How should a well-defined thyroid nodule in the right lobe of a 60-year-old euthyroid woman be evaluated and managed?

Management of Well-Defined Thyroid Nodule in a 60-Year-Old Euthyroid Woman

Proceed directly to high-resolution thyroid ultrasound to characterize the nodule's sonographic features, followed by ultrasound-guided fine-needle aspiration (FNA) if the nodule is ≥1 cm or if suspicious ultrasound features are present regardless of size. 1, 2

Initial Diagnostic Workup

Step 1: High-Resolution Ultrasound Evaluation

• Perform high-resolution ultrasound using a high-frequency transducer to assess nodule size, composition (solid vs. cystic), echogenicity, margins, presence of calcifications, and vascularity pattern. 1, 3
• Document the following high-risk sonographic features that increase malignancy probability:
  • Solid composition (higher risk than cystic nodules) 1
  • Marked hypoechogenicity (darker than surrounding thyroid tissue) 1, 3
  • Microcalcifications (highly specific for papillary thyroid carcinoma) 1, 3
  • Irregular or microlobulated margins 1, 3
  • Absence of peripheral halo 1
  • Central hypervascularity with chaotic blood flow 1
• Evaluate cervical lymph nodes for suspicious features such as loss of fatty hilum, microcalcifications, cystic change, or hypervascularity. 2

Step 2: Thyroid Function Testing

• Measure serum TSH before proceeding with FNA, as higher TSH levels are associated with increased risk of differentiated thyroid cancer. 1, 2, 4
• If TSH is suppressed (low), obtain a radionuclide thyroid scan with 99mTc to determine if the nodule is hyperfunctioning ("hot"). 4, 5
  • Hot nodules are rarely malignant and do not require FNA. 4
  • Manage hyperfunctioning nodules with radioactive iodine or surgery based on symptoms. 1
• If TSH is normal or elevated, proceed with FNA based on ultrasound characteristics. 4, 5

Indications for Fine-Needle Aspiration Biopsy

Size and Ultrasound-Based Criteria

• Perform ultrasound-guided FNA for any nodule ≥1 cm with ≥2 suspicious ultrasound features (solid, hypoechoic, irregular margins, microcalcifications, central hypervascularity). 1, 2
• Perform FNA for any nodule >4 cm regardless of ultrasound appearance due to increased false-negative rate and higher malignancy risk. 1
• For nodules <1 cm, perform FNA only if suspicious ultrasound features are present plus high-risk clinical factors:
  • History of head and neck irradiation (increases risk 7-fold) 1
  • Family history of thyroid cancer, particularly medullary carcinoma or familial syndromes 1
  • Suspicious cervical lymphadenopathy 1
  • Rapidly growing nodule 1
  • Firm, fixed nodule on palpation 1

Special Considerations for Mixed Cystic-Solid Nodules

• If the nodule has both solid and cystic components, target the solid portion for FNA, as it carries the highest malignancy risk. 1, 6
• Nodules with >50% solid component have a higher malignancy rate (7.4%) compared to predominantly cystic nodules (2.2%). 6
• Eccentric positioning of the solid component and presence of microcalcifications significantly increase malignancy risk in mixed nodules. 6

Additional Diagnostic Testing

Serum Calcitonin Measurement

• Consider measuring serum calcitonin as part of the initial workup to screen for medullary thyroid cancer, which has higher sensitivity than FNA alone and can detect 5-7% of thyroid cancers that FNA may miss. 1, 2, 7

Management Based on FNA Results (Bethesda Classification)

Bethesda II (Benign) – Malignancy Risk 1-3%

• Initiate surveillance with repeat ultrasound at 12-24 months to monitor for interval growth or development of suspicious features. 1
• Surgery is indicated only if:
  • Compressive symptoms develop (dysphagia, dyspnea, voice changes) 1
  • Significant cosmetic concerns 1
  • Nodule grows ≥3 mm in any dimension during surveillance 1
  • Discordance between benign cytology and highly suspicious clinical/ultrasound features (false-negative rate 11-33%) 1

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

• Consider molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations to refine malignancy risk (97% of mutation-positive nodules are malignant). 1
• Repeat FNA under ultrasound guidance if initial sample was inadequate. 1
• For Bethesda IV with normal TSH and "cold" appearance on scan, surgery is recommended for definitive diagnosis, as follicular carcinoma cannot be distinguished from adenoma on cytology alone. 1, 2

Bethesda V (Suspicious) or VI (Malignant)

• Refer immediately to an endocrine surgeon for total or near-total thyroidectomy for nodules ≥1 cm. 1, 2
• Perform pre-operative neck ultrasound to assess lymph node status and plan compartment-oriented lymph node dissection if metastases are suspected. 1

Common Pitfalls to Avoid

• Do not rely on thyroid function tests alone to assess malignancy risk—most thyroid cancers present with normal thyroid function. 1
• Do not perform radionuclide scanning in euthyroid patients to determine malignancy risk; ultrasound features are far more predictive. 1, 5
• Do not override a benign FNA result when worrisome clinical findings persist, as false-negative rates can reach 11-33%. 1
• Avoid FNA on purely cystic nodules without solid components or suspicious features, as these can be safely observed. 1
• Do not routinely perform FNA on nodules <1 cm without high-risk features to avoid overdiagnosis of clinically insignificant papillary microcarcinomas. 1

Summary Algorithm

1. High-resolution ultrasound → Document size, composition, echogenicity, margins, calcifications, vascularity 1, 3
2. Measure TSH → If low, obtain thyroid scan; if normal/high, proceed based on ultrasound 2, 4
3. FNA if: ≥1 cm with ≥2 suspicious features, OR >4 cm regardless of features, OR <1 cm with suspicious features + high-risk clinical factors 1, 2
4. Consider serum calcitonin to screen for medullary thyroid cancer 1, 2
5. Manage based on Bethesda classification: surveillance for benign, molecular testing for indeterminate, surgery for malignant 1, 2