What is a sensitive test for medullary thyroid cancer (MTC)?

Sensitive Tests for Medullary Thyroid Cancer

Serum calcitonin measurement is the most sensitive test for medullary thyroid cancer (MTC), serving as both a diagnostic biomarker and prognostic indicator. 1 When measured with a sensitive immunometric assay, calcitonin provides high diagnostic accuracy for MTC detection and post-treatment surveillance.

Diagnostic Testing Options

Primary Diagnostic Tests

• Serum Calcitonin:

  • Highly sensitive marker produced exclusively by thyroid C-cells
  • Baseline measurements can detect MTC in patients with nodular thyroid disease
  • Approximately 3% of patients with nodular thyroid disease have elevated calcitonin; 40% of these will have MTC at thyroidectomy 1

• Fine Needle Aspiration (FNA) with Calcitonin Immunohistochemistry:

  • FNA is the first-line diagnostic test for thyroid nodules
  • Medullary carcinoma requires additional immunohistochemical staining for calcitonin to confirm diagnosis 1
  • Calcitonin measurement in FNA washout fluid (FNAB-CT) shows exceedingly higher values in MTC compared to other thyroid conditions 2

Genetic Testing

• RET Proto-oncogene Mutation Testing:
  • Gold standard for inherited MTC detection
  • Can identify disease carriers before clinical symptoms appear
  • Should be performed for all patients with newly diagnosed clinically sporadic MTC 1
  • Mutations found in at least 95% of MEN 2A kindreds and 88% of familial MTC 1

Surveillance Testing

• Post-operative Calcitonin Monitoring:

  • Cornerstone of MTC surveillance
  • Undetectable calcitonin (<2 pg/mL) indicates better prognosis than merely normalized levels (2-10 pg/mL)
  • Patients with normalized calcitonin have 25% risk of recurrence vs. 3% in those with undetectable levels 3

• Carcinoembryonic Antigen (CEA):

  • Complements calcitonin in post-operative assessment 1

Interpretation of Calcitonin Results

Diagnostic Considerations

• European guidelines recommend calcitonin measurement as an integral part of thyroid nodule evaluation 1
• NCCN does not recommend routine calcitonin screening for all thyroid nodules due to:
  • Cost considerations
  • Lack of confirmatory pentagastrin stimulation testing in the US
  • Potential for unnecessary thyroidectomies in patients with benign disease 1

False Results

• False Positives:

  • Minimal calcitonin elevations may be false positives
  • Previously confirmed with pentagastrin stimulation testing (unavailable in US) 1

• False Negatives:

  • Rare cases of MTC with undetectable serum calcitonin exist despite tumors showing strong immunohistochemical calcitonin staining 4
  • In such cases, procalcitonin may be elevated and serve as an alternative marker 4

Clinical Algorithm for MTC Detection

1. For patients with thyroid nodules:

   • Perform FNA as first-line diagnostic test
   • Request calcitonin immunohistochemistry if cytology suggests neuroendocrine features
   • Consider measuring serum calcitonin in patients with suspicious FNA results

2. For patients with known or suspected inherited MTC:

   • Perform RET proto-oncogene mutation testing
   • Serum calcitonin measurement for baseline and surveillance

3. For post-operative surveillance:

   • Regular calcitonin and CEA measurements
   • Target undetectable calcitonin levels (<2 pg/mL) for optimal outcomes
   • More frequent monitoring for patients with detectable markers

Important Caveats

• Calcitonin stimulation testing with calcium gluconate (used since pentagastrin became unavailable) may show up to 5-fold increases in non-MTC patients, requiring judicious interpretation 5
• After total thyroidectomy for non-MTC conditions, calcium-stimulated calcitonin increases more than 2-fold might indicate residual MTC 5
• Hürthle cell neoplasms can sometimes mimic MTC cytologically, requiring careful pathological assessment 1
• Approximately 6% of apparently sporadic MTC cases carry germline RET mutations, allowing identification of previously undiagnosed familial cases 1

In conclusion, while serum calcitonin measurement is highly sensitive for MTC detection and monitoring, its interpretation requires consideration of clinical context, potential false results, and complementary testing methods including genetic analysis and immunohistochemistry.