Tryptophan PET in pretreatment delineation of newly-diagnosed gliomas: MRI and histopathologic correlates

Abstract

Pretreatment delineation of infiltrating glioma volume remains suboptimal with current neuroimaging techniques. Gadolinium-enhanced T1-weighted (T1-Gad) MR images often underestimate the true extent of the tumor, while T2-weighted images preferentially highlight peritumoral edema. Accumulation of α-[11C]methyl-l-tryptophan (AMT) on positron emission tomography(PET) has been shown in gliomas. To determine whether increased uptake on AMT–PET would detect tumor-infiltrated brain tissue outside the contrast-enhancing region and differentiate it from peritumoral vasogenic edema, volumes and spatial concordance of T1-Gad and T2 MRI abnormalities as well as AMT–PET abnormalities were analyzed in 28 patients with newly-diagnosed WHO grade II–IV gliomas. AMT-accumulating grade I meningiomas were used to define an AMT uptake cutoff threshold that detects the tumor but excludes peri-meningioma vasogenic edema. Tumor infiltration in AMT-accumulating areas was studied in stereotacticallyresected specimens from patients with glioblastoma. In the 28 gliomas, mean AMT–PET-defined tumor volumes were greater than the contrast-enhancing volume, but smaller than T2 abnormalities. Volume of AMT-accumulating tissue outside MRI abnormalities increased with higher tumor proliferative index and was the largest in glioblastomas. Tumor infiltration was confirmed by histopathology from AMT-positive regions outside contrast-enhancing glioblastoma mass, while no or minimal tumor cells were found in AMT-negative specimens. These results demonstrate that increased AMT accumulation on PET detects glioma-infiltrated brain tissue extending beyond the contrast-enhanced tumor mass. While tryptophan uptake is low in peritumoral vasogenic edema, AMT–PET can detect tumor-infiltrated brain outside T2-lesions. Thus, AMT–-PET may assist pretreatment delineation of tumor infiltration, particularly in high-grade gliomas.

Tryptophan PET-defined gross tumor volume offers better coverage of initial progression than standard MRI-based planning in glioblastoma patients

“…However, these thresholds seem to be tracer specific and thus need to be tested for each tracer separately. Our threshold of 36 % above uninvolved cortical SUV, is based on previously presented meningioma tumoral AMT-PET data, and has been shown to be reasonable on preliminary histopathologic correlation in glioma [23]. When the analysis was repeated with the more inclusive uptake threshold of 18 % above uninvolved cortex, the mean volume generated was predictably larger (80.0 vs. 48.8 cm 3 ) than the volume obtained using 36 % thresholding, but did not significantly improve upon coverage of the recurrent volume when used either alone (mean coverage, 78.9 vs. 72 %; p =0.083) or when composite PET-MRI volumes were generated (mean coverage, 80.9 vs. 76.2 %; p =0.062).…”

“…To determine the extent of increased gliomatous AMT uptake, a tumoral SUV threshold of 36 % above the calculated mean cortical SUV was utilized. This threshold was selected to exclude vasogenic edema, based on studies of AMT uptake patterns in primary brain tumors [23]. …”

“…We have previously demonstrated increased local AMT uptake on PET in all scanned patients with high-grade gliomas [20]. Additionally, we have histologically identified the presence of tumor-infiltrated tissue outside of the contrast-enhanced region, and indirectly differentiated it from vasogenic edema in a recent study comparing MRI and AMT-PET imaging modalities [23]. …”

Clinical Significance of Tryptophan Metabolism in the Nontumoral Hemisphere in Patients with Malignant Glioma

“…Moreover, under pathologic conditions, AMT-PET can also track the upregulation of the immunosuppressive kynurenine pathway (leading to enhanced conversion of tryptophan to kynurenine metabolites) in tumor tissue and epileptic foci (4–8). Increased tumoral AMT uptake is a hallmark of grade III–IV gliomas (9,10) and is also a strong imaging marker of poor survival when detected after initial glioma treatment (surgery and chemoradiation) (11). …”

PET for Therapy Response Assessment in Glioblastoma

“…The value of new amino acid PET tracers, such as α-11 C-methyl-tryptophan and 18 F-Fluciclovine as well as glutamine-based amino acid PET tracers has been evaluated with promising results in glioma patients in terms of tumor delineation, prognostication, and the differentiation of tumor recurrence from radiation injury (31,(118)(119)(120)(121)(122). Another interesting new PET target is the translocator protein (TSPO), a mitochondrial membrane protein highly expressed in activated microglia, macrophages, and neoplastic cells.…”