Brainstem gliomas in childhood …

Roger J Packer MD

Neuro-Oncology

Updated 12.28.2023
Released 10.14.1996
Expires For CME 12.28.2026

Brainstem gliomas in childhood

Author: Roger J Packer MD

See Contributor Disclosures

Brainstem gliomas in childhood

In This Article

Quick Link

Introduction

Overview

The management of brainstem gliomas remains problematic. Approximately 80% of children have diffuse, intrinsic pontine tumors, which carry a dismal prognosis. Children with cervicomedullary and tectal tumors have markedly better outcomes. The author reviews outcomes after clinical trials and new biological insights that open exciting innovative avenues of molecularly-targeted treatment.

Key points

	• Brainstem gliomas occur most frequently in children, with the majority being diffuse pontine gliomas.
	• Approximately 20% of childhood brainstem gliomas are not diffuse pontine tumors; these non-diffuse pontine lesions, such as tectal gliomas and exophytic cervicomedullary tumors, are often low-grade gliomas and have a relatively good prognosis.
	• Over 90% of children with diffuse pontine gliomas will die of disease within 18 months of diagnosis.
	• Radiotherapy remains the only effective, albeit transient, therapy for diffuse pontine gliomas.
	• Biopsy and autopsy studies have disclosed biological subtypes of diffuse pontine gliomas, which most frequently have mutations of chromatin remodeling genes.

Historical note and terminology

Brainstem gliomas are, by definition, glial tumors that primarily arise within the brainstem. Concepts concerning brainstem gliomas have changed remarkably since the advent of MRI. Although the majority of brainstem gliomas arise in the pons, subsets of patients have been identified with more caudal or rostral tumors (61; 62). In addition, MR has more clearly identified the extent of lesions and the tendency of some brainstem tumors to infiltrate the diencephalon, the cervical cord, and even the cerebellum (06).

The pathology of brainstem gliomas is complex. Although pure low-grade and high-grade tumors do exist, more commonly a mixed glial pattern is seen, with areas of low-grade glioma in contiguity with regions of frank anaplasia (51). For unclear reasons, the location of the tumor within the brainstem is often related to pathology, as benign lesions tend to occur more frequently in the mesencephalon and the low medulla. Therefore, brainstem gliomas are separated into three relatively distinct, but overlapping, groups: (1) diffuse pontine gliomas, (2) tectal lesions, and (3) cervicomedullary masses. As of 2016, due to the recognition that nearly 80% of diffuse intrinsic gliomas of the brainstem have a H3K27M mutation and that infiltrating gliomas of pons behave similarly to those of the midbrain or thalamus, the WHO created a new tumor category: diffuse midline glioma, H3 K27M; this essentially replaces the nomenclature of these tumors as diffuse intrinsic pontine gliomas (DIPGs) (52). The most recent update of that classification has not altered that categorization (53).

Diffuse intrinsic brainstem gliomas almost always involve the pons, with or without extension to other brainstem sites, and constitute the majority of childhood tumors. These primarily pontine or diffuse intrinsic tumors make up approximately 80% of all brainstem gliomas and are highly resistant to treatment. Pathologically intrinsic diffuse brainstem tumors usually display mixed features, including areas of malignancy.

Up to 10% of brainstem gliomas arise in the medulla or at the cervicomedullary junction (20; 81). These tumors tend to be dorsally exophytic and histopathologically low grade--the majority being pilocytic astrocytomas. Such cervicomedullary tumors carry a more favorable prognosis and may be amenable to total, or near-total, surgical resection.

Focal, or localized, tumors of the mesencephalon may also occur. Such lesions, especially those of the tectum, are often indolent and histopathologically low-grade (85).

Children with neurofibromatosis type 1 are at increased risk to develop abnormalities, which can be confused with brainstem gliomas (59; 70). The patterns of growth and presentation for children with brainstem lesions and neurofibromatosis are variable, with some patients being asymptomatic at the time when lesions are radiographically identified and others having stable neurologic deficits. Once again, the understanding of brainstem gliomas in children with neurofibromatosis has changed dramatically since the advent of MRI, especially with routine screening of asymptomatic newly diagnosed patients with neurofibromatosis. It is now believed that many such lesions are hamartomas that will not grow over time. In any event, all lesions in children with neurofibromatosis should be evaluated circumspectly, and treatment should only follow documented progression.

Despite the initial variability in clinical presentation and histopathologic features at the time of diagnosis, later in the course of disease, the majority of patients with progressive brainstem gliomas will be found to harbor tumors that show areas of malignancy. It is unclear whether this finding represents a dedifferentiation of the tumor or whether malignant foci were present in the tumor at the time of diagnosis. At the time of progression, intrinsic brainstem gliomas tend to be extremely bulky and infiltrative, essentially destroying the normal architecture of the brainstem. Leptomeningeal dissemination is not rare at the time of disease progression, occurring in up to one third of patients at initial relapse.

Clinical manifestations

Presentation and course

Diffuse intrinsic brainstem gliomas classically present with the triad of cranial neuropathies, ataxia, and long tract signs (66). The type of neurologic compromise present is obviously dependent on the location of the tumor. Because the majority of diffuse intrinsic brainstem gliomas arise in the pons, sixth and seventh nerve dysfunction are most frequent. Lower cranial nerve deficits may also occur but are infrequently the first sign of diffuse intrinsic lesions. Rarely, patients will present with an isolated cranial neuropathy, such as peripheral seventh nerve palsy. The majority of patients will have some type of gait disturbance at the time of diagnosis. This disturbance is often an intermixture of long tract signs and ataxia. The classical presentation of crossed hemiparesis, with a seventh nerve palsy on one side and arm and leg weakness on the other side, clearly points to intrinsic lateralized brainstem involvement. Although the majority of tumors occur in young school-age children, tumors may arise in adolescents and young adults. Older children, comprising about 20% of all pediatric age patients with diffuse midline gliomas, tend to present with a longer symptom duration than younger children (21).

