-
Current Oncology Reports Aug 2022To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults. (Review)
Review
PURPOSE OF REVIEW
To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults.
RECENT FINDINGS
Ependymomas may occur either in the brain or in the spinal cord. Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis. The new WHO classification of CNS tumors of 2021 has subdivided ependymomas into different histomolecular subgroups with different outcome. The majority of studies have shown a major impact of extent of resection; thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation. Conformal radiotherapy is recommended for grade 3 or incompletely resected grade II tumors. Proton therapy is increasingly employed especially in children to reduce the risk of neurocognitive and endocrine sequelae. Craniospinal irradiation is reserved for metastatic disease. Chemotherapy is not useful as primary treatment and is commonly employed as salvage treatment for patients failing surgery and radiotherapy. Standard treatments are still the mainstay of treatment: the discovery of new druggable pathways will hopefully increase the therapeutic armamentarium in the near future.
Topics: Adult; Brain Neoplasms; Child; Ependymoma; Humans; Prognosis; Salvage Therapy
PubMed: 35384591
DOI: 10.1007/s11912-022-01260-w -
Neuro-oncology Mar 2018Ependymal 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... (Review)
Review
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 -
Pathologica Dec 2022Ependymal neoplasms are a heterogenous group of neoplasms arising from the progenitors of the cells lining the ventricular system and the spinal central canal. During... (Review)
Review
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 -
Radiographics : a Review Publication of... 2019
Topics: Adult; Ependymoma; Humans; Magnetic Resonance Imaging; Middle Aged; Neuroimaging; Spinal Cord; Spinal Cord Neoplasms
PubMed: 30844350
DOI: 10.1148/rg.2019184014 -
Pediatric and Developmental Pathology :... 2022Ependymomas (EPN) are commonly encountered brain tumors in the pediatric population. They may arise in the supratentorial compartment, posterior fossa and spinal cord....
Ependymomas (EPN) are commonly encountered brain tumors in the pediatric population. They may arise in the supratentorial compartment, posterior fossa and spinal cord. Histopathologic grading of EPN has always been challenging with poor interobserver reproducibility and lack of correlation between histologic grade and patient outcomes. Recent studies have highlighted that, despite histopathological similarities among variants of EPN at different anatomical sites, they possess site-specific genetic and epigenetic alterations, transcriptional profiles and DNA copy number variations. This has led to a molecular and location-based classification for EPN which has been adopted by the World Health Organization Classification of Central Nervous System Tumors and more accurately risk-stratifies patients than histopathologic grading alone. Given the complexity of this evolving field, the purpose of this paper is to offer a practical approach to the diagnosis of EPN, including the selection of the most appropriate molecular surrogate immunohistochemical stains, basic molecular studies and more sophisticated techniques if needed. The goal is to reach a rapid, sound diagnosis, providing essential information regarding prognosis and guiding clinical decision-making.
Topics: Brain Neoplasms; Child; DNA Copy Number Variations; Ependymoma; Humans; Prognosis; Reproducibility of Results
PubMed: 35168420
DOI: 10.1177/10935266211018928 -
Nature Cell Biology Feb 2023Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase...
Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.
Topics: Humans; Adaptor Proteins, Signal Transducing; Carcinogenesis; Cell Cycle Proteins; Cell Transformation, Neoplastic; Ependymoma; Nuclear Proteins; Transcription Factors; YAP-Signaling Proteins; Cell Nucleus; Transcription, Genetic
PubMed: 36732631
DOI: 10.1038/s41556-022-01069-6 -
Cancer Cell Jul 2020Ependymoma is a heterogeneous entity of central nervous system tumors with well-established molecular groups. Here, we apply single-cell RNA sequencing to analyze...
Ependymoma is a heterogeneous entity of central nervous system tumors with well-established molecular groups. Here, we apply single-cell RNA sequencing to analyze ependymomas across molecular groups and anatomic locations to investigate their intratumoral heterogeneity and developmental origins. Ependymomas are composed of a cellular hierarchy initiating from undifferentiated populations, which undergo impaired differentiation toward three lineages of neuronal-glial fate specification. While prognostically favorable groups of ependymoma predominantly harbor differentiated cells, aggressive groups are enriched for undifferentiated cell populations. The delineated transcriptomic signatures correlate with patient survival and define molecular dependencies for targeted treatment approaches. Taken together, our analyses reveal a developmental hierarchy underlying ependymomas relevant to biological and clinical behavior.
