ABSTRACT
Pediatric ependymomas are enigmatic tumors that continue to present a clinical management challenge despite advances in neurosurgery, neuroimaging techniques, and radiation therapy. Difficulty in predicting tumor behavior from clinical and histological factors has shifted the focus to the molecular and cellular biology of ependymoma in order to identify new correlates of disease outcome and novel therapeutic targets. This article reviews our current understanding of pediatric ependymoma biology and includes a meta-analysis of all comparative genomic hybridization (CGH) studies done on primary ependymomas to date, examining more than 300 tumors. From this meta-analysis and a review of the literature, we show that ependymomas in children exhibit a different genomic profile to those in adults and reinforce the evidence that ependymomas from different locations within the central nervous system (CNS) are distinguishable at a genomic level. Potential biological markers of prognosis in pediatric ependymoma are assessed and the ependymoma cancer stem cell hypothesis is highlighted with respect to tumor resistance and recurrence. We also discuss the shifting paradigm for treatment modalities in ependymoma that target molecular alterations in tumor-initiating cell populations.
Subject(s)
Ependymoma/genetics , Ependymoma/pathology , Adolescent , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Child , Child, Preschool , Comparative Genomic Hybridization , Ependymoma/diagnosis , Ependymoma/metabolism , Genomics , Humans , InfantABSTRACT
Pediatric ependymomas are enigmatic tumors, and their clinical management remains one of the more difficult in pediatric oncology. The identification of biological correlates of outcome and therapeutic targets remains a significant challenge in this disease. We therefore analyzed a panel of potential biological markers to determine optimal prognostic markers. We constructed a tissue microarray from 97 intracranial tumors from 74 patients (WHO grade II-III) and analyzed the candidate markers nucleolin, telomerase catalytic subunit (hTERT; antibody clone 44F12), survivin, Ki-67, and members of the receptor tyrosine kinase I (RTK-I) family by immunohistochemistry. Telomerase activity was determined using the in vitro-based telomere repeat amplification protocol assay, and telomere length was measured using the telomere restriction fragment assay. Primary tumors with low versus high nucleolin protein expression had a 5-year event-free survival of 74%+/-13% and 31%+/-7%, respectively. Multivariate analysis identified low nucleolin expression to be independently associated with a more favorable prognosis (hazard ratio=6.25; 95% confidence interval, 1.6-24.2; p=0.008). Ki-67 and survivin correlated with histological grade but not with outcome. Immunohistochemical detection of the RTK-I family did not correlate with grade or outcome. Telomerase activity was evident in 19 of 22 primary tumors, with telomere lengthening and/or maintenance occurring in five of seven recurrent cases. Low nucleolin expression was the single most important biological predictor of outcome in pediatric intracranial ependymoma. Furthermore, telomerase reactivation and maintenance of telomeric repeats appear necessary for childhood ependymoma progression. These findings require corroboration in a clinical trial setting.
Subject(s)
Biomarkers, Tumor/analysis , Brain Neoplasms/mortality , Ependymoma/mortality , Phosphoproteins/biosynthesis , RNA-Binding Proteins/biosynthesis , Adolescent , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Child , Child, Preschool , Ependymoma/metabolism , Ependymoma/pathology , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Infant , Kaplan-Meier Estimate , Male , Prognosis , Telomerase/biosynthesis , Telomere/metabolism , Tissue Array Analysis , NucleolinABSTRACT
BACKGROUND: Metastatic medulloblastoma has a poorer prognosis than localised disease in part due to inherent properties of the tumour. 1H magnetic resonance spectroscopy (MRS) provides a powerful method for investigating tumour metabolism in vivo. METHODS: Magnetic resonance imaging and short echo time (Te 30 ms) single voxel MRS were performed on the primary tumour of 16 children with medulloblastoma prior to surgical resection. Tumour volumes were calculated using a segmentation technique and the MRS was analysed using LCModel. RESULTS: Patients with metastatic disease had primary tumours which were smaller (p=0.01), had higher levels of total choline (p=0.03) and lower levels of mobile lipids (p=0.04). CONCLUSION: Metastatic medulloblastomas have metabolite profiles indicative of increased cell growth and decreased cell death compared with localised tumours reflecting intrinsic differences in underlying biology. Localised tumours with an MRS metabolite profile similar to those with metastatic disease may be at increased risk of metastatic relapse.
