Many gliomas infiltrate brain tissue diffusely and irregularly.
Astrocytomas are the most common gliomas. They are classified histologically and, in some cases, based on the presence of specific genetic markers, according to the World Health Organization (WHO) classification (1).
In ascending order of malignancy, astrocytomas are classified as
Grade I: Pilocytic astrocytomas and subependymal giant cell astrocytomas (most common in tuberous sclerosis)
Grade II: Low-grade astrocytomas, including pleomorphic xanthoastrocytoma
Grade III: Anaplastic astrocytomas
Grade IV: Glioblastomas and diffuse midline gliomas
Pilocytic, other low-grade, or anaplastic astrocytomas tend to develop in younger patients. Anaplastic astrocytomas, in particular, can later evolve into glioblastomas (called secondary glioblastomas). Glioblastomas can also develop de novo (called primary glioblastomas), usually in middle-aged or older people. Glioblastomas contain chromosomally heterogeneous cells. Both primary and secondary glioblastomas have distinct genetic characteristics, which can change as the tumors evolve. Secondary glioblastomas typically have mutations in the IDH1 or IDH2 genes.
Rarely, astrocytomas contain astrocytoma and oligodendroglioma cells. These tumors used to be designated oligoastrocytomas; however, that term is no longer used to refer to a single tumor type but rather to a mixed neoplasm.
Oligodendrogliomas (WHO grade II) are among the slowest-growing gliomas. They are most common in the forebrain, particularly the frontal lobes. Oligodendrogliomas are typically characterized by deletion of the p arm of chromosome 1 and the q arm of chromosome 19 (1p/19q codeletion). These deletions are diagnostic for oligodendroglial tumors, predict longer survival, and predict a better response to radiation therapy and chemotherapy. Like astrocytomas, oligodendrogliomas can evolve into more aggressive forms, such as anaplastic oligodendrogliomas (WHO grade III), which are managed accordingly.
Both astrocytomas and oligodendrogliomas may express mutations of the IDH1 or IDH2 genes that result in the abnormal production of 2-hydroxyglutarate; this metabolite can modify DNA methylation of normal neural and glial progenitor cells causing them to produce neoplastic glioma cells. Patients with the IDH1/2 mutation tend to have a better prognosis than those with IDH1/2 wild-type tumors, partly because patients have a better response to alkylating chemotherapy such as temozolomide. Oligodendrogliomas tend to have the 1p/19q-codeletion and IDH1/2 mutation. Astrocytomas typically have the IDH1/2 mutation but not the 1p/19q codeletion; instead, they more typically express mutations or loss of the ATRX gene and mutations in pTP53 (2).
Diffuse midline gliomas are high-grade (WHO grade III to IV) astrocytic tumors that primarily affect children. These tumors include diffuse intrinsic pontine gliomas, which are aggressive and typically lethal tumors that infiltrate the brain stem with rostral extension into the hypothalamus and thalamus and that infiltrate the medulla and spinal cord inferiorly. Children with neurofibromatosis type 1 are at an increased risk of developing these tumors.
Ependymomas occur primarily in children and young adults; they are uncommon after adolescence. They are classified as
All ependymomas typically arise from the ventricular wall and hence may arise in the brain, brain stem, or spinal cord. As such, they are classified based on location: as supratentorial, posterior fossa, or spinal cord. Each of these categories includes 3 molecularly and histologically defined subsets, resulting in 9 types of phenotypically and molecularly distinct ependymomas, whose treatment and prognosis differ significantly from one another. Ependymomas of the 4th ventricle in particular can manifest with obstructive hydrocephalus and may therefore manifest earlier than other ependymomas (3).
1. Louis DN, Perry A, Reifenberger G, et al: The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol 131 (6):803–820, 2016. doi: 10.1007/s00401-016-1545-1
2. Reifenberger G, Wirsing H, Knobbe-Thomsen CB, Weller M: Advances in the molecular genetics of gliomas - implications for classification and therapy. Nat Rev Clin Oncol 14 (7):434-452 2017. doi: 10.1038/nrclinonc.2016.204
3. Pajtler K, Mack S, Ramaswamy V, et al: The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Neuropathologica 133:5–12, 2017. https://doi.org/10.1007/s00401-016-1643-0
Diagnosis of gliomas is based primarily on MRI, including both standard T1- and T2-weighted imaging, preferably with gadolinium enhancement, followed by biopsy with histopathology and molecular profiling. Histopathology includes classical pathologic analysis of cellular morphology, immunohistochemical stains (eg, for IDH1/2 mutations), and in situ hybridization (eg, for EGFR mutations). Depending on results of generation sequencing of DNA, selected oncogene panels, targeted or whole-exome sequencing, RNA sequencing, and/or methylation analysis may be done.
