Central Nervous System Tumors Research Articles

Study of Molecular Markers in Glioma and Their Association with Clinicopathological Features

Abstract Context: Central nervous system tumors are a major cause of morbidity and mortality worldwide. The most prevalent type of primary brain tumor is glioma. The exploration of significant genetic, epigenetic, and transcriptional abnormalities has not only improved our understanding of glioma pathogenesis but has also revealed that these molecular alterations can serve as useful diagnostic markers for more precise classification and are linked to better treatment response and prognosis. Hence, incorporating molecular markers into routine tumor classification is a major priority in modern glioma diagnostics. Aim: The aim is to assess the mutation status of isocitrate dehydrogenase (IDH)-1, alpha-thalassemia/mental retardation syndrome X-linked (ATRX), and tumor protein 53 in glioma, and look for their association with various clinicopathological features. Methodology: A single-center prospective cohort study, where all biopsies of glioma (January 2019 to July 2020) were evaluated, and immunohistochemistry was performed to assess the expression of IDH-1, ATRX, p53, and Ki-67 index. The data were analyzed using IBM SPSS-24 software. Results: Immunohistochemistry was performed in 123 consecutive cases of glioma. IDH-1 mutation was noted in 54 (43.9%) cases and these patients frequently presented with “seizures” (P = 0.006). The expression was maximum in World Health Organization (WHO) grade 2 tumors (65.4%) (P < 0.001), with the highest frequency in oligodendrogliomas (100% in WHO grade 2 and 3). Furthermore, these tumors showed lower proliferative indices (P = 0.001). ATRX mutation was noted in 59 (48%) and p53 overexpression was noted in 76 (61.8%) cases. These mutations were significantly associated with astrocytic phenotype (P = 0.03). Conclusions: Molecular characterization of glioma is an important step in modern glioma diagnostics and immunohistochemistry can play an important role. IDH-1 mutation is commonly observed in adults, frontal lobe location, patients presenting with seizures, and WHO grade 2 tumors with the highest frequencies in oligodendrogliomas. ATRX and p53 can be used as surrogate markers for tumors of astrocytic lineage.

Case report: Polymorphous low-grade neuroepithelial tumor of the young and supratentorial ependymoma diagnosed in an adult male

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a rare central nervous system (CNS) pathology predominantly observed in the pediatric population. Ependymomas also exhibit a peak incidence in early childhood, with rare presentations after early adulthood. In this report, we describe a rare case of a 41-year-old man diagnosed sequentially with a polymorphous low-grade neuroepithelial tumor of the young, followed by a supratentorial ependymoma within a year. He underwent tumor resection for both tumors, as well as adjuvant radiation therapy for the ependymoma. Despite these interventions, he ultimately succumbed to tumor progression and postoperative complications. Currently, no genetic syndromes are known to link these two primary CNS tumors. Two commonalities at the chromosomal and cellular level include histone gene H3F3A mutations and positive glial fibrillary acidic protein staining on immunohistochemistry. To the best of our knowledge, this unique dual pathology has not been previously described in the literature, making this case an avenue for further investigation and research into connections between these two distinct CNS pathologies.

Rapid Intraoperative Amplicon Sequencing of CNS Tumor Markers

Currently, central nervous system tumors are diagnosed with an integrated diagnostic approach that combines histopathological examination with molecular genetic profiling, which requires days to weeks to achieve a precise and informative classification of CNS tumors. This study demonstrated the feasibility of rapid multiplexed amplicon nanopore sequencing for identifying critical mutations relevant to molecular stratification of brain tumors within the timeframe of standard resection surgery. Utilizing live analysis of nanopore sequencing data, we evaluated the brain tumor-associated molecular markers IDH1 R132, IDH2 R172, pTERT C228 and C250, H3F3A K27 and G34, Hist1H3B K27, and BRAF V600. Our method achieved a turnaround time of 105minutes at the point-of-care from receipt of a tumor biopsy to result with the potential to impact surgical strategy. Our approach can be integrated with recently developed DNA methylation-based diagnostic classification systems, corroborating diagnoses and even further specifying tumor grades, thus enabling a multimodal diagnostic intraoperative assessment of CNS malignancies.

