• Pusztaszeri, Marc P.
• Hier, Michael P.
• Payne, Alexandra E.
• Forest, Véronique-Isabelle
• Payne, Richard J.
• Hudson, Thomas
• Elsherbini, Noha
• Kim, Dong Hyun

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The <jats:italic>EIF1AX</jats:italic> mutation has been identified in various benign and malignant thyroid lesions, with a higher prevalence in poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma, especially when combined with <jats:italic>RAS</jats:italic> or <jats:italic>TP53</jats:italic> mutation. However, data and clinical significance of <jats:italic>EIF1AX</jats:italic> mutations in thyroid nodules is still limited. We investigated the prevalence of <jats:italic>EIF1AX</jats:italic> mutations and co-mutations in cytologically indeterminate thyroid nodules at our institution. </jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A 5-year retrospective analysis was performed on surgically resected thyroid nodules with identified <jats:italic>EIF1AX</jats:italic> mutations on molecular testing with ThyroseqV3<jats:sup>®</jats:sup>. Mutation type and presence of co-mutations were correlated with histopathologic diagnosis and clinical characteristics. Histopathology diagnoses were subsequently categorized as benign, borderline, malignant or aggressive malignant (≥ 10% PDTC component). Chi-square test was used to compare the malignancy associations of the: 1) A113_splice mutation compared to non-A113_splice mutations 2) singular A113_splice mutations compared to singular non-A113_splice mutations. Fisher’s Exact Test was used to determine the association of A113_splice mutation with aggressive malignancies compared to non-A113_splice mutations. A <jats:italic>p</jats:italic> value of 0.05 or less was considered statistically significant. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Out of 1583 patients who underwent FNA, 621 had further molecular testing. 31 cases (5%) harbored <jats:italic>EIF1AX</jats:italic> mutations. Of these cases, 12 (38.7%) were malignant, 2 (6.5%) were borderline, and 17 (55%) were benign. 4/31 cases (13%) were aggressive malignant (≥ 10% PDTC component). The most prevalent mutation was the A113_splice mutation at the junction of intron 5 and exon 6 (48%). All other mutations, except one, were located at the N-terminal in exon 2. 7/31 cases (22.6%) harbored ≥ 1 co-mutation(s), including 4 <jats:italic>RAS, 3 TP53, 1 TERT and 1 PIK3CA,</jats:italic> with 86% of them being malignant. All 4 nodules with <jats:italic>RAS</jats:italic> co-mutations were malignant including one PDTC.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our study reports the largest cohort of <jats:italic>EIF1AX</jats:italic> mutations in Bethesda III/IV FNA samples with surgical follow-up to our knowledge. The presence of the <jats:italic>EIF1AX</jats:italic> mutation confers a 45.2% risk of malignancy (ROM) or borderline after surgery. However, the coexistence of <jats:italic>EIF1AX</jats:italic> mutations with other driver mutations such as <jats:italic>RAS, TERT</jats:italic> or <jats:italic>TP53</jats:italic> conferred an 86% ROM. While 55% of thyroid nodules were benign at the time of surgery, the possible malignant transformation of these nodules, had they not been resected, is unknown. Finally, 13% of the nodules with <jats:italic>EIF1AX</jats:italic> mutations were aggressive with a significant PDTC component. These findings can further aid in clinical decisions for patients with thyroid nodules.</jats:p></jats:sec><jats:sec><jats:title>Graphic Abstract</jats:title></jats:sec>

Topics

• impedance spectroscopy
• laser emission spectroscopy
• size-exclusion chromatography