EPID-18. TRENDS IN INCIDENCE AND SURVIVAL OF MALIGNANT PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS IN THE NETHERLANDS

BACKGROUND Variation in survival of pediatric central nervous system (CNS) tumors is large between countries. Within Europe, the Netherlands had one of the worst reported survival rates of malignant CNS (mCNS) tumors during 2000–2007. METHODS Using the Netherlands Cancer Registry, we evaluated trends in incidence and survival of pediatric mCNS tumors (behavior /3, 5th digit in the morphology code) diagnosed between 1990–2017. RESULTS 839 newly-diagnosed mCNS tumor patients <18 years were registered between 1990–2017. Incidence of mCNS tumors remained stable (average incidence rate, 21.6 per million person-years). However, an increased incidence of malignant gliomas, NOS was found (Estimated Annual Percentage Change (EAPC) 11.6% p<0.001). This appears to be related to a registration shift between 1990–1999 and 2000–2009 as brainstem tumors increased (+25%, n=79) for astrocytomas and other gliomas but decreased (-31%, n=32) for unspecified intracranial and intraspinal neoplasms. Overall, 5-year observed survival (5Y-OS) of mCNS tumors increased from 51% in 1990–1999 to 61% in 2010–2017 (P-for-trend<0.001). This increase was not constant over time, as 5Y-OS for the period 2000–2009 was 47%. The only significant decrease in survival was found for malignant astrocytomas and other gliomas with a 5Y-OS of 56% in 1990–1999 decreasing to 48% in 2010–2017 (P-for-trend<0.001). CONCLUSION Between 1990–2017 incidence of mCNS tumors in the Netherlands remained stable and survival increased. However, a decrease in survival was seen for malignant astrocytomas and other gliomas, which is partially explained by the registration shift of brainstem tumors. The impact of this shift on survival for all mCNS tumors is subject to further research.

PATH-11. THE PROGNOSTIC ROLE OF IDH MUTATIONS IN HOMOGENEOUSLY TREATED PATIENTS WITH MALIGNANT DIFFUSE ASTROCYTOMAS

Detection of IDH mutations in patients with diffuse malignant astrocytomas resulted in substantial modifications in the WHO classification. An important observation was that patients with anaplastic astrocytomas (AA) IDH-wt had a clinical course similar to that glioblastoma (GBM) patients. The observations of the GGN and NOA-04, were based on mixed cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually only had radiotherapy or chemotherapy. This shortcoming raises the question whether AA IDH-wt patients did not behave prognostically better than GBM patients when receiving combined radiochemotherapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of IDH mutations are important if vascular proliferation or necrosis are undetectable. All patients investigated here with diagnosis of a malignant astrocytoma received combined standard radiochemotherapy independently of the histopathological diagnosis. Thus, the analysis allows to clarify whether patients with AA of IDH-wt have a prognosis similar to that of GBM patients under equivalent therapeutic conditions. We determined the IDH1/2 status by sequencing, the MGMT status by pyrosequencing. Patients with the histopathological diagnosis of an AA IDH-wt showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a glioblastoma (mOS 13 months). Instead, patients with an AA IDH-mut receiving same therapy had a mOS of 54 months. Thus, it can be concluded that in absence of IDH mutations, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and IDH mutations are examined, there is a difference between patients showing necrosis and/or vascular proliferation and those whose tumors do not. Accordingly, for patients with malignant astrocytomas with IDH mutations it can be concluded that differentiation between AA IDH-mut and GBM IDH-mut remains beneficial from a prognostic perspective.

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.