INTRODUCTION — Gliomas arising in the brainstem (midbrain, pons, and medulla oblongata) account for 10 to 20 percent of all central nervous system (CNS) tumors in children. Brainstem gliomas are heterogeneous, ranging from low-grade tumors that need little or no treatment to high-grade lesions that are rapidly fatal despite aggressive therapy [1]. Prognosis and treatment depend upon histologic features and the location within the brainstem (figure 1).
Focal brainstem gliomas typically arise in the midbrain and medulla, and typically are discrete, well-circumscribed tumors. Histologically, these tumors are most often pilocytic or diffuse astrocytomas, or rarely, gangliogliomas, all of which are considered low-grade tumors. Focal brainstem gliomas share many biologic features with posterior fossa and supratentorial low-grade gliomas, and significant advances in the analysis of the signaling pathways involved in their pathogenesis have been identified.
Focal brainstem gliomas are discussed here. Diffuse intrinsic pontine gliomas are discussed separately. (See "Diffuse intrinsic pontine glioma".)
EPIDEMIOLOGY — Brainstem tumors are more common in children than adults, with approximately 500 pediatric and 300 adult cases reported each year in the United States [2-6]. Brainstem gliomas account for approximately 13 percent of all intracranial neoplasms in children under the age of 14 years.
In children, the median age at diagnosis is five to nine years of age. Within this age group, brainstem malignancies are nearly as common as cerebral malignancies. The incidence is approximately equal between males and females [7-10].
The only known inheritable risk factor for both low-grade and high-grade brainstem gliomas is neurofibromatosis type 1. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Other central nervous system neoplasms'.)
PATHOLOGY
Histopathology — Focal brainstem gliomas typically arise in the midbrain and medulla, and typically are discrete, well-circumscribed tumors. Histologically, these tumors are most often pilocytic or diffuse astrocytomas, or rarely, gangliogliomas, all of which are considered low-grade tumors [11]. Especially in tumors with nonpilocytic histology, evidence of locally invasive growth or edema may be present. Focal brainstem gliomas share many biologic features with posterior fossa and supratentorial low-grade gliomas, including key molecular genetic changes. (See 'Molecular genetics' below.)
Up to 80 percent of brainstem gliomas that occur outside the pons are low grade (World Health Organization [WHO] grade 1 and 2 tumors, (table 1 and table 2)) [2,3,12-15]. The remaining 20 percent are high-grade gliomas [12,13]. The WHO grading system for gliomas is based upon both histopathologic and molecular features [16] (see "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors"). Low-grade astrocytomas are characterized by varying degrees of cellularity and occasional nuclear atypia, although they lack other features of malignancy. The histology of grade 1 tumors (pilocytic astrocytomas) is distinctive, usually consisting of biphasic microcystic areas interspersed between more compacted and cellular areas with extensive fibrillary processes and associated Rosenthal fibers (composed of alpha-B crystallin) [17]. Occasionally there may be a large macrocystic structure containing a mural nodule. Pilocytic astrocytomas can possess a few mitoses and vascular proliferation without elevation to a higher grade. (See "Uncommon brain tumors", section on 'Pilocytic astrocytoma'.)
Molecular genetics — Whenever possible, histologic diagnosis should be supplemented by molecular diagnostics, which can provide important diagnostic, prognostic, and therapeutic information [16,18-20]. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Key molecular diagnostic tests'.)
Advances in the molecular analysis of pediatric low-grade gliomas, including those of the brainstem, have identified frequent recurring alterations in the mitogen-activated protein kinase (MAPK) pathway, including characteristic duplications involving the BRAF gene in pilocytic astrocytomas (KIAA1549-BRAF fusion) and mutation (BRAF V600E), as well as activating mutations and fusions in fibroblast growth factor receptor (FGFR) genes. Molecular profiling therefore provides important diagnostic, prognostic, and therapeutic information [21].
CLINICAL FEATURES — Most children with low-grade brainstem gliomas have a relatively long history of minor symptoms and signs, which may have been present for many years [2,3,12-15,22,23].
