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|Year : 2016 | Volume
| Issue : 2 | Page : 287-288
Prognostic factors in ependymal tumors: Molecular biology trumps histopathology
Tejpal Gupta1, Sridhar Epari2, Aliasgar Moiyadi3
1 Department of Radiation Oncology, Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra, India
2 Department of Surgical Pathology, Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra, India
3 Department of Neurosurgery, Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra, India
|Date of Web Publication||3-Mar-2016|
Department of Neurosurgery, Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Gupta T, Epari S, Moiyadi A. Prognostic factors in ependymal tumors: Molecular biology trumps histopathology. Neurol India 2016;64:287-8
Ependymal tumors are a heterogeneous group of tumors arising within the central nervous system (CNS) with distinct demographics, location, presentation, and outcomes. They can occur anywhere in the neuraxis and are classified into spinal, posterior fossa, and supratentorial ependymomas based on their site of origin. The contemporary standard of care for ependymal tumors is maximal safe resection with or without post-operative adjuvant radiotherapy based on age, extent of resection, and histological grade. As these tumors are not very chemo- responsive, chemotherapy is generally offered either to defer radiotherapy in younger patients or as salvage therapy after recurrence/progression. Despite significant advancements in neurosurgery, emergence of high-precision radiotherapeutic techniques, and newer chemotherapeutic agents, the outcomes of ependymoma have not changed significantly over the last two decades. Histomorphology has been the mainstay for grading of ependymal tumors. Subependymomas (SE) and myxopapillary ependymomas (MPE), in view of their distinct clinicobiological features, are assigned grade I and never exhibit high-grade histological features. The other ependymal tumours (Grades II-III), however, have been conventionally graded essentially along the lines of other glial tumours (astrocytic and oligodendroglial) viz. based on the mitotic activity (i.e., >5 mitoses per 10 high power fields), microvascular proliferation and/or large confluent areas of necrosis. Though the histological grading was essentially for predicting aggressive biological behavior and poor outcomes, it is widely recognized that histological grading can be imprecise and subjective, thereby limiting its utility for accurate prognostication. In this issue of Neurology India, Benson et al., provide a comprehensive narrative review of the diverse molecular and genetic aberrations for prognostication and prediction of survival in ependymomas. As a prelude to the introduction of molecular markers, the authors discuss the contradictory reports on MIB-1 labeling index as a prognostic factor in ependymomas, suggesting that it may only have some positive correlation with the histological grade rather than be an independent prognostic factor. Subsequently, they summarize the age and location-specific differences amongst the most common genetic abnormalities (loss or gain of chromosomal arms) seen in ependymomas and their correlation with disease-related outcomes. The postulated role of receptor tyrosine kinase (RTK) family proteins, telomeric alterations, nuclear factor kappaB (NFk B) signaling, and mitogen-activated protein kinase (MAPK) pathway in the malignant progression and aggressive biological behavior of ependymomas lends credence to the potential for targeted therapy. Methylation of putative tumor-suppressor genes and acetylation of histone proteins confer worse outcomes in these tumors suggesting that epigenetic events may be the real triggers of malignant progression. In the last section, the authors discuss the predictive factors of therapy resistance in ependymal tumors and highlight the role of p-53 mediated growth arrest as the likely mechanism of radio-resistance. Epigenetic silencing of a DNA repair protein, O 6-methylguanine-DNA-methyltransferase (MGMT) through hypermethylation is a predictive factor of response to alkylating chemotherapy. Absence of such hypermethylation in a vast majority of patients with ependymomas makes them resistant to chemotherapy. In addition, low-grade ependymomas particularly have a high expression of chemo-resistance related proteins (metallothioneins, glutathione S-transferase pi, and P-glycoprotein) rendering them remarkably resistant to chemotherapy. Of all the varied genetic alterations, chromosome 1q gains in posterior fossa (PF) ependymal tumours, and homozygous deletion of the CDKN2A/B locus in supratentorial tumors (STs) have consistently been shown to be predictive of an unfavorable outcome.
Recently Pajtler et al., in a large multi-institutional cohort of 500 cases, using DNA methylation profiling, have demonstrated a comprehensive and robust molecular subgrouping of ependymal tumors dividing ependymomas into nine subgroups (across all central nervous system compartments, histological grades, and age groups). More importantly, their study was on formalin-fixed paraffin-embedded blocks. They demonstrated these molecular subgroups as genetically, epigenetically, transcriptionally, demographically, and clinically distinct. In addition, they also showed that the risk stratification using molecular grouping was far more superior to histological grading. Both the PF-EPN-A and ST-EPN-RELA subgroups show a dismal outcome, with 10-year overall survival rates of ~50% and progression free survival rates of ~20%. Notably, patients comprising these subgroups were mostly children. Interestingly, the spinal tumours in their cohort had the most favourable prognosis. Subependymoma (SE)-like molecular subgroups from the PF and ST compartments (including histological grade II and III tumors) also showed favorable outcomes. This study points towards the necessary changes required in the prevalent approach to risk-stratification and therapy. Multivariate analyses confirmed the independent prognostic impact of molecular subgrouping, extent of surgical resection, and gain of 1q (but not of histological grade) as independent prognostic factors. The two most common molecular subgroups viz. the posterior fossa subtype A ependymoma (PF-EPN-A) characterised by a stable genome and CpG island methylator phenotype (CIMP) positivity, and the supratentorial ependymoma characterized by expression of C11orf95-RELA fusion transcripts (ST-EPN-RELA), constitute over two-thirds of all ependymal tumors, tend to affect younger children, are remarkably resistant to therapy, and have universally poor outcomes. This partly explains the poor outcomes seen in infants and younger children with an ependymoma irrespective of the histological grade. Both these molecular subtypes share similar gene set pathway enrichments (cell cycle, cell migration, and MAPK signalling) as well as chromosome 1q gain (which in itself is an independent prognostic factor). There is no doubt that these studies have unravelled the hitherto unknown biological mysteries of ependymal tumours to a certain extent and also possibly open up an entirely new paradigm for classification of ependymomas. However, nothing much could be deciphered regarding the molecular mechanisms of resistance in these subgroups. This calls for further research for identification of targets for development of effective targeted therapy. Gene sequencing studies , have repeatedly demonstrated that ependymal tumors in general have very few mutations suggesting that either epigenetic events, copy number aberrations, or other structural alterations may actually be driving these tumors. The recent identification of several new oncogenes and candidate tumor-suppressor genes in ependymomas  should provide further impetus to the development of novel molecular targeted agents in this otherwise resistant disease.
Given that molecular biology is superior to histological grading for predicting outcomes in ependymal tumors, molecular subtyping should be performed routinely for robust risk-stratification to aid in therapeutic decision-making for optimizing outcomes. The ability to conduct this test on small amounts of deoxyribonucleic acid (DNA) extracted from archival samples makes it suitable for widespread usage. The development of specific and robust antibodies for easy and rapid identification of the two worst subgroups on immunohistochemistry could be the next logical step and would go a long way in ensuring their generalizability and applicability in contemporary neuro-oncologic practice.
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