Brainstem Gliomas

Overview
Background

Brainstem gliomas are tumors that occur in the region of the brain referred to as the brain
stem, which is the area between the aqueduct of Sylvius and the fourth ventricle. Although
various systems are used to classify these tumors, the authors have divided brainstem gliomas
into 3 distinct anatomic locations—diffuse intrinsic pontine,[3] tectal, and cervicomedullary.
Intrinsic pontine gliomas carry a grave prognosis. Longer survival is associated with the
tectal and cervicomedullary gliomas. Tumors also are characterized on the basis of site of
origin, focality, direction and extent of tumor growth, degree of brainstem enlargement,
degree of exophytic growth, and presence or absence of cysts, necrosis, hemorrhage, and
hydrocephalus.[4]

Pathophysiology

These tumors have a predilection to originate from the left side. Most are located in the pons;
however, medulla and midbrain may be involved as well. Brainstem gliomas are highly
aggressive brain tumors. Anatomic location determines the pathophysiological manifestation
of the tumor. With tectal lesions, hydrocephalus may occur as a result of fourth ventricular
compression. With pontine and cervicomedullary lesions, cranial nerve or long tract signs are
observed commonly.

Histopathologically, brainstem gliomas can range from WHO Grade 1 to 4. Grade 1 is the
juvenile pilocytic astrocytoma, Grade 2 is the diffuse astrocytoma, Grade 3 is the anaplastic
astrocytoma, and grade 4 is the glioblastoma multiforme. The grading is based on the
presence of nuclear atypia, vascular proliferation, mitoses, and necrosis. Typically, the
necrosis is seen in Grade 4 (glioblastoma multiforme).

Molecular profiling is now an important part of glioma classification. An IDH1 mutation

carries an improved prognosis over the IDH1 wildtype, no matter what the tumor grade.
Codeletions of Chromosome 1p and 19q along with an IDH1 mutation indicates an
oligodendroglioma in Grade 1-3 gliomas. For pediatric diffuse gliomas, a newly defined
entity termed diffuse midline glioma, H3 K27M-mutant is characterized by K27M mutations
in the histone H3 gene, a diffuse growth pattern and a midline location. This newly defined
entity occurs primarilty in children, but can be seen in adults, and includes tumors previously
referred to as diffuse intrinsic pontine glioma (DIPG).[5]

Although biopsy or resection is not typically performed on brainstem gliomas, vascular

endothelial growth factor (VEGF) receptors are an important pathway in the invasion and
growth of supratentorial glioblastomas by promoting the growth of new blood vessels.
Epidermal growth factor receptors (EGFR) are present in 25% of glioblastomas and are
important in the growth of these neoplasms as well. The presence of these receptors may aid
in the response to various targeted therapies, as is discussed in Medical Care.
Frequency
United States

Brainstem gliomas have been reported to make up 2.4% of all intracranial tumors in adults
and 9.4% of intracranial tumors in children. Brainstem gliomas account for approximately
10-20% of all childhood brain tumors. The incidence in adults is lower than that in children
younger than 16 years. A tendency for brainstem gliomas to follow a more indolent course in
adults than in children has been noted; in adults, these tumors are more likely to be low grade
and remain localized.

Mortality/Morbidity

Morbidity is due to the location of the space-occupying lesion and compression of

surrounding structures; because these structures regulate basic body functions of blood
pressure, respiration, and swallowing as well as motor and sensory functions, compression
can produce substantial neurological disability.

Sudden death can result from increased intracranial pressure and subsequent cerebral
herniation. This may be a consequence either of edema induced by the tumor or of
hemorrhage into the neoplasm.

Epidemiology
Race-, sex-, and age-related demographics

CNS tumors vary in incidence by age, sex, ethnic group, and country, and also over time.
How much of this variation is due to artifactual influences or etiologic differences has been
the subject of many debates.

Some reports have suggested a slight male preponderance, whereas others have failed to
observe any sex predilection.

Bimodal age distribution has been noted, with a peak incidence in the latter half of the first
decade of life and a second peak in the fourth decade. Approximately three fourths of patients
are younger than 20 years.

Neoplasms of the brain stem have been identified in children younger than 1 year.

Presentation
History

Common presenting symptoms include double vision, weakness, unsteady gait, difficulty in
swallowing, dysarthria, headache, drowsiness, nausea, and vomiting. Rarely, behavioral
changes or seizures may be seen in children. Older children may have deterioration of
handwriting and speech.
Pontine lesions usually present with any or all of the above signs and symptoms, depending
on location and extension. Midbrain and lower brainstem/upper spinal cord signs and
symptoms may be seen with extension of the neoplasm to involve these structures.