The duration between the onset of symptoms and the diagnosis of a brainstem lesion has changed with the improvement in neuroimaging techniques (06; 43). The majority of patients are now being diagnosed within two months of the insidious onset of symptoms, whereas prior to CT and MRI, most patients were diagnosed between three and six months of clinical presentation. Approximately one third of patients with brainstem tumors will have headache associated with nausea and vomiting. Although brainstem tumors can be bulky at diagnosis, with both anterior and posterior extension, only one third of patients will have hydrocephalus. Interestingly, patients may also experience significant personality changes prior to diagnosis. The reasons for such personality changes are unclear but may be due, in part, to the interruption of thalamic projections. In children less than five years of age, unexplained irritability is a frequent initial symptom.

The presentation of patients with localized cervicomedullary lesions differs from that of patients with diffuse intrinsic tumors. The patients with cervicomedullary lesions often have long histories of nonspecific headaches and vomiting (81). The headaches and vomiting rarely just occur early in the morning and are likely to occur at variable times during the day. Vomiting is usually projectile and is often unrelated to food intake. At time of diagnosis, patients may have little in the way of focal neurologic deficits or may have swallowing difficulties associated with lower cranial nerve (9, 10, 11, 12) dysfunctions. Swallowing difficulties and drooling tend to occur in young children.

Tumors of the midbrain or upper tectum often present with little, if any, focal neurologic deficits (85; 69; 75). Tectal masses most commonly result in hydrocephalus with associated headaches, nausea, and vomiting. After diversion of cerebrospinal fluid, there may be a complete disappearance of symptoms. Less frequently, patients with tectal lesions will have frank extraocular movement dysfunction including Parinaud syndrome (paralysis of upgaze, lid retraction, convergence nystagmus, and pupils that react better to accommodation than to light).

Occasionally, focal pontine lesions will arise, presenting with isolated seventh nerve palsies. These lesions are usually pilocytic astrocytomas and seem to carry a better prognosis (18).

Prognosis and complications

The overall prognosis for the majority of patients with brainstem gliomas is poor. Patients with diffuse intrinsic brainstem gliomas rarely survive as less than 10% of patients are alive and free of progressive disease 18 months following diagnosis and treatment with radiotherapy (51; 61; 62; 37). Most patients relapse 5 to 12 months after initial treatment. Up to 20% of children will have evidence of leptomeningeal dissemination prior to death (33). Younger children, especially those less than three years of age at diagnosis, may be more responsive to chemotherapy and have a better prognosis (11).

The prognoses for patients with more focal, often histologically benign, lesions are more favorable. After standard radiotherapy, nearly 50% of patients with focal lesions can be expected to be alive and free of progressive disease five years after diagnosis (01). Patients with cervicomedullary lesion tend to have a relatively favorable prognosis. In some series, there is short term disease control (three years) in the majority of patients (20). However, it is unclear whether this translates into long-term, disease-free survival. Similarly, children with isolated tectal lesions tend to have a better prognosis, with the majority of patients being alive and free of progressive disease for at least two to three years following initial diagnosis, many of whom have not received any specific anticancer treatment (85; 69; 75).

Clinical vignette

A 12-year-old boy developed double vision approximately two weeks prior to this evaluation. In addition, he had increased clumsiness, and, during the week prior to his assessment, had developed some difficulty swallowing. His speech had become garbled, and he had mild but constant headaches. Two days before the evaluation there had been some associated nausea and intermittent vomiting.

On examination, the child was alert and oriented. His pupils were equal and reactive, and his discs were flat. Extraocular movements were abnormal, and the child had a right sixth nerve palsy. Gaze to the right was limited, with incomplete abduction of the left eye. There was a mild right facial weakness. His gag was decreased, and the uvula pulled slightly to the left. Tongue movements were normal. On motor and coordination testing, dysmetria was more marked in the right upper extremity than on the left. When the child walked, he tended to fall to the right. There was mild drift of the left upper extremity. Reflexes were increased on the left as compared to the right.

The CT scan disclosed marked enlargement of the brainstem, which was hypodense as compared to normal brain. The fourth ventricle was flat and pushed posteriorly. There was no associated hydrocephalus. MRI scan showed a large, ill-defined hypointense abnormality on T1-weighted images that was hyperintense on T2-weighted images. There was minimal contrast enhancement.

Biological basis

Etiology and pathogenesis

The etiology for the vast majority of patients with brainstem gliomas remains unknown. There is a higher incidence of tumors in children with neurofibromatosis type 1. Usually these are low-grade gliomas, but anaplastic piloid tumors may occur with concomitant CDKN2A/B and ATRX mutations (74).

The biological underpinnings of brainstem gliomas are better understood. Pediatric brainstem gliomas biologically differ from cortical high-grade gliomas (54). Using postmortem tissue and more recently tissue obtained at the time of diagnosis by stereotactic biopsy, gains in platelet-derived growth factor receptor alpha (PDGFRA) and poly (ADP-ribose) polymerase (PARP-1) have been identified as potential therapeutic targets (92; 49; 58). Further work demonstrated focal amplifications of genes within the receptor tyrosine kinase-RAS-phosphoinoside 3-kinase pathway in nearly one half of patients, suggesting that PDGFRA and MET are potential druggable targets (68; 58). This work also suggested that diffuse intrinsic brainstem gliomas had distinct gene expression signatures related to developmental processors different from non-brainstem and low-grade brainstem gliomas.

Subsequently, whole-genome sequencing found that the majority of diffuse intrinsic brainstem gliomas also had mutations of histone H3 (87; 54), suggesting that defects of chromatin architecture is critical in pathogenesis. Diffuse midline glioma, which is defined by loss of H3 K27 trimethylation is due primarily to an H3 K27 M mutation, but may less frequently be due to over expression of EZHIP (13).

