Stefanie Quach

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.

BACKGROUND: MRI and PET imaging using radiolabeled amino acids offer a valuable adjunct for defining the extent of tumor growth in gliomas, assessing treatment response, and distinguishing true progression from pseudoprogression. OBSERVATIONS: The authors report the case of a 37-year-old patient with intractable epilepsy and suspected recurrence of an oligodendroglioma. MRI revealed progressive gadolinium enhancement in the right frontal lobe, and both fluorethylthyrosine PET and translocator protein imaging demonstrated high tracer uptake in the same region, raising concern for tumor recurrence and progression. The patient underwent extensive resection of the right frontal lobe beyond contrast enhancement. Postoperatively, seizures were well controlled. Interestingly, histopathological analysis revealed predominantly normal brain tissue next to a limited area of tumor recurrence, demonstrating that the observed MRI and PET abnormalities were seizure-induced changes rather than tumor recurrence. LESSONS: In patients with epileptic seizures, MRI and PET abnormalities may overestimate tumor recurrence and should be interpreted with caution. https://thejns.org/doi/10.3171/CASE25589

The rising incidence of meningiomas, coupled with the aggressive behavior observed in a subset of these tumors, presents significant clinical challenges. Accurate diagnosis and risk stratification are essential for effective patient management. This review offers a comprehensive overview of the evolving diagnostic landscape for meningiomas. It examines the roles of MRI, CT, and PET imaging - particularly somatostatin receptor type 2 (SSTR2) PET - in tumor detection and differentiation. In addition, it discusses the integration of molecular markers into the 2021 WHO classification and highlights the potential of multiomics analyses to enhance tumor classification and prognostication. It also addresses challenges related to standardization, clinical implementation, and accessibility of these advanced diagnostic tools. A literature search was conducted using PubMed and clinicaltrials.gov to identify clinical trials exploring the use of SSTR2 PET and treatments informed by molecular diagnostic findings. The integration of molecular data with advanced imaging techniques offers significant promise for the development of an integrated diagnostic framework for meningiomas. This approach has the potential to improve risk stratification and support the implementation of personalized treatment strategies. However, achieving this will require extensive correlative research and the establishment of large, high-quality datasets that combine imaging, molecular, and clinical information.

Characteristics of the cohort.

Contralateral TSPO-PET signal elevation is associated with tumor phenotype and localization. A and B, Correlation of contralateral TSPO-PET signals in patients with glioblastoma (n = 38) with the TSPO-PET signal of the tumor (A) and the tumor volume in TSPO-PET, FET-PET (B, left), and MRI (B, right). C, Examples of TSPO-PET images derived from patients with distinct tumor extent and TSPO expression in PET indicate distinct contralateral PET signal elevation. D, Overall correlation between corresponding areas of the tumor and the contralateral hemispheres including all 123 brain sub-regions of each individual patient. E, Correlation of regionally defined tumor seed regions with TSPO-PET signals of the 123 sub-regions in the contralateral hemisphere. Surface projection of tumor seed localization (top rows: seed region, colored in black) and corresponding contralateral coefficients of correlation (bottom rows). IFG, inferior-frontal gyrus; ITG, inferior-temporal gyrus; MesTemp, mesio-temporal; MFG, mid-frontal gyrus; Motor, motor area; MTG, mid-temporal gyrus; OFG, orbitofrontal gyrus; SFG, superior-frontal gyrus; STG, superior-temporal gyrus. F, Correlation of both hemispheres within 15 previously defined anatomically and functionally connected brain regions. Highest coefficients of correlation are colored in red, significant correlations are highlighted by thick boundaries.

