Central Nervous System Tumors - Brain Tumors
- Diagnosis
- Background
- Pediatrics
- Lab Tests
- References
- Related Topics
- Videos
Indications for Testing
- New onset of headaches associated with focal neurological deficits in patient without previous headaches
- Change in character of headaches in patient with previous headaches
- New onset of seizures
Laboratory Testing
- Nonspecific testing to rule out other disease processes (eg, meningitis)
- CBC, chemistry profile, C-reactive protein (CRP)
- If CRP not available, order erythrocyte sedimentation rate (ESR) (Choosing Wisely: 15 Things Physicians and Patients Should Question, 2016; American Society for Clinical Pathology)
- Lumbar tap with CSF studies may be indicated
- CBC, chemistry profile, C-reactive protein (CRP)
Histology
- Gold standard is biopsy for histologic classification
- May be helpful if histology does not give clear diagnosis
- Immunohistochemistry
- Glial tumors – Ki-67, GFAP, S-100, p53, IDH1
- Dysgerminomas – PLAP, CD117 (c-Kit), beta-hCG, AFP
- Capillary hemangioblastomas – inhibin, D2-40
- Meningioma – Ki-67, claudin1
- Medulloblastoma – synaptophysin
- Mutation testing
- 1p/19q deletion (FISH)
- Presence of codeletion establishes diagnosis of oligodendroglioma (versus gliosis)
- Gain of chromosome 19 supports diagnosis of high-grade astrocytoma
- IDH1 R1324 (IHC) – use to differentiate tumors from gliosis
- For brain tumors in children, consider genetic testing for hereditary CNS tumors (eg, Li-Fraumeni)
- 1p/19q deletion (FISH)
Imaging Studies
- CT, MRI – MRI is more sensitive than CT for diagnosis and possible identification of tumor type
- PET – used for diagnosis, grading gliomas, and differentiating between tumor recurrence and radiation necrosis
Genetic Testing
- Should be offered to individuals with (Hampel, ACMG, 2015)
- Brain tumor diagnosis at <18 years if any of the following criteria are met
- Café-au-lait macules and/or other signs of neurofibromatosis type 1, or hypopigmented skin lesions
- Consanguineous parents
- Family history of Legius syndrome (LS)-associated cancer
- Second primary cancer
- Sibling with a childhood cancer
- Brain tumor and 2 additional cases of any LS-associated cancer in the same person or in relatives
- Brain tumor and 1 additional Li-Fraumeni syndrome tumor in the same person or in 2 relatives, 1 diagnosed at ≤45 years
- Astrocytoma and melanoma in the same person or in 2 first-degree relatives
- Subependymal giant cell astrocytoma and 1 additional tuberous sclerosis complex criterion in the same person
- Medulloblastoma and ≥10 cumulative adenomatous colon polyps in the same person
- Medulloblastoma (PNET) diagnosis at <18 years and 1 additional nevoid basal cell carcinoma syndrome criterion in the same person
- Brain tumor diagnosis at <18 years if any of the following criteria are met
Prognosis
- Differentiation of astrocytomas from oligodendrogliomas has prognostic and therapeutic importance
- Mutations
- 1p/19q deletion (FISH)
- Combined loss of short arm of chromosome 1 (1p) and long arm of chromosome 19 (19q) – prognostic marker of oligodendrogliomas
- 1p/19q codeletion
- Patients with 1p/19q codeletion have a better prognosis than those with a single or no deletion
- Mutually exclusive for TP53 and EGFR amplification
- Frequently associated with IDH1 or IDH2 mutations
- Loss of 1p may identify treatment-sensitive malignant glioma in particular subtypes of anaplastic oligodendroglioma
- Prognostic relevance in low-grade tumors less well characterized
- 1p/19q codeletion
- Combined loss of short arm of chromosome 1 (1p) and long arm of chromosome 19 (19q) – prognostic marker of oligodendrogliomas
- IDH1/IDH2 mutations (PCR)
- Favorable outcomes in WHO grade I and II gliomas
- SNP rs11554137 associated with unfavorable prognosis
- MGMT promoter methylation (PCR)
- Prognostic in glioma
- Methylation is associated with significantly increased overall and progression-free survival
- Improved survival in those treated with alkylating agents
- Markers may affect prognosis if present together
- Methylation is associated with better prognosis in the absence of IDH1/IDH2 mutations
- Promising mutations
- TERT – may co-occur with IDH1/IDH2 and 1p19q deletion (triple-positive tumor)
- 1p/19q deletion (FISH)
Differential Diagnosis
- Infections
- Meningitis
- Encephalitis
- Brain abscess
- Parasites
- Seizure disorder
- Migraine headache
- Stroke
- Vasculitis
- Autoimmune CNS syndrome (eg, systemic lupus erythematosus cerebritis)
1p/19q Deletion by FISH 2008604
Method: Fluorescence in situ Hybridization
Use to diagnose oligodendroglioma brain tumors; indicated in both low-grade and high-grade (anaplastic) oligodendrogliomas
Predict response to therapy in oligodendrogliomas
Fix in formalin for optimal results
Test should not be used alone for diagnosis of malignancy
IDH1 and IDH2 Mutation Analysis, exon 4 2006444
Method: Polymerase Chain Reaction/Sequencing