Two subgroups of recurrent H3F3A mutations associated with pediatric high-grade gliomas have been identified, confirming disrupted epigenetic regulatory elements. Those with brainstem gliomas predominately have K27 cluster mutations; the same cluster being seen primarily in other midline glioblastoma multiforme tumors of childhood, namely those of the thalamus and spinal cord (82). For this reason, diffuse midline glioma H3 K27M-mutant was incorporated into the 2016 WHO classification schema (52). Both histone H3.3 and H3.1 substitutions are seen (73). The same tumors also have frequent TP53 mutations (82). A recurring activation in the ACVR1 gene, which encodes a type 1 activin receptor serine/threonine kinase has been found on 20% of diffuse brainstem gliomas and may activate the BMP-TGF-beta signaling pathway (83). These latter findings suggest a novel molecular target for diffuse brainstem gliomas. Overall, H.3.3K27M are seen in approximately 80% of diffuse pontine gliomas, with cosegregation of other genes being location dependent, as PDGFRA alterations are most frequent in the pons and FGFR1 in the thalamus. Brainstem gliomas also have CCND2 amplification. H3.3K27M are also associated with ATRX mutations, which are more common in older children (21). H3.1K27M tumors primarily occur more often in the pons, especially in younger patients, than those arising in the H3.3 variant and carry a slightly better prognosis. There is an enrichment of P13K pathway mutations. In H3.3 or H3.1 wild-type cases, there is a great deal of molecular genetic heterogeneity (54). They may be driven by EGFR or PDGFR (54).

Infant brainstem gliomas have the best prognosis, tend to be low-grade, and may harbor NTRK fusions (54). These gene fusions may also involve other tyrosine kinases, including ALK and ROS1 (31; 15). Comparative multidimensional molecular analysis of pediatric diffuse intrinsic pontine gliomas demonstrates relatively distinct subtypes characterized by upregulation of MyC(N-MyC) or Hedgehog (Hh) signaling. Within the Hh subgroup there is upregulation of PTCH (77).

It is unclear whether the histone mutation is a driver of tumor development, and it is likely that other molecular genetic changes are required for tumor development and growth (65; 36). As more tumor tissue has become available, various animal models have been developed; however, most have not been as informative as initially hoped. New technologies, such as in utero electroporation have shown promise in unlocking the significance of the recognized pathohistological heterogeneity of diffuse intrinsic brainstem gliomas and overcoming some of the limitations of previous mouse modeling (67; 80).

Differential diagnosis

Distinctions between brainstem gliomas of childhood and other posterior fossa tumors are usually not difficult to recognize. The insidious nature of brainstem gliomas and their tendency to sequentially cause progressive cranial neuropathies separates them from the other posterior fossa tumors. Cerebellar astrocytomas are much more likely to present with lateralized cerebellar ataxia and symptoms of increased intracranial pressure early in the course of illness. Similarly, medulloblastomas usually cause midline cerebellar dysfunction associated with headaches and vomiting. Ependymomas may mimic brainstem gliomas but tend to cause less cranial nerve dysfunction and are more likely to present with symptoms and signs of increased intracranial pressure. Rarely, other types of central nervous system malignancies will arise within the brainstem. Both primitive neuroectodermal tumors and medulloepitheliomas may arise within the brainstem and cause cranial neuropathies, ataxia, and long tract signs. In these cases, clinical distinction is difficult. In general, primitive neuroectodermal tumors arise in slightly younger patients and tend to be more localized (91).

Other abnormalities that may mimic brainstem gliomas include brainstem encephalitis, intrabrainstem abscesses, and vascular malformations. Vascular malformations and abscesses tend to present more acutely and cause focal neurologic deficits. Brainstem encephalitis, although extremely rare, usually occurs in the setting of fever and more diffuse symptoms of central nervous system infection. Cerebrospinal fluid analysis may help separate brainstem encephalitis from intrinsic brainstem gliomas; however, because the majority of patients with brainstem tumors do not undergo cerebrospinal fluid analysis prior to diagnosis, these data are often missing. Chronic meningitides, including fungal and tuberculomatous infections of the base of the brain, may result in multiple cranial neuropathies, ataxia, and headaches. Neuroradiographic studies should be able to distinguish between these entities and a brainstem tumor.

On computed tomographic analysis, diffuse intrinsic brainstem gliomas cause diffuse enlargement of the brainstem (51). These tumors tend to hypodense or isodense, and approximately one third will show some degree of contrast enhancement. Various contrast enhancement patterns have been seen, including relatively localized ring enhancement. There has been some suggestion that the tumors that demonstrate ring enhancement may have a more favorable prognosis, but this has not been confirmed in larger series. The upper extent, lower extent, and exophytic nature of brainstem tumors are less than optimally imaged on computed tomography. For these reasons, MRI has supplanted CT as the procedure of choice for the diagnosis and evaluation of patients with brainstem gliomas.

On MR, diffuse intrinsic brainstem gliomas are usually hypointense, with respect to surrounding brain on short TR/TE images and are hyperintense to surrounding brain on long TR/TE images (06). Relatively few tumors are limited to the primary anatomical site, with the majority of tumors involving the pons and at least one other brainstem site. Tumors of the pons are often exophytic, growing ventrally into the prepontine cistern and extending around the basilar artery. Longitudinal infiltration into the midbrain or medulla and axial extension into the middle cerebellar peduncle or cerebellum are common. As was observed in CT studies, enhancement of brainstem gliomas on MR is variable. Once again, various patterns of enhancement have been noted and have not been related to different prognoses.

Tumors of the cervicomedullary junction often have the same neuroimaging characteristics as pilocytic astrocytomas of the cerebellum. On CT, the tumor is usually hypointense and has the same neuroimaging characteristics as diffuse intrinsic brainstem tumors have, without enhancement, on MR. Cervicomedullary tumors may have associated cystic components, and often enhance on both CT and MR.

Tectal masses tend to be localized within the tectal region, with occasional involvement of contiguous mesencephalic regions. These lesions present with associated hydrocephalus. Tectal lesions may contrast enhance on either MR or CT.

Focal pontine lesions are limited to a portion of the pons. They may be cystic, and the solid portions enhance readily on either MR or CT (18).

Diagnostic workup

The diagnostic evaluation of a patient with a presumed brainstem glioma usually begins and ends with MR. This usually displays the extent of the lesion and shows if the tumor is exophytic; MR also shows if there is associated cystic or necrotic change within the tumor. Given the infrequent tendency of primary intrinsic brainstem gliomas to disseminate through the leptomeninges at the time of diagnosis, myelography, and cerebrospinal fluid cytology is rarely indicated. When there is associated hydrocephalus, cerebrospinal fluid cytological examination from the lumbar spaces is contraindicated. Some have recommended MRI of the entire brain and spine, with and without enhancement, for patients with newly diagnosed brainstem tumors. Although the information obtained from these studies can sometimes be helpful, the infrequency of positive results makes it difficult to recommend routine employment of such staging studies.

