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The revised 4th edition of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) has introduced the integrated diagnostic classification that combines molecular and histological diagnoses for diffuse gliomas. In this study, we evaluated the molecular alterations for consecutive 300 diffuse glioma cases (grade 2, 56; grade 3, 62; grade 4, 182) based on this classification. Mutations in the isocitrate dehydrogenase (IDH) genes were common in lower grade glioma (LGG: grade2-3), and when combined with 1p/19q status, LGGs could be stratified into three groups except for four cases (Astrocytoma, IDH-mutant: 44; Oligodendroglioma, IDH-mutant and 1p/19q codeleted: 37; Astrocytoma, IDH-wildtype: 33). 1p/19q-codeleted oligodendrogliomas were clinically the most favorable subgroup even with upfront chemotherapy. In contrast, IDH-wildtype astrocytomas had a relatively worse prognosis; however, this subgroup was more heterogeneous. Of this subgroup, 11 cases had TERT promoter (pTERT) mutation with shorter overall survival than 12 pTERT-wildtype cases. Additionally, a longitudinal analysis indicated pTERT mutation as early molecular event for gliomagenesis. Therefore, pTERT mutation is critical for the diagnosis of molecular glioblastoma (WHO grade 4), regardless of histological findings, and future treatment strategy should be considered based on the precise molecular analysis., (© 2021. The Japan Society of Brain Tumor Pathology.)

In this study, we reclassified 400 consecutive glioma cases including pediatric cases, using the revised 2016 WHO classification with samples collected from the Kyushu University Brain Tumor Bank. The IDH1/2, H3F3A, key genetic markers in the 2016 classification, were analyzed using high-resolution melting, with DNA extracted from frozen tissues. The 1p/19q codeletions were evaluated using a microsatellite-based loss of heterozygosity analysis, with 18 markers, to detect loss of the entire chromosome arm. In the integrated diagnosis, 29 oligodendroglioma cases and 28 anaplastic oligodendroglioma cases were diagnosed as "IDH-mutant and 1p/19q-codeleted," while 2 oligodendroglioma cases and 5 anaplastic oligodendroglioma cases were diagnosed as not otherwise specified (NOS). These "NOS" cases were either IDH-mutants or 1p/19q-codeleted, although characteristic oligodendroglial features were evident histologically. Better overall survival of patients with oligodendroglioma correlated with the molecular characteristic of "IDH-mutant and 1p/19q-codeleted," rather than the WHO grade. Eleven "glioblastoma, IDH-wild-type" cases were classified as "1p/19q-codeleted", however, chromosome 10 loss was also detected in 10 out of 11 cases. The 2016 WHO criteria for glioma classification leads to better diagnosis of patients. However, there are technical pitfalls and problems to be solved in the molecular analysis of routine diagnostics.

A recurrent glycine-to-arginine/valine alteration at codon 34 (G34R/V) within H3F3A, a gene that encodes the replication-independent histone variant H3.3, reportedly occurs exclusively in pediatric glioblastomas. However, the clinicopathological and biological significances of this mutation have not been completely elucidated; especially, no such data exist for tumor samples from Japanese patients. We analyzed 411 consecutive glioma cases representing patients of all ages. Our results demonstrated that 14 patients (3.4%) harbored H3F3A mutations, of which four had G34R mutations and 10 had K27M mutations. G34R-mutant tumors were located in the parietal region in two patients and the basal ganglia in one patient. One patient showed multi-lobular extension similar to the pattern observed in gliomatosis cerebri. Regarding neuroradiological features, intratumoral calcification was evident in two cases and all cases showed no or scarce contrast enhancement on MRI. Histopathologically, the four G34R-mutant cases included three glioblastomas and one astroblastoma. We have also investigated alterations in histone methylation including H3K27me3, H3K9me3, and H3K4me3 in G34R-mutant samples by immunohistochemistry. These results indicate that G34R-mutant tumors are likely to show extensive infiltration and alterations in global histone trimethylation might also play an important role in G34R mutant tumors.