The engagement of Ras/Raf/MEK/ERK and PLCγ1/PKC pathways regulated by TrkB receptor in resistance of glioma cells to elimination upon apoptosis induction

The most aggressive tumors of human central nervous system are anaplastic astrocytoma (AA, III grade) and glioblastoma multiforme (GBM, IV grade) with an extremely bad prognosis. Their malignant character and resistance to standard therapy are correlated to the over-expression of survival pathways such as Ras/Raf/MEK/ERK and PLCγ1/PKC regulated by TrkB receptor. Therefore, the aim of this study was to investigate the engagement of those pathways in human glioma cells resistance for apoptosis induction by Temozolomide treatment. Two cancer MOGGCCM (AA) and T98G (GBM) and normal human astrocytes (NHA) cell lines were utilized. The tested inhibitors single and simultaneous action with Temozolomide affection on apoptosis induction was analyzed by MTT, microscopic observations and flow cytometry. Bcl-2:beclin-1 complexes occurrence was also assessed. siRNAs were used for direct proof of tested pathways engagement in gliomas resistance to apoptosis elimination. The most effective in eliminating gliomas with minimal astrocyte damage was 5 μM PLCγ1 inhibitor (U-73122) for MOGGCCM and 15 μM for T98G cells, and 1 μM LOXO-101 for all cancer cells. Sorafenib, Temozolomide, U-73122, and LOXO-101 effectively eliminate cancer cells. Single applications of sorafenib and Temozolomide were effective, but had lower efficiency than U-73122 and LOXO-101. These drugs induced apoptosis, affecting mitochondrial membrane potential and caspases 3, 8, and 9 activity. The study found that a Bcl-2:beclin-1 complex formation was observed when apoptosis was dominant. Inhibiting the pathways regulated by TrkB receptor combined with Temozolomide action, led to successful gliomas elimination. Those results might serve as basis for modern targeted treatment development.

Comparative analysis of stereotactic radiosurgery outcomes for supratentorial hemangioblastomas in von hippel-lindau disease and sporadic cases: A multi-center international study

BackgroundHemangioblastomas (HBs) are rare, benign central nervous system (CNS) neoplasms that rarely occur in the supratentorial. Resection with the goal of gross total resection (GTR) is often considered the primary treatment. Stereotactic radiosurgery (SRS) has been utilized more commonly in unresectable or partially resected cases. In this study, we aimed to evaluate SRS’s effectiveness and clinical outcomes in supratentorial HBs. MethodsA retrospective analysis of multi-centers from 1993 to 2022 was conducted on patients with supratentorial HB treated with SRS. ResultsThe study included 13 patients with 30 supratentorial HBs (24 von Hippel-Lindau (VHL), 6 sporadic). Median age was 26 years. Most tumors were solid (86.2 %). SRS was primary treatment in 86.7 % of cases and adjuvant in 13.3 %. VHL lesions were significantly smaller than sporadic ones (0.2 vs. 3.7 cc, p = 0.009). Median margin dose was higher in VHL cases (17 vs. 13.0 Gy, P = 0.031). For VHL cases, local control (LC) was 100 % at 6 months, 96 % (95 % CI: 88 %, 100 %) from 12 to 60 months post-SRS. For sporadic cases, LC was 100 % at 6 months, 80 % (95 % CI: 52 %, 100 %) from 12 to 60 months post-SRS (p = 0.39). No adverse radiation events or mortality occurred. ConclusionSRS demonstrated a promising role in the clinical course of supratentorial HBs. It can be considered an effective alternative to surgical resection and even a first-line therapeutic option in appropriately selected cases.

Large language models as a diagnostic support tool in neuropathology.

