreservation 2, 5

4. Advanced/Metastatic MTC

• Molecular testing to guide therapy selection
• RET-specific inhibitors (selpercatinib, pralsetinib) for RET-mutant MTC
• Alternative targeted therapies: vandetanib and cabozantinib
• Palliative procedures for symptomatic metastases 2

Follow-up and Surveillance

• Post-thyroidectomy:

  • Serum calcitonin and CEA at 2-3 months
  • Additional imaging if calcitonin >150 pg/mL or elevated CEA
  • Levothyroxine therapy to maintain TSH in normal range (not suppressed) 2

• Lifelong surveillance:

  • Annual screening for pheochromocytoma
  • Serum calcium and PTH monitoring for hyperparathyroidism in MEN2A 2

Prognostic Factors

• Age at diagnosis (<40 years has better prognosis)
• Tumor stage (AJCC staging)
• RET mutation status
• Postoperative calcitonin levels 2
• Surgical cure rates for MTC significantly higher in presymptomatic carriers (89%) compared to symptomatic patients (25%) 2

Common Pitfalls to Avoid

1. Failure to screen for pheochromocytoma before thyroid surgery - can lead to fatal hypertensive crisis 1, 2
2. Delayed diagnosis in MEN2B - early diagnosis and treatment within first year of life is critical for improved outcomes 1
3. Inadequate thyroid surgery - total thyroidectomy with appropriate neck dissection is required for optimal outcomes 1, 2
4. Overlooking family screening - all first-degree relatives should undergo genetic testing 1, 2
5. Inappropriate TSH suppression - unlike differentiated thyroid cancer, TSH suppression is not indicated as C-cells lack TSH receptors 1

By following these evidence-based guidelines, mortality and morbidity from MEN2 can be significantly reduced, particularly through early identification and prophylactic surgery for at-risk individuals.