SUN-320 Etv6-ntrk3 Fusion-positive Papillary Thyroid Carcinoma: A Rare And Aggressive Presentation

Abstract Disclosure: A. Chahine: None. W. Harkens: None. S. Sandhu: None. Introduction: Papillary thyroid carcinoma (PTC) usually exhibits an indolent clinical course, but specific genetic alterations can drive aggressive disease. The ETV6-NTRK3 fusion, resulting from chromosomal translocation, produces a constitutively active chimeric tyrosine kinase, associated with more invasive tumor behavior.[1] ETV6-NTRK3 fusions have been identified in various malignancies, including secretory carcinoma, acute myeloid leukemia, and PTC.[2] Within PTC, this fusion is more frequently observed in radiation-associated cases and is associated with aggressive features.[2] We describe a rare case of ETV6-NTRK3 fusion-positive PTC with significant clinical implications in a young adult. Clinical Case: A 27-year-old male presented with a painless, enlarging right neck mass. He was otherwise asymptomatic and with no known radiation exposure. Physical examination revealed a firm, non-tender right thyroid mass without palpable lymphadenopathy. Thyroid US showed a 5×3.7×4.1 cm right-sided TI-RADS 4 nodule, prompting FNA. Initial labs: TSH 0.79 μIU/mL (0.4-4.0), free T4 1.1 ng/dL (0.8-1.8), T3 91 ng/dL (80-200), anti-TPO IgG 36 IU/mL (normal <35), anti-thyroglobulin antibodies <15 IU/mL. FNA cytology showed Bethesda III atypia with Hürthle cell and cystic degeneration (5-15% malignancy risk). Molecular testing (ThyroSeq) revealed an ETV6-NTRK3 fusion, strongly suggestive of PTC.The patient underwent total thyroidectomy with central neck dissection. Pathology confirmed extrathyroidal extension and metastatic PTC in 11/15 lymph nodes (pT3aN1b). Radioactive iodine therapy was administered. Subsequent imaging showed mild diffuse lung uptake. Chest CT was obtained and showed stable pulmonary micronodules (≤3 mm), concerning for micro-metastatic disease, though insufficient size for biopsy. Given the aggressive pathology, he is currently undergoing yearly imaging to monitor nodular growth. Conclusion: This case underscores the aggressive behavior of ETV6-NTRK3 fusion-positive PTC despite the typically favorable prognosis of PTC in young adults. Recognition and molecular characterization of NTRK fusion-driven tumors are critical for risk stratification, aggressive disease management, and potential use of targeted therapies.[1] Although NTRK fusions are actionable genomic targets with FDA-approved TRK inhibitors (larotrectinib and entrectinib), the optimal integration of these therapies into the clinical management of thyroid cancer remains an area of ongoing investigation. [1,3,4,5] References: [1] Solomon JP, Hechtman JF. Cancer Res. 2019;79(13):3163-3168. [2] Prasad ML, et al. Cancer. 2016;122(7):1097-1107. [3] Cocco E, et al. Nat Rev Clin Oncol. 2018;15(12):731-747. [4] Hong DS, et al. J Clin Oncol. 2020;38(4):536-536. [3] Drilon A, et al. Lancet Oncol. 2020;21(2):271-282. Presentation: Sunday, July 13, 2025