Topics: Cell Differentiation; Cell Proliferation; Central Nervous System Neoplasms; Child; Ependymoma; Genomics; Humans; Neurons; Prognosis; Sequence Analysis, RNA; Single-Cell Analysis; Survival Analysis
PubMed: 32663469
DOI: 10.1016/j.ccell.2020.06.004 -
Journal of Child Neurology Oct 2016Over the past 150 years since Virchow's initial characterization of ependymoma, incredible efforts have been made in the classification of these tumors and in the care... (Review)
Review
Over the past 150 years since Virchow's initial characterization of ependymoma, incredible efforts have been made in the classification of these tumors and in the care of pediatric patients with this disease. While the advent of modern neurosurgery and the optimization of radiation have provided significant gains, a more complex but incomplete picture of pediatric ependymomas has begun to form through a combination of international collaborations and detailed genetic and histologic characterizations. This review includes and synthesizes the clinical understanding of pediatric ependymoma and their developing molecular insight into what is truly a family of malignancies in which distinct members require different surgical approaches, radiation plans, and targeted therapies.
Topics: Central Nervous System Neoplasms; Child; Child, Preschool; Ependymoma; Humans
PubMed: 26503805
DOI: 10.1177/0883073815610428 -
Journal of Clinical Oncology : Official... Apr 2019The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery,... (Clinical Trial)
Clinical Trial
Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma.
PURPOSE
The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery, radiation therapy, and-selectively-with chemotherapy. Treatment was administered according to tumor location, histologic grade, and extent of resection. The impacts of histologic grade, focal copy number gain on chromosome 1q, and DNA methylation profiles were studied for those undergoing surgery and immediate postoperative conformal radiation therapy (CRT).
METHODS
ACNS0121 included 356 newly diagnosed patients (ages 1 to 21 years). Patients with classic supratentorial ependymoma were observed after gross total resection (GTR). Those undergoing subtotal resection received chemotherapy, second surgery, and CRT. The remaining patients received immediate postoperative CRT after near-total resection or GTR. CRT was administered with a 1.0-cm clinical target volume margin. The cumulative total dose was 59.4 Gy, except for patients who underwent GTR and were younger than age 18 months (who received 54 Gy). Patients were enrolled between October 2003 and September 2007 and were observed for 5 years. Supratentorial tumors were evaluated for fusion; infratentorial tumors, for chromosome 1q gain. Classification of posterior fossa groups A and B was made by methylation profiles.
RESULTS
The 5-year EFS rates were 61.4% (95% CI, 34.5% to 89.6%), 37.2% (95% CI, 24.8% to 49.6%), and 68.5% (95% CI, 62.8% to 74.2%) for observation, subtotal resection, and near-total resection/GTR groups given immediate postoperative CRT, respectively. The 5-year EFS rates differed significantly by tumor grade ( = .0044) but not by age, location, fusion status, or posterior fossa A/posterior fossa B grouping. EFS was higher for patients with infratentorial tumors without 1q gain than with 1q gain (82.8% [95% CI, 74.4% to 91.2%] 47.4% [95% CI, 26.0% to 68.8%]; = .0013).
CONCLUSION
The EFS for patients with ependymoma younger than 3 years of age who received immediate postoperative CRT and for older patients is similar. Irradiation should remain the mainstay of care for most subtypes.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Child; Child, Preschool; Cytoreduction Surgical Procedures; Ependymoma; Female; Humans; Infant; Male; Progression-Free Survival; Radiotherapy, Conformal; Supratentorial Neoplasms; Transcription Factor RelA; Treatment Outcome; Young Adult
PubMed: 30811284
DOI: 10.1200/JCO.18.01765 -
Seminars in Neurology Feb 2018Ependymoma can arise throughout the whole neuraxis. In children, tumors predominantly occur intracranially, whereas the spine is the most prevalent location in adults.... (Review)
Review
Ependymoma can arise throughout the whole neuraxis. In children, tumors predominantly occur intracranially, whereas the spine is the most prevalent location in adults. Significant variance in the grade II versus grade III distinction of ependymomas has led to the acknowledgment that the clinical utility of histopathological classification is limited. Epigenomic profiling efforts have identified molecularly distinct groups of ependymomas that adequately reflect the biological, clinical, and histopathological heterogeneities across anatomical compartments, age groups, and grades. The recent update of the World Health Organization classification of central nervous system tumors has already integrated one of these groups, and molecular classification will be part of future clinical trials to improve risk stratification. Clinical management of this rare disease is challenging, making professional experience and intensified multidisciplinary cooperation pivotal factors for treatment success. Novel research strategies are currently applied for target discovery in ependymomas since for most molecular groups, genetic drivers are unknown.
Topics: Adolescent; Adult; Central Nervous System Neoplasms; Child; Ependymoma; Humans
PubMed: 29548057
DOI: 10.1055/s-0038-1636503