Neuroimaging findings such as MR spectroscopy using multiparametric imaging (86) and FDG positron emission tomography (93) may be helpful in confirming the presence of a brainstem glioma and have been found to be associated with outcome.

A major unsettled issue in the diagnostic evaluation of patients with brainstem gliomas is whether surgical intervention, except for diversion of cerebrospinal fluid in patients with hydrocephalus, is indicated. Studies have emphasized the specificity of MRI in the diagnosis of brainstem gliomas (02). However, given the grim prognosis, studies are evaluating the safety of stereotactic biopsy and the yield of useful biological information gained from such procedures (76).

Brainstem glioma in childhood (1)

These images demonstrate a heterogenous signal and minimally enhancing mass within the cerebellar vermis consistent with a pilocytic astrocytoma. This mass was initially found in a young female at the age of 8 years, but subtle gr...
Brainstem glioma in childhood (2)

(A) Postcontrast coronal T1- and (B) sagittal T1-weighted images demonstrate the extent and minimal enhancement of this pilocytic astrocytoma. (Contributed by Dr. Diana Gomez-Hassan.)

Although in adult series other pathologies have been found on biopsy, finding of anything other than a brainstem glioma on biopsy in children with neuroradiographically diagnosed brainstem tumors is infrequent. Given the poor prognosis of patients with brainstem gliomas and the lack of biological information on which to base new therapeutic approaches, there continues to be interest in biopsying diffuse intrinsic tumors to obtain tissue for biological study. However, to date, study of such tissue has not been shown to change management, and, until it does, the rationale for biopsy remains highly problematic. Some prospective studies are using biopsy tissue to guide adjuvant therapy, and this increases the rationale for biopsy, as it may have direct benefit for patients (32; 60).

Some subsets of patients, especially those with cervicomedullary tumors, may benefit from the resection of brainstem glial tumors. However, for patients with diffuse (pontine) lesions, such resections have not been shown to be of therapeutic benefit (02). Biopsies of brainstem tumors have been performed by multiple groups (16; 23). Even after stereotactic procedures, a significant percentage of patients will have increased neurologic dysfunction. The tissue removed at the time of diagnostic biopsy is usually small and may not be representative of the tumor as a whole. Studies performed in the mid-1970s and early 1980s suggested that up to one third of tissue obtained was nondiagnostic. With wider experience with stereotactic means to biopsy the brainstem, surgical morbidity seems somewhat less, and the tissue obtained is more useful for histopathological and biological analysis (76). Despite this, it is unclear how the information obtained at the time of biopsy alters therapy. If the tissue is found to show areas of anaplasia, prognosis is poor. However, in contradistinction, a low-grade biopsy has not been shown to correlate with improved outcome in diffuse intrinsic lesions, either because of sampling error or the tendency for such lesions to dedifferentiate over time. If more effective means become available to treat brainstem gliomas, or if biological study can be shown to more reliably separate patients into definite risk groups, then biopsy of brainstem gliomas may take on more importance.

Management

The most appropriate management for patients with brainstem gliomas remains unsettled. After radiographic diagnosis, most patients are treated without pathologic confirmation (22). However, biopsies at the time of diagnosis are indicated in lesions without classical imaging finding, ruling out brainstem primitive neuroectodermal tumors and other pathology. In addition, stereotactic biopsies may be indicated as part of prospective trials, incorporating molecular-targeted therapies dependent on biopsy results (88; 32; 60). Relatively large, prospective multicentered series have demonstrated that stereotactic biopsies by “experienced” neurosurgeons are relatively safe, as transient neurologic worsening occurs in approximately 10% of those biopsied and permanent neurologic deficits in approximately 5% (32; 60). It is possible that this incidence of surgically related sequalae may increase as the approach becomes more widespread. Reassuring, in the majority of cases, the tissue obtained at the time of biopsy is adequate for extensive molecular analysis (32; 60). Radiotherapy is of at least transient benefit for the majority of patients with diffuse intrinsic tumors. However, conventional doses of radiotherapy, in the range of 5000 to 5500 cGy, cure few, if any, children with diffuse brainstem tumors. There has been interest in increasing the dose of radiotherapy by using hyperfractionated radiation therapy techniques (19; 63; 79; 26). Hyperfractionated radiation therapy is potentially better tolerated by the brain and allows more radiotherapy to be delivered without causing neurologic damage.

Based on these assumptions, different trials have been undertaken over the past 10 years utilizing doses of radiotherapy ranging between 6400 and 7800 cGy in dose fractions ranging between 100 to 126 cGy of radiation delivered twice daily. Despite initial encouraging results in these studies, other multi-institution cooperative trials have disclosed that the majority of children with brainstem gliomas treated at these high doses of radiotherapy will succumb to disease within 18 months of diagnosis (63; 61; 26). Compared to more conventional (once daily) radiotherapy approaches, in trials hyperfractionated radiotherapy has possibly resulted in a higher rate of objective tumor initial shrinkage but has not improved the duration of survival. In one randomized trial, hyperfractionated radiotherapy did not improve event-free or overall survival (55). In addition, nearly one third of patients treated on these higher-dose radiation therapy studies have been steroid-dependent, and intralesional tumor necrosis with associated increased neurologic dysfunction has been noted in nearly 10% of treated patients.

Other radiotherapy techniques have been suggested for children with brainstem gliomas. Hypofractionated radiotherapy trials have shown similar survival rates and toxicity profiles (39; 89; 90; 35).

The published experience with chemotherapy for children with brainstem gliomas is surprisingly scant (63; 27). A variety of drugs, including cisplatinum, carboplatinum, various nitrosoureas, cyclophosphamide, and ifosfamide have been used both singularly and in combination for children with recurrent brainstem gliomas. The results are disappointing, with most series reporting objective response rates of less than 20%, independent of the type of agent or agents used. In one report, a form of interferon, beta interferon, was utilized in nine children with recurrent brainstem gliomas (03). Two patients had a greater than 50% reduction in tumor bulk after treatment, and four others had significant periods of stabilization. However, when beta-interferon was added during and after radiotherapy, no improvement in outcome was found (64). Temozolomide plus 0-6-benzylguanine was not an effective approach (86). Reirradiation was used in the past and is still being used for children with recurrent disease following radiation at diagnosis; some patients have had at least transient benefit (28).

