The Intratumoral Heterogeneity Reflects the Intertumoral Subtypes of Glioblastoma Multiforme: A Regional Immunohistochemistry Analysis

Abstract

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor in adults. Despite extensive therapy the prognosis for GBM patients remains poor and the extraordinary therapy resistance has been attributed to intertumoral heterogeneity of glioblastoma. Different prognostic relevant GBM tumor subtypes have been identified based on their molecular profile. This approach, however, neglects the heterogeneity within individual tumors, that is, the intratumoral heterogeneity. Here, we detected the regional immunoreactivity by immunohistochemistry and immunofluorescence using nine different markers on resected GBM specimens (IDH wildtype, WHO grade IV). We found repetitive expression profiles, that could be classified into clusters. These clusters could then be assigned to five pathophysiologically relevant groups that reflect the previously described subclasses of GBM, including mesenchymal, classical, and proneural subtype. Our data indicate the presence of tumor differentiations and tumor subclasses that occur within individual tumors, and might therefore contribute to develop adapted, individual-based therapies.

Immunohistochemically Characterized Intratumoral Heterogeneity Is a Prognostic Marker in Human Glioblastoma

“…Newer studies propose the influence of contamination with surrounding normal brain tissue, since this subtype was mostly found at the tumor border [ 13 ]. In a recent study, we began to apply the concept of intratumoral heterogeneity by immunohistochemistry and defined different tumor regions, e.g., region of hypoxia, proliferative region and stem cell region [ 16 ]. Although, the current study focused on applying the established subtypes on human tumor tissue.…”

“…Just recently, we published our first study with a morphological approach by using immunohistochemistry. We defined different tumor regions including region of hypoxia and stem cell region [ 16 ]. In this current study, we, again, chose the broadly applicable technique immunohistochemistry, but focused on applying the established subtypes on human tumor tissue with the aim to prove that immunohistochemistry is a valid method for detecting these diverse subtypes in an individual tumor.…”

Molecular and Cellular Complexity of Glioma. Focus on Tumour Microenvironment and the Use of Molecular and Imaging Biomarkers to Overcome Treatment Resistance

“…Despite an increase in overall survival, the prognosis remains poor because of the development of GBM resistance to TMZ [6]. Alternative treatments are under evaluation, but the high intra-and inter-tumour heterogeneity of GBM and its intracranial localisation make the development of new therapies for this tumour a big challenge [7]. An important role in lesion heterogeneity is played by the tumour microenvironment (TME), composed by different cell populations, as immune cells, fibroblasts, precursor cells, endothelial cells, signalling molecules, and extracellular matrix (ECM) components [8,9].…”

Radiomic Immunophenotyping of GSEA-Assessed Immunophenotypes of Glioblastoma and Its Implications for Prognosis: A Feasibility Study

“…Due to intratumoral heterogeneity within different regions of individual tumors, tumor biopsy may suffer under-sampling when representing the pathological molecular profile in a whole tumor [ 20 , 21 ]. Magnetic resonance imaging (MRI) is a noninvasive approach for characterizing the anatomical, functional, microstructural, and metabolic properties of tissues.…”