Simple SummaryAround 25% of patients who undergo an ultrasound-guided thyroid biopsy end up with an indeterminate result based on cytology. This has propelled the use of other modalities, such as molecular testing, to further stratify these patients. The aim of our retrospective study was to report and compare two genetic mutations in our patient population. These mutations are RET/PTC and THADA/IGF2BP3 translocations, which have been hypothesized as oncogenic events in thyroid neoplasms. We confirm that our patient population exhibited these mutations, and all underwent a final histopathology analysis where surgery was the preferred treatment modality. We also report that the RET/PTC fusion exhibited more aggressive features than the THADA/IGF2BP3 fusion and was more likely to need post-surgical treatment.AbstractBackground: Molecular testing has been used as an adjunct to morphological evaluation in the workup of thyroid nodules. This study investigated the impact of two gene fusions,RET/PTCandTHADA/IGF2BP3, that have been described as oncogenic events in thyroid neoplasms. Methods: We performed a retrospective, single-centered study at a McGill University teaching hospital in Montreal, Canada, from January 2016 to August 2021. We included patients who underwent surgery for thyroid nodules that pre-operatively underwent molecular testing showing eitherRET/PTCorTHADA/IGF2BP3gene fusion. Results: This study included 697 consecutive operated thyroid nodules assessed using molecular testing, of which five had theRET/PTCfusion and seven had theTHADA/IGF2BP3fusion. Of the five nodules in theRET/PTCgroup, 100% were malignant and presented as Bethesda V/VI. Eighty percent (4/5) were found to have lymph node metastasis. Twenty percent (1/5) had extrathyroidal extensions. Sixty percent (3/5) were a diffuse sclerosing variant of papillary thyroid carcinoma, and the rest were the classical variant. Of the sevenTHADA/IGF2BP3nodules, all presented as Bethesda III/IV and 71.4% (5/7) were malignant based on the final pathology analysis, and 28.6% (2/7) were NIFTP. All theTHADA/IGF2BP3fusion malignancies were a follicular variant of papillary thyroid carcinoma. None had lymph node metastasis or displayed extrathyroidal extensions. Conclusions:RET/PTCnodules presented as Bethesda V/VI and potentially had more aggressive features, whereasTHADA/IGF2BP3nodules presented as Bethesda III/IV and had more indolent behavior. This understanding may allow clinicians to develop more targeted treatment plans, such as the extent of surgery and adjuvant radioactive iodine treatment.