Review

Authors: Roberta Rudà, Guido Reifenberger, Didier Frappaz...

Ependymal tumors are rare CNS tumors and may occur at any age, but their proportion among primary brain tumors is highest in children and young adults. Thus, the level of evidence of diagnostic and therapeutic interventions is higher in the pediatric compared with the adult patient population.The diagnosis and disease staging is performed by craniospinal MRI. Tumor classification is achieved by histological and molecular diagnostic assessment of tissue specimens according to the World Health Organization (WHO) classification 2016. Surgery is the crucial initial treatment in both children and adults. In pediatric patients with intracranial ependymomas of WHO grades II or III, surgery is followed by local radiotherapy regardless of residual tumor volume. In adults, radiotherapy is employed in patients with anaplastic ependymoma WHO grade III, and in case of incomplete resection of WHO grade II ependymoma. Chemotherapy alone is reserved for young children <12 months and for adults with recurrent disease when further surgery and irradiation are no longer feasible. A gross total resection is the mainstay of treatment in spinal ependymomas, and radiotherapy is reserved for incompletely resected tumors. Nine subgroups of ependymal tumors across different anatomical compartments (supratentorial, posterior fossa, spinal) and patient ages have been identified with distinct genetic and epigenetic alterations, and with distinct outcomes. These findings may lead to more precise diagnostic and prognostic assessments, molecular subgroup-adapted therapies, and eventually new recommendations pending validation in prospective studies.

Topics: Ependymoma; Humans; Practice Guidelines as Topic; Prognosis

PubMed: 29194500
DOI: 10.1093/neuonc/nox166

Review

Authors: Catena Kresbach, Sina Neyazi, Ulrich Schüller...

Ependymal neoplasms occur at all ages and encompass multiple tumor types and subtypes that develop in the supratentorial compartment, the posterior fossa, or the spinal cord. Clinically, ependymomas represent a very heterogeneous group of tumors from rather benign subependymomas to very aggressive and often deadly childhood ependymomas of the posterior fossa. Newly identified biological markers and classification schemes, e. g. based on global DNA methylation profiling, have led to the definition of 10 types of ependymal tumors and an improved prediction of patients' outcome by applying the new classification system. While the exact genetic basis for several ependymoma types still remains unclear, the knowledge about ependymoma driving events has significantly increased within the last decade and contributed to a classification based on molecular characteristics and localization rather than histological features alone. Convincing evidence is now pointing towards gene fusions involving ZFTA or YAP1 causing the development of supratentorial ependymomas. Also, H3, EZHIP, or TERT mutations have been detected in a fraction of infratentorial ependymal tumors. Finally, MYCN amplifications have recently been identified in spinal ependymomas, in addition to the previously known mutations in NF2. This review summarizes how recent findings regarding biology, molecular tumor typing, and clinical outcome have impacted the classification of ependymomas as suggested by the updated 2021 WHO CNS tumor classification system. We focus on changes compared to the previous classification of 2016 and discuss how a formal grading could evolve in the future and guide clinicians to treat ependymoma patients.

Topics: Brain Neoplasms; Child; Ependymoma; Humans; Infratentorial Neoplasms; Supratentorial Neoplasms; World Health Organization

PubMed: 35307892
DOI: 10.1111/bpa.13068

Authors: Kristian W Pajtler, Hendrik Witt, Martin Sill...

Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Age Factors; Aged; Central Nervous System Neoplasms; Child; Child, Preschool; DNA Methylation; Ependymoma; Female; Gene Dosage; Gene Expression Profiling; Gene Fusion; Humans; Infant; Male; Middle Aged; Phosphoproteins; Transcription Factors; Transcription, Genetic; YAP-Signaling Proteins; Young Adult

PubMed: 25965575
DOI: 10.1016/j.ccell.2015.04.002

Review

Authors: Luca Bertero, Alessia Andrea Ricci, Cristian Tampieri...

Ependymal neoplasms are a heterogenous group of neoplasms arising from the progenitors of the cells lining the ventricular system and the spinal central canal. During the last few years, significant novel data concerning oncogenesis, molecular characteristics and clinical correlations of these tumours have been collected, with a strong relevance for their pathological classification. The recently published 5th edition of WHO Classification of Central Nervous System Tumours integrates this novel knowledge and represents a substantial update compared to the previous edition. Concerning supratentorial ependymomas, the previous fusion-positive ependymoma has been renamed into fusion-positive and the novel fusion-positive ependymoma subtype has been added. Posterior fossa ependymomas should now be allocated either to the Type A or Type B subtypes based on molecular profiling or using the H3 K27me3 immunohistochemical surrogate. Regarding spinal ependymomas, a novel subtype has been added based on a distinctive molecular trait, presence of amplification, and on the unfavourable outcome. Finally, myxopapillary ependymoma is now classified as a grade 2 tumour in accordance with its overall prognosis which mirrors that of conventional spinal ependymomas. The aim of this review is to present these changes and summarize the current diagnostic framework of ependymal tumours, according to the most recent updates.

