Local detection of microvessels in IDH-wildtype glioblastoma using relative cerebral blood volume: an imaging marker useful for astrocytoma grade 4 classification

Abstract

[EN] Background The microvessels area (MVA), derived from microvascular proliferation, is a biomarker useful for high-grade glioma classification. Nevertheless, its measurement is costly, labor-intense, and invasive. Finding radiologic correlations with MVA could provide a complementary non-invasive approach without an extra cost and labor intensity and from the first stage. This study aims to correlate imaging markers, such as relative cerebral blood volume (rCBV), and local MVA in IDH-wildtype glioblastoma, and to propose this imaging marker as useful for astrocytoma grade 4 classification. Methods Data from 73 tissue blocks belonging to 17 IDH-wildtype glioblastomas and 7 blocks from 2 IDH-mutant astrocytomas were compiled from the Ivy GAP database. MRI processing and rCBV quantification were carried out using ONCOhabitats methodology. Histologic and MRI co-registration was done manually with experts' supervision, achieving an accuracy of 88.8% of overlay. Spearman's correlation was used to analyze the association between rCBV and microvessel area. Mann-Whitney test was used to study differences of rCBV between blocks with presence or absence of microvessels in IDH-wildtype glioblastoma, as well as to find differences with IDH-mutant astrocytoma samples. Results Significant positive correlations were found between rCBV and microvessel area in the IDH-wildtype blocks (p < 0.001), as well as significant differences in rCBV were found between blocks with microvascular proliferation and blocks without it (p < 0.0001). In addition, significant differences in rCBV were found between IDH-wildtype glioblastoma and IDH-mutant astrocytoma samples, being 2-2.5 times higher rCBV values in IDH-wildtype glioblastoma samples. Conclusions The proposed rCBV marker, calculated from diagnostic MRIs, can detect in IDH-wildtype glioblastoma those regions with microvessels from those without it, and it is significantly correlated with local microvessels area. In addition, the proposed rCBV marker can differentiate the IDH mutation status, providing a complementary non-invasive method for high-grade glioma classification.This work was funded by grants from the National Plan for Scientific and Technical Research and Innovation 2017-2020, No. PID2019-104978RB-I00) (JMGG); H2020-SC1-2016-CNECT Project (No. 727560) (JMGG), and H2020SC1-BHC-2018-2020 (No. 825750) (JMGG). M.A.T was supported by DPI201680054-R (Programa Estatal de Promocion del Talento y su Empleabilidad en I + D + i). EFG was supported by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 844646. The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.Álvarez-Torres, MDM.; Fuster García, E.; Juan-Albarracín, J.; Reynes, G.; Aparici-Robles, F.; Ferrer Lozano, J.; Garcia-Gomez, JM. (2022). Local detection of microvessels in IDH-wildtype glioblastoma using relative cerebral blood volume: an imaging marker useful for astrocytoma grade 4 classification. BMC Cancer. 22(1):1-13. https://doi.org/10.1186/s12885-021-09117-4113221Louis N, Perry A, Reifenberge RG, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:808.Louis DN, Wesseling P, Aldape K, et al. cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading. Brain Pathol. 2020;30(4):844–56.Das S, Marsden PA. Angiogenesis in Glioblastoma. N Engl J Med. 2013;369(16):1561–3.Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011;17:1359–65.De Palma M, Biziato D, Petrova TV, et al. Microenviromental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17:13.Wu H, Tong H, Du X, et al. Vascular habitat analysis based on dynamic susceptibility contrast perfusion MRI predicts IDH mutation status and prognosis in high-grade gliomas. Eur Radiol. 2020;30(6):3254–65.Ziyad S, Iruela-Arispe ML. Molecular mechanisms of tumor angiogenesis. Genes Cancer. 2011;2(12):1085–96.Ling C, Pouget C, Rech F, et al. Endothelial cell hypertrophy and microvascular proliferation in Meningiomas are correlated with higher histological grade and shorter progression-free survival. J Neuropathol Exp Neurol. 