What is the recommended surveillance and management for a thyroid nodule with a follicular lesion of undetermined significance (FLUS)?

Management of Thyroid Nodules with Follicular Lesion of Undetermined Significance (FLUS)

For thyroid nodules with FLUS cytology, the recommended approach is molecular diagnostic testing (BRAF V600E, RET/PTC, RAS, PAX8/PPARγ) to guide management: if molecular testing indicates a benign lesion, active surveillance is appropriate; if molecular testing suggests malignancy, proceed to lobectomy or total thyroidectomy for definitive diagnosis and treatment. 1

Initial Risk Stratification

FLUS (also termed AUS - atypia of undetermined significance) represents an indeterminate cytology category with an estimated malignancy risk of 5-15%. 1 This intermediate-risk category requires careful clinical correlation with ultrasound features and patient-specific factors before determining the optimal management strategy.

Molecular Testing as Primary Decision Tool

Molecular diagnostics should be utilized to reclassify FLUS lesions as either more or less likely to be benign or malignant based on genetic profile. 1 The NCCN guidelines specifically recommend testing for BRAF V600E, RET/PTC, RAS, and PAX8/PPARγ mutations, as the presence of any mutation is a strong indicator of cancer (approximately 97% of mutation-positive nodules are malignant). 1

Management Based on Molecular Results:

• If molecular testing indicates benign lesion: Active surveillance is the recommended approach. 1 Lobectomy may still be considered for definitive diagnosis/treatment based on patient preference and clinical context. 1

• If molecular testing suggests malignancy: Consider lobectomy or total thyroidectomy for definitive diagnosis and treatment. 1 If BRAF V600E mutation is detected (suggesting papillary thyroid carcinoma), more aggressive surgical management may be warranted. 1

• If molecular testing predicts malignancy risk ≤5% (comparable to benign FNA): Active surveillance is appropriate when combined with favorable clinical and ultrasound features. 1

Alternative Approach: Repeat FNA

If molecular testing is not available or not performed, repeat FNA is the traditional recommended follow-up. 2 However, this approach has important limitations:

• Repeat FNA after initial FLUS yields another inconclusive result (nondiagnostic or AUS/FLUS) in 45-49% of cases. 3

• Core needle biopsy (CNB) is superior to repeat FNA for reducing inconclusive diagnoses (26.7% vs. 49.1% inconclusive results, p<0.001) and has higher sensitivity for malignancy (78.5% vs. 55.4%, p<0.001). 3

• Timing of repeat FNA (<3 months vs. ≥3 months) does not alter diagnostic results or management decisions. 4

Ultrasound Features That Modify Management

Specific ultrasound characteristics should be integrated with cytology and molecular results to guide decision-making: 1

• High-risk features: Hypoechogenicity, microcalcifications, irregular margins, absence of peripheral halo, solid composition, intranodular blood flow, and taller-than-wide shape. 1, 5

• Peripheral vascularization and hypoechogenicity are the most predictive ultrasound features for malignancy in FLUS nodules. 6

• Multiple suspicious ultrasound features increase specificity but decrease sensitivity when used alone. 1

Clinical Risk Factors Requiring Lower Threshold for Surgery

The following clinical factors should prompt consideration of surgical management even with equivocal molecular testing: 5

• History of head and neck irradiation 5
• Family history of thyroid cancer (particularly medullary thyroid carcinoma or familial syndromes) 5
• Age <15 years or male gender 5, 4
• Rapidly growing nodule 5
• Firm, fixed nodule on palpation 5
• Vocal cord paralysis or compressive symptoms 5
• Suspicious cervical lymphadenopathy 5

Special Considerations for Hürthle Cell Neoplasms

Molecular diagnostics are NOT recommended for Hürthle cell neoplasms, as molecular testing does not perform well for these lesions. 1 Clinical risk factors, sonographic patterns, and patient preference should guide the decision between active surveillance and lobectomy. 1

Nodules with Two Consecutive FLUS Results

Thyroid nodules with two consecutive AUS/FLUS results have a significantly elevated malignancy risk of at least 31% and should be considered for surgery regardless of ultrasound features. 7 These nodules have a higher proportion of follicular variant of papillary thyroid carcinoma (46.7% vs. 13.6% in single FLUS, p=0.009). 7

Surveillance Protocol When Active Surveillance is Chosen

When active surveillance is selected based on molecular testing suggesting benign disease: 1

• Continue monitoring with ultrasound at appropriate intervals
• Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient 1
• Maintain low threshold for surgical intervention if nodule characteristics change or new concerning features develop

Critical Pitfalls to Avoid

• Do not rely on ultrasound features alone to determine management, as they are insufficient predictors when used in isolation for FLUS nodules. 6

• Do not delay repeat evaluation beyond what is clinically necessary, as the traditional 3-month waiting period for repeat FNA does not improve diagnostic accuracy. 4

• Do not use thyroid function tests (TSH, T3, T4) or thyroglobulin measurement for malignancy assessment, as they provide little diagnostic value. 1

• Consider core needle biopsy over repeat FNA when additional tissue diagnosis is needed, as CNB provides superior diagnostic information. 3