How to manage a patient with a thyroid nodule showing atypia of undetermined significance on Fine Needle Aspiration (FNA) biopsy, a negative ThyGenX (thyroid genetic testing) result, and a moderate ThyraMIR (thyroid mirna testing) result?

Management of Thyroid Nodule with AUS/FLUS, Negative ThyGenX, and Moderate ThyraMIR

Given the moderate ThyraMIR result indicating intermediate malignancy risk (approximately 20-30% based on molecular testing data), combined with negative genetic testing, you should proceed with either diagnostic thyroid lobectomy or repeat FNA with ultrasound correlation, with the decision based on ultrasound features and clinical risk factors. 1

Risk Stratification Framework

The combination of atypia of undetermined significance (AUS/FLUS) with negative ThyGenX but moderate ThyraMIR creates an intermediate-risk scenario that requires careful assessment:

• Baseline malignancy risk for AUS/FLUS: The surgical malignancy rate for AUS/FLUS ranges from 22-56% across studies, with most contemporary series showing 37-56% malignancy when surgery is performed 2, 3
• Molecular testing interpretation: Negative genetic testing (ThyGenX) reduces but does not eliminate malignancy risk, while moderate ThyraMIR maintains intermediate concern 1
• Combined risk assessment: This molecular profile suggests a malignancy risk in the 20-40% range, which falls between "benign" and "suspicious for follicular neoplasm" categories 4

Algorithmic Management Approach

Step 1: Evaluate Ultrasound Features

High-risk ultrasound features mandate surgical intervention regardless of molecular testing results:

• Microcalcifications, irregular borders, central hypervascularity, taller-than-wide shape, or extrathyroidal extension 5
• Nodules <1.5 cm with two or more suspicious ultrasound features have significantly higher malignancy rates 6
• If high-risk ultrasound features are present: Proceed directly to diagnostic thyroid lobectomy 1

Step 2: Assess Clinical Risk Factors

High-risk clinical features lower the threshold for immediate surgery:

• Age <15 years or male gender 5
• History of head and neck irradiation 5, 1
• Family history of thyroid cancer or associated syndromes (MEN 2A/2B, familial adenomatous polyposis, Cowden's syndrome) 5
• Firm nodule, fixed to adjacent structures, rapid growth, enlarged regional lymph nodes, or vocal cord paralysis 5
• If ≥2 high-risk clinical features present: Proceed to diagnostic thyroid lobectomy 1

Step 3: Decision Algorithm for Intermediate-Risk Cases

For nodules without high-risk ultrasound or clinical features, choose between two management pathways:

Option A: Repeat FNA (Preferred Initial Approach)

• Perform ultrasound-guided repeat FNA to improve diagnostic accuracy 5
• Request on-site cytopathology evaluation if available to reduce inadequacy rates 5
• Critical caveat: Only 5.26% of patients with repeat AUS/FLUS findings who underwent surgery had confirmed malignancy, suggesting repeat AUS may indicate lower risk 3
• If repeat FNA shows benign findings, continue surveillance with ultrasound every 6-12 months 3
• If repeat FNA shows AUS/FLUS again (≥2 AUS results), this is a significant risk factor for malignancy and warrants surgical intervention 6

Option B: Diagnostic Thyroid Lobectomy

• Proceed directly to surgery if patient preference favors definitive diagnosis or if clinical anxiety is high 1, 2
• Lobectomy is appropriate for unifocal disease <4 cm without suspicious lymphadenopathy or bilateral nodularity 1
• Avoid total thyroidectomy as initial surgery unless bilateral disease, suspicious lymph nodes, or confirmed BRAF mutation 1

Critical Pitfalls to Avoid

• Do not assume benignity based solely on negative genetic testing: False-negative FNA results occur, and reassuring cytology should not override worrisome clinical findings 7
• Do not delay evaluation in nodules <1.5 cm: Smaller nodules with AUS/FLUS and suspicious ultrasound features have paradoxically higher malignancy rates 6
• Do not perform total thyroidectomy initially unless preoperative imaging shows bilateral disease or suspicious lymph nodes, as this leads to unnecessary morbidity in patients with benign final pathology 1
• Ensure expert pathology review: Have cytology slides reviewed by a pathologist with thyroid expertise at your treating institution, as interpretation variability significantly affects management 7
• Consider calcitonin measurement: Medullary thyroid carcinoma can be missed on routine FNA and may require immunohistochemical studies 5, 7

Surveillance Protocol if Conservative Management Chosen

If repeat FNA shows benign findings or patient declines surgery:

• Thyroid ultrasound every 6-12 months for at least 2 years 3
• Measure serum TSH, as higher levels correlate with increased malignancy risk 5, 8
• Maintain low threshold for surgical referral if nodule growth, new suspicious features, or clinical concern develops 5
• Do not continue indefinite observation if nodule demonstrates growth or changing characteristics 5