L-type amino acid transporter (LAT) 1 expression in 18F-FET-negative gliomas

Abstract

Background: O-(2-[¹⁸F]-fluoroethyl)-L-tyrosine (¹⁸F-FET) is a highly sensitive PET tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1). However, 30% of low- and 5% of high-grade gliomas do not present enhanced ¹⁸F-FET uptake at primary diagnosis ("¹⁸F-FET-negative gliomas") and the pathophysiologic basis for this phenomenon remains unclear. The aim of this study was to determine the expression of LAT1 in a homogeneous group of newly diagnosed ¹⁸F-FET-negative gliomas and to compare them to a matched group of ¹⁸F-FET-positive gliomas. Forty newly diagnosed IDH-mutant astrocytomas without 1p/19q codeletion were evaluated (n = 20 ¹⁸F-FET-negative (tumour-to-background ratio (TBR) < 1.6), n = 20 ¹⁸F-FET-positive gliomas (TBR > 1.6)). LAT1 immunohistochemistry (IHC) was performed using SLC7A5/LAT1 antibody. The percentage of LAT1-positive tumour cells (%) and the staining intensity (range 0-2) were multiplied to an overall score (H-score; range 0-200) and correlated to PET findings as well as progression-free survival (PFS).

Results: IHC staining of LAT1 expression was positive in both, ¹⁸F-FET-positive as well as ¹⁸F-FET-negative gliomas. No differences were found between the ¹⁸F-FET-negative and ¹⁸F-FET-positive group with regard to percentage of LAT1-positive tumour cells, staining intensity or H-score. Interestingly, the LAT1 expression showed a significant negative correlation with the PFS (p = 0.031), whereas no significant correlation was found for TBR_max, neither in the overall group nor in the ¹⁸F-FET-positive group only (p = 0.651 and p = 0.140).

Conclusion: Although LAT1 is reported to mediate the uptake of ¹⁸F-FET into tumour cells, the levels of LAT1 expression do not correlate with the levels of ¹⁸F-FET uptake in IDH-mutant astrocytomas. In particular, the lack of tracer uptake in ¹⁸F-FET-negative gliomas cannot be explained by a reduced LAT1 expression. A higher LAT1 expression in IDH-mutant astrocytomas seems to be associated with a short PFS. Further studies regarding mechanisms influencing the uptake of ¹⁸F-FET are necessary.

Keywords: FET PET; Glioma; LAT1; Molecular imaging.

Fig. 1

Patient example with a A ¹⁸F-FET-positive, WHO grade II glioma with a high ¹⁸F-FET-uptake (TBR_max 4.36) and small nodular contrast enhancement on MRI but with very low LAT1 tumour cell expression (H-score 9.0) and slightly positive vessels in the SLC7A5 immunohistochemical (IHC) staining in contrast to a B ¹⁸F-FET-negative, WHO grade II glioma (TBR_max 1.27) with T2 alterations and missing contrast enhancement on MRI but a very high LAT1 expression (H-score 102.0) and intensive vessel staining

Fig. 2

LAT1 overall H-score (A), the LAT1 H-score tumour cells (B) and the LAT1 H-score vessels (C) in the ¹⁸F-FET-negative and ¹⁸F-FET-positive gliomas

Fig. 3

Distribution of the TBR_max (A) and TBR_mean (B) over the LAT1 overall H-score in the three groups of ¹⁸F-FET-photopenic, ¹⁸F-FET-negative and ¹⁸F-FET-positive gliomas: no correlation was found for the LAT1 overall score and the ¹⁸F-FET-PET parameter. R² values are displayed in the legend (A)

Fig. 4

Survival analysis of the LAT1 expression in the overall group (A), in WHO grade II astrocytomas (B), of ¹⁸F-FET-positive versus ¹⁸F-FET-negative astrocytomas (C) and of the WHO grade II and III astrocytomas (D)