Thyroid Cancer

Papillary, follicular, medullary, and anaplastic subtypes — molecular drivers, risk stratification, radioactive iodine, targeted therapy, and MEN2 hereditary screening

Key Points

Epidemiology and Classification

Thyroid cancer is the most rapidly increasing cancer diagnosis in the United States, with approximately 44,000 new cases estimated annually in 2024. Women are affected roughly 3× more frequently than men for differentiated thyroid cancer; this sex ratio is less pronounced for medullary and anaplastic thyroid cancer. The age at diagnosis varies by histologic type: PTC peaks at ages 30–50; FTC at 40–60; MTC at any age (hereditary MTC may present in childhood or early adulthood); ATC predominantly in patients >65 years. **The "overdiagnosis epidemic":** The dramatic increase in thyroid cancer…

Papillary Thyroid Carcinoma (PTC)

Papillary thyroid carcinoma is the most common endocrine malignancy and the most common thyroid cancer worldwide, accounting for approximately 85% of all cases. **Pathologic Features:** - Defined by characteristic nuclear features: nuclear grooves, intranuclear pseudoinclusions (Orphan Annie eyes), nuclear overlap/crowding, and powdery chromatin. - **Psammoma bodies** (calcified concentric laminations) are nearly pathognomonic for PTC when found in a thyroid FNA specimen. - Most common primary site: isthmus or lateral thyroid lobes; often multifocal within the same or contralateral lobe.…

Follicular Thyroid Carcinoma (FTC)

Follicular thyroid carcinoma (FTC) accounts for approximately 10–12% of thyroid cancers. Unlike PTC, it lacks the characteristic papillary nuclear features and cannot be diagnosed on fine-needle aspiration (FNA) cytology — capsular and vascular invasion can only be assessed on histologic sections of the entire follicular neoplasm after surgical excision. **FNA and the Bethesda System:** FNA cytology for follicular lesions yields a "Bethesda IV — follicular neoplasm" result in approximately 10–25% of thyroid nodule aspirates. The risk of malignancy for Bethesda IV is approximately 25–40%,…

Medullary Thyroid Carcinoma (MTC)

Medullary thyroid carcinoma arises from parafollicular C-cells (calcitonin-secreting neuroendocrine cells of neural crest origin) and accounts for approximately 4% of thyroid cancers. It is clinically and biologically distinct from differentiated thyroid cancers — it is not iodine-concentrating, does not produce thyroglobulin, and is not treated with RAI. **Hereditary vs. Sporadic MTC:** - **Sporadic MTC (~75%):** Somatic RET mutations (~50%) or other somatic mutations; typically unifocal, later onset (median age ~50–60 years); presents as a solitary thyroid nodule or with neck mass. -…

Anaplastic Thyroid Carcinoma (ATC)

Anaplastic thyroid carcinoma (ATC) is one of the most lethal human malignancies. Although it accounts for only 1–2% of thyroid cancers by incidence, it is responsible for approximately 40% of thyroid cancer deaths. Median overall survival is approximately 5 months from diagnosis; fewer than 10% of patients survive one year. It occurs almost exclusively in patients >60 years of age, often arising from a long-standing differentiated or poorly differentiated thyroid cancer (dedifferentiation). **Presentation:** Rapidly growing, painful, fixed neck mass; often already invading trachea,…

Molecular Landscape and Targeted Therapy Overview

Thyroid cancer harbors some of the most actionable molecular alterations in solid tumor oncology, with approved targeted therapies for the most common drivers: **BRAF V600E:** - Frequency: ~60% of PTC; ~40–50% of ATC. - Targeted agents: Dabrafenib + trametinib (approved for ATC); vemurafenib (activity in BRAF V600E–mutant RAI-refractory DTC). - In DTC, BRAF inhibition also has a "RAI-resensitization" role — MEK inhibition can restore RAI avidity (NIS re-expression) in BRAF-mutant RAI-refractory DTC; selumetinib (MEK inhibitor) demonstrated RAI resensitization in 12/20 patients (NEJM 2013)…

Staging and ATA Risk Stratification

**AJCC 8th Edition Staging for DTC:** The most impactful change in the AJCC 8th edition (vs. 7th edition) was the age threshold change for DTC staging: - **Age cutoff increased from 45 to 55 years.** Patients 95% disease-specific survival at 10 years - RAI: Not routinely recommended - TSH target: Low-normal (0.5–2.0 mU/L) **ATA Intermediate Risk:** - Minor extrathyroidal extension, vascular invasion, >5 pathologic N1 nodes (all 4 foci (FTC) - Expected: <85% (often <50%) disease-specific survival at 10 years - RAI: Strongly recommended; high-dose RAI - TSH target: Suppressed (<0.1 mU/L)

Surgery

Surgery is the primary treatment for all thyroid cancers and the only curative modality for MTC and ATC (when resectable). **Hemithyroidectomy (Thyroid Lobectomy) vs. Total Thyroidectomy:** For DTC, the 2015 ATA guidelines liberalized the surgical approach for low-risk PTC: - **Hemithyroidectomy is acceptable** for PTC ≤4 cm, confined to the thyroid (no extrathyroidal extension), no clinical nodal metastasis, and no distant metastasis — if the patient will not require postoperative RAI (i.e., ATA low risk). The NIFTP designation further expands lobectomy applicability. - **Total…

Radioactive Iodine (RAI / I-131) Therapy

Radioactive iodine (I-131, RAI) leverages the unique ability of differentiated thyroid cells (PTC, FTC) to concentrate iodine via the sodium-iodide symporter (NIS) — the same mechanism exploited physiologically for thyroid hormone synthesis. MTC and ATC do not express functional NIS and are not treated with RAI. **Indications:** - ATA low risk: RAI NOT routinely indicated (the benefit does not outweigh risk of unnecessary radiation exposure; high-level evidence: Leboulleux et al., NEJM 2012 — 1.1 Ci vs. 3.7 GBq vs. observation for low-risk DTC showed no difference in remission rates). - ATA…

TSH Suppression and Thyroid Hormone Replacement

For DTC survivors, levothyroxine (LT4) serves a dual purpose: (1) physiologic thyroid hormone replacement and (2) TSH suppression to reduce TSH-driven growth stimulation of residual or metastatic DTC cells (TSH is a trophic hormone for thyroid-derived cells via TSHR signaling). **Risk-Adapted TSH Targets (ATA 2015 Guidelines):** | ATA Risk | TSH Target | Rationale | |---|---|---| | High risk | <0.1 mU/L (suppressed) | Aggressive disease requires strong TSH suppression | | Intermediate risk | 0.1–0.5 mU/L | Moderate suppression | | Low risk / remission | 0.5–2.0 mU/L (low-normal) | Minimal…

Surveillance and Thyroglobulin Monitoring

For DTC after total thyroidectomy ± RAI, surveillance integrates thyroglobulin (Tg) measurement, anti-Tg antibody (TgAb) monitoring, neck ultrasound, and functional/anatomic imaging as clinically indicated. **Thyroglobulin (Tg) as Tumor Marker:** - Tg is produced exclusively by thyroid follicular cells (normal or DTC); after total thyroidectomy + RAI ablation, Tg should be undetectable (basal or stimulated). - **Stimulated Tg** (after THW or rhTSH): More sensitive; used in initial post-RAI assessment and periodically for high-risk patients. - **Basal Tg** (on suppressive LT4): Followed…