CNS tumor
Diffuse astrocytic and oligodendroglial tumors
Diffuse midline glioma, H3 K27M mutant
Author: John DeWitt, M.D., Ph.D.
Editor-in-Chief: Debra Zynger, M.D.
Topic Completed: 28 March 2019
Minor changes: 3 August 2020
Copyright: 2019-2020, PathologyOutlines.com, Inc.
PubMed Search: Diffuse midline glioma, H3 K27M mutant
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Grading | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review answer #1 | Board review style question #2 | Board review answer #2 | Board review style question #3 | Board review answer #3Cite this page: DeWitt J. Diffuse midline glioma, H3 K27M mutant. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumordmgh3k27m.html. Accessed August 6th, 2020.
Definition / general
- WHO 2016 definition: an infiltrative midline high grade glioma with predominantly astrocytic differentiation and a K27M mutation in either H3F3A or HIST1H3B / C
Essential features
- Predominates in children but also occurs in adults
- Arises in the midline, with the brain stem, thalamus and spinal cord being the most common locations
- High grade features such as mitotic activity, microvascular proliferation and necrosis may be seen but are not necessary for the diagnosis
- Diffusely infiltrative of both adjacent and distant brain structures
- Poor prognosis with 2 year survival rate of < 10%
Terminology
- Brain stem and pontine lesions previously termed brain stem glioma and diffuse intrinsic pontine glioma (DIPG)
ICD coding
- ICD-10: C71.9
Epidemiology
- Incidence data not available as infiltrative gliomas arising in the midline have not historically been distinguished from other infiltrative gliomas in large registries
- M = F
- Median patient age at diagnosis is 5 - 11 years, with tumors arising in the pons occurring at a younger age (~7 years) than those arising in the thalamus (~11 years) (Neuro Oncol 2014;16:iv1)
Sites
- Most commonly found in the spinal cord, pons and thalamus
- Occasionally arises in the cerebellum
Etiology
- Common genetic and epigenetic characteristics of midline gliomas are suggestive of a distinct developmental origin (Nat Rev Cancer 2014;14:651, Nat Rev Cancer 2014;14:92)
- Nestin- / Olig2- expressing neural precursor-like cell has been suggested as the possible cell of origin in one study (Proc Natl Acad Sci USA 2011;108:4453)
- Another found the majority of tumor cells resembled an oligodendrocyte precursor cell (Science 2018;360:331)
Clinical features
- Patients typically present with evidence of cerebrospinal fluid obstruction or brain stem dysfunction such as cranial nerve abnormalities, ataxia and long tract signs developing over a short period of time (Front Oncol 2012;2:205)
- Tumors arising in the thalamus are often associated with motor weakness and gait disturbance (Neuro Oncol 2011;13:680)
Grading
- Grade IV of IV
- Presence of H3 K27M mutation in an infiltrative glioma arising in the midline is sufficient for a grade IV designation, even in the absence of necrosis or microvascular proliferation (Acta Neuropathol 2014;128:573)
Radiology description
- On MRI, typically T1 hypointense and T2 hypertintense
- Contrast enhancement (typically < 25% of tumor volume), hemorrhage or necrosis may be seen (J Neurooncol 2011;105:119)
- Tumors arising in the pons typically present as large expansile masses occupying > 67% of the pons (Front Oncol 2012;2:205)
- Exophytic component may be present
- Infiltration into adjacent structures such as the cerebellar peduncles, midbrain or medulla is frequent
Radiology images
Contributed by Rawia Mubarak Mohamed, M.D. and Najla Saleh Ben Gashir, M.D.
Case of the Week #477
Images hosted on other servers:
CT - axial noncontrast: pontine tumor
MRI - axial T2: pontine tumor
MRI - sagittal T1: pontine tumor
MRI - sagittal T2: pontine tumor
MRI - axial T2: pontine tumor
Prognostic factors
- Prognosis almost universally poor
- Presence of an H3 K27M mutation confers a worse prognosis over wild type diffuse midline gliomas (Acta Neuropathol 2014;128:573, Acta Neuropathol 2012;124:439)
Case reports
- 5 year old girl with headache and vomiting for one week (Case of the Week #477)
- 13 year old girl with a diffuse leptomeningeal tumor exhibiting H3.3 K27M mutation and 1p / 19q codeletion (Brain Tumor Pathol 2018;35:186)
- 20 year old woman with a nonmidline H3F3A K27M mutated tumor (Acta Neuropathol Commun 2017;5:38)
- 30 year old woman and 69 year old man with mosaic H3.3 K27M protein expression (Acta Neuropathol 2017;134:961)
- 45 year old man with an H3.1 K27M mutant cerebellar diffuse astrocytoma (Brain Tumor Pathol 2018;35:29)
- 51 year old woman with a diffuse midline glioma with primitive neuroectodermal tumor-like appearance and neuropil-like islands (Neuropathology 2018;38:165)
Treatment
- Surgical resection is often highly limited due to involvement of critical brain structures (PDQ Cancer Information Summaries: Childhood Astrocytomas Treatment [Accessed 25 February 2019])
- Radiation or chemotherapy is standard
Gross description
- Infiltrative nature causes enlargement and distortion of involved anatomical structures
- Focal discoloration and softening indicating hemorrhage or necrosis may be present (Neurol Med Chir (Tokyo) 2003;43:375)
Microscopic (histologic) description
- Tumor cells typically have an astrocytic morphology and may be small and monomorphic to occasionally large and pleomorphic (Neurol Med Chir (Tokyo) 2003;43:375)
- Show an infiltrative growth pattern with tumor cells diffusely growing among native neurons and invading into adjacent structures
- Occasionally, an oligodendroglial-like pattern with halos may be seen
- Some cases will not show mitoses, necrosis or microvascular proliferation consistent with a WHO grade II histologic appearance; however, in the presence of an H3 K27M mutation, WHO grade IV is warranted given the aggressive nature of these tumors (Acta Neuropathol 2014;128:573)
Microscopic (histologic) images
Contributed by John DeWitt, M.D., Ph.D.
