Hypermetabolism and impaired cerebrovascular reactivity beyond the standard MRI-identified tumor border indicate diffuse glioma extended tissue infiltration

Abstract

Background: Diffuse gliomas exhibit diffuse infiltrative growth, often beyond the magnetic resonance imaging (MRI)-detectable tumor lesion. Within this lesion, hypermetabolism and impaired cerebrovascular reactivity (CVR) are found, but its exact distribution pattern into the peritumoral environment is unknown. Our aim was to better characterize the extent of diffuse glioma tissue infiltration, beyond the visible lesion (ie, beyond the T1-contrast-enhancing lesion and/or T2/FLAIR-defined tumor border), with metabolic positron emission tomography (PET), and functional MRI CVR (blood oxygenation-level-dependent CVR [BOLD-CVR]) mapping.

Methods: From a prospective glioma database, 18 subjects (19 datasets) with diffuse glioma (n = 2 with anaplastic astrocytoma, n = 10 with anaplastic oligodendroglioma, and n = 7 with glioblastoma) underwent a BOLD-CVR and metabolic PET study between February 2016 and September 2019, 7 of them at primary diagnosis and 12 at tumor recurrence. In addition, 19 matched healthy controls underwent an identical BOLD-CVR study. The tumor lesion was defined using high-resolution anatomical MRI. Volumes of interest starting from the tumor lesion outward up to 30 mm were created for a detailed peritumoral PET and BOLD-CVR tissue analysis. Student's t test was used for statistical analysis.

Results: Patients with diffuse glioma exhibit impaired BOLD-CVR 12 mm beyond the tumor lesion (P = .02) with normalization of BOLD-CVR values after 24 mm. Metabolic PET shows a difference between the affected and contralateral hemisphere of 6 mm (P = .05) with PET values normalization after 12 mm.

Conclusion: We demonstrate hypermetabolism and impaired CVR beyond the standard MRI-defined tumor border, suggesting active tumor infiltration in the peritumoral environment.

Keywords: BOLD fMRI; PET; cerebrovascular reactivity; glioma; metabolism.

Figure 1.

Study flow chart. From the prospective database with 140 subjects who underwent BOLD-CVR study, 60 patients were diagnosed with glioma and 80 were healthy subjects. From 60 glioma patients, 24 patients underwent BOLD and PET imaging prior to treatment (*no treatment [ie, no surgery] done for primary gliomas, no second-line therapy initiated for recurrent glioma) in the time frame of 6 weeks. Two patients with non-diffuse glioma and 3 patients with more than 6 weeks interval between BOLD-CVR and PET scans were excluded from the study. Nineteen subjects with diffuse glioma (either WHO grade III or IV) were eligible for further analysis. **The diagnosis was confirmed with histopathological analysis for all primary diffuse gliomas, and if available for recurrent gliomas. For the remaining recurrent gliomas, diagnosis of progression was done by the treating physicians and based on RANO criteria. From 80 healthy subjects who underwent the BOLD-CVR study, we extracted 19 age- and sex-matched controls eligible for inclusion. In the final analysis, 38 subjects were included (19 age- and sex-matched pairs).

Figure 2.

Representative imaging data of one patient with glioblastoma. A 52-year-old male patient with left-sided temporal glioblastoma (WHO grade IV) was diagnosed and macroscopically completely resected in February 2016. In November 2017, the patient presented with recurrent tumor temporal on the left side. He underwent a BOLD-CVR and PET study in a time frame of 6 days and before the microsurgical resection of the recurrent glioma. BOLD-CVR showed impaired CVR clearly beyond the tumor borders as seen in T1-contrast-enhanced images. FET-PET images showed hypermetabolism in the tumor area as well as in the first VOI. The histopathological examination has confirmed the diagnosis of recurrent WHO grade IV glioma.

Figure 3.

CVR and PET impact of diffuse gliomas on surrounding brain tissue. (A) Line plot of mean CVR values around diffuse glioma. The plot depicts the increase in mean CVR values from the diffuse glioma outward in the surrounding “healthy” brain tissue and also shows lower CVR values in the affected hemisphere. BOLD-CVR values represent the mean values of the 2 hemispheres (red line for affected hemisphere and blue line for flipped hemisphere). (B) Line plot of mean PET values around diffuse glioma. The plot depicts the decrease in mean PET values from the diffuse glioma outward in the surrounding “healthy” brain tissue and also shows higher PET values in the affected hemisphere. PET values represent the mean values of the 2 hemispheres (red line for affected hemisphere and blue line for flipped hemisphere).