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

Abstract

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.

Keywords: Anaplastic astrocytomas; EGFR; Glioblastomas; Grading; IDH1; IDH2; MGMT; Prognosis.

Fig. 1

Kaplan Meier plots a series of 139 patients with malignant astrocytomas, which shows an association between (a) overall survival and an age below and above 65 years. b A significance is also found in the cohort between a Karnofsky Performance Scale (KPS) below and above 70. c The univariate analysis of the extent of tumor resection (EOR) did not show a significant difference, yet in multivariate analysis EOR appeared as an independent prognostic factor. d However, there is a clear association between the pure histopathological diagnosis of anaplastic astrocytoma (AA) and a glioblastoma (GBM)

Fig. 2

Kaplan Meier plots derived from 139 patients diagnosed with an anaplastic astrocytoma or glioblastoma. a There is an association between overall survival and IDH status and (b) between overall survival and MGMT status. c There is a significant effect in the combination of histopathological diagnosis and IDH status. Patients with anaplastic astrocytoma and IDH mutation show better overall survival than patients with anaplastic astrocytoma without IDH mutation and patients diagnosed with glioblastoma with/without IDH mutation. The overall survival of the patients of the latter three subgroups appears similar in the Kaplan Meier analysis. d The same significant effect regarding histopathological diagnosis and IDH status became evident when only patients were subject to analysis below the age of 65 years. e Combining IDH and MGMT status patients with a positivity for both markers performed better than those patients with a negative IDH status independent from the MGMT status. Because only one tumor showed the combination IDH+ and MGMT- this group was not plotted. f Analyzing the histopathological diagnosis in combination with the MGMT status patients with an anaplastic astrocytoma with MGMT promoter methylation showed a better overall survival than the other groups. However, only 3 patients with an anaplastic astrocytoma revealed a negative MGMT promoter status so no further conclusion could be drawn from this group. AA: anaplastic astrocytoma, GBM: glioblastoma, IDH+: IDH1 or IDH2 mutation, IDH-: no IDH1 or IDH2 mutation, MGMT+: promoter methylation, MGMT-: no promoter methylation