Diffusely infiltrating astrocytic tumor cells
Necrosis
H3 K27M
R132H-IDH1
ATRX
p53
Contributed by Rawia Mubarak Mohamed, M.D. and Najla Saleh Ben Gashir, M.D.
Case of the Week #477
Olig2
H3 K27M
Positive stains
Negative stains
- R132H-IDH1
- Keratins (although cocktails may show cross reactivity with GFAP)
- H3K27me3: H3 K27M mutated tumors show loss of H3K27me3 staining, a finding that by itself is not specific
Molecular / cytogenetics description
- Characterized by recurrent heterozygous mutations at position K27 in the histone coding genes H3F3A, HIST1H3B and HIST1H3C in high grade gliomas from the pons (~80% of cases), thalamus (~50%) and spinal cord (~60%) (Nat Genet 2014;46:451, Nat Genet 2014;46:462, Nature 2012;482:226, Nat Genet 2014;46:457, Nat Genet 2012;44:251, Nat Genet 2014;46:444)
- Additional mutations seen in diffuse midline glioma, H3 K27M mutated (Nat Genet 2014;46:451, Nat Genet 2014;46:457, Nat Genet 2014;46:444, J Neurosurg 1999;90:833):
- TP53 (~50%)
- PDGFRA amplification (~30%)
- CDK4 / 6 or CCND1 - 3 amplification (~20%)
- ACVR1 mutation (~20%)
- PPM1D mutation (~15%)
- MYC / PVT1 amplification (~15%)
- ATRX mutation (~15%)
- CDKN2A / B homozygous deletion (< 5%)
Sample pathology report
- Brain, pons, biopsy:
- Integrated diagnosis: diffuse midline glioma, H3 K27M mutant, WHO grade IV of IV (see comment)
- Histological diagnosis: diffuse astrocytoma, WHO (histological) grade II of IV
- Molecular information:
- IDH: negative (R132H immunohistochemistry; consistent with wild type)
- ATRX: nuclear expression retained (immunohistochemistry; consistent with wild type)
- p53: negative (immunohistochemistry; consistent with wild type)
- H3K27M: positive (immunohistochemistry; consistent with mutant)
- Comment: The specimen consists of core biopsy specimens of white matter with moderately atypical infiltrating astrocytic tumor cells. There is no evidence of vascular proliferation or necrosis. No mitoses are seen. Although the histologic grade is that of a grade II astrocytoma, the positivity for H3K27M is consistent with a diagnosis of diffuse midline glioma, H3 K27M mutant, which are considered grade IV lesions due to their historically aggressive clinical behavior.
- Integrated diagnosis: diffuse midline glioma, H3 K27M mutant, WHO grade IV of IV (see comment)
Differential diagnosis
- Diffuse astrocytoma, IDH mutant: grade II histology with IDH mutation present
- Diffuse astrocytoma, IDH wildtype: grade II histology lacking IDH or H3 K27M mutations
- Anaplastic astrocytoma, IDH mutant: grade III histology with IDH mutation present
- Anaplastic astrocytoma, IDH wildtype: grade III histology lacking IDH or H3 K27M mutations
- Glioblastoma, IDH mutant: grade IV histology with IDH mutation present
- Glioblastoma, IDH wildtype: grade IV histology lacking IDH or H3 K27M mutations
Additional references
Board review style question #1
This tumor was found to be arising in the pons of a 7 year old boy. The presence of what molecular alteration would warrant a WHO grade IV designation?
- 1p / 19q codeletion
- H3 K27M mutation
- IDH1 mutation
- KIA1549-BRAF fusion
- TP53 mutation
Board review answer #1
Board review style question #2
A work up of a biopsy of a diffusely infiltrating glial tumor from an 11 year old girl reveals sequencing results with the presence of a methionine substitution for a lysine at position 27 in the H3F3A gene (H3 K27M). Where is this tumor most likely arising from?
- Cerebellar hemisphere
- Frontal lobe
- Lateral ventricle
- Temporal lobe
- Thalamus
Board review answer #2
Board review style question #3
Which statement about diffuse midline glioma, H3 K27M mutant is true?
A. Despite its name, it is typically NOT found in the midline.
B. It often lacks high grade histologic features but is still considered grade IV.
C. This diagnosis includes midline gliomas that are diffusely infiltrating but have not been tested for the H3 K27M mutation.
D. The prognosis varies based on the histologic features.
A. Despite its name, it is typically NOT found in the midline.
B. It often lacks high grade histologic features but is still considered grade IV.
C. This diagnosis includes midline gliomas that are diffusely infiltrating but have not been tested for the H3 K27M mutation.
D. The prognosis varies based on the histologic features.
Board review answer #3
B. This tumor is considered grade IV regardless of the histologic features and all of these tumors are considered to have a dismal prognosis. Most of these tumors appear in the midline. Molecular or IHC testing to confirm the mutation is required for this diagnosis.
