Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities

Abstract

In this multi-institutional study we compiled a retrospective cohort of 86 posterior fossa tumors having received the diagnosis of cerebellar glioblastoma (cGBM). All tumors were reviewed histologically and subjected to array-based methylation analysis followed by algorithm-based classification into distinct methylation classes (MCs). The single MC containing the largest proportion of 25 tumors diagnosed as cGBM was MC anaplastic astrocytoma with piloid features representing a recently-described molecular tumor entity not yet included in the WHO Classification of Tumours of the Central Nervous System (WHO classification). Twenty-nine tumors molecularly corresponded to either of 6 methylation subclasses subsumed in the MC family GBM IDH wildtype. Further we identified 6 tumors belonging to the MC diffuse midline glioma H3 K27 M mutant and 6 tumors allotted to the MC IDH mutant glioma subclass astrocytoma. Two tumors were classified as MC pilocytic astrocytoma of the posterior fossa, one as MC CNS high grade neuroepithelial tumor with BCOR alteration and one as MC control tissue, inflammatory tumor microenvironment. The methylation profiles of 16 tumors could not clearly be assigned to one distinct MC. In comparison to supratentorial localization, the MC GBM IDH wildtype subclass midline was overrepresented, whereas the MCs GBM IDH wildtype subclass mesenchymal and subclass RTK II were underrepresented in the cerebellum. Based on the integration of molecular and histological findings all tumors received an integrated diagnosis in line with the WHO classification 2016. In conclusion, cGBM does not represent a molecularly uniform tumor entity, but rather comprises different brain tumor entities with diverse prognosis and therapeutic options. Distinction of these molecular tumor classes requires molecular analysis. More than 30% of tumors diagnosed as cGBM belong to the recently described molecular entity of anaplastic astrocytoma with piloid features.Electronic supplementary materialThe online version of this article (10.1186/s40478-019-0801-8) contains supplementary material, which is available to authorized users.

EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood

“…Special attention should be given to diffuse astrocytomas in the brainstem or cerebellum with histo logies corresponding to WHO grades 2, 3 and 4. Among infratentorial astrocytomas, the frequency of non-canonical IDH mutations is ~80%, in contrast with <10% in those of the supratentorial compartment 27,28 . Infratentorial diffuse gliomas therefore tend to be classified incorrectly if examined by IDH1 R132H immunohistochemistry only; accordingly, DNA sequencing for rare mutations in IDH1 and IDH2 is required.…”

“…Infratentorial diffuse gliomas therefore tend to be classified incorrectly if examined by IDH1 R132H immunohistochemistry only; accordingly, DNA sequencing for rare mutations in IDH1 and IDH2 is required. In addition, infratentorial IDH-mutant astrocytomas have a loss of nuclear ATRX expression as well as MGMT promoter methylation in only ~50% of patients 27 , 28 .…”

Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation

“…DNA methylation, targeted next-generation sequencing (NGS) and RNA sequencing DNA (84) and RNA (53) were extracted from formalinfixed and paraffin-embedded (FFPE) target tumor tissue samples using the automated Maxwell system (Promega, Madison, WI, USA) [15,16]. DNA was analyzed using the Illumina Human Methylation 450 k or 850 k/EPIC BeadChip array as described [5,6,14,16,22,23]. Briefly, DNA methylation analyses were performed in R version 3.3.0 (R Development Core Team).…”

“…In total, 428,799 probes were kept for analysis. The t-distributed stochastic neighbor embedding (t-SNE) plots were computed via the R package Rtsne [5,16,23]. Copy number profiles were generated using the 'conumee' package for R. Using the "Heidelberg brain tumor classifier; v11b4" (www.molec ularn europ athol ogy.org;), highly characteristic methylation classes of 84 institutionally diagnosed CNS-PNET were established, for which correlations to the respective brain tumor entities in the WHO classification ("reference tumor set") were evident [5,6].…”

Cerebellar anaplastic astrocytoma in adult patients: 15 consecutive cases from a single institution and literature review

“…However, no incidence of cAA has been reported due to its' utmost scarcity. This is not surprising that literature dealing with malignant gliomas of the cerebellum mostly consists of cerebellar glioblastomas, including both pediatric and adult patients, and brainstem tumours involving cerebellum [5,8,11,15,17,21,32,34].…”