Diffuse midline glioma H3 K27M-mutant

Diffuse midline glioma H3 K27M-mutant

Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the World Health Organization Classification of Tumors of the Central Nervous System 2016 grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histone H3 tail.

In the past, pediatric diffuse gliomas were grouped with their adult counterparts, despite known differences in behavior between pediatric and adult gliomas with similar histological appearances. Information on the distinct underlying genetic abnormalities in pediatric diffuse gliomas is beginning to allow the separation of some entities from histologically similar adult counterparts.

One narrowly defined group of tumors primarily occurring in children (but sometimes in adults too) is characterized by K27M mutations in the histone H3 gene H3F3A, or less commonly in the related HIST1H3B gene, a diffuse growth pattern, and a midline location (e.g., thalamus, brain stem, and spinal cord). This newly defined entity is termed diffuse midline glioma, H3 K27M–mutant and includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG). The identification of this phenotypically and molecularly defined set of tumors provides a rationale for therapies directed against the effects of these mutations.


Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults.


see Diffuse midline glioma H3 K27M-mutant diagnosis.

Differential diagnosis

After the start of the era of biopsy, Diffuse intrinsic pontine gliomas (DIPG)s bearing Histone H3K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group 1).


see Diffuse midline glioma H3 K27M-mutant treatment.


Prognosis remains poor, with a 2-year survival of less than 10%


Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study 2).

Eight patient-derived orthotopic xenograft models were obtained after direct stereotactic injection of a mixed cell suspension containing tumor cells and stromal cells in the brainstem or thalamus of nude mice and serially passaged thereafter. In parallel, we developed 6 cell-derived xenograft models after orthotopic injection of tumor-initiating cells cultured from stereotactic biopsies. Cells were modified to express luciferase to enable longitudinal tumor growth monitoring, and fluorescent reporter proteins to trace the tumor cells in the brain.These models do not form a tumor mass, they are invasive, show the H3K27 trimethylation loss in vivo and the tumor type diversity observed in patients in terms of histone H3 mutations and lineage markers. Histological and MRI features at 11.7 Tesla show similarities with treatment naïve human DIPG, and in this respect, both direct and indirect orthotopic xenograft looked alike. These DIPG models will therefore constitute valuable tools for evaluating new therapeutic approaches in this devastating disease 3).

Case series

Diffuse midline glioma H3 K27M-mutant case series.

Case reports

A 36-year-old man presented with subacute progressive cognitive and visual deterioration, and hydrocephalus requiring ventricular shunting. MRI revealed a diffusely infiltrating lesion with a gliomatosis cerebri growth pattern, multiple foci of contrast enhancement, and diffuse leptomeningeal involvement. Suboccipital craniotomy with exploration of the posterior fossa revealed a subtle capsular lesion infiltrating into the choroid plexus. Although histologically low-grade, the tumor was found to have an H3K27 M mutation establishing the diagnosis.

In spite of diverse clinicopathologic characteristics, H3K27M-mutant diffuse midline gliomas are incurable, WHO grade IV lesions with poor prognosis. Yekula et al. discussed the case in the context of a review of published reports of H3K27-mutant diffuse midline gliomas in adults. Findings late in the disease course may mimic inflammatory or infectious pathologies radiographically, and low-grade infiltrative neoplasms histologically.

The diverse clinical, radiographic and molecular features of H3K27M-mutant diffuse midline gliomas in adults remain to be completely characterized. A high index of suspicion is required to avoid missing the diagnosis. Early biopsy and detailed molecular characterization are critical for accurate diagnosis and patient counseling 4).



Porkholm M, Raunio A, Vainionpää R, Salonen T, Hernesniemi J, Valanne L, Satopää J, Karppinen A, Oinas M, Tynninen O, Pentikäinen V, Kivivuori SM. Molecular alterations in pediatric brainstem gliomas. Pediatr Blood Cancer. 2017 Aug 9. doi: 10.1002/pbc.26751. [Epub ahead of print] PubMed PMID: 28792659.

Cooney T, Lane A, Bartels U, Bouffet E, Goldman S, Leary SES, Foreman NK, Packer RJ, Broniscer A, Minturn JE, Shih CS, Chintagumpala M, Hassall T, Gottardo NG, Dholaria H, Hoffman L, Chaney B, Baugh J, Doughman R, Leach JL, Jones BV, Fouladi M, Warren KE, Monje M. Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro Oncol. 2017 Sep 1;19(9):1279-1280. doi: 10.1093/neuonc/nox107. PubMed PMID: 28821206.

