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Background: FDG (2-[18F]Fluoro-2-D-deoxyglucose-positron emission tomography (PET)/computed tomography (CT), which can detect a change in glucose metabolism in cancer cells, has been introduced as a diagnostic and prognostic tool in papillary thyroid carcinoma (PTC). However, differences in the clinicopathological and biological characteristics between primary PTCs with FDG uptake and those without FDG uptake are not well established. Methods: A total of 188 patients with PTC who had preoperative PET/CT scans were enrolled to compare the differences of clinicopathological parameters between FDG-avid (F-PTC; n=150) and non-FDG-avid tumors (FN-PTC; n=38). Immunohistochemical staining for glucose transporter (GLUT)-1 and hypoxia-inducible factor-1 alpha (HIF-1α) was performed. Results: FN-PTCs were smaller; had a lower incidence of lymphatic invasion, vascular invasion, multifocality, and central lymph node metastasis; and had a lower maximum standardized uptake value than F-PTCs. After exclusion of high-risk patients for recurrence, FN-PTCs remained smaller ( p<0.001) and had less lymphatic invasion ( p=0.061). Among tumors larger than the spatial resolution of the PET/CT scan, macrocalcification was more frequent in FN-PTC than in F-PTC ( p=0.043). While FN-PTC and F-PTC showed no difference in GLUT-1 expression (50% vs. 75%, p=0.363), FN-PTC showed lower HIF-1α immunoreactivity than F-PTC (25.0% vs. 75.0%, p=0.032). Conclusion: Tumor size and macrocalcification are clinicopathological differences between FN-PTC and F-PTC. Biologically, HIF-1α may be responsible for increased FDG uptake in PTC. [ABSTRACT FROM AUTHOR]