Thyroid disease - thyroid nodules
Description
- *The question is never "is there a nodule" - it is "does this one need a needle"*
- Palpable in ~5% of adults; found on ultrasound in ~50-70%, rising with age
- *Only ~5-10% are malignant*
Differential
- Benign (the great majority)
- Dominant nodule in a multinodular goitre
- Colloid nodule; haemorrhage or degeneration into a nodule (sudden painful enlargement)
- Follicular adenoma
- Simple cyst; Hashimoto pseudonodule; subacute thyroiditis
- Malignant
- Papillary (~85%), follicular (~10%), medullary (~2-3%), anaplastic, poorly differentiated
- Lymphoma (rapidly growing, in a background of Hashimoto)
- Metastasis (renal, breast, lung, melanoma)
- Functioning ("hot") nodule - toxic adenoma; *virtually never malignant*
Epidemiology
- F>M ~4:1; prevalence rises ~10% per decade of life
- Incidental detection is the dominant route - carotid Doppler, CT, MRI, PET
- Thyroid cancer incidence has risen several-fold with imaging, while mortality has not moved
- *This is over-diagnosis of indolent papillary microcarcinoma, not an epidemic* - the reason guidelines have become more conservative
- Risk factors for malignancy: childhood head/neck irradiation, radiation fallout exposure, family history of thyroid cancer or MEN2, age <20 or >60, male sex, rapid growth
Aetiopathogenesis
- Nodules arise from clonal proliferation of follicular cells, or from colloid accumulation and degeneration
- Iodine deficiency -> TSH-driven hyperplasia -> multinodular goitre (less relevant in iodine-replete Australia since bread fortification)
- Somatic drivers
- BRAF V600E - classical papillary carcinoma; more aggressive behaviour
- RAS - follicular pattern, follicular adenoma/carcinoma and NIFTP
- RET/PTC rearrangements - radiation-associated papillary carcinoma
- TERT promoter mutations - add markedly to risk when combined with BRAF
- Activating TSH-receptor and GNAS mutations -> autonomous, hyperfunctioning ("hot") nodule
- Autonomy explains why hot nodules are not malignant - the transformation pathway is different
Diagnosis
1. History and examination
- Red flags: rapid growth, new hoarseness (recurrent laryngeal nerve), dysphagia, dyspnoea, pain, hard fixed mass, cervical lymphadenopathy
- Childhood neck irradiation, family history of thyroid cancer, MEN2 or FMTC
- Compressive symptoms; retrosternal extension - Pemberton sign
2. TSH first - always
- *TSH suppressed -> radionuclide uptake scan before anything else*
- A hot (autonomously functioning) nodule needs no FNA - manage the thyrotoxicosis
- TSH normal or high -> proceed to ultrasound
- Routine calcitonin is not recommended in Australia; measure it if there is a family history of MTC/MEN2, or the FNA is suspicious
- Calcitonin above ~50-100 ng/L strongly suggests medullary carcinoma
- Thyroglobulin has no role in nodule assessment - only in post-thyroidectomy cancer surveillance
3. Ultrasound - and a risk-stratification system (ATA, ACR TI-RADS or EU-TIRADS)
- High-risk sonographic features
- Marked hypoechogenicity (relative to strap muscle)
- Solid composition
- Irregular margins - infiltrative, microlobulated, spiculated
- Microcalcifications
- Taller-than-wide on transverse view
- Extrathyroidal extension or abnormal cervical nodes
- Lowering risk: purely cystic, spongiform, isoechoic/hyperechoic
- Nodes matter more than the nodule - a suspicious node mandates FNA of the node itself, with washout thyroglobulin
4. FNA - size threshold depends on the ultrasound pattern
| Sonographic pattern | Risk | FNA at |
|---|---|---|
| High suspicion | 70-90% | >=1 cm |
| Intermediate | 10-20% | >=1.5 cm |
| Low | 5-10% | >=1.5-2 cm |
| Very low (spongiform) | <3% | >=2 cm, or observe |
| Purely cystic | <1% | No FNA |
- *Aspirate regardless of size or appearance if: firm fixed mass, neck pain, cough, voice change, dysphagia, rapid growth, childhood neck irradiation, family history of thyroid cancer or MEN2/FMTC, prior thyroid carcinoma, focal FDG uptake on PET*, raised calcitonin, or nuclear fallout exposure