Plessier A, Dret LL, Varlet P, Beccaria K, Lacombe J, Mériaux S, Geffroy F, Fiette L, Flamant P, Chrétien F, Blauwblomme T, Puget S, Grill J, Debily MA, Castel D. New in vivo avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis. Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15002. [Epub ahead of print] PubMed PMID: 28178670.

Yekula A, Gupta M, Coley N, U HS. Adult H3K27M-mutant diffuse midline glioma with gliomatosis cerebri growth pattern: Case report and review of the literature. Int J Surg Case Rep. 2020 Feb 28;68:124-128. doi: 10.1016/j.ijscr.2020.02.046. [Epub ahead of print] PubMed PMID: 32145563.



The term “glioma” could technically be used to refer to all tumors of any glial lineage (i.e., from glial cells such as oligodendrogliaependymal cells, Schwann cells, microglia…), but in its common usage, “glioma” usually refers only to astrocytic tumors.

Gliomas comprise a heterogeneous group of benign and malignant neoplasms.

The body of glioma-related literature has grown significantly over the past 25 years. Despite this growth in the amount of published research, gliomas remain one of the most intransigent cancers. The purpose of a study was to analyze the landscape of glioma-related research over the past 25 years using machine learning and text analysis.

In April 2019, Feng et al. downloaded glioma-related publications indexed in PubMed between 1994 and 2018. They used Python to extract the title, publication date, MeSH terms, and abstract from the metadata of each publication for bibliometric assessment. Latent Dirichlet allocation (LDA) was applied to the abstracts to identify publications’ research topics with greater specificity.

They identified and analyzed a total of 52,625 publications. They found that research on prognosis and the treatment of glioblastoma increased the most in terms of volume and rate of publications over the past 25 years. However, publications regarding clinical trials accounted for <5% of all publications considered in this study. The current research landscape covers clinical, pre-clinical, biological, and technical aspects of glioblastoma; at present, researchers appear to be less concerned with glioblastoma’s psychological effects or patients’ end-of-life care.

Publication of glioma-related research has expanded rapidly over the past 25 years. Common topics include the disease’s molecular background, patients’ survival, and treatment outcomes; more research needs to be done on the psychological aspects of glioblastoma and end-of-life care 1)

Studies on gliomas suggested that the microenvironment of human gliomas contains both glioma stem cells (GSCs) and glioma associated (GA)-mesenchymal stem cells (MSCs; (GA-MSCs). Also, studies have suggested that nano- sized vesicles, termed exosomes, have been recently observed to contribute towards intercellular communication within the tumor niche 2).


Gliomas are the second most common primary brain tumors, with an incidence of 4–5/100 000 individuals. Gliomas are the second leading cause of cancer mortality in adults under the age of 35, the fourth leading cause in those under the age of 54, and result in death in approximately 13 770 individuals per year in the United States.

Approximately 89,000 new primary brain tumors are diagnosed in the United States each year, for which 27% are gliomas and 32.8% are malignant glioma3).

The are more frequent among males 4).


They encompass two principle subgroups: diffuse gliomas and gliomas showing a more circumscribed growth pattern (‘non-diffuse gliomas’). In the revised 4th edition of the World Health Organization Classification of Tumors of the Central Nervous System published in 2016, classification of especially diffuse gliomas has fundamentally changed: for the first time a large subset of these tumours is now defined based on presence/absence of IDH mutation and 1p/19q codeletion. Following this approach, the diagnosis of (anaplastic) oligoastrocytoma can be expected to largely disappear 5).

see Glioma classification.

