Chromosomal anomalies and prognostic markers for intracranial and spinal ependymomas

Abstract

Ependymomas are neoplasms that can occur anywhere along the craniospinal axis. They are the third most common brain tumor in children, representing 10% of pediatric intracranial tumors, 4% of adult brain tumors, and 15% of all spinal cord tumors. As the heterogeneity of ependymomas has severely limited the prognostic value of the World Health Organization grading system, numerous studies have focused on genetic alterations as a potential basis for classification and prognosis. However, this endeavor has proven difficult due to variations of findings depending on tumor location, tumor grade, and patient age. While many have evaluated chromosomal abnormalities for ependymomas as a whole group, others have concentrated their efforts on specific subsets of populations. Here, we review modern findings of chromosomal analyses, their relationships with various genes, and their prognostic implications for intracranial and spinal cord ependymomas.

Introduction

Ependymomas are rare neoplasms that can occur anywhere along the craniospinal axis. Recent findings suggest that they are derived from radial glial cells,[1], [2] which give rise to ependymal cells during normal cellular development.³ Ependymomas are the third most common brain tumor in children,¹ representing 8% to 10% of pediatric intracranial tumors and approximately 4% of adult brain tumors.[4], [5] They constitute 60% of spinal cord gliomas and 15% of all spinal cord tumors.[4], [5], [6] Interestingly, they have also been reported in the sacrococcygeal region, mediastinum, and ovaries,[7], [8], [9] indicating that abnormalities in cellular migration or differentiation may have a role in ependymoma development.⁷

The World Health Organization (WHO) established the following classification system for ependymomas in 2007: WHO grade 1 (subependymomas and myxopapillary ependymomas), WHO grade 2 (classic ependymomas), and WHO grade 3 (anaplastic ependymomas).⁴ WHO grade 2 ependymomas have been further subdivided into cellular, papillary, clear cell, and tanycytic variants (Supplementary Fig. 1).¹⁰ However, this WHO classification has been a subject of controversy regarding its prognostic capabilities and overall usefulness. While a meta-analysis of 2400 patients showed that WHO grading was an independent outcome predictor,[11], [12] other studies have suggested that ependymoma grading, especially differentiation between grades 2 and 3, is highly dependent upon the experience of the neuropathologist[11], [13], [14], [15], [16], [17], [18] and a poor clinical correlate. Some authors have failed to find any association between survival and grading,[4], [19], [20] while others have reported an obvious improvement in overall and progression-free survival (PFS) for lower grade ependymomas.[4], [15], [16], [21], [22], [23] One study reported that WHO grading was the most powerful prognostic factor for ependymomas in the adult population.[4], [24]

As the incidence of ependymomas is relatively low,[4], [5], [25] many researchers have chosen to pool data from both pediatric and adult populations, as well as combine grade 2 and grade 3 lesions in their reports. These retrospective studies have often analyzed data collected over several decades, during which diagnostic criteria and treatment strategies were being modified. As such, providing evidence to support universally accepted prognostic factors and implementing a standardized treatment protocol have been difficult endeavors.⁴ Given these difficulties in grading and prognosis, potential genetic markers may serve as a more reliable risk stratification for patients with ependymomas. Here, we review the most promising chromosomal gains and losses common to ependymomas within the mixed population (adults and children), as well as unique findings in specific subgroups (for instance in the pediatric population, for tumor location, for tumor grade) and their potential for prognostic significance.