What is the recommended management for Multiple Endocrine Neoplasia Type II (MENII)?

Management of Multiple Endocrine Neoplasia Type II (MEN2)

The cornerstone of MEN2 management is risk-stratified prophylactic total thyroidectomy based on the specific RET proto-oncogene mutation, with timing determined by mutation risk level, combined with lifelong surveillance for pheochromocytoma and hyperparathyroidism (in MEN2A). 1, 2

Genetic Testing and Initial Diagnosis

• All patients with medullary thyroid carcinoma (MTC), even those appearing sporadic, require RET genetic testing since approximately 6% harbor germline mutations 2
• Testing should be performed in all first-degree relatives of confirmed MEN2 patients, as 25% of all MTC is familial 3
• The de novo mutation rate is 9% in MEN2A and up to 50% in MEN2B, making genetic testing essential even without family history 2, 4

Risk Stratification and Timing of Prophylactic Thyroidectomy

The specific RET codon mutation dictates surgical timing based on three risk categories:

Highest Risk (Grade 1) Mutations

• Codons 883,918,922 (primarily MEN2B): Total thyroidectomy within the first year of life 3, 2
• Over 95% of MEN2B patients have codon 918 mutations, associated with 100% lifetime MTC risk and the most aggressive disease 3, 4

High Risk (Grade 2) Mutations

• Codons 609,611,618,620,630,634: Total thyroidectomy before age 5-6 years 3, 2
• Codon 634 mutations are the most common in MEN2A and carry highest risk for pheochromocytoma and hyperparathyroidism 3, 4
• MTC has been documented as early as age 4-5 years in these patients 5, 6

Moderate Risk (Grade 3) Mutations

• Codons 768,790,791,804,891: Surgery may be deferred beyond age 5 if annual basal calcitonin and neck ultrasound remain normal, family history shows no aggressive MTC, and family agrees 3
• These mutations have lower lethality and later MTC onset 3

Preoperative Evaluation Protocol

Critical: Pheochromocytoma must be excluded and treated BEFORE any thyroid surgery to prevent hypertensive crisis. 3, 2

Mandatory Preoperative Screening

• Pheochromocytoma screening: Plasma or 24-hour urine metanephrines and catecholamines 3
• Hyperparathyroidism screening (MEN2A only): Serum calcium and intact PTH 3
• Neck ultrasound: Identify thyroid nodules and lymph node metastases 3, 2
• Serum calcitonin and CEA: Baseline tumor markers 3
• Vocal cord assessment: Document preoperative function 2

If Pheochromocytoma Detected

• Laparoscopic adrenalectomy with α-adrenergic blockade (phenoxybenzamine) or α-methyltyrosine BEFORE thyroidectomy 3
• Forced hydration and α-blockade prevent hypotension after tumor removal 3
• β-adrenergic blockade may be added after α-blockade for tachyarrhythmias 3

Surgical Management

Prophylactic Surgery (Asymptomatic Carriers)

• Total thyroidectomy alone if basal calcitonin is normal (<10 pg/mL) 3, 5
• Surgery should be performed by surgeons experienced in pediatric thyroid surgery given complication risks in young children 3
• Surgical cure rate is 89% in asymptomatic converters versus only 25% in symptomatic patients 3, 2

Therapeutic Surgery (Elevated Calcitonin or Palpable Disease)

• Total thyroidectomy with bilateral central neck dissection (level VI) for tumors ≥1 cm or bilateral disease 3
• Consider ipsilateral or bilateral modified neck dissection (levels II-V) if central nodes positive or tumor >1 cm 3
• Consider more extensive lymph node dissection if high-volume central disease present 3

Common pitfall: Failing to perform adequate central neck dissection when calcitonin is elevated preoperatively leads to persistent disease. Calcitonin levels >20 pg/mL predict ipsilateral nodal metastases; >50 pg/mL predict contralateral central nodes; >200 pg/mL predict contralateral lateral nodes; >500 pg/mL suggest distant metastases. 3

Postoperative Management

Immediate Postoperative Care

• Levothyroxine replacement to maintain TSH in normal range (NOT suppressed, as C-cells lack TSH receptors) 3
• Measure serum calcitonin and CEA at 60-90 days postoperatively 3

Biochemical Cure Definition

• Postoperative basal calcitonin <10 pg/mL indicates biochemical cure with 97.7% 10-year survival 3
• However, 3% with normal postoperative calcitonin experience biochemical recurrence within 7.5 years 3

Surveillance for Persistent/Recurrent Disease

• If calcitonin remains detectable or elevated postoperatively, perform contrast-enhanced CT or MRI of neck, chest, abdomen with liver protocol 3
• Consider bone scan, FDG-PET, and MRI of axial skeleton if calcitonin very elevated 3
• Serial calcitonin and CEA measurements every 6-12 months 3

Calcitonin and CEA Doubling Times

Doubling times are the best available predictors of tumor behavior and survival. 3

• Calculate from at least four consecutive measurements over 2 years using same laboratory and assay 3
• Calcitonin doubling time >6 months: 5-year survival 92%, 10-year survival 37% 3
• Calcitonin doubling time <6 months: 5-year survival 25%, 10-year survival 8% 3
• Rapidly increasing CEA with stable calcitonin predicts worse prognosis and poorly differentiated disease 3

Lifelong Surveillance for Other MEN2 Manifestations

Pheochromocytoma Surveillance

• Occurs in 50% of MEN2A and MEN2B patients 2, 4
• Annual screening with plasma or urine metanephrines starting at age 8 years (or earlier if symptomatic) 3, 1
• Codon 634 mutations carry highest pheochromocytoma risk 4

Hyperparathyroidism Surveillance (MEN2A Only)

• Occurs in 20-30% of MEN2A patients, particularly codon 634 mutations 2, 4
• Does NOT occur in MEN2B 4
• Annual screening with serum calcium and intact PTH 3, 1
• During primary thyroid surgery, if hyperparathyroidism present, perform subtotal parathyroidectomy or total parathyroidectomy with autotransplantation 3

Management of Advanced/Metastatic Disease

Locoregional Recurrence

• Surgical resection ± postoperative external beam radiotherapy if resectable 3
• Consider radiotherapy alone if symptomatic progressive disease or unresectable 3

Distant Metastatic Disease

• Cabozantinib or vandetanib (FDA-approved tyrosine kinase inhibitors) for progressive or symptomatic metastatic MTC in adults 2
• Reserve for progressive or symptomatic disease only, NOT for biochemical disease alone 2
• Neither drug has demonstrated survival benefit 2
• Consider clinical trial (preferred), palliative resection, radiofrequency ablation, or embolization 3

Multidisciplinary Care Coordination

• Treatment should be provided at specialized referral centers with multidisciplinary teams including endocrinologists, surgeons, radiologists, nuclear medicine specialists, and clinical nurse specialists 1
• Consider "virtual outpatient department" approach coordinating multiple specialist appointments on same day 1

Key prognostic factors: Age <40 years at diagnosis (5-year survival 95% vs 65% for age >40), exon 16 mutations (more aggressive), and postoperative calcitonin doubling time are the strongest predictors of outcome. 3