The WHO guidelines for classifying central nervous system (CNS) tumours are changing considerably with each release. The classification of CNS tumours is uniquely complex among most other solid tumours as it incorporates not just morphology, but also genetic and epigenetic features. Keeping current with these changes across medical fields can be challenging, even for clinical specialists. Large language models (LLMs) have demonstrated their ability to parse and process complex medical text, but their utility in neuro-oncology has not been systematically tested. We hypothesised that LLMs can effectively diagnose neuro-oncology cases from free-text histopathology reports according to the latest WHO guidelines. To test this hypothesis, we evaluated the performance of ChatGPT-4o, Claude-3.5-sonnet, and Llama3 across 30 challenging neuropathology cases, which each presented a complex mix of morphological and genetic information relevant to the diagnosis. Furthermore, we integrated these models with the latest WHO guidelines through Retrieval-Augmented Generation (RAG) and again assessed their diagnostic accuracy. Our data show that LLMs equipped with RAG, but not without RAG, can accurately diagnose the neuropathological tumour subtype in 90% of the tested cases. This study lays the groundwork for a new generation of computational tools that can assist neuropathologists in their daily reporting practice.

Metastatic glioblastoma multiforme on skin and subcutaneous tissue

Glioblastoma multiforme (GBM) is characterized by its infiltrative growth pattern and high recurrence rate despite treatment. While local progression within the central nervous system (CNS) is the rule, manifestations outside the CNS, particularly skin and subcutaneous metastases, are very infrequent and seldom reported in the literature. The authors reviewed the current understanding of this rare condition, with the main purpose of giving visibility to its clinical presentation and prognostic implications, thus improving clinical management and encouraging research in this area. A PubMed, Cochrane Library, and EMBASE search from database inception through March 2024 was conducted. In this way, we compiled a total of thirty-five cases in our review. As far as we know, our work gathers the largest number of patients with this condition. Remarkably, we observed that the typical presentation of soft-tissue high-grade glioma metastases is the finding of subcutaneous erythematous nodules in patients previously operated on for a primary CNS tumor, within the craniotomy site and nearby, mostly in the first year after the initial surgery. It was also noted that there is a trend of developing a concomitant CNS recurrence and/or other metastases in different locations, either simultaneously or subsequently. From here, we propose some possible mechanisms that explain the extracranial spread of GBM. We concluded that a poor outcome is expected from the diagnosis of skin and subcutaneous metastases: the mean overall survival was 4.38 months. Yet, assessing individual characteristics is always mandatory; a palliative approach seems to be the best option for the majority of cases.

Molecular Testing of Central Nervous System Tumours - Recommendations of the Canadian Association of Neuropathologists.

Molecular Testing of Central Nervous System Tumours - Recommendations of the Canadian Association of Neuropathologists.

A patient with heterochronous double primary tumor of basal ganglia germ cell tumors followed by diffuse hemispheric glioma: a case report.

Basal ganglia germ cell tumor (BGGCT) is a rare central nervous system (CNS) tumor. Diffuse hemispheric gliomas, H3 G34-mutant (DHGs) is an invasive glioma involving the cerebral hemispheres. The diagnosis of DHGs depends on the integration of histopathology and molecular pathology. We reported a patient with an initial diagnosis of BGGCT that was sensitive to subsequent chemoradiotherapy. Unfortunately, a second high-grade glioma was found on magnetic resonance imaging (MRI) six years later. Subsequently, the tumor was completely removed after surgery and the following histopathology plus next generation sequencing (NGS) testing confirmed the diagnosis of DHGs. Interestingly, we found a germline likely pathogenic variant in FANCA. After surgery, the patient received Stupp regimen. The patient had a relapse 13months after the Stupp regimen and was doing well after surgery. This is the first report of a patient with heterochronous double primary tumor of BGGCT followed by DHGs.