Topics: Humans; Ependymoma; Prognosis

PubMed: 36534422
DOI: 10.32074/1591-951X-817

Review

Authors: Weiya Mu, Hisham Dahmoush

Ependymal tumors arise from the ependymal cell remnants of the cerebral ventricles, the central canal of the spinal cord, or the filum terminale or conus medullaris, although most pediatric supratentorial ependymomas do not exhibit clear communication or abutment of the ventricles. In this article, we discuss the classification, imaging characteristics, and clinical settings of these tumors. The WHO 2021 classification system has categorized ependymal tumors based on histopathologic and molecular features and location, in which they are grouped as supratentorial, posterior fossa (PF), and spinal. The supratentorial tumors are defined by either the ZFTA (formerly RELA) fusion or the YAP1 fusion. Posterior fossa tumors are divided into group A and group B based on methylation. On imaging, supratentorial and infratentorial ependymomas may arise from the ventricles and commonly contain calcifications and cystic components, with variable hemorrhage and heterogeneous enhancement. Spinal ependymomas are defined by MYCN amplification. These tumors are less commonly calcified and may present with the "cap sign," with T2 hypointensity due to hemosiderin deposition. Myxopapillary ependymoma and subependymoma remain tumor subtypes, with no change related to molecular classification as this does not provide additional clinical utility. Myxopapillary ependymomas are intradural and extramedullary tumors at the filum terminale and/or conus medullaris and may also present the cap sign. Subependymomas are homogeneous when small and may be heterogeneous and contain calcifications when larger. These tumors typically do not demonstrate enhancement. Clinical presentation and prognosis vary depending on tumor location and type. Knowledge of the updated WHO classification of the central nervous system in conjunction with imaging features is critical for accurate diagnosis and treatment.

PubMed: 37287627
DOI: 10.3389/fped.2023.1181211

Review

Authors: Manfred Westphal, Malte Mohme

Spinal ependymomas are strictly to be subdivided into intramedullary lesions and extramedullary lesions as they are histologically and genetically distinct. Whereas the intramedullary lesions (SPE) are assigned to the WHO grade 2 and very rarely grade 3, the extramedullary lesions or myxopapilary tumors (MPE) are only as recently also assigned to WHO grade 2. The major difference is that in general, an intramedullary lesion of grade 2 remains confined to the local site of origin, even when rarely recurring after complete resection. In contrast, the MPEs have the capacity to spread throughout the cerebrospinal fluid compartment but can also be controlled by cautious complete resection. We here review the clinical features of spinal ependymomas, contrasting the entities, and describe the treatment found best from the literature to manage these lesions including interdisciplinary approaches.

PubMed: 39430387
DOI: 10.1093/noajnl/vdad138

Review

Authors: Prashant Kesharwani, Kratika Halwai, Saurav Kumar Jha...

Chitosan nanoparticles (NPs) are well-recognized as promising vehicles for delivering anticancer drugs due to their distinctive characteristics. They have the potential to enclose hydrophobic anticancer molecules, thereby enhancing their solubilities, permeabilities, and bioavailabilities; without the use of surfactant, i.e., through surfactant-free solubilization. This allows for higher drug concentrations at the tumor sites, prevents excessive toxicity imparted by surfactants, and could circumvent drug resistance. Moreover, biomedical engineers and formulation scientists can also fabricate chitosan NPs to slowly release anticancer agents. This keeps the drugs at the tumor site longer, makes therapy more effective, and lowers the frequency of dosing. Notably, some types of cancer cells (fallopian tube, epithelial tumors of the ovary, and primary peritoneum; lung, kidney, ependymal brain, uterus, breast, colon, and malignant pleural mesothelioma) have overexpression of folate receptors (FRs) on their outer surface, which lets folate-drug conjugate-incorporated NPs to target and kill them more effectively. Strikingly, there is evidence suggesting that the excessively produced FR&αgr (isoforms of the FR) stays consistent throughout treatment in ovarian and endometrial cancer, indicating resistance to conventional treatment; and in this regard, folate-anchored chitosan NPs can overcome it and improve the therapeutic outcomes. Interestingly, overly expressed FRs are present only in certain tumor types, which makes them a promising biomarker for predicting the effectiveness of FR-targeted therapy. On the other hand, the folate-modified chitosan NPs can also enhance the oral absorption of medicines, especially anticancer drugs, and pave the way for effective and long-term low-dose oral metronomic scheduling of poorly soluble and permeable drugs. In this review, we talked briefly about the techniques used to create, characterize, and tailor chitosan-based NPs; and delved deeper into the potential applications of folate-engineered chitosan NPs in treating various cancer types.

Topics: Chitosan; Humans; Folic Acid; Nanoparticles; Drug Carriers; Antineoplastic Agents; Neoplasms; Animals; Drug Delivery Systems

PubMed: 39482651
DOI: 10.1186/s12943-024-02163-z

Review

Authors: Norman L Lehman

PURPOSE

Review of the clinicopathologic and genetic features of early ependymal tumor with MN1-BEND2 fusion (EET MN1-BEND2), classical astroblastomas, and recently described related pediatric CNS tumors. I also briefly review general mechanisms of gene expression silencing by DNA methylation and chromatin remodeling, and genomic DNA methylation profiling as a powerful new tool for CNS tumor classification.

