Recent developments and future directions in adult lower-grade gliomas: Society for Neuro-Oncology (SNO) and European Association of Neuro-Oncology (EANO) consensus

Abstract

The finding that most grades II and III gliomas harbor isocitrate dehydrogenase (IDH) mutations conveying a relatively favorable and fairly similar prognosis in both tumor grades highlights that these tumors represent a fundamentally different entity from IDH wild-type gliomas exemplified in most glioblastoma. Herein we review the most recent developments in molecular neuropathology leading to reclassification of these tumors based upon IDH and 1p/19q status, as well as the potential roles of methylation profiling and deletional analysis of cyclin-dependent kinase inhibitor 2A and 2B. We discuss the epidemiology, clinical manifestations, benefit of surgical resection, and neuroimaging features of lower-grade gliomas as they relate to molecular subtype, including advanced imaging techniques such as 2-hydroxyglutarate magnetic resonance spectroscopy and amino acid PET scanning. Recent, ongoing, and planned studies of radiation therapy and both cytotoxic and targeted chemotherapies are summarized, including both small molecule and immunotherapy approaches specifically targeting the mutant IDH protein.

Keywords: IDH mutation; astrocytoma; glioma; lower-grade; oligodendroglioma.

Fig. 1

Astrocytoma. H&E shows a hypercellular tumor composed of pleomorphic tumor cells (A). This tumor is immunoreactive for IDH1 R132H (B) and TP53 (C), but has lost ATRX expression (D). Fluorescence in situ hybridization (FISH) showed retention of 1p (E) and 19q (F). Scale bar A–D = 100 microns; scale bar E–F = 20 microns. FISH images courtesy of Kathleen A. Kaiser-Rogers, PhD.

Fig. 2

Oligodendroglioma. H&E shows a hypercellular tumor composed of atypical cells with round, regular nuclei and perinuclear halos (A). This tumor is immunoreactive for IDH1 R132H (B) and ATRX (D), but not TP53 (C). Fluorescence in situ hybridization (FISH) showed deletion of both 1p (E) and 19q (F). Scale bar A–D = 100 microns; scale bar E–F = 20 microns. FISH images courtesy of Kathleen A. Kaiser-Rogers, PhD.

Fig. 3

Molecular diagnostics of diffuse gliomas. Use of custom pyrosequencing to detect wild-type (A) and R132H mutant (B, C > T) IDH1 on reverse strand pyrograms. Bisulfite pyrosequencing detects CpG methylation within the MGMT promoter as increased C peaks (≥10%) at five indicated sites (C, negative; D, positive). Lack of the C peak highlighted in gold indicates complete bisulfite conversion. Sanger sequencing detects the 124 C > T (C228T) and 146 C > T (C250T) mutations in the TERT promoter. Only C is present at the indicated position in samples with wild-type TERT promoter (E); a T peak at this site (146) indicates mutation (courtesy of Jonathan Galeotti and Karen Weck).

Fig. 4

Schema of NRG BN005.