Can a 4 cm thyroid nodule be benign?

Can a 4 cm Thyroid Nodule Be Benign?

Yes, a 4 cm thyroid nodule can absolutely be benign—in fact, the majority (approximately 78-80%) of thyroid nodules ≥4 cm are benign, though size alone warrants thorough evaluation with ultrasound-guided fine needle aspiration biopsy (FNA) to exclude malignancy. 1, 2

Understanding the Malignancy Risk in Large Nodules

The evidence regarding 4 cm nodules shows important nuances:

• The malignancy rate in nodules ≥4 cm ranges from 20-23% in surgical series where all patients underwent thyroidectomy, meaning 77-80% were benign 1, 2
• One study found even lower malignancy rates (23%) in nodules ≥4 cm compared to smaller nodules (53%), suggesting size alone does not predict cancer 2
• Guidelines recommend evaluation of thyroid nodules larger than 2 cm, even without suspicious features, due to increased risk considerations 3

Critical Diagnostic Approach for 4 cm Nodules

Mandatory Initial Evaluation

All nodules ≥4 cm require ultrasound-guided FNA regardless of ultrasound appearance because:

• The absence of suspicious ultrasound features does NOT reliably exclude malignancy—in nodules ≥4 cm with no suspicious US features, the cancer risk remains 20% 1
• Ultrasound features (hypoechogenicity, microcalcifications, irregular borders, solid composition) have poor discriminatory value when considered individually in large nodules 4, 3, 1

FNA Performance and Limitations in Large Nodules

The accuracy of FNA in 4 cm nodules is controversial and institution-dependent:

Studies showing FNA is reliable:

• False-negative rate of benign cytology was 5.2% in nodules ≥4 cm versus 5.9% in smaller nodules (no significant difference) 2
• FNA accuracy actually increased to 80.3% in nodules ≥4 cm compared to 68.5% in smaller nodules 5
• Overall false-negative rate of 7% across all nodule sizes 5

Studies showing FNA is unreliable:

• False-negative rate of benign cytology was 10.4% in one large surgical series 1
• In another study, 43.7% of nodules ≥4 cm with benign FNA were actually malignant at surgery—an alarmingly high false-negative rate 6
• Benign cytology does not rule out malignancy in thyroid nodules larger than 4 cm according to recent evidence 6

Surgical Decision-Making Algorithm

Given the conflicting evidence on FNA reliability, the approach depends on clinical context:

Strong Indications for Total Thyroidectomy (Any Present):

• Known distant metastases 4
• Cervical lymph node metastases 4
• Extrathyroidal extension 4
• Tumor >4 cm in diameter 4
• Prior radiation exposure (category 2B) 4

When Lobectomy May Be Considered:

Only if ALL of the following criteria are met:

• No prior radiation exposure 4
• No distant metastases 4
• No cervical lymph node metastases 4
• No extrathyroidal extension 4
• Benign FNA cytology (Bethesda II) 3

Critical Clinical Caveat:

At minimum, thyroid lobectomy should be strongly considered for all nodules ≥4 cm given the 22% malignancy rate and 10.4% false-negative rate of benign cytology in the highest quality surgical series 1. This recommendation is particularly important because:

• Even with benign cytology, the false-negative rate can be unacceptably high (up to 43.7% in some series) 6
• Diagnostic lobectomy may be necessary because the false-negative rate of FNA is especially high in nodules ≥4 cm 6
• Indeterminate results (AUS/FN) have higher malignancy risk in nodules ≥4 cm compared to smaller nodules 6

Additional Diagnostic Considerations

• Measure serum calcitonin as part of the diagnostic workup to screen for medullary thyroid cancer, which has higher sensitivity than FNA alone 4, 3
• Consider molecular testing (BRAF, RAS, RET/PTC, PAX8/PPARγ) as an adjunct to FNA—97% of mutation-positive nodules are malignant 3
• Perform neck ultrasound including central and lateral compartments to assess lymph node status 4
• Evaluate vocal cord mobility if there are concerns about invasion 4

Common Pitfalls to Avoid

• Do not rely on the absence of suspicious ultrasound features to exclude malignancy in 4 cm nodules 1
• Do not assume benign FNA cytology definitively rules out cancer—the false-negative rate is significant 1, 6
• Do not use thyroid function tests (TSH, T3, T4) for malignancy assessment—most thyroid cancers present with normal thyroid function 3
• Do not defer surgery based solely on benign cytology if the nodule is ≥4 cm, especially with any additional risk factors 1, 6