What is the next step in managing a 4 cm thyroid nodule?

Management of a 4 cm Thyroid Nodule (TI-RADS 2, Bethesda I)

Proceed directly to diagnostic thyroid lobectomy (at minimum) for this 4 cm nodule, regardless of the benign-appearing ultrasound features (TI-RADS 2) or nondiagnostic cytology (Bethesda I). 1, 2

Why Surgery is Indicated Despite Benign Imaging

Size alone (≥4 cm) mandates surgical evaluation because ultrasound features have poor discriminatory value in large nodules, and the absence of suspicious features does NOT reliably exclude malignancy. 2, 3

• The malignancy rate in nodules ≥4 cm is 13.5-22%, even when ultrasound appears benign 3, 4
• In nodules ≥4 cm without any suspicious ultrasound features, the cancer risk remains 20% 3
• Guidelines specifically recommend evaluation of thyroid nodules larger than 2 cm even without suspicious features due to increased malignancy risk 1, 2

The Problem with Bethesda I (Nondiagnostic) Cytology in Large Nodules

Nondiagnostic FNA results in nodules ≥4 cm carry a 27.3% risk of malignancy, making repeat biopsy futile and surgery the appropriate next step. 4

• Even when FNA is technically adequate and reads as "benign" in nodules ≥4 cm, the false-negative rate is unacceptably high at 50%, with half of these turning out to be neoplastic or malignant 4
• The overall false-negative rate of FNA in nodules ≥4 cm is 11.9% 5
• Repeat FNA is not recommended in this scenario because the size itself creates sampling error that cannot be overcome with additional biopsies 4

Surgical Approach

Total thyroidectomy should be performed if any of the following are present: 2

• Cervical lymph node metastases on preoperative ultrasound
• Extrathyroidal extension suspected clinically or on imaging
• Bilateral nodular disease
• History of head and neck radiation

Thyroid lobectomy is acceptable if: 2

• No suspicious lymphadenopathy on comprehensive neck ultrasound (central and lateral compartments)
• No extrathyroidal extension
• No prior radiation exposure
• Unilateral disease

Essential Preoperative Workup Before Surgery

Complete the following studies before proceeding to surgery: 2

• Comprehensive neck ultrasound including central and lateral lymph node compartments to assess for metastatic disease 2
• Serum calcitonin measurement to screen for medullary thyroid cancer, which has higher sensitivity than FNA alone 6, 2
• Vocal cord assessment (laryngoscopy) if there are any voice changes or concerns about recurrent laryngeal nerve involvement 2
• TSH level to assess thyroid function, though normal thyroid function does NOT exclude malignancy 2

Common Pitfalls to Avoid

• Do not attempt repeat FNA in a 4 cm nodule with initial nondiagnostic results—the size creates inherent sampling limitations that repeat biopsy cannot overcome 4
• Do not rely on benign ultrasound appearance (TI-RADS 2) to defer surgery in nodules ≥4 cm, as ultrasound features lose predictive value at this size threshold 2, 3
• Do not pursue observation even with "benign" cytology in nodules this large, as the false-negative rate approaches 50% 4
• Do not use thyroid function tests (TSH, T3, T4) for malignancy risk assessment—most thyroid cancers present with normal thyroid function 2

Why This Aggressive Approach is Justified

The combination of large size (4 cm) and nondiagnostic cytology creates a clinical scenario where:

• The pretest probability of malignancy is 13.5-22% based on size alone 3, 4
• Nondiagnostic FNA increases this risk to 27.3% 4
• Even "benign" FNA results would have a 10.4% false-negative rate in this size range 3
• Ultrasound features cannot reliably stratify risk when nodules exceed 4 cm 2, 3

At minimum, diagnostic lobectomy should be strongly considered for all nodules ≥4 cm, with total thyroidectomy reserved for cases with additional high-risk features identified on preoperative workup. 1, 2, 3