In infants and children presenting with failure to thrive, pontine glioma should be considered
in the differential diagnosis.

Tectal lesions typically present with headache, nausea, and vomiting.

Hydrocephalus is a common presentation, especially for tumors in periaqueductal or fourth

ventricle outflow locations, because these regions have less tolerance of growth and higher
risk of obstructive hydrocephalus.

Cervicomedullary lesions usually present with dysphagia, unsteadiness, nasal speech,

vomiting, and weakness.

Physical

Common clinical findings can be summarized as constituting a triad of cranial nerve deficits,
long tract signs, and ataxia (of trunk and limbs). Papilledema may be seen.

Sixth and seventh cranial nerves are involved commonly. Facial sensory loss and a primary
position, upbeating nystagmus may be seen. Involvement of cranial nerve III or IV suggests a
mesencephalic component.

Tectal lesions may present with diplopia reflecting an internuclear ophthalmoplegia,

indicating involvement of the medial longitudinal fasciculus. Parinaud syndrome also may be
seen, with paralysis of upward gaze and accommodation, light-near dissociation (loss of
pupillary reflex to light with preservation of pupilloconstriction in response to convergence),
eyelid retraction, and convergence-retraction nystagmus.

Cervicomedullary lesions may present with sensory loss of the face (involvement of the
trigeminal nucleus), dysphagia and/or dysphonia from lower cranial nerve involvement
(commonly IX and X), long tract signs, and ataxia. Downbeating nystagmus and
oculomyoclonus often are seen with medullary involvement.

Causes

Although no familial tendency is prominent overall, an increased incidence of brainstem

glioma has been observed consistently in patients with neurofibromatosis (up to 14% in some
reports).

Thus far, no genetic or molecular markers have been recognized for brainstem gliomas.

In children irradiated for tinea capitis, an increased incidence of CNS tumors, especially
meningiomas, gliomas, and nerve sheath tumors, has been reported. No specific reference is
made in these reports to tumors of the brain stem. Radiotherapy-induced neoplasms tend to
be more aggressive in their natural history than their de novo counterparts.
Differential Diagnoses
 Brain Metastasis
 Glioblastoma Multiforme
 Low-Grade Astrocytoma
 Meningioma
 Neurosarcoidosis
 Pediatric Ependymoma
 Pediatric Medulloblastoma
 Tolosa-Hunt Syndrome
 Vascular Surgery for Arteriovenous Malformations

Workup
Laboratory Studies

Lab studies of blood chemistry and related body fluids are not helpful as a rule, though
cerebrospinal fluid (CSF) examination is often important for differential diagnosis. The
protein content of CSF may be elevated. Because of the risk of increased intracranial pressure
due to obstructive hydrocephalus, caution in clinical and imaging assessment prior to lumbar
puncture is stressed.

Imaging Studies
MRI

MRI of the head is the diagnostic test of choice. MRI can differentiate vascular
malformations and other processes that can be misdiagnosed as a brainstem glioma on CT
scan.[6]

The typical MRI appearance of a brainstem glioma is an expansile, infiltrative process with
low-to-normal signal intensity on T1-weighted images and heterogeneous high-signal
intensity on T2-weighted images, with or without contrast enhancement (see the images
below).

T2-weighted image of a diffuse intrinsic pontine glioma.

T2-weighted image of a right tectal glioma.

MR spectroscopy has been used to help distinguish between tumor and nontumor lesions in
the brain. An elevated choline peak suggests neoplasm.

MRI can delineate the extent of infiltration of the leptomeninges and the surrounding
structures.

High midbrain tumors, especially those arising in the tectum, are typically low-grade lesions
by histologic criteria. They commonly appear hypointense on T1 and hyperintense on T2
images even without contrast enhancement.

The occurrence of contrast enhancement in a tectal lesion should raise suspicion of a

metastatic lesion, especially in an adult, with or without a known history of cancer.

CT scan

Although CT imaging is an appropriate choice when MRI is not available, the appearance of
brainstem gliomas is variable on CT scan, and the sensitivity of and characterization of
tumors by CT are poorer.

CT identifies calcifications, cystic changes, and displacement of the ventricular system;

however, lower brainstem lesions are often not apparent on CT scan.

Other Tests

Arteriography occasionally is useful in differentiating vascular lesions, including tumors,

from gliomas.

