Should we screen for medullary thyroid carcinoma in asymptomatic individuals without risk factors, and what is the recommended screening protocol for patients with a RET mutation or a family history of MEN 2?

Medullary Thyroid Carcinoma Screening

Do not screen asymptomatic individuals without risk factors for medullary thyroid carcinoma, but immediately perform RET proto-oncogene genetic testing in all patients with known RET mutations or family history of MEN 2, followed by prophylactic thyroidectomy at mutation-specific ages.

Screening in the General Population

The NCCN explicitly recommends against routine calcitonin screening in asymptomatic individuals with thyroid nodules. 1 The rationale is compelling:

• Only approximately 3% of patients with nodular thyroid disease have elevated calcitonin on sensitive assays 1
• Of those with elevated calcitonin, only 40% actually have MTC at thyroidectomy 1
• The cost of screening all thyroid nodules to detect rare MTC cases is prohibitive 1
• Pentagastrin stimulation testing for confirmation is no longer available in the United States 1
• False-positive results lead to unnecessary thyroidectomies in patients with benign disease 1

Sporadic MTC is typically discovered incidentally after fine-needle aspiration of a solitary thyroid nodule, not through systematic screening programs. 2

Mandatory Screening Protocol for High-Risk Individuals

Who Requires Genetic Testing

All first-degree relatives of patients with confirmed hereditary MTC, MEN 2A, or MEN 2B must undergo RET proto-oncogene mutation testing immediately. 2 This is non-negotiable because:

• RET mutations are found in ≥95% of MEN 2A kindreds and 88% of familial MTC families 1
• Approximately 6% of patients with apparently sporadic MTC harbor germline RET mutations, revealing previously unrecognized familial cases 1, 2
• Every patient with newly diagnosed clinically apparent sporadic MTC should undergo RET mutation testing 1, 2

Prophylactic Thyroidectomy Timing Based on RET Mutation

The timing of prophylactic total thyroidectomy is dictated by the specific RET mutation and follows a strict age-based algorithm 1, 2:

MEN 2B (Highest Risk: codons 918,883)

• Perform total thyroidectomy within the first year of life, ideally before age 1 2
• These mutations carry the most aggressive phenotype with earliest MTC onset 1, 2

MEN 2A High-Risk Mutations (codon 634)

• Perform total thyroidectomy by age 5 years, or immediately when mutation is identified if diagnosed later 1, 2
• If elevated calcitonin, CEA, or ultrasound abnormalities are present, add therapeutic bilateral central neck dissection (level VI) 1

MEN 2A Lower-Risk Mutations (codons 609,611,618,620,630,768,790,791,804,891)

• Perform total thyroidectomy by age 5 years as the standard approach 1, 2
• Surgery may be delayed only if ALL of the following criteria are met: 1, 2
  • Annual basal calcitonin remains normal
  • Annual neck ultrasound is unremarkable
  • No history of aggressive MTC in the family
  • Family is in agreement with delayed approach
• This delayed approach applies particularly to codons 768,790,791,804, and 891, which have later MTC onset 1, 2

Critical Pre-Operative Screening

Before any thyroid surgery in RET mutation carriers, you must complete this mandatory workup to prevent fatal complications: 1, 2

1. Screen for pheochromocytoma (MEN 2A and 2B):

   • Measure plasma metanephrines and normetanephrines OR 24-hour urine metanephrines 2
   • Pheochromocytoma must be diagnosed and treated before thyroidectomy to avoid intra-operative hypertensive crisis 1, 2
   • This is a life-threatening pitfall if missed

2. Screen for hyperparathyroidism (MEN 2A only):

   • Measure serum calcium and intact parathyroid hormone 1, 2

3. Measure baseline tumor markers:

   • Basal serum calcitonin 1, 2
   • Carcinoembryonic antigen (CEA) 1, 2

4. Perform neck ultrasound to evaluate thyroid and nodal status 1, 2

Post-Operative Surveillance Protocol

For all RET mutation carriers after prophylactic or therapeutic thyroidectomy: 1, 2

• Measure serum calcitonin and CEA every 6-12 months 1, 2
• Continue lifelong annual screening for pheochromocytoma (MEN 2A and 2B) 1, 2
• Continue lifelong annual screening for hyperparathyroidism (MEN 2A) 1, 2
• For lower-risk mutations (codons 768,790,804,891), less frequent surveillance may be appropriate 1, 2

Why Calcitonin Screening is Obsolete in Hereditary Cases

The traditional approach of stimulating calcitonin secretion with pentagastrin or calcium infusion is no longer recommended because: 1, 2

• Elevated calcitonin is neither specific nor adequately sensitive for MTC 1
• Pentagastrin is no longer available in the United States 1
• RET genetic testing identifies disease carriers long before clinical symptoms or biochemical abnormalities appear 1, 2
• Genetic testing provides superior identification of carriers compared to calcitonin-based screening 2, 3

Evidence Supporting Early Intervention

The Washington University experience demonstrates the critical importance of prophylactic thyroidectomy based on genetic testing rather than waiting for biochemical evidence: 4

• Among 14 children with MEN 2A who underwent prophylactic thyroidectomy based on genetic testing, none had biochemical or clinical evidence of MTC after 3 years of follow-up 4
• In contrast, among 16 children with MEN 2A who had thyroidectomy based on elevated calcitonin, 25% had persistent or recurrent MTC after mean follow-up of 7.6 years 4
• Among 11 patients with MEN 2B who underwent thyroidectomy during childhood based on clinical/biochemical diagnosis, 70% had recurrent MTC after mean follow-up of 11 years 4

Common Pitfalls to Avoid

1. Never proceed to thyroidectomy without first confirming absence of pheochromocytoma in hereditary or RET-positive cases 1, 2 — this can cause fatal hypertensive crisis

2. Do not rely solely on calcitonin screening in known RET mutation carriers 2, 3 — genetic testing determines the timing of prophylactic surgery, not calcitonin levels

3. Do not assume sporadic MTC is truly sporadic without RET testing 1, 2 — approximately 6% harbor germline mutations

4. Refer very young children to surgeons and multidisciplinary teams experienced in pediatric thyroid surgery 1 — the risks of thyroidectomy in young children require specialized expertise

5. Do not perform routine calcitonin screening in all thyroid nodules 2, 3 — it is not cost-effective and leads to unnecessary thyroidectomies for false-positive results