Signs and symptoms generally reflect the location of the tumor, the presence of hydrocephalus, and/or the age of the child. Most tumors produce some neck stiffness or discomfort; some patients may even present with torticollis. (See "Acquired torticollis in children", section on 'Central nervous system tumor' and "Approach to neck stiffness in children", section on 'Central nervous system lesions'.)
●Small focal tumors of the midbrain or medulla usually present insidiously, with a long history of localizing findings such as an isolated cranial nerve deficit or contralateral hemiparesis. Signs and symptoms of raised intracranial pressure (ICP) are uncommon.
●Dorsally exophytic tumors and focal tumors of the tectum, the dorsal aspect of the rostral or upper midbrain, typically present with headache, vomiting, and ataxia secondary to aqueductal occlusion and hydrocephalus. Cranial nerve deficits are seen in approximately one-half of patients, but long tract signs are distinctly unusual. Symptoms referable to brainstem dysfunction (eg, Parinaud syndrome) may occur (table 3). (See "Ocular gaze disorders", section on 'Parinaud syndrome'.)
●Medullary tumors can be associated with cranial nerve dysfunction, dysphagia, nasal speech, and apnea. Patients may also have weakness, ataxia, nausea, and vomiting. Rarely, a focal pontine tumor can produce facial and auditory nerve dysfunction.
●Cervicomedullary junction tumors can cause hemiparesis or quadriparesis from upper motor neuron dysfunction, as well as weakness, muscle atrophy, and loss of reflexes from lower motor nerve dysfunction. Hydrocephalus is uncommon, but patients may have apnea, sensory deficits, headache, vomiting, and cranial neuropathies [14,23].
DIAGNOSTIC EVALUATION — Imaging studies are the standard initial method to diagnose and classify brainstem tumors.
Findings on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) often permit the differentiation of circumscribed low-grade brainstem gliomas from other tumor types including high-grade lesions [12,24,25]. A stereotactic biopsy is indicated if the diagnosis cannot be established by imaging. Tumors that are felt to be resectable are typically diagnosed at the time of surgery, without a preceding biopsy. (See 'Surgery' below.)
MRI appearance — MRI of the brain with and without contrast is the method of choice to image tumors in the brainstem, since many of these lesions are isointense on computed tomography (CT) [23,26,27].
On MRI, focal low-grade brainstem gliomas most often appear as masses of limited size (<2 cm) that may be cystic, well demarcated, noninfiltrating, and without associated edema. They are typically isointense or hypointense on T1-weighted images, hyperintense on T2-weighted images, and enhance uniformly and brightly with intravenous contrast [24,25,28,29]. Diffusion tensor imaging (DTI) and white matter tractography are very useful in documenting axonal degeneration of the motor and sensory tracts in focal brainstem tumors. These imaging sequences may assist in surgical planning for biopsy or tumor debulking. Additionally, advanced imaging may assist in prognostication of possible functional tract recovery following therapy [30]. Focal tumors of the midbrain can contain calcifications and enhance poorly with contrast [3].
MRI is particularly helpful for tectal gliomas, whose imaging appearance typically is uniform, with a nonenhancing thickening of the tectal plate (image 1) [26,28]. The noninfiltrative nature of these masses, their dorsal exophytic growth pattern, and associated hydrocephalus all suggest a low-grade tumor. The pattern of enhancement may also lend support, as grade 1 tumors are often diffusely enhanced with gadolinium, grade 2 tumors are often nonenhancing, while high-grade pontine gliomas often demonstrate ring enhancement [31]. Tectal plate tumors are usually diagnosed based upon their characteristic MRI appearance and presence of hydrocephalus [26]. (See "Diffuse intrinsic pontine glioma", section on 'Neuroimaging'.)
The MRI signal characteristics of cervicomedullary lesions are similar to those of other low-grade astrocytomas, with intense T2 signal and low T1 signal [23]. A cystic area is usually present, often within a dorsal exophytic component (image 2). Tumors with a dorsally exophytic component are usually associated with hydrocephalus [2].
Magnetic resonance spectroscopy — MRS is a supplemental diagnostic technique for brain tumors and can be helpful for the differentiation of locally infiltrative brain tumors from other well-circumscribed intracranial lesions. MRS measurement of tumor-associated choline and N-acetylaspartate and their ratio (Cho:NAA) may help distinguish high-grade from low-grade lesions [32-34].
