Diffuse intrinsic pontine glioma

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 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).

A retrospective review of magnetic resonance imaging (MRI) scanning in a pure population of DIPG was undertaken. Baseline diagnostic MRI findings included; local tumour extension in upper medulla (74%) or midbrain (62%), metastatic disease (3%), basilar artery encasement (82%), necrosis (33%), intratumoural haemorrhage (26%), hydrocephalus (23%) and dorsal exophytic component (18%). Post-treatment MRI scans demonstrated increases in; leptomeningeal metastatic disease (16%), cystic change/necrosis (48%), enhancement (72%) and intratumoural haemorrhage (32%). Response rates were calculated according to both RECIST (4%) and WHO (24%) criteria. No MRI parameter in either the diagnostic or response scans had prognostic significance 5).


Accurately determining diffuse intrinsic pontine glioma (DIPG) tumor volume is clinically important.

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 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 study-information 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

Outcome

Complications

Case series

As part of a trial using CED for diffuse intrinsic pontine glioma (DIPG), Bander et al. measured treatment-related volumetric alterations in the brainstem and ventricles.

Enrolled patients underwent a single infusion of radioimmunotherapy. Between 2012 and 2019, 23 patients with volumetric pre- and postoperative day 1 (POD1) and day 30 (POD30) MRI scans were analyzed using iPlan® Flow software for semiautomated volumetric measurements of the ventricles and pontine segment of the brainstem.

Children in the study had a mean age of 7.7 years (range 2-18 years). The mean infusion volume was 3.9 ± 1.7 ml (range 0.8-8.8 ml). Paired t-tests demonstrated a significant increase in pontine volume immediately following infusion (p < 0.0001), which trended back toward baseline by POD30 (p = 0.046; preoperative 27.6 ± 8.4 ml, POD1 30.2 ± 9.0 ml, POD30 29.5 ± 9.4 ml). Lateral ventricle volume increased (p = 0.02) and remained elevated on POD30 (p = 0.04; preoperative 23.5 ± 15.4 ml, POD1 26.3 ± 16.0, POD30 28.6 ± 21.2). Infusion volume had a weak, positive correlation with pontine and lateral ventricle volume change (r2 = 0.22 and 0.27, respectively). Four of the 23 patients had an increase in preoperative neurological deficits at POD30. No patients required shunt placement within 90 days.

CED infusion into the brainstem correlates with immediate but self-limited deformation changes in the pons. The persistence of increased ventricular volume and no need for CSF diversion post-CED are inconsistent with obstructive hydrocephalus. Defining the degree and time course of these deformational changes can assist in the interpretation of neuroimaging along the DIPG disease continuum when CED is incorporated into the treatment algorithm 9).

1)

Ballester LY, Wang Z, Shandilya S, Miettinen M, Burger PC, Eberhart CG, Rodriguez FJ, Raabe E, Nazarian J, Warren K, Quezado MM. Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am J Surg Pathol. 2013 Sep;37(9):1357-64. doi: 10.1097/PAS.0b013e318294e817. PubMed PMID: 24076776; PubMed Central PMCID: PMC3787318.
2)

Taylor IC, Hütt-Cabezas M, Brandt WD, Kambhampati M, Nazarian J, Chang HT, Warren KE, Eberhart CG, Raabe EH. Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition. J Neuropathol Exp Neurol. 2015 Jun 25. [Epub ahead of print] PubMed PMID: 26115193.
3)

Coca HA, Cebula H, Benmekhbi M, Chenard MP, Entz-Werle N, Proust F. Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note. Neurochirurgie. 2016 Dec;62(6):327-331. doi: 10.1016/j.neuchi.2016.07.005. PubMed PMID: 28120771.
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.
5)

Hargrave D, Chuang N, Bouffet E. Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma. J Neurooncol. 2008 Feb;86(3):313-9. Epub 2007 Oct 2. PubMed PMID: 17909941.
6)

Singh R, Zhou Z, Tisnado J, Haque S, Peck KK, Young RJ, Tsiouris AJ, Thakur SB, Souweidane MM. A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume. J Neurosurg Pediatr. 2016 Jul 8:1-8. [Epub ahead of print] PubMed PMID: 27391980.
7)

Beuriat PA, Szathmari A, Di Rocco F, Kanold J, Mottolese C, Frappaz D. Diffuse Intrinsic Pontine Glioma in children : document or treat ? World Neurosurg. 2016 Jul 12. pii: S1878-8750(16)30533-2. doi: 10.1016/j.wneu.2016.07.011. [Epub ahead of print] PubMed PMID: 27422681.
8)

Puget S, Blauwblomme T, Grill J. Is biopsy safe in children with newly diagnosed diffuse intrinsic pontine glioma? Am Soc Clin Oncol Educ Book. 2012:629-33. doi: 10.14694/EdBook_AM.2012.32.629. PubMed PMID: 24451809.
9)

Bander ED, Tizi K, Wembacher-Schroeder E, Thomson R, Donzelli M, Vasconcellos E, Souweidane MM. Deformational changes after convection-enhanced delivery in the pediatric brainstem. Neurosurg Focus. 2020 Jan 1;48(1):E3. doi: 10.3171/2019.10.FOCUS19679. PubMed PMID: 31896089.

