Should a thyroid nodule larger than 3 cm be biopsied with fine‑needle aspiration?

Should Thyroid Nodules Larger Than 3 cm Be Biopsied?

Yes, thyroid nodules larger than 3 cm should undergo ultrasound-guided fine-needle aspiration biopsy, as recommended by the American College of Surgeons and the National Comprehensive Cancer Network, due to increased malignancy risk even in the absence of suspicious ultrasound features. 1

Size-Based Risk Stratification

• Nodules ≥3 cm carry a 3-times greater risk of malignancy compared to smaller nodules, making size alone a worrisome feature that warrants tissue diagnosis 1
• The American College of Surgeons and National Comprehensive Cancer Network recommend evaluation of thyroid nodules larger than 2 cm, even without suspicious features 1
• For nodules >4 cm, FNA should be performed regardless of ultrasound appearance due to an increased false-negative rate 1

Diagnostic Accuracy in Large Nodules

The evidence shows that ultrasound-guided FNA maintains reasonable accuracy even in large nodules, though with important caveats:

• In nodules ≥3 cm, US-guided FNA demonstrates 96.7% sensitivity, 85.9% specificity, and 98.2% negative predictive value, with a false-negative rate of approximately 2% 2
• For nodules ≥4 cm, the overall false-negative rate increases to 11.9%, with variation based on ultrasound characteristics 3
• One study reported a 4.7% false-negative rate in nodules >3 cm, meaning cancer could evolve undetected in approximately 1 in 20 cases if FNA is falsely reassuring 4

Ultrasound Features That Modify Accuracy

The reliability of FNA in large nodules depends critically on ultrasound characteristics:

• Sensitivity is significantly higher (97.9%) in nodules with any calcifications (micro- or macro-) compared to those without (87%) 3
• In nodules ≥4 cm without any suspicious ultrasound features, the false-negative rate drops to 0% (0/15 cases), suggesting benign FNA results are highly reliable when imaging is reassuring 3
• Suspicious features include: solid composition, ill-defined margins, hypoechogenicity or marked hypoechogenicity, microcalcifications, irregular borders, absence of peripheral halo, and central hypervascularity 1, 3

Clinical Algorithm for Large Nodules

For nodules ≥3 cm, follow this approach:

1. Perform high-resolution ultrasound to characterize composition, echogenicity, margins, calcifications, and vascularity 1

2. Proceed with ultrasound-guided FNA for all nodules ≥3 cm, as size alone justifies biopsy 1

3. Interpret FNA results in context of ultrasound features:

   • If FNA is benign (Bethesda II) AND ultrasound shows no suspicious features, surveillance with repeat ultrasound at 12-24 months is appropriate 1, 3
   • If FNA is benign BUT ultrasound shows suspicious features (solid, hypoechoic, irregular margins, calcifications), strongly consider surgery due to false-negative rates of 11.9-17.9% in this scenario 3, 4
   • If FNA is malignant or suspicious (Bethesda V/VI), refer immediately for total or near-total thyroidectomy 1

4. For indeterminate results (Bethesda III/IV), consider molecular testing (BRAF, RAS, RET/PTC, PAX8/PPARγ) or repeat FNA/core needle biopsy 1

Critical Pitfalls to Avoid

• Do not rely on a single benign FNA result to exclude malignancy in large nodules with suspicious ultrasound features, as false-negative rates can reach 11.9% overall and 17.9% in solid nodules 3
• The false-negative rate is highest (33.3%) in nodules with microcalcifications or macrocalcifications, so maintain high suspicion even with benign cytology in this setting 3
• Do not delay surgical intervention for potentially suspicious nodules >3 cm based solely on FNA results, given the non-negligible risk of allowing cancer evolution in 1 of 20 cases 4
• Nodules without any suspicious ultrasound features have a 0% false-negative rate, so benign FNA can be trusted in this specific scenario 3

Additional High-Risk Features That Lower Threshold

Even for nodules <3 cm, FNA should be performed if any of these factors are present:

• History of head and neck irradiation (increases risk 7-fold) 1
• Family history of thyroid cancer, particularly medullary carcinoma 1
• Age <15 years or male gender 1
• Rapidly growing nodule 1
• Firm, fixed nodule on palpation 1
• Vocal cord paralysis or compressive symptoms 1
• Suspicious cervical lymphadenopathy 1