Trials utilizing adjuvant chemotherapy for children with brainstem gliomas have also been disappointing (40). To date, there has been no benefit seen for the use of any type of adjuvant chemotherapy including temozolomide or medtronic regimens, either given prior to or after radiotherapy (25; 41; 10; 48; 78; 17; 14). Despite this fact, given the poor results of available means of treatment, studies have been completed evaluating chemotherapy prior to the initiation of radiation therapy, as an attempt to both identify active agents for patients with brainstem gliomas and improve survival (50; 41). In a COG study of 32 patients with newly diagnosed brainstem gliomas, only 10 + 5% of patients responded to chemotherapy with drug regimens of carboplatin, etoposide, and vincristine, or cisplatin, etoposide, cyclophosphamide, and vincristine. Another study utilizing more intensive pre-irradiation chemotherapy that included intravenous high-dose methotrexate suggested a somewhat higher median survival time but increased toxicity, requiring frequent hospitalizations (24; 30). Another multiagent regimen concurrent and following radiation therapy using thiotepa and antiangiogenic therapy has demonstrated good tolerability and a possible increase in long-term survivors (72).

Similarly, studies are presently underway coupling chemotherapy with radiotherapy in an attempt to increase tumor control, partially by increasing the effectiveness of radiotherapy (42). One study utilizing topotecan during radiotherapy did not demonstrate an improvement in survival (08). Motexafin-gadolinium, a potential radio sensitizer, also did not improve outcome when coupled with radiotherapy (09). Another approach under investigation is utilizing molecular-targeted agents, with radiosensitization characteristics, during radiotherapy, without clear-cut benefit to date (34; 71). Similarly, the addition of temozolomide during and after radiotherapy did not improve survival (05).

Because of the abnormalities in epigenetic regulation at or near critical regulatory histone residues, there is also significant interest in the utilization of drugs affecting chromatin remolding (82; 88; 58).

Other molecular targets are being explored. Nimotuzumab, an anti-EGFR monoclonal antibody, has shown possible benefit in a subset of patients (07; 57). Multiagent molecular-targeted approaches following radiation based on extensive targeted sequencing are actively being employed; such approaches are feasible, but efficacy and safety are still to be shown (47; 60; 58). Immunotherapy approaches, using check-point inhibitors, T-Cell, Car-t-cell, and vaccine studies are underway (58; 56).

Younger children, especially those less than three years of age, may be more responsive to chemotherapy, and, in some, a chemotherapy-alone approach has been successful (11).

In patients with recurrent diffuse intrinsic tumors, reirradiation may be of some benefit (38).

A major limitation of the efficacy of chemotherapy, molecular-targeted therapy, or, likely, immunotherapy is lack of agent delivery to the tumor due to an intact blood-brain barrier in the often nonenhancing, diffuse lesions. To date, means to safely disrupt the barrier have failed. A new approach is coupling microbubble infusion with low-intensity focused ultrasound (LIFU) to transiently and selectively open the barrier in the brainstem, thus, allowing for better agent delivery.

The management for patients with exophytic brainstem gliomas, especially those arising at the cervicomedullary junction, remains somewhat controversial. Some have suggested observation alone, after confirmation of histology by biopsy (29). There have been reports to suggest that such tumors can be extensively resected and are usually pilocytic astrocytomas (20; 81; 45; 46). Short-term follow-up studies suggest that patients, after extensive resection, can be carefully followed without any other forms of specific intervention. However, such resections will result in increased neurologic morbidity in a sizable majority of patients, with some patients becoming respirator-dependent. It is unclear whether the best management of those patients with exophytic cervicomedullary tumors is complete resection or partial resection followed by either radiotherapy or chemotherapy. Because the majority of patients with such lesions harbor low-grade tumors, there is hesitancy to utilize radiotherapy—especially in young patients. There is some information that the use of various drugs, such as the combination of carboplatinum and vincristine, may be effective in patients with recurrent or progressive low-grade brainstem tumors (62).

The management of patients with tectal lesions also is unsettled (85). It is unclear whether such patients require surgical conformation of the pathology of the tumor or can just be followed neuroradiographically. Most observers now suggest that patients with isolated tectal lesions presenting with hydrocephalus can be watched carefully without any specific intervention after cerebrospinal fluid diversion, provided there is no evidence of tumor progression (69; 75). Larger lesions, especially those having a tumor volume of greater than 10 cm3 at presentation, are at higher risk of progressing (84). At the time of tumor progression, the majority of patients have been given local radiotherapy. Long-term disease control for patients with localized midbrain tumors after irradiation is poorly documented; however, in older CT-based studies, patients with such lesions had a relatively favorable prognosis after radiotherapy, with greater than 50% alive and free of progressive disease five years after treatment.

The management of localized pontine lesions is unclear but includes surgical resection alone or biopsy followed by local radiotherapy (18). Juvenile pilocytic astrocytomas may also occur in other regions of the brainstem with similar variable results (44; 46).

At time of recurrence, reirradiation has been used and may result in short-term clinical benefit and some prolongation of survival (38; 04; 12).

