Pediatrics

Brainstem Gliomas

OVERVIEW: What every practitioner needs to know

Are you sure your patient has diffuse intrinsic pontine glioma? What are the typical findings for this disease?

Brainstem gliomas are a heterogeneous group of tumors. The majority (80%) are diffusely infiltrating gliomas of the ventral pons (diffuse intrinsic pontine glioma [DIPG]), ranging in grade from World Health Organization (WHO) grade II–IV, and carrying a universally poor prognosis. In contrast, tumors arising in the dorsal pons, midbrain, or medulla are usually WHO grade I pilocytic astrocytomas or ganglioglimas with a markedly better prognosis.

The classic presentation is a brief (less than 1 month) history of cranial neuropathy, motor weakness, and incoordination. The child and her family will typically report one eye "turning in" and clumsiness and/or weakness. Examination typically reveals a sixth nerve palsy (unilaterally or bilaterally), pyramidal tract signs, and ataxia. Other brainstem tumors (such as focal, low-grade brainstem glioma) may present with some of these symptoms and signs, but usually not with this classic triad.

Headache is sometimes a presenting symptom of DIPG, particularly when the tumor has obstructed the fourth ventricle and caused hydrocephalus.

DIPG is typically limited to the brainstem at the time of diagnosis. At the time of recurrence/progression, disease is occasionally noted supratentorially. Rarely, leptomeningeal spread is observed. As a rule, the disease does not spread beyond the central nervous system.

How far does diffuse intrinsic pontine glioma spread?

DIPG is typically limited to the brainstem at the time of diagnosis. At the time of recurrence/progression, disease is occasionally noted supratentorially. Rarely, leptomeningeal spread is observed. As a rule, the disease does not spread beyond the central nervous system.

What other disease/condition shares some of these symptoms?

The differential diagnosis of a brainstem lesion, in addition to DIPG, includes focal brainstem tumors (ganglioglioma or pilocytic astrocytoma), brainstem primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumor, brainstem hemangioblastoma, inflammatory lesions such as those attributable to acute disseminated encephalomyelitis, and central pontine myelinolysis. Classic imaging characteristics of DIPG help to determine the diagnosis, and biopsy is reserved for atypical cases.

What caused this disease to develop at this time?

There are no known risk factors for DIPG. Recent research has indicated that DIPG arises from a primitive neural precursor cell present in the ventral pons during mid-childhood that appears to generate glial cells important in maturation of the nervous system. What goes wrong in this cell type to give rise to DIPG is an area of active research.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There are no laboratory studies that confirm the diagnosis.

Would imaging studies be helpful? If so, which ones?

Diagnosis of DIPG is typically made by magnetic resonance imaging (MRI) of the brain, with and without gadolinium. Neuroimaging reveals a diffusely enlarged ventral pons (“pregnant pons” on saggital view). MRI shows a lesion involving greater than two thirds of the pons that is dark on T1 imaging and bright on T2 imaging and minimally enhancing. Engulfment of the basilar artery is virtually pathopneumonic.

Focal brainstem gliomas, in contrast, appear more circumscribed, may enhance avidly, and are typically located outside of the ventral pons.

Confirming the diagnosis

Diagnosis is usually made by MRI imaging alone. Biopsy is currently reserved for cases with atypical clinical or imaging features when the diagnosis is in doubt. As progress is made toward defining molecular subtypes of DIPG, stereotactic biopsy may be increasingly used in the context of clinical trials for stratification to appropriate treatment arms.

If you are able to confirm that the patient has a brainstem glioma, what treatment should be initiated?

DIPG

Since brainstem gliomas are relatively uncommon and require complex management, children with such tumors deserve evaluation in a comprehensive cancer center, where the coordinated services of dedicated pediatric neurosurgeons, child neurologists, pediatric oncologists, radiation oncologists, neuropathologists, and neuroradiologists are available. In particular for DIPG, because of its rarity and poor prognosis, children and their families should be encouraged to participate in clinical trials attempting to improve survival with innovative therapy.

Radiation: Conventional radiotherapy, limited to the involved area of tumor, is the only intervention to date that has been demonstrated to increase survival. A total radiation dosage ranging from 5400 to 6000 cGy, administered in daily fractions of 150 to 200 cGy over 6 weeks, is standard. Hyperfractionated (twice daily) radiotherapy was used previously to deliver higher radiation doses, but such treatment did not lead to improved survival. Radiosurgery (e.g., gamma knife, Cyberknife) has no role in the treatment of DIPG.

Reirradiation at the time of recurrence/progression is sometimes performed, but evidence for this is currently at the case report level.

Surgery: Surgical resection of the lesion is not possible, as the tumor is intrinsic to the pons and diffusely intertwined with normal brainstem tissue. Surgical intervention to treat obstructive hydrocephalus (shunt or third ventriculostomy) is required in less than half of cases.