TREATMENT — Treatment of focal brainstem gliomas requires a consideration of the anatomic location of the tumor, which determines both symptoms and accessibility to surgical resection. The long-term prognosis of patients with brainstem low-grade glioma is excellent [35].
Optimal treatment requires a team that includes experienced neurosurgeons, radiation oncologists, and neurooncologists, as well as psychosocial workers, educational specialists, and physical and occupational therapists. Such multidisciplinary care is best delivered at a specialized tertiary care center with a dedicated neurooncology program.
Therapeutic approaches — Surgical resection, radiation therapy (RT), and chemotherapy each can play a role in the management of patients with focal brainstem gliomas.
Surgery — Historically, the location of focal brainstem gliomas in one of the most eloquent areas of the central nervous system (CNS) was thought to preclude surgery, and most patients were treated with RT.
However, improved intraoperative imaging and guidance technologies have enhanced the surgeon's ability to maximally resect these tumors while preserving normal tissue and function [36-43]. Although there are no randomized trials, resection has become the preferred treatment for focal brainstem gliomas in surgically accessible locations, such as at the cervicomedullary junction in selected cases [44] and for dorsal exophytic lesions. Positron emission tomography (PET) imaging can improve the localization of higher-grade regions within brainstem tumors and help guide the location of biopsy [45]. In patients for whom resection is contraindicated, stereotactic biopsy can provide important histologic and molecular information to guide further therapy in both pediatric [46] and adult patients [47].
Approximately 30 percent of resected tumors will progress and require further therapy. A second operation can be considered for patients with surgically accessible disease [48,49]. For others, the most reasonable option is chemotherapy in children and focal RT in adults.
Radiation therapy — RT provides an important alternative for focal brainstem lesions that are surgically inaccessible. Treatment with external beam RT, using standard fractionation, controls approximately 50 to 70 percent of focal lesions [2,50-53]. With this approach, the total radiation dose is 54 Gy, delivered in once-daily fractions, five days a week for six weeks to a limited volume with a 0.5 to 1 cm margin.
Advances in the use of RT for brainstem gliomas have focused on decreasing morbidity by limiting the radiation dose to normal tissue. Newer conformal RT techniques, including stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (SRT), intensity-modulated radiation therapy (IMRT), volumetric modulated arc radiotherapy (VMAT), and proton radiotherapy, help to minimize radiation to the normal brain at large and are particularly important for the delivery of radiation to brainstem tumors, which are often in close proximity to critical structures such as the pituitary gland and the optic nerves.
Although these approaches have not been compared with conventional external beam RT in patients with focal low-grade brainstem gliomas, clinical practice has been influenced by trials performed in more common tumors, such as low-grade optic pathway gliomas or medulloblastomas. Selection of a specific technique in patients with brainstem tumors is individualized based on the availability of the technology and consideration of the technique that would provide the best coverage of the tumor with sparing of critical organs and normal tissue.
Although RT may result in long-term progression-free survival, it can be associated with significant morbidity, especially in very young children. Long-term effects include reduced growth and other endocrinopathies secondary to dose to the pituitary gland and hypothalamus, cognitive and hearing deficits, vascular stenosis leading to stroke, as well as a risk of secondary treatment-induced malignancy. Thus, RT should be limited to older children and adults whenever possible to minimize late morbidity. The delayed complications of cranial irradiation are discussed elsewhere. (See "Delayed complications of cranial irradiation".)
Chemotherapy — Chemotherapy is playing an increasing role in the treatment of brainstem gliomas in order to avoid or delay using RT in children [54-58].
Few clinical studies have evaluated the efficacy of chemotherapy in treating focal low-grade gliomas of the brainstem. As with RT, clinical practice has been influenced by the experience in treating supratentorial and fourth ventricular low-grade gliomas.
Tumor growth can be stabilized by chemotherapy and can have a dramatically positive impact on quality of life by delaying or obviating the need for RT in young children [59-62]. This is achieved without reducing the efficacy of definitive treatment, as tumors that progress on or after chemotherapy have not been found to be less responsive to RT.
