OVERVIEW: What every practitioner needs to know
Are you sure your patient has high-grade astrocytomas? What are the typical findings for this disease?
High-grade gliomas (HGG), also referred to as “malignant gliomas,” represent highly aggressive tumors that arise throughout the neuraxis, but most commonly in the supratentorial compartment of the central nervous system (CNS). The HGGs that occur in children most frequently are glioblastoma (World Health Organization [WHO]) grade IV) and anaplastic astrocytoma (WHO grade III).
Diffuse intrinsic pontine glioma (DIPG) has historically been considered a HGG, yet there is some debate regarding this designation. Accordingly, DIPG will be discussed in an independent chapter with other brainstem tumors, given its distinguishing location/presentation, clinical behavior, and biology. Rare HGG histological entities include gliomatosis cerebri, anaplastic oligodendroglioma and gliosarcoma with only the former noted, albeit rarely, in the older pediatric population.
HGG is most commonly unilateral, involving one of the cerebral hemispheres, sometimes cortical but also found deeper, involving the thalami. Spread from one hemisphere to the other across commissures is not uncommon. Unlike the insidious onset of indolent low-grade gliomas, patients with HGGs develop symptoms in a much shorter course, and a small percentage of patients present abruptly in extremis from intratumoral hemorrhage. Otherwise, symptoms of increased intracranial pressure resulting from obstruction of cerebrospinal fluid (CSF) flow (e.g., headache, vomiting, papilledema, ataxia) and / or focal neurological deficit are the norm. The latter are dictated by the specific area(s) involved and may manifest as changes in strength, sensation, speech and language, and cognition. Thus, on physical exam, one might encounter findings ranging from decreased sensorium or deficits on mental status exam to more focal decreases in strength and/or coordination, sensation and general or focal hyperreflexia.
HGG is currently a tissue diagnosis (with the exception of DIPG); therefore, the certainty of the diagnosis comes only after careful review of the surgical specimen / biopsy by a trained neuropathologist. However, radiologic features can hint at a diagnosis of HGG. In particular, glioblastomas appear on MRI as irregular masses displaying signal heterogeneity and post-contrast ring enhancement surrounding a necrotic core. There are often signs of recent and remote hemorrhage, and vasogenic edema that can be impressive and add significantly to the mass effect. However, other high-grade intracranial tumors and even lower grade lesions such as pleomorphic xanthoastrocytoma can have a similar appearance to glioblastoma.
What other disease/condition shares some of these symptoms?
Any brain lesion that results in an obstruction of CSF outflow and increased intracranial pressure can cause symptoms similar to that of HGG. Other disease processes to consider which result in a ring-enhancing mass lesion on MRI include infectious lesions (bacterial, fungal or parasitic), especially in case of fever or immune incompetence (toxoplasmosis).
Other primary brain tumors, such as supratentorial PNET, low-grade gliomas and non-CNS neoplastic processes, such as metastases to the brain, can share these symptoms (although rare in children). The more diffusely and infiltrative appearance of gliomatosis cerebri can mimic (or be mimicked by) leukoencephalopathic and neuroinflammatory processes or by other non-CNS neoplastic processes, such as CNS lymphoma.
What caused this disease to develop at this time?
The cause for the vast majority of glioblastomas is unknown. However, several inherited conditions are associated with an increased incidence of HGG. These include neurofibromatosis Type 1, Turcot / colonic polyposis syndrome (especially those resulting from deficiency of mismatch repair genes), and Li-Fraumeni syndrome (caused by mutations in the P53 gene). Nonetheless, development of HGGs in these conditions is still rare, and individuals with these syndromes are more likely to develop other forms of tumors / cancer.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Confirmation of HGG and the specific type of HGG comes only after histopathological review of the biopsy / surgical specimen. As mentioned, certain characteristics suggestive of HGG can be seen on neuroimaging and MRI of the brain with and without gadolinium, which is the current standard. Spinal MRI should also be obtained at some point to survey for disseminated disease; however, HGGs prefer to invade surrounding parenchymal structures rather than seed extra-axial spaces. Leptomeningeal dissemination is rare in comparison to embryonal tumors such as supratentorial PNET and medulloblastoma.
