Expression of Olig2, Nestin, NogoA and AQP4 have no impact on overall survival in IDH-wildtype glioblastoma.

Despite many years of research efforts and clinical trials the prognosis of patients diagnosed with glioblastoma remains very poor. The oligodendrocyte transcription factor 2 (Olig2) was identified as a marker for glioma stem cells, which are believed to be responsible for glioma recurrence and therapy resistance. In this retrospective analysis we assessed the prognostic value of oligodendroglial and glioma stem cell markers in 113 IDH-wildtype glioblastomas. Immunohistochemical staining for Olig2, NogoA, AQP4 and Nestin was performed in combination with sequencing of IDH1 and IDH2 as well as promotor methylation analysis of the MGMT gene. Even though differences in overall survival according to Olig2 expression were observed, univariate and multivariate survival analysis did not reveal a firm significant prognostic impact of Olig2, NogoA, AQP4 or Nestin expression. Additionally, no differences in the expression of these markers depending on clinical status, age or gender were found. The established independent prognostic factors age<65, Karnofsky Performance Status> = 70 and methylated MGMT gene promoter were significant in the multivariate analysis. In conclusion expression of oligodendroglial and glioma stem cell markers do not have an independent prognostic effect in IDH-wildtype glioblastoma.

The prognostic role of IDH mutations in homogeneously treated patients with anaplastic astrocytomas and glioblastomas.

The detection of IDH mutations in patients with diffusely infiltrating malignant astrocytomas resulted in substantial modifications in the concept of WHO classification of these tumors. An important underlying observation was that patients with anaplastic astrocytomas (AA) without IDH mutation had a clinical course similar to that of patients with glioblastomas (GBM). The underlying observations of the German Glioma Network and NOA-04, however, were based on mixed patient cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually had radiotherapy or chemotherapy only. This intrinsic shortcoming of the study raised the question of whether patients with AA, IDH wildtype, WHO grade III, might have better prognosis if treated with combined radiochemotherapy than patients with GBM receiving the same combination therapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of an IDH mutation are still important if neither vascular proliferation nor necrosis are detectable. All patients in the cohort investigated here with the diagnosis of AA or GBM were subjected to a combined radiochemotherapy according to the Stupp protocol independently of the histopathological diagnosis. Thus, the analysis of these patients allows to clarify whether patients with AA, IDH wildtype, WHO grade III have a prognosis similar to that of GBM, IDH wildtype, WHO grade IV, even under equivalent therapeutic conditions. We determined the IDH1 and IDH2 status by sequencing, the MGMT status by pyrosequencing after bisulfite treatment and the EGFR status of the patients by FISH. In fact, the patients with the histopathological diagnosis of an AA IDH wild-type under similar aggressive therapy showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a GBM (mOS 13 months). Instead, patients with an AA and an IDH mutation receiving the same therapy had a mOS of 54 months. Thus, it can be concluded that in the absence of an IDH mutation, the established histopathological grading criteria 'necrosis' and 'vascular proliferation' actually lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and an IDH mutation are examined, there is still a difference between patients with necrosis and/or vascular proliferation and those whose tumors do not show such characteristics. Accordingly, in patients with malignant astrocytomas with IDH mutation it can be concluded that a histological differentiation between AA IDH mutated and GBM IDH mutated remains beneficial from a prognostic perspective.