Diffuse intrinsic pontine glioma

see also Diffuse midline glioma H3 K27M-mutant. Diffuse midline glioma H3 K27M-mutant 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. Epidemiology Approximately 300 children are diagnosed with diffuse intrinsic pontine gliomas (DIPG) each year, usually between the ages of 5 and 9. They account for 10% to 25% of pediatric brain tumors. The majority of DIPGs are astrocytic, infiltrative, and localized to the pons. Etiology The majority of the tumors were positive for GFAP (24/24), MIB1 (23/24), OLIG2 (22/24), p16 (20/24), p53 (20/24), SOX2 (19/24), EGFR (16/24), and BMI1 (9/24). The results suggest that dysregulation of EGFR and p53 may play an important role in the development of DIPGs. The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors . Results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation . Clinical Features The symptoms of DIPG usually develop very rapidly prior to diagnosis, reflecting the fast growth of these tumors. Most patients start experiencing symptoms less than three months—and often less than three weeks—before diagnosis. The most common symptoms include: Rapidly developing problems controlling eye movements, facial expressions, speech, chewing, and swallowing (due to problems in the cranial nerves) Weakness in the arms and legs Problems with walking and coordination. Diagnosis Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis .

Diffuse midline glioma H3 K27M-mutant 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.

Epidemiology
Approximately 300 children are diagnosed with diffuse intrinsic pontine gliomas (DIPG) each year, usually between the ages of 5 and 9.
They account for 10% to 25% of pediatric brain tumors.
The majority of DIPGs are astrocytic, infiltrative, and localized to the pons.

Etiology
The majority of the tumors were positive for GFAP (24/24), MIB1 (23/24), OLIG2 (22/24), p16 (20/24), p53 (20/24), SOX2 (19/24), EGFR (16/24), and BMI1 (9/24). The results suggest that dysregulation of EGFR and p53 may play an important role in the development of DIPGs. The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors 1) . Results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation 2) .

Clinical Features
The symptoms of DIPG usually develop very rapidly prior to diagnosis, reflecting the fast growth of these tumors. Most patients start experiencing symptoms less than three months-and often less than three weeks-before diagnosis. The most common symptoms include: Rapidly developing problems controlling eye movements, facial expressions, speech, chewing, and swallowing (due to problems in the cranial nerves) Weakness in the arms and legs Problems with walking and coordination.

Diagnosis
Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis 3) .
After the start of the era of biopsy, DIPGs 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 4) . Platelet-derived growth factor receptor A is altered by amplification and/or mutation in diffuse intrinsic pontine glioma (DIPG).
Eight patients from a Phase I clinical trial testing convection-enhanced delivery (CED) of a therapeutic antibody were included in the study. Pre-CED, post-radiation therapy axial T2-weighted images were analyzed using 2 methods requiring high degrees of subjective judgment (picture archiving and communication system [PACS] polygon and Volume Viewer auto-contour methods) and 1 method requiring a low degree of subjective judgment (k-means clustering segmentation) to determine tumor volumes. Lin's concordance correlation coefficients (CCCs) were calculated to assess interobserver agreement. RESULTS The CCCs of measurements made by 2 observers with the PACS polygon and the Volume Viewer auto-contour methods were 0.9465 (lower 1-sided 95% confidence limit 0.8472) and 0.7514 (lower 1-sided 95% confidence limit 0.3143), respectively. Both were considered poor agreement. The CCC of measurements made using k-means clustering segmentation was 0.9938 (lower 1-sided 95% confidence limit 0.9772), which was considered substantial strength of agreement.
The poor interobserver agreement of PACS polygon and Volume Viewer auto-contour methods highlighted the difficulty in consistently measuring DIPG tumor volumes using methods requiring high degrees of subjective judgment. k-means clustering segmentation, which requires a low degree of subjective judgment, showed better interobserver agreement and produced tumor volumes with delineated borders 6) .

Biopsy
The place of stereotactic biopsy in the management of Diffuses Intrinsic Pontine Gliomas (DIPG) in children has changed over the years.
Due to the improvement of neurosurgical technics, it regained credit. Moreover, the era of targeted therapy with molecular and genomic discoveries paved the way to research protocol that requires a biopsy to include the patient. Nonetheless, stereotactic biopsy remains a surgical procedure with its risks. A complication has never been reported in case of a biopsy of a DIPG : metastatic seeding along the tract of the biopsy. Beuriat et al report the first two cases in the literature 7) . Nevertheless, most neurosurgical teams are reluctant to perform biopsy in pediatric patients, citing 2021/05/13 14:42 Diffuse intrinsic pontine glioma Operative Neurosurgery -https://operativeneurosurgery.com/ potential risks and lack of direct benefit. Yet, in reviewing 90 patients with and the published data on brainstem biopsy, these procedures have a diagnostic yield and morbidity and mortality rates similar to those reported for other brain locations. In addition, the quality and quantity of the material obtained confirm the diagnosis and inform an extended molecular screen, including biomarker studyinformation important to designing next-generation trials with targeted agents. Stereotactic biopsies can be considered a safe procedure in well-trained neurosurgical teams and could be incorporated in well-defined protocols for patients with DIPG 8) . Treatment see Diffuse intrinsic pontine glioma treatment.
Outcome see Diffuse intrinsic pontine glioma outcome.

Complications
see Diffuse intrinsic pontine glioma complications.

Case series
Diffuse intrinsic pontine glioma case series.