Molecular Classification and Therapeutic Targets in Ependymoma

Abstract

Ependymoma is a biologically diverse tumor wherein molecular classification has superseded traditional histological grading based on its superior ability to characterize behavior, prognosis, and possible targeted therapies. The current, updated molecular classification of ependymoma consists of ten distinct subgroups spread evenly among the spinal, infratentorial, and supratentorial compartments, each with its own distinct clinical and molecular characteristics. In this review, the history, histopathology, standard of care, prognosis, oncogenic drivers, and hypothesized molecular targets for all subgroups of ependymoma are explored. This review emphasizes that despite the varied behavior of the ependymoma subgroups, it remains clear that research must be performed to further elucidate molecular targets for these tumors. Although not all ependymoma subgroups are oncologically aggressive, development of targeted therapies is essential, particularly for cases where surgical resection is not an option without causing significant morbidity. The development of molecular therapies must rely on building upon our current understanding of ependymoma oncogenesis, as well as cultivating transfer of knowledge based on malignancies with similar genomic alterations.

Extra-Neural Metastases From Primary Intracranial Ependymomas: A Systematic Review

“…Ten subgroups, each carrying singular molecular features, have been identified and divided based on anatomical location: three supratentorial, three infratentorial, three spinal, and one (subependymoma) found in all three compartments ( 2 ). Supratentorial ependymomas encompass: 1) supratentorial ependymomas with YAP1-fusion, grade 2-3 pediatric tumors with good prognosis, which maybe targeted by YAP/TAZ inhibitors such as dasatinib and pazopanib; 2) supratentorial ependymomas with ZFTA-fusion, grade 3 entities with worse prognosis and intraventricular predilection, previously classified as RELA-fusion positive; 3) supratentorial ependymomas NOS/NEC, grade 2-3 tumors with no-YAP1/ZFTA fusion, which represent a subgroup of exclusion ( 80 ). Infratentorial ependymomas include: 1) posterior fossa ependymomas group A, grade 3 tumors with poor prognosis, loss of H3K27me3 expression, and EZHIP mutations, whose pharmaceutical interruption may block tumorigenesis; 2) posterior fossa ependymomas group B, grade 2 H3K27me3-positive neoplasms with better prognosis and mostly occurring in young adults, characterized by higher chromosomal instability and FOXJ1 hyperactivity; 3) posterior fossa ependymomas NOS/NEC, grade 2-3 lesions with other or not analyzable molecular features that mostly arise from the ependymal lining of the fourth ventricle ( 80 ).…”

“…Supratentorial ependymomas encompass: 1) supratentorial ependymomas with YAP1-fusion, grade 2-3 pediatric tumors with good prognosis, which maybe targeted by YAP/TAZ inhibitors such as dasatinib and pazopanib; 2) supratentorial ependymomas with ZFTA-fusion, grade 3 entities with worse prognosis and intraventricular predilection, previously classified as RELA-fusion positive; 3) supratentorial ependymomas NOS/NEC, grade 2-3 tumors with no-YAP1/ZFTA fusion, which represent a subgroup of exclusion ( 80 ). Infratentorial ependymomas include: 1) posterior fossa ependymomas group A, grade 3 tumors with poor prognosis, loss of H3K27me3 expression, and EZHIP mutations, whose pharmaceutical interruption may block tumorigenesis; 2) posterior fossa ependymomas group B, grade 2 H3K27me3-positive neoplasms with better prognosis and mostly occurring in young adults, characterized by higher chromosomal instability and FOXJ1 hyperactivity; 3) posterior fossa ependymomas NOS/NEC, grade 2-3 lesions with other or not analyzable molecular features that mostly arise from the ependymal lining of the fourth ventricle ( 80 ). Spinal ependymomas comprise: 1) myxopapillary ependymomas, grade 2 tumors involving the cauda equina/filum terminale and showing overexpression of HOX, NEFL, and PDGFRA genes; 2) spinal ependymomas, grade 3 lesions characterized by NF2 (Merlin gene) alterations that can be targeted by MEK inhibitors and VEGF inhibitors; 3) spinal ependymomas with MYCN amplification, grade 3 entities with worse prognoses and higher propensity of leptomeningeal spread, but with no available clinical trials on MYCN-targeting inhibitors ( 80 ).…”

“…Infratentorial ependymomas include: 1) posterior fossa ependymomas group A, grade 3 tumors with poor prognosis, loss of H3K27me3 expression, and EZHIP mutations, whose pharmaceutical interruption may block tumorigenesis; 2) posterior fossa ependymomas group B, grade 2 H3K27me3-positive neoplasms with better prognosis and mostly occurring in young adults, characterized by higher chromosomal instability and FOXJ1 hyperactivity; 3) posterior fossa ependymomas NOS/NEC, grade 2-3 lesions with other or not analyzable molecular features that mostly arise from the ependymal lining of the fourth ventricle ( 80 ). Spinal ependymomas comprise: 1) myxopapillary ependymomas, grade 2 tumors involving the cauda equina/filum terminale and showing overexpression of HOX, NEFL, and PDGFRA genes; 2) spinal ependymomas, grade 3 lesions characterized by NF2 (Merlin gene) alterations that can be targeted by MEK inhibitors and VEGF inhibitors; 3) spinal ependymomas with MYCN amplification, grade 3 entities with worse prognoses and higher propensity of leptomeningeal spread, but with no available clinical trials on MYCN-targeting inhibitors ( 80 ). Lastly, subependymomas are considered slow-growing WHO grade 1 tumors, presenting with CSF obstruction if intracranial or myelopathy/radiculopathy if spinal, and with tumorigenesis likely driven by loss of chromosome 6q and alterations in topoisomerase and p-STAT3/HIF-1α inhibitors, which represent viable molecular therapeutic targets ( 81 ).…”

WHO CNS5 2021 classification of gliomas: a practical review and road signs for diagnosing pathologists and proper patho-clinical and neuro-oncological cooperation

“…The fourth ventricle is the most common localization of posterior fossa ependymomas, being more common in children with median age of 6 years. Spinal ependymomas are usually located in the cervical and thoracic region, most commonly in the age of 25-45 [40]. For all ependymomas, morphological and immunohistochemical features are still crucial for the diagnosis.…”

Recent Molecular and Genetic Findings in Intramedullary Spinal Cord Tumors

“…Compared to other subtypes of ependymomas, these groups had worse median progression-free survival (17 months) and median overall survival (87 months). These tumors were also characterized by a favored location of the cervical and thoracic spine, and were predominantly intradural and extramedullary [ 63 ]. The presence of diffuse leptomeningeal spread and dissemination has also been revealed as a distinctive feature of these tumors.…”