Detects IDH1 and IDH2 mutations in whole blood or bone marrow
May have prognostic significance in patients with hematologic malignancies, depending on the clinical and genetic context
For FFPE tissues, please use IDH1 and IDH2 mutation analysis, exon 4 FFPE tissue test
Refer to Additional Technical Information document for further content
Negative test result does not exclude mutations below the limit of detection and presence of mutations other than those detected by the test
This marker should be interpreted within the group of CN-AML prognostic markers
IDH1 and IDH2 Mutation Analysis, Exon 4, Formalin-Fixed, Paraffin-Embedded (FFPE) Tissue 2014188
Method: Polymerase Chain Reaction/Sequencing
IDH1/IDH2 mutational status is a prognostic marker in individuals with low- and high-grade gliomas
Aids in distinguishing a primary from a secondary glioblastoma
Refer to Additional Technical Information document for further content
Negative test result does not exclude mutations below the limit of detection and presence of mutations other than those detected by the test
This marker should be interpreted within the group of CN-AML prognostic markers
IDH1 R132H by Immunohistochemistry 2005857
Method: Immunohistochemistry
Use when morphology indicates tumor may be a glioma
Use to differentiate tumors from reactive gliosis
Stained and returned to client pathologist for interpretation; consultation available if needed
Test should not be used alone for diagnosis of malignancy
MGMT Methylation Detection by PCR 2009310
Method: Real-Time Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer
Aid in therapeutic decisions in individuals with gliomas
Recommended for WHO grade II-IV astrocytic, oligodendroglial, and oligoastrocytic brain tumors
Methylation at locations other than those covered by the primers and probes not detected
Results of this test must always be interpreted within the clinical context and other relevant data
Results should not be used as a sole determinant of alkylating chemotherapy in standard clinical practice
Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and resulted by ARUP
Glial Fibrillary Acidic Protein (GFAP) by Immunohistochemistry 2003899
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and returned to client pathologist for interpretation; consultation available if needed
S-100 Protein by Immunohistochemistry 2004127
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and returned to client pathologist for interpretation; consultation available if needed
CD56 (NCAM) by Immunohistochemistry 2003589
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and returned to client pathologist for interpretation; consultation available if needed
p53 with Interpretation by Immunohistochemistry 0049250
Method: Immunohistochemistry
Aid in diagnosing and prognosing CNS tumor
Stained and resulted by ARUP
CD117 (c-Kit) by Immunohistochemistry 2003806
Method: Immunohistochemistry
Aid in the histologic diagnosis of CNS tumors
Stained and returned to client pathologist for interpretation; consultation available if needed
Placental Alkaline Phosphatase (PLAP) by Immunohistochemistry 2004097
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and returned to client pathologist for interpretation; consultation available if needed
Human Chorionic Gonadotropin (Beta-hCG) by Immunohistochemistry 2003920
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and returned to client pathologist for interpretation; consultation available if needed
Alpha-1-Fetoprotein (AFP) by Immunohistochemistry 2003436
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and returned to client pathologist for interpretation; consultation available if needed
Inhibin by Immunohistochemistry 2003969
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and returned to client pathologist for interpretation; consultation available if needed
D2-40 by Immunohistochemistry 2003857
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and returned to client pathologist for interpretation; consultation available if needed
Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry
Aid in diagnosing CNS tumor
Stained and returned to client pathologist for interpretation; consultation available if needed
Guidelines
Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med. 2015; 372(26): 2481-98. PubMed
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Jan 2017]
Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. 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. PubMed
NCCN Clinical Practice Guidelines in Oncology, Central Nervous Systen Cancers. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]
Olson JJ, Fadul CE, Brat DJ, Mukundan S, Ryken TC. Management of newly diagnosed glioblastoma: guidelines development, value and application. J Neurooncol. 2009; 93(1): 1-23. PubMed
Preusser M, Capper D, Hartmann C, Euro-CNS Research Committee. IDH testing in diagnostic neuropathology: review and practical guideline article invited by the Euro-CNS research committee. Clin Neuropathol. 2011; 30(5): 217-30. PubMed