References

01: Albright AL, Guthkelch AN, Packer RJ, Price RA, Rorke LB. Prognostic factors in pediatric brainstem gliomas. J Neurosurg 1986;65:751-5. PMID 3772472
02: Albright AL, Packer RJ, Zimmerman R, Rorke LB, Boyett J, Hammond GD. Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brainstem gliomas: a report from the Children’s Cancer Group. Neurosurgery 1993;33(6):1026-30. PMID 8133987
03: Allen J, Packer R, Bleyer A, Zeltzer P, Prados M, Nirenberg A. Recombinant interferon beta: a phase I-II trial in children with recurrent brain tumors. J Clin Oncol 1991;9(5):783-8. PMID 2016620
04: Amsbaugh MJ, Mahajan A, Thall PF, et al. A phase 1/2 trial of reirradiation for diffuse intrinsic pontine glioma. Int J Radiat Oncol Biol Phys 2019;104(1):144-8. PMID 30610915
05: Bailey S, Howman A, Wheatley K, et al. Diffuse intrinsic pontine gliomas treated with prolonged temozolomide and radiotherapy--results of a United Kingdom phase II trial (CNS 2007 04). Eur J Cancer 2013;49(18):3856-62. PMID 24011536
06: Barkovich AJ, Krischer J, Kun LE, et al. Brain stem gliomas: a classification system based on magnetic resonance imaging. Pediatr Neurosurg 1991;16:73-83. PMID 2132928
07: Bartels U, Wolff J, Gore L, et al. Phase 2 study of safety and efficacy of nimotuzumab in pediatric patients with progressive diffuse intrinsic pontine glioma. Neuro Oncol 2014;16(11):1554-9. PMID 24847085
08: Bernier-Chastagner V, Grill J, Doz F, et al. Topotecan as a radiosensitizer in the treatment of children with malignant diffuse brainstem gliomas. Cancer 2005;104(12):2792-97. PMID 16265674
09: Bradley KA, Zhou T, Mcnall-Knapp RY, et al. Motexafin-gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a children’s oncology group phase 2 study. Int J Radiation Oncol Biol Phys 2013;85(1):e55-60. PMID 23092726
10: Broniscer A, Iacono L, Chintagumpala M, et al. Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem gliomas in children. Results of a multi-institutional study (SJHG-98). Cancer 2005;103:133-8. PMID 15565574
11: Broniscer A, Laningham FH, Sanders RP, et al. Young age may predict a better outcome for children with diffuse pontine glioma. Cancer 2008;113(3):959-64. PMID 18484645
12: Cacciotti C, Liu KX, Haas-Kogan DA, Warren KE. Reirradiation practices for children with diffuse intrinsic pontine glioma. Neurooncol Pract 2020;8(1):68-74. PMID 33664971
13: Castel D, Kergrohen T, Tauziède-Espariat A, et al. Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation. Acta Neuropathol 2020;139(6):1109-13. PMID 32193787
14: Chassot A, Canale S, Varlet P, et al. Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol 2012;106:399-407. PMID 21858607
15: Clarke M, Mackay A, Ismer B, et al. Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes. Cancer Discov 2020;10(7):942-63. PMID 32238360
16: Coffey RJ, Lunsford LD. Stereotactic surgery for mass lesions of the midbrain and pons. Neurosurgery 1985;17:12-8. PMID 3895028
17: Cohen KJ, Heideman RL, Zhou T, et al. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children’s Oncology Group. Neuro Oncol 2011;13(4):410-16. PMID 21345842
18: Edwards MS, Wara WM, Ciricillo SF, Barkovich AJ. Focal brain-stem astrocytomas causing symptoms of involvement of the facial nerve nucleus: long-term survival in six pediatric cases. J Neurosurg 1994;80:20-5. PMID 8271016
19: Edwards MS, Wara WM, Urtasun RC, et al. Hyperfractionated radiation therapy for brain-stem glioma: a phase I-II trial. J Neurosurg 1989;70(5):691-700. PMID 2709109
20: Epstein F, McCleary EL. Intrinsic brain-stem tumors of childhood: surgical indications. J Neurosurg 1986;64:11-4. PMID 3941334
21: Erker C, Lane A, Chaney B, et al. Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry. Neuro Oncol 2022;24(1):141-52. PMID 34114629
22: Fischbein NJ, Prados MD, Wara W, Russo C, Edwards MS, Barkovich AJ. Radiologic classification of brain stem tumors: correlation of magnetic resonance imaging appearance with clinical outcome. Pediatr Neurosurg 1996;24(1):9-23. PMID 8817611
23: Franzini A, Allegranza A, Melcarne A, Giorgi C, Ferraresi S, Broggi G. Serial stereotactic biopsy of brain stem expanding lesions: Consideration on 45 consecutive cases. Acta Neurochir Suppl (Wien) 1988;42:170-6. PMID 3055827
24: Frappaz D, Schell M, Thiesse P, et al. Preradiation chemotherapy may improve survival in pediatric diffuse intrinsic brainstem gliomas: final results of BSG 98 prospective trial. Neuro Oncol 2008;10(4):599-607. PMID 18577561
25: Freeman CR, Kepner J, Kun LE, et al. A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas. Int J Radiation Oncology Biol Phys 2000;47(3):561-4. PMID 10837936
26: Freeman CR, Krischer JP, Sanford RA, et al. Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study. Int J Radiat Oncol Biol Phys 1993;27:197-206. PMID 8407392
27: Freeman CR, Perilongo G. Chemotherapy for brain stem gliomas. Childs Nerv Syst 1999;15:545-53. PMID 10550585
28: Freese C, Takiar V, Fouladi M, et al. Radiation and subsequent reirradiation outcomes in the treatment of diffuse intrinsic pontine glioma and a systematic review of the reirradiation literature. Pract Radiat Oncol 2017;7(2):86-92. PMID 28274399
29: Fried I, Hawkins C, Scheinemann K, et al. Favorable outcome with conservative treatment for children with low grade brainstem tumors. Pediatr Blood Cancer 2012;58:556-60. PMID 21618421
30: Gokce-Samar Z, Beuriat PA, Faure-Conter C, et al. Pre-radiation chemotherapy improves survival in pediatric diffuse intrinsic pontine gliomas. Childs Nerv Syst 2016;32(8):1415-23. PMID 27379495
31: Guerreiro Stucklin AS, Ryall S, Fukuoka K, et al. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat Commun 2019;10(1):4343. PMID 31554817
32: Gupta N, Goumnerova LC, Manley P, et al. Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma. Neuro Oncol 2018;20(11):1547-55. PMID 29741745
33: Gururangan S, McLoughlin CA, Brashears J, et al. Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma. J Neuro-Oncol 2006;77:207-12. PMID 16568209
34: Haas-Kogan DA, Banerjee A, Kocak M, et al. Phase I trial of tipifarnib in children with newly diagnosed intrinsic diffuse brainstem glioma. Neuro Oncol 2008;10(3):341-7. PMID 18417739
35: Hankinson TC, Patibandla MR, Green A, et al. Hypofractionated radiotherapy for children with diffuse intrinsic pontine gliomas. Pediatr Blood Cancer 2016;63(4):716-8. PMID 26544789
36: Hoffman LM, DeWire M, Ryall S, et al. Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun 2016;4:1. PMID 26727948
37: Hoffman LM, Veldhuijzen van Zanten SE, Colditz N, et al. Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG Registries. J Clin Oncol 2018;36(19):1963-72. PMID 29746225
38: Janssens GO, Gandola L, Bolle S, et al. Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: a matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group. Eur J Cancer 2017;73:38-47. PMID 28161497
39: Janssens GO, Jansen MH, Lauwers SJ, et al. Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis. Int J Radiation Oncol Biol Phys 2013;85(2):315-20. PMID 22682807
40: Jenkins RD, Goesel C, Ertel I, et al. Brainstem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, FCR, and prednisone. J Neurosurg 1987;66:227-33. PMID 3806204
41: Jennings MT, Sposto R, Boyett JM, et al. Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children’s Cancer Group. J Clin Oncol 2002:20(16):3431-7. PMID 12177103
42: Kadota RP, Mandell LR, Fontanesi J, et al. Hyperfractionated irradiation and concurrent cisplatin in brain stem tumors: a Pediatric Oncology Group pilot study 9139. Pediatr Neurosurg 1994;20:221-5. PMID 8043459
43: Kaplan AM, Albright AL, Zimmerman RA, et al. Brainstem gliomas in children. A Children’s Cancer Group review of 119 cases. Pediatr Neurosurg 1996;24:185-92. PMID 8873160
44: Kestle J, Townsend JJ, Brockmeyer DL, Walker ML. Juvenile pilocytic astrocytoma of the brainstem in children. J Neurosurg 2004;101(1 Suppl):1-6. PMID 16206964
45: Khatib AZ, Heideman RL, Kovnar EH, et al. Predominance of pilocytic histology in dorsally exophytic brain stem tumors. Pediatr Neurosurg 1994;20(1):2-10. PMID 8142279
