For a patient with a multinodular goiter and a dominant moderately suspicious right thyroid nodule measuring 4.1 cm, should I perform a fine‑needle aspiration biopsy and what follow‑up is recommended?

Management of 4.1 cm Moderately Suspicious Thyroid Nodule in Multinodular Goiter

Yes, perform ultrasound-guided fine-needle aspiration biopsy immediately on the dominant 4.1 cm right thyroid nodule, as nodules exceeding 4 cm warrant FNA regardless of ultrasound appearance due to increased false-negative rates and higher malignancy risk. 1

Rationale for Immediate FNA

Size alone mandates tissue diagnosis in this case. The 4.1 cm measurement places this nodule well above multiple critical thresholds:

• Any thyroid nodule >1 cm requires FNA evaluation regardless of other features, and this nodule is more than four times that threshold 1, 2
• Nodules ≥3 cm carry a 3-times greater malignancy risk compared to smaller nodules 1
• Nodules >4 cm should undergo FNA regardless of ultrasound appearance because larger nodules have increased false-negative rates and higher risk of harboring malignancy 1
• The combination of large size (4.1 cm) with moderately suspicious features substantially increases overall malignancy risk 1

Technical Approach

Use ultrasound guidance for the FNA procedure rather than palpation-guided technique:

• Ultrasound guidance provides real-time needle visualization, confirms accurate sampling of the dominant nodule, and is superior to palpation in terms of accuracy, patient comfort, and cost-effectiveness 1
• Target the solid components of the nodule if mixed solid-cystic, as solid tissue carries the highest malignancy risk 1
• Obtain 2-4 aspirations from different areas of the nodule to ensure adequate sampling 3

Expected Diagnostic Accuracy and Limitations

FNA achieves approximately 95% diagnostic accuracy for thyroid nodules, making it the most reliable preoperative diagnostic method 2, 4, 5

Be aware of two major limitations:

• Nondiagnostic/inadequate samples occur in 5-20% of cases and require repeat FNA under ultrasound guidance 1, 4
• Indeterminate results (follicular neoplasm, Bethesda III/IV) may require surgical excision for definitive diagnosis, as FNA cannot distinguish follicular adenoma from carcinoma 1, 2

Management Based on FNA Results

Benign (Bethesda II)

• Surveillance with repeat ultrasound at 12-24 months is appropriate, as malignancy risk is only 1-3% 1
• However, do not override clinical suspicion if worrisome features persist, as false-negative results occur in up to 11-33% of cases 1
• Consider surgery if compressive symptoms develop (dysphagia, dyspnea, voice changes) or if the nodule continues to enlarge 1, 6

Indeterminate (Bethesda III/IV)

• Consider molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations to refine malignancy risk 1, 2
• The presence of any mutation is a strong indicator of cancer, with 97% of mutation-positive nodules being malignant 1
• For follicular neoplasia (Bethesda IV) with normal TSH and "cold" appearance on thyroid scan, surgery should be considered for definitive diagnosis 1, 2

Suspicious or Malignant (Bethesda V/VI)

• Refer immediately to an endocrine surgeon for total or near-total thyroidectomy 1, 2
• Perform pre-operative neck ultrasound to assess cervical lymph node status 1
• Compartment-oriented lymph node dissection is indicated when lymph node metastases are suspected or proven 1

Additional Diagnostic Considerations

Measure serum calcitonin as part of the initial workup to screen for medullary thyroid cancer, which has higher sensitivity than FNA alone and accounts for 5-7% of thyroid cancers 1, 2

Measure serum TSH to determine functional status:

• If TSH is suppressed with elevated T4, consider radionuclide scanning to assess for autonomous function 1
• Hot nodules on scan are rarely malignant and may be managed with radioactive iodine rather than surgery 1
• Most thyroid cancers present with normal thyroid function, so normal TSH does not exclude malignancy 1, 2

Surveillance of Other Nodules in Multinodular Goiter

Prioritize the largest nodule (4.1 cm) for initial FNA, as this is the standard approach when multiple nodules are present 1

• If FNA of the larger nodule yields benign results but clinical suspicion remains high, other suspicious nodules can be evaluated in subsequent procedures 1
• Continue ultrasound surveillance of the remaining nodules at 12-24 month intervals 1
• Perform FNA on additional nodules if they develop suspicious features, grow significantly (≥3 mm in any dimension), or exceed 1 cm with concerning ultrasound characteristics 1

Critical Pitfalls to Avoid

• Do not rely on thyroid function tests alone to assess malignancy risk, as most thyroid cancers occur in euthyroid patients 1, 2
• Do not use radionuclide scanning as a first-line test in euthyroid patients, as it does not reliably determine malignancy 1
• Do not defer FNA based on benign-appearing features when nodule size exceeds 4 cm, as size alone is an independent indication 1
• Do not accept a single nondiagnostic FNA result—repeat the procedure under ultrasound guidance 1, 4