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.
Highlights
Glioblastoma (GBM) of cerebellar localization constitutes less than 1% of all GBMs [1, 16]
Difficult is the histological separation from the recently described anaplastic astrocytomas with piloid features (AAP) which exhibit a more favorable clinical outcome compared to GBM IDH mutant glioma subclass astrocytoma (IDH) wt and which have been shown to harbor MAPK pathway alterations as potential therapeutic targets [25]
Patients with cerebellar glioblastoma (cGBM) present at a younger age than patients with supratentorial GBM (sGBM) Within the cohort of 86 patients with cGBM, 73 patients were adults with a median age of 56 years comparing well with median ages ranging from 50 to 58 years reported in previous studies on adult patients with cGBM, respectively [1, 37]
Summary
Glioblastoma (GBM) of cerebellar localization (cGBM) constitutes less than 1% of all GBMs [1, 16]. GBMs can be divided into molecular subgroups based on their epigenetic profiles [7, 33]. Several studies and case reports have shown that patients with cGBM are younger at first diagnosis than patients with supratentorial GBM (sGBM) [2, 10, 16, 37]. Two previous studies on methylation profiles of cGBMs have reported assignment to the MCs diffuse midline glioma H3 K27 M mutant (DMG K27), GBM RTK I, GBM MID and IDH mutant glioma subclass astrocytoma (A IDH). Molecular markers and epigenetic profiles of cGBMs have not yet been comprehensively evaluated. Definition of clinical and molecular features warranting the designation as a distinct GBM variant is still controversially discussed [5, 9, 13]
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