What is the management approach for a patient with a left thyroid nodule and a fine needle aspiration (FNA) biopsy result of Bethesda category 3, atypia of undetermined significance?

Management of Bethesda Category 3 (AUS/FLUS) Thyroid Nodules

Primary Management Decision

For a thyroid nodule with Bethesda category 3 cytology, the critical first step is determining whether nuclear atypia is present on cytology—if nuclear atypia is documented, proceed directly to surgical resection or molecular testing for risk stratification; if nuclear atypia is absent, pursue molecular testing first to guide management. 1

Risk Stratification Based on Cytologic Subtype

The malignancy risk for Bethesda III nodules varies significantly based on cytologic features:

• Nuclear atypia (AUS) carries a malignancy risk of 42-79%, substantially higher than other Bethesda III subtypes 1
• Follicular lesion of undetermined significance (FLUS) without nuclear atypia has a lower malignancy risk of 10.8% compared to 41.3% for AUS 2
• The overall malignancy risk for Bethesda III nodules ranges from 5-34%, depending on the specific cytologic subtype 3, 4

Algorithmic Management Approach

Step 1: Assess for Nuclear Atypia

• Review the cytology report specifically for documentation of nuclear atypia features 1
• If nuclear atypia is present, the combination with high-risk ultrasound features independently increases malignancy risk 1

Step 2: Ultrasound Risk Stratification

Evaluate the nodule using ACR TI-RADS or ATA sonographic patterns:

• High-risk ultrasound features include: hypoechogenicity, microcalcifications, irregular margins, taller-than-wide shape, and lobulated borders 3, 4, 2
• Nodules with suspicious ultrasound features (ACR TI-RADS 5) have malignancy rates up to 55.2% in Bethesda III category 4
• Combined risk assessment: Nodules with both nuclear atypia and suspicious ultrasound features have malignancy rates up to 87%, while FLUS nodules with benign ultrasound features have only 3.9% malignancy risk 2

Step 3: Molecular Testing Strategy

For nodules WITHOUT nuclear atypia:

• Pursue molecular diagnostic testing (BRAF V600E, RET/PTC, RAS, PAX8/PPARγ) to reclassify the nodule 3
• BRAF V600E mutation has 100% specificity for papillary thyroid carcinoma 1
• Mutation-positive nodules have approximately 97% malignancy rate 3
• Exception: Do not use molecular testing for Hürthle cell neoplasms, as it performs poorly in this subtype 3

For nodules WITH nuclear atypia:

• Molecular testing may be used for further risk stratification, but direct surgery is also appropriate 1
• High-risk ultrasound features combined with nuclear atypia warrant proceeding directly to surgery 1

Step 4: Surgical Decision-Making

Proceed directly to surgery if:

• Nuclear atypia is present on cytology 1
• BRAF V600E mutation is confirmed 1
• High-risk clinical factors are present: history of head and neck irradiation, family history of thyroid cancer, age <15 years, male gender, rapidly growing nodule 1, 3
• Suspicious cervical lymphadenopathy is identified 1
• Ultrasound assessment is "suspicious for malignancy" (100% malignancy rate in this scenario) 5

Surgical extent:

• Lobectomy is acceptable for unifocal disease <4 cm without suspicious lymphadenopathy 1
• Total thyroidectomy is recommended if BRAF mutation confirmed, bilateral nodules present, or suspicious cervical lymph nodes identified 1

Step 5: Active Surveillance Option

Consider active surveillance with repeat FNA if:

• Molecular testing indicates benign lesion 3
• Ultrasound features are "probably benign" (7.7% malignancy rate) 5
• No nuclear atypia present and FLUS subtype confirmed 2
• No high-risk clinical factors present 3

Critical Clinical Pitfalls

• Do not rely on thyroid function tests (TSH, T3, T4) or thyroglobulin for malignancy assessment—these provide little diagnostic value 3
• Measure serum calcitonin to screen for medullary thyroid carcinoma, which has higher sensitivity than FNA alone 1
• Ensure pathology review by an experienced thyroid pathologist, as FNA can have false-negative results that should not override worrisome clinical findings 6
• Repeat FNA may be considered for nodules with low-risk features, but 48.6% will remain Bethesda III on repeat biopsy 4

Special Considerations for Hürthle Cell Lesions

• Hürthle cell AUS/FLUS nodules have lower malignancy rates compared to other Bethesda III subtypes 7
• Molecular diagnostics are not recommended for Hürthle cell neoplasms 3
• Management should be guided by clinical risk factors, sonographic patterns, and patient preference rather than molecular testing 3