[18F]FET PET enables histopathology-validated detection of non-contrast-enhancing glioblastoma

Accurate visualization of glioblastoma is essential for guiding biopsy, resection and radiotherapy. Contrast-enhanced MRI is routine in clinical practice, yet it can miss metabolically active tumor outside areas of blood-brain barrier disruption. In a histopathology-validated cohort with 472 tissue samples of 61 patients with IDH-wildtype glioblastoma, we show that O-(2-[¹⁸F]fluoroethyl)-L-tyrosine PET ([ 18 F]FET PET) depicts tumor tissue significantly better than contrast-enhanced MRI (CE-MRI), especially in regions that show no enhancement on MRI. [ 18 F]FET PET achieves substantially higher sensitivity for tumor detection (91.2% vs 52.6%) and maintains high reliability in non-enhancing tissue (positive predictive value 98.3%), findings that are consistent across newly diagnosed and recurrent disease and in both cohorts undergoing either resection or biopsy. These results indicate that [ 18 F]FET PET complements MRI by revealing MRI-occult tumor burden. Incorporating amino acid PET into routine planning may therefore improve the accuracy of tumor visualization and, ultimately, patient management.