METHODS

Literature review and illustration of tumor histopathologic features and prenatal gene expression timelines.

RESULTS

Astroblastoma, originally descried by Bailey and Cushing in 1926, has been an enigmatic tumor. Whether they are of ependymal or astrocytic derivation was argued for decades. Recent genetic evidence supports existence of both ependymal and astrocytic astroblastoma-like tumors. Studies have shown that tumors exhibiting astroblastoma-like histology can be classified into discrete entities based on their genomic DNA methylation profiles, gene expression, and in some cases, the presence of unique gene fusions. One such tumor, EET MN1-BEND2 occurs mostly in female children, and has an overall very good prognosis with surgical management. It contains a gene fusion comprised of portions of the MN1 gene at chromosomal location 22q12.1 and the BEND2 gene at Xp22.13. Other emerging pediatric CNS tumor entities demonstrating ependymal or astroblastoma-like histological features also harbor gene fusions involving chromosome X, 11q22 and 22q12 breakpoint regions.

CONCLUSIONS

Genomic DNA profiling has facilitated discovery of several new CNS tumor entities, however, traditional methods, such as immunohistochemistry, DNA or RNA sequencing, and cytogenetic studies, including fluorescence in situ hybridization, remain necessary for their accurate biological classification and diagnosis.

Topics: Child; Female; Humans; Brain Neoplasms; Central Nervous System Neoplasms; Glioma; In Situ Hybridization, Fluorescence; Neoplasms, Neuroepithelial; Prognosis; Supratentorial Neoplasms; Trans-Activators; Tumor Suppressor Proteins

PubMed: 36604386
DOI: 10.1007/s11060-022-04222-1

Leptomeningeal disease and tumor dissemination in a murine diffuse intrinsic pontine glioma model: implications for the study of the tumor-cerebrospinal fluid-ependymal microenvironment.

Authors: Shelei Pan, Dezhuang Ye, Yimei Yue...

BACKGROUND

Leptomeningeal disease and hydrocephalus are present in up to 30% of patients with diffuse intrinsic pontine glioma (DIPG), however there are no animal models of cerebrospinal fluid (CSF) dissemination. As the tumor-CSF-ependymal microenvironment may play an important role in tumor pathogenesis, we identified characteristics of the Nestin-tumor virus A (Nestin-Tva) genetically engineered mouse model that make it ideal to study the interaction of tumor cells with the CSF and its associated pathways with implications for the development of treatment approaches to address CSF dissemination in DIPG.

METHODS

A Nestin-Tva model of DIPG utilizing the 3 most common DIPG genetic alterations (H3.3K27M, PDGF-B, and p53) was used for this study. All mice underwent MR imaging and a subset underwent histopathologic analysis with H&E and immunostaining.

RESULTS

Tumor dissemination within the CSF pathways (ventricles, leptomeninges) from the subependyma was present in 76% (25/33) of mice, with invasion of the choroid plexus, disruption of the ciliated ependyma and regional subependymal fluid accumulation. Ventricular enlargement consistent with hydrocephalus was present in 94% (31/33). Ventricle volume correlated with region-specific transependymal CSF flow (periventricular T2 signal), localized anterior to the lateral ventricles.

CONCLUSIONS

This is the first study to report CSF pathway tumor dissemination associated with subependymal tumor in an animal model of DIPG and is representative of CSF dissemination seen clinically. Understanding the CSF-tumor-ependymal microenvironment has significant implications for treatment of DIPG through targeting mechanisms of tumor spread within the CSF pathways.

PubMed: 35733516
DOI: 10.1093/noajnl/vdac059

Review

Authors: Giuseppe Lombardi, Alessandro Della Puppa, Marco Pizzi...

Ependymomas are rare primary central nervous system tumors. They can form anywhere along the neuraxis, but in adults, these tumors predominantly occur in the spine and less frequently intracranially. Ependymal tumors represent a heterogenous group of gliomas, and the WHO 2016 classification is based essentially on a grading system, with ependymomas classified as grade I, II (classic), or III (anaplastic). In adults, surgery is the primary initial treatment, while radiotherapy is employed as an adjuvant treatment in some cases of grade II and in all cases of anaplastic ependymoma; chemotherapy is reserved for recurrent cases. In recent years, important and interesting advances in the molecular characterization of ependymomas have been made, allowing for the identification of nine molecular subgroups of ependymal tumors and moving toward subgroup-specific patients with improved risk stratification for treatment-decisions and future prospective trials. New targeted agents or immunotherapies for ependymoma patients are being explored for recurrent disease. This review summarizes recent molecular advances in the diagnosis and treatment of intracranial ependymomas including surgery, radiation therapy and systemic therapies.

PubMed: 34885237
DOI: 10.3390/cancers13236128