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

Initial Workup for Thyroid Nodules

The initial workup for a thyroid nodule consists of three essential components: serum TSH measurement, high-resolution thyroid ultrasound with cervical lymph node evaluation, and ultrasound-guided fine-needle aspiration (FNA) for nodules ≥1 cm or smaller nodules with suspicious features. 1

Step 1: Serum TSH Measurement

• Measure serum TSH before any imaging or biopsy, as this determines the subsequent diagnostic pathway and higher TSH levels are associated with increased risk of differentiated thyroid cancer 1
• If TSH is suppressed (low), proceed to thyroid scintigraphy with 99mTc to identify autonomous functioning nodules ("hot nodules"), which are rarely malignant and do not require FNA 2, 3
• If TSH is normal or elevated, proceed directly to ultrasound characterization and consider FNA based on sonographic features 1, 3

Step 2: High-Resolution Thyroid Ultrasound

• Perform complete neck ultrasound to characterize the nodule and evaluate cervical lymph node chains bilaterally 1
• Ultrasound is the only appropriate initial imaging modality—CT, MRI, and radionuclide scanning in euthyroid patients do not help determine malignancy risk 2

Suspicious Ultrasound Features Requiring FNA:

• Microcalcifications (highly specific for papillary thyroid carcinoma) 2, 1
• Marked hypoechogenicity (darker than surrounding thyroid tissue) 2, 1
• Irregular or microlobulated margins (infiltrative borders) 2, 1
• Absence of peripheral halo 2, 1
• Solid composition (higher malignancy risk than cystic) 2
• Taller-than-wide shape on transverse view 1
• Central hypervascularity with chaotic blood flow pattern 2, 1

Reassuring Features (Lower Risk):

• Pure cystic or spongiform appearance 2, 4
• Smooth, regular margins with thin peripheral halo 2
• Peripheral vascularity only (blood flow limited to capsule) 2

Step 3: Ultrasound-Guided Fine-Needle Aspiration (FNA)

Indications for FNA:

• Any nodule >1 cm regardless of ultrasound features 2, 1, 4
• Nodules <1 cm with suspicious ultrasound features (≥2 suspicious features listed above) 2, 1
• Any nodule >4 cm regardless of appearance (due to increased false-negative rate) 2
• Any size nodule with high-risk clinical factors (see below) 2, 1

High-Risk Clinical Factors That Lower FNA Threshold:

• History of head and neck irradiation (increases malignancy risk 7-fold) 2, 1
• Family history of thyroid cancer, particularly medullary carcinoma or familial syndromes (MEN 2A/2B, familial adenomatous polyposis, Carney complex, Cowden syndrome) 2, 1
• Age <15 years or male gender 2, 1
• Rapidly growing nodule 2, 1
• Firm nodule fixed to adjacent structures 1
• Vocal cord paralysis 2, 1
• Suspicious cervical lymphadenopathy 2, 1

FNA Technique:

• Ultrasound guidance is mandatory—it is superior to palpation-guided biopsy in accuracy, safety, and cost-effectiveness 2, 1
• Sample the solid portion of mixed solid-cystic nodules 2
• Cytology should be reported using the Bethesda System (6-category classification) 2, 1

Step 4: Additional Testing (Selected Cases)

Serum Calcitonin:

• Consider measuring serum calcitonin as part of the initial workup to screen for medullary thyroid cancer, which has higher sensitivity than FNA alone and detects 5-7% of thyroid cancers that FNA may miss 2, 1

Molecular Testing:

• Reserve molecular testing (BRAF, RAS, RET/PTC, PAX8/PPARγ, TERT, PIK3CA, TP53) for indeterminate cytology (Bethesda III/IV categories), where it helps distinguish benign from malignant nodules 2, 1, 4
• Not indicated for Bethesda II (benign) results, as pretest probability is too low (1-3%) 2

Management Based on FNA Results:

• Bethesda II (Benign): Surveillance with repeat ultrasound at 12-24 months 2
• Bethesda III/IV (Indeterminate): Consider molecular testing or repeat FNA; surgery may be needed for definitive diagnosis 2, 1
• Bethesda V/VI (Suspicious/Malignant): Immediate referral to endocrine surgeon for total or near-total thyroidectomy with pre-operative lymph node assessment 2, 1
• Nondiagnostic/Inadequate: Repeat ultrasound-guided FNA 2, 1

Critical Pitfalls to Avoid:

• Do not perform FNA on "hot" nodules identified on scintigraphy—these are managed medically with radioactive iodine, not surgery 2
• Do not rely on thyroid function tests (TSH, T3, T4) to assess malignancy risk—most thyroid cancers present with normal thyroid function 2
• Do not override a worrisome clinical presentation based on reassuring FNA alone—false-negative results occur in 11-33% of cases 2, 1
• Do not routinely screen asymptomatic patients with thyroid ultrasound—this leads to overdiagnosis of clinically insignificant papillary microcarcinomas 2, 4
• Do not use CT, MRI, or radionuclide scanning as initial imaging in euthyroid patients—ultrasound features are far more predictive of malignancy 2

Special Considerations:

• Isthmic nodules carry 2.4 times higher malignancy risk compared to lower lobe nodules and warrant lower threshold for FNA 5
• Most benign solid nodules grow over time (89% increase in volume over 5 years), so growth alone is not a reliable predictor of malignancy 6
• Pure cystic nodules without solid components can be safely observed without FNA 2