Glioblastoma phenotypic and genetic heterogeneity, comparison of MRI and PET/CT parameters with tumor molecular genetic characteristics

Abstract

Glioblastoma (GB) is an extremely heterogeneous tumor, which is caused by genomic instability, high growth rate, and neovascularization. Molecular and genetic characteristics of GB play a major role in the prognosis of the disease, which is reflected in the new WHO classification of CNS tumors from 2021. Purpose of this research is comparison MRI parameters (ADC CBF), metabolic activity on 11C-MET PET/СT with glioblastoma genetic profile. 40 patients (age 55±12 years, sex M/F = 31/9) with newly diagnosed GB were examined by MRI with assessment of diffusion parameters (ADCmin) and ASL perfusion (CBFmax) and 11С-МЕТ PET/CT with the calculation of tumor to normal index (METmax). Since these VOI (1cm3) did not always coincide, it was decided to measure all parameters in each VOI on all image maps (PMOD automatic contour transfer). A total of 9 measurements were obtained for each patient: METmax, METcbf, METadc; ADCmin, ADCmet, ADCcbf; CBFmax, CBFmet, CBFadc. Comparative and correlation analysis was carried out both in the total GB group and separately in the groups MGMT+/and EGFR+/and different Ki67 levels (cut-off 20%). In results 45% of patients had CBFmax, ADCmin and METmax mismatch. Significant correlations were found in the METmax VOI between METmaxADCmet (Rs = -0.37) and METcbfADCcbf (Rs = -0.05). CBFmax and CBFmet correlated with Ki67 (Rs = 0.38 and Rs = 0.48, respectively) and increased in Ki67 20% GB group. GB genetic subgroup analysis showed: MGMT+ had significantly higher ADCmin1.01 (10-3 mm2/sec), Se = 78%, Sp = 74%, AUC = 0.77, it means that cells were more tightly packed. In METmax VOI, METmax was negatively correlated with ADCmet (Rs = -0.72) and CBFmet was positively correlated with Ki-67 (Rs = 0.89); EGFR+ tumors had significantly higher METmax 3.29 (Se = 88%, Sp = 70%, AUC = 0.82), that was negatively correlated with ADCmet (Rs = -0.85). In case when Ki67 20% GB demonstrated significantly higher CBFmax 108.177ml/100/min (Se = 70%, Sp = 94%, AUC 0.75) and a strong negative correlation between METmax and ADCmet, (Rs = -0,65) in METmax VOI. Our study shown that CBFmax, ADCmin and METmax localization coincide in 45% of cases, which proves the presence of variety in the structure and functional activity of different areas of GB. The correlation of MGMT methylation and ADC (ADCmin 1.01 (10-3 mm2/sec), Se = 78%, Sp = 74%, AUC = 0.77) confirms the recent studies results of this tumor subtype lower needs of the new membranes construction, that’s due to the inhibition of the mechanism of the DNA repair system. EGFR amplification presence in our patient sample was associated with a significant higher MET metabolism (МЕTmax 3.29, Se = 88%, Sp = 70%, AUC = 0.82) and correlated with height level of Ki67 (Rs = -0.85), confirming the fact of GB cells amino acids increased consumption for membrane synthesis. The obtained correlations MET with ADC and the absence of those with CBF, confirms the dependence glioma methionine metabolism of the new cell membranes building, rather than on neovascularization. Revealed mismatch of MRI and PET/CT parameters confirmed GB structure heterogeneity phenomenon, as well as their significant differences in various genetic status GB subgroups.