What is the next step in management for a patient with a thyroid fine-needle aspiration biopsy (FNAB) result showing Bethesda category III atypia of undetermined significance?

Management of Thyroid Nodule with Bethesda Category III Atypia of Undetermined Significance

For a thyroid fine-needle aspiration biopsy showing Bethesda category III atypia of undetermined significance (AUS/FLUS), molecular diagnostic testing should be performed as the next step to guide further management decisions.

Understanding Bethesda Category III (AUS/FLUS)

Bethesda Category III represents a challenging diagnostic category with intermediate risk of malignancy. According to the 2017 Bethesda System for Reporting Thyroid Cytopathology, this category includes:

• Atypia of undetermined significance (AUS)
• Follicular lesion of undetermined significance (FLUS)

The estimated risk of malignancy in this category ranges from 5-15% 1, though some studies have reported higher rates up to 22.8% 2.

Management Algorithm

1. Molecular Diagnostic Testing

   • Recommended as first-line approach for risk stratification
   • Tests detect individual mutations (BRAF V600E, RET/PTC, RAS, PAX8/PPARγ) or use pattern recognition approaches 1
   • Helps determine if the nodule is more likely benign or malignant

2. Based on Molecular Testing Results:

   • If molecular testing indicates benign lesion:

     • Active surveillance is appropriate
     • Follow with serial ultrasound examinations 1

   • If molecular testing suggests malignancy:

     • Consider lobectomy or total thyroidectomy for definitive diagnosis/treatment 1

   • If molecular testing is unavailable or inconclusive:

     • Consider repeat FNA (discussed below)
     • Consider clinical risk factors and ultrasound features to guide decision

3. Alternative Approach - Repeat FNA:

   • Can be considered if molecular testing is unavailable
   • Note: Repeat FNA often results in another indeterminate diagnosis (64% of cases) 3
   • Timing: Traditional recommendation was to wait 3 months, but evidence suggests timing does not significantly alter diagnostic results 4

Risk Factors to Consider

When evaluating AUS/FLUS nodules, consider these risk factors that may increase suspicion for malignancy:

• Ultrasound features:

  • Hypoechogenicity
  • Peripheral vascularization 2
  • Microcalcifications
  • Irregular borders 1

• Clinical factors:

  • Male gender (higher risk) 4
  • Age (younger patients have higher risk) 4
  • History of head and neck irradiation
  • Family history of thyroid cancer 1

Important Considerations

• The malignancy rate in AUS/FLUS may be higher than initially reported in the Bethesda system, with some studies showing rates of 19.8-24.3% 2.

• Molecular testing has high negative predictive value (100% in some studies), making it particularly useful for ruling out malignancy 3.

• Avoid the common pitfall of assuming AUS/FLUS is benign. The NCCN guidelines specifically state: "clinicians should continue evaluation of patients with a cystic neck mass, as determined by FNA or imaging studies, until a diagnosis is obtained and should not assume that the mass is benign" 1.

• Core biopsy may be considered as an alternative to repeat FNA in selected cases, with reported high adequacy rates (95%) and accuracy (94-96%) 1.

• For Hürthle cell neoplasms, molecular diagnostics may not perform well, and clinical risk factors and sonographic patterns should guide management 1.

By following this algorithm, you can appropriately risk-stratify patients with AUS/FLUS cytology and determine the optimal management approach to minimize unnecessary surgeries while ensuring that potentially malignant nodules are appropriately treated.