Approximately 40 percent of children who are treated with weekly vincristine and carboplatin for low-grade gliomas have an objective response to treatment, and a higher percentage may achieve periods of disease stability [60,61,63]. In one report, for example, the two- and three-year progression-free survival rates were 75 and 68 percent, respectively [61]. Similar results have been obtained with other chemotherapy regimens (eg, 6-thioguanine, procarbazine, lomustine, and vincristine [TPCV]) [64].
The optimal chemotherapy regimen for pediatric low-grade gliomas is unclear, and most trials have included patients with tumors throughout the brain and spine, not just those localized to the brainstem. The weekly carboplatin/vincristine regimen has been compared with TPCV in a national trial of pediatric CNS low-grade gliomas, and these regimens have approximately equal efficacy [65]. Single-agent monthly carboplatin without vincristine appears to have similar efficacy [66,67]. In most centers, carboplatin-based chemotherapy is considered the first choice for upfront therapy, given its more favorable toxicity profile compared with TPCV.
Some preliminary data suggest a possible role for vinblastine [68], bevacizumab [69], metronomic therapy [70], lenalidomide [71], and temozolomide [72] in patients who have progressed after other chemotherapy or RT. Since all of these studies were conducted in small groups of heterogenous low-grade glioma patients, more definitive clinical trials are required to assess their full activity and long-term toxicity.
Agents that target specific pathways in pediatric low-grade gliomas have also entered clinical trials. While early data are encouraging in selected populations [73], some therapies have resulted in stimulation rather than inhibition of tumor growth [74], emphasizing the complex signaling of pediatric low-grade gliomas [74,75]. These targeted inhibitors should therefore only be used in the context of prospective clinical trials.
Cyst expansion in pediatric low-grade gliomas can cause significant morbidity. In patients with enlarging cysts where the solid component of the tumor is stable, there is little evidence that systemic chemotherapy or radiotherapy is an optimal approach to control further cyst expansion. A number of approaches in which therapy to the cyst is provided through a reservoir have been developed; these include radioactive phosphorus (P32) [76], bleomycin [77], and interferon alfa [78].
Tectal tumors — Small tectal gliomas arising in the dorsal midbrain typically cause aqueductal obstruction, with symptoms of increased intracranial pressure (ICP) [13]. The initial treatment for tectal tumors is shunting the cerebrospinal fluid (CSF) with a ventriculoperitoneal (VP) drainage, or, preferably, third ventriculostomy [79]. The latter procedure avoids the implantation of a foreign object and can be performed as a day surgery [26,59,80-84].
The natural history of tectal gliomas is usually prolonged, and even modern neurosurgical methods may be associated with significant morbidity [85]. A biopsy is not needed unless atypical features are present, and many low-grade tectal gliomas can be observed initially without any intervention other than shunting [81,86-88]. Among tectal gliomas that have been sampled pathologically, most have histopathologic features similar to pilocytic astrocytoma. In a series including molecular analysis, evidence of BRAF fusion or BRAF V600E mutation was detected in 25 and 8 percent of tectal gliomas, respectively, with no tumor harboring a histone H3 K27M mutation [89].
A high percentage of patients who undergo shunting alone remain progression free without further therapy [26,81,83,86]. In a single-institution series of 46 children with tectal glioma over a 25-year period, 86 percent of patients required CSF diversion, 23 percent received RT, and 18 percent required systemic therapy [89]. Ten-year progression-free and overall survival were 49 and 84 percent, respectively.
Risk factors for progression of tectal gliomas include size greater than 10 cm3, contrast enhancement, and cystic changes at presentation [89-91].
Following relief of increased ICP, persistently symptomatic or progressively enlarging tumors should be treated with surgery (rarely possible), chemotherapy, or focal RT if chemotherapy is not possible [92]. Progression in very young children is managed with a trial of chemotherapy with the aim of stabilizing growth. (See 'Chemotherapy' above.)
Dorsal exophytic gliomas — The approach to dorsal exophytic gliomas relies upon surgical resection whenever possible. Safe resection generally requires intraoperative guidance to achieve a maximal degree of tumor resection. However, since many of these lesions arise from the floor of the fourth ventricle, there may not be a definite tumor-brainstem interface, and even an optimal resection can leave a small rind of tumor behind on the floor of the fourth ventricle.
Although resection is often incomplete, the majority of children do well long term. In two separate series, 12 of 16 and 7 of 10 patients undergoing surgery alone remained free of progression with median follow-up duration of 113 and 26 months, respectively [15,29]. In both series, recurrent tumors were subsequently controlled by reexcision, RT, or both.
Routine postoperative RT is not indicated and should only be considered for the rare patient with a high-grade lesion or for those with low-grade lesions who progress rapidly after initial resection [2]. Later recurrences can be managed with reresection, RT, or chemotherapy.
In addition to low-grade astrocytomas, gangliogliomas are observed in this region [93]. The diagnostic and therapeutic approaches to these tumors are similar to those used for low-grade astrocytoma. In addition, approximately 60 percent of gangliogliomas harbor the BRAF V600E mutation [94]. Clinical trials of targeted therapies are underway, but the signaling pathways regulating BRAF are complex, and tumor stimulation rather than inhibition of tumor growth has been observed with some targeted therapies in pediatric low-grade glioma, depending upon the underlying molecular abnormality [74]. (See "Uncommon brain tumors", section on 'Ganglioglioma and gangliocytoma'.)
Tumors of the medulla — Tumors that are intrinsic to the medulla, or at the level of the facial colliculus (located on the pontine floor of the fourth ventricle), are generally not approached surgically. At these locations, resection would be associated with unacceptable morbidity [2]. Thus, chemotherapy, or in adults RT, is the preferred approach.
Cervicomedullary tumors — These tumors are often considered tumors of the spinal cord and are treated similarly. (See "Spinal cord tumors", section on 'Astrocytomas'.)
Surgery is the treatment of choice, and a gross total resection can be achieved in approximately 75 percent of cases [95]. The probability of long-term survival is excellent for the typical low-grade lesion, and postoperative chemotherapy or RT is not indicated [23,96]. Lesions that recur or progress after surgery are treated with chemotherapy (in children) or radiotherapy (in adults). Since many gangliogliomas in this location harbor the BRAF V600E mutation, resection or biopsy may provide important genetic information to guide targeted therapy, if needed [97].
Cystic tumors — Some low-grade gliomas present with cystic components. In this situation, their biologic behavior may be independent of the solid component of the tumor. Accumulation of cyst fluid can produce neurologic dysfunction and symptoms, necessitating therapy.
Management of these cysts can be difficult. Primary therapy includes drainage. Approaches to treatment of reaccumulated fluid include repeated drainage, an attempt to remove the cyst wall, systemic chemotherapy for low-grade gliomas, focal RT, or occasionally intracavitary instillation of bleomycin [77,98] or interferon alfa [78].
PROGNOSIS — Long-term survival for children with brainstem low-grade gliomas approaches 100 percent in many series [35,99]. On the other hand, progression-free survival is approximately 40 to 70 percent [35,65,100,101], and chronic disability is common. This disability results from both treatment-related morbidity and tumor-related neurologic damage resulting from compression of the brainstem, long nerve tracts, and cranial nerves [14,15,95,102,103]. Molecular features have emerged as significant prognostic markers, including the identification of cyclin dependent kinase inhibitor 2A (CDKN2A) deletion as a high-risk feature [18,19].
Neurologic and cognitive outcome — Survivors of childhood central nervous system (CNS) tumors generally have some degree of neurocognitive deficit. The extent of the deficit primarily depends upon the age at the time of treatment and the dose of radiation. These complications are discussed elsewhere. (See "Overview of the management of central nervous system tumors in children", section on 'Long-term morbidity'.)
For survivors of focal brainstem tumors, the duration of symptoms at presentation and the severity of the tumor-associated disability are the most important variables in predicting long-term neurologic outcome [13-15,104]. Tumors that require placement of a ventriculoperitoneal (VP) shunt have added long-term morbidities associated with chronic catheter placement, including the risk of infection and the need for surgical revision of the shunt.
