Brain tumors comprise a heterogeneous group of abnormal collections of benign or malignant cells that may present with a variety of symptoms, including cognitive dysfunction, psychiatric disorders, and seizures. Brain tumors are diagnosed and classified using a combination of histology and molecular markers (eg, IDH1/2 variants and 1p/19q codeletion ). Molecular tests may also be used for prognosis/risk stratification, treatment decision-making (eg, MGMT promoter methylation), and to determine clinical trial eligibility.
Quick Answers for Clinicians
Targeted and whole exome genomic tests are promoted as tools for identifying clinically relevant genomic variants that can inform targeted therapy, immunotherapy, and clinical trial enrollment. These tests may be marketed by private companies and used for drug development purposes. The yield of useful clinical information from pangenomic tests is currently low. However, targeted testing for specific, well-validated variants is more frequently utilized in routine patient care.
Analysis of cerebrospinal fluid (CSF) may be useful to rule out other causes of symptoms in an initial evaluation, to investigate for metastases, and in monitoring. CSF should be obtained via lumbar puncture when possible, safe, and not contraindicated. Lumbar puncture should not be performed before imaging studies or within 2 weeks after surgery due to the possibility of false-positive results. CSF analysis should include a cell count with differential, as well as glucose and protein analysis. For solid tumors, cytology is recommended.
Indications for Testing
After thorough physical and neurologic examinations, imaging, and cerebrospinal fluid (CSF) analysis (if appropriate), individuals with brain tumors should undergo biopsy and/or resection for histology and molecular marker testing.
Brain tumors are often classified according to the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System. Classification involves histology and molecular marker testing and is important for diagnosis, prognosis, and treatment decision-making.
|Diffuse astrocytic and oligodendroglial tumorsa||
|Other astrocytic tumors||Pilocytic astrocytoma|
|Choroid plexus tumors||Choroid plexus carcinoma|
|Neuronal and mixed neuronal-glial tumors||
|Tumors of the pineal region||Pineoblastoma|
|Tumors of the cranial and paraspinal nerves||
|Mesenchymal, nonmeningothelial tumors||
|Melanocytic tumors||Meningeal melanoma|
|Lymphomas||Diffuse large B-cell lymphoma of the central nervous system|
|Histiocytic tumors||Histiocytic sarcoma|
|Germ cell tumors||
|Tumors of the sellar region||
|Tumors of the cranial and paraspinal nerves||
aTesting for molecular markers, including IDH variants and 1p/19q codeletion, is required for the classification of diffuse astrocytic and oligodendroglial tumors.
bRELA fusion testing is recommended in the classification of gliomas.
cWNT activation, SHH activation, and TP53 variant testing is used in the classification of genetically defined medulloblastomas.
PNET, pancreatic neuroendocrine tumor
For most brain tumors, diagnosis and classification are based on a combination of histology and molecular findings. Enough tissue should be obtained from biopsy or resection for both histology and molecular testing.
Specimens obtained via needle biopsy may not be suitable for histology, given that brain tumors (particularly gliomas) may exhibit differences in cellularity, mitoses, or necrosis across regions. According to the 2016 WHO classification system, if molecular data are unavailable, classification of tumors can be based on histology, provided that the appropriate caveats are noted. For example, tumors cannot be classified as oligoastrocytomas unless molecular data cannot be obtained, in which case a tumor may be designated an “oligoastrocytoma, not otherwise specified.”
Molecular tests on tumor samples are recommended as a complement to histology in diagnosis, for prognosis/risk stratification, and in treatment decision-making. Molecular markers are also useful in determining clinical trial eligibility.