Back-translation into a glioblastoma mouse model pinpoints myeloid cells as the cellular source of contralateral TSPO-PET signal elevations. A, Glioblastoma mice (n = 15) show higher TSPO-PET signal in the contralateral hemisphere compared to sham injected animals (n = 14). B, Coronal slices of group average TSPO-PET images of SB28 glioblastoma mice (top row; n = 15) and sham injected mice (bottom row; n = 14). Analyzed planes are indicated upon a CT template. Arrows point to the PET signal elevation in the contralateral hemisphere of SB28 mice. Tumor hemisphere is blurred. C, Whole brain tumor seed correlation analysis shows dependency of contralateral TSPO-PET signals (white arrows) from tumor TSPO-PET signals in SB28 mice (n = 15). Tumor TSPO-PET signals were extracted using a spherical volume of interest with 1.5 mm diameter and included as a seed in a voxel-wise statistical parametric mapping regression model. D, CD11b positive myeloid cells of the contralateral hemisphere of glioblastoma mice (n = 13) show higher single-cell TSPO tracer uptake than myeloid cells of sham injected (n = 14) or healthy control mice (n = 8; left). Non-myeloid cells show no difference in TSPO tracer uptake between the three conditions (right). E and F, Immunohistochemistry shows higher myeloid cell abundance and increased TSPO in IBA1 positive myeloid cells in contralateral hemispheres of SB28 glioblastoma mice (n = 3) compared to sham (n = 4). G, qPCR was used to exclude infiltration of SB28 glioblastoma cells into the contralateral hemispheres in SB28 glioblastoma mice (n = 8; left). Tumor tissue was used as a positive control. While tumor cells could only be detected in the tumor tissue, TSPO expression was observed in contralateral hemispheres of SB28 glioblastoma mice and exceeded TSPO expression in sham injected (n = 4) and healthy control mice (n = 4, right). (Adapted from an image created with BioRender.com.)

Elevated TSPO-PET signals in the non-lesional hemisphere of patients with glioblastoma. A, Patient selection process. Patients receiving TSPO-PET imaging at initial diagnosis of glioma were allocated. Patients with unilateral manifestation of glioblastoma (WHO IV; n = 41) or isocitrate dehydrogenase mutant astrocytoma WHO grade 2 (IDHmut astrocytoma WHO 2; n = 7) at the time of PET were selected for further analysis. B, Patients with newly diagnosed glioblastoma but not patients with IDHmut astrocytoma WHO 2 indicate higher TSPO-PET signal in the contralateral hemisphere compared to healthy controls. Images represent examples of TSPO-PET images of patients with newly diagnosed glioblastoma (left) and IDHmut astrocytoma WHO 2 (middle) in comparison to a healthy control (right). C, Surface projections and axial slices of the group average contralateral TSPO-PET signal of patients with glioblastoma, IDHmut astrocytoma WHO 2, and healthy controls. The non-lesional hemispheres were parcellated into 123 sub-regions using the Brainnetome Atlas. Axial slices show TSPO-PET signals of basal ganglia regions (masked cortical regions). D, Significant TSPO-PET signal elevation in brain regions of the contralateral hemisphere of patients with glioblastoma but not with IDHmut astrocytoma WHO 2 compared to healthy controls. E, Pronounced contralateral TSPO expression in orbito-frontal, superior-temporal, mid-temporal, and mesio-temporal regions of patients with glioblastoma. *, P < 0.01.

Supplementary Figures 1, 2 Supplementary Tables 1 - 3 inlucing Representativeness of Study Participants" supplementary table (Supplementary Table 1)

Contralateral hemispheres of SB28 glioblastoma mice indicate signatures of disease-associated myeloid cells and immunosuppression. A, Volcano plot highlights genes with significant upregulation and downregulation in the contralateral hemisphere of SB28 glioblastoma mice (red and blue, respectively) compared to sham. B, qPCR reveals higher expression of genes related to an inflammatory myeloid cell state in contralateral hemispheres of SB28 glioblastoma mice in contrast to sham. C, Illustration of the 50 pathways with highest elevation in immune cells of the contralateral hemisphere of SB28 glioblastoma mice (informed by IPA). Note that 40 out of the 50 pathways with highest activation were related to cell migration (phagocytes, leukocytes), phagocytosis, and immune cell activation (indicated in blue). D, IPA network analysis based on altered gene expression signatures in contralateral hemispheres of SB28 glioblastoma mice in contrast to sham. Depicted is a network plot showing TSPO-mediated associations with poor prognosis (e.g., CCL2) and immunosuppression (e.g., CHI3L1).