Pilocytic astrocytoma and glioneuronal tumor with histone H3 K27M mutation
© The Author(s). 2016
Received: 1 August 2016
Accepted: 1 August 2016
Published: 12 August 2016
KeywordsGlioblastoma Histone H3 K27M Pilocytic astrocytoma Glioneuronal tumor
Pediatric glioblastoma (GBM) can be sub-classified into several molecular subgroups, including a group defined by a mutation in histone H3 at position amino acid 27 resulting in the replacement of lysine by methionine (K27M) . K27M GBMs are located in the midline, often occur in children, and have been shown to have worse prognosis than other GBM subgroups, with a median survival of 6 months [2–5]. The 2016 revision of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System now recognizes “diffuse midline glioma, H3 K27M-mutant” as a distinct clinic-pathological entity and recommends grading as Grade 4 . A robust immunohistochemical stain has been recently developed to specifically detect the K27M mutation. It can be used to help diagnose these high-grade tumors, particularly in the setting of a small biopsy where the amount of tissue is insufficient for molecular studies . Here we report two patients with midline pilocytic astrocytoma and a glioneuronal tumor, respectively, harboring a K27M mutation. Our findings show that K27M mutations may be present in a spectrum of brain tumors with less aggressive clinical behavior and prolonged survival. Our data indicates that the entity of H3 K27M-mutant tumors may represent a spectrum including not only diffuse gliomas  but also less aggressive tumors than previously recognized, and that histone H3 K27M mutation should not be used as the sole criterion for the diagnosis of WHO Grade IV and to imply a dismal prognosis and aggressive management.
While molecular analysis of tumors adds important information, it cannot replace histological assessment. The two patients here were diagnosed with Grade I and Grade III tumors respectively and were both treated with surgical resection and the latter also with radiation therapy and adjuvant chemotherapy. Due to the difficulty in achieving significant resection and high risk of morbidity, patients with midline tumors are often only biopsied for diagnosis. The K27M immunohistochemical marker is often used as a diagnostic tool to confirm a midline high-grade astrocytoma and patients are typically treated with radiation and chemotherapy. However despite aggressive treatment, the 3-year overall survival (OS) of patients with K27M GBMs is 5 %. Therefore many consider identifying the K27M mutation as a strong indication of a high-grade glioma. The cases presented show that the K27M mutation may be present in less aggressive “lower grade” gliomas as well as glioneuronal tumors. Our tumors did not show histological features of diffuse infiltrating glioma/GBM on imaging or histopathology. One possible molecular clue arguing against the diagnosis of GBM in our cases may be a copy number profile without the typical genomic gains or losses seen in GBM (Figs. 1i and 2i). Our report highlights a morphological as well as clinical spectrum of histone H3 K27M mutant tumors. Our findings imply that, especially in cases where only a small biopsy is obtained, a sample positive for H3K27M by immunohistochemistry may be inappropriately diagnosed as a high-grade astrocytoma or even GBM and routinely receive aggressive adjuvant treatment. Therefore, the presence of a histone H3 K27M mutation should be evaluated in the context of the histology and other genomic features to ensure accurate diagnosis. The significance of histone H3 K27M mutations in tumors that are histologically not diffuse gliomas is currently unknown; therefore additional studies are necessary to elucidate the prognostic impact of this molecular alteration.
CT, computed tomography; FISH, fluorescence in situ hybridization; GBM, glioblastoma; K27M, mutation in histone 3 of K27 residue; OS, overall survival; WHO, World Health Organization
The authors would like to thank Stefan Pfister, David T. W. Jones, Martin Sill and Volker Hovestadt for their help with optimization of the 450 k Illumina Infinium methylation profiling for copy number analysis.
The study was supported by the Friedberg Charitable Foundation to M.A.K. and M.S. and the Rachel Molly Markoff Foundation to M.S.
Availability of data and material
CT, DZ and MS made the initial observation, CO, YD, ETH, JGG, and JHW analyzed clinical data and imaging. MS, MAK, DZ and CT performed molecular studies. CO, MAK and MS wrote the manuscript. All authors read and edited the manuscript and approved the final version of the manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The study has been approved by the NYU Institutional Review Board (study number i14-00948).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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