Thyroid Nodule and Thyroid Cancer
Common finding; majority benign. Risk-stratify by ultrasound and FNA, then treat by histology.
Also known as: thyroid nodule, thyroid cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, Bethesda system
Overview
A thyroid nodule is a discrete lesion within the thyroid gland radiologically distinct from surrounding parenchyma. Thyroid cancer encompasses papillary (~85%), follicular (~10%), medullary (~3%), and anaplastic (~1%) carcinomas, plus lymphoma.
Epidemiology
Palpable nodules in ~5% of women and 1% of men; ultrasound detects nodules in ~50% of adults >60. Only ~5-10% of nodules are malignant. Thyroid cancer incidence rising (largely papillary, partly detection bias). Female-to-male ratio 3:1 except medullary (equal) and anaplastic (slight female predominance).
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Risk factors
- Childhood head/neck radiation (papillary)
- Family history of thyroid cancer or MEN2 (medullary)
- Iodine deficiency (follicular) or excess (papillary)
- Cowden, Carney, Werner, familial adenomatous polyposis
- Female sex, age extremes (<20 or >70 raise concern for any given nodule)
- Hashimoto thyroiditis (thyroid lymphoma)
Pathophysiology
Nodules arise from clonal proliferation of follicular cells (benign or malignant), focal hyperplasia, or cyst formation. Papillary cancer typically harbors BRAF V600E or RET/PTC rearrangements; follicular cancer harbors RAS or PAX8/PPARγ; medullary cancer (C-cell derived) harbors RET mutations and produces calcitonin; anaplastic cancer arises from dedifferentiation with TP53 mutations.
Clinical presentation
Symptoms
- Most asymptomatic; found incidentally on exam or imaging
- Compressive: dysphagia, hoarseness, dyspnea, stridor (concerning)
- Rapid growth, fixation, lymphadenopathy (concerning)
- Hyperthyroid symptoms if autonomous
Signs / physical exam
- Solitary firm nodule, irregular or fixed (suspicious)
- Cervical lymphadenopathy
- Hoarseness (RLN involvement)
- MEN2B features: marfanoid habitus, mucosal neuromas, pheochromocytoma
Classic findings
Papillary cancer: psammoma bodies + Orphan Annie eye nuclei + nuclear grooves. Medullary cancer: amyloid stroma and elevated calcitonin.
Differential diagnosis
- Benign colloid nodule — Most common; spongiform appearance on US; Bethesda II on FNA
- Follicular adenoma — Encapsulated follicular lesion; cannot distinguish from carcinoma on FNA — requires surgical resection to assess capsular/vascular invasion
- Papillary thyroid carcinoma — Most common malignancy; psammoma bodies, Orphan Annie nuclei, nuclear grooves; lymphatic spread; excellent prognosis
- Follicular thyroid carcinoma — Hematogenous spread (lung, bone); cannot diagnose by FNA; requires histology showing capsular/vascular invasion
- Medullary thyroid carcinoma — C-cell origin; elevated calcitonin and CEA; sporadic or familial (MEN2A, MEN2B, FMTC); screen for pheochromocytoma BEFORE surgery
- Anaplastic thyroid carcinoma — Elderly patient with rapidly enlarging neck mass, fixed to surrounding structures, compressive symptoms; dismal prognosis
- Thyroid lymphoma — Rapidly growing mass in long-standing Hashimoto thyroiditis; treat with chemoradiation, not surgery
- Hyperfunctioning (toxic) nodule — Suppressed TSH; hot on RAIU scan; very rarely malignant — skip FNA
Diagnostic workup
Diagnostic criteria
FNA is the gold standard. Surgical histology required for follicular neoplasms (Bethesda IV) — capsular or vascular invasion defines malignancy.
Labs
- TSH first — if suppressed, perform RAIU scan (hot nodules rarely malignant, skip FNA)
- If TSH normal/elevated, proceed to ultrasound
- Calcitonin and CEA if medullary cancer suspected or family history of MEN2
- Thyroglobulin (post-thyroidectomy tumor marker for differentiated cancer)
- Plasma metanephrines BEFORE any thyroid surgery in MEN2 to exclude pheochromocytoma
Imaging
- Ultrasound with TI-RADS or ATA risk stratification — assesses size, composition (cystic vs solid), echogenicity, margins, shape (taller-than-wide), calcifications (microcalcifications worrisome)
- FNA criteria (ATA 2015): high suspicion ≥1 cm, intermediate ≥1 cm, low suspicion ≥1.5 cm, very low suspicion ≥2 cm (or observe), benign no FNA
- Bethesda System for FNA reports: I non-diagnostic, II benign, III AUS/FLUS, IV follicular neoplasm, V suspicious for malignancy, VI malignant
- CT/MRI for substernal extension or compressive symptoms (avoid iodinated contrast if possible — delays RAI therapy)
- Whole-body iodine scan and thyroglobulin for surveillance after thyroidectomy
Diagnostic algorithm
| Bethesda Category | Description | Risk of Malignancy | Management |
|---|---|---|---|
| I | Non-diagnostic / unsatisfactory | 5-10% | Repeat FNA |
| II | Benign | 0-3% | Clinical follow-up, US in 12-24 months |
| III | AUS / FLUS | 10-30% | Repeat FNA, molecular testing, or lobectomy |
| IV | Follicular neoplasm / suspicious for follicular neoplasm | 25-40% | Lobectomy (histology needed) |
| V | Suspicious for malignancy | 50-75% | Lobectomy or near-total thyroidectomy |
| VI | Malignant | 97-99% | Total thyroidectomy ± neck dissection ± RAI |
Complications
- Surgical: recurrent laryngeal nerve injury (hoarseness, airway), hypoparathyroidism (transient or permanent), bleeding/hematoma
- RAI: sialadenitis, dry mouth, secondary malignancy (rare), infertility (high cumulative doses)
- Lifelong levothyroxine dependence after total thyroidectomy
- Recurrence — monitored with thyroglobulin + neck ultrasound (differentiated cancers) or calcitonin (medullary)
PANCE pearls
- Suppressed TSH → RAIU scan first (skip FNA if hot).
- Microcalcifications, taller-than-wide shape, hypoechogenicity, irregular margins, and extrathyroidal extension are the most worrisome US features for papillary cancer.
- Follicular neoplasm on FNA (Bethesda IV) cannot differentiate adenoma from carcinoma — requires lobectomy for definitive histology.
- Always screen for pheochromocytoma BEFORE thyroidectomy in patients with medullary cancer or MEN2.
- Post-thyroidectomy thyroglobulin should be undetectable in patients without residual disease (assuming negative anti-thyroglobulin antibody).
- A rapidly enlarging thyroid mass in long-standing Hashimoto → think thyroid lymphoma.
References
- ATA 2015 — American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer (Haugen et al., Thyroid 2016)
- ATA Medullary 2015 — Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma (Wells et al., Thyroid 2015)
- ATA Anaplastic 2021 — 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer (Bible et al., Thyroid 2021)
- Bethesda System 2023 — The 2023 Bethesda System for Reporting Thyroid Cytopathology (Ali et al., Thyroid 2023)
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