What is the best confirmatory investigation for a patient with a thyroid nodule larger than 1.3 cm and normal Thyroid-Stimulating Hormone (TSH), Triiodothyronine (T3), and Thyroxine (T4) levels?

Best Confirmatory Investigation for Thyroid Nodule >1.3 cm with Normal Thyroid Function Tests

The best confirmatory investigation for a thyroid nodule larger than 1.3 cm with normal TSH, T3, and T4 levels is Fine Needle Aspiration Cytology (FNAC). 1

Rationale for FNAC as First-Line Investigation

• FNAC is recommended as the gold standard confirmatory test for thyroid nodules >1 cm regardless of thyroid function test results, as it provides the most sensitive and specific method for differentiating between benign and malignant nodules 1
• Thyroid cancer is relatively rare (approximately 5% of all thyroid nodules), making FNAC crucial for appropriate risk stratification in patients with thyroid nodules 1
• Normal thyroid function tests (TSH, T3, T4) do not rule out malignancy, as most thyroid cancers present with normal thyroid function 1
• FNAC allows for direct cytological examination of the nodule, which is essential for definitive diagnosis and treatment planning 1

Role of Ultrasound in the Diagnostic Algorithm

• Ultrasound should be used as a first-line imaging procedure to characterize the nodule and guide FNAC, but is not sufficient alone for definitive diagnosis 1
• Ultrasound features associated with increased malignancy risk include hypoechogenicity, microcalcifications, absence of peripheral halo, irregular borders, solid aspect, and abnormal blood flow 1
• Ultrasound measurement of nodule size has relatively good correlation with final pathologic size (R² = 0.748), though correlation decreases with larger nodules 2, 3

Limitations of Other Imaging Modalities

• MRI and CT are not recommended as first-line investigations for thyroid nodules as they provide less specific information about nodule characteristics compared to ultrasound followed by FNAC 1
• Thyroid scintigraphy is now rarely used in the work-up of a thyroid nodule except in the presence of a low TSH value 4

Important Clinical Considerations

• Nodule size alone is not a reliable predictor of malignancy 5
• Some studies suggest that smaller nodules may actually have higher malignancy rates than larger ones 2, 6
• Multiple nodules may be associated with a higher risk of malignancy (41.1% vs. 26.4%) compared to solitary nodules 6
• For nodules with indeterminate FNAC results, molecular testing for mutations (BRAF, RAS, RET/PTC, PAX8/PPARc) may provide additional diagnostic information 1
• False negative FNAC diagnoses are highest (6-8%) in nodules 3-6 cm, mostly due to encapsulated follicular variant of papillary carcinoma 2

Management Algorithm for Thyroid Nodule >1.3 cm with Normal Thyroid Function

1. Perform ultrasound to characterize the nodule and determine exact size 1
2. Proceed with ultrasound-guided FNAC as the confirmatory investigation 1
3. Based on FNAC results (using Bethesda classification):
   • If benign: follow-up with periodic ultrasound 1
   • If malignant: proceed with appropriate surgical management 1
   • If indeterminate/suspicious: consider molecular testing and/or surgical consultation 1
4. If FNAC yields inadequate samples, the procedure should be repeated 1

Therefore, among the options provided (A. MRI, B. US, C. CT, D. FNAC), the correct answer is D. FNAC as the best confirmatory investigation for a thyroid nodule >1.3 cm with normal thyroid function tests.