Protocol for the Examination of Specimens from Patients with Tumors of the Brain/Spinal Cord. No AJCC/UICC TNM Staging System. Protocol web posting date: Dec 2014. College of American Pathologists (CAP). Northfield, IL [Revised Dec 2014; Accessed: Jun 2017]
General References
Brain and Spinal Cord Tumors in Adults. American Cancer Society. Atlanta, GA [Accessed: Dec 2016]
Buckner JC, Brown PD, O'Neill BP, Meyer FB, Wetmore CJ, Uhm JH. Central nervous system tumors. Mayo Clin Proc. 2007; 82(10): 1271-86. PubMed
Dhall G. Medulloblastoma. J Child Neurol. 2009; 24(11): 1418-30. PubMed
Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, Pekmezci M, Rice T, Kosel ML, Smirnov IV, Sarkar G, Caron AA, Kollmeyer TM, Praska CE, Chada AR, Halder C, Hansen HM, McCoy LS, Bracci PM, Marshall R, Zheng S, Reis GF, Pico AR, O'Neill BP, Buckner JC, Giannini C, Huse JT, Perry A, Tihan T, Berger MS, Chang SM, Prados MD, Wiemels J, Wiencke JK, Wrensch MR, Jenkins RB. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med. 2015; 372(26): 2499-508. PubMed
Frühwald MC, Rutkowski S. Tumors of the central nervous system in children and adolescents. Dtsch Arztebl Int. 2011; 108(22): 390-7. PubMed
Jansen M, Yip S, Louis DN. Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers. Lancet Neurol. 2010; 9(7): 717-26. PubMed
Magdum SA. Neonatal brain tumours - a review. Early Hum Dev. 2010; 86(10): 627-31. PubMed
Manoranjan B, Provias JP. Congenital brain tumors: diagnostic pitfalls and therapeutic interventions. J Child Neurol. 2011; 26(5): 599-614. PubMed
Nikiforova MN, Hamilton RL. Molecular diagnostics of gliomas. Arch Pathol Lab Med. 2011; 135(5): 558-68. PubMed
Perkins A, Liu G. Primary Brain Tumors in Adults: Diagnosis and Treatment. Am Fam Physician. 2016; 93(3): 211-7. PubMed
Pfister S, Hartmann C, Korshunov A. Histology and molecular pathology of pediatric brain tumors. J Child Neurol. 2009; 24(11): 1375-86. PubMed
Pytel P, Lukas RV. Update on diagnostic practice: tumors of the nervous system. Arch Pathol Lab Med. 2009; 133(7): 1062-77. PubMed
Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre J. Primary brain tumours in adults. Lancet. 2012; 379(9830): 1984-96. PubMed
Takei H, Bhattacharjee MB, Rivera A, Dancer Y, Powell SZ. New immunohistochemical markers in the evaluation of central nervous system tumors: a review of 7 selected adult and pediatric brain tumors. Arch Pathol Lab Med. 2007; 131(2): 234-41. PubMed
van den Bent MJ, Kros JM. Predictive and prognostic markers in neuro-oncology. J Neuropathol Exp Neurol. 2007; 66(12): 1074-81. PubMed
Weller M, Pfister SM, Wick W, Hegi ME, Reifenberger G, Stupp R. Molecular neuro-oncology in clinical practice: a new horizon. Lancet Oncol. 2013; 14(9): e370-9. PubMed
References from the ARUP Institute for Clinical and Experimental Pathology®
Cohen A, Sato M, Aldape K, Mason CC, Alfaro-Munoz K, Heathcock L, South ST, Abegglen LM, Schiffman JD, Colman H. DNA copy number analysis of Grade II-III and Grade IV gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status Acta Neuropathol Commun. 2015; 3: 34. PubMed
Layfield LJ, Willmore C, Tripp S, Jones C, Jensen RL. Epidermal growth factor receptor gene amplification and protein expression in glioblastoma multiforme: prognostic significance and relationship to other prognostic factors. Appl Immunohistochem Mol Morphol. 2006; 14(1): 91-6. PubMed
Lloyd IE, Clement PW, Salzman KL, Jensen RL, Salama ME, Palmer CA. An unusual and challenging case of HIV-associated primary CNS Lymphoma with Hodgkin-like morphology and HIV encephalitis Diagn Pathol. 2015; 10: 152. PubMed
Modzelewska K, Boer EF, Mosbruger TL, Picard D, Anderson D, Miles RR, Kroll M, Oslund W, Pysher TJ, Schiffman JD, Jensen R, Jette CA, Huang A, Stewart RA. MEK Inhibitors Reverse Growth of Embryonal Brain Tumors Derived from Oligoneural Precursor Cells. Cell Rep. 2016; 17(5): 1255-1264. PubMed
Paxton CN, Rowe LR, South ST. Observations of the genomic landscape beyond 1p19q deletions and EGFR amplification in glioma Mol Cytogenet. 2015; 8: 60. PubMed
Tomsic J, Senter L, Liyanarachchi S, Clendenning M, Vaughn CP, Jenkins MA, Hopper JL, Young J, Samowitz W, de la Chapelle A. Recurrent and founder mutations in the PMS2 gene. Clin Genet. 2013; 83(3): 238-43. PubMed
Tripp SR, Willmore-Payne C, Layfield LJ. Relationship between EGFR overexpression and gene amplification status in central nervous system gliomas. Anal Quant Cytol Histol. 2005; 27(2): 71-8. PubMed
Walter AW, Ennis S, Best H, Vaughn CP, Swensen JJ, Openshaw A, Gripp KW. Constitutional mismatch repair deficiency presenting in childhood as three simultaneous malignancies. Pediatr Blood Cancer. 2013; 60(11): E135-6. PubMed
Medical Reviewers
Chin, Steven S., MD, PhD, Medical Director, Neuropathology at ARUP Laboratories; Associate Professor, Director of Neuropathology, University of Utah
Last Update: April 2017