An Overview of Reviews on Predictors of Neurorehabilitation in Surgical or Non-Surgical Patients with Brain Tumours

(1) Background. People suffering from brain cancer, regardless of histological tumour characteristics, often experience motor disturbances, cognitive–behavioural difficulty, language impairments, and functional and social limitations. The current treatment approach entails surgery and adjuvant therapy such as chemotherapy and radiotherapy combined with intensive rehabilitation. The primary focus of rehabilitation is usually motor and functional recovery, without specifically addressing the patient’s quality of life. The present systematic review identifies and evaluates the predictors of functional and cognitive rehabilitation outcomes and their influence on quality of life in adult patients with brain cancer. (2) Methods. Three electronic databases (PubMed, Elsevier, Cochrane) were searched for reviews about functional, cognitive, and quality-of-life outcomes in patients with central nervous system tumours, including articles published between January 2018 and May 2024. (3) Results. The search retrieved 399 records, 40 of which were reviewed. Five main areas of predictive factors were identified: diagnosis, therapy, complications, outcomes (in the motor, cognitive, and quality-of-life categories), and tailored rehabilitation. (4) Conclusions. These indicators may inform integrated care pathways for patients with primary central nervous system tumours.

Carbon monoxide poisoning is associated with an increased risk of epilepsy and status epilepticus: a nationwide population-based cohort study conducted in the Republic of Korea between 2002–2021

Introduction Carbon monoxide poisoning may result in various neurological injuries, including acute symptomatic seizures. We aimed to investigate the long-term risk of epilepsy and status epilepticus in patients with previous carbon monoxide poisoning. Methods The study population was derived from the National Health Insurance Service database of the Republic of Korea between 1 January 2002 and 31 December 2021. We included adults with at least one documented visit to medical facilities because of carbon monoxide poisoning (International Classification of Diseases, Tenth Revision, code T58). Patients were matched, on the same index date, with controls, without a T58 code, for age, sex, insurance type, income level, and residence location in a 1:1 ratio. Follow-up continued until death, migration, or the end of the observation period (31 December 2021). The primary outcome was the incidence of epilepsy (codes G40 or R56) and status epilepticus (code G41). Results This study included 53,380 patients with carbon monoxide poisoning and 53,380 controls, with 44.2% women and a mean age of 45.7 years. The mean (±SD) follow-up period was 5.7 ± 4.3 years in the carbon monoxide poisoned group and 6.4 ± 4.4 years in controls. The overall risk of epilepsy (adjusted hazard ratio 2.60; 95% CI: 2.43–2.78; P < 0.001) and status epilepticus (adjusted hazard ratio 4.10; 95% CI: 2.84–5.92; P < 0.001) was significantly increased in the carbon monoxide poisoned group compared to controls. The risk of epilepsy and status epilepticus was increased in patients with previous carbon monoxide poisoning, regardless of sex, age or a history of stroke, neurodegenerative diseases, or central nervous system tumour or infection. However, in the subgroup analysis according to age, the highest risk of epilepsy and status epilepticus was observed in patients less than 40 years of age. Discussion In this population-based cohort study, previous carbon monoxide poisoning was associated with an increased risk of epilepsy and status epilepticus. The risk was more noticeable in patients aged less than 40 years. Further studies are needed to confirm such an association in other populations. Conclusions Previous carbon monoxide poisoning was associated with an increased risk of epilepsy and status epilepticus, particularly in the younger population. The long-term management of survivors of carbon monoxide poisoning should include monitoring for epilepsy and status epilepticus.