Treatment involves surgery, radiation therapy, and chemotherapy to reduce tumor mass. Safely excising as much tumor as possible (without unduly damaging areas of eloquent brain) prolongs survival and improves neurologic function.
After surgery, patients receive a full tumor dose of radiation therapy (60 Gy over 6 weeks); ideally, conformal radiation therapy, which targets the tumor and spares normal brain tissue, is used.
For glioblastomas, chemotherapy with temozolomide is now routinely given with radiation therapy. The dose is
During treatment with temozolomide, trimethoprim/sulfamethoxazole 800 mg/160 mg is given 3 times a week to prevent Pneumocystis jirovecii pneumonia.
Patients receiving chemotherapy require a complete blood count (CBC) at varying intervals.
Implantation of chemotherapy wafers during surgical resection may be appropriate for some patients.
Use of tumor-treating fields plus adjuvant temozolomide may be appropriate for some patients. Tumor-treating fields interfere with glioblastoma mitosis and organelle assembly by delivering alternating electric fields to the scalp. In one randomized clinical trial, tumor-treating fields appeared to improve survival in patients with glioblastoma (1).
Investigational therapies (eg, stereotactic radiosurgery, new chemotherapeutic drugs, gene or immune therapy) should also be considered. Clinical trials of numerous immune checkpoint inhibitors, in particular of CTLA4- and PD1-dependent immune modulation, are underway.
After conventional multimodal treatment, the survival rate for patients with glioblastomas is about 50% at 1 year, 25% at 2 years, and 10 to 15% at 5 years. Prognosis is better in the following cases:
Patients are < 45 years.
Histology is that of anaplastic astrocytoma or a lower-grade tumor (rather than glioblastoma).
Initial excision improves neurologic function and leaves minimal or no residual tumor.
Tumors have the IDH1 mutation.
MGMT (methylguanine-methyltransferase) promoter methylation is present.
With standard treatment, the median survival time is about 30 months for patients with anaplastic astrocytoma and about 15 months for patients with glioblastomas. A wide range of clinical trials, in particular those including a number of investigational immunotherapy and immune checkpoint inhibitors, are being done. Ongoing and recently completed trials are referenced in clinical trials.gov.
Maximal safe surgical resection is indicated for low-grade astrocytomas and oligodendrogliomas. After complete resection in patients < 40, observation may be considered. For other patients, radiation therapy plus adjuvant chemotherapy prolongs survival (2).
Median survival ranges from 1 to 2 years in high-risk patients (without the IDH1 mutation, with incomplete resection) to > 10 years in those with favorable prognostic factors. In high-risk patients, malignancy is likely to progress further.
In patients with diffuse midline gliomas, radiation therapy may be used to slow disease progression, although its use is largely palliative because survival is typically less than a year. These tumors typically express the H3K27M mutation in a histone protein; epigenetic strategies that modify DNA and DNA-associated proteins in the cell to change gene expression are being studied (3).
Biopsy with genetic analysis, cerebrospinal fluid sampling, and craniospinal imaging should be used to stage ependymomas and to assess their spread in the central nervous system.
Treatment of ependymomas includes maximal safe surgical resection for unifocal disease or symptomatic tumors. For higher-grade tumors, radiation therapy can be directed locally or include the entire craniospinal axis depending on how far the tumor has spread. The role of chemotherapy is not well-defined.
Prognosis varies with tumor location, genetics and stage (4). In general, with treatment, overall 5-year survival rate is about 50%; however, for patients with no residual tumor, the 5-year survival rate is > 70%.
1. Stupp R, Taillibert S, Kanner A, et al: Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA 318 (23):2306–2316, 2017. doi: 10.1001/jama.2017.18718
2. Buckner JC, Shaw EG, Pugh SL, et al: Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374 (14):1344-1355, 2016. doi: 10.1056/NEJMoa1500925
3. Miklja Z, Pasternak A, Stallard S, et al Molecular profiling and targeted therapy in pediatric gliomas: Review and consensus recommendations. Neuro Oncol 21:968–980, 2019.
4. Pajtler K, Mack S, Ramaswamy V, et al: The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Neuropathologica 133:5–12, 2017. https://doi.org/10.1007/s00401-016-1643-0
Gliomas are primary tumors that originate in brain parenchyma; they include astrocytomas, oligodendrogliomas, and ependymomas.
Gliomas vary in location, degree of malignancy, treatment, and prognosis.
For most gliomas, surgically excise as much tumor as possible (gross total resection) without unduly damaging areas of eloquent brain, then follow with radiation therapy and/or chemotherapy.
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