Central Nervous System Tumors - Brain Tumors

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

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

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)

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 (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

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
    • 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 (so called triple positive tumors)

Differential Diagnosis

Central nervous system (CNS) tumors cause either focal or generalized neurologic symptoms.

Epidemiology

  • Incidence
    • New brain tumor – 6.4/100,000 (Perkins, 2015)​
    • ~50% are benign
  • Prevalence
    • Malignant – ~21/100,000 (Perkins, 2015)
    • Small percentage are hereditary
    • Most malignant CNS tumors are metastatic and not primary (10 times more frequent than primary tumors [NCCN, 2015])
  • Sex – over all
    • M<F (minimal)
    • Meningioma – M<F
  • Age – increased incidence >70 years
    • Peak incidence for anaplastic glioma/glioblastoma is 45-55 years

Risk Factors

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

Pathophysiology

  • Histologically classified as glioma or non-glioma
    • Gliomas (~50% of primary brain tumors) – most common
      • Astrocytomas – includes glioblastoma multiforme (GBM)
        • GBM – 50% of gliomas; ~15% of all CNS tumors
        • Low-grade astrocytoma can transform into glioblastoma within 5-10 years
      • Oligodendrogliomas
      • Mixed oligoastrocytomas
      • Ependymomas – occur more often in spinal canal
    • Non-gliomas
      • Pituitary adenomas – usually benign
      • Meningiomas – usually benign
      • Primary CNS lymphoma – typically non-Hodgkin subtype
        • Increased risk in HIV patients
      • Cranial PNETs – includes medulloblastoma and supratentorial PNETs
        • Predominately childhood tumors
      • Primary spinal cord tumors – extradural, intradural-extramedullary, 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

Genetics

  • Clinical Presentation

    • Neurological deficits
      • Seizures – more common with gliomas, in particular oligodendrogliomas
      • Focal deficits
      • Executive/cognitive dysfunction
      • Tremors
      • Cranial nerve palsies – common with ependymomas
    • Visual deficits
      • Visual field deficits
      • Upgaze paresis (setting sun sign)
    • Papilledema

    Clinical Background

    Epidemiology

    • Incidence – 2-5/100,000

    Risk Factors

    • Irradiation
    • Familial syