Thyroid Cancer

Contents

  1. Overview of Thyroid Cancer
  2. The Four Types of Thyroid Cancer
  3. Molecular Drivers and Genetics
  4. Multiple Endocrine Neoplasia (MEN2) and Medullary Thyroid Cancer
  5. Diagnosis and Staging
  6. Treatment of Differentiated Thyroid Cancer
  7. Targeted Therapy for Refractory and Advanced Disease
  8. Prognosis and Survivorship
  9. Key Research Papers
  10. Connections

Overview of Thyroid Cancer

Thyroid cancer is the most common endocrine malignancy, with an estimated 43,720 new cases in the U.S. in 2023 (ACS). Incidence has tripled since the 1970s, largely due to incidental detection of small papillary cancers on neck imaging. It predominantly affects women (3:1 female:male ratio). Four main histological types exist: papillary (~80%), follicular (~10–15%), medullary (~3–5%), and anaplastic (<2%). Survival varies dramatically by type, from >95% 10-year survival for papillary to <10% for anaplastic.

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The Four Types of Thyroid Cancer

Papillary thyroid carcinoma (PTC): Derived from follicular cells; grows slowly; spreads to regional lymph nodes but rarely distant metastasis; excellent prognosis (10-year survival ~95%). Characterized by Orphan Annie eye nuclei, psammoma bodies on pathology, and BRAF V600E mutation in ~60% of cases.

Follicular thyroid carcinoma (FTC): Also from follicular cells; distinguished from adenoma only by capsular or vascular invasion; spreads hematogenously to bone and lung; prognosis slightly worse than PTC. RAS mutations and PAX8-PPARG fusions are characteristic.

Medullary thyroid carcinoma (MTC): Derived from C cells (parafollicular cells) that secrete calcitonin; 25% are hereditary, associated with RET proto-oncogene mutations in MEN2A (RET C634) and MEN2B (RET M918T); calcitonin is the tumor marker.

Anaplastic thyroid carcinoma (ATC): Undifferentiated, extremely aggressive; mean survival 3–5 months from diagnosis; often arises from dedifferentiation of PTC or FTC; may harbor BRAF V600E, TP53, TERT mutations.

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Molecular Drivers and Genetics

BRAF V600E: Present in ~60% of PTC; substitution of valine for glutamate at codon 600 constitutively activates the MAPK/ERK pathway; associated with extra-thyroidal extension, lymph node metastasis, and radioiodine refractoriness.

RAS mutations (HRAS, KRAS, NRAS): Common in follicular-variant PTC and FTC.

RET/PTC rearrangements: Common in radiation-associated PTC (e.g., Chernobyl-related cases).

RET point mutations (germline): Causative in hereditary MTC — all patients with MTC should undergo germline RET testing.

TP53 mutations: Found in anaplastic transformation.

TERT promoter mutations: Associated with more aggressive PTC and FTC; poor prognosis marker.

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Multiple Endocrine Neoplasia (MEN2) and Medullary Thyroid Cancer

MEN2 is an autosomal dominant syndrome caused by activating germline RET mutations.

MEN2A (most common): MTC (nearly 100% penetrance) + pheochromocytoma (50%) + hyperparathyroidism (25%).

MEN2B: MTC (earlier onset, more aggressive) + pheochromocytoma + mucosal neuromas + marfanoid habitus; caused by RET M918T mutation.

Familial MTC (FMTC): MTC alone.

Prophylactic total thyroidectomy is recommended for RET mutation carriers; timing depends on codon-specific risk: highest-risk (M918T) by age 6 months, high-risk by age 5 years, moderate-risk by age 5–10 years.

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Diagnosis and Staging

Evaluation of a thyroid nodule: Neck ultrasound is the first-line imaging study (>1 cm nodules with suspicious features warrant fine-needle aspiration biopsy — FNAB). Bethesda classification (I–VI) guides management of FNAB results.

Serum TSH: Low TSH suggests autonomous nodule (rarely malignant); elevated TSH correlates with higher malignancy risk.

Serum calcitonin: Diagnostic for MTC.

Thyroglobulin: Post-thyroidectomy tumor marker for PTC and FTC.

Staging: TNM system (AJCC 8th edition, 2017). Age ≥55 at diagnosis significantly worsens prognosis for differentiated thyroid cancer. Low-risk PTC <1 cm (microcarcinoma) may be managed with active surveillance.

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Treatment of Differentiated Thyroid Cancer

Total thyroidectomy is the primary treatment for thyroid cancers >1 cm. Lymph node dissection (central compartment) is recommended when nodes are clinically involved or in high-risk tumors.

Radioactive iodine (RAI, I-131) ablation: Used post-thyroidectomy to destroy residual thyroid tissue and metastatic disease in differentiated cancers. Requires TSH stimulation (either thyroid hormone withdrawal or recombinant human TSH, rhTSH/Thyrogen). Only effective in tumors that retain NIS (sodium-iodide symporter) expression — BRAF V600E-positive, RAI-refractory tumors require targeted therapy.

TSH suppression: Levothyroxine given at doses to suppress TSH below normal, reducing TSH-driven tumor growth. Target TSH <0.1 mIU/L for high-risk; 0.1–0.5 mIU/L for low-risk (balance against long-term risks of osteoporosis, atrial fibrillation).

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Targeted Therapy for Refractory and Advanced Disease

RAI-refractory differentiated thyroid cancer: Sorafenib (multikinase inhibitor targeting VEGFR, RAF, PDGFR) is FDA-approved; median PFS 10.8 months (DECISION trial, PMID 24691639). Lenvatinib: FDA-approved for RAI-refractory DTC; median PFS 18.3 months vs 3.6 months placebo (SELECT trial, PMID 25671254).

BRAF V600E-positive ATC: Dabrafenib + trametinib (BRAF + MEK inhibition) received FDA approval in 2018; response rate ~69%.

Medullary thyroid cancer: Vandetanib and cabozantinib are FDA-approved for progressive, unresectable MTC; both target RET, VEGFR, and EGFR kinases.

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Prognosis and Survivorship

Papillary thyroid cancer: 10-year disease-specific survival >95% for low-risk localized disease; 5-year survival drops to ~57% with distant metastasis.

Follicular: 5-year survival ~91% localized, ~57% distant.

Medullary: 5-year survival ~83% localized, ~28% distant.

Anaplastic: Median survival 3–5 months; 5-year survival <5%.

Post-treatment surveillance: Thyroglobulin + antithyroglobulin antibody measurement every 6–12 months; neck ultrasound at 6 and 12 months post-thyroidectomy, then annually.

Hypothyroidism is universal after total thyroidectomy and requires lifelong levothyroxine. Quality-of-life issues: voice changes (recurrent laryngeal nerve injury), hypoparathyroidism (calcium supplementation), and anxiety from ongoing surveillance are common.

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Key Research Papers

PubMed Research Searches

Connections