Exploring the mechanism of 18F-fluorodopa uptake in recurrent high-grade gliomas: A comprehensive histomolecular-positron emission tomography analysis

Background: Dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-FDOPA) positron emission tomography (PET) is a valuable tool for managing high-grade gliomas (HGGs), but there is a lack of literature on its relationship with glioma subtypes since the 2021 reclassification of brain tumors. There is also debate surrounding the mechanism of 18F-FDOPA uptake, particularly after chemoradiation therapy. This study aimed to investigate the correlation between 18F-FDOPA uptake and histomolecular characteristics, particularly L-amino acid transporter 1 (LAT1) expression, in recurrent gliomas, and examine their impact on survival in HGGs.

Methods: Thirty-nine patients with recurrent HGGs (14 isocitrate dehydrogenase [IDH]-mutant, 25 IDH-wildtype) who underwent a brain 18F-FDOPA PET/computed tomography (CT) or PET/magnetic resonance imaging (MRI) followed by surgical resection of the 18F-FDOPA-avid lesion within 6 months, were retrospectively reviewed. PET results were compared with histological examination and for SCL7A5/LAT1 immunostaining. The study also examined the relationship between PET parameters, LAT1 expression, and survival outcomes.

Results: Astrocytoma IDH-mutant G4 had higher 18F-FDOPA uptake than glioblastoma IDH-wildtype G4 (maximum tumor-to-normal brain ratio [TBRmax] 5 [3.4-9] vs. 3.8 [2.8-5.9], p = 0.02). IDH-mutant gliomas had higher LAT1 expression than IDH-wildtype gliomas (100 [14-273] vs. 15.5 [0-137], p < 0.05) as well as higher TBRmax (5 [2.4-9] vs. 3.8 [2.8-6], p < 0.05). In survival analysis, LAT1 score >100 was a predictor for longer progression-free survival in IDH-mutant HGGs.

Conclusions: To our knowledge, our study is the first to suggest a link between LAT1 expression and IDH mutation status. We showed that higher TBRmax was associated with higher LAT1 expression and IDH mutation status. Further studies are needed to better understand the mechanisms underlying amino acid PET tracers uptake, especially in the post-radiation and chemotherapy settings.