Medullary Thyroid Carcinoma (MTC)

Medullary thyroid carcinoma (MTC) is a malignant neuroendocrine tumor arising from parafollicular C-cells of the thyroid (originating embryologically from neural crest), distinct from differentiated thyroid cancers (papillary, follicular) which arise from follicular epithelial cells. C-cells produce calcitonin, which is the most important tumor marker for MTC. Annual incidence approximately 0.5-1 per 100,000, accounting for 1-3% of thyroid cancers but 13% of thyroid cancer deaths due to relatively aggressive behavior. Two main forms: sporadic (75% — single tumor, no family history), hereditary (25% — multiple bilateral tumors, autosomal dominant inheritance with RET proto-oncogene germline mutations).

Hereditary MTC syndromes: MEN2A (90% of hereditary MTC — MTC + pheochromocytoma 50% + primary hyperparathyroidism 20-30%, RET codons 634, 618, 620, 609, 611), MEN2B (5% — MTC + pheochromocytoma + mucosal neuromas + marfanoid habitus, more aggressive, RET codon 918), familial MTC (FMTC, 5% — MTC only, less aggressive, various RET codons). Genetic counseling and screening of family members critical when hereditary MTC suspected. Sporadic MTC: somatic RET mutations in ~50% (most commonly M918T, also extracellular cysteine mutations), RAS mutations (HRAS, KRAS) in 10-15%, BRAF rare. Pathophysiology: C-cell hyperplasia (precursor lesion in hereditary cases, neoplastic or reactive), progresses through stages to invasive MTC. Stromal amyloid deposition (calcitonin-derived) characteristic, immunohistochemistry positive for calcitonin (>95%), CEA, chromogranin A, synaptophysin, TTF-1.

Clinical presentation and diagnosis: thyroid nodule (often as solitary mass, usually upper-mid third of thyroid lobe), cervical lymphadenopathy (40-70% at diagnosis — drains to central, then lateral compartments), hoarseness, dysphagia with locally advanced. Distant metastases sites: liver, lung, bones, less commonly brain — present in 10-20% at diagnosis. Paraneoplastic syndromes: secretory diarrhea (calcitonin, CGRP, serotonin, prostaglandins — sometimes severe with hepatic metastases), Cushing's syndrome (ectopic ACTH, occasional). Diagnosis by fine needle aspiration with cytology (may be challenging, calcitonin staining helpful), serum calcitonin (>100 pg/mL highly suspicious, >500 pg/mL strongly suggestive of MTC, basal levels correlate with tumor burden), serum CEA, calcium and parathyroid hormone (rule out hyperparathyroidism in MEN2A), plasma metanephrines or urinary metanephrines (rule out pheochromocytoma BEFORE thyroid surgery — life-threatening if missed), genetic testing for RET germline mutations (essential for all MTC patients), neck ultrasound, neck/chest CT, liver MRI, bone scan, PET-CT for advanced disease assessment. Treatment: total thyroidectomy with central neck dissection (compartment 6) is standard for all MTC; lateral neck dissection (compartments 2-5) ipsilateral or bilateral if positive lymph nodes or calcitonin >200 pg/mL preop; pheochromocytoma must be excluded and treated first if present (alpha-blockade then surgery). Hereditary MTC: prophylactic thyroidectomy in childhood for MEN2B (within first year), MEN2A (around 5 years), FMTC (5-10 years). Postoperative monitoring: calcitonin every 6 months, CEA, calcium replacement if needed. Persistent/recurrent disease: re-operation if localized, external beam radiotherapy for selected, systemic therapy for metastatic — selpercatinib and pralsetinib (selective RET inhibitors — FDA-approved 2020-2021, dramatic responses in RET-altered MTC), vandetanib and cabozantinib (multikinase inhibitors, FDA-approved before selective inhibitors), local therapies (hepatic artery embolization, RFA). Five-year survival: stage I 100%, stage II 93%, stage III 71%, stage IV 21%.