Diffuse intrinsic pontine glioma

INTRODUCTION — 

Diffuse intrinsic pontine gliomas (DIPGs) are rare and aggressive primary brain tumors primarily affecting children between 5 and 10 years of age. Treatment is challenging based on their critical location, infiltrative nature, and resistance to conventional therapies.

Children with DIPG typically present with a combination of cranial nerve palsies, hemiparesis, and ataxia. When biopsied, DIPG most commonly corresponds to a pathologic diagnosis of diffuse midline glioma (DMG), H3 K27-altered. DIPG carries a uniformly poor prognosis despite standard therapies.

In contrast with DIPG, most other brainstem tumors in children involving the tectum, dorsal midbrain or medulla, or cervicomedullary junction are low-grade gliomas such as pilocytic astrocytoma. These and other pediatric low-grade gliomas are reviewed separately. (See "Focal brainstem glioma" and "Overview of pediatric low-grade gliomas".)

The epidemiology, clinical features, diagnosis, and treatment of DIPG will be reviewed here. Other high-grade gliomas in childhood are reviewed separately. (See "Infant-type hemispheric gliomas" and "High-grade gliomas in children and adolescents".)

EPIDEMIOLOGY — 

Diffuse intrinsic pontine glioma (DIPG) accounts for 10 to 20 percent of all central nervous system tumors in children and approximately one-third of high-grade gliomas in children [1]. The yearly incidence is estimated at two to three cases per 1 million children [1,2].

CLINICAL FEATURES

Clinical presentation — The median age at diagnosis of diffuse intrinsic pontine glioma (DIPG) is 6.8 years (range 0 to 27 years) [3]. Approximately 20 percent of patients are 10 years of age or older [4]. Males and females are affected in equal proportions.

Most patients present with a combination of cranial nerve palsies, hemiparesis, and/or ataxia. Cranial nerve VI (CNVI) and VII (CNVII) are most commonly affected, resulting in diplopia and facial weakness, respectively. Cranial nerves III, IV, IX, and X may also be involved. Symptoms tend to present subacutely and progress over days to weeks. Symptom duration leading up to diagnosis is 6 to 12 weeks or less in the vast majority of patients [3,5].

Hydrocephalus with elevated intracranial pressure (ICP) is observed in less than 10 percent of patients at presentation. Patients may be minimally symptomatic or present with typical signs of increased ICP (eg, headache, nausea and vomiting, lethargy). Those with obstructive hydrocephalus may benefit from cerebrospinal fluid (CSF) diversion. (See 'Symptomatic therapies' below.)

Significant intratumoral hemorrhage is present in approximately 6 percent of patients at the time of diagnosis, although small punctate hemorrhages can be seen in a higher percentage of cases [6]. Symptomatic hemorrhage may eventually occur in up to 20 percent of children, usually in necrotic areas of tumor.

Most patients present with localized disease, although spinal metastasis can be found in a small subset of patients at the time of initial diagnosis [7]. Diffuse brainstem gliomas tend to progress along established fiber tracts, especially into the thalamus and cerebellum, and distant disease dissemination involving the brain and/or spine are often seen at the end stages of the disease [8,9].

Neuroimaging — DIPGs are high-grade, expansile, infiltrative tumors centered within the pons. As with all other brain tumors, they are best visualized on brain magnetic resonance imaging (MRI) with contrast, which may require anesthesia for sedation in younger children.

●Computed tomography (CT) – On head CT, DIPGs are hypodense to isodense and may be relatively subtle on noncontrast images. Internal calcification is unusual. Expansion of the pons and mass effect on surrounding structures is often apparent and signals the need for MRI.

●Brain MRI – On MRI, DIPGs are expansile lesions that are typically hypointense on T1-weighted images and hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (image 1). T2 hyperintensity may extend into adjacent areas including the medulla or midbrain. Axial growth is commonly observed through the cerebellar peduncles and into the cerebellum, and the tumors expand the pons instead of displacing it. They frequently have exophytic components extending into the prepontine cistern and often encircle the basilar artery. On sagittal images, DIPGs appear to respect the pontomedullary boundary.

Contrast enhancement is variable and may be ring-enhancing with central areas of necrosis. Many DIPGs have no contrast enhancement. Lack of enhancement may be associated with improved prognosis. (See 'Prognosis' below.)

