What are the symptoms and treatment options for Medullary Thyroid Cancer (MTC)?

Symptoms and Treatment of Medullary Thyroid Cancer (MTC)

Medullary thyroid cancer presents with elevated calcitonin levels, neck mass, diarrhea, and flushing, and requires total thyroidectomy with lymph node dissection as primary treatment, with vandetanib approved for advanced disease. 1

Clinical Presentation and Symptoms

Medullary thyroid cancer (MTC) is a rare form of thyroid cancer, accounting for 5-8% of all thyroid malignancies. It arises from the parafollicular calcitonin-producing C cells of the thyroid gland 1, 2. Patients with MTC typically present with:

• Thyroid nodule or neck mass - Often the first clinical manifestation
• Cervical lymphadenopathy - Present in over 50% of cases at diagnosis
• Elevated serum calcitonin levels - A highly specific marker for MTC
• Diarrhea - Due to hypersecretion of calcitonin and other peptides
• Facial flushing - Related to hormone production by tumor cells
• Symptoms of metastatic disease - When spread to liver, lungs, or bones has occurred

Diagnostic Workup

When MTC is suspected, the following diagnostic approach is recommended:

1. Biochemical evaluation:

   • Basal serum calcitonin - Key diagnostic marker
   • Carcinoembryonic antigen (CEA) - Additional tumor marker
   • Calcium levels - To rule out hyperparathyroidism in hereditary cases
   • Plasma metanephrines/normetanephrines - To rule out pheochromocytoma in hereditary cases 1

2. Imaging studies:

   • Neck ultrasound - First-line imaging for all patients
   • Additional imaging for patients with calcitonin >400 pg/ml or documented lymph node metastases:
     • Chest CT
     • Neck CT
     • Three-phase contrast-enhanced liver CT/MRI 1

3. Genetic testing:

   • RET proto-oncogene mutation analysis - To identify hereditary cases (25% of MTC cases) 3, 2

Treatment Algorithm

1. Primary Treatment - Surgery

For patients without evidence of lymph node metastases:

• Total thyroidectomy with bilateral prophylactic central lymph node dissection 1

For patients with positive preoperative imaging:

• Total thyroidectomy with central lymph node dissection plus lateral neck dissection (levels IIA, III, IV, V) 1

For patients with distant metastatic disease:

• Consider less aggressive neck surgery to preserve speech, swallowing, and parathyroid function while maintaining locoregional disease control 1

2. Post-Surgical Management

• Thyroid hormone replacement: Levothyroxine to maintain serum TSH within normal range (not suppressive as in differentiated thyroid cancer) 1

• Surveillance:

  • Serum calcitonin and CEA measurements every 6-12 months
  • If post-surgery calcitonin is undetectable: Continue monitoring every 6 months for 2-3 years, then annually 1
  • If calcitonin <150 pg/ml: Neck ultrasound
  • If calcitonin >150 pg/ml: Screen for distant metastases 1

3. Management of Recurrent or Persistent Disease

For Locoregional Disease:

• Surgical resection when feasible 1
• Consider radiotherapy if surgery is incomplete or symptomatic disease is unresectable 1

For Distant Metastases:

• Symptomatic disease:

  • FDA-approved targeted therapy: Vandetanib for unresectable locally advanced or metastatic disease 4
  • Consider palliative resection or ablation (radiofrequency, embolization) 1
  • Consider bisphosphonate therapy for bone metastases 1

• Asymptomatic disease:

  • Observation or
  • Consider resection/ablation if progressive disease 1

Advanced Treatment Options

Targeted Therapy

• Vandetanib (Caprelsa):

  • FDA-approved for symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease
  • Recommended dose: 300 mg orally once daily
  • Mechanism: Multikinase inhibitor targeting RET, VEGFR, and EGFR
  • Major side effect: QT prolongation - requires careful monitoring 4

• Other targeted therapies:

  • Cabozantinib - Another FDA-approved option
  • Selective RET inhibitors (selpercatinib, pralsetinib) - Newer options for RET-mutated tumors 5

Special Considerations

Hereditary MTC

• Part of Multiple Endocrine Neoplasia (MEN) type 2A or 2B, or Familial MTC
• Requires screening of family members for RET proto-oncogene mutations
• Prophylactic thyroidectomy recommended for mutation carriers at different ages based on specific mutation risk 2

Prognostic Factors

Poor prognostic factors include:

• Reduced calcitonin doubling time
• Advanced age at diagnosis
• Extensive primary tumor
• Nodal disease
• Distant metastases 1

Treatment Pitfalls to Avoid

1. Delaying surgery in patients with confirmed MTC - Surgery is the only potentially curative treatment

2. Inadequate lymph node dissection - Central compartment dissection is essential even in clinically node-negative patients

3. Failure to screen for pheochromocytoma in hereditary cases - Can lead to life-threatening complications during surgery

4. Starting vandetanib without QT interval assessment - Can lead to fatal arrhythmias; contraindicated in patients with QTcF >450 ms 4

5. Overlooking family screening in hereditary cases - Early detection through genetic testing can lead to curative prophylactic surgery