What is the recommended workup to exclude medullary thyroid carcinoma?

How to Rule Out Medullary Thyroid Carcinoma

Measure serum calcitonin when medullary thyroid carcinoma (MTC) is suspected—it is the most sensitive and specific tumor marker for MTC, far superior to fine-needle aspiration alone, which correctly identifies MTC in only about half of cases. 1, 2

Initial Diagnostic Workup

Serum Biomarkers (Essential First Step)

• Measure basal serum calcitonin as the primary screening test when MTC is suspected, with levels >150 pg/mL warranting immediate screening for distant metastases 3, 1
• Measure carcinoembryonic antigen (CEA) as an additional tumor marker, which helps with prognosis and monitoring 3, 1
• Calcitonin levels >400 pg/mL indicate the need for comprehensive staging imaging including chest CT and liver imaging 1
• Note that stimulation testing with pentagastrin or calcium is no longer routinely recommended in the United States due to pentagastrin unavailability, though calcium stimulation may be considered in borderline cases 3, 4

Imaging Studies

• Perform thyroid and central neck ultrasound in all patients with suspected MTC 3, 1
• Look for suspicious features including central hypervascularity, microcalcifications, irregular borders, and cervical lymphadenopathy 1
• For calcitonin >400 pg/mL or documented lymph node involvement, obtain contrast-enhanced chest CT and three-phase contrast-enhanced liver CT or MRI 3, 1

Fine-Needle Aspiration Limitations

• FNA has suboptimal sensitivity for MTC (12.5-88.2%, with meta-analysis showing 56.5% overall sensitivity), making it unreliable as the sole diagnostic test 5, 2
• MTC is called "the great mimicker" because it can resemble various other tumors cytologically, leading to frequent misdiagnosis 5
• If FNA is performed and MTC is suspected but not confirmed, measure calcitonin in the FNA washout fluid—this significantly improves diagnostic accuracy 2

Genetic Testing (Mandatory for All Confirmed or Suspected MTC)

• All patients with confirmed or suspected MTC must undergo DNA analysis for RET proto-oncogene mutations to distinguish sporadic from hereditary forms 3, 1, 6
• Approximately 25% of MTC cases are hereditary, associated with Multiple Endocrine Neoplasia (MEN) type 2A, MEN 2B, or familial MTC 3, 6, 7
• Even patients with apparently sporadic MTC should be tested, as approximately 6% carry germline RET mutations, allowing identification of previously undiagnosed familial cases 3

Screening for Associated Endocrinopathies (Critical in Hereditary Forms)

For MEN 2A and MEN 2B

• Screen for pheochromocytoma with plasma metanephrines and normetanephrines OR 24-hour urine collection for metanephrines 3, 1
• Pheochromocytoma must be diagnosed and treated BEFORE any thyroid surgery to avoid hypertensive crisis 3
• Measure serum calcium and intact parathyroid hormone to screen for hyperparathyroidism (MEN 2A only) 3

Ongoing Surveillance

• Annual screening for pheochromocytoma and hyperparathyroidism should continue in patients with MEN 2A and 2B 3
• For certain lower-risk RET mutations (codons 768,790,804,891), less frequent screening may be appropriate 3

Clinical Context That Raises Suspicion for MTC

• Age <15 years or male gender increases baseline risk 1
• Family history of MTC, MEN 2A, or MEN 2B 1
• Thyroid nodule typically located in the upper portion of thyroid lobes 1
• Symptoms of diarrhea, Cushing's syndrome, or facial flushing due to hormone secretion 1
• Very firm nodules, rapidly growing nodules, or nodules fixed to adjacent structures 1

Common Diagnostic Pitfalls to Avoid

• Do NOT rely on FNA cytology alone—calcitonin measurement is far more sensitive and should be obtained when MTC is in the differential 1, 5, 2
• Do NOT proceed to thyroid surgery without screening for pheochromocytoma in patients with confirmed or suspected hereditary MTC—this can be fatal 3
• Do NOT assume MTC is sporadic without genetic testing—failure to identify hereditary forms means missing associated endocrinopathies and failing to screen at-risk family members 3, 6
• Do NOT dismiss intermediate calcitonin values—these require careful interpretation and may warrant calcium stimulation testing or close surveillance 4

Algorithmic Approach Summary

1. Suspect MTC based on clinical features, family history, or thyroid nodule characteristics
2. Measure basal serum calcitonin and CEA immediately
3. Perform neck ultrasound to assess primary tumor and lymph nodes
4. If calcitonin elevated:
   • Order RET genetic testing
   • Screen for pheochromocytoma and hyperparathyroidism
   • Obtain staging imaging if calcitonin >150-400 pg/mL
5. FNA may be performed but should not delay calcitonin measurement; consider measuring calcitonin in FNA washout fluid if cytology is indeterminate 2