Sorting and grading of glial tumors by the WHO grade classification provide clinicians with guidance as to the predicted course of the disease and choice of treatment. Nonetheless, histologically identical tumors may have very different outcome and response to treatment. Molecular biomarkers that carry both diagnostic and prognostic information add useful tools to traditional classification by redefining tumor subtypes within each WHO category. Therefore, molecular markers have become an integral part of tumor assessment in modern neurooncology and biomarker status now guides clinical decisions in some subtypes of gliomas. The routine assessment of IDH status improves histological diagnostic accuracy by differentiating diffuse glioma from reactive gliosis. It carries a favorable prognostic implication for all glial tumors and it is predictive for chemotherapeutic response in anaplastic oligodendrogliomas with codeletion of 1p19q chromosomes. Glial tumors that contain chromosomal codeletion of 1p/19q are defined as tumors of oligodendroglial lineage and have favorable prognosis. MGMT promoter methylation is a favorable prognostic marker in astrocytic high-grade gliomas and it is predictive for chemotherapeutic response in anaplastic gliomas with wild-type IDH1/2 and in elderly glioblastoma 6).


see Gliomagenesis


see Glioma spread

Clinical Features

Many gliomas become symptomatic with either seizures or focal neurological deficits and are subsequently detected via MRI.


see Glioma Diagnosis.


see MRI for glioma.


see Glioma treatment.


see Glioma outcome.


see Glioma Books.

Case series

Glioma case series.



Feng C, Wu Y, Gao L, Guo X, Wang Z, Xing B. Publication Landscape Analysis on Gliomas: How Much Has Been Done in the Past 25 Years? Front Oncol. 2020 Jan 17;9:1463. doi: 10.3389/fonc.2019.01463. eCollection 2019. PubMed PMID: 32038995; PubMed Central PMCID: PMC6988829.

Xu H, Zhang K, Zong H, Shang M, Li K, He X. Exosomal communication in glioma – a review. J BUON. 2016 Nov-Dec;21(6):1368-1373. PubMed PMID: 28039693.

Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro Oncol. 2015 Oct;17 Suppl 4:iv1-iv62. doi: 10.1093/neuonc/nov189. Epub 2015 Oct 27. PubMed PMID: 26511214; PubMed Central PMCID: PMC4623240.

Ohgaki H and Kleihues P (2005) Epidemiology and etiology of gliomas. Acta Neuropathol 109: 93–108.

Wesseling P, Capper D. WHO 2016 Classification of Gliomas. Neuropathol Appl Neurobiol. 2017 Aug 16. doi: 10.1111/nan.12432. [Epub ahead of print] PubMed PMID: 28815663.

Siegal T. Clinical Relevance of Prognostic and Predictive Molecular Markers in Gliomas. Adv Tech Stand Neurosurg. 2016;43:91-108. doi: 10.1007/978-3-319-21359-0_4. PubMed PMID: 26508407.

Pediatric low-grade glioma treatment

Pediatric low grade glioma treatment

Low-grade gliomas (LGGs) constitute the largest, yet clinically and (molecular-) histologically heterogeneous group of pediatric brain tumors of WHO grades I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest. Around 40% of all LGG patients can be cured by complete neurosurgical resection and are followed by close observation. In case of relapse, the second resection often is possible. Following incomplete resection, observation is recommended, as long as there is no radiologic tumor growth and the patient does not suffer from significant, tumor-related symptoms. This also applies to patients with a diagnosis of LGG on the basis of radiological criteria. By contrast, clinical worsening and/or radiologic progression are an indication of treatment with either chemo- or radiotherapyOverall survival is around 90%, and many patients survive with residual tumor, i. e. they suffer from chronic disease. All patients need comprehensive neuro-oncological care, the principles, and details of which are summarized in the current guidelines. These represent the standard of care for diagnostic work-up (including neuroimaging and neuropathology), and for therapeutic decisions (including the indications to non-surgical treatment) as well as concepts for neurosurgical intervention, chemotherapy, and radiotherapy as well as surveillance and rehabilitation. The current treatment algorithm was compiled by members of the LGG working group of the SIOP-E brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports 1).

Within the multidisciplinary tumor board, all decisions concerning biopsy or resection at the time of diagnosis and progression must be carefully made weighing the potential risk of surgery vs. the therapeutic benefit of elucidating the histologic and molecular subtype of the tumor 2).

A treatment algorithm was compiled by members of the LGG working group of the SIOPE brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports 3).

Since 2006 the German federal joint committee (G-BA, Gemeinsamer Bundesausschuss) has established that in line with all other pediatric hematological and oncological diseases – newly diagnosed low grade gliomas (LGG) patients must be treated within the current active society of pediatric oncology and hematology (Gesellschaft fuer paediatrische Onkologie und Haematologie, GPOH) trial or registry to ensure high quality standards of care and use of established referral systems 4).