The Glioma Book

The Glioma Book

Michael E. Sughrue

List Price: $179.99

Buy

Glioblastoma (GBM) is an extremely aggressive and malignant brain tumor, with cell infiltration, rapid invasion, and a high frequency of relapse. The Glioma Book by neurosurgeon Michael Sughrue is a highly personal book — a culmination of two years of writing and more than 1,000 surgeries. It presents a unique viewpoint with the potential to transform the traditional paradigm that too often informs treatment of this universally fatal brain tumor. The book reinterprets the role of the cerebrum and sub-cortex, leverages scientific advances to improve cytoreduction and reduce neurological deficits, and challenges the myth of the “inoperable” glioma.

This is the first step-by-step technical guide focused on aggressively resecting different types of gliomas. The book is logically organized, starting with a foundation of fundamental knowledge, then progressing to practical applications. Chapters focus on the skills necessary to perform glioma surgery, specific techniques, and systematic approaches to gliomas in different brain regions.

Numerous case examples illuminate concepts introduced earlier in the book and explain how to perform these procedures

About 30 high-quality videos posted online provide insightful procedural guidance The role of connectomic imaging in visualizing the cerebrum, and other innovative techniques including awake brain mapping and diffusion tensor tractography

Neurosurgeons who embrace the concepts in this book will realize they can change the glioma treatment paradigm. Continually improving techniques and viewing a glioma diagnosis as a battle for a patient’s life, rather than an exercise in inevitable failure can impart progress in treating this devastating disease.

This book includes complimentary access to a digital copy on https://medone.thieme.com

High risk low grade glioma

High risk low grade glioma

On the basis of two randomized studies from the European Organization for Research and Treatment of Cancer (EORTC1) 2). and a synthesis by Pignatti et al, 3) high-risk low grade glioma LGG were defined by any three of five characteristics, including astrocytic histology, large tumor size (> 6 cm in diameter), midline tumor involvement, neurologic deficits ascribed to the tumor and not to surgery, and age older than 40 years.

This definition differ significantly from the definition used in the RTOG 9802 trial4).

Radiation Therapy Oncology Group (RTOG) 9802 has established postoperative radiation therapy (RT) and chemotherapy sequentially as the new standard of care for patients with high-risk low-grade glioma (LGG) meeting trial criteria. Although this trial investigated sequential chemoradiation therapy (sCRT) with RT followed by chemotherapy, it is unknown whether concurrent chemoradiation therapy (cCRT) may offer advantages over sCRT.

The National Cancer Database (NCDB) was queried for newly diagnosed World Health Organization (WHO) grade II glioma. Patients with unknown surgery, RT, or chemotherapy status were excluded, along with patients below 40 years old who underwent gross total resection to coincide with RTOG 9802 exclusion criteria. The χ, the Fisher exact, or Wilcoxon rank-sum tests evaluated differences in characteristics between groups. Kaplan-Meier analysis was used to evaluate overall survival (OS) between groups (sCRT vs. cCRT). Cox proportional hazards modeling determined variables associated with OS.

In total, 496 patients were analyzed (n=416 [83.9%] cCRT, n=80 [16.1%] sCRT). Sequencing or concurrency of therapy did not independently influence survival on univariable/multivariable analysis. Factors associated with worse OS on multivariable analysis included advanced age (P<0.001), whereas mixed glioma (P=0.017) and oligodendroglioma (P=0.005) were associated with better OS than astrocytoma histologies.

This is the only analysis of which we are aware of cCRT versus sCRT for LGG. There is no evidence that cCRT improves outcomes over sCRT 5).


The level of evidence for adjuvant treatment of diffuse WHO grade II glioma (low-grade gliomaLGG) is low. In so-called “high risk low grade glioma” patients most centers currently apply an early aggressive adjuvant therapy after surgery. The aim of a assessment was to compare progression free survival (PFS) and overall survival (OS) in patients receiving radiation therapy (RT) alone, chemotherapy (CT) alone, or a combined/consecutive RT+CT, with patients receiving no primary adjuvant treatment after surgery.

