CNS tumor
Diffuse astrocytic and oligodendroglial tumors
Diffuse midline glioma, H3 K27M mutant


Topic Completed: 28 March 2019

Revised: 29 April 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: Diffuse midline glioma, H3 K27M mutant

John DeWitt, M.D., Ph.D.
Page views in 2019 to date: 1,354
Cite this page: DeWitt J. Diffuse midline glioma, H3 K27M mutant. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cnstumordmgh3k27m.html. Accessed October 13th, 2019.
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
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
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
Case reports
Treatment
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
  • H3F3A K27M (specific immunostain)
  • S100
  • ATRX (positive in ~85% of cases but may be lost in up to 15% of cases indicating an underlying mutation)
  • GFAP (variably positive)
  • Olig2, MAP2
  • p53 (strong positivity in ~50% of cases)
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
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.
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
Board review 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?



  1. 1p / 19q codeletion
  2. H3 K27M mutation
  3. IDH1 mutation
  4. KIA1549-BRAF fusion
  5. TP53 mutation
Board review answer #1
B. H3 K27M mutation

Comment Here
Board review 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?

  1. Cerebellar hemisphere
  2. Frontal lobe
  3. Lateral ventricle
  4. Temporal lobe
  5. Thalamus
Board review answer #2
E. Thalamus

Comment Here
Board review 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.
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.
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