DIPGs often demonstrate areas of restricted diffusion with low apparent diffusion coefficient (ADC) values indicative of high cellularity. Perfusion imaging may show increased relative cerebral blood volume (rCBV). Magnetic resonance spectroscopy (MRS) often shows an increase in the choline-to-N-acetylaspartate (Cho:NAA) ratio [10,11]. Where available, detection of 2-hydroxyglutarate (2HG) by MRS may be useful in noninvasive diagnosis of isocitrate dehydrogenase (IDH)-mutant glioma [12-15], which may occur in the brainstem [16,17]. (See 'Differential diagnosis' below.)

DIAGNOSIS — 

Diffuse intrinsic pontine glioma (DIPG) has traditionally been a clinical diagnosis, but biopsies are increasingly being performed to confirm an integrated histopathologic molecular diagnosis.

Clinical diagnosis — A clinical diagnosis of DIPG can be made without a biopsy in patients with a compatible clinical history, age, and imaging findings.

Brain MRI with and without contrast is the neuroimaging study of choice. We obtain advanced sequences, including perfusion-weighted imaging, whenever possible, and we obtain magnetic resonance spectroscopy (MRS) selectively when there is diagnostic uncertainty. (See 'Neuroimaging' above.)

Spine MRI and lumbar puncture (LP) for cerebrospinal fluid (CSF) cytology are generally not performed unless there is clinical or radiographic concern for dissemination or an alternative diagnosis. LP should not be performed in the presence of hydrocephalus or effacement of the third or fourth ventricle.

Of note, minimally invasive molecular diagnostics (ie, "liquid biopsy" of blood or CSF) have become technically feasible and are beginning to enter clinical practice [18]. Such testing may aid in noninvasive molecular identification of brainstem gliomas [19].

Role of biopsy — Biopsy of a brainstem tumor is a high-risk procedure that should only be performed by a specialized neurosurgical team with pediatric oncology expertise. The main indications for biopsy of a suspected DIPG are [20]:

●Atypical clinical or imaging findings suggestive of an alternative tumor that would be treated differently from DIPG. This includes older patients (eg, ≥12 years) who have an increased likelihood of having an isocitrate dehydrogenase (IDH)-mutant astrocytoma. (See 'Differential diagnosis' below.)

●Enrollment in a clinical trial in which biopsy tissue is used to identify aberrant molecular pathways in DIPG and/or guide eligibility for an investigational therapy [20]. (See 'Investigational therapies' below.)

Advances in neurosurgical techniques have permitted biopsy of DIPG to be performed safely at specialized centers [20-23]. The feasibility and safety of biopsy has been demonstrated in a multicenter prospective study of 53 children with presumed DIPG, in which 50 patients underwent stereotactic biopsy [24]. Two patients had procedural grade 3 adverse events (hypertension, apnea), and one patient developed a hemiparesis with incomplete recovery. There were no biopsy-related deaths, and all but one patient went on to receive planned radiation therapy at a median of 10 days postbiopsy. All but four samples yielded sufficient tissue for molecular analysis, including O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation and whole genome sequencing.

Differential diagnosis — The differential diagnosis of DIPG includes both neoplastic and nonneoplastic etiologies.

●Pediatric low-grade gliomas – Pediatric low-grade gliomas (eg, pilocytic astrocytoma, ganglioglioma) are the main tumors on the differential diagnosis in the brainstem in children (table 1). They are typically distinguished from DIPG by their location outside of the pons (eg, cervicomedullary junction, tectum) and a more focal/circumscribed or dorsal exophytic appearance on brain MRI (image 2 and image 3). (See "Overview of pediatric low-grade gliomas", section on 'Clinical features' and "Focal brainstem glioma".)

●IDH-mutant astrocytomas – In adolescents and young adults, the differential diagnosis of DIPG includes infratentorial IDH-mutant astrocytoma [4,16,25]. Such tumors are more likely to be noncontrast enhancing than DIPGs and are often (but not always) associated with fewer clinical symptoms and/or a longer symptom duration. IDH-mutant astrocytomas make up approximately one-quarter of brainstem gliomas in adults and are more likely than hemispheric IDH-mutant tumors to harbor non-R123H variants in IDH1 or IDH2 [16,17,26]. They are important to distinguish from DIPG because treatment and prognosis are different, and multiple effective therapies are available. (See "Treatment and prognosis of IDH-mutant astrocytomas in adults".)

