Deceptive morphologic and epigenetic heterogeneity in diffuse intrinsic pontine glioma.

Marianna Bugiani,Viola Caretti,Pieter Wesseling,William P Vandertop,Sophie E.M Veldhuijzen Van Zanten,Dannis G Van Vuurden,David P Noske,Gertjan J.L Kaspers,Eleonora Aronica,Esther Hulleman,Pepijn Schellen

doi:10.18632/oncotarget.19726

Abstract

Historically, the diagnosis of diffuse intrinsic pontine glioma (DIPG) was based on typical imaging findings and clinical characteristics instead of pathology. However, the discovery of mutations in histone H3 variants, and the availability of tumor material for molecular analysis, has led to a paradigm shift in DIPG research and clinical practice. Using data from whole-brain autopsies in a series of nine DIPG patients with known histone mutational status, we here aim to review histopathological characteristics with special focus on intratumoral heterogeneity (ITH) and histone 3 K27 trimethylation (H3 K27me3). All DIPGs showed marked histologic ITH, with 56% even showing focal areas resembling a WHO grade I phenotype. As expected, H3 K27me3 immunoreactivity was lost in the tumors that were H3 K27M-mutated (seven patients; 67% H3.3, 11% H3.1). Strikingly, the H3K27 wildtype tumors (two patients; 22%) also contained H3 K27me3-immunonegative areas. Our study underscores the importance of the choice of the biopsy site, as ITH in DIPGs could theoretically lead to erroneous histological diagnoses with small biopsies. New in this respect is our finding that a substantial number of otherwise typical DIPGs has areas resembling WHO grade I tumors (esp. pilocytic astrocytoma, subependymoma). Furthermore, our study shows that negative H3 K27me3 immunohistochemistry in a DIPG does not imply a H3 K27-mutant tumor.

Highlights

Diffuse intrinsic pontine glioma (DIPG), one of the deadliest childhood cancers [1], shows marked intratumoral heterogeneity (ITH) in terms of histological phenotype and malignancy grade [2]
Our study shows that negative H3 K27me3 immunohistochemistry in a diffuse intrinsic pontine glioma (DIPG) does not imply a H3 K27-mutant tumor
Based on our findings in an autopsy series of nine DIPG patients evaluated in the last eight years at the VU University Medical Center Amsterdam, we underscore that DIPG ITH may lead to misinterpretation in biopsy specimens at two distinct levels when using histochemistry only: 1. Histologic phenotype.Without exception, all DIPGs showed marked histologic ITH

Summary

Introduction

Diffuse intrinsic pontine glioma (DIPG), one of the deadliest childhood cancers [1], shows marked intratumoral heterogeneity (ITH) in terms of histological phenotype and malignancy grade [2]. Because of this heterogeneity and the possible risks associated with biopsy procedures, DIPG diagnoses have been made solely on clinical and radiological grounds for decades. Owing to the reintroduction of stereotactic and open surgical biopsies and subsequent molecular characterization of these tumors, it was recently demonstrated that over 90% of DIPGs carry a histone H3 K27M mutation in the genes encoding H3.3 (H3F3A), H3.2 (HIST2H3C), or H3.1 (HIST1H3B and HIST1H3C). Autopsies were performed according to an established protocol [5] that was approved by the medical ethical committee of the VU University Medical Centre, Amsterdam, The Netherlands

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