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Medullary Thyroid Carcinoma (MTC)

Epidemiology

  • Accounts for ~5% of thyroid malignancies.
  • Female-to-male ratio: 1.5:1.
  • Age of Presentation:
    • Most patients: 50-60 years old.
    • Familial cases: Younger age.

Origin and Cell Type

  • Arises from parafollicular (C) cells of the thyroid.
  • Derived from ultimobranchial bodies.
  • C cells are concentrated superolaterally in thyroid lobes.
  • Function of C cells: Secrete calcitonin (lowers serum calcium; minimal effect in humans).

Genetics

  • Sporadic Cases: Majority (~75%).
  • Inherited Syndromes (~25%):
    • Familial MTC
    • MEN2A
    • MEN2B
  • Common Mutation: Germline mutations in the RET proto-oncogene.
  • Genotype-Phenotype Correlations: Specific mutations lead to particular clinical manifestations.

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Clinical Presentation

  • Neck Mass: Common presenting symptom.
  • Palpable Cervical Lymphadenopathy: 15-20% of cases.
  • Pain or Aching: More frequent in MTC patients.
  • Local Invasion Symptoms:
    • Dysphagia
    • Dyspnea
    • Dysphonia
  • Distant Metastases:
    • Liver
    • Bone (frequently osteoblastic)
    • Lung
  • Secreted Substances:
    • Calcitonin
    • Carcinoembryonic Antigen (CEA)
    • Other Peptides: Calcitonin gene–related peptide, histaminidas, prostaglandins E2/F2α, serotonin.
  • Associated Symptoms in Metastatic Disease:
    • Diarrhea (from increased intestinal motility)
    • Cushing’s Syndrome: 2-4% (due to ectopic ACTH production).

Pathology

  • Tumor Laterality:
    • Sporadic MTC: Unilateral in 80%.
    • Familial MTC: Multicentric, bilateral in up to 90%.
  • C-Cell Hyperplasia: Premalignant lesion in familial cases.
  • Microscopic Features:
    • Sheets of infiltrating neoplastic cells.
    • Separated by collagen and amyloid.
    • Cell Shapes: Polygonal or spindle-shaped.
  • Diagnostic Markers:
    • Amyloid Presence
    • Immunohistochemistry:
      • Calcitonin (common diagnostic marker)
      • CEA
      • Calcitonin Gene–Related Peptide

Diagnosis

  • Clinical Evaluation: History and physical examination.
  • Biochemical Markers:
    • Raised Serum Calcitonin
    • Raised CEA Levels
  • Cytology: Fine-Needle Aspiration Biopsy (FNAB) of thyroid mass.
  • Genetic Screening:
    • All new MTC patients screened for RET point mutations, pheochromocytoma, and HPT.
  • Family History: Crucial as ~25% have familial disease.
  • Tumor Marker Monitoring:
    • Calcitonin: More sensitive.
    • CEA: Better predictor of prognosis.

Treatment

Surgical Management

  • Primary Treatment: Total Thyroidectomy due to:
    • High incidence of multicentricity.
    • Aggressive course.
    • 131I Therapy: Usually ineffective.
  • Neck Surgery:
    • Central Neck Node Dissection: Bilateral prophylactic due to early involvement.
    • Lateral Neck Dissection:
      • Performed if palpable/imaging-detected nodes, symptoms, distant disease, or calcitonin >500 pg/mL.
      • Levels IIA, III, IV, V.
      • Prophylactic Lateral Neck Dissection: Controversial; considered based on calcitonin levels and tumor size (≥1.5 cm).

Management of Associated Conditions

  • Pheochromocytoma: Operated first if present.
  • Primary Hyperparathyroidism (HPT): Treated during thyroidectomy.
    • Parathyroid Glands: Preserve and mark if normocalcemic.
    • Autotransplantation: If normal parathyroid cannot be maintained on a vascular pedicle.

Advanced Disease Treatment

  • Tumor Debulking: For pain, flushing, diarrhea, and reducing recurrence risk.
  • Radiotherapy:
    • Controversial.
    • Considered for resected T4 disease, unresectable residual/recurrent tumors, symptomatic bony metastases.
  • Liver Metastases:
    • Chemoembolization may be helpful.
    • Resection/Percutaneous Ablation: Typically not amenable.
  • Chemotherapy: No effective regimen available.

Targeted Therapies

  • RET Kinase Inhibitors:
    • Multikinase Inhibitors: Sorafenib, sunitinib, lenvatinib, cabozantinib.
    • VEGFR-Only Inhibitors: Axitinib, pazopanib.
    • Vandetanib: Inhibits RET, VEGFR, and EGF receptor.
    • Cabozantinib: Targets c-MET, RET, and VEGFR.
  • FDA and EMA Approved:
    • Vandetanib
    • Cabozantinib
  • Monoclonal Antibody:
    • Labetuzumab (anti-CEA) shows antitumor response in some patients.
  • Clinical Trials: Recommended for recurrent/metastatic disease.

Prophylactic Surgery

  • RET Mutation Carriers:
    • Prophylactic Total Thyroidectomy once mutation confirmed.
    • ATA Guidelines: Stratify mutations into risk levels to determine age for surgery.
      • Moderate-Risk Mutations: Delay thyroidectomy >5 years if appropriate.
      • High-Risk (e.g., MEN2A codon 634): Thyroidectomy before 5 years.
      • Highest-Risk (MEN2B): Thyroidectomy before 1 year.
    • Central Neck Dissection: Avoid if RET-positive and calcitonin-negative with normal ultrasound.

Postoperative Follow-Up and Prognosis

  • Follow-Up Protocol:
    • Annual Measurements:
      • Calcitonin Levels
      • CEA Levels
    • History and Physical Examination
    • Imaging for Recurrence:
      • Ultrasound
      • CT/MRI
      • FDG-PET/CT Scans
  • Prognostic Factors:
    • Disease Stage:
      • 10-Year Survival Rate: ~80% overall.
      • With Lymph Node Involvement: Decreases to 45%.
    • Disease Type:
      • Best: Non-MEN familial MTC.
      • Intermediate: MEN2A.
      • Worst: Sporadic MTC and MEN2B (35% 10-year survival).
  • Prophylactic Surgery Benefits:
    • Improves survival rates.
    • Renders most patients calcitonin-free.