What management approach is recommended for individuals with an inherent predisposition to thyroid malignancy?

Management of Individuals with Inherited Predisposition to Thyroid Malignancy

For individuals with germline pathogenic variants predisposing to thyroid cancer, risk-reducing thyroidectomy should be offered based on specific genetic mutation risk stratification, with timing determined by the variant's aggressiveness rather than waiting for clinical disease to develop. 1

Genetic Testing and Referral Indications

Refer patients for cancer predisposition assessment when they meet specific criteria 1:

• Medullary thyroid cancer (MTC) at any age (25% are familial) 1
• Nonmedullary thyroid cancer with one additional Carney complex criterion 1
• Nonmedullary thyroid cancer with two or more Cowden syndrome criteria 1
• Papillary thyroid cancer (cribriform-morular variant) 1
• Family history of MEN2-related endocrine abnormalities 1

Risk-Stratified Surgical Management by Syndrome

Multiple Endocrine Neoplasia Type 2 (MEN2)

MEN2 carries a 95% lifetime risk of MTC in MEN2A and 100% in MEN2B 1. Risk-reducing thyroidectomy timing is determined by the specific RET mutation 1:

Highest Risk (Level D)

• RET codon 918 (p.Met918Thr): Total thyroidectomy within the first year of life 1
• RET codon 883 (p.A883F): Total thyroidectomy within the first year of life 1
• Compound heterozygous variants (V804M + E805K, V804M + Y806C, V804M + S904C): Total thyroidectomy within the first year of life 1

High Risk (Level B)

• RET codon 634 mutations: Total thyroidectomy before age 5 years 1
• RET codons 609,611,618,620,630: Total thyroidectomy before age 5 years 1

Moderate Risk (Level A)

• RET codons 768,790,791,804,891: Surgery may be delayed beyond 5 years with annual surveillance 1
• Surveillance includes annual basal calcitonin testing and thyroid ultrasound 1
• Total thyroidectomy performed if calcitonin becomes elevated or ultrasound shows abnormalities 1

Cowden Syndrome (PTEN Mutations)

PTEN germline pathogenic variants confer a 35% lifetime risk of thyroid cancer 1. Management includes:

• Annual thyroid ultrasound surveillance beginning at diagnosis 1
• Thyroidectomy considered when nodules develop meeting surgical criteria 1
• No specific age-based prophylactic thyroidectomy recommendation 1

Familial Adenomatous Polyposis (FAP)

Papillary thyroid cancer (cribriform-morular variant) is associated with FAP 1, 2. Management includes:

• Thyroid surveillance with ultrasound as part of FAP screening protocol 1
• Surgical intervention when thyroid nodules are detected 1

Carney Complex

Nonmedullary thyroid cancer occurs in Carney complex 1, 2. Management includes:

• Regular thyroid surveillance with ultrasound 1
• Thyroidectomy when clinically indicated nodules develop 1

Surgical Approach

Preoperative Evaluation for MEN2

Before any thyroid surgery in suspected or confirmed MEN2, exclude pheochromocytoma 1:

• Measure plasma metanephrines and normetanephrines or 24-hour urine collection 1
• Screen for hyperparathyroidism with serum calcium 1
• Pheochromocytomas must be removed first with α-adrenergic blockade (phenoxybenzamine) to avoid hypertensive crisis 1

Surgical Technique

For prophylactic surgery in germline mutation carriers 1:

• Total thyroidectomy is mandatory (C cells are bilateral) 1
• Bilateral central neck dissection (level VI) for highest and high-risk RET mutations 1
• Referral to surgeons experienced in pediatric thyroid surgery for young children 1
• Intraoperative confirmation of complete thyroid tissue removal 1

Postoperative Management

• Levothyroxine replacement to maintain TSH in normal range (not suppressed, as C cells lack TSH receptors) 1
• Measure serum calcitonin at 2-3 months postoperatively 1
• If calcitonin undetectable: repeat every 6 months for 2-3 years, then annually 1
• If calcitonin detectable: indicates residual disease requiring further evaluation 1

Surveillance as Alternative to Surgery

For moderate-risk RET mutations only (codons 768,790,791,804,891), surveillance may be acceptable 1:

• Annual basal serum calcitonin measurement 1
• Annual thyroid ultrasound 1
• Requires family agreement and no family history of aggressive MTC 1
• Proceed to surgery if calcitonin elevates or ultrasound abnormalities develop 1

This approach is NOT appropriate for highest-risk or high-risk RET mutations where prophylactic surgery is mandatory 1.

Common Pitfalls to Avoid

• Never delay surgery in highest-risk RET mutations (codon 918,883): MTC typically presents with metastatic disease if diagnosis occurs after age 5 years 1
• Always exclude pheochromocytoma before thyroid surgery in MEN2 to prevent intraoperative hypertensive crisis 1
• Do not suppress TSH postoperatively in MTC patients, as this provides no benefit 1
• Recognize that 50% of MEN2B cases are de novo mutations: absence of family history does not exclude diagnosis 1
• Avoid partial thyroidectomy or lobectomy in hereditary MTC, as disease is bilateral 1