Targeting Retinaldehyde Dehydrogenases to Enhance Temozolomide Therapy in Glioblastoma

Glioblastoma (GB) is an aggressive malignant central nervous system tumor that is currently incurable. One of the main pitfalls of GB treatment is resistance to the chemotherapeutic standard of care, temozolomide (TMZ). The role of aldehyde dehydrogenases (ALDHs) in the glioma stem cell (GSC) subpopulation has been related to chemoresistance. ALDHs take part in processes such as cell proliferation, differentiation, invasiveness or metastasis and have been studied as pharmacological targets in cancer treatment. In the present work, three novel α,β-acetylenic amino thiolester compounds, with demonstrated efficacy as ALDH inhibitors, were tested in vitro on a panel of six human GB cell lines and one murine GB cell line. Firstly, the expression of the ALDH1A isoforms was assessed, and then inhibitors were tested for their cytotoxicity and their ability to inhibit cellular ALDH activity. Drug combination assays with TMZ were performed, as well as an assessment of the cell death mechanism and generation of ROS. A knockout of several ALDH genes was carried out in one of the human GB cell lines, allowing us to discuss their role in cell proliferation, migration capacity and resistance to treatment. Our results strongly suggest that ALDH inhibitors could be an interesting approach in the treatment of GB, with EC50 values in the order of micromolar, decreasing ALDH activity in GB cell lines to 40–50%.

Comparative Analysis of Treatment Patterns in DoD Beneficiaries With Malignant Central Nervous System Tumors: A Focus on Care Setting.

Malignant brain and other central nervous system tumors (MBT) are deadly and disproportionately affect younger men and women in the age range of most active-duty service members. Timely and appropriate treatment is important to both survival and quality of life of patients. Information on treatment factors across direct care (DC) and private sector care (PSC) networks may be important for provider training and staffing for the DoD. The aim of this study was to analyze treatment patterns for patients with MBT within the DoD's universal access Military Health System (MHS), comparing DC and PSC networks. The Military Cancer Epidemiology database was used to identify patients 18 years and older who were diagnosed with an MBT between 1999 and 2014 who received primary treatment. Differences in first treatment type and time from diagnosis to initial treatment between DC and PSC were assessed using chi-square and Wilcoxon-Mann-Whitney tests, respectively. Frequency of treatment initiation beyond the 28-day TRICARE Prime access standard for Specialty Care was also compared between care settings using chi-square and Fisher's exact tests. Then logistic regression models generated odds of treatment initiation beyond 28 days and 95% confidence intervals (CIs) associated with care setting. Kaplan-Meier survival curves and log-rank tests compared survival between DC and PSC. The study included 857 patients, with n = 540 treated in DC and n = 317 treated in PSC. The proportion of patients receiving each initial treatment type did not differ by care setting (P = .622). Median time from diagnosis to initial treatment (interquartile range) varied significantly between DC at 6 (0 to 25) days and PSC at 12 (0 to 37) days for all treatment types combined (P < .001). For all years combined, treatment was initiated beyond 28 days for 21% of patients using DC compared to 31% of patients using PSC (P = .001). The odds of treatment initiation beyond 28 days for a patient treated in PSC were 1.61 (95% CI, 1.11 to 2.33, P = .012) compared to patients treated in DC when controlling for demographic, military, tumor, and patient variables. Survival did not differ by care setting (P = 1.000). Based on the available data between 1999 and 2014, care setting was associated with differences in time to initial treatment and odds of treatment initiation beyond 28 days among DoD beneficiaries with MBT receiving care in the MHS. Information on these differences may help inform MHS leadership decisions on the most appropriate location for military provider training and staffing.

Survival of pediatric patients with ependymoma in a tertiary cancer center in Rio de Janeiro, Brazil

IntroductionEpendymoma is the third most frequent central malignant nervous system tumor in the pediatric age group. There is scarce data in the literature on survival of these patients, especially in upper and lower middle-income countries. We aimed to describe the clinical and demographic characteristics, treatment, and outcome of pediatric patients with ependymoma admitted to a public cancer hospital.MethodsRetrospective analysis of medical records of patients with ependymoma, admitted to the Pediatric Oncology department (0-20 years) during the period of 2000-2022. Data on patient, disease characteristics, and treatment were analyzed. Overall survival (OS) was calculated using the Kaplan-Meier method.ResultsSeventy-two patients were evaluated; median age at diagnosis was 6.5 years (range: 1-20), 63% were male, 54% of the tumors were in the posterior fossa (PF-EPN), 45% were classified as WHO grade 3, and 68% were operated on in other institutions before referral. Regarding treatment, 72% underwent radiotherapy and 33% of patients underwent chemotherapy. Almost 70% percent of the patients had relapses. The median follow-up time was 5.2 years (Range: 0,1-21,4). The OS in 5 years was 67%. Totally resected tumors had OS in 5 years of 88% (p: 0.028).ConclusionThe results achieved in this series show a survival gap between UMIC and HIC. Relapses occurred mainly in the first ten years and then reached a plateau, with the majority of patients experiencing endocrinological and neurological sequelae.

