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Updates on the 2016 World Health Organization Classification of Pediatric Tumors of the Central Nervous System - a systematic review.

ABSTRACT: Tumors of the central nervous system (CNS) represent the main cause of death through solid tumors in children and the second most frequent neoplasm in this patient group. The poor survival rate is due to many factors, such as the large diversity of morphological features, the particular micro-environmental characteristics of the nervous tissue, the relative rareness in relation to other childhood diseases, which leads to late diagnosis and the limited effectiveness of the available treatment options. Up until 2016, brain tumors were classified according to their histologic features. The new 2016 World Health Organization (WHO) Classification of CNS tumors incorporates molecular features, alongside the immunohistology, in order to provide a more accurate understanding of the disease. The treatment consists of surgery, radiation therapy and chemotherapy. We decided to review the literature on this pathology, in order to show the importance of the recent discoveries in this field.

SUBMITTER: Cosnarovici MM

PROVIDER: S-EPMC8357361 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Updates on the 2016 World Health Organization Classification of Pediatric Tumors of the Central Nervous System - a systematic review.

Cosnarovici Maria Margareta MM Cosnarovici Rodica Voichiţa RV Piciu Doina D

Medicine and pharmacy reports 20210729 3

Tumors of the central nervous system (CNS) represent the main cause of death through solid tumors in children and the second most frequent neoplasm in this patient group. The poor survival rate is due to many factors, such as the large diversity of morphological features, the particular micro-environmental characteristics of the nervous tissue, the relative rareness in relation to other childhood diseases, which leads to late diagnosis and the limited effectiveness of the available treatment opt ...[more]

PMID: 34430849

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Project description:Introduction The 2021 World Health Organization (WHO) classification of tumors of the central nervous system (CNS) has introduced significant changes to tumor taxonomy. One of the most significant changes in the isolation of isocitrate dehydrogenase (IDH) mutant forms of glioblastoma multiforme (GBM) into separate entities, as well as no longer allowing for entries to be classified as not otherwise specified (NOS). As a result, this entity now includes only the most aggressive adult-type tumors. As such, established prognostic factors no longer apply, as they now form the criteria of different disease entries or have been established based on a mixed cohort. Herein, we aimed to reclassify glioblastoma cases diagnosed per the 2016 WHO tumors of the CNS classification into the 2021 WHO tumors of the CNS classification and establish a patient survival pattern based on age, gender, tumor location, and size as well as tumor O-6-methylguanine-DNA methyltransferase (MGMT) mutation. Materials and methods A retrospective, non-clinical approach was utilized. Biopsy specimens of adults diagnosed with GBM, WHO grade 4, NOS in the period February 2018-February 2021 were reevaluated. The data regarding the patient's gender and age were withdrawn from the medical documentation. Immunohistochemistry was performed with mouse monoclonal anti-IDH R132H and rabbit polyclonal anti-MGMT. Radiology data on tumor location and size were pulled from the radiology repository. Data were statistically analyzed for significance, using Kaplan-Meier survival analysis, with a 95% confidence interval and p<0.05 defined as significant. Results A total of 58 cases fit the set criteria, with eight of them (13.7%) harboring an IDH R132H mutation and were hence reclassified as diffuse astrocytoma IDH-mutant, WHO CNS grade 4. The cases that retained their GBM classification included n=28 males and n=22 females, a male to female ratio of 1.27:1, and a mean age of 65.3 years (range 43-86 years). The MGMT mutational status revealed a total of n=17 positive cases (35%), while the remaining cases were negative. No hemispheric predilection could be established. Lobar predilection was as follows: temporal (37.78%), parietal (28.89%), frontal (24.44%), and occipital (8.89%). The mean tumor size measured on neuroradiology across the cohort was 50.51 mm (range 20-76 mm). The median survival across cases was 255.96 days (8.41 months), with a range of 18-1150 days (0.59-37.78 months). No statistical correlation could be established between patient survival and gender, hemispheric location, lobar location, and tumor size. A significant difference in survival was established only when comparing the 41-50 age groups to the 71-80 and 81-90 age groups and MGMT positive versus negative tumors (p=0.0001). Conclusion From a practical standpoint, the changes implemented in the new classification of CNS tumors define GBM as the most aggressive adult type of tumor. Based on their significantly more favorable prognosis, the reclassification of IDH mutant forms of astrocytomas has had little epidemiological impact on this relatively common malignancy but has significantly underlined the dismal prognosis. The changes have also led to MGMT promoter methylation status being the only significant prognostic factor for patient survival in clinical use, based on its prediction for response to temozolomide therapy in this nosological unit clinically presenting when it has already reached immense size.

Project description:BackgroundNucleotide-specific 5-hydroxymethylcytosine (5hmC) remains understudied in pediatric central nervous system (CNS) tumors. 5hmC is abundant in the brain, and alterations to 5hmC in adult CNS tumors have been reported. However, traditional approaches to measure DNA methylation do not distinguish between 5-methylcytosine (5mC) and its oxidized counterpart 5hmC, including those used to build CNS tumor DNA methylation classification systems. We measured 5hmC and 5mC epigenome-wide at nucleotide resolution in glioma, ependymoma, and embryonal tumors from children, as well as control pediatric brain tissues using tandem bisulfite and oxidative bisulfite treatments followed by hybridization to the Illumina Methylation EPIC Array that interrogates over 860,000 CpG loci.ResultsLinear mixed effects models adjusted for age and sex tested the CpG-specific differences in 5hmC between tumor and non-tumor samples, as well as between tumor subtypes. Results from model-based clustering of tumors was used to test the relation of cluster membership with patient survival through multivariable Cox proportional hazards regression. We also assessed the robustness of multiple epigenetic CNS tumor classification methods to 5mC-specific data in both pediatric and adult CNS tumors. Compared to non-tumor samples, tumors were hypohydroxymethylated across the epigenome and tumor 5hmC localized to regulatory elements crucial to cell identity, including transcription factor binding sites and super-enhancers. Differentially hydroxymethylated loci among tumor subtypes tended to be hypermethylated and disproportionally found in CTCF binding sites and genes related to posttranscriptional RNA regulation, such as DICER1. Model-based clustering results indicated that patients with low 5hmC patterns have poorer overall survival and increased risk of recurrence. Our results suggest 5mC-specific data from OxBS-treated samples impacts methylation-based tumor classification systems giving new opportunities for further refinement of classifiers for both pediatric and adult tumors.ConclusionsWe identified that 5hmC localizes to super-enhancers, and genes commonly implicated in pediatric CNS tumors were differentially hypohydroxymethylated. We demonstrated that distinguishing methylation and hydroxymethylation is critical in identifying tumor-related epigenetic changes. These results have implications for patient prognostication, considerations of epigenetic therapy in CNS tumors, and for emerging molecular neuropathology classification approaches.

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Updates on the 2016 World Health Organization Classification of Pediatric Tumors of the Central Nervous System - a systematic review.

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Updates on the 2016 World Health Organization Classification of Pediatric Tumors of the Central Nervous System - a systematic review.

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