What is the recommended management for a 27-year-old female patient with a history of an incidental thyroid mass, now presenting with multiple thyroid nodules, including some classified as TR3 (Thyroid Imaging Reporting and Data System - Mildly Suspicious) and TR4 (Thyroid Imaging Reporting and Data System - Moderately Suspicious), and pending thyroid function tests (TFTs)?

Management of Multiple Thyroid Nodules with TR3 and TR4 Classifications

Immediate Recommendation

Proceed with ultrasound-guided fine-needle aspiration (FNA) biopsy of the right lower pole nodule (4.9 x 6.0 cm, TR3) and the left midpole nodule (1.0 x 0.7 x 0.8 cm, TR4) while awaiting thyroid function tests. 1

Rationale for FNA Selection

Right Lower Pole Nodule (Priority #1)

• Size alone mandates FNA: At 4.9 x 6.0 cm, this nodule exceeds the 4 cm threshold where FNA is recommended regardless of ultrasound appearance due to increased false-negative rates and higher malignancy risk 1
• The predominantly solid composition with ill-defined margins adds additional concern, as solid nodules carry higher malignancy risk than cystic lesions 1
• Even though classified as TR3, nodules >2 cm warrant evaluation due to increased malignancy risk, and this nodule is more than double that threshold 1

Left Midpole Nodule (Priority #2)

• TR4 classification with taller-than-wide orientation: This is a moderately suspicious nodule with 6 TI-RADS points, and the taller-than-wide shape is a concerning feature associated with malignancy 1, 2
• At 1.0 cm, this nodule meets the size threshold for FNA in TR4 nodules 1
• The solid, hyper/isoechoic appearance with taller-than-wide morphology warrants tissue diagnosis despite smooth margins 1

Additional Nodules Requiring FNA

Isthmus Nodule (Priority #3)

• Size exceeds 2 cm threshold: At 2.6 x 1.9 x 1.0 cm, this solid nodule warrants FNA evaluation despite TR3 classification 1
• Nodules at the junction of isthmus and thyroid lobe can have clinical significance due to location 1

Right Upper Pole Nodule (Consider)

• At 2.0 x 2.1 x 2.1 cm, this solid nodule exceeds 2 cm and should be considered for FNA, though it is lower priority than the three nodules above 1

Nodules That Can Be Observed

The remaining smaller nodules (left upper pole 0.9 cm, left lower pole 0.6 cm) are TR3 and <1 cm without high-risk features, so surveillance is appropriate unless high-risk clinical factors emerge 1, 2

Role of Pending Thyroid Function Tests

• If TSH is suppressed: Obtain a thyroid radionuclide scan to determine if any nodules are autonomously functioning ("hot") 1

  • Hot nodules rarely harbor malignancy and may be managed medically with radioactive iodine rather than requiring FNA 1
  • Cold nodules in the setting of suppressed TSH still require FNA as outlined above 1

• If TSH is normal or elevated: Proceed directly with ultrasound-guided FNA of the prioritized nodules without radionuclide scanning 1, 3

• Do not delay FNA while awaiting thyroid function tests for nodules meeting size and suspicious feature criteria, as most thyroid cancers present with normal thyroid function 1, 2

Technical Approach to FNA

• Ultrasound guidance is mandatory: This allows real-time needle visualization, confirms accurate sampling, and is superior to palpation-guided biopsy 1, 2
• Perform 2-4 aspirations from different areas of each nodule to ensure adequate sampling 4
• For the large right lower pole nodule with cystic spaces, target the solid components specifically, as these carry the highest malignancy risk 1
• Consider marker clip placement during FNA for future reference 2

Management Based on FNA Results (Bethesda Classification)

Bethesda II (Benign)

• Surveillance with repeat ultrasound at 12-24 months 1
• Malignancy risk drops to 1-3% 1
• Critical caveat: A reassuring FNA should not override concerns if worrisome clinical findings persist, as false-negative results occur in up to 11-33% of cases 1, 2

Bethesda III (AUS/FLUS) or IV (Follicular Neoplasm)

• Consider molecular testing (BRAF, RAS, RET/PTC, PAX8/PPARγ) to refine malignancy risk 1
• Repeat FNA or core needle biopsy if initial sample inadequate 1
• For Bethesda IV with normal TSH and "cold" scan, surgery should be considered for definitive diagnosis 1

Bethesda V (Suspicious) or VI (Malignant)

• Immediate referral to endocrine surgeon for total or near-total thyroidectomy 1
• Pre-operative neck ultrasound to assess cervical lymph node status 1
• Compartment-oriented lymph node dissection if metastases suspected 1

Nondiagnostic/Inadequate

• Repeat FNA under ultrasound guidance is mandatory 1, 4
• If repeat FNA remains nondiagnostic, consider core needle biopsy 1

High-Risk Clinical Factors to Document

Assess for features that would lower the threshold for FNA of smaller nodules 1, 2:

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

Critical Pitfalls to Avoid

• Do not defer FNA based on TR3 classification alone when nodules exceed 2 cm, as size supersedes TI-RADS category for larger nodules 1
• Do not rely solely on thyroid function tests for malignancy assessment, as most thyroid cancers are euthyroid 1, 2
• Do not perform radionuclide scanning in euthyroid patients to determine malignancy risk, as ultrasound features are far more predictive 1, 5
• Do not biopsy the heterogeneous thyroid parenchyma itself—only discrete, measurable nodules warrant FNA 5
• Do not assume growth equals malignancy: Most benign solid nodules grow over time (89% show volume increase after 5 years), so growth alone is not a reliable predictor of malignancy 6

Surveillance Strategy

For nodules not undergoing immediate FNA:

• Repeat ultrasound at 12-24 months to assess for interval growth or development of suspicious features 1
• Monitor for compressive symptoms including dysphagia, dyspnea, or voice changes 1
• Re-evaluate need for FNA if nodules develop additional suspicious features or exceed size thresholds 1

Special Consideration: Molecular Testing

If FNA results are indeterminate (Bethesda III/IV), molecular testing may assist in management decisions 1:

• Presence of BRAF, RAS, RET/PTC, or PAX8/PPARγ mutations strongly indicates malignancy (97% of mutation-positive nodules are malignant) 1
• This can help guide surgical decision-making and avoid unnecessary procedures for benign lesions 1, 7