P03.26.A LACK OF LAT1/CD98 EXPRESSION ON TUMOR CELLS OF [¹⁸F]FET PET POSITIVE IDH-MUTANT GLIOMA: REVISITING THE MOLECULAR BASIS FOR AMINO ACID PET IMAGING AND THERANOSTICS

Abstract BACKGROUND Based on in vitro data it is assumed that O-(2-[18F]-fluoroethyl)-L-tyrosine ([¹⁸F]FET) PET positivity corresponds to tracer uptake by glioma cells via large neutral amino acid transporters (LAT), such as the heterodimer LAT1/CD98. We investigated protein expression of its subunits, LAT1 and CD98hc, in tumor tissue samples of patients with IDH-mutant glioma with and without [¹⁸F]FET uptake on PET imaging. MATERIAL AND METHODS A retrospective cohort of patients with IDH-mutant glioma with [¹⁸F]FET PET before initial diagnosis and available tumor tissue was identified to enable comparison between PET-positive and PET-negative cases (with and without “measurable disease” according to PET RANO 1.0 criteria, respectively) and correlation with LAT1/CD98 expression. LAT1 and CD98hc protein expression were assessed semi-quantitatively via immunohistochemistry. Microvascular density (MVD) was determined by semiautomatic quantification of CD34+ vessels within tumor regions. Imaging and histological evaluations were conducted blinded to PET data. RESULTS Eighteen patients were identified, 13 (72%) PET-positive and 5 (28%) PET-negative cases. Diagnoses included 7 astrocytomas (grade 2, n=4; grade 3, n=3) and 11 oligodendrogliomas (grade 2, n=5; grade 3, n=6). In all cases, LAT1 and CD98hc subunits were strongly and almost exclusively expressed on endothelial cells with the vast majority of tumor cells lacking strong immunostaining. There was no difference of LAT1 or CD98hc expression between PET-positive and PET-negative cases, and no correlation with target to background ratio (TBR) values or tumor grade. Oligodendrogliomas demonstrated significantly higher expression of LAT1 (p=0.004), but not CD98hc, on tumor cells compared to astrocytomas. MVD was higher in PET-positive than in PET-negative cases (113.4 vs. 73.1 vessels/mm², p=0.010), showed a moderate positive correlation with TBRmax (r=0.5142; p=0.029), and was higher in oligodendrogliomas than in astrocytomas (127.6 vs. 74.0 vessels/mm²; p=0.008). CONCLUSION LAT1 and CD98hc immunostaining in IDH-mutant gliomas labels mainly endothelial but not tumor cells, irrespectively of [¹⁸F]FET uptake. These findings are not in line with the assumed molecular basis of [¹⁸F]FET uptake in glioma cells and may be relevant for theranostic approaches.