Based on a retrospective multicenter cohort of 288 patients (≥ 18 years old) with diffuse WHO grade II gliomas, a subgroup analysis of patients with confirmed isocitrate dehydrogenase mutation was performed. The influence of primary adjuvant treatment after surgery on PFS and OS was assessed using Kaplan-Meier estimates and multivariate Cox regression models, including age (≥ 40 years), complete tumor resection (CTR), recurrent surgery, and astrocytoma versus oligodendroglioma.

One hundred forty-four patients matched the inclusion criteria. Forty patients (27.8%) received adjuvant treatment. The median follow-up duration was 6 years (95% confidence interval 4.8-6.3 years). The median overall PFS was 3.9 years and OS 16.1 years. PFS and OS were significantly longer without adjuvant treatment (p = 0.003). A significant difference in favor of no adjuvant therapy was observed even in high-risk patients (age ≥ 40 years or residual tumor, 3.9 vs 3.1 years, p = 0.025). In the multivariate model (controlled for age, CTR, oligodendroglial diagnosis, and recurrent surgery), patients who received no adjuvant therapy showed a significantly positive influence on PFS (p = 0.030) and OS (p = 0.009) compared to any other adjuvant treatment regimen. This effect was most pronounced if RT+CT was applied (p = 0.004, hazard ratio [HR] 2.7 for PFS, and p = 0.001, HR 20.2 for OS). CTR was independently associated with longer PFS (p = 0.019). Age ≥ 40 years, histopathological diagnosis, and recurrence did not achieve statistical significance.

In this series of IDH-mutated LGGs, adjuvant treatment with RT, CT with temozolomide (TMZ), or the combination of both showed no significant advantage in terms of PFS and OS. Even in high-risk patients, the authors observed a similar significantly negative impact of adjuvant treatment on PFS and OS. These results underscore the importance of a CTR in LGG. Whether patients ≥ 40 years old should receive adjuvant treatment despite a CTR should be a matter of debate. A potential tumor dedifferentiation by administration of early TMZ, RT, or RT+CT in IDH-mutated LGG should be considered. However, these data are limited by the retrospective study design and the potentially heterogeneous indication for adjuvant treatment 6).


There was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices.

The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma 7).

References

1)

van den Bent MJ, Afra D, de Witte O, et al. (2005) Long term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: The EORTC 22845 randomised trial. Lancet 366:985–990.
2)

Karim AB, Afra D, Cornu P, et al. (2002) Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council Study BRO4—An interim analysis. Int J Radiat Oncol Biol Phys 52:316–324.
3)

Pignatti F, van den Bent M, Curran D, et al. (2002) Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20:2076–2084.
4)

Chamberlain MC. Does RTOG 9802 change practice with respect to newly diagnosed low-grade glioma? J Clin Oncol. 2013 Feb 10;31(5):652-3. doi: 10.1200/JCO.2012.46.7969. Epub 2013 Jan 7. PubMed PMID: 23295807.
5)

Ryckman JM, Appiah AK, Lyden E, Verma V, Zhang C. Concurrent Versus Sequential Chemoradiation for Low-grade Gliomas Meeting RTOG 9802 Criteria. Am J Clin Oncol. 2019 Feb 12. doi: 10.1097/COC.0000000000000519. [Epub ahead of print] PubMed PMID: 30768441.
6)

Paľa A, Coburger J, Scherer M, Ahmeti H, Roder C, Gessler F, Jungk C, Scheuerle A, Senft C, Tatagiba M, Synowitz M, Wirtz CR, Schmitz B, Unterberg AW. To treat or not to treat? A retrospective multicenter assessment of survival in patients with IDH-mutant low-grade glioma based on adjuvant treatment. J Neurosurg. 2019 Jul 19:1-8. doi: 10.3171/2019.4.JNS183395. [Epub ahead of print] PubMed PMID: 31323633.
7)

Reijneveld JC, Taphoorn MJ, Coens C, Bromberg JE, Mason WP, Hoang-Xuan K, Ryan G, Hassel MB, Enting RH, Brandes AA, Wick A, Chinot O, Reni M, Kantor G, Thiessen B, Klein M, Verger E, Borchers C, Hau P, Back M, Smits A, Golfinopoulos V, Gorlia T, Bottomley A, Stupp R, Baumert BG. Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1533-1542. doi: 10.1016/S1470-2045(16)30305-9. Epub 2016 Sep 27. PubMed PMID: 27686943.
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