What is the appropriate workup for a patient presenting with a thyroid nodule?

Workup of a Thyroid Nodule

Begin with serum TSH measurement, followed by high-resolution ultrasound for all nodules, then proceed to ultrasound-guided fine-needle aspiration (FNA) for nodules ≥1 cm with suspicious features or any nodule >4 cm regardless of appearance. 1, 2

Initial Laboratory Assessment

• Measure serum TSH first before any imaging studies to guide the diagnostic pathway 2
• If TSH is subnormal (suppressed), the patient has thyrotoxicosis—proceed to ultrasound first to evaluate thyroid morphology, then perform radioiodine uptake scan to determine if the nodule is hyperfunctioning ("hot") 2, 3
  • Hot nodules are rarely malignant and typically do not require FNA 2
• If TSH is normal or elevated, proceed directly to ultrasound evaluation without radionuclide scanning 2, 3
• Consider measuring serum calcitonin to screen for medullary thyroid carcinoma, which has higher sensitivity than FNA alone (detects 5-7% of thyroid cancers that FNA may miss) 1

Common Pitfall

Do not proceed directly to radionuclide uptake scan without first checking TSH levels—radionuclide scanning is not helpful in determining malignancy in euthyroid patients 2, 3

Ultrasound Evaluation

High-resolution ultrasound is the preferred imaging modality for thyroid nodule evaluation due to its accuracy, safety, and ability to detect nodules as small as 5mm 1, 4

Suspicious Ultrasound Features (Warrant FNA)

• Microcalcifications (highly specific for papillary thyroid carcinoma) 1
• Marked hypoechogenicity (solid nodules darker than surrounding thyroid parenchyma) 1
• Irregular or microlobulated margins (infiltrative borders rather than smooth contours) 1
• Absence of peripheral halo (loss of the thin hypoechoic rim normally surrounding benign nodules) 1
• Solid composition (carries higher malignancy risk compared to cystic nodules) 1
• Central hypervascularity (chaotic internal vascular pattern on Doppler) 1

Reassuring Features (Low Risk)

• Purely cystic or spongiform appearance 1, 4
• Peripheral vascularity only (blood flow limited to capsule rather than central) 1
• Smooth, regular margins with thin halo 1

Fine-Needle Aspiration (FNA) Indications

Perform ultrasound-guided FNA when:

• Any nodule ≥1 cm with ≥2 suspicious ultrasound features (solid, hypoechoic, irregular margins, microcalcifications, central hypervascularity) 1
• Any nodule >4 cm regardless of ultrasound appearance due to increased false-negative rate and higher risk of compressive symptoms 1
• Nodules <1 cm only if suspicious features PLUS high-risk clinical factors are present 1

High-Risk Clinical Factors That Lower FNA Threshold

• History of head and neck irradiation (increases malignancy risk approximately 7-fold) 1
• Family history of thyroid cancer, particularly medullary carcinoma or familial syndromes 1
• Age <15 years or male gender (higher baseline malignancy probability) 1, 5
• Rapidly growing nodule 1
• Firm, fixed nodule on palpation (indicates extrathyroidal extension) 1
• Vocal cord paralysis or compressive symptoms (suggest invasive disease) 1
• Suspicious cervical lymphadenopathy 1

FNA Technique

Use ultrasound guidance for all FNA procedures—it allows real-time needle visualization, confirms accurate sampling, and is superior to palpation-guided biopsy in terms of accuracy, patient comfort, and cost-effectiveness 1

Interpretation of FNA Results (Bethesda Classification)

The Bethesda System stratifies thyroid nodules into six categories with specific malignancy risks 1:

• Bethesda I (Nondiagnostic): Repeat FNA under ultrasound guidance 1
• Bethesda II (Benign): 1-3% malignancy risk—manage with surveillance ultrasound at 12-24 months 1
• Bethesda III (AUS/FLUS): Consider molecular testing (BRAF, RAS, RET/PTC, PAX8/PPARγ) or repeat FNA 1
• Bethesda IV (Follicular Neoplasm): Consider surgery for definitive diagnosis, as FNA cannot distinguish follicular adenoma from carcinoma 1
• Bethesda V (Suspicious for Malignancy): Refer immediately for total or near-total thyroidectomy 1
• Bethesda VI (Malignant): Refer immediately for total or near-total thyroidectomy 1

Management Based on Risk Stratification

For Benign Nodules (Bethesda II)

• Surveillance with repeat ultrasound at 12-24 months to assess for interval growth or development of suspicious features 1
• Surgery only indicated for compressive symptoms (dysphagia, dyspnea, voice changes) or cosmetic concerns 1

For Indeterminate Cytology (Bethesda III/IV)

• Molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations—97% of mutation-positive nodules are malignant 1
• Consider repeat FNA or core needle biopsy if initial sample inadequate 1

For Malignant or Suspicious Cytology (Bethesda V/VI)

• Immediate referral to endocrine surgeon for total or near-total thyroidectomy 1
• Pre-operative neck ultrasound to assess cervical lymph node status 1
• Compartment-oriented lymph node dissection indicated when lymph node metastases suspected or proven 1

Special Considerations

For Nodules in Toxic Patients (Low TSH)

• Perform radioiodine uptake scan after ultrasound to determine if nodule is "hot" 2, 3
• Hot nodules causing thyrotoxicosis can be treated with radioactive iodine therapy (98% success rate) 3
• Cold nodules in toxic patients require FNA evaluation 2

For Multiple Nodules

• Prioritize the largest nodule for FNA, as nodule size ≥3 cm is associated with 3-times greater risk of malignancy 1
• If FNA of larger nodule is benign but clinical suspicion remains high, evaluate additional nodules 1

Pre-Procedure Laboratory Tests

• Consider complete blood count and coagulation function assessment, especially if patient is on anticoagulant therapy 2

Critical Pitfalls to Avoid

• Do not rely on thyroid function tests (TSH, T3, T4) for malignancy assessment—most thyroid cancers present with normal thyroid function 1
• Do not perform FNA on nodules <1 cm without high-risk features—this leads to overdiagnosis and overtreatment of clinically insignificant cancers 1, 6
• Do not override a reassuring FNA when worrisome clinical findings persist—false-negative results occur in up to 11-33% of cases 1
• Do not use radionuclide scanning to determine malignancy in euthyroid patients—ultrasound features are far more predictive 2, 3