- Ultrasound-guided, not palpation-guided
5. Bethesda cytology
| Category | Malignancy risk | Action | |
|---|---|---|---|
| I | Non-diagnostic | - | Repeat FNA under ultrasound |
| II | Benign | 0-3% | Follow up clinically/sonographically |
| III | AUS/FLUS | ~10-30% | Repeat FNA, molecular testing, or lobectomy |
| IV | Follicular neoplasm | 25-40% | Diagnostic lobectomy or molecular testing |
| V | Suspicious for malignancy | 50-75% | Surgery |
| VI | Malignant | 97-99% | Surgery |
- *Cytology cannot distinguish follicular adenoma from follicular carcinoma - the diagnosis requires capsular or vascular invasion* on histology. Hence Bethesda IV always goes to lobectomy or molecular testing
- Molecular testing (Afirma, ThyroSeq) reclassifies indeterminate nodules and avoids diagnostic surgery; limited Australian availability
Management
Benign nodule (Bethesda II)
- Observation - no routine repeat FNA
- Ultrasound at 12-24 months for high-suspicion patterns; less often, or not at all, for low-risk appearance
- Repeat FNA only if it grows >20% in two dimensions (or >50% volume) or develops suspicious features
- *Levothyroxine suppression is NOT recommended* - marginal shrinkage, real risk of AF and bone loss
- Symptomatic or cosmetically troubling benign nodule
- Surgery (lobectomy), or thermal ablation (radiofrequency, microwave) / ethanol ablation for cysts - increasingly used, avoids lifelong thyroxine
- Cyst: aspirate for symptoms; recurrence is common -> ethanol ablation or surgery
Autonomously functioning ("hot") nodule
- Radioiodine or surgery - does not remit spontaneously
- Thionamide is only a bridge
Multinodular goitre
- Observe if euthyroid and asymptomatic
- Surgery for compressive symptoms, retrosternal extension, cosmetic concern, or suspicion of malignancy
- Check for tracheal deviation/compression and thoracic inlet obstruction with CT before operating
Malignant or suspicious cytology
- Lobectomy for low-risk unifocal papillary carcinoma <4 cm without extrathyroidal extension or nodal disease
- Total thyroidectomy for larger, multifocal, extrathyroidal, node-positive, or prior irradiation
- Active surveillance is now an accepted option for papillary microcarcinoma (<1 cm) without nodal or extrathyroidal disease
- Selective radioiodine ablation; TSH suppression titrated to recurrence risk (not for everyone - it costs bone and rhythm)
- Medullary carcinoma: exclude phaeochromocytoma first, germline RET testing, total thyroidectomy + central node dissection
Nodule in pregnancy
- Ultrasound and FNA are safe; radionuclide scanning is contraindicated
- Differentiated cancer: surgery can usually be deferred to postpartum
Associations
- Hashimoto thyroiditis - pseudonodules; primary thyroid lymphoma arises almost exclusively in this background
- MEN2A/2B and familial medullary thyroid carcinoma
- Familial syndromes with papillary/follicular cancer: Cowden (PTEN), familial adenomatous polyposis (cribriform-morular variant), Carney complex, Werner syndrome, DICER1
- Childhood head and neck irradiation; Chernobyl/Fukushima fallout exposure
- Iodine deficiency (goitre), acromegaly (multinodular goitre)
- Obesity - modest independent association with thyroid cancer
Natural history & complications
- Most benign nodules stay stable or grow slowly; a minority regress
- Growth alone is a poor predictor of malignancy - the sonographic pattern is far more informative
- Papillary carcinoma: indolent, lymphatic spread, 10-year survival >95%; recurrence in cervical nodes
- Follicular carcinoma: haematogenous spread to bone and lung; worse than papillary but still good
- Medullary carcinoma: 10-year survival >95% node-negative, ~40-50% with distant disease; calcitonin doubling time predicts progression
- Anaplastic carcinoma: elderly, rapidly enlarging fixed mass with hoarseness and stridor; *median survival ~6 months - a genuine emergency, and BRAF-mutant disease now has targeted therapy*
- Post-lobectomy: ~20-30% need thyroxine; post-total thyroidectomy, all do
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