Pediatric Intracranial Ependymomas: Prognostic Relevance of Histological, Immunohistochemical, and Flow Cytometric Factors

Abstract

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-IIalpha, 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-IIalpha 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.

Pediatric Ependymoma: Biological Perspectives

“…The tenascin c (TNC) gene on chromosome 9 seems upregulated in infant ependymomas (76), and its protein expression seems relatively high in pediatric cases (35), whereas the presence of intercellular tenascin has been identified as an adverse prognostic marker in an albeit small immunohistochemical study of pediatric ependymomas (129). The authors also found that unfavorable outcome was associated with increased expression of topoisomerase II-α, bcl2, and cyclin D1 and p53 (128). Analysis of a further mixed age cohort provides support for aberrant p53 expression as a prognostic marker in ependymoma (127), although p53 gene mutations in pediatric ependymomas are rare (159)(160)(161)(162), whereas its regulator MDM2 has failed to establish a prognostic role in this tumor group (114).…”

“…This could explain why other large pediatric studies, using lower Ki-67 LI prognostic cutoffs, found no association between this marker and patient survival (32,127). Nevertheless Ki-67 has been associated with survival in small pediatric series using very low LI thresholds of 1% and 7% (108,128,129), making definitive conclusions on its use as a pediatric prognostic marker difficult. Moreover Ki-67 has been shown to correlate with tumor grade, supporting the view that increased proliferation seems to be a feature of anaplasia (32,(140)(141)(142).…”

Ki-67 is a Valuable Prognostic Factor in Gliomas: Evidence from a Systematic Review and Meta-analysis

“…Of the candidate studies, 13 articles failed to completely describe the available survival data. Finally, 51 published studies in total were included in the analysis after eliminating articles unsatisfying the selection criteria and duplicates (Jaros et al, 1992;Torp et al, 1992;Montine et al, 1994;Ellison et al, 1995;Heegaard et al, 1995;Kros et al, 1996;Coons et al, 1997;Pollack et al, 1997;Dehghani et al, 1998;McKeever et al, 1998;Ritter et al, 1998;Figarella-Branger et al, 2000;Rodriguez-Pereira et al, 2000;Ho et al, 2001;ReaveyCantwell et al, 2001;Zhong et al, 2001;Bredel et al, 2002;Pollack et al, 2002;Bowers, 2003;Chiang et al, 2003;Neder et al, 2003;Wessels et al, 2003;Zamecnik et al, 2003;Preusser et al, 2005;Uematsu et al, 2005;Kleinschmidt-DeMasters et al, 2006;Donato et al, 2007;Kanamori et al, 2008;Kuo et al, 2009;Laks et al, 2009;Li et al, 2009;Armstrong et al, 2010;Nabika et al, 2010;Watanabe et al, 2010;Yoshida et al, 2010;Habberstad et al, 2011;Margraf et al, 2011;Qiang et al, 2011;Shen et al, 2011;Zawrocki et al, 2011;…”

Expression of glial acidic fibrillary protein delta and E-cadherin in ependymomas; clinic-pathological and immunohistochemistry correlation

“…Ependymoma is usually considered non-infiltrative tumor [3][4][5][6][7][8]. The location of the tumor is an important factor for prognosis [8,9].…”

“…Classical WHO, grade I including; Myxopapillary ependymoma (MPE) that occur in the phylum terminalis of the spinal cord, grade II ependymoma (include cellular, papillary, tanacytic, giant cell, epithelioid, and clear cell variants) and grade III corresponding the anaplastic ependymoma subtype [1]. Different histological or immunohistochemical criteria have been proposed as prognostic factors [3][4][5][6][7] and [8]. However, WHO classification, extent of surgical resection are the most important variable in predicting outcome [8,9].…”