Central Nervous System Tumors - Brain Tumors

  • Diagnosis
  • Background
  • Pediatrics
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Central nervous system (CNS) tumors cause either focal or generalized neurologic symptoms
    • Focal neurological deficits
      • Seizures
      • Changes in vision and/or papilledema
      • Changes in hearing
      • Changes in speech or swallowing
      • Change in cognition/executive function and/or personality
      • Other motor weakness
    • Generalized neurological symptoms
      • Severe headaches – either new onset or change in previous headache characteristics 
  • Nonspecific symptoms
    • Nausea
    • Vomiting
    • Fatigue

Laboratory Testing

  • Nonspecific testing to rule out other disease processes (eg, meningitis)
    • CBC, chemistry profile, C-reactive protein (CRP)
    • Lumbar puncture with collection of cerebrospinal fluid (CSF) may be indicated – do not perform before imaging studies due to risk of increased intracranial pressure and herniation
      • Protein
      • Glucose
      • Culture and Gram stain
      • Cell count and differential
      • Oligoclonal bands
      • Cytology

Histology

  • Diagnosis is based on a combination of histology (phenotyping) and molecular findings (genotyping) which direct therapy and provide prognostic information
  • Immunohistochemical staining – determine tumor cell origin
  • Genotyping – assist with classification (National Comprehensive Cancer Network [NCCN], 2017)
    • 1p/19q deletion status by fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR)
      • Codeletion, uni-deletion, or no deletion
    • IDH1 and IDH2 by PCR or pyrosequencing
    • IDH1 R1324 by immunohistochemistry

Imaging Studies

  • Magnetic resonance imaging (MRI)/contrast-enhanced computed tomography (CT) – diagnosis and possible classification of tumor
    • Perform prior to lumbar puncture
  • Magnetic resonance (MR) spectroscopy, MR perfusion – specialized circumstances
  • CT myelogram – evaluate spinal lesions
  • CT chest, abdomen, pelvis – tumor staging
  • Bone scan – suspected bone metastases
  • Positron emission tomography (PET) – may aid in diagnosis, grading gliomas, and differentiating between tumor recurrence and radiation necrosiss

Familial Genetic Testing

Indications for genetic testing are fairly rare and fully outlined in American College of Medical Genetics (ACMG) guidelines (Hampel, ACMG, 2015).

Prognosis

  • Differentiation of astrocytomas from oligodendrogliomas has prognostic and therapeutic importance
  • Mutations
    • 1p/19q codeletion (FISH or PCR)
      • 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
    • IDH1/IDH2 mutations (PCR)
      • Favorable outcomes in World Health Organization (WHO) gliomas
      • SNP rs11554137 associated with unfavorable prognosis
    • MGMT promoter methylation (PCR)
      • Prognostic in glioma
      • 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)

Differential Diagnosis

Central nervous system (CNS) tumors are abnormal collections of benign or malignant cells. Integrated phenotypic and genotypic CNS tumor classification parameters are the hallmark of the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System.

Epidemiology

  • Incidence
    • New brain tumor – 6.4/100,000 (Perkins, 2016)​
    • ~50% are benign
  • Prevalence
    • Malignant – ~23,380 cases in U.S. in 2014  (Perkins, 2016; National Comprehensive Cancer Network [NCCN], 2017)
    • Small percentage are hereditary
    • Metastatic malignant CNS tumors are 10 times more frequent than primary tumors (NCCN, 2017)
  • Sex
    • All CNS tumors – M<F, minimal
    • Meningioma – M<F
  • Age – peak 55-64 years (Perkins, 2016)

Risk Factors

  • Viral infection – HIV infection associated with CNS lymphoma
  • High dose ionizing radiation
  • Genetic syndromes (see table in Genetics)

Classification

For a list of the classification for various CNS tumors, see the 2016 WHO summary

