Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations

Abstract

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.

cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”

“…Therefore, if the clinical, radiologic and histopathologic features are definitive for a diffusely infiltrative astrocytic glioma, TERT promoter mutations can be considered as a marker for WHO grade IV behavior. However, it should be emphasized that other types of IDH-wildtype glial neoplasms without WHO grade IV histology or aggressive behavior have also been reported to occasionally harbor TERT promoter mutations, including tumors classified as pleomorphic xanthoastrocytoma, ganglioglioma, anaplastic glioma with piloid features, and ependymoma [12, 25, 27, 31]. In addition, almost all oligodendrogliomas have TERT promoter mutations, and therefore this diagnostic consideration should be ruled out by testing for IDH mutations and 1p/19q codeletion.…”

“…Another subset of IDH-wildtype astrocytic gliomas has recently been delineated as anaplastic astrocytoma with piloid features, characterized by frequent CDKN2A/B deletions and typically accompanied by BRAF pathway gene alterations and ATRX mutation or loss of nuclear expression. The respective patients have a more favorable clinical outcome than patients with IDH-wildtype glioblastoma[25]. Therefore, by itself, CDKN2A/B deletion is not sufficient as a marker for WHO grade IV behavior in an IDH-wildtype astrocytic glioma.…”

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…A graphical summary of the evolution of the field within the context of brain tumours is displayed in Figure . DNA methylation is further gaining importance for tumour entity definition and is increasingly being used for the allocation of rare cancers into either known tumour classes or the identification of new entities , a collection of which are summarized in Figure .…”

Biomarkers in tumors of the central nervous system – a review

“…A recent, retrospective study by Reinhardt et al. of 102 cases, demonstrated that such tumors could reliably be identified by DNA methylation profiling, and that they often harbored deletions of CDKN2A/B , MAPK pathway gene alterations (most frequently NF1 , but also BRAF and FGFR1 ) and loss of ATRX expression (in 45% of the cases) . These patients were older than those with regular pilocytic astrocytomas (median age 41.5 years) and had a prognosis more in line with IDH ‐mutated glioblastomas.…”