Thyroid Cancer — Modern Diagnosis, Risk Stratification, and Treatment

Thyroid cancer comprises four major histologic subtypes with distinct biology: papillary thyroid carcinoma (PTC, 80-85%), follicular thyroid carcinoma (FTC, 10-15%), medullary thyroid carcinoma (MTC, 3-5% from parafollicular C cells), and anaplastic thyroid carcinoma (ATC, 1-2% with extreme aggressiveness). Differentiated thyroid cancer (DTC) encompasses PTC and FTC, generally maintaining iodine-concentrating ability and TSH responsiveness.

Molecular drivers vary by subtype: PTC harbors BRAF V600E mutations (60%), RET fusions (10-20%), or NTRK fusions in pediatric/young adult cases. FTC features RAS mutations and PAX8-PPARγ fusions. MTC shows germline RET mutations in MEN2A/2B/familial MTC (25%) or somatic RET M918T in sporadic disease (50%). ATC arises from dedifferentiation, often acquiring TP53 and TERT promoter mutations on a background of pre-existing BRAF or RAS-mutated DTC.

Diagnostic evaluation begins with thyroid ultrasound (TI-RADS classification) and fine-needle aspiration biopsy of suspicious nodules with Bethesda System cytopathology. Indeterminate nodules (Bethesda III-IV) increasingly undergo molecular testing (Afirma GSC, ThyroSeq) to refine surgical decision-making. Treatment intensity is risk-stratified: low-risk PTC may receive lobectomy alone, while high-risk DTC undergoes total thyroidectomy with selective radioactive iodine. MTC requires total thyroidectomy with central compartment dissection. ATC demands urgent multimodal therapy with surgery, radiation, and BRAF-targeted or systemic therapy.