●Other pediatric-type diffuse high-grade gliomas – A small proportion of tumors with an imaging appearance consistent with DIPG are proven to be diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype at the time of biopsy (image 4 and table 2). Such tumors have a similarly poor prognosis compared with DIPG. Treatment is reviewed separately. (See "High-grade gliomas in children and adolescents".)

●Nonneoplastic mimics – Vascular malformations, encephalitis, rare parasitic cysts, demyelinating disorders (eg, multiple sclerosis), and hamartomas in patients with neurofibromatosis type 1 (NF1) are the most common causes of nonneoplastic lesions in the brainstem in children. These entities can typically be distinguished from DIPG by clinical context and neuroimaging. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Differential diagnosis'.)

PATHOLOGY AND MOLECULAR PATHOGENESIS

Diffuse midline glioma, H3 K27-altered — In the vast majority of cases, a clinical diagnosis of diffuse intrinsic pontine glioma (DIPG) corresponds to a pathologic diagnosis of diffuse midline glioma (DMG), H3 K27-altered (table 2) [27,28]. Most tumors have high-grade features (ie, mitotic figures, microvascular proliferation, necrosis) and are histologically consistent with World Health Organization (WHO) grade 4.

H3 K27-altered DMGs are pediatric-type high-grade gliomas occurring predominantly but not exclusively in children. Although the pons is the most common location, they also occur in the thalamus, spinal cord, and other midline sites and can affect both children and adults [29-31]. Of note, subsets of adult patients have a somewhat better prognosis compared with children [30,31].

Most H3 K27-altered DMGs harbor a characteristic mutation in one of the gene variants encoding histone 3 (H3). The mutations involve a substitution of lysine 27 to methionine (H3 K27M), which is present in all tumor cells [32-34] and results in altered binding of mutant histone H3 to polycomb repressive complex 2 (PRC2), a key developmental regulator of gene expression [35]. PRC2 inactivation by K27M results in a global reduction of levels of H3 lysine 27 trimethylation (H3K27me3) [35-37]. The less common K27-wildtype DMGs are characterized by a loss of K27me3 resulting from overexpression of EZHIP rather than K27M [38].

Co-occurring oncogenic driver alterations are present in the vast majority of H3 K27-altered DMGs and most commonly involve DNA repair (TP53, PPM1D), chromatin remodeling (ATRX), and tyrosine kinases (ACVR1, PDGFRA, PIK3CA) [29,38]. Depending on the primary genomic alteration, H3 K27-altered DMGs may be further subclassified as follows:

●DMG, H3.3 K27-mutant – Such tumors harbor an H3.3 K27M mutation, frequently co-occurring with TP53/PPM1D mutations and platelet-derived growth factor receptor A (PDGFRA) alterations [39]. This is the most common subclass, frequently seen in pontine, thalamic, and spinal cord tumors.

●DMG, H3.1 or H3.2 K27-mutant – Such tumors harbor an H3.1 or H3.2 pK28M (K27M) mutation, frequently co-occurring with mutations in ACVR1 and PIK3CA, PIK3R1, or PTEN. This subclass can be found in pontine tumors but is rare among thalamic and spinal cord tumors.

Recurrent somatic mutations in ACVR1, a gene that encodes a bone morphogenetic protein (BMP) type 1 receptor, have been identified in up to one-third of pediatric DIPGs [40-43]. Mutations result in activation of the BMP pathway and increased expression of a variety of downstream effectors, including Smad proteins and members of the ID gene family, which may represent potential therapeutic targets. These mutations are often associated with concurrent mutations in PI3K [42,44] and the H3.1 gene [42,43]; they may be associated with slightly better prognosis [45].

●DMG, H3-wildtype with EZHIP overexpression – Such tumors exhibit loss of K27me3 resulting from overexpression of EZHIP [38] rather than K27M. ACVR1 and/or PIK3CA mutations are also frequently found in this group. This subclass is enriched for brainstem and thalamic tumors.

●DMG, EGFR- (and H3 K27-) mutant – This subclass is characterized by EGFR mutations (insertion/deletion within exon 20 or p.A289T or p.A289V mutation), frequently co-occurring with TP53 mutations. This subclass is typically found in bithalamic DMGs.

The presence of mitogen-activated protein kinase (MAPK) pathway alterations in H3 K27-altered DMGs (eg, FGFR1, BRAF, KRAS, NF1, PTPN11) and the absence of TP53 alterations have been associated with prolonged survival compared with tumors lacking these alterations [46-49]. Conversely, the presence of an H3 K27M mutation in MAPK-altered low-grade gliomas is associated with more aggressive biologic behavior and worse outcomes compared with other low-grade gliomas. (See "Overview of pediatric low-grade gliomas", section on 'Prognosis'.)

