Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification (original) (raw)
Related papers
Prognostic marker analysis in pediatric intracranial ependymomas
Journal of Neuro-Oncology, 2015
Histologic grading methods dependent upon H&E staining review have not been shown to reliably predict survival in children with intracranial ependymomas due to the subjectivity of the analytical methods. We hypothesized that the immunohistochemical detection of MIB-1, Tenascin C, CD34, VEGF, and CA IX may represent objective markers of post-operative survival (Progression Free and Overall Survival; PFS, OS) in these patients. Intracranial ependymomas from patients aged 22 years or less were studied. The original histologic grade was recorded, H&E sections were reviewed for vascular proliferation status, and immunohistochemistry was used to determine MIB-1, Tenascin C, CD34, VEGF, and CA IX status. Based upon the World Health Organization (WHO) grading system, 3 Grade I, 18 Grade II and 9 Grade III ependymomas were studied. Median follow-up time was 9.0 years; median PFS was, 6.1 years. Original WHO grade did not correlate with PFS or OS. Peri-necrotic CA IX localization correlated with PFS (Log rank = 0.0181) and OS (Log rank p = 0.0015). All patients with a CA IX B 5 % total area localization were alive at last follow-up. Perinecrotic CA IX staining was also associated with vascular proliferation (p = 0.006), though not with VEGF expression score. MIB-1 labeling index (LI) correlated with OS (HR 1.06, 95 % CI 1.01, 1.12) and PFS (HR 1.08, 95 % CI 1.02, 1.14). MIB-1 LI and perinecrotic CA IX individually correlated with PFS. The effect of perinecrotic CA IX remained when grade was added to a Cox model predicting PFS. Immunodetection of CA IX and MIB-1 expression are predictive biomarkers for survival in children with posterior fossa ependymomas. These markers represent objective indicators of survival that supplement H&E grading alone.
Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma
Neuro-Oncology, 2008
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% 6 13% and 31% 6 7%, respectively. Multivariate analysis identified low nucleolin expression to be independently associated with a more favorable prognosis (hazard ratio 5 6.25; 95% confidence interval, 1.6-24.2; p 5 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 telo mere 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, telo merase reactivation and maintenance of telomeric repeats appear necessary for childhood ependymoma progression. These findings require corroboration in a clinical trial setting. Neuro-Oncology 10, 675-689, 2008 (Posted to Neuro-Oncology [serial online], Doc. 07-00243, August 13, 2008
Acta Neuropathologica Communications, 2016
Intracranial classic (WHO grade II) and anaplastic (WHO grade III) ependymomas are among the most common tumors in pediatric patients and have due to frequent recurrences and late relapses a relatively poor outcome. The impact of histopathological grading on patient outcome is controversial and therefore, molecular prognostic and predictive markers are needed to improve patient outcome. To date, the most promising candidate marker is chromosome 1q gain, which has been associated in independent studies with adverse outcome. Furthermore, gene expression and methylation profiles revealed distinct molecular subgroups in the supratentorial and posterior fossa (PF) compartment and Laminin alpha-2 (LAMA2) and Neural Epidermal Growth Factor Like-2 (NELL2) were suggested as surrogate markers for the two PF subgroups PF-EPN-A and PF-EPN-B. PF-EPN-A tumors were also characterized by tenascin-C (TNC) expression and tenascin-C has been suggested as candidate gene on 9q, involved in tumor progression. Therefore, we have analyzed the status of chromosome 1q, TNC, LAMA2, and NELL2 expression in a series of pediatric PF ependymomas in terms of their frequency, associations among themselves, and clinical parameters, as well as their prognostic impact. We confirm the negative prognostic impact of 1q gain and TNC expression and could classify PF ependymomas by these two markers into three molecular subgroups. Tumors with combined 1q gain and TNC expression had the poorest, tumors without 1q gain and TNC expression had a favorable and TNC positive 1q non-gained cases had an intermediate outcome. We found also differences in age and tumor grade in the three subgroups and thus, provide evidence that PF pediatric ependymomas can be divided by chromosome 1q status and TNC expression in three molecular subgroups with distinct clinico-pathological features. These analyses require only few amounts of tumor tissue, are broadly available in the routine clinical neuropathological setting and thus, could be used in further therapy trials to optimize treatment of ependymoma patients.
Immunohistochemical markers for intracranial ependymoma recurrence
Journal of the Neurological Sciences, 2000
Intracranial ependymomas are the third most common primary brain tumor in children. Although clinical and histological criteria for ependymoma prognosis are recognized, studies have reported contradictory results. Prognostic significance based on immunohistochemistry of ependymomas has been reported in a few studies. Eighty-eight patients with intracranial ependymomas were examined retrospectively for immunoexpression of various tumor-associated antigens and apoptosis. The results demonstrated significant preponderance of expression of the tenascin, vascular endothelial growth factor protein (VEGF), epidermal growth factor (EGFR), and p53 protein in high-grade tumors. Also high-grade ependymomas revealed more prominent labeling indices (LI) for proliferative marker Ki-S1 and lower LI for cyclin-dependent kinase inhibitor p27 / Kip1. For low-grade ependymomas the progression free survival time (PFS) was found to be significantly shorter for Ki-S1 LI$5%, and for tenascin, VEGF, and EGFR positivity. For high-grade ependymomas PFS was found to be significantly reduced for age ,16 years, subtotal tumor removal, p27 LI ,20%, p53 positivity, and for apoptotic index (AI) ,1%. The classification regression tree analysis exhibited four groups of ependymomas; (1) low-grade tenascin negative (32 cases, recurrence rate50), (2) high-grade with AI $1% (21 cases, recurrence rate557%), (3) low-grade tenascin-positive (10 cases, recurrence rate589%), and (4) high-grade with AI ,1% (25 cases, recurrence rate5100%). So, the immunohistochemical variables were found to be strongest predictors of ependymoma recurrence and they seem to be useful for assessing individual tumor prognosis in routinely processed biopsy specimen.
