• Sign Up

Low Grade Gliomas


Low Grade Gliomas

Article Author:
Wajeeha Aiman
Article Editor:
Appaji Rayi
Updated:
7/31/2020 2:27:40 PM
For CME on this topic:
Low Grade Gliomas CME
PubMed Link:
Low Grade Gliomas

Introduction

Tumors of the central nervous system (CNS) are classified based on their cell lineage of origin. Gliomas are a type of neuroepithelial tumors that originate from the supporting glial cells within the CNS. Glial cell tumors are further classified based on involved cell type, for example, astrocytomas, ependymomas oligodendroglioma, and mixed oligoastrocytomas.[1] Here in this review, diffuse gliomas with lower grade pathology, more specifically grade 2 (diffuse infiltrating) gliomas, are reviewed.

In 2016, the World Health Organization (WHO) published the updated version of the classification of CNS tumors. There has been major restructuring in the classification of these tumors, and for the first time, molecular features are included in addition to the previously described histopathological features.[2]

The histological features used include cytological atypia, mitotic activity, anaplasia, microvascular proliferation, and necrosis. All the features are present in high-grade gliomas and either none or only cytological atypia in the lower grade tumors. Low-grade gliomas (LGGs) are typically slow-growing tumors compared to high-grade gliomas. Over time, greater than 70% of these can transform into a higher grade or become aggressive in behavior within a decade.[3]

A study on serial MRI scans before treatment showed that these lesions typically grow steadily at an average rate of 4.1 mm annually.[4] The survival is relatively long in low-grade gliomas compared to the more aggressive types. Thus various factors should be considered, including the toxicity of chemotherapy, radiation therapy, and complications with surgical interventions to appropriately manage and improve overall outcomes.

Etiology

There are no known causes of gliomas, and the risk factors favoring the development are poorly understood. Therapeutic irradiation is the only major environmental factor increasing the risk of all brain tumors, including low-grade gliomas.[5] Factors like a diet containing N-nitroso compounds, environmental carcinogens, and several occupations are responsible for sporadic mutations e.g., TP53. Some hereditary mutations are frequent in gliomas.[6] Brain tumors present in various inherited tumor predisposing syndromes like neurofibromatosis (NF), Li-Fraumeni cancer syndrome, Lynch syndrome, etc. These syndromes constitute a very small proportion of the overall glioma cases.

Epidemiology

The precise incidence of low-grade gliomas is a shifting target since the adoption of 2016 WHO CNS classification among tumor registries is just beginning. Based on the studies using the previous classification, the incidence of grade 2 oligodendrogliomas is 0.25, for astrocytomas is 0.51, and the mixed glioma is 0.20 per 100000 per year in the United States.[7]Low-grade gliomas occur more commonly in the younger age group between 20 and 40 years.[8] The peak incidence for oligodendrogliomas is 40 to 45 years, whereas for astrocytomas is 30 to 40 years. Low-grade gliomas are slightly more common in males.[7]

Pathophysiology

LGGs grow slowly and can be followed over years without treatment unless they cause symptoms and grow. Multiple acquired genetic mutations are found in gliomas. Tumor suppressor protein 53 (p53), phosphatase and tensin homolog (PTEN), and epidermal growth factor receptor (EGFR) are involved in the pathogenesis of these tumors. p53 is the "guardian of the genome" and makes sure the DNA is copied correctly, it destroys the cell if the DNA is mutated. p53 usually mutated early in the disease and other mutations can survive. EGFR normally stimulates cells to divide, but if it gets amplified then stimulates cells to divide too much. Together these mutations cause uncontrollable cell division that is a hallmark of cancer. [9] 

The most common presenting symptom in LGGs is headache. Tumors are abnormal growths and when they increase in size cause pressure effects in surroundings. The pathophysiology behind the headache is due to the increased pressure in the microvasculature due to obstruction and leads to hydrocephalus. Other symptoms due to obstructive hydrocephalus are changes in vision, nausea, and vomiting. [1]

Histopathology

Atypia, anaplasia, microscopic proliferation, and necrosis are the histological features that are used to differentiate low-grade from high-grade tumors. Well-differentiated and hypercellular glia with nuclear atypia and rare mitotic activity are the histological features of LGGs. Type of tumor can be differentiated on the basis of the appearance of cells e.g. fried egg appearance and pleomorphic giant cells are present in oligodendrogliomas and astrocytomas respectively. Therefore, histological classification is possible for these tumors. [10]

History and Physical

The presenting symptoms depend on the location of the tumor in the brain. For example, behavioral changes are present in frontal lobe tumors; receptive aphasia in temporal lobe mass and parietal lobe tumor can vary in presentations.[11]However, it is relatively less common for these tumors to present with focal neurological deficits such as unilateral weakness or aphasia. These tumors tend to infiltrate rather than destroy or compress the cortex, thus not causing any functional deficit. Cognitive dysfunction may develop over time, and it is again mainly influenced by tumor location and size.[12]

The most common presenting symptoms in low-grade gliomas are headache and seizures. Seizures are especially common in oligodendrogliomas since these tend to invade the cortex. The seizure can be either partial/focal or sometimes generalized tonic-clonic type. The focal seizures may be unrecognized for a while before an actual diagnosis is concluded. As the tumor size increases, there is a rise in intracranial pressure. Headache manifests due to the increased pressure in the microvasculature and obstruction of the vessels. Other symptoms due to the raised intracranial pressure are changes in vision, nausea, and vomiting. It is important to note that asymptomatic patients are not uncommon, without any obstruction or compression symptoms.[1]

A comprehensive physical examination is necessary to check for any focal neurological deficits and other organ involvement, especially in genetic predisposition syndromes. Papilledema may be seen on fundoscopy.

Evaluation

Once, the history and physical examination findings are determined to be concerning for a brain tumor, additional workup using radiographic diagnostic studies should be performed to understand the condition in more detail. The findings on the imaging studies vary according to the type and grade of the tumor.[11][13][14] After the radiological workup, surgery is typically indicated if large and causing neurological deficits and also to obtain a tissue sample for determining the diagnosis and classifying the tumor. The long-term outcomes are dependent on the type, grade, and molecular characteristics of the tumor in addition to medical co-morbidities and the age of the individual.

Radiological Evaluation:

Computed Tomography (CT) Scan: CT scan is typically the initial study obtained due to the acute presentation of patients to the emergency department. On CT scans, the low-grade tumors are usually low density in appearance, and over 95% of these tumors are located in the supratentorial compartment, mainly either the frontal or the temporal lobes. Calcification can be seen in about 20% of these tumors, particularly in oligodendrogliomas. Contrast enhancement is usually not seen, but when present is patchy in contrast to ring-enhancing typically seen in high-grade gliomas.

Magnetic Resonance Imaging (MRI) Brain: MRI is a more sensitive imaging study to delineate low-grade tumors and soft tissue in general compared to CT scan. Low-grade gliomas appear hypointense on T1 and hyperintense on T2-fluid attenuated inversion recovery (FLAIR) sequences. Calcification can be evident on susceptibility-weighted imaging (SWI) sequence.[15] Low-grade tumors typically do not enhance and, when present is patchy and not ring-enhancing. Since contrast enhancement is associated with a breach in the blood-brain barrier, its presence would favor and indicate a more aggressive or a higher-grade tumor.

Advanced Imaging Techniques: Functional MRI, diffusion MRI, perfusion MRI, MR spectroscopy, and positron emission tomography (PET) scan are more advanced diagnostic studies used and add a modest value in the diagnosis of low-grade tumors. These tests are not routinely performed.[16] They help to identify changes in the tumor and its surrounding microenvironment to monitor the response to treatments and progression during the surveillance phase. In PET scan, the accumulation of [18F]-fluorodeoxyglucose can help to distinguish low-grade from high-grade tumors based on the uptake.[17] Other radiolabelled amino acids are also used for these scans.[18]

Neuro-pathological Diagnosis:

After a decision to move forward with surgery or biopsy is made by the treating physician or tumor board/multidisciplinary team discussion, the tissue is obtained. The tissue is then subjected to histopathological examination to determine the diagnosis. This is considered the gold standard test to confirm the type of tumor. In addition, molecular markers are also tested to classify the tumor per 2016 WHO CNS classification.

Histopathology: The main histopathological features used to classify brain tumors include atypia, anaplasia, microscopic proliferation, and necrosis. Histologically, low-grade tumors are well-differentiated and demonstrate hypercellular glia with nuclear atypia and rare mitotic activity. An indicator of mitotic activity, the Ki-67 labeling index, is usually below 10% for low-grade gliomas. The appearance of the cells depends upon the type of tumor. Oligodendrogliomas tend to have a classic ‘fried egg appearance’ with clear, scant cytoplasm, and isomorphic round nuclei and fine delicate branching vessels, sometimes described as ‘chicken wire vasculature.’ Astrocytomas have pleomorphic giant cells with prominent cytoplasmic processes creating a fibrillary stroma. And these stains intensely with vimentin and glial fibrillary acidic protein (GFAP).[1][10] Oligoastrocytomas have mixed histology, either focally or diffusely distributed.

Molecular Neuropathology: A major restructuring in the WHO classification in 2016 has been the result of the findings and understanding of molecular neuropathology of low-grade gliomas. [19] TP53 has been known to be present in most low-grade astrocytomas and rare to absent in oligodendrogliomas. It has also been well known that most of the oligodendrogliomas have co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q). Both these mutations (TP53 and 1p/19q co-deletion) are mutually exclusive in almost all low-grade gliomas.[20]The discovery about mutations of IDH, the gene coding for an enzyme in the Krebs cycle, isocitrate dehydrogenase being present in over 75% of low-grade glioma has been a breakthrough.[21][22] 

The majority are IDH1 mutations (R132H) and less commonly IDH2 mutations. These mutations lead to altered enzyme function, ultimately leading to the production of 2-hydroxyglutarate, which is an oncometabolite and has a broad range of effects on gene expression.[23] Thus from a molecular neuropathology perspective, low-grade gliomas may be classified into three categories: a) group with IDH mutation and 1p/19q co-deletion, which comprises of oligodendrogliomas, b) group with IDH mutation and without 1p/19q co-deletion where most of these have TP53 mutations and ATRX mutations and comprise of astrocytomas, and c) group with neither IDH mutation nor 1p/19q co-deletion.

Thus, when a glioma is suspected on clinical presentation, imaging, and tissue is obtained, it is strongly recommended to test for IDH mutation and 1p/19q co-deletion to have definitive tumor classification. In the 2016 WHO CNS classification, the diagnosis of oligoastrocytoma has been strongly discouraged since molecular studies can almost always aid in the classification of either oligodendroglioma or astrocytoma. Oligoastrocytomas can be diagnosed with a NOS (Not Otherwise Specified) designation and are indicated only when molecular studies are unavailable or not feasible.[2]

Treatment / Management

After presenting with clinical symptoms and imaging findings compatible with a low-grade glioma, the question about intervening surgically comes up. Surgery is indicated in patients with a significant mass effect, and neurological deficits secondary to the tumor, and the decision-making becomes obvious. The major challenge arises when the tumor is detected incidentally when an individual presents with a seizure or other neurological symptoms like headache, which is medically controlled and is otherwise asymptomatic. Multiple factors need to be taken into consideration while making this decision, which includes, preference of the patient, prognostic factors like age, tumor size, and location. For cases where observation is the chosen strategy, serial imaging should be performed with a plan to revisit the decision appropriately based on follow up studies.

Surgical Management:

When surgery is pursued, there is a lack of level 1 evidence about whether resection or a biopsy should be undertaken. Based on the overall experience, most authorities in the field favor a maximal safe resection over biopsies.[24] Moreover, the diagnostic accuracy is improved with resection compared to needle biopsies.[25]

There are multiple techniques available to perform gross total resection (GTR) of the tumors and avoid neurological deficits in extended surgery or when tumors are not well demarcated. These include stereotactic neuronavigation, intraoperative MRI, fluorescence-guided glioma surgery, and intraoperative functional mapping.[26][27][28][29]

Postoperatively, to plan subsequent therapy, MRI is performed in the first 24-72 hours. Observation is recommended to detect any neurologic deficits afterward.[30]

Radiation and Chemotherapy:

The timing and sequence of additional treatment options like radiotherapy and chemotherapy in the management of low-grade gliomas is a challenging question in neuro-oncology. One prospective study observing patients who have undergone a gross total resection of the low-grade glioma and younger than 40 years of age found that slightly over 50% have recurred within five years post-surgery.[31][32] Thus, when the observation is undertaken in lower-risk patients, it requires a long-term follow up comparing MRI scans to the early postoperative scans to accurately detect changes. When a treatment decision is reached in low-grade gliomas after resection, the options include radiation therapy, chemotherapy, or a combination of both.

Radiation Therapy: The dose of radiation therapy (RT) and target volume depends on the tumor stage, subtype, location, pattern of spread, and age of the patient.[33] Radiotherapy techniques used include three-dimensional conformal RT, conventional external beam RT, and stereotactic radiosurgery. A dose of 50 Gy to 54 Gy to the tumor margins over a 5 to 6 weeks period with 1.8 Gy to 2 Gy fractions has become present standard.[34] Surveillance after RT might be challenging due to delayed white matter changes secondary to RT due to its resemblance to tumor progression. There is a slightly higher incidence of radiation necrosis with high dose radiation therapy.[34]

Chemotherapy: When treatment after surgery is planned, long-term follow up from an older low-grade glioma trial indicates that RT alone is insufficient for low-grade gliomas. A phase 3 trial started in 1998 comparing radiation followed by with or without adjuvant PCV (procarbazine, limestone, and vincristine) chemotherapy in patients with low-grade glioma initially reported no advantage in overall survival (OS) between the groups in 2012, even though there was an improvement in progression-free survival (PFS).[35] However, six years later, with additional follow up, there was a statistically significant benefit in OS in the PCV arm (13.3 versus 7.8 years).[36]

Thus, patients with low-grade tumors who require additional treatment should strongly be considered for combination therapy. More recently, another phase 3 trial is conducted to compare RT with adjuvant temozolomide versus RT with adjuvant PCV in anaplastic or low-grade co deleted gliomas (CODEL). (NCT00887146) Clinical trials targeting the mutant IDH protein are also underway.[37]

Regardless of the initial management, low-grade gliomas ultimately regrow. Increasing enhancement might develop, and when operated, the tissue might have transformed into a high-grade glioma by histopathology. This phenomenon is called malignant transformation. Management of patients at this stage would be to treat the alternative treatment, which they did not receive previously.

Differential Diagnosis

Multiple conditions can clinically present similar to low-grade gliomas, and therefore a long list of differential diagnoses needs to be considered carefully as listed below.[38][39]

  • Meningioma
  • Primary CNS lymphoma
  • Cerebral metastasis
  • Spinal tuberculosis
  • Brain abscess
  • Cavernous malformation
  • Cavernous sinus syndrome
  • Intracranial hemorrhage
  • Stroke
  • Progressive multifocal leukoencephalopathy[40]
  • Acute disseminated encephalomyelitis (ADEM)

Prognosis

A spectrum of outcomes is seen in patients with low-grade gliomas. Patient groups can be recognized with a median survival as low as two years to greater than 12 years, depending on the grade according to the 2016 WHO CNS classification. A good understanding of the prognostic factors is thus critical in making a treatment decision and patient education in the overall management of these tumors. The clinical prognostic factors include:[41]

  • Age: Younger patients do better compared to older patients, with some studies classifying the age of below and above 40 years being low and high risk, respectively.
  • Symptoms at presentation: Presenting symptoms like seizures are associated with a good prognosis as well, likely due to the earlier diagnosis of the condition leading to close monitoring. This could well be due to lead-time bias. While fixed neurological deficits are associated with a poor prognosis.
  • Tumor size and area involved: Tumor size is also important, with larger tumors associated with a poor prognosis and involvement of corpus callosum is associated with adverse outcomes.

Molecular tests allow for a more refined estimation of prognosis. The presence of 1p/19q co-deletion is associated with a favorable diagnosis. One study showed that the median survival of 1p/19q co-deleted tumors (oligodendrogliomas) was 12 years compared to 8 years in non-co deleted gliomas.[41] IDH mutation is also associated with a favorable prognosis in most low-grade gliomas. A French study showed an OS of 11 years versus seven years in gliomas with and without IDH mutation in low-grade gliomas treated with temozolomide, indicating a favorable prognosis with chemosensitivity.[42]

Complications

Gliomas tend to grow and increase in size. If the decision is to only observe and leave the tumor unresected, the growth can lead to brain herniation and, ultimately, death. Even a smaller increase in the size of the tumor in a closed space like cranium can cause a massive shift in intracranial pressure and downstream effects.

There are several complications associated with RT, and severity depends on duration from the treatment.

Radiation-induced Effects: Acute reactions can occur immediately after treatment and are mainly due to local inflammation in the brain. These changes can cause headaches, nausea, drowsiness, and fever, etc. Early-delayed radiation-induced effects can occur after a few weeks to months. They can be due to peritumoral edema, tumor response, and demyelination. Symptoms can be transient neurological deficits and extreme sleepiness. Late-delayed radiation-induced changes occur after three months, and they are worse as are irreversible. These changes include findings like radiation-induced necrosis, vasculopathy, and secondary malignancies.[43]

Different strategies can be used to prevent these side effects. Decreasing the dose of the treatment and using a different technique (depending on the tumor and patient features) can be helpful to prevent these side effects. For example, proton radiation therapy is a newer technology that can be combined with chemotherapy to reduce side effects.[44]

There are various side effects experienced during chemotherapy treatment, as well. These include hair loss, constipation, flu-like symptoms, and CNS toxicity like weakness, loss of balance, headache, unsteadiness, drowsiness, or dizziness. Vincristine is associated with neuropathy. Bone marrow suppression with low blood counts is seen with lomustine.[45] Medications used for the management of seizures and vasogenic edema are also associated with adverse effects that can impair the quality of life in these patients. In addition, anti-convulsant and radiation treatment are associated with cognitive changes that are difficult to differentiate from the decline secondary to the tumor growth itself.[46] Long-term side effects of steroids, which are typically used for the management of vasogenic edema, should also be considered.[47]

Postoperative and Rehabilitation Care

Postoperatively, routine follow-ups are required to address complications like wound infection and other surgery-related complications.[48] Rehabilitation care is required if neurological deficits occur after extensive resection. Cancer affects the quality of life by harming primary components such as physical, social, and mental aspects of life. Rehabilitation aims are to strengthen the individual physically, mentally, and socially by providing support and appropriate measures in all areas.[49]

Deterrence and Patient Education

Educating the patients about the tumor, its grade, complications, and treatments is critical. It is important to emphasize about follow up appointment and long-term surveillance in patients with low-grade gliomas. A multidisciplinary approach to patient care is crucial, and any adverse events during treatment should be immediately addressed when necessary. Non-compliance should be discouraged. Referral to a higher center should be pursued if not available locally. Since the patient plays a key role in the decisions about the management of the low-grade glioma, it is important to keep them abreast of the condition and the available option with respect to their risk. This would be useful to ultimately make the best decisions to improve the overall outcome and quality of life.

Enhancing Healthcare Team Outcomes

Brain tumors are serious conditions that require immediate attention and appropriate treatment. An interprofessional support group is required to manage these conditions. A collaborative effort by the neurosurgeons, neuro-oncologists, radiation oncologists, neuroradiologists, pharmacists, nurse practitioners, nurses, and other support medical staff is essential to enhance patient care and to achieve a good prognosis and overall outcome. Important treatment decisions are made through multidisciplinary tumor board conferences that help the treating physician in the management of the patients. Thus an enhanced team performance and educating the patient is crucial in managing low-grade gliomas.[50]


References

[1] Forst DA,Nahed BV,Loeffler JS,Batchelor TT, Low-grade gliomas. The oncologist. 2014 Apr;     [PubMed PMID: 24664484]
[2] Louis DN,Perry A,Reifenberger G,von Deimling A,Figarella-Branger D,Cavenee WK,Ohgaki H,Wiestler OD,Kleihues P,Ellison DW, The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta neuropathologica. 2016 Jun     [PubMed PMID: 27157931]
[3] Jooma R,Waqas M,Khan I, Diffuse Low-Grade Glioma - Changing Concepts in Diagnosis and Management: A Review. Asian journal of neurosurgery. 2019 Apr-Jun;     [PubMed PMID: 31143247]
[4] Mandonnet E,Delattre JY,Tanguy ML,Swanson KR,Carpentier AF,Duffau H,Cornu P,Van Effenterre R,Alvord EC Jr,Capelle L, Continuous growth of mean tumor diameter in a subset of grade II gliomas. Annals of neurology. 2003 Apr;     [PubMed PMID: 12666121]
[5] Ohgaki H,Kleihues P, Epidemiology and etiology of gliomas. Acta neuropathologica. 2005 Jan;     [PubMed PMID: 15685439]
[6] Takei H,Rouah E,Bhattacharjee MB, Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1: a case report and literature review. International journal of clinical and experimental pathology. 2015;     [PubMed PMID: 26261671]
[7] Ostrom QT,Gittleman H,Xu J,Kromer C,Wolinsky Y,Kruchko C,Barnholtz-Sloan JS, CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009-2013. Neuro-oncology. 2016 Oct 1     [PubMed PMID: 28475809]
[8] Ostrom QT,Cioffi G,Gittleman H,Patil N,Waite K,Kruchko C,Barnholtz-Sloan JS, CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro-oncology. 2019 Nov 1;     [PubMed PMID: 31675094]
[9] von Deimling A,Eibl RH,Ohgaki H,Louis DN,von Ammon K,Petersen I,Kleihues P,Chung RY,Wiestler OD,Seizinger BR, p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma. Cancer research. 1992 May 15;     [PubMed PMID: 1349850]
[10] Schiff D, Low-grade gliomas. Continuum (Minneapolis, Minn.). 2015 Apr     [PubMed PMID: 25837900]
[11] Celano E,Salehani A,Malcolm JG,Reinertsen E,Hadjipanayis CG, Spinal cord ependymoma: a review of the literature and case series of ten patients. Journal of neuro-oncology. 2016 Jul;     [PubMed PMID: 27154165]
[12] van Loon EM,Heijenbrok-Kal MH,van Loon WS,van den Bent MJ,Vincent AJ,de Koning I,Ribbers GM, Assessment methods and prevalence of cognitive dysfunction in patients with low-grade glioma: A systematic review. Journal of rehabilitation medicine. 2015 Jun;     [PubMed PMID: 25994416]
[13] Jiang YF,Liu Y,Wang YL,Cao HY,Wang L,Xu HT,Li QC,Qiu XS,Wang EH, Angiomatous pleomorphic xanthoastrocytoma: a case report and literature review. Diagnostic pathology. 2016 Aug 9;     [PubMed PMID: 27506610]
[14] Smits M, Imaging of oligodendroglioma. The British journal of radiology. 2016;     [PubMed PMID: 26849038]
[15] Larsen J,Wharton SB,McKevitt F,Romanowski C,Bridgewater C,Zaki H,Hoggard N, 'Low grade glioma': an update for radiologists. The British journal of radiology. 2017 Feb     [PubMed PMID: 27925467]
[16] Fouke SJ,Benzinger T,Gibson D,Ryken TC,Kalkanis SN,Olson JJ, The role of imaging in the management of adults with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. Journal of neuro-oncology. 2015 Dec     [PubMed PMID: 26530262]
[17] Kim MM,Lawrence TS,Cao Y, Advances in Magnetic Resonance and Positron Emission Tomography Imaging: Assessing Response in the Treatment of Low-Grade Glioma. Seminars in radiation oncology. 2015 Jul;     [PubMed PMID: 26050587]
[18] la Fougère C,Suchorska B,Bartenstein P,Kreth FW,Tonn JC, Molecular imaging of gliomas with PET: opportunities and limitations. Neuro-oncology. 2011 Aug     [PubMed PMID: 21757446]
[19] Bourne TD,Schiff D, Update on molecular findings, management and outcome in low-grade gliomas. Nature reviews. Neurology. 2010 Dec     [PubMed PMID: 21045797]
[20] Schiff D,Brown PD,Giannini C, Outcome in adult low-grade glioma: the impact of prognostic factors and treatment. Neurology. 2007 Sep 25     [PubMed PMID: 17893297]
[21] Balss J,Meyer J,Mueller W,Korshunov A,Hartmann C,von Deimling A, Analysis of the IDH1 codon 132 mutation in brain tumors. Acta neuropathologica. 2008 Dec     [PubMed PMID: 18985363]
[22] Yan H,Parsons DW,Jin G,McLendon R,Rasheed BA,Yuan W,Kos I,Batinic-Haberle I,Jones S,Riggins GJ,Friedman H,Friedman A,Reardon D,Herndon J,Kinzler KW,Velculescu VE,Vogelstein B,Bigner DD, IDH1 and IDH2 mutations in gliomas. The New England journal of medicine. 2009 Feb 19     [PubMed PMID: 19228619]
[23] Dang L,White DW,Gross S,Bennett BD,Bittinger MA,Driggers EM,Fantin VR,Jang HG,Jin S,Keenan MC,Marks KM,Prins RM,Ward PS,Yen KE,Liau LM,Rabinowitz JD,Cantley LC,Thompson CB,Vander Heiden MG,Su SM, Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009 Dec 10     [PubMed PMID: 19935646]
[24] Pouratian N,Asthagiri A,Jagannathan J,Shaffrey ME,Schiff D, Surgery Insight: the role of surgery in the management of low-grade gliomas. Nature clinical practice. Neurology. 2007 Nov     [PubMed PMID: 17982433]
[25] Muragaki Y,Chernov M,Maruyama T,Ochiai T,Taira T,Kubo O,Nakamura R,Iseki H,Hori T,Takakura K, Low-grade glioma on stereotactic biopsy: how often is the diagnosis accurate? Minimally invasive neurosurgery : MIN. 2008 Oct     [PubMed PMID: 18855292]
[26] Orringer DA,Golby A,Jolesz F, Neuronavigation in the surgical management of brain tumors: current and future trends. Expert review of medical devices. 2012 Sep     [PubMed PMID: 23116076]
[27] Liang D,Schulder M, The role of intraoperative magnetic resonance imaging in glioma surgery. Surgical neurology international. 2012     [PubMed PMID: 23230537]
[28] Liu JT,Meza D,Sanai N, Trends in fluorescence image-guided surgery for gliomas. Neurosurgery. 2014 Jul     [PubMed PMID: 24618801]
[29] De Witt Hamer PC,Robles SG,Zwinderman AH,Duffau H,Berger MS, Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012 Jul 10     [PubMed PMID: 22529254]
[30] Hollon T,Hervey-Jumper SL,Sagher O,Orringer DA, Advances in the Surgical Management of Low-Grade Glioma. Seminars in radiation oncology. 2015 Jul;     [PubMed PMID: 26050588]
[31] Shaw EG,Berkey B,Coons SW,Bullard D,Brachman D,Buckner JC,Stelzer KJ,Barger GR,Brown PD,Gilbert MR,Mehta M, Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial. Journal of neurosurgery. 2008 Nov     [PubMed PMID: 18976072]
[32] Karim AB,Maat B,Hatlevoll R,Menten J,Rutten EH,Thomas DG,Mascarenhas F,Horiot JC,Parvinen LM,van Reijn M,Jager JJ,Fabrini MG,van Alphen AM,Hamers HP,Gaspar L,Noordman E,Pierart M,van Glabbeke M, A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. International journal of radiation oncology, biology, physics. 1996 Oct 1     [PubMed PMID: 8948338]
[33] Jablonska PA,Diez-Valle R,Pérez-Larraya JG,Moreno-Jiménez M,Idoate MÁ,Arbea L,Tejada S,Garcia de Eulate MR,Ramos L,Arbizu J,Domínguez P,Aristu JJ, Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience. PloS one. 2019;     [PubMed PMID: 31170245]
[34] Shaw E,Arusell R,Scheithauer B,O'Fallon J,O'Neill B,Dinapoli R,Nelson D,Earle J,Jones C,Cascino T,Nichols D,Ivnik R,Hellman R,Curran W,Abrams R, Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002 May 1;     [PubMed PMID: 11980997]
[35] Shaw EG,Wang M,Coons SW,Brachman DG,Buckner JC,Stelzer KJ,Barger GR,Brown PD,Gilbert MR,Mehta MP, Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012 Sep 1     [PubMed PMID: 22851558]
[36] Buckner JC,Shaw EG,Pugh SL,Chakravarti A,Gilbert MR,Barger GR,Coons S,Ricci P,Bullard D,Brown PD,Stelzer K,Brachman D,Suh JH,Schultz CJ,Bahary JP,Fisher BJ,Kim H,Murtha AD,Bell EH,Won M,Mehta MP,Curran WJ Jr, Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. The New England journal of medicine. 2016 Apr 7;     [PubMed PMID: 27050206]
[37] Kaminska B,Czapski B,Guzik R,Król SK,Gielniewski B, Consequences of {i}IDH1/2{/i} Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins. Molecules (Basel, Switzerland). 2019 Mar 9     [PubMed PMID: 30857299]
[38] Wang H,Ye JT,Yao HX,Li D,Dong Y, [Clinicopathologic features of infant dysembryoplastic neuroepithelial tumor: a case report and literature review]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences. 2017 Oct 18;     [PubMed PMID: 29045978]
[39] Zhang XP,Liu Y,Zhang D,Zheng Q,Wang C,Wang L,Li QC,Qiu XS,Wang EH, Cerebellar ependymoma with overlapping features of clear-cell and tanycytic variants mimicking hemangioblastoma: a case report and literature review. Diagnostic pathology. 2017 Mar 20;     [PubMed PMID: 28320419]
[40] Kantorová E,Bittšanský M,Sivák Š,Baranovičová E,Hnilicová P,Nosáľ V,Čierny D,Zeleňák K,Brück W,Kurča E, Anaplastic astrocytoma mimicking progressive multifocal leucoencephalopathy: a case report and review of the overlapping syndromes. BMC cancer. 2017 Jun 19;     [PubMed PMID: 28629398]
[41] Pignatti F,van den Bent M,Curran D,Debruyne C,Sylvester R,Therasse P,Afra D,Cornu P,Bolla M,Vecht C,Karim AB, Prognostic factors for survival in adult patients with cerebral low-grade glioma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002 Apr 15     [PubMed PMID: 11956268]
[42] Houillier C,Wang X,Kaloshi G,Mokhtari K,Guillevin R,Laffaire J,Paris S,Boisselier B,Idbaih A,Laigle-Donadey F,Hoang-Xuan K,Sanson M,Delattre JY, IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010 Oct 26     [PubMed PMID: 20975057]
[43] Plimpton SR,Stence N,Hemenway M,Hankinson TC,Foreman N,Liu AK, Cerebral radiation necrosis in pediatric patients. Pediatric hematology and oncology. 2015 Feb;     [PubMed PMID: 23647507]
[44] Shih HA,Sherman JC,Nachtigall LB,Colvin MK,Fullerton BC,Daartz J,Winrich BK,Batchelor TT,Thornton LT,Mancuso SM,Saums MK,Oh KS,Curry WT,Loeffler JS,Yeap BY, Proton therapy for low-grade gliomas: Results from a prospective trial. Cancer. 2015 May 15;     [PubMed PMID: 25585890]
[45] Jutras G,Bélanger K,Letarte N,Adam JP,Roberge D,Lemieux B,Lemieux-Blanchard É,Masucci L,Ménard C,Bahary JP,Moumdjian R,Berthelet F,Florescu M, Procarbazine, lomustine and vincristine toxicity in low-grade gliomas. Current oncology (Toronto, Ont.). 2018 Feb     [PubMed PMID: 29507493]
[46] Klein M,Heimans JJ,Aaronson NK,van der Ploeg HM,Grit J,Muller M,Postma TJ,Mooij JJ,Boerman RH,Beute GN,Ossenkoppele GJ,van Imhoff GW,Dekker AW,Jolles J,Slotman BJ,Struikmans H,Taphoorn MJ, Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study. Lancet (London, England). 2002 Nov 2     [PubMed PMID: 12423981]
[47] Dietrich J,Rao K,Pastorino S,Kesari S, Corticosteroids in brain cancer patients: benefits and pitfalls. Expert review of clinical pharmacology. 2011 Mar     [PubMed PMID: 21666852]
[48] Jackson C,Westphal M,Quiñones-Hinojosa A, Complications of glioma surgery. Handbook of clinical neurology. 2016     [PubMed PMID: 26948356]
[49] Ronson A,Body JJ, Psychosocial rehabilitation of cancer patients after curative therapy. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2002 May;     [PubMed PMID: 12029427]
[50] Robinson GW,Rudneva VA,Buchhalter I,Billups CA,Waszak SM,Smith KS,Bowers DC,Bendel A,Fisher PG,Partap S,Crawford JR,Hassall T,Indelicato DJ,Boop F,Klimo P,Sabin ND,Patay Z,Merchant TE,Stewart CF,Orr BA,Korbel JO,Jones DTW,Sharma T,Lichter P,Kool M,Korshunov A,Pfister SM,Gilbertson RJ,Sanders RP,Onar-Thomas A,Ellison DW,Gajjar A,Northcott PA, Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. The Lancet. Oncology. 2018 Jun;     [PubMed PMID: 29778738]