Pathophysiology

  • CNS tumors are classified as glioma or nonglioma through histology and genetic testing – classification of not otherwise specified (NOS) is possible if genetic testing is unavailable
    • Gliomas (~50% of primary brain tumors) – most common
      • Astrocytomas – includes glioblastoma  
        • Glioblastoma – 50% of gliomas; ~15% of all CNS tumors
        • Low-grade astrocytoma can transform into glioblastoma within 5-10 years
      • Oligodendrogliomas
      • Ependymomas – occur more often in spinal canal
      • Other astrocytic tumors and gliomas
    • Nongliomas
      • Region specific tumors (pineal region, choroid plexus, sellar region, cranial and paraspinal nerves) and glioneuronal tumors
        • Pituitary adenomas – usually benign
      • Meningiomas – usually benign but can be atypical meningiomas (WHO grade II) or anaplastic (WHO Grade III)
        • Atypical graded based on the following characteristics (WHO, 2016)
          • Brain invasion or
          • >4 mitoses or
          • 3 of 5 histological features (spontaneous necrosis, sheeting, prominent nucleoli, high cellularity, and small cell change)
      • Mesenchymal tumors – solitary fibrous tumors
        • Characterized by inversions at 12q13 with NAB2-STAT6 fusion
        • Graded I-III with cellularity, “staghorn” vasculature, and mitoses as key features
      • Melanocytic tumors
      • Embryonal tumors – see Pediatrics section
    • Primary spinal cord tumors – extradural, intradural-extramedullary, and intradural-intramedullary
      • Extradural tumors are usually metastatic
    • Metastases
      • Leptomeningeal metastases – 50% of patients with cancer
      • Spinal metastases – arise most commonly from breast, lung, prostate, and renal cancers
      • Brain metastases – arise most commonly from lung and breast cancers, and melanoma
    • Hematopoietic/lymphoid tumors

Genetics

  •  

    Clinical Background

    Epidemiology

    Incidence – 2-5/100,000

    Risk Factors

    • Irradiation
    • Familial syndromes (refer to Background section)

    Genetics

    Refer to Background section

    Indications

    • See Indications for Testing in Diagnosis section
    • Nausea, emesis, and headaches are more common in the pediatric population

    Specific tumors​

    • Gliomas
      • Incidence
        • 6/100,000
        • 60% of childhood central nervous system (CNS) tumors
      • Age – 5-10 years; peak 6 years
      • Clinical presentation – seizures
      • Do not routinely possess IDH mutations
      • Have 1p/19q codeletions like adult counterparts
      • Pilocytic astrocytoma (World Health Organization [WHO] grade I)
        • Most common glioma of children and adolescents
        • Cerebellum, midline (optic nerve/chiasm, hypothalamus, thalamus, basal ganglia, brain stem, and spinal cord), and intraventricular locations
        • BRAF fusions (KIAA1549-BRAF) found in 90% of cerebellar and 50% of supratentorial cases
        • BRAF V600E in 5% of cases but in other CNS tumors as well
        • Absence of BRAF mutation has no diagnostic significance, but a positive result is confirmatory
        • Pilomyxoid variant has similar distribution but worse overall prognosis
      • Diffuse midline glioma, H3K27-mutant (WHO grade IV)
    • Embryonal tumors
      • Incidence
        • <1/100,000 (National Comprehensive Cancer Network [NCCN], 2017)
        • Most common childhood malignant CNS tumor
      • Age – peak 6 years
      • Sex – M>F; 1.6:1
      • Ethnicity – more common in Caucasians
      • Nonmedulloblastoma (supratentorial) tumors
        • Cerebral neuroblastoma
        • Pineoblastoma
        • Olfactory neuroblastoma
      • Medulloblastoma tumors
        • The most common childhood malignant CNS tumor
        • Diagnosis is now histologically and genetically modular
          • Medulloblastoma Classification

            Medulloblastoma

            Histology

            Prevalence

            Risk

            WNT activated

            Classic

             

            Low

            Large cell/anaplastic

            Very rare

            Uncertain significance

            SHH activated, TP53 mutant

            Classic

             

            High (uncommon)

            Large cell/anaplastic

            Children 7-17 yrs

            High

            Desmoplastic/nodular

            Very rare

            Uncertain significance

            SHH activated, TP53 wildtype

            Classic

             

            Standard

            Large cell/anaplastic

             

            Uncertain significance

            Desmoplastic/nodular

            Infants and adults

            Low (in infants)

            Extensive nodularity

            Infants

            Low

            Non-WNT/non-SHH, group 3

            Classic

             

            Standard

            Large cell/anaplastic

             

            High

            Non-WNT/non-SHH, group 4

            Classic

             

            Standard

            Large cell/anaplastic

            Rare

            Uncertain significance

            Adapted from Louis, 2016

    • Ependymomas
      • Incidence – 10% of childhood tumors
      • Clinical presentation – predilection for sixth and seventh nerve palsies, loss of hearing, and swallowing difficulties
    • Craniopharyngiomas (WHO grade I)
      • Incidence – 5-10% of all childhood CNS tumors
      • Age – 6-15 years
      • Clinical presentation – visual defects and endocrine abnormalities
      • Adamantinomatous craniopharyngiomas show CTNNB1 mutations and aberrant nuclear beta-catenin expression in 95% of cases
      • Papillary craniopharyngiomas show BRAF V600E mutations in 81-95% of cases
    • Teratomas
      • Incidence – rare (1-3/million live births)
      • Age – neonate (usually <1 year)
      • Includes components of astrocytoma, primitive neuroectodermal, and choroid plexus papillomas
      • Clinical presentation
        • Often diagnosed prenatally by ultrasound
        • Bulging fontanelle, failure to thrive, apnea, emesis, abnormal head circumference
        • Benign tumors often exhibit malignant behavior in this age group
    • Diffuse leptomeningeal glioneuronal tumor (no WHO grade assigned)
      • Commonly harbor BRAF fusions
      • Deletions of 1p and occasionally 19q
      • Absence of IDH mutations
      • Variable prognosis
    • Embryonal tumor with multilayered rosettes, C19MC-altered
      • Amplification of C19MC region on chromosome 19 (19q13.42)
      • Consider embryonal tumor with multilayered rosettes, not otherwise specified (NOS), and medulloepithelioma in the absence of C19MC amplification
    • Atypical teratoid/rhabdoid tumor (AT/RT) (WHO grade IV)
      • Defined by alterations of INI1 or very rarely BRG1
      • Loss of nuclear expression correlates with genetic alteration

    Diagnosis

    Refer to Diagnosis section

    Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

    1p/19q Deletion by FISH 2008604
    Method: Fluorescence in situ Hybridization

    Limitations 

    Test should not be used alone for diagnosis of malignancy

    IDH1 and IDH2 Mutation Analysis, exon 4 2006444
    Method: Polymerase Chain Reaction/Sequencing

    Limitations 

    Negative test result does not exclude mutations below 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

    Limitations 

    Negative test result does not exclude mutations below 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

    ATRX by Immunohistochemistry 2014499
    Method: Immunohistochemistry

    IDH1 R132H by Immunohistochemistry 2005857
    Method: Immunohistochemistry

    Limitations 

    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

    Limitations 

    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

    Glial Fibrillary Acidic Protein (GFAP) by Immunohistochemistry 2003899
    Method: Immunohistochemistry

    S-100 Protein by Immunohistochemistry 2004127
    Method: Immunohistochemistry

    CD56 (NCAM) by Immunohistochemistry 2003589
    Method: Immunohistochemistry

    p53 with Interpretation by Immunohistochemistry 0049250
    Method: Immunohistochemistry

    CD117 (c-Kit) by Immunohistochemistry 2003806
    Method: Immunohistochemistry

    Placental Alkaline Phosphatase (PLAP) by Immunohistochemistry 2004097
    Method: Immunohistochemistry

    Human Chorionic Gonadotropin (Beta-hCG) by Immunohistochemistry 2003920
    Method: Immunohistochemistry

    Alpha-1-Fetoprotein (AFP) by Immunohistochemistry 2003436
    Method: Immunohistochemistry

    Inhibin by Immunohistochemistry 2003969
    Method: Immunohistochemistry

    D2-40 by Immunohistochemistry 2003857
    Method: Immunohistochemistry

    Synaptophysin by Immunohistochemistry 2004139
    Method: Immunohistochemistry

    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: Sep 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

    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 Neuropathol. 2016; 131(6): 803-20. PubMed

    NCCN Clinical Practice Guidelines in Oncology, Central Nervous System Cancers. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Aug 2017]

    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: Aug 2017]

    General References

    Brain and spinal cord tumors in adults. American Cancer Society. Atlanta, GA [Accessed: Aug 2017]

    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

    Content Reviewed: 
    August 2017

    Last Update: October 2017