Diffuse midline gliomas are rare and aggressive brain tumors that occur in midline structures like the brainstem, thalamus, or spinal cord. They mainly affect children and have a very poor prognosis, with median survival of 9-20 months. A defining characteristic is a mutation in the H3K27 gene. Treatment involves biopsy for diagnosis, followed by radiation and chemotherapy, but there is no standard chemotherapy regimen. Even with treatment, less than 10% of patients survive more than 2 years.

1. Diffuse Midline Gliomas
Presented By:
Dr. Rahul Jain
SR-2 Neurosurgery
Moderated by:
Dr V. C. Jha
Dr Nitish Kumar
Dr Gaurav Verma

2. Introduction
• Diffuse midline gliomas are primary central nervous
system (CNS) tumors.
• This means they begin in the brain or spinal cord.
Diffuse midline glioma is a rare subtype of glial
tumors.
• Diffuse midline glioma (DMG), previously called
diffuse intrinsic pontine glioma (DIPG), is a high-
grade malignant pediatric tumor originating in the
midline of the brain.

3. • Often occurs during middle childhood, with an
incidence of 0.8 in 100,000 children per year at a
median age of 6–7 years old in the United States.
• In children, involvement tends to be in brainstem
(formerly called brainstem glioma), pons (formerly
called diffuse infiltrating pontine glioma [DIPG]), or
bithalamic; males > feamles.
• In adolescents or adults, they occur unilaterally in
the thalamus or in the spinal cord.

4. • DMG is still uncurable and is the leading cause of
pediatric brain tumor-related deaths
• In the latest 5th edition of the WHO classification, the
nomenclature of DMG H3 K27M-mutant has been
changed to DMG H3 K27-altered.
• It is classified as WHO grade IV regardless of histological
findings, and the prognosis is known to be poor.
• Leptomeningeal involvement was found in 40% in
autopsy series.
• People with gene changes that can be passed down
through families, such as Li-Fraumeni syndrome and
neurofibromatosis type I, are at increased risk for
developing a diffuse midline glioma

5. • Definition – diffuse glioma centered in a midline
structure of the CNS (e.g., thalamus, brainstem,
cerebellum, or spinal cord) harboring a recurrent lysine-
to-methionine missense mutation (p.K27M) involving
codon 27 in one of the histone H3 genes (H3F3A,
H3F3B, HIST1H3B, or HIST1H3C).
• Any diffuse gliomas located within midline structures of
the CNS harboring a histone H3 K27M mutation are
assigned as WHO grade IV irrespective of having high-
grade histologic features.
• Subtypes :-
• diffuse midline glioma, H3.3 K27–mutant
• diffuse midline glioma, H3.1 or H3.2 K27–mutant
• diffuse midline glioma, H3-wildtype with EZHIP
overexpression
• diffuse midline glioma, EGFR-mutant

6. Clinical features
• Diffuse midline gliomas are fast-growing
tumors and can spread to other areas of
the CNS through cerebrospinal fluid (CSF).
• Depending on the tumor’s location
• Double vision
• Problems swallowing
• Weakness on one or both sides
of the body
• Loss of balance
• Due to hydrocephalus (nausea, vomiting,
headache, blurring of vision)

7. • In the spine may have:
• Progressive weakness
• Numbness
• Problems with bowel and bladder control
• Patients typically present with a short course with
brainstem findings (triad: multiple cranial nerve
palsies, long tract signs and ataxia) or obstructive
hydrocephalus.
• Evidence of thalamic involvement includes signs of
increased ICP, motor weakness (e.g., hemiparesis),
and gait disturbance.

8. Genomic Understanding

9. • The presence of the H3K27M mutation is
associated with a significant decrease (by 2.3 years)
in overall survival as compared to other pHGGs.
• H3 K27M-mutant diffuse midline gliomas uniformly
lack the IDH1 p.R132 or IDH2 p.R172 mutation that
genetically characterizes diffuse lower-grade
gliomas within the cerebral hemispheres of young
adults.
• H3 K27M-mutant diffuse midline gliomas do not
typically harbor TERT promoter mutation or EGFR
amplification that characterizes most IDH wild-type
glioblastomas within the cerebral hemispheres of
older adults.

10. Diagnostic criteria for diffuse
midline glioma, H3 K27M-altered

11. Evaluation
• High rate of leptomeningeal spread, imaging of the
entire neuraxis is recommended.
• Current trends favor obtaining a biopsy in most
cases.
• Biopsy confirms H3 K27M-mutation and can
determine if there is MGMT promoter gene
methylation.

12. Imaging
• Pontine lesions enlarge the pons, which is low intensity on
T1 and increased intensity on T2. Enhancement is minimal.
• Compression of the 4th ventricle may produce
hydrocephalus. Encasement of the basilar artery is common.
There may be an exophytic component.

13. Treatment
• The first treatment for diffuse midline glioma
is surgery, if possible.
• The goal of surgery is to obtain tissue to determine
the tumor type and to remove as much tumor as
possible without causing more symptoms for the
person.
• The brainstem, thalamus, and spinal cord are
sensitive locations in the CNS and surgery in these
areas can cause serious loss of function.

14. • The negative prognostic implications and the
increasing trials for novel therapies have prompted
neurosurgeons and oncologists to advocate for
biopsy of these lesions.
• The standard of care includes radiation and
chemotherapy.
• However, there is no standard chemotherapy
regimen, and each plan should be tailored to each
patient.

18. Prognosis
• Even with current therapies, 2-year survival is < 10%.
• Prognosis is better for subtypes involving H3.1 or H3.2
K27-mutation or EZHIP overexpression than the H3.3
K27 mutation.
• Median survival in the literature ranges between 9.1
and 19.6 months.
• However, studies have shown that despite its dismal
prognosis, median survival for diffuse midline gliomas is
still better compared with high-grade IDH wild-type
tumors (17.6 months versus 7.7 months).

19. References
1. Greenberg’s Handbook of Neurosurgery 10th ed
2. Youmans and winn’s neurological surgery 8th ed
3. cancer.gov/rare-brain-spine-
tumor/tumors/diffuse-midline-gliomas
4. Jovanovich et al.: Diffuse midline glioma future
therapeutics.
https://doi.org/10.1093/noajnl/vdad040