Relevant mouse models based on these molecular insights have been developed to aid in the identification of targeted therapies for DIPGs. (See 'Investigational therapies' below.)

Other histologies — Less commonly, biopsies of clinically-diagnosed DIPGs show either H3-wildtype/isocitrate dehydrogenase (IDH)-wildtype diffuse pediatric-type high-grade glioma or, in older patients, IDH-mutant astrocytoma. In such cases, the patient should be treated according to the alternative integrated histopathologic and molecular diagnosis. (See 'Differential diagnosis' above.)

TREATMENT — 

Diffuse intrinsic pontine gliomas (DIPGs) are inoperable, malignant tumors that are refractory to standard therapies. Management consists primarily of symptomatic therapies and radiation therapy. Participation in clinical trials is encouraged, particularly as the molecular pathogenesis of these tumors is unraveled and targeted therapies begin to enter clinical trials.

Symptomatic therapies — Symptomatic management consists primarily of glucocorticoids for control of peritumoral edema and surgical management of hydrocephalus, when necessary.

●Glucocorticoids – The administration of glucocorticoids (eg, dexamethasone) is an important initial step in the treatment of patients with high-grade brainstem tumors. Peritumoral edema often contributes prominently to symptoms, which can improve rapidly after steroid therapy. Although steroids do not treat the underlying problem, improved clinical performance can be an important matter for quality of life in patients with a limited life span. Dexamethasone therapy is generally tailored to the clinical situation, with no standardized dosing or schedule [50].

Unfortunately, many patients require prolonged administration of dexamethasone, resulting in significant steroid-related complications. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors", section on 'Complications and prophylaxis'.)

●Bevacizumab – Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is commonly used in adult high-grade glioma patients to improve peritumoral edema and limit the long-term complications of glucocorticoids. However, the benefit in children with DIPG appears much more limited [51]. Successful treatment of radiation necrosis in patients with DIPG has been reported [52].

●Cerebrospinal fluid (CSF) diversion – Approximately one-quarter of patients with DIPG require treatment for hydrocephalus either at diagnosis or within the next several months [5]. CSF diversion is most commonly achieved with ventriculoperitoneal shunt placement [53]. If feasible, endoscopic third ventriculostomy is an attractive alternative that obviates the need for implanted hardware [54]. (See "Hydrocephalus in children: Management and prognosis", section on 'CSF diversion procedures'.)

Radiation therapy — For all patients with DIPG, we recommend radiation therapy as the primary therapeutic modality. Radiation should be initiated as soon as possible after diagnosis. Patients with severe symptoms may require urgent initiation for control of symptoms.

●Standard fractionation – The standard treatment dose is 1.8 gray (Gy) daily given five days per week, to a total dose of between 54 and 59.4 Gy [55]. The treatment field consists of the tumor volume on T2-weighted images plus a 1 to 2 cm margin [56].

●Hypofractionated course – Hypofractionated radiation therapy, which delivers higher doses of radiation each day over fewer total days, has been evaluated to minimize the time spent in treatment [57-61]. This approach may be considered to provide improved quality of life and reduced financial burden to families, especially in young children requiring anesthesia for treatment.

In the largest of the trials of hypofractionated radiation among 253 children with newly diagnosed DIPG, overall survival ranged from 8.2 to 9.6 months and was similar across three randomized treatment groups: 39 Gy in 13 fractions (HF1), 45 Gy in 15 fractions (HF2), and 54 Gy in 30 fractions (standard fractionation) [61]. Acute and delayed side effects and toxicities were also similar across groups. However, for the subgroup of patients two to five years of age, the HF2 regimen appeared less effective compared with the HF1 and standard fractionation regimens.

Radiation therapy, which has been administered for more than half a century and typically results in transient improvement of both symptoms and imaging findings [62,63], remains the only treatment that appears to alter the clinical course of DIPG. As a result, no randomized clinical trials have been performed that did not include upfront adjuvant radiation therapy for all patients. Despite multiple trials of dose escalation, altered fractionation, concurrent chemotherapy, and radiosensitization, none of these modulations have been proven more effective than conventionally delivered radiation therapy [64-68].