2016;75(12):1160–70.Hu LS, Eschbacher JM, Dueck AC, et al. Correlations between perfusion MR imaging cerebral blood volume, microvessel quantification, and clinical outcome using stereotactic analysis in recurrent high-grade glioma. J Neuradiol. 2012;33:69–76.Sharma S, Sharma MC, Sarkar C, et al. Morphology of angiogenesis in human cancer: a conceptual overview, histoprognostic perspective and significance of neoangiogenesis. Histopathology. 2005;46:481–9.Pathak AP, Schmainda KM, Douglas B, et al. MR-derived cerebral blood volume maps: issues regarding histological validation and assessment of tumor angiogenesis. Magn Reson Med. 2001;46:735–47.Hu LS, Haawkins-Daarud A, Wang L, et al. Imaging of intratumoral heterogeneity in high-grade glioma. Cancer Lett. 2020;477:97–103.Cha S, Johnson G, Wadghiri YZ, et al. Dynamic, contrast-enhanced perfusion MRI in mouse gliomas: correlation with histopathology. Magn Reson Med. 2003;49:848–55.Chakhoyan A, Yao J, Leu K, et al. Validation of vessel size imaging (VSI) in high-grade human gliomas using magnetic resonance imaging, imageguided biopsies, and quantitative immunohistochemistry. Sci Rep. 2019;9:2846.Sadegui N, D’Haene N, Decaestecker C, et al. Apparent diffusion coefficient and cerebral blood volume in brain gliomas: relation to tumor cell density and tumor microvessel density based on stereotactic biopsies. Am J Neuroradiol. 2008;29:476–82.Sugahara T, Kiorogi Y, Kochi M, et al. Correlation of MR imaging determined cerebral blood volume maps with histologic and angiographic determination of vascularity of gliomas. Am J Neuroradiol. 1998;171:1479–86.Birner P, Piribauer M, Fischer I, et al. Vascular patterns in glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins: evidence for distinct angiogenic subtypes. Brain Pathol. 2003;13:133–43.Folkerth RD. Histologic measures of angiogenesis in human primary brain tumors. Cancer Treat Res. 2004;117:79–95.Donahue KM, Krouwer HGJ, Rand SD, et al. Utility of simultaneously-acquired gradient-echo and spin-echo cerebral blood volume and morphology maps in brain tumor patients. Magn Reson Med. 2000;43:845–53.Aronen HJ, Gazit IE, Louis DN, et al. Cerebral blood volume maps of gliomas: comparison with tumor grade and histological findings. Radiology. 1994;191:41–51.Li X, Tang Q, Yu J, et al. Microvascularity detection and quantification in glioma: a noveldeep-learning-based framework. Lab Investig. 2019;99(10):1515–26. https://doi.org/10.1038/s41374-019-0272-3.Álvarez-Torres M, Juan-Albarracín J, Fuster-Garcia E, et al. Robust association between vascular habitats and patient prognosis in glioblastoma: an international multicenter study. J Magn Reson Imaging. 2020;51(5):1478–86.Juan-Albarracín J, Fuster-García E, Pérez-Girbés, et al. Glioblastoma: vascular habitats detected at preoperative dynamic susceptibilityweighted contrast-enhanced perfusion MR imaging predict survival. Radiology. 2018;287:944–54.Juan-Albarracín J, Fuster-García E, García-Ferrando GA, et al. ONCOhabitats: a system for glioblastoma heterogeneity assessment through MRI. Int J Med Inform. 2019;128:53–61.Weibel ER. Estimation of basic Stereologic parameters: theoretical foundations of stereology. Academic Press, vol. 2; 1980.Essig M, Shiroishi MS, Nguyen TB, et al. Perfusion MRI: the five Most frequently asked technical questions. AJR Am J Roentgenol. 2013;200(1):24–34.Puchalski RB, Shah N, Miller J, et al. An anatomic transcriptional atlas of human glioblastoma. Science. 2018;360:660–3.Boxerman JL, Schmainda KM, Weisskoff RM, et al. Relative cerebral blood volume maps corrected for contrast agent extravasation significantly correlate with glioma tumor grade, whereas uncorrected maps do not. Am J Neuroradiol. 2006;27(4):859–67.Álvarez-Torres M, Fuster-García E, Reynes G, et al. Differential effect of vascularity between long- and short-term survivors with IDH1/2 wild-type glioblastoma. NMR Biomed. 2021;34(4):e4462.Fuster-Garcia E, Lorente ED, Álvarez-Torres M, et al. MGMT methylation may benefit overall survival in patients with moderately vascularized glioblastomas. Eur Radiol. 2021;31:1738–47.Álvarez-Torres M, Chelebian E, Fuster-García E, et al. ONCOhabitats results for ivy glioblastoma atlas project (ivy gap): segmentation and hemodynamic tissue signature (version 1.0) [data set]. Zenodo; 2021. https://doi.org/10.5281/zenodo.4704106