Survival is the most important long-term outcome, but other factors must be considered since most patients will survive for decades. With a number of other treatment options available, surgical efforts should be directed at confirming tumor biology; minimizing morbidity is the primary goal rather than complete tumor removal. Similarly, the delayed morbidity of radiation therapy (RT) supports the use of slightly less effective therapies (eg, chemotherapy) for which long-term morbidity is significantly less.
Treatment strategies must be individualized and consider physical, genetic, and cognitive factors. As an example, for some patients, particularly those with neurofibromatosis type 1, treatment may be deferred if tumor progression remains limited and asymptomatic. For most other patients, incompletely resected lesions will recur, and treatment should probably not be deferred.
Mounting evidence suggests that multidisciplinary evaluation of CNS tumor survivors is important. In addition to the physical and medical issues associated with therapy (eg, seizure control, physical and occupational rehabilitation), attention must be paid to cognition. Even patients receiving only surgery for a low-grade brainstem glioma can have significant functional impairment, indicating that all patients should be considered at risk [105]. To deal with these issues, psychologists, neuropsychologists, and school liaison specialists are needed. Since childhood is a fluid period of attainment of different abilities, age-appropriate performance at one time point does not ensure continued attainment of future milestones.
Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group [106].
BRAINSTEM GLIOMAS IN ADULTS — Brainstem gliomas are less common in adults than in children [88,107,108]. With the exception of dorsal midbrain (tectal) gliomas, their clinical behavior more closely resembles supratentorial gliomas in adults [88,107,109]. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas" and "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors" and "Treatment and prognosis of IDH-mutant astrocytomas in adults".)
Tectal gliomas are rare in adults, making up less than 10 percent of brainstem tumors. Patients may be asymptomatic, with the mass discovered incidentally, or they may present with secondary obstructive hydrocephalus. As in children, hydrocephalus is managed with ventriculoperitoneal (VP) shunting. Some patients require radiation therapy for progressive enlargement, while those who are asymptomatic are often observed with serial imaging. The natural history in adults is not well described, with median survival exceeding 10 years [107,110].
SUMMARY AND RECOMMENDATIONS
●Epidemiology and pathology – Focal brainstem gliomas are uncommon tumors typically seen in children. Most of these arise in the midbrain (image 1), medulla, or cervicomedullary junction (image 2). Pathologically, most are low-grade gliomas. (See 'Epidemiology' above and 'Pathology' above.)
●Neuroimaging – On MRI, focal low-grade brainstem gliomas most often appear as masses of limited size (<2 cm) that may be cystic, well demarcated, noninfiltrating, and without associated edema (image 2). Tectal gliomas have a distinct appearance, with uniform, nonenhancing thickening of the tectal plate (image 1). (See 'Diagnostic evaluation' above.)
●Diagnosis – Whenever possible, histologic diagnosis should be supplemented by molecular diagnostics, which can provide important diagnostic, prognostic, and therapeutic information. Molecular targeted therapy is being studied in ongoing clinical trials and represents a rapidly emerging treatment option for pediatric low-grade glioma patients. (See 'Molecular genetics' above.)
●Management
•Nontectal tumors – For patients with newly diagnosed focal brainstem gliomas other than tectal gliomas, we suggest surgical resection if this can be accomplished without excessive surgical morbidity (Grade 2C). (See 'Surgery' above.)
For patients with tumors that are unresectable or only partially resectable, radiation therapy (RT) offers an alternative to surgery. Because of the risk of delayed complications from RT, chemotherapy is warranted in order to avoid or delay radiation in children. (See 'Radiation therapy' above and 'Chemotherapy' above.)
•Tectal gliomas – For patients with small tectal gliomas arising in the dorsal midbrain, symptoms generally are due to increased intracranial pressure (ICP) from aqueductal obstruction. In this situation, shunting the cerebrospinal fluid (CSF) using a third ventriculostomy to relieve the hydrocephalus is required. Since the natural history of these lesions tends to be prolonged, we suggest that these patients be observed without any definitive intervention following shunting in the absence of evidence of progression (Grade 2C). (See 'Tectal tumors' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mark Kieran, MD, PhD, who contributed to an earlier version of this topic review.
