Brainstem Gliomas

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, many 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]

Approximately 60% of brainstem gliomas are centered within the pons, but can originate in the medulla or midbrain and may extend beyond the brainstem. 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 classified as juvenile pilocytic astrocytoma, Grade 2 is diffuse astrocytoma, Grade 3 is anaplastic astrocytoma, and grade 4 is glioblastoma. The grading is based on the presence of nuclear atypia, vascular proliferation, mitoses, and necrosis. Typically, necrosis is seen in Grade 4 (glioblastoma multiforme). Increasing tumor grade is associated with poorer prognosis.

Molecular profiling is now an important part of glioma classification. An IDH1 mutation carries a significantly improved prognosis over the IDH1 wildtype, no matter the tumor grade. Codeletions of chromosome 1p and 19q along with an IDH1 mutation indicates an oligodendroglioma, and is rarely found in brainstem 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]  MGMT promoter methylation has not been well studied in brainstem gliomas, however, one series suggested that more than 60% of brainstem gliomas are unmethylated.[6]

Mutations in the histone H3 gene suggest epigenetic dysregulation as an important contributor to the pathogenesis of diffuse intrinsic pontine glioma, particularly in children. Notably, histone H3 mutations rarely occur in adult patients with supratentorial glioblastoma.

Morbidity from brainstem gliomas occur 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.

Pediatric diffuse intrinsic pontine glioma (DIPG) is associated with a dismal prognosis of approximately 10 months with only 10% of patients living > 2 years beyond initial diagnosis. However, median survival for adult patients with brainstem gliomas is in the range of 30–40 months.[2]  Because presentation in adults varies widely, prognostication can be difficult. Other factors that have been shown to negatively influence survival include contrast enhancement within the tumor on MRI, location within the brainstem (pons > medulla > midbrain), and advanced age (> 60 years).[2, 7]

Frequency

Brainstem gliomas represent < 2% of all intracranial tumors in adults and approximately 20% of brain tumors in children, with a slight male predominance. Median age at diagnosis in adults is in the mid-30s, but can present at any age. Brainstem gliomas are uncommon in adults and account for only 1%–2% of intracranial gliomas.[8]

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.

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.[9]

Squires et al, in a study of 12 children with midbrain tectal tumors, reported a median survival duration of more than 50 months.[10]

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.[11]

• 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%.[12]

• 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.[13]

• 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.[14]

• 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.

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.

Common presenting symptoms of brainstem gliomas 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.

Common clinical findings in brainstem gliomas 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.

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).

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.

Complications of brainstem gliomas 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

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.

MRI

MRI of the head is the diagnostic test of choice for brainstem gliomas. MRI can differentiate vascular malformations and other processes that can be misdiagnosed as a brainstem glioma on CT scan.[15]

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. Contrast enhancement may be seen in only up to 40% of adult patients.

Axial T2 FLAIR image showing a pontine-centered lesion consistent with a brainstem glioma.

Axial T2 image showing a pontine mass consistent with brainstem glioma.

MR spectroscopy can be useful to distinguish between tumor and non-neoplastic lesions in the brain. An elevation of the choline/NAA ratio suggests neoplasm.

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.

PET-CT is rarely used, but may be helpful in differentiating aggresive lesions from indolent ones.

Arteriography occasionally is useful in differentiating vascular lesions, including tumors, from gliomas.

While not required for diagnosis, biopsy should be considered in all patients where obtaining tissue is safe and feasible. This allows for histologic classification, and more importantly, molecular testing, which may aid in prognosis. Further, this may have therapeutic implications as our understanding of the pathophysiology is evolving and may allow for enrollment into clinical trials.

Treatment of brainstem gliomas has been frustrating. To date, most trials (particularly in the pediatric population) have failed to show a significant benefit to any systemic agent beyond radiotherapy.

Adjuvant chemotherapy is not often used in children because efficacy has not been proven. Data have suggested that preradiation chemotherapy may improve survival in pediatric diffuse intrinsic brainstem gliomas.[16]  The effectiveness of combined radiotherapy and chemotherapy has not been exstensively evaluated in adults. However, retrospective data suggest that upfront temozolomide along with radiation may improve survival in adult patients.[2] 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 such as bevacizumab have been used with varying success in supratentorial glioblastomas, however, their role in brainstem gliomas is less clear. Small studies have suggested that a small number of patients may benefit in the shortmterm, but the outcomes are worse than for supratentorial gliomas.[2]  Patients and families should be encouraged to enroll on clinical trials whenever possible.

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 to 60 Gy, and is considered standard upfront therapy. 

Response to radiotherapy 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 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)

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.

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.

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: Physicians with expertise in central nervous sytem radiation should be consulted, when available.

• Neuropathologist

• Neuroradiologist

• Neuropsychologist for pretreatment and posttreatment evaluations, when clinically indicated

• Rehabilitation medicine specialist

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.

Temozolomide (Temodar)