TTF-1 immunohistochemistry in primary CNS tumors: A systematic review.

Thyroid transcription factor-1 (TTF-1) is a nuclear protein primarily recognized for its role in the development and differentiation of thyroid, lung, and certain diencephalic tissues. Although well-established as an immunohistochemical marker in thyroid and lung cancers, recent studies have explored its expression and diagnostic value in primary central nervous system (CNS) tumors. This systematic review aims to consolidate current knowledge on TTF-1 immunohistochemistry in primary CNS tumors, assessing its prevalence, diagnostic utility, and clinical implications. The review encompasses various CNS tumor types, including subependymal giant cell astrocytoma, chordoid glioma, pituicytoma, ependymomas, astrocytomas, glioblastomas, medulloblastomas, and choroid plexus tumors, highlighting the potential role of TTF-1 in differentiating these neoplasms from other CNS and metastatic tumors. By synthesizing findings from multiple studies, this review underscores the diagnostic value of TTF-1 in the neuropathological evaluation of CNS tumors and suggests directions for future research to refine its clinical application.

Response assessment in pediatric neurooncology (RAPNO) criteria revisited: a practical navigation guide for neuroradiologists.

The Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group is an international, collaborative network of experts dedicated to pediatric central nervous system (CNS) tumors that was created in 2011. Since then, six RAPNO articles with imaging guidelines for response assessment in diverse pediatric tumor subgroups have been published, namely: 1) medulloblastomas and leptomeningeal seeding tumors (2018), 2) pediatric high-grade gliomas (2020), 3) pediatric low-grade gliomas (2020), 4) diffuse intrinsic pontine gliomas (2020), 5) pediatric intracranial ependymomas (2022) and 6) pediatric craniopharyngiomas (2023). The purpose of this article is to review all current available RAPNO criteria using a systematized and comparative approach centered on the role of neuroradiologists and supported by neuroimaging examples. Special emphasis will be placed on clarification of core concepts as well as practical adoption aspects of the RAPNO guidelines, namely how and when to image the brain and/or the spine; how to interpret the imaging findings; which other clinical, therapeutic and laboratory variables to consider; and finally how to apply the information to attribute the final appropriate response assessment classification.

Comparative Analysis of Transcription Factors TWIST2, GATA3, and HES5 in Glioblastoma Multiforme : Evaluating Biomarker Potential and Therapeutic Targets Using In Silico Methods.

Glioblastoma multiforme (GBM) is characterized by substantial heterogeneity and limited therapeutic options. As molecular approaches to central nervous system (CNS) tumors have gained prominence, this study examined the roles of three genes, TWIST2, GATA3, and HES5, known to be involved in oncogenesis, developmental processes, and maintenance of cancer stem cell properties, which have not yet been extensively studied in GBM. This study is the first to present gene expression data for TWIST2, GATA3, and HES5 specifically within the context of GBM patient survival. Gene expression data for TWIST2, GATA3, and HES5 were collected from GBM and normal brain tissues using datasets from The Cancer Genome Atlas (TCGA) via the Genomic Data Commons (GDC) portal and the Genotype-Tissue Expression (GTEx) database. These data were rigorously analyzed using in silico methods. All three genes were significantly more expressed in GBM tissues than in normal tissues. TWIST2 and GATA3 were linked to lower survival rates in GBM patients. Interestingly, higher HES5 levels were associated with better survival rates, suggesting a complex role that needs more investigation. This study shows that TWIST2, GATA3, and HES5 could help predict outcomes in GBM patients. Our multigene model offers a better understanding of GBM and points to new treatment options, bringing hope for improved therapies and patient outcomes. This research advances our knowledge of GBM and highlights the potential of molecular diagnostics in oncology.

