Performance of Afirma genomic sequencing classifier and histopathological outcome are associated with patterns of atypia in Bethesda category III thyroid nodules

BACKGROUND: Data on Afirma’s genomic sequencing classifier (GSC) performance in atypia of undetermined significance (AUS) subcategories is limited. This study investigated GSC performance in AUS nodules with architectural atypia (AUS‐A), cytological atypia (AUS‐C), architectural and cytological atypia (AUS‐AC), and predominantly Hürthle cells (AUS‐HC). METHODS: This study retrieved consecutive thyroid nodules having a recurrent cytologic diagnosis of AUS with qualifiers and a concurrent GSC diagnostic result. All nodules were followed by either surgical intervention or clinical and/or ultrasound monitoring (≥6 months). GSC benign call rate (BCR), rate of histology‐proven malignancy, and diagnostic parameters of GSC were calculated for individual AUS subcategories. Statistical analysis was performed using the Fisher exact test. RESULTS: A total of 135 AUS nodules fulfilled inclusion criteria, including 79 AUS‐A, 9 AUS‐C, 29 AUS‐AC, and 18 AUS‐HC. BCR was 72.2%, 66.7%, 44.8%, and 77.8% in AUS‐A, AUS‐C, AUS‐AC, and AUS‐HC, respectively. AUS‐A showed a greater BCR than AUS‐AC (p < .05). All GSC‐benign nodules were considered benign on clinical or surgical follow‐up. Among GSC‐suspicious nodules, histology‐proven malignancies represented 4.5% of AUS‐A, 0% of AUS‐C, 56.3% of AUS‐AC, and 25.0% of AUS‐HC cases. AUS‐AC demonstrated a higher malignant rate compared with AUS‐A (p < .05). GSC offers 100% NPV and a wide range (5%–56%) of PPV across all AUS subcategories. AUS‐AC demonstrated a greater PPV compared with AUS‐A (p < .05). CONCLUSION: BCR of GSC and malignant rates associated with suspicious GSC may differ in various AUS subcategories. GSC‐suspicious nodules with both architectural and cytologic atypia are more likely to be malignant. These findings may improve clinical triage and/or management of patients with AUS thyroid nodules.