Would imaging studies be helpful? If so, which ones?
If there is any clinical suspicion for raised intracranial pressure, rapid imaging via head computed tomography (CT) is necessary to evaluate for evidence of impending herniation to inform the need for urgent neurosurgical evaluation / intervention. Otherwise, brain and spine MRI with and without gadolinium contrast is required during the initial evaluation as well as non-urgent MRI of the entire spine for staging purposes.
It is rare for primary brain tumors in children to have metastases outside the CNS at presentation; thus, radiographic evaluations of the body are unnecessary unless the patient’s clinical presentation warrants otherwise.
Confirming the diagnosis
Currently, there are no clinical decision algorithms established to help differentiate a diagnosis of HGG from another intracranial neoplasms or disease processes at the time of clinical presentation. Accordingly, involvement of neurosurgical colleagues should be initiated early in the course upon suspicion of HGG. Once surgical resection (gross total if possible) and/or biopsy is achieved, neuropathological review can confirm the diagnosis.
In addition, a central, multidisciplinary review (‘Tumor Board’) of the clinical, radiographic, and pathological data from newly diagnosed patients and patients with recurrent tumors is often the routine at larger pediatric brain tumor centers. Request by families and / or practitioners for outside review at such conferences is common, especially if there is unclear histology or a complicated management decision.
If you are able to confirm that the patient has high-grade astrocytomas, what treatment should be initiated?
The standard of care is continually evolving for pediatric HGG patients. Unfortunately, very few treatments to date have resulted in durable response and long-term survival for patients. Currently, therapy is multimodal and involves maximal surgical resection followed by radiotherapy (5400 cGy) to the tumor bed with concomitant adjuvant chemotherapy, most commonly in the form of temozolomide.
In children less than 3 years of age, radiotherapy is especially toxic and results in lifelong neurological disability. Therefore, radiotherapy is often delayed or obviated by a more aggressive chemotherapy regimen. Current evidence suggests better overall survival in infants with HGG as a whole. Moreover, recent studies from large clinical trial cohorts have established that: 1) intensive chemotherapy concomitant with and after radiotherapy for patients with fully resected tumors may improve overall survival for pediatric HGG patients compared with historical controls, and 2) high-dose methotrexate may show some promise in improving survival.
New therapeutic targets are also rapidly being identified from ongoing molecular studies of HGG. Importantly, these studies show that although there are some molecular characteristics shared by pediatric and adult HGGs, significant differences also exist. Thus, treatment algorithms established for managing adult HGGs cannot simply be extrapolated to the pediatric population. For example, epidermal growth factor receptor (EGFR) amplifications commonly seen in adult HGGs are a much smaller percentage of pediatric HGG, while activation of the platelet-derived growth factor receptor (PDGFR) signaling pathway is more prevalent in pediatric HGGs. There are currently clinical trials enrolling patients for treatment with inhibitors to both of these receptor tyrosine kinases as well as other molecular targets.
What are the adverse effects associated with each treatment option?
Although gross total resection of the tumor has been shown in multiple large studies to represent the most significant predictor of overall survival in HGG, most patients present with extensive and infiltrative tumors involving sensitive regions of the brain that preclude full resection. Thus, radical resection of a child’s tumor must be tempered by potential neurological and neurocognitive consequences.
Adverse effects of radiation therapy can be broadly categorized into acute, subacute, and late effects. Acute symptoms include nausea, vomiting, skin irritation / breakdown at the site of therapy, and alopecia. Subacute symptoms include decreased appetite and energy levels / somnolence. Late effects include cognitive decline, which in younger patients is characterized by frank loss of intelligence and in older individuals, problems with memory, concentration and executive functioning. These effects are particularly evident in patients who require whole brain or whole ventricle radiation fields. Secondary malignancy or stroke are other late effects that can occur anywhere along the treatment field even decades out from treatment.
