Increased tryptophan transport in epileptogenic dysembryoplastic neuroepithelial tumors

Abstract

Dysembryoplastic neuroepithelial tumors (DNTs) are typically hypometabolic but can show increased amino acid uptake on positron emission tomography (PET). To better understand mechanisms of amino acid accumulation in epileptogenic DNTs, we combined quantitative α-[(11)C]methyl-L: -tryptophan (AMT) PET with tumor immunohistochemistry. Standardized uptake values (SUVs) of AMT and glucose were measured in 11 children with temporal lobe DNT. Additional quantification for AMT transport and metabolism was performed in 9 DNTs. Tumor specimens were immunostained for the L: -type amino acid transporter 1 (LAT1) and indoleamine 2,3-dioxygenase (IDO), a key enzyme of the immunomodulatory kynurenine pathway. All 11 tumors showed glucose hypometabolism, while mean AMT SUVs were higher than normal cortex in eight DNTs. Further quantification showed increased AMT transport in seven and high AMT metabolic rates in three DNTs. Two patients showing extratumoral cortical increases of AMT SUV had persistent seizures despite complete tumor resection. Resected DNTs showed moderate to strong LAT1 and mild to moderate IDO immunoreactivity, with the strongest expression in tumor vessels. These results indicate that accumulation of tryptophan in DNTs is driven by high amino acid transport, mediated by LAT1, which can provide the substrate for tumoral tryptophan metabolism through the kynurenine pathway, that can produce epileptogenic metabolites. Increased AMT uptake can extend to extratumoral cortex, and presence of such cortical regions may increase the likelihood of recurrent seizures following surgical excision of DNTs.

Fig. 1

Co-registered coronal slices of MRI (a), FDG PET (b), and AMT PET (c) images of a 10 year-old girl (patient #4) with a non-enhancing left inferior temporal DNT (arrow). FDG PET showed hypometabolism (FDG SUV tumor/cortex ratio: 0.45), while AMT PET demonstrated markedly increased tryptophan uptake (AMT SUV tumor/cortex ratio: 1.27) in the lesion

Fig. 2

Co-registered axial SPGR MRI (a), FDG PET (b), and AMT PET (c) images of a 6 year-old boy (patient #9) with a left medial temporal DNT (arrow). FDG PET demonstrated glucose hypometabolism of the tumor (FDG SUV tumor/contralateral cortex ratio: 0.29), and AMT PET showed no prominent tryptophan accumulation in the tumor volume (AMT SUV ratio: 0.99). However, an extensive area of ipsilateral cortex (mostly temporal, extending into parietal and occipital regions) showed a marked increase of AMT uptake (arrowheads) (SUV ipsilateral/contralateral cortex ratio: 1.21). Note that AMT accumulation seen in the bilateral occipital cortex and in the visualized portions of the basal ganglia is physiologic

Fig. 3

Immunohistochemistry for expression of the LAT1 and IDO in two DNTs. a A highly vascular tumor (patient #1, with the highest AMT SUV and VD-ratio of all patients) with prominent LAT1 and moderate to strong IDO expression in tumor blood vessels (such as the ones indicated by solid arrows). DNT neuronal cells showed variable (most commonly mild) staining for both proteins. The dashed arrows indicate tumor neurons with mild to moderate LAT1 (left) and IDO (right) staining intensity. Oligodendroglioma-like tumor cells rarely showed immuno-positivity for either protein in this case. b Patient #4, whose MRI and PET scans are shown in Fig. 1. As in most cases, tumor blood vessels showed strong LAT1 expression (solid arrow) along with mild immunostaining of cytoplasm of most neurons (dashed arrow on the left). Expression of IDO was variable with some cells showing moderate (dashed arrow) and a few cells with strong IDO staining intensity. Original magnification at ×20; scale bar 50 μm

Fig. 4

Variable IDO expression in both tumor neurons (black solid arrow) and oligodendroglioma-like cells (black dashed arrow) in the DNT of a 3 year-old boy (patient #3). Intense and widespread staining was seen in tumor blood vessels (white arrow). Original magnification at ×20; scale bar 50 μm