Pediatric low grade gliomas (LGG) that are unresectable often require adjuvant chemotherapy such as carboplatin/vincristine. Small phase II studies have suggested equivalent efficacy of single agent 4-weekly carboplatin. A single-institution retrospective review captured all patients aged 0 to 18 years diagnosed with LGG between 1996 and 2013 and treated with carboplatin monotherapy. The response and survival according to tumor site was compared to published results for multi-agent chemotherapy. Of 268 children diagnosed with LGG diagnosed in this period, 117 received chemotherapy and 104 children received single agent carboplatin as first line chemotherapy. All patients received carboplatin at 560mg/m2 , four-weekly for a median of 12 courses. The mean age at diagnosis was 5.8 years (range 3m-16y) and 32% had neurofibromatosis type 1. With a mean followup of 54 months, 86% of patients achieved stabilisation or better (SD/PR/CR). 3-year progression free survival (PFS) 66% (95% C.I. 57% – 76%), and 5-year PFS was 51% (95% C.I. 41% – 63%). 5-year overall survival was 97%. Multivariate analysis showed poorer PFS for those with chiasmatic/hypothalamic tumors. In this retrospective analysis single agent carboplatin shows comparable efficacy to historical multiagent chemotherapy for the treatment of patients with unresectable LGG. Equivalent outcomes are achieved with less chemotherapy, reduced side effects and fewer hospital visits. Further research is required to establish the place of this simplified regimen in the up-front treatment of unresectable LGG 5).


Tumor measurement is important in unresectable pediatric low-grade gliomas (pLGGs) to determine either the need for treatment or assess response. Standard methods measure the product of the largest 2 lengths from transverse, anterior-posterior, and cranio-caudal dimensions (SM, cm). This single-institution study evaluated tumor volume measurements (VM, cm) in such pLGGs. Of 50 patients treated with chemotherapy for surgically inaccessible pLGG, 8 met the inclusion criteria of having 2 or more sequential MRI studies of T1-weighted Fast-Spoiled Gradient Recalled acquisition. SM and VM were performed by 2 independent neuroradiologists. Associations of measurement methods with defined therapeutic response criteria and patient clinical status were assessed. The mean tumor size at the first MRI scan was 20 cm and 398 cm according to SM and VM, respectively. VM results did not differ significantly from SM-derived spherical volume calculations (Pearson correlation, P<0.0001) with a high interrater reliability. Both methods were concordant in defining the tumor response according to the current criteria, although radiologic progressive disease was not associated with clinical status (SM: P=0.491, VM: P=0.208). In this limited experience, volumetric analysis of unresectable pLGGs did not seem superior to the standard linear measurements for defining tumor response 6).



Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, Driever PH, Meeteren AYNS, Thomale UW, Schuhmann MU, Czech T, Goodden JR, Warmuth-Metz M, Bison B, Avula S, Kortmann RD, Timmermann B, Pietsch T, Witt O. SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma. Klin Padiatr. 2019 May;231(3):107-135. doi: 10.1055/a-0889-8256. Epub 2019 May 20. Erratum in: Klin Padiatr. 2019 May;231(3):e2. PubMed PMID: 31108561.

PackerRJ,Pfister S,BouffetEetal.Pediatric low-grade gliomas: implications of the biologic era. Neuro-oncology 2017; 19: 750–761
3) , 4)

Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, Driever PH, Meeteren AYNSV, Thomale UW, Schuhmann MU, Czech T, Goodden JR, Warmuth-Metz M, Bison B, Avula S, Kortmann RD, Timmermann B, Pietsch T, Witt O. SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma. Klin Padiatr. 2019 May;231(3):107-135. doi: 10.1055/a-0889-8256. Epub 2019 May 20. PubMed PMID: 31108561.

Dodgshun AJ, Maixner WJ, Heath JA, Sullivan MJ, Hansford JR. Single agent carboplatin for pediatric low-grade glioma: A retrospective analysis shows equivalent efficacy to multi-agent chemotherapy. Int J Cancer. 2015 Aug 1. doi: 10.1002/ijc.29711. [Epub ahead of print] PubMed PMID: 26235348.

Kilday JP, Branson H, Rockel C, Laughlin S, Mabbott D, Bouffet E, Bartels U. Tumor volumetric measurements in surgically inaccessible pediatric low-grade glioma. J Pediatr Hematol Oncol. 2015 Jan;37(1):e31-6. doi: 10.1097/MPH.0000000000000168. PubMed PMID: 25517914.

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