Multivariate Analysis of Clinical Prognostic Factors in Children with Intracranial Ependymomas
Journal of Neuro-Oncology, 2000
We investigated the influence of various clinical prognostic factors in patients with glioblastoma multiforme (GBM) treated with a combined modality approach. A total of 175 patients with GBM was treated in four consecutive prospective phase II studies using surgery, hyperfractionted or accelerated hyperfractionated radiotherapy (RT) and either adjuvant or concurrent or pre-irradiation chemotherapy (CHT) between Janaury 1988 and December 1993. The median survival time for all 175 patients was 14 months and 1-3-year survival (OS) rates were 57%, 34% and 24%, respectively. The median time to tumour progression was 12 months, and 1-3-year progression-free survival (PFS) rates were 43%, 11% and 7%, respectively. Survival analysis showed that of all investigated prognostic factors, only gender did not influence survival. Patients £ 55 years did better than those >55 years; patients with KPS 80-100 did better than those with KPS 50-70; patients with frontal tumours did better than those with tumours in other locations; patients with tumours up to 4 cm did better than those with larger tumours, as did patients with either subtotal or gross total tumour resection when compared to those undergoing biopsy only. Multivariate analysis showed that gender and tumour location did not independently influence survival. When PFS was used as the endpoint, only gender did not influence PFS, as confirmed by multivariate analysis.
Current and evolving knowledge of prognostic factors for pediatric ependymomas
Future Oncology, 2013
Ependymomas are one of the most common pediatric malignant brain tumors. Prognosis, especially in young children, remains poor due to their inherent chemo- and radio-resistance and effective treatment remains one of the more difficult tasks in pediatric oncology: up to half of the patients may die from the disease. The only reproducible prognostic factor is the extent of surgery; neither histological grading nor other biomarkers can be used to reliably make treatment decisions in clinical practice. None of the studies identifying new biomarkers have been conducted prospectively, only few have been undertaken within the context of a clinical trial and most have been conducted with limited samples (often including adults and childhood samples). International collaboration is needed to improve ependymoma prognostication.
Neuro-Oncology, 2020
Background A prospective 2002–2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients’ molecular features. Methods Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68. Results Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66–126 mo), surviving after relapse no longer than those relapsing earlier (0–5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS ...
Neuro-Oncology, 2019
BACKGROUND Outcomes for patients with intracranial ependymoma remain poor in the current era of cancer treatment. This study aims to investigate the prognostic value of demographic and clinical variables to predict survival using the largest current database of patients with intracranial ependymoma. METHODS The Surveillance, Epidemiology and End Results (SEER) registry was queried for prognostic factors and survival outcomes of adult (≥18 years) patients diagnosed with intracranial ependymoma from 2004–2016. Survival was estimated using Kaplan Meier curves. Cox proportional hazards modeling was used to identify correlates of survival. RESULTS We identified a cohort of 229 primary intracranial ependymoma patients. The cohort showed a slight male predominance (52%) and had a mean age of 43 ± 17 years. 107 patients (47%) had WHO grade II tumors and 122 patients (53%) had WHO grade III tumors. One year survival was 85% for the entire cohort. Increasing age at diagnosis (HR: 1.05, 95% CI...
Modern Pathology, 2003
The correlation between the histological features and clinical outcome remains poor in pediatric intracranial ependymomas. We performed a retrospective study of a group of 31 patients (diagnosed from 1985 to 1995) to assess prognostic implications of the current grading system, of histological and immunohistochemical features, and of ploidy status estimated by flow cytometry. Immunoexpression of a broad spectrum of antigens was evaluated, including MIB-1, topoisomerase-II␣, cyclin D1, glial and epithelial proteins (GFAP, EMA, cytokeratins), molecules involved in controlling apoptosis (bcl-2, caspase-3/CPP32), and p53 oncoprotein. Univariate and multivariate statistical analyses were performed to evaluate the influence of each variable on both the progression free survival (PFS) and the overall survival (OS) with at least 7-year follow up. Although we showed a significant correlation between histological grade and prognosis, the current grading system failed in predicting outcome in nearly one third of individual cases. Problems with interpathologist reproducibility were also demonstrated. The extent of surgical resection was the only clinical factor that was associated with survival. Both the PFS and the OS were significantly decreased for the following pathological variables: increased cellularity (>300 nuclei per HPF), mitotic activity of >7 per 10 HPF, increased MIB-1 labeling index (LI), topoisomerase-II␣ LI, S-phase fraction, and p53 and bcl-2 positivity. Increased cyclin D1 LI was demonstrated to have only a marginally significant impact on PFS. A flow chart modeling was further performed to formulate a scheme for discriminating of prognostic subgroups. Based on that, p53 immunopositivity and/or MIB-1 LI of >5% (after subtotal resection) or MIB-1 LI of >15% (after complete resection) were the strongest indicators of the tumor's aggressive behavior and of a poor prognosis of the disease. Foci of hypercellularity should be specifically looked for in ependymomas for assessing the immunohistochemical studies.