Central Nervous System (CNS) tumors are rare with an overall incidence of 7% including both benign and malignant ones, but they account for a disproportionate burden of cancer mortality because of their high fatality rate. CNS tumors comprise a diverse group of many distinct subtypes with varying epidemiology, clinical characteristics, treatments, and outcomes. Tumors originating from glial cells called gliomas are one of the most common and have been the subject of intense research because they possess a mortality rate of over 75%.
In order to unify the diagnosis and management, the World Health Organization (WHO) classified CNS tumors into 4 grades. Grade 1 tumors are benign tumors, Gliomas in adults belong to grade 2 to 4. Grade 2 is assigned to slow developing tumors, whereas grade III tumors show features of aggressiveness in terms of microscopy, radiology and clinical symptoms. Both Grade 2 and 3 tumors may progress to grade 4 gliomas. Grade 4 gliomas, or glioblastomas (GBM), are the most aggressive tumors of the central nervous system and show fast pre and postoperative development.
Irrespective of grade, gliomas have an infiltrative nature and complete surgical resection of gliomas is highly challenging, as it is difficult to ascertain the extent of tumor in brain unlike in other organs. Moreover, the remaining tumor cells are resistant to traditional therapies such as radiotherapy, chemotherapy and these tumors almost always recur despite of adequate resection. However, early and adequate surgical resection improves the outcome by delaying their transformation into higher grade tumors.
Until 2016, these tumors were divided into four grades based upon microscopic features alone. In last two decades, with substantial advances in molecular understanding of these tumors,
WHO integrated the molecular information in the microscopic diagnosis in 2016. Since then, a consortium on Molecular and Practical Approaches to CNS Tumor Taxonomy – not official WHO ( cIMPACT- NOW) was formed in order to update the practicing pathologists and clinicians regarding the recent updates.
Based on the advances and information provided by this Consortium (cIMPACT-NOW), classification of CNS tumors have been revised in 2021 (also called as CNS 5), to provide better understanding of prognosis and open more avenues for targeted therapies.
The new classification (WHO CNS 5) now differentiates gliomas into adult type and paediatric type. Adult type gliomas are broadly divided into 3 types : Astrocytoma, IDH-mutant, Oligodendroglioma, IDH-mutant and 1p-19q co-deleted and Glioblastoma, IDH-wild type. Inclusion of molecular information in the reports is important, as it predicts the prognosis more reliably than histological appearance and has surpassed the latter, for eg. despite of absence of hallmark features of grade 3 or grade 4 tumors on histology, an IDH mutant grade 2 astrocytoma upgrades to grade 4, if it shows CDKN 2A/B homozygous deletion. Similarly, an IDH wild type astrocytoma without microscopic features of glioblastoma (grade 4), if have any single molecular marker: TERT promoter mutation, EGFR gene amplification or combined gain of entire chromosome 7 & loss of entire chromosome 10 (+7/-10) will also qualify for glioblastoma, grade 4.
Thus a complete pathology report of brain tumor provides both microscopic and molecular information to the medical oncologists and neurosurgeons.
Similary the available molecular information has also been included in pediatric low grade and high grade gliomas and majority of other types of CNS tumors. But surprisingly, with rapid evolution in molecular information, development of specific and effective therapeutic designs have not been successful for most of the brain tumors except for limited available options. The Heterogeneity of Glioma Cancer Stem Cells, presence of multiple genetic alterations in single tumor, distinct vascular, immune compartment and microenvironment of brain are some of the main reasons for the failure of development of targeted therapies for these tumors.
To chase down these most elusive cancers, laboratories now need to have molecular tests not only to classify them, but also to predict their behaviour and guide the clinicians to provide a multifaceted approach to hit these dynamic evolving tumors.
References:
- David N. Louis, Arie Perry , Pieter Wesseling et al. The 2021 WHO Classification of Tumours of the Central Nervous System – a summary Neuro-Oncology. 2021; 23 (8) 1231-1251.
- Takashi Komori. Grading of adult diffuse gliomas according to the 2021 WHO classification pftumours of the central nervous system. Laboratory Investigation,. 2022;102,126-133.
- Simon Gritsch , Tracy T Batchelor, L. Nicolas Gonzalez Castro. Diagnositic , therapeutic and prognostic implications of the 2021 WHO classification of tumours of the central nervous system. Cancer. 2022; 128 (1), 47-58.
- Ricardo Gargini, Berta Segura-Collar, Pilar Sánchez-Gómez. Cellular Plasticity and Tumor Microenvironment in Gliomas: The Struggle to Hit a Moving Target, 2020, 12, 1622.
- Kimberly D. Miller, Quinn T. Ostrom, Carol Kruchko, Nirav Patil, Brain and Other Central Nervous System Tumor Statistics. Cancer j clin.2021;71:381–406
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