[18F]DOPA PET identifies metabolically active tumor beyond contrast-enhancing margins in IDH-WT glioblastoma: A histopathology and fluorescence validation study

Abstract Background Supramaximal resection in IDH-wildtype glioblastoma (GB) improves survival, yet identifying tumor infiltration within FLAIR-hyperintense peritumoral areas remains challenging. This study aims to validate the use of [18F]DOPA PET for identifying metabolically active tumor beyond contrast-enhancing (CE) margins, correlating imaging with histopathology and intraoperative fluorescence. Methods Patients with newly diagnosed IDH-WT GB scheduled for supramaximal resection and undergoing preoperative DOPA-PET and MRI were prospectively enrolled from the ResPGlioma study. The Biological Tumor Volume (BTV) was semi-automatically delineated using the contralateral striatal SUVmean as the PET positivity threshold. Before resection, biopsy samples were collected from five radiologically distinct areas: CE, FLAIR+PET (FP), PET-only (Po), FLAIR-only (Fo), and normal tissue (N). Each sample was blindly assessed for neoplastic, necrotic, and infiltrative components, mitotic count, microvascular proliferation. Intraoperative 5-aminolevulinic acid (5-ALA) and fluorescein sodium (FS) uptake were also recorded. Results Twenty-five samples from 5 patients were analyzed. The BTV, defined using a striatal SUVmean threshold, extended beyond CE-MRI margins in 100% of cases (mean BTV 30.4 ± 17.6 cm³ vs. mean CE volume 20.6 ± 16.9 cm³). PET-positive areas (FLAIR+/PET+ and PET-only) showed significantly higher neoplastic cell density and mitotic counts compared to FLAIR-only (P < .005) and normal areas (P < .005). No significant histopathological differences were found between PET-only and CE regions, whereas FLAIR-only samples primarily exhibited white matter infiltration and reactive changes. Uptake of 5-ALA and SF was significantly more intense and frequent in PET-positive areas (CE, FP, Po) compared to Fo and N areas (P = .015 and P < .001, respectively). Conclusions This preliminary study provides histopathological and fluorescence validation that [18F]DOPA PET identifies areas of high tumor burden within the peritumoral zone, comparable to the contrast-enhancing core. The integration of amino acid PET in preoperative planning should be considered to guide targeted supramaximal resection of metabolic hotspots in IDH-wildtype glioblastoma.