Procedures

Typically, biopsy is not required for diagnosis of diffuse intrinsic pontine or tectal gliomas,
and cannot be recommended routinely; diagnosis can be made by MRI alone. Especially in
clinical trials, however, biopsy of diffuse intrinsic pontine gliomas can be used to ascertain
biological characteristics of the tumor, which may enhance understanding and targeting of
treatments.
Tissue confirmation is frequently not feasible with infiltrating, expansile tumors unless an
exophytic component exists. Even then, a biopsy cannot always be obtained.

Histologic Findings

The histopathology is variable; most gliomas in the brain stem are fibrillary, pilocytic
astrocytomas, or the more malignant glioblastoma multiforme. Hemorrhage and necrosis are
associated with the more malignant forms. Cysts may be seen with either the high- or low-
grade forms.

Treatment
Medical Care

Treatment of brainstem gliomas has been frustrating; at this point, new therapies have yielded
little benefit over conventional treatment with radiotherapy alone.

Adjuvant chemotherapy is not used in children because efficacy has not been proven. Data
have suggested that preradiation chemotherapy may improve survival in pediatric diffuse
intrinsic brainstem gliomas.[2] Its efficacy in adults is similarly unproven, and at present,
postradiotherapy adjuvant chemotherapy cannot be recommended. The effectiveness of
combined radiotherapy and chemotherapy (typically temozolomide) has not been thoroughly
evaluated. The effectiveness of chemotherapy at relapse is uncertain, but it may benefit some
patients.

Chemotherapy options, when considered for use in brainstem gliomas, may include
conventional agents such as temozolomide and carboplatin/vincristine. Antiangiogenesis
agents have been used with success in supratentorial glioblastomas. These include
thalidomide and bevacizumab. Bevacizumab is a VEGF receptor inhibitor, approved as
monotherapy for recurrent glioblastoma multiforme in May 2009.[7] Drugs (such as erlotinib)
targeted against EGFR, when present, have been modestly effective in supratentorial
glioblastoma. If chemotherapy is desired adjuvantly or concurrently with radiotherapy,
particularly in the pediatric population, the physician should consider entrance into a clinical
trial.

Focal radiotherapy is the cornerstone of treatment of brainstem gliomas and can improve or
stabilize the patient's condition.[1] The conventional dose of radiotherapy ranges from 54-60
Gy, with doses up to 72 Gy given with hyperfractionation. At present, no benefit has been
demonstrated with doses greater than 72 Gy; however, this therapy has not demonstrated
efficacy in children.

Response to radiotherapy, in addition to the dose of radiation, depends on several variables

such as tumor location, histologic type, and response to early treatment. Patients who
underwent radiation therapy for exophytic tumors have been reported to have better survival
rates than those treated for tumors without an exophytic component.

Radiotherapy should be administered to any patient with significant and progressive

neurologic symptoms. Some adult patients with a tectal or cervicomedullary lesion, or with
mild symptoms of long duration, may be candidates for observation alone; radiotherapy can
be reserved for patients with clear evidence of tumor progression.

Surgical Care

Surgical resection is performed in conjunction with radiation therapy, chemotherapy, or both.

Surgery is most appropriate in the following cases:

 Tumors of the cervicomedullary junction

 Dorsal exophytic tumors protruding into the fourth ventricle
 Cystic tumors
 Enhancing tumors with clear margins that exert a space-occupying effect
 Benign tumors (ie, those with slow clinical progression)

Typically, surgery is not required for treatment of diffuse intrinsic pontine gliomas or tectal
gliomas.

Ancillary Procedures

Patients with hydrocephalus may require ventriculostomy or ventriculoperitoneal shunting for

symptomatic relief.

Patients with difficulties in swallowing and diminished gag reflex may need feeding by
gastrostomy, such as percutaneous esophagogastrostomy (PEG).

Those patients who have had multiple upper respiratory infections, pneumonia, or altered
voice may need postoperative ventilatory assistance.

Consultations

Consultation with the following may prove helpful:

 Neuro-oncologist: The neuro-oncologist should be the primary physician supervising the care
of these patients. If a neuro-oncologist is not available, a medical oncologist with expertise
in treating brain tumors may be consulted for guidance. Otherwise, the patient should be
referred to a reputable institution that specializes in the care of patients with CNS
neoplasms.
 Neurosurgeon: The treating neurosurgeon should have significant experience in resection of
CNS neoplasms.
 Radiation oncologist
 Neuropathologist
 Neuroradiologist
 Neuropsychologist for pretreatment and posttreatment evaluations, when clinically
indicated
 Rehabilitation medicine specialist

Medication
Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Corticosteroids
Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic
effects. Corticosteroids modify the body's immune response to diverse stimuli.