The degree of tumor shrinkage induced by radiation therapy can be dramatic, and many patients experience improvement in symptoms. The response is generally transient, however, and the approach is ultimately palliative and not curative. Median survival is approximately 11 months, and the two-year and five-year overall survival rates are 10 and 2 percent, respectively [5]. (See 'Prognosis' below.)

Recurrent/progressive disease — Patients invariably progress despite standard radiation therapy at a median of six months after diagnosis [5]. Treatment failures are usually local and occur within the radiation therapy field [56]. Although up to one-third of patients have evidence of central nervous system dissemination at the time of progression, most symptoms are referred to the primary site [7,69].

Fractionated reirradiation of DIPG at the time of progression may be considered to temporarily extend palliation, although increased toxicities may result from this approach [70-72]. Treatment decisions must be individualized, taking into account the functional status of the patient and overall goals of care.

In a small prospective dose-escalation study, the lowest dose level (24 Gy in 12 fractions) was well tolerated and achieved imaging, clinical, and/or quality-of-life improvement in most patients; in all 12 patients, progression-free and overall survival from the start of reirradiation were 4.5 and 5.8 months, respectively [73]. Similarly, hypofractionated reirradiation with 20 to 30 Gy in 2 Gy fractions or 30 to 36 Gy in 3 Gy fractions was shown to be effective in a retrospective study [74].

Chemotherapy (ineffective) — Outside of a clinical trial, we do not administer temozolomide or any other systemic therapy during or after radiation therapy in patients with DIPG.

Numerous treatment protocols (including single chemotherapy agents, multidrug combination regimens, and high-dose therapy with stem cell rescue) have all been tested in both adults and children with DIPG without clear evidence of benefit [75-78]. The addition of temozolomide in particular has shown no survival benefit in phase II trials in children with DIPG when compared with historical controls treated with radiation alone [79,80] and in one small open-label randomized trial of radiation therapy with or without concurrent and adjuvant temozolomide [81].

Investigational therapies — A number of emerging preclinical insights are under investigation in clinical trials in DIPG [82-88]. Promising examples include use of an H3 K27M-mutant vaccine [89] and use of chimeric antigen receptor (CAR)-expressing T cells with specific targeting against either GD2, a disialoganglioside that is highly expressed on the surface of H3 K27M-mutant glioma cells [88,90,91], or B7-H3, an immune regulatory protein expressed on DIPG [92,93].

In the largest published experience with investigational GD2 CAR-T cell therapy, 11 patients with H3 K27M-mutant diffuse midline glioma (DMG; nine with DIPGs and two with spinal tumors) who had received standard radiation therapy at least four weeks before enrollment were treated with lymphodepleting chemotherapy followed by intravenous (IV) GD2-CAR-T cells; nine patients also received one or more doses of intracerebroventricular (ICV) CAR-T cells [91]. Cytokine release syndrome (CRS) was dose-limiting at dose level 2 with IV delivery; immune effector cell-associated acute neurotoxicity syndrome (ICANS) occurred in four of eight patients treated at dose level 2 and in none of the patients treated with ICV infusions. More than half of patients exhibited tumor shrinkage (including 4 of 11 with >50 percent volumetric tumor reduction), although direct attribution to CAR-T cell therapy was confounded by most patients having recently completed radiation therapy. Two patients were alive at 30 and 33 months after first infusion, respectively, including one with an ongoing complete response. Of note, genomic features that have been associated with prolonged survival [46,47] were present in both tumors. Based on these promising yet preliminary results, an ongoing clinical trial is focusing on ICV delivery.

The investigational oral compound ONC201 (dordaviprone) is under active investigation in H3 K27-altered midline gliomas [94,95]. The mechanism of action is not well defined but may involve mitochondrial metabolism and the stress response pathway [96]. In a molecularly unselected phase II trial of ONC201, a near-complete imaging response was observed in a patient with a recurrent H3 K27M-mutant thalamic glioma [94]. This finding prompted several prospective trials in children and adults with H3 K27M-mutant gliomas. In a summary of 50 patients with recurrent H3 K27M-mutant DMG treated with ONC201 on one of four clinical trials (46 adults, 4 children), the overall response rate was 20 percent with a median duration of response of 11.2 months (95% CI 3.8 to not yet reached) [97]. The drug was well tolerated, with a low rate of treatment-emergent adverse events (20 percent, most commonly fatigue, all grade 3 or lower). An international placebo-controlled randomized phase III trial is underway for patients with newly diagnosed H3 K27M-mutant diffuse gliomas excluding DIPG and spinal tumors (NCT05580562) [98].