The most common chemotherapy regimen used to treat children (and adults) with HGG is temozolomide. In addition to myelosuppression, the most common adverse effects are nausea and vomiting. Almost all other cytotoxic chemotherapy agents acutely cause alopecia, nausea and vomiting, pancytopenia, and loss of appetite and weight. Etoposide has been associated with the development of acute myelogenous leukemia as a secondary malignancy. The side effect profiles for targeted agents such as tyrosine kinase inhibitors vary.
What are the possible outcomes of high-grade astrocytomas?
Long-term survival for children diagnosed with HGG continues to be a challenge. In a large North American series, the overall survival rates for HGG in children ranged from 10%-30% at 5 years. Patients with Grade III tumors (anaplastic astrocytoma) had higher an overall survival rate of ~27% at 5 years (compared to 4% for patients with Grade IV glioblastomas). Infants appeared to have better overall survival than older children and adults.
As mentioned, gross total resection was identified as the strongest predictor of survival in children with HGG. For well-demarcated tumors with clearly resectable margins, gross total resection is the priority. However, patients often present with extensive and infiltrative tumors involving sensitive regions of the brain, making gross total resection impossible. In these cases, the goal is to remove as much of the tumor as possible while preserving neurological and neurocognitive functions.
There are currently ongoing efforts to identify molecular markers that are useful as prognostic indicators in pediatric HGG. As in adult HGG, evidence for MGMT promoter methylation in pediatric HGGs has been identified and associated with prolonged survival and responsiveness to temozolomide. A marker for poor prognosis has been P53 immunopositivity and P53 gene mutation. IDH1 gene mutations, first described in adult glioblastoma patients who had longer survival, have been identified in adolescent patients with HGG as well. IDH1 mutations do not occur in younger children, and the association with improved outcome in a pediatric series has not yet been substantiated.
What causes this disease and how frequent is it?
The cause for the vast majority of glioblastoma is unknown.
Although HGGs, namely glioblastoma, are the most common type of primary brain tumor in adults, they represent only ~5%-10% of childhood brain tumors. They occur in only ~2 cases per million children / year.
Several inherited conditions are associated with an increased incidence of HGG. These include neurofibromatosis Type 1, Turcot / colonic polyposis syndrome (especially those resulting from deficiency of mismatch repair genes), and Li-Fraumeni syndrome (caused by mutations in the P53 gene). Nonetheless, development of HGGs in these conditions is still rare, and individuals with these syndromes are more likely to develop other forms of tumors / cancer.
Cranial irradiation may cause glioblastoma or gliosarcoma years after exposure to radiation.
How do these pathogens/genes/exposures cause the disease?
Again, glioblastomas have been reported in patients with iatrogenic exposure to ionizing radiation (eg., as prior treatment for brain tumor or cancer). This is a rare occurrence, however.
What complications might you expect from the disease or treatment of the disease?
Other late effects of chemotherapy are well detailed in the Children’s Oncology Group Long-Term Survivorship Follow-Up Guidelines at www.survivorshipguidelines.org
Are additional laboratory studies available; even some that are not widely available?
Genomic or molecular profiling of pediatric glioblastomas is not yet mandated, nor would it currently have any direct impact on treatment decisions. However, consent by patients/families to submit such materials as part of a research study is highly recommended as it will enable the development of more effective and more targeted treatment strategies in the future.
How can high-grade astrocytomas be prevented?
No preventive measures exist for these aggressive cancers.
What is the evidence?
Broniscer, A, Chintagumpala, M, Fouladi, M. “Temozolomide after radiotherapy for newly diagnosed high-grade glioma and unfavorable low-grade glioma in children”. J Neurooncol. vol. 76. 2006. pp. 313-9. (Multi-institutional study evaluating effectiveness of temozolamide following radiotherapy showing no alteration of overall outcome, unlike adult glioblastoma.)
“CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2005”. . (Registry publishing the incidence and prevalence of brain tumors in the United States with breakdown by diagnosis and demographics.)
(Website providing information on cancer survivorship.)
Donson, AM, Addo-Yobo, SO, Handler, MH. “MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma”. Pediatr Blood Cancer. vol. 48. 2007. pp. 403-7. (Study attempts to identify whether, as in adult glioblastomas, childhood glioblastomas that have MGMT promoter methylation portend response to temozolamide.)