Dexamethasone (Decadron)

Can be used to reduce tumor- and radiotherapy-associated cerebral edema.

Follow Up
Further Outpatient Care

Follow-up neuroimaging with MRI (unless contraindicated) is recommended within 72 hours

after surgery and every 2-3 months to monitor response to therapy and progression of disease.
This should be considered standard care for these patients.

Further Inpatient Care

Typically, patients are monitored for worsening signs/symptoms. Admission to the hospital
may be required to enable therapeutic intervention and stabilization.

Complications

Complications may include the following:

 Hydrocephalus, commonly obstructive

 Growth and developmental delay (in children)
 Cerebral herniation
 Deep cerebral vein thrombosis
 Paralysis/paresis
 Cranial nerve deficits
 Meningitis
 Radiation necrosis
 Hypopituitarism/hypothyroidism
 Bone marrow suppression
 Cognitive dysfunction

Prognosis

Pontine tumors are the most common variety of brainstem tumor. They also carry the worst
prognosis; in children, the median survival duration is 9-12 months even with treatment.
Kaplan et al reported a 37% survival rate at 1 year, 20% at 2 years, and 13% at 3 years, with a
median survival of 10 months. Only 9 of 119 patients in their study were alive for more than
3 years after diagnosis.[8]

Squires et al, in a study of 12 children with midbrain tectal tumors, reported a median
survival duration of more than 50 months.[9]

Favorable prognostic factors include (1) neurofibromatosis, (2) symptoms of at least 12

months' duration before diagnosis, (3) exophytic location, (4) pathology suggestive of low-
grade tumor histology, (5) focal tectal and cervicomedullary tumors, and (6) calcification on
CT scan.

Poor prognostic indicators include (1) age younger than 2 years, (2) multiple brainstem signs,
(3) cranial nerve palsies, (4) diffuse intrinsic lesions of the pons, (5) short duration of signs
and symptoms prior to the time of diagnosis, and (6) high-grade histology on tumor biopsy.

Hydrocephalus and tumor necrosis do not affect survival.

Race and gender do not affect survival.

The limited available data suggest that adults fare better than children with brainstem
gliomas.

 Grigsby et al reported a 10-year disease-free survival rate of 15.4% for adult patients with
gliomas involving the midbrain, thalamus, or hypothalamus, and 29.6% for adults with
pontine or medullary tumors. However, thalamic/hypothalamic neoplasms are not included
historically in the classification of brainstem tumors. [10]
 Landolfi et al studied 19 adults with brainstem gliomas, which included 13 diffuse intrinsic
pontine, 4 cervicomedullary, and 2 tectal gliomas. They noted a trend that higher Karnofsky
performance status conferred a better prognosis. Other factors did not affect survival.
Median survival duration of patients in this study was 54 months, with a 5-year survival rate
of 45%. [11]
 Hamilton et al studied 16 adults with focal midbrain gliomas; they reported a median
survival of 84 months. This indolent growth pattern is in marked contradistinction to the
natural history of this disease in children. This is also the reverse of the usual behavior of
hemispheric gliomas in which children typically fare better than older patients. [12]
 Kesari et al reported on 101 adult patients with brainstem glioma. The overall survival for all
patients at 5 and 10 years was 58% and 41%, respectively. The median survival was 85
months. They identified 4 factors that were significantly associated with survival in adults
with brainstem gliomas. These factors included ethnicity, tumor location, age at diagnosis,
and tumor grade. [13]
 No explanation has been identified for the better outcome in adults; however, the possibility
of prolonged survival with limited neurologic impairment must be recognized when
counseling adults with brainstem gliomas.

Patient Education

Patients and families of patients acquire information from multiple sources, including, but not
limited to, physician, patients, support groups, pharmaceutical companies, and the Internet.
Physicians should be aware of this and have an open, informative relationship with their
patients, empowering patients to become active members of the team with regard to the
decision-making process involving their care.

Hyperosmolar agents
Class Summary

These agents may reduce ICP and cerebral edema by creating an osmotic gradient across an
intact blood-brain barrier. As water diffuses from the brain into the intravascular
compartment, ICP decreases.

View full drug information

Mannitol (Osmitrol)

May reduce subarachnoid space pressure by creating osmotic gradient between cerebrospinal
fluid in arachnoid space and plasma. Not for long-term use.