Central nervous system tumors in adolescents and young adults: A Society for Neuro-Oncology consensus review on diagnosis, management, and future directions.

Adolescents and young adults (AYAs; ages 15-39 years) are a vulnerable population facing challenges in oncological care, including access to specialized care, transition of care, unique tumor biology, and poor representation in clinical trials. Brain tumors are the second most common tumor type in AYA, with malignant brain tumors being the most common cause of cancer-related death. The 2021 WHO Classification for central nervous system (CNS) Tumors highlights the importance of integrated molecular characterization with histologic diagnosis in several tumors relevant to the AYA population. In this position paper from the Society for Neuro-Oncology (SNO), the diagnosis and management of CNS tumors in AYA is reviewed, focusing on the most common tumor types in this population, namely glioma, medulloblastoma, ependymoma, and CNS germ cell tumor. Current challenges and future directions specific to AYA are also highlighted. Finally, possible solutions to address barriers in the care of AYA patients are discussed, emphasizing the need for multidisciplinary and collaborative approaches that span the pediatric and adult paradigms of care, and incorporating advanced molecular testing, targeted therapy, and AYA-centered care.

Pediatric Atypical Teratoid Rhabdoid Tumor of Central Nervous System: A Case Series with Review of Literature

Pediatric Atypical Teratoid Rhabdoid Tumor of Central Nervous System: A Case Series with Review of Literature

CIC/ATXN1-rearranged tumors in the central nervous system are mainly represented by sarcomas: A comprehensive clinicopathological and epigenetic series.

CIC fusions have been described in two different central nervous system (CNS) tumor entities. On one hand, fusions of CIC or ATXN1 genes belonging to the same complex of transcriptional repressors, were reported in the CIC-rearranged, sarcoma (SARC-CIC). The diagnosis of this tumor type, which was recently added to the World Health Organization (WHO) Classification of CNS tumors, is difficult mainly because the data concerning its histopathology (as compared to its soft tissue counterpart), immunoprofile, and clinical as well as radiological characteristics are scarce in the literature. On the other hand, a recent study, based on DNA-methylation profiling, has identified a novel high-grade neuroepithelial tumor characterized by recurrent CIC fusions (HGNET-CIC). The aim of this multicentric study was to characterize a cohort of 15 primary CNS tumors harboring a CIC or ATXN1 fusion in terms of clinical, radiological, histopathological, immunophenotypical, and epigenetic characteristics. According to the integrated diagnoses, 14/15 tumors corresponded to SARC-CIC, and only one to HGNET-CIC. The tumors showed similar clinical (mainly pediatric), radiological (mostly supratentorial, cystic, and contrast enhancing), immunophenotypical (common expression of glioneuronal markers), and genetic (similar spectrum of fusions) profiles but their histopathological appearance was clearly distinct. Moreover, we found a novel fusion transcript (CIC::EWSR1) in a SARC-CIC. Most DNA methylation profiles using the Heidelberg Brain Tumor Classifier (v12.8) annotated the samples to the methylation class "SARC-CIC" (9/14 tumors with available data). By using uniform manifold approximation and projection analysis, four other samples were classified as SARC-CIC and another clustered within the methylation class of HGNET-CIC. Our findings confirm that CNS CIC-fused tumors do not represent a single molecular tumor entity. Further analyses are needed to characterize HGNET-CIC in more detail. These results may help to refine the essential diagnostic criteria for SARC-CIC and their terminology (with a suggested consensual name of sarcoma, CIC/ATXN1-complex rearranged).