46: Klimo P Jr, Pai Panandiker AS, Thompson CJ, et al. Management and outcome of focal low-grade brainstem tumors in pediatric patients: the St. Jude experience. J Neurosurg Pediatr 2013;11(3):274-81. PMID 23289916
47: Kline CN, Joseph NM, Grenert JP, et al. Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy. Neuro Oncol 2017;19(5):699-709. PMID 28453743
48: Korones DN, Fisher PG, Kretschmar C, et al. Treatment of children with diffuse intrinsic brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children’s Oncology Group phase II study. Pediatr Blood Cancer 2008;50(2):227-30. PMID 17278121
49: Koschmann C, Wu Y-M, Kumar-Sinha C, et al. Clinically integrated sequencing alters therapy in children and young adults with high-risk glial brain tumors. JCO Precis Oncol 2018;2:1-34. PMID 32832832
50: Kretschmar CS, Tarbell NJ, Barnes PD, Krischer JP, Burger PC, Kun L. Pre-irradiation chemotherapy and hyperfractionated radiation therapy 66 Gy for children with brain stem tumors. A phase II study of the Pediatric Oncology Group, Protocol 8833. Cancer 1993;72(4):1404-13. PMID 8339231
51: Littman P, Jarrett P, Bilaniuk LT, et al. Pediatric brainstem gliomas. Cancer 1980;45:2787-92. PMID 7379009
52: Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016;131(6):803-20. PMID 27157931
53: Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the central nervous system: a summary. Neuro Oncol 2021;23(8):1231-51. PMID 34185076
54: Mackay A, Burford A, Carvalho D, et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 2017;32(4):520-37. PMID 28966033
55: Mandell LR, Kadota R, Freeman C, et al. There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional versus hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 1999;43:959-64. PMID 10192340
56: Majzner RG, Ramakrishna S, Yeom KW, et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 2022;603(7903):934-41. PMID 35130560
57: Massimino M, Biassoni V, Miceli R, et al. Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood. J Neurooncol 2014;118(2):305-12. PMID 24696052
58: Miklja Z, Pasternak A, Stallard S, et al. Molecular profiling and targeted therapy in pediatric gliomas: review and consensus recommendations. Neuro Oncol 2019;21(8):968-80. PMID 30805642
59: Milstein JM, Geyer JR, Berger MS, Bleyer WA. Favorable prognosis for brainstem gliomas in neurofibromatosis. J Neurooncol 1989;7(4):367-71. PMID 2511279
60: Mueller S, Jain P, Liang WS, et al. A pilot precision medicine trial for children with diffuse intrinsic pontine glioma – PNOC003: a report from the Pacific Pediatric Neuro-Oncology Consortium. Int J Cancer 2019;145(7):1889-1901. PMID 30861105
61: Packer RJ, Boyett JM, Zimmerman RA, et al. Hyperfractionated radiation therapy (72 Gy) for children with brain stem gliomas. A Children’s Cancer Group Phase I-II Trial. Cancer 1993a;72(4):1414-21. PMID 8339232
62: Packer RJ, Lange B, Ater J, et al. Carboplatin and vincristine for progressive low-grade gliomas of childhood. J Clin Oncol 1993b;11:850-7. PMID 8487049
63: Packer RJ, Nicholson HS, Johnson DL, Vezina G. Dilemmas in the management of childhood brain tumors: brainstem gliomas. Pediatr Neurosurg 1992;17(1):37-43. PMID 1811712
64: Packer RJ, Prados M, Phillips P, et al. Treatment of children with newly diagnosed brain stem gliomas with intravenous recombinant-interferon and hyperfractionated radiation therapy: a children’s cancer group phase I-II study. Cancer 1996;77(10):2150-6. PMID 8640684
65: Panditharatna E, Yaeger K, Kilburn LB, et al. Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape. Cancer Genet 2015;208(7):367-73. PMID 26206682
66: Panitch ES, Berg BO. Brain stem tumors of childhood and adolescence. Am J Dis Child 1970;119:465-72. PMID 4315314
67: Patel SK, Hartley RM, Wei X, et al. Generation of diffuse intrinsic pontine glioma mouse models by brainstem-targeted in utero electroporation. Neuro Oncol 2020;22(3):381-92. PMID 31638150
68: Paugh BS, Qu C, Jones C, et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 2010;28(18):3061-8. PMID 20479398
69: Pollack IF, Pang D, Albright AL. The long-term outcome in children with late-onset aqueductal stenosis resulting from benign intrinsic tectal tumors. J Neurosurg 1994;80:681-8. PMID 8151347
70: Pollack IF, Shultz B, Mulvihill JJ. The management of brainstem gliomas in patients with neurofibromatosis 1. Neurology 1996;46:1652-60. PMID 8649565
71: Pollack IF, Stewart CF, Kocak M, et al. A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: A report from the Pediatric Brain Tumor Consortium. Neuro Oncol 2011;13(3):290-7. PMID 21292687
72: Porkholm M, Valanne L, Lönnqvist T, et al. Radiation therapy and concurrent topotecan followed by maintenance triple anti‐angiogenic therapy with thalidomide, etoposide, and celecoxib for pediatric diffuse intrinsic pontine glioma. Pediatr Blood Cancer 2014;61(9):1603-9. PMID 24692119
73: Ramaswamy V, Remke M, Taylor MD. An epigenetic therapy for diffuse intrinsic pontine gliomas. Nat Med 2014;20(12):1378-9. PMID 25473916
74: Reinhardt A, Stichel D, Schrimpf D, et al. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol 2018;21:1-9. PMID 29564591
75: Robertson PL, Muraszko KM, Brunberg JA, Axtell RA, Dauser RC, Turrisi AT. Pediatric midbrain tumors: a benign subgroup of brainstem gliomas. Pediatr Neurosurg 1995;22:65-73. PMID 7710975
76: Roujeau T, Machado G, Garnett MR, et al. Stereotactic biopsy of diffuse pontine lesions in children. J Neurosurg 2007;107(1 Suppl):1-4. PMID 17647306
77: Saratsis AM, Kambhampati M, Snyder K, et al. Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes. Acta Neuropathol 2014;127(6):881-95. PMID 24297113
78: Sharp JR, Bouffet E, Stempak, et al. A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma. Europ J Cancer 2010;46:3271-9. PMID 20656474
79: Shrieve DC, Wara WM, Edwards MS, et al. Hyperfractionated radiation therapy for gliomas of the brainstem in children and in adults. Int J Radiat Oncol Biol Phys 1992;24:599-610. PMID 1429081
80: Siddaway R, Hawkins C. Modeling DIPG in the mouse brainstem. Neuro Oncol 2020;22(3):307-8. PMID 31907541
81: Stroink AR, Hoffman HJ, Hendrick EB, Humphreys RP, Davidson G. Transependymal benign dorsally exophytic brain stem gliomas in childhood: diagnosis and treatment recommendations. Neurosurgery 1987;20(3):439-44. PMID 3574621
82: Sturm D, Witt H, Hovestadt V, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 2012;22(4):425-37. PMID 23079654
83: Taylor KR, Mackay A, Truffaux N, et al. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nature Genetics 2014;46(5):457-61. PMID 24705252
84: Ternier J, Wray A, Puget S, Bodaert N, Zerah M, Sainte-Rose C. Tectal plate lesions in children. J Neurosurg 2006;104(S6):369-76. PMID 16776370
85: Vandertop WP, Hoffman HJ, Drake JM, et al. Focal midbrain tumors in children. Neurosurgery 1992;31:186-94. PMID 1308661
86: Warren KE, Gururangan S, Geyer JR, et al. A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study. J Neurooncol 2012;106:643-9. PMID 21968943
87: Wu G, Broniscer A, McEachron TA, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 2012;44(3):251-3. PMID 22286216
88: Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 2014;46(5):444-50. PMID 24705251
89: Zaghloul MS, Eldebawy E, Ahmed S, et al. Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): a randomized controlled trial. Radiother Oncol 2014;111(1):35-40. PMID 24560760
90: Zaghloul MS, Nasr A, Tolba M, et al. Hypofractionated radiation therapy for diffuse intrinsic pontine glioma: a noninferiority randomized study including 253 children. Int J Radiat Oncol Biol Phys 2022;113(2):360-8. PMID 35150788
91: Zagzag D, Miller DC, Knopp E, et al. Primitive neuroectodermal tumors of the brainstem: Investigation of seven cases. Pediatrics 2000;106:1045-53. PMID 11061774
92: Zarghooni M, Bartels U, Lee E, et al. Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 2010;28(8):1337-44. PMID 20142589
93: Zukotynski KA, Fahey FH, Kocak M, et al. Evaluation if 18F-FDG PET and MRI associations in pediatric diffuse intrinsic brain stem glioma: A report from the Pediatric Brain Tumor Consortium. J Nuclear Medicine 2011;52(2):188-95. PMID 21233173

