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Clinical Trial
. 2019 Nov 14;7(1):181.
doi: 10.1186/s40478-019-0820-5.

Improved risk-stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features - a retrospective analysis of the HIT ependymoma trial cohort

Stephanie T Jünger  1   2 , Martin Mynarek  3 , Inken Wohlers  4   5 , Evelyn Dörner  1 , Anja Zur Mühlen  1 , Natalia Velez-Char  1 , Katja von Hoff  3 , Stefan Rutkowski  3 , Monika Warmuth-Metz  6 , Rolf-Dieter Kortmann  7 , Beate Timmermann  8 , Sven Rahmann  4 , Ludger Klein-Hitpass  9 , Andre O von Bueren  3   10 , Torsten Pietsch  11
Affiliations
Clinical Trial

Improved risk-stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features - a retrospective analysis of the HIT ependymoma trial cohort

Stephanie T Jünger et al. Acta Neuropathol Commun. .

Abstract

Introduction: Risk stratification of children with ependymomas of the posterior fossa in current therapeutic protocols is mainly based on clinical criteria. We aimed to identify independent outcome predictors for this disease entity by a systematic integrated analysis of clinical, histological and genetic information in a defined cohort of patients treated according to the German HIT protocols.

Methods: Tumor samples of 134 patients aged 0.2-15.9 years treated between 1999 and 2010 according to HIT protocols were analyzed for histological features including mitotic activity, necrosis and vascular proliferation and genomic alterations by SNP and molecular inversion probe analysis. Survival analysis was performed by Kaplan-Meier method with log rank test and multivariate Cox regression analysis.

Results: Residual tumor after surgery, chromosome 1q gain and structural genomic alterations were identified as predictors of significantly shorter event-free (EFS) and overall survival (OS). Furthermore, specific histological features including vascular proliferation, necrosis and high mitotic activity were predictive for shorter OS. Multivariate Cox regression revealed residual tumor, chromosome 1q gain and mitotic activity as independent predictors of both EFS and OS. Using these independent predictors of outcome, we were able to build a 3-tiered risk stratification model that separates patients with standard, intermediate and high risk, and which outperforms current stratification procedures.

Conclusion: The integration of defined clinical, histological and genetic parameters led to an improved risk-stratification model for posterior fossa ependymoma of childhood. After validation in independent cohorts this model may provide the basis for risk-adapted treatment of children with ependymomas of the posterior fossa.

Keywords: Ependymoma; Genetics; Neuropathology; Posterior fossa; Risk stratification.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Virtual karyotypes of posterior fossa ependymomas obtained from MIP analysis. Cumulative chromosomal gains are depicted in blue to the right of the chromosome; chromosomal losses are presented in red to the left. Three different genomic groups could be identified, the numerical (top), balanced (middle) and structural (lower panel) genomic group. Patients showed differences in age at diagnosis (right panels)
Fig. 2
Fig. 2
Survival analysis. Kaplan-Meier survival curves show the prognostic impact of a, residual tumour; b, genomic group, c, chromosome 1q gain and d, histology (only OS). Coloured pie charts indicate the frequency of the defined subgroups
Fig. 3
Fig. 3
Risk stratification model including the independent parameters residual disease, chromosome 1q gain and mitotic activity. a Venn diagram indicating the frequency of these parameters; b Kaplan-Meier survival analysis shows different outcomes of the patients with standard, intermediate and high risk. Survival was significantly different between all risk groups for EFS and OS (p < 0.001 for all comparisons)
See this image and copyright information in PMC

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