Chemotherapy: Extensive efforts to identify a useful chemotherapeutic strategy for DIPG have thus far failed to extend survival. Conventional chemotherapies, high-dose chemotherapy with autologous bone marrow transplant or peripheral blood stem cell rescue, immunotherapy with beta-interferon and targeted therapies against angiogenesis (e.g., bevacizumab) or cell signaling pathways (e.g., imatinib) have all been disappointing.

Agents such as temozolomide, demonstrating efficacy in adult high-grade gliomas, have not been useful in DIPG. Trials using epidermal growth factor (EGF) pathway inhibitors have shown a glimmer of effect in a subset of patients but have not significantly improved the median survival.

A number of novel therapies are currently under phase I investigation. A therapeutic strategy using a combinatorial approach to target multiple molecular pathways will likely be needed, but such a treatment protocol is still in the preclinical stages.

Steroids: Corticosteroids (e.g., dexamethasone) should be used sparingly! Steroids are useful to reduce brainstem swelling acutely and should be reserved for symptomatic edema. Steroids are often required during radiotherapy, but should be discontinued as soon as possible. Steroids should never be given prophylactically.

Supportive care: Ultimately, the vast majority of children with DIPG require palliative care services. Hospice nursing care in the home is the preference of most families. Involving in-home nursing services early can provide the family and child with much needed support.

Focal Brainstem Gliomas

Treatment: Focal brainstem gliomas are surgically resected to the extent possible. When residual tumor demonstrates evidence of progression, chemotherapy such as carboplatin/vincristine, procarbizine/CCNU/vincristine, bevacizumab, or temozolomide may be useful. In children younger than 3 years, chemotherapy may be preferable to radiotherapy because of the deleterious effects of radiation on the developing brain. Use of steroids should be minimized.

Supportive care: Physical and/or occupational therapy and/or speech therapy should be initiated early to facilitate rehabilitation of neurologic deficits attributable to the tumor.

What are the adverse effects associated with each treatment option?

Focal radiation therapy can cause transient edema that may exacerbate clinical symptoms temporarily.

Corticosteroids can cause weight gain, mood changes, fluid retention, glucose instability, increased risk of infection, and high blood pressure.

What are the possible outcomes of brainstem gliomas?

DIPG: The prognosis for DIPG is abysmal. The median survival is 9 months. The 5-year survival is reported as 1%, although that still may be an overestimate.

Focal brainstem gliomas: As noted above, focal brainstem gliomas are typically WHO grade I, relatively indolent tumors that are frequently amenable to surgical resection. Prognosis is very good, with a 5-year overall survival approaching 90%.

What causes this disease and how frequent is it?

DIPG is the second most common malignant brain tumor in children, accounting for about 10% of all pediatric brain tumors. It is the leading cause of brain cancer–related death. There are probably about 400 new cases of DIPG each year in the United States. (A frequently quoted number of 150 cases/year in the United States is an underestimation.) DIPG occurs in school-aged children, peaking in incidence at age 6.8 years. DIPG is extremely rare in infants and adults.

Focal brainstem tumors account for 20% of brainstem gliomas, or 3% of all childhood brain tumors. In contrast to DIPG, focal brainstem glioma is not as specific to the middle childhood period and can be seen in infants.

How can brainstem glioma be prevented?

There is no known prevention for brainstem glioma.

What is the evidence?

Fisher, PG, Breiter, SN, Carson, BS. "A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities". Cancer. vol. 89. 2000. pp. 1569-76.

Donaldson, SS, Laningham, F, Fisher, PG. "Advances toward an understanding of brainstem gliomas". J Clin Oncol. vol. 24. 2006. pp. 1266-72.

Pollack, IF, Shultz, B, Mulvihill, JJ. "The management of brainstem gliomas in patients with neurofibromatosis 1". Neurology. vol. 46. 1996. pp. 1652-60.

Jennings, MT, Sposto, R, Boyett, JM. "Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children's Cancer Group". J Clin Oncol. vol. 20. 2002. pp. 3431-7.

Pollack, IF, Jakacki, RI, Blaney, SM. "Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report". Neuro Oncol. vol. 9. 2007. pp. 145-60.

Pollack, IF, Stewart, CF, Kocak, M. "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. vol. 13. 2011. pp. 290-7.

Hargrave, D, Bartels, U, Bouffet, E. "Diffuse brainstem glioma in children: critical review of clinical trials". Lancet Oncol. vol. 7. 2006. pp. 241-8.

Ronghe, M, Hargrave, D, Bartels, U. "Vincristine and carboplatin chemotherapy for unresectable and/or recurrent low-grade astrocytoma of the brainstem". Pediatr Blood Cancer. vol. 55. 2010. pp. 471-7.

Geoerger, B, Hargrave, D, Thomas, F. "Innovative Therapies for Children with Cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors". Neuro Oncol. vol. 13. 2011. pp. 109-18.

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