Patient Profile

Age range of presentation: 0 month to 18 years
Sex preponderance: male=female
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Brainstem gliomas in childhood

Associated Disorders

Childhood brain tumors
Neurofibromatosis and central nervous system tumors
Posterior fossa tumors

Differential Diagnosis

Other posterior fossa tumors
Cerebellar astrocytomas
Medulloblastomas
Midline cerebellar dysfunction
Ependymomas
- Increased intracranial pressure
- Other types of central nervous system malignancies
- Primitive neuroectodermal tumors
- Medulloepitheliomas
- Brainstem encephalitis
- Intrabrainstem abscesses
- Vascular malformations
- Chronic meningitides
- Fungal and tuberculomatous infections of the base of brain
- Vascular abscess

Also Relevant

Brain tumors in infancy and early childhood
Cerebellar astrocytoma
Hemispheric low-grade gliomas and neuronal and glioneuronal tumors of childhood
Molecular diagnosis of brain tumors
Neurofibromatosis 1
- Neurofibromatosis 1 and intracranial neoplasms of childhood
- Optic pathway gliomas
- Pilocytic astrocytoma in adults

Brainstem gliomas in childhood …

Brainstem gliomas in childhood

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Anesthesia

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Acute cerebellar ataxia in children

Overview of neuropathology updates for infiltrating gliomas

Zika virus: neurologic complications

Anti-LGI1 encephalitis

Cerebral edema in childhood

CNS germinoma

Vein of Galen malformations

Vestibular schwannoma

Brainstem gliomas in childhood

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Anesthesia

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Acute cerebellar ataxia in children

Overview of neuropathology updates for infiltrating gliomas

Zika virus: neurologic complications

Anti-LGI1 encephalitis

Cerebral edema in childhood

CNS germinoma

Vein of Galen malformations

Vestibular schwannoma

This is an article preview.
Start a Free Account
to access the full version.