Prognostic Indicators of EIF1AX-Mutated Thyroid Tumor Malignancy and Cancer Aggressiveness

SIMPLE SUMMARY: Ultrasound-guided fine-needle aspiration (USFNA) biopsy is a widely used first-line diagnostic approach to differentiate between benign and malignant tumors. However, 15–30% of all thyroid nodules investigated by USFNA cytology are indeterminate. To address the elusive clinical management of such nodules, molecular markers for common mutations in thyroid cancer have been researched to serve as prognostic indicators. EIF1AX is a rare mutation with no clear prognostic indicators. In this multicenter study of 42 EIF1AX-mutated thyroid nodules, we found that 47.6% of nodules were malignant with distinctive risks of malignancy depending on the location of the mutation and the presence of co-mutation(s). An EIF1AX A113_splice site mutation in tandem with a RAS and/or TP53 mutation is associated with aggressive malignancies that have an inherent potential to progress toward poorly differentiated thyroid carcinoma. ABSTRACT: The risk of malignancy (ROM) of EIF1AX-mutated thyroid nodules has been theorized to be contingent on the position of the mutation within the gene and the presence of co-existing mutations. However, due to EIF1AX’s low mutation frequency, sample sizes currently reported in the literature are too diminutive to appraise the clinical utility of molecular diagnostic testing. The objective of this study was to elucidate prognostic indicators of EIF1AX-mutated thyroid tumors and cancer aggressiveness by examining a large cohort of cytologically indeterminate thyroid nodules (CITNs) that underwent molecular testing and subsequent surgical resection. This is a multicenter study involving 764 subtotal and total thyroidectomy patients that underwent preoperative molecular testing at two quaternary care hospitals. A five-year retrospective review was performed on the 42 charts of patients that opted for surgery following a positive EIF1AX mutation on ThyroseqV3 results from January 2018 to May 2022. Patient demographics, cytopathology results, molecular testing results, and postoperative histopathology were reviewed. Of the 42 surgically resected nodules that harbored an EIF1AX mutation, 16 (38.1%) were benign, six (14.3%) were non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs) or well-differentiated thyroid neoplasms of uncertain malignant potential (WDT-UMPs), and 20 (47.6%) were malignant. An isolated EIF1AX mutation conferred a ROM of 47.6%, whereas the ROM for nodules with at least one additional molecular alteration was 72.7%. The ROM increased to 100% for nodules with at least one additional molecular alteration and the A113_splice site mutation. Six malignant nodules were aggressive, with five having variegated components of poorly differentiated thyroid carcinoma (PDTC). EIF1AX-mutated thyroid nodules are more susceptible to malignancy in the presence of the A113_splice site mutation and when co-mutated with RAS and/or TP53. This deleterious amalgam is associated with aggressive disease and renders these nodules PDTC. A preoperative molecular test finding of an EIF1AX mutation can be a useful tool for thyroid specialists to optimize clinical management.