The aim of this study was to investigate the underlying mechanisms associated with fluorine-18 fluorodeoxyglucose (F-18 FDG) uptake in an incidentally detected thyroid cancer during nonthyroid cancer evaluation. Among 92 patients (10 men and 82 women; mean age, 56.2 +/- 10.9 years; age range, 26-78 years) with focal thyroid FDG uptake during nonthyroid cancer evaluation, 14 patients with cytologically confirmed papillary thyroid cancer were included. For semiquantitative analysis, the maximal standardized uptake value was calculated. Immunohistochemical studies were performed for hypoxia inducible factor 1 alpha (HIF1alpha), HIF2alpha, glucose transporter 1 (GLUT1), GLUT3, carbonic anhydrase IX (CA-IX), hexokinase type II (HK II), and vascular endothelial growth factor (VEGF). The significant findings of this study were as follows: (1) a lack of HIF1alpha and HIF2alpha expression; (2) low-degree expression of GLUT1 (1 patient), GLUT3 (5 of 14 patients), HK II (3 of 14 patients), and CA-IX (1 patient); and (3) high degree expression of VEGF (all 14 patients). The data presented in this study indicate that F-18 FDG uptake in incidentally detected thyroid cancer was not related to hypoxia-induced upregulation of GLUT1, GLUT3, CA-IX, and HK II. Ki-67 expression was not associated with F-18 FDG uptake. However, all incidentally detected thyroid cancers showed a high degree of expression of VEGF.