|Marker||Use of Laboratory Testing||Analysis Techniques||Clinical Implications|
|1p/19q codeletion||Recommended in oligodendrogliomas||
Massively parallel sequencing
Codeletion associated with:
Codeletion mutually exclusive with wild-type IDH and not usually found with ATRX variants
Presence of both codeletion and IDH variant defines oligodendroglioma
|ATRX variants (decreased ATRX expression)||Strongly recommended for gliomas||
ATRX variants associated with:
ATRX variants rarely found with 1p/19q codeletion
IDH sequencing is recommended if ATRX expression is absent and IDH1 R132H is negative by IHC
|BRAF fusion/variants||Recommended if clinically appropriate||
RNA sequencing (fusions)
Sequencing (V600E and other variants)
Fusions associated with:
|H3F3A and HIST1H3B variants||Recommended if clinically appropriate||Antibody testing (H3K27M variant)||
K27M variant associated with poor prognosis
Histone variants suggest infiltrative glioma
|IDH1 and IDH2 variants||
Recommended in all gliomas
Sequencing recommended if IDH1 R132H negative by IHC
IHC (R132H variant)
Presence of both variant and 1p/19q codeletion defines oligodendroglioma
Variants associated with:
Variants not present in:
Wild type is mutually exclusive with 1p/19q codeletion
|MGMT promoter methylation||Recommended for all grade 3 and 4 gliomas||
PCR (methylation specific)
Methylation associated with:
|RELA fusions||Recommended if clinically appropriate||
Fusions associated with:
|TERT variants||Recommended for gliomas||Sequencing||
TERT variant in the presence of 1p/19q codeletion and IDH variant is typical of oligodendroglioma
Variants associated with:
Wild-type TERT in the presence of an IDH variant is characteristic of astrocytoma
FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PCR, polymerase chain reaction
Other Molecular Markers
Molecular markers, including SHH activation, TP53 variants, and WNT activation, are used in the classification of medulloblastomas. These markers are not specific to, or diagnostic of, medulloblastoma. WNT-activated tumors have a better prognosis than non-WNT/non-SHH, SHH-activated/TP53 variant, and SHH-activated/TP53 wild-type tumors. The National Comprehensive Cancer Network (NCCN) recommends that testing for these markers be performed by a center with specialized expertise.
Many other potential molecular markers are currently being investigated for use in the classification, diagnosis, and prognosis of gliomas (eg, CDKN2A/B loss or deletion, EGFR amplification, PTEN loss or promoter methylation).
Familial Genetic Testing
A number of genetic syndromes have been associated with brain tumors (particularly pediatric brain cancer), including tuberous sclerosis complex. Genetic testing for tuberous sclerosis and referral to genetic counseling should be considered in patients diagnosed with a subependymal giant cell astrocytoma. For more information, see the Tuberous Sclerosis Complex Test Fact Sheet.
Other indications for referral to genetic counseling include, but are not limited to, pediatric diagnosis of a brain tumor with signs of a related genetic disorder, a brain tumor in the presence of additional Lynch syndrome-associated cancers in the individual or family, and both astrocytoma and melanoma in the individual or in two first-degree relatives. Several other indications should prompt referral to genetic counseling, and the list of indications continues to expand. For more details, see the American College of Medical Genetics (ACMG) guidelines.
Endocrine disorders commonly occur in patients with brain tumors, and such disorders may be affected by treatment. Evaluation of adrenal, hypothalamic, pituitary, and thyroid function is recommended for patients who report decreased quality of life. Long-term monitoring of the hypothalamic-pituitary-adrenal axis may be appropriate in patients who were treated with radiation. Monitoring of the effects of steroid therapy, including monitoring for adrenal insufficiency if a patient is being weaned off of long-term steroid therapy, is recommended.
ARUP Laboratory Tests
Aids in diagnosis and classification of brain tumors
Aids in diagnosis, classification, prognosis, and treatment decision-making in oligodendrogliomas
Aids in diagnosis, classification, prognosis, and treatment decision-making in gliomas
Polymerase Chain Reaction/Sequencing
Aids in prognosis and treatment decision-making in high-grade gliomas
Aids in diagnosis and classification of gliomas
Aids in classification, prognosis, and treatment decision-making in some brain tumors
Polymerase Chain Reaction/Pyrosequencing
May be useful in diagnosis and prognosis in solid tumors
Includes BRAF, IDH1, IDH2, TERT promoter, TP53, NOTCH1, PTEN, and EGFR
For additional test information, including genes tested, refer to the Solid Tumor Mutation Panel by Next Generation Sequencing Test Fact Sheet
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, central nervous system cancers, Version 4.2020. [Updated: Mar 2021; Accessed: Mar 2021]
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. 2016;131(6):803-820.
Hampel H, Bennett RL, Buchanan A, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17(1):70-87. Reaffirmed with Addendum: Genet Med. 2019;21(12):2844.