Adult-type diffuse glioma
Oligodendroglioma IDH-mutant and 1p/19q-codeleted
Adult-type diffuse gliomas represent a group of highly infiltrative central nervous system tumors with a prognosis that significantly varies depending on the specific subtype and histological grade. Traditionally, adult-type diffuse gliomas have been classified based on their morphological features with a great interobserver variability and discrepancy in patient survival even within the same histological grade. Over the last few decades, advances in molecular profiling have drastically changed the diagnostic approach and classification of brain tumors leading to the development of an integrated morphological and molecular classification endowed with a more clinically relevant value. These concepts were largely anticipated in the revised fourth-edition of WHO classification of central nervous system tumors published in 2016. The fifth-edition (WHO 2021) moved molecular diagnostics forward into a full integration of molecular parameters with the histological features into an integrative diagnostic approach. Diagnosis of adult type diffuse gliomas, IDH mutant and IDH-wildtype has been simplified by introducing revised diagnostic and grading criteria 1).
Immunohistochemistry
Diffuse gliomas exhibits different molecular and genetic profiles with a wide range of heterogeneity and prognosis. Recently, molecular parameters including ATRX gene mutation, P53, and IDH mutation status or absence or presence of 1p/19q co-deletion have become a crucial part of diffuse glioma diagnosis. Shabanzadeh Nejabad et al. tried to analyze the routine practice of the above-mentioned molecular markers focusing on the IHC method in cases of adult diffuse gliomas to evaluate their utility in the integrated diagnosis of adult diffuse gliomas. Totally, 134 cases of adult diffuse glioma were evaluated. Using the IHC method, 33,12, and 12 cases of IDH mutant Astrocytoma grade 2, 3, 4, and 45 cases of glioblastoma, IDH wild type, were molecularly diagnosed. By adding the FISH study for 1p/19q co-deletion, 9 and 8 cases of oligodendroglioma grades 2 and 3 also were included. Two IDH mutant cases were negative for IDH1 in IHC but revealed a positive mutation in further molecular testing. Finally, we were not able to incorporate a complete integrated diagnosis in 16/134(11.94%) of cases. The main molecularly unclassified group was histologically high-grade diffuse glial tumors in patients less than 55 years old and negative IDH1 immunostaining. P53 was positive in 23/33 grade 2, 4/12 grade 3, and 7/12 grade 4 astrocytomas, respectively. Four out of 45 glioblastomas showed positive immunostain, and all oligodendrogliomas were negative. In conclusion, a panel of IHC markers for IDH1 R132H, P53, and ATRX significantly improves the molecular classification of adult diffuse gliomas in daily practice and can be used as a tool to select limited cases for co-deletion testing in the low resources area 2).
TERT promoter mutations are one of the most common genetic alterations in adult-type diffuse gliomas and show specific patterns compared with other genetic alterations according to glioma subtypes. This mutation has variable impacts on patient outcomes in association with other genetic alterations, including IDH1/2 mutations or histological types. Arita et al. reviewed the knowledge on the values of TERT promoter mutations in the diagnosis and prognostication of adult-type diffuse gliomas. Although its impact on prognosis is somewhat complicated and enigmatic, the mutational status of the TERT promoter provides highly useful information for predicting patients' outcomes in the conventional classification of gliomas defined by IDH1/2 and 1p/19q co-deletion status 3).
Complications
Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH wild-type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contribute to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures are often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, D-2-hydroxyglutarate, rapidly synchronizes neuronal spike firing in a seizure-like manner, but only when nonneoplastic glial cells are present. In vitro and in vivo models can recapitulate IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibit seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients 4).
Guidelines
The Korean Society for Neuro-Oncology (KSNO) published guidelines for managing adult glioma in 2019, and the National Comprehensive Cancer Network and European Association of Neuro-Oncology published guidelines in September 2021 and March 2021, respectively. However, these guidelines have several different recommendations in practice, including tissue management, adjuvant treatment after surgical resection, and salvage treatment for recurrent/progressive gliomas. Currently, the KSNO guideline working group is preparing an updated version of the guideline for managing adult gliomas. In this review, common features have been verified and different points are analyzed. Consequently, this review is expected to be informative and helpful to provide high quality evidence and a strong recommendation level for the establishment of new KSNO guidelines for managing gliomas 5).