Local therapies are also being studied, including DNX-2401, an oncolytic adenovirus administered by catheter infusion into the cerebellar peduncle [99].

Studies of systemic checkpoint inhibitor immunotherapies have thus far shown no clear signal of efficacy [100].

PROGNOSIS — 

The prognosis of diffuse intrinsic pontine glioma (DIPG) is generally poor, with a median overall survival of 10 to 11 months [3,56,77,101,102]. Five-year survival is less than 3 percent, and many long-term survivors have evidence of moderate or severe cognitive impairment, likely as a consequence of radiation therapy [3,103].

Several studies have suggested that younger patients (age <3 years) and older patients (age >10 years) may have a somewhat better prognosis [4,101,103-105]. Other favorable prognostic factors include long interval between the onset of symptoms and diagnosis, lack of pontine cranial nerve palsies, and atypical radiologic characteristics (eg, lack of enhancement) [3,75,101,103,106,107].

Accumulating data also suggest that certain molecular markers in H3 K27-altered diffuse midline gliomas (DMGs) are associated with improved survival. (See 'Diffuse midline glioma, H3 K27-altered' above.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Diffuse intrinsic pontine gliomas (DIPGs) are rare and aggressive primary brain tumors primarily affecting children between 5 and 10 years of age. They account for 10 to 20 percent of all central nervous system tumors in children. (See 'Epidemiology' above.)

●Clinical features – Most patients present with a combination of cranial nerve palsies, hemiparesis, and/or ataxia. The median age at diagnosis is 6.8 years. Symptoms tend to present subacutely and progress over days to weeks. (See 'Clinical presentation' above.)

On MRI, DIPGs are expansile, infiltrative tumors that are typically hypointense on T1-weighted images and hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (image 1). Contrast enhancement is variable and may be ring-enhancing with central areas of necrosis. (See 'Neuroimaging' above.)

●Diagnosis – A clinical diagnosis of DIPG can be made without a biopsy in patients with compatible clinical histories, ages, and imaging findings. Minimally invasive molecular diagnostics (ie, "liquid biopsy" of blood or cerebrospinal fluid [CSF]) have become technically feasible and are beginning to enter clinical practice. (See 'Clinical diagnosis' above.)

Biopsy of a brainstem tumor is a high-risk procedure that should only be performed by a specialized neurosurgical team with pediatric oncology expertise. The main indications for biopsy of a suspected DIPG are older age, atypical clinical or neuroimaging features, and anticipated clinical trial enrollment. (See 'Role of biopsy' above.)

●Pathology – The vast majority of biopsied DIPGs represent H3 K27-altered diffuse midline gliomas (DMGs) (table 2). Less commonly, biopsies of clinically-diagnosed DIPGs show either H3-wildtype/isocitrate dehydrogenase (IDH)-wildtype diffuse pediatric-type high-grade glioma or, in older patients, IDH-mutant astrocytoma. (See 'Pathology and molecular pathogenesis' above and 'Differential diagnosis' above.)

●Treatment – DIPGs are inoperable, and management consists primarily of symptomatic therapies to control peritumoral edema and radiation therapy. Participation in clinical trials is encouraged.

•Glucocorticoids are used to control tumor-associated edema in symptomatic patients. Approximately one-quarter of patients with DIPG require treatment for hydrocephalus either at diagnosis or within the next several months. (See 'Symptomatic therapies' above.)

•For all patients with DIPG, we recommend radiation therapy as the primary therapeutic modality (Grade 1C). The standard approach is to give a total dose of 54 to 59.4 gray (Gy) in fractions of 1.8 Gy five times per week. Alternatively, hypofractionation with 45 Gy in 15 fractions may be considered to provide improved quality of life and reduced financial burden to families, especially in young children requiring anesthesia for treatment. (See 'Radiation therapy' above.)

•Outside of a clinical trial, we do not administer temozolomide or any other systemic therapy in patients with DIPG. Clinical trial participation is encouraged to evaluate novel therapies. (See 'Chemotherapy (ineffective)' above and 'Investigational therapies' above.)

●Prognosis – Despite aggressive therapy, the prognosis remains generally poor, with an average survival of less than one year. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Mark Kieran, MD, PhD, who contributed to an earlier version of this topic review.