Ganigi, PM, Santosh, V, Anandh, B. “Expression of p53, EGFR, pRb and bcl-2 proteins in pediatric glioblastoma multiforme: a study of 54 patients”. Pediatr Neurosurg. vol. 41. 2005. pp. 292-9. (Retrospective analysis of 54 pediatric glioblastomas for prevalence of expression of EGFR, BCL2, pRB and p53 by immunohistochemistry; revealed expression of p53 in approximately half the tumors and expression of EGFR and BCL2 in a quarter and a third of tumors, respectively.)
Lee, JY, Park, CK, Park, SH. “MGMT promoter gene methylation in pediatric glioblastoma: analysis using MS-MLPA”. Childs Nerv Syst. vol. 27. 2011. pp. 1877-83. (Analysis of 19 pediatric glioblastomas for prevalence of MGMT promoter methylation; revealed that only 3/19 (16%) had MGMT promoter methylation.)
Louis, DN, Ohgaki, H, Wiestler, OD. “The 2007 WHO classification of tumours of the central nervous system”. Acta Neuropathol. vol. 114. 2007. pp. 97-109. (Catalog/reference of histopathological descriptions of brain and central nervous system tumors.)
Parsons, DW, Jones, S, Zhang, X. “An integrated genomic analysis of human glioblastoma multiforme”. Science. vol. 321. 2008. pp. 1807-12. (Seminal description of large-scale sequencing of glioblastoma, revealing novel mutations in IDH1 in adult glioblastomas.)
Paugh, BS, Qu, C, Jones, C. “Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease”. J Clin Oncol. vol. 28. 2010. pp. 3061-8. (Analysis of 78 pediatric high grade gliomas by gene expression and copy number analysis, which highlighted differences between pediatric and adult forms of this disease.)
Qaddoumi, I, Sultan, I, Gajjar, A. “Outcome and prognostic features in pediatric gliomas: a review of 6212 cases from the Surveillance, Epidemiology, and End Results database”. Cancer. vol. 115. 2009. pp. 5761-70.
Sanders, RP, Kocak, M, Burger, PC. “High-grade astrocytoma in very young children”. Pediatr Blood Cancer. vol. 49. 2007. pp. 888-93. (Retrospective analysis of The Surveillance, Epidemiology, and End Results (SEER) database.)
Wolff, JE, Driever, PH, Erdlenbruch, B. “Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol”. Cancer. vol. 116. 2010. pp. 705-12. (Study of intensified chemotherapy following fractionated radiotherapy in pediatric high grade glioma, comparing results from previous studies.)
Wolff, JE, Kortmann, RD, Wolff, B. “High dose methotrexate for pediatric high grade glioma: results of the HIT-GBM-D pilot study”. J Neurooncol. vol. 102. 2011. pp. 433-42. (Phase II study of methotrexate prior to radiotherapy followed by multiagent chemotherapy, with results compared to previous studies. )
Sturm, D, Witt, H, Hovestadt, V. “Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma”. Cancer Cell. vol. 22. 2012. pp. 425-37. (Genomic analysis of pediatric glioblastoma identifying distinct molecular subgroups of disease based on global DNA methylation patterns, hotspot mutations, DNA copy-number alterations, and transcriptomic patterns; this study enables the development of novel treatment strategies and more refined molecular stratification of pediatric high grade gliomas.)
Schwartzentruber, J, Korshunov, A, Liu, XY. “Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma”. Nature. vol. 482. 2012. pp. 226-31. (Landmark paper reporting on next-generation sequencing analysis of pediatric glioblastomas; identified high prevalence of novel mutations in H3F3A and ATRX in pediatric glioblastoma.)
Ongoing controversies regarding etiology, diagnosis, treatment
There have been recent discussions in the lay press regarding cell phone use as a cause of brain tumors. To date, there has been no substantive data to support this association. No environmental risk factors have been identified as causative of HGG.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has high-grade astrocytomas? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
- If you are able to confirm that the patient has high-grade astrocytomas, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of high-grade astrocytomas?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can high-grade astrocytomas be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment