Venous Thromboembolism (VTE) - Central Nervous System Cancers

Central Nervous System Cancers

6. Venous Thromboembolism (VTE)

• See the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease.

Allied Services

• Physical therapy, occupational therapy, and speech therapy may be helpful for many patients with CNS tumors, either benign or malignant.

Surgical intervention is not a prerequisite for referral, and these therapies should not be withheld from patients because of the uncertain course of certain malignant tumors. Many patients with aggressive, malignant primary brain tumors or CNS metastases can benefit from inpatient rehabilitation.

• Practitioners are encouraged to serve as a resource and to refer patients to social services, support groups, and cancer patient advocacy organizations. Institutional or community resources that can assist patients and families in dealing with financial, insurance, and legal issues are important.

• Practitioners should be familiar with their state laws concerning seizures and driving so that they can advise patients and families appropriately.

PRINCIPLES OF BRAIN AND SPINE TUMOR MANAGEMENT

Central Nervous System Cancers

Version 5.2020 , 04/15/21 © 2021 National Comprehensive Cancer Network^® (NCCN^®), All rights reserved. NCCN Guidelines^® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

BRAIN-F 1 OF 8 PRINCIPLES OF BRAIN TUMOR PATHOLOGY

• Incorporation of relevant diagnostic markers, including histopathologic and molecular information, as per the WHO 2016 Classification of Tumors of the Central Nervous System should be considered standard practice for tumor classification.

• Molecular/genetic characterization complements standard histologic analysis, providing additional diagnostic and prognostic information that can greatly improve diagnostic accuracy, influence treatment selection, and possibly improve management decision-making.

Standard Histopathologic Examination and Classification

• Histologic subgrouping of CNS neoplasms provides valuable prognostic information, as is described in the WHO Classification of Tumors of the Central Nervous System.¹

• Inter-observer discrepancies in histologic diagnosis and grading are a recognized issue, due to the inherently subjective nature of certain aspects of histopathologic interpretation (eg, astrocytic vs. oligodendroglial morphology). Also, surgical sampling does not always capture all the relevant diagnostic features in morphologically heterogeneous tumors.

• Even so, the traditional histologic classification of CNS neoplasms into primary neuroectodermal neoplasms (eg, glial, neuronal, embryonal), other primary CNS neoplasms (eg, lymphoma, germ cell, meningeal), metastatic neoplasms, and non-neoplastic conditions mimicking tumors remains fundamental to any pathologic assessment.

Molecular Characterization

• With the use of genetic and molecular testing, histologically similar CNS neoplasms can be differentiated more accurately in terms of prognosis and, in some instances, response to different therapies.^2-6

• Molecular characterization of primary CNS tumors has substantially impacted clinical trial eligibility and risk stratification in the past 10 years, thereby evolving the standard of care towards an integrated tumor diagnosis in neuro-oncology.

• Molecular/genetic characterization does not replace standard histologic assessment, but serves as a complementary approach to provide additional diagnostic and prognostic information that often enhances treatment selection.

• There are no identified targeted agents with demonstrated efficacy in glioblastoma. However, the panel encourages molecular testing of tumor because if a driver mutation is detected, it may be reasonable to treat with a targeted therapy on a compassionate use basis and/

or the patient may have more treatment options in the context of a clinical trial. Molecular testing also has a valuable role in improving diagnostic accuracy and prognostic stratification that may inform treatment selection.

Continued References

Central Nervous System Cancers

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

BRAIN-F 2 OF 8 PRINCIPLES OF BRAIN TUMOR PATHOLOGY MOLECULAR MARKERS

Isocitrate Dehydrogenase 1 and 2 (IDH1 and IDH2) Mutation

• Recommendation: IDH mutation testing is required for the workup of glioma.

• Description: IDH1 and IDH2 are metabolic enzymes. Specific mutations in genes encoding these enzymes lead to the aberrant production of D-2-hydroxyglutarate, an oncometabolite that causes epigenetic modifications in affected cells.⁷

• Detection: The most common IDH1 mutation (R132H) is reliably screened by mutation-specific immunohistochemistry, which is

recommended for all glioma patients. If the R132H immunostain result is negative, in the appropriate clinical context, sequencing of IDH1 and IDH2 is highly recommended to detect less common IDH1 and IDH2 mutations. Prior to age 55 years, sequencing of IDH1 and IDH2 is required if the R132H immunostain result is negative. Standard sequencing methods include Sanger sequencing, pyrosequencing, and next-generation sequencing, and should be performed on formalin-fixed, paraffin-embedded tissue.⁷

• Diagnostic value:

IDH mutations define WHO grade II and III astrocytomas and oligodendrogliomas, and the secondary grade IV glioblastomas into which astrocytomas often evolve. Their presence distinguishes lower-grade gliomas from primary glioblastomas, which are IDH-wild type.^8,9 Detection of these mutations in a specimen that is otherwise equivocal for tumor may also be regarded as evidence that a diffusely infiltrative glioma is present.⁷

True grade I non-infiltrative gliomas, such as pilocytic astrocytomas and gangliogliomas, do not contain IDH mutations. In such cases, detection of an IDH mutation indicates that the tumor is at least a grade II diffusely infiltrative glioma.⁷

• Prognostic value:

IDH mutations are commonly associated with MGMT promoter methylation.⁴

IDH1 or 2 mutations are associated with a relatively favorable prognosis and are important in stratification for clinical trials.¹⁰

In grade II or III infiltrative gliomas, wild-type IDH1 or 2 is associated with increased risk of aggressive disease.⁴

IDH1 or 2 mutations are associated with a survival benefit for patients treated with radiation or alkylating chemotherapy.^11,12

References The following molecular markers are often used by neuropathologists to facilitate characterization of gliomas and/or by

neuro-oncologists to guide treatment decisions:

Continued

Central Nervous System Cancers

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Codeletion of 1p and 19q

• Recommendation: 1p19q testing is an essential part of molecular diagnostics for oligodendroglioma.

• Description: This codeletion represents an unbalanced translocation (1;19)(q10;p10), leading to whole-arm deletion of 1p and 19q.¹³

• Detection: The codeletion of 1p and 19q is detectable by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).

Additional methods, including array-based genomic copy number testing and next-generation sequencing, may also be employed.

• Diagnostic value: It is strongly associated with oligodendroglial histology and helps confirm the oligodendroglial character of tumors with equivocal or mixed histologic features.¹⁴

IDH-mutated gliomas that do NOT show loss of ATRX (for example, by IHC) should be strongly considered for 1p19q testing, even if not clearly oligodendroglial by histology. Conversely, IDH1 wild-type gliomas do not contain true whole-arm 1p/19q codeletion.¹⁵ Therefore, 1p/19q testing is unnecessary if a glioma is not IDH-mutant, and a glioma should not be regarded as 1p/19q-codeleted without an

accompanying IDH mutation, regardless of test results.

A tumor should only be diagnosed as an oligodendroglioma if it contains both an IDH mutation and 1p/19q codeletion. Furthermore, the term “oligoastrocytoma” should no longer be used, as such morphologically ambiguous tumors can reliably be resolved into astrocytomas and oligodendrogliomas with molecular testing.¹⁶

• Prognostic value: The codeletion confers a favorable prognosis and is predictive of response to alkylating chemotherapy and combination therapy with radiation and alkylating chemotherapy.^17,18

MGMT Promoter Methylation

• Recommendation: MGMT promoter methylation is an essential part of molecular diagnostics for all high-grade gliomas (grade III and IV).

• Description: MGMT (O⁶-methylguanine-DNA methyltransferase) is a DNA repair enzyme that reverses the DNA damage caused by alkylating agents, resulting in tumor resistance to temozolomide and nitrosourea-based chemotherapy. Methylation of the MGMT promoter silences MGMT, making the tumor more sensitive to treatment with alkylating agents.¹⁹

• Detection: Methylation of the MGMT promoter is detectable by methylation-specific PCR,²⁰ pyrosequencing,²¹ or array-based technologies.²²

• Prognostic value:

MGMT promoter methylation is strongly associated with IDH mutations and genome-wide epigenetic changes (G-CIMP phenotype).⁴

MGMT promoter methylation confers a survival advantage in glioblastoma and is used for risk stratification in clinical trials.²³

MGMT promoter methylation is particularly useful in treatment decisions for elderly patients with high-grade gliomas (grades III–IV).^24,25

Patients with glioblastoma that are not MGMT promoter methylated derive less benefit from treatment with temozolomide compared to those whose tumors are methylated.²³

BRAIN-F 3 OF 8 The following molecular markers are often used by neuropathologists to facilitate characterization of gliomas and/or by

neuro-oncologists to guide treatment decisions:

ReferencesContinued PRINCIPLES OF BRAIN TUMOR PATHOLOGY MOLECULAR MARKERS

Central Nervous System Cancers

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

ATRX Mutation

• Recommendation: ATRX mutation testing is strongly recommended but not required for glioma.

• Description: ATRX encodes a chromatin regulator protein. Loss of function mutations enable alternative lengthening of telomeres (ALT).²⁶

• Detection: ATRX mutations can be detected by IHC for wild-type ATRX (loss of wild-type expression) and/or sequencing.²⁷

• Diagnostic value: ATRX mutations in glioma are strongly associated with IDH mutations, and are nearly always mutually exclusive with 1p/19q codeletion.²⁷ ATRX deficiency, coupled with IDH mutation, is typical of astrocytoma. A lack of ATRX immunostaining in glioblastoma should trigger IDH1/2 sequencing if IDH1 R132H immunostaining is negative, due to the frequent co-occurrence of ATRX and IDH

mutations.^5,27 TERT Mutation

• Recommendation: TERT mutation testing is recommended but not required for gliomas.

• Description: TERT encodes the catalytic active site of telomerase, the enzyme responsible for maintaining telomere length in dividing cells.

TERT mutations found in gliomas are located in its noncoding promoter region, and cause increased expression of the TERT protein.²⁸

• Detection: TERT mutations can be detected by sequencing of the promoter region.²⁹

• Diagnostic value: TERT mutations are almost invariably present in 1p/19q codeleted oligodendroglioma, and are found in most

glioblastomas. TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristic of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma.

• Prognostic value: In the absence of an IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared to gliomas lacking TERT mutations.^4,30,31

Combined TERT and IDH mutations in the absence of 1p/19q codeletion is an uncommon event, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations.^4,30

BRAIN-F 4 OF 8 The following molecular markers are often used by neuropathologists to facilitate characterization of gliomas and/or by

neuro-oncologists to guide treatment decisions:

PRINCIPLES OF BRAIN TUMOR PATHOLOGY MOLECULAR MARKERS

ReferencesContinued

Central Nervous System Cancers

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

H3F3A Mutation

• Recommendation: H3F3A and HIST1H3B mutation testing is recommended in the appropriate clinical context.

• Description: The most common histone mutation in brain tumors, H3K27M, is caused by a lysine-to-methionine substitution in the H3F3A gene and inhibits the trimethylation of H3.3 histone. G34 mutations are more common in cortical gliomas in children.^32-34

• Detection: Although a K27M histone antibody is available,³⁵ it is not 100% specific and interpretation can be difficult for non-experts.

Therefore, screening by H3F3A and HIST1H3B sequencing is a viable alternative and the preferred approach, especially since it will also detect mutations in G34.

• Diagnostic value: Histone mutations most commonly occur in pediatric midline gliomas (eg, diffuse intrinsic pontine gliomas [DIPG]), although midline gliomas in adults can also contain histone mutations.³⁶Their presence can be considered solid evidence of an infiltrative glioma, which is often helpful in small biopsies of midline lesions that may not be fully diagnostic with light microscopy or do not fully resemble infiltrative gliomas.^32,33,36

• Prognostic value: K27M gliomas typically do not have MGMT promoter methylation, and the mutation is an adverse prognostic marker in children and adults. The G34 mutation does not appear to have any prognostic significance once the diagnosis of a glioblastoma has been established.^33,36,37

BRAF Mutation

• Recommendation: BRAF fusion and/or mutation testing is recommended in the appropriate clinical context.

• Description: Activating mutations in BRAF, most commonly the V600E variant seen in other cancers (eg, melanoma), are present in 60%–

80% of supratentorial grade II–III pleomorphic xanthoastrocytomas (PXA), 30% of dysembryoplastic neuroepithelial tumors, 20% of grade I gangliogliomas, and 5% of grade I pilocytic astrocytomas (PA). Diffusely infiltrative gliomas can also harbor a BRAF mutation, especially in children. BRAF V600E has even been found in nonneoplastic cortical dysplasia. In contrast, activating BRAF fusions occur predominately in PA of the posterior fossa, although some supratentorial PA also have this fusion.^38-40

• Detection: BRAF V600E is best detected by sequencing, and BRAF fusions can be detected with RNA-Seq or other PCR-based breakpoint methods that capture the main 16–9, 15–9, and 16–11 breakpoints between BRAF and its main fusion partner, KIAA1549. FISH is too unreliable to detect BRAF fusions.³⁸

• Diagnostic value: The presence of a BRAF fusion is reliable evidence that the tumor is a pilocytic astrocytoma, provided the histology is compatible. BRAF V600E is more complicated, as it can occur in a variety of tumors over all four WHO grades and requires integration with histology.³⁸

• Prognostic value: Tumors with BRAF fusions tend to be indolent, with occasional recurrence but only rare progression to lethality. BRAF V600E tumors show a much greater range of outcomes and need to be considered in context with other mutations and clinicopathologic findings (eg, CDKN2A/B deletion). BRAF V600E tumors may respond to BRAF inhibitors such as vemurafenib, but comprehensive clinical trials are still ongoing.^41-43

BRAIN-F 5 OF 8 The following molecular markers are often used by neuropathologists to facilitate characterization of gliomas and/or by

neuro-oncologists to guide treatment decisions:

PRINCIPLES OF BRAIN TUMOR PATHOLOGY MOLECULAR MARKERS

ReferencesContinued

Central Nervous System Cancers

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

BRAIN-F 6 OF 8 RELA Fusion

• Recommendation: RELA fusion testing is recommended in the appropriate clinical context.

• Description: Ependymomas arising in the supratentorium often contain activating fusions of RELA. Increased RELA activity leads to

increased NF-kappa-B signaling and more aggressive behavior. This event is more common in children than in adults, and occurs only in the supratentorium, not the posterior fossa or spine.^44,45

• Detection: The most common RELA fusion partner is C11orf95. This can be detected with RNA-Seq or a break-apart FISH probe set.⁴⁶

• Diagnostic value: Detection of RELA fusion is not required for the diagnosis of ependymoma, as this entity is still diagnosed by light microscopy.

• Prognostic value: RELA fusion-positive ependymomas are now a distinct entity in the WHO classification of CNS tumors, as this subset of ependymomas tends to be far more aggressive than other supratentorial ependymomas.^1,44,45,47

Medulloblastoma Molecular Subtyping

• Recommendation: Medulloblastoma testing should be referred to academic tertiary centers with expertise in this area.

• Description: Medulloblastomas are WHO grade IV tumors that predominantly arise from the cerebellum in pediatric patients, but can also occur in adults. The WHO committee on CNS tumors now recommends subclassification of these tumors into four distinct groups: i) WNT-activated; ii) Sonic hedgehog (SHH)-activated and TP53-mutant; iii) SHH-activated and TP53-wild type; and iv) non-WNT/non-SHH.^1,48

• Detection: Virtually all WNT-driven medulloblastomas will contain mutations in either CTNNB1 or, less commonly, APC (the latter mutation may be germline if the patient has Turcot syndrome). Unlike in children, 50% of adult medulloblastomas with loss of 6q and positive nuclear catenin had no CTNNB1 mutations, pointing towards the possibility of alternative mechanisms of WNT pathway activation in adult medulloblastoma.⁴⁹ Adult and pediatric medulloblastomas are genetically distinct and require different algorithms for molecular risk stratification. WNT-driven tumors will also usually contain monosomy 6.6q loss is not confined to WNT in adults; it is also described in SHH and Group 4. Monosomy 6 is a specific marker for pediatric WNT, but not for adult WNT.⁵⁰Nuclear immunoreactivity for beta-catenin is a very useful way to identify WNT medulloblastomas, in conjunction with CTNNB1 sequencing and chromosome 6 FISH. Differentiating between WNT-activated, SHH-activated, and non-WNT/non-SHH tumors is best classified by expression arrays, DNA methylation arrays, or an

immunohistochemistry panel composed of beta-catenin, GAB1, and YAP1. Because there are a variety of hotspots in TP53, gene sequencing is recommended in SHH-activated medulloblastomas.^51-54

• Diagnostic value: None of the molecular markers associated with each medulloblastoma subtype is specific to medulloblastomas; the diagnosis of medulloblastoma is still made on the basis of light microscopy.

• Prognostic value: The most important aspect of medulloblastoma molecular diagnostics is that the WNT-activated subset has a markedly better prognosis relative to the other three subtypes, regardless of age at diagnosis. Among SHH-activated medulloblastomas, detection of TP53 mutations is associated with more aggressive behavior, often in the setting of germline TP53 mutations, wildtype SHH-activated medulloblastomas have a variable course, and are uncommon in adults.^55-57 Non-WNT/non-SHH medulloblastomas also show a variable course.^1,48,55WNT tumors have worse prognosis in adults compared to children based on retrospective data.⁵⁰ 6q loss and positive nuclear catenin have no clear prognostic role in adult medulloblastomas.

The following molecular markers are often used by neuropathologists to facilitate characterization of gliomas and/or by neuro-oncologists to guide treatment decisions:

PRINCIPLES OF BRAIN TUMOR PATHOLOGY MOLECULAR MARKERS

References

Central Nervous System Cancers

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

BRAIN-F 7 OF 8 PRINCIPLES OF BRAIN TUMOR PATHOLOGY

REFERENCES

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3Hegi ME, Stupp R. Withholding temozolomide in glioblastoma patients with unmethylated MGMT promoter--still a dilemma? Neuro Oncol 2015;17:1425-1427.

4Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med 2015;372:2499-2508.

5Cancer Genome Atlas Research N, Brat DJ, Verhaak RG, et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med 2015;372:2481-2498.

6Dubbink HJ, Atmodimedjo PN, Kros JM, et al. Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial. Neuro Oncol 2016;18:388-7Horbinski C. What do we know about IDH1/2 mutations so far, and how do we use it? Acta 400.

Neuropathol 2013;125:621-636.

8Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 2009;118:469-474.

9Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360:765-773.

10Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 2009;27:4150-4154.

11Hartmann C, Hentschel B, Wick W, et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 2010;120:707-718.

12Houillier C, Wang X, Kaloshi G, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 2010;75:1560-1566.

13Jenkins RB, Blair H, Ballman KV, et al. A t(1;19)(q10;p10) mediates the combined

deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma.

Cancer Res 2006;66:9852-9861.

14Burger PC, Minn AY, Smith JS, et al. Losses of chromosomal arms 1p and 19q in the diagnosis of oligodendroglioma. A study of paraffin-embedded sections. Mod Pathol 2001;14:842-853.

15Labussiere M, Idbaih A, Wang XW, et al. All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology 2010;74:1886-1890.

16Sahm F, Reuss D, Koelsche C, et al. Farewell to oligoastrocytoma: in situ molecular

genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol 2014;128:551-559.

17van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 2013;31:344-350.

18Cairncross G, Wang M, Shaw E, et al. Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG 9402. J Clin Oncol 2013;31:337-343.

19Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000;343:1350-1354.

20Vlassenbroeck I, Califice S, Diserens AC, et al. Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. J Mol Diagn 2008;10:332-337.

21Xie H, Tubbs R, Yang B. Detection of MGMT promoter methylation in glioblastoma using pyrosequencing. Int J Clin Exp Pathol 2015;8:636-642.

22Bady P, Sciuscio D, Diserens AC, et al. MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol 2012;124:547-560.

23Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997-1003.

24Malmstrom A, Gronberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 2012;13:916-926.

25Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 2012;13:707-715.

26Koschmann C, Calinescu AA, Nunez FJ, et al. ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Sci Transl Med 2016;8:328ra28.

27Reuss DE, Sahm F, Schrimpf D, et al. ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an

"integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol 2015;129:133-146.

28Arita H, Narita Y, Fukushima S, et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 2013;126:267-276.

29Nikiforova MN, Wald AI, Melan MA, et al. Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors.

Neuro Oncol 2016;18:379-387.

Continued

Central Nervous System Cancers

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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