What is the recommended management approach for a Bethesda 3 (Atypia of Undetermined Significance) thyroid nodule?

Management of Bethesda 3 (AUS/FLUS) Thyroid Nodules

For Bethesda 3 thyroid nodules (Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance), repeat fine-needle aspiration (FNA) is recommended as the first step in management, followed by surgical intervention if repeat FNA remains inconclusive or shows suspicious features. 1

Risk Assessment and Initial Approach

The management of Bethesda 3 thyroid nodules should be guided by risk stratification using ultrasound features and clinical factors:

Ultrasound Risk Stratification

• Use the TI-RADS or K-TIRADS classification system to assess malignancy risk 1, 2
• Risk of malignancy varies significantly based on ultrasound features:
  • Low suspicion nodules: 27-60% malignancy risk 2
  • Intermediate suspicion nodules: 83-88% malignancy risk 2
  • High suspicion nodules: 88-100% malignancy risk 2

Risk Factors for Malignancy

Several factors are associated with higher malignancy risk in Bethesda 3 nodules:

• Ultrasound features:
  • Microcalcifications (OR=2.26) 3
  • Irregular shape (OR=4.37) 3
  • Hypoechogenicity, particularly highly hypoechoic nodules (58.3% malignancy risk) 4
  • Solid or nearly solid composition (28.7% malignancy risk) 4
  • Taller-than-wide shape (50% malignancy risk) 4
  • Lobulated margins (45.5% malignancy risk) 4
• Clinical factors:
  • Younger patient age 3, 5
  • Smaller nodule size (<2cm) (34.6% malignancy risk) 4, 3
  • Elevated TSH levels (>4.5 mIU/L) (35% malignancy risk) 4
  • Positive anti-thyroid peroxidase antibodies (OR=4.78) 3

Management Algorithm

1. Initial Diagnosis of Bethesda 3 (AUS/FLUS)

   • Confirm the diagnosis with expert cytopathology review

2. Risk Stratification

   • Perform comprehensive ultrasound evaluation and classify using TI-RADS/K-TIRADS
   • Assess clinical risk factors (age, TSH, antibody status)

3. Management Options Based on Risk

   a) High-Risk Features (TI-RADS 4-5, high suspicion on K-TIRADS, or multiple risk factors):

   • Consider surgical intervention (hemithyroidectomy or thyroidectomy) 1
   • Malignancy risk may be as high as 37.8-55.2% in these cases 4, 5

   b) Intermediate-Risk Features:

   • Repeat FNA in 3-6 months 1
   • If repeat FNA yields:
     • Benign: Follow with ultrasound surveillance
     • AUS/FLUS again: Consider surgery (26.3% malignancy risk with two consecutive AUS/FLUS diagnoses) 5
     • Suspicious or malignant: Proceed to surgery

   c) Low-Risk Features (TI-RADS 3, low suspicion on K-TIRADS, no risk factors):

   • Consider repeat FNA or observation 2
   • Conclusive results on repeat FNA are less likely (58.3%) compared to higher risk categories 2

Important Considerations

• The overall malignancy risk in Bethesda 3 nodules is higher than traditionally estimated at 5-15%, with recent studies showing rates of 26.6-37.8% 5, 6

• Papillary thyroid carcinoma (PTC) and its follicular variant are the most common malignancies found in AUS/FLUS nodules (39% PTC follicular variant, 27% classical PTC) 4

• K-TIRADS classification is excellent for predicting papillary carcinoma but less reliable for follicular carcinoma 2

• When surgery is performed, consider the following:

  • Nodules causing compressive symptoms
  • Cosmetic concerns
  • Nodules ≥2cm with gradual growth
  • Suspicious features on imaging or cytology 1

• For patients who undergo observation, regular monitoring with ultrasound at 3-6 month intervals is recommended 1

Pitfalls to Avoid

• Do not assume low malignancy risk based solely on the Bethesda 3 classification; consider ultrasound features and clinical risk factors
• Avoid overtreatment of low-risk nodules with no suspicious features
• Do not underestimate the malignancy risk in Bethesda 3 nodules, particularly in high-volume or referral centers where rates may exceed 25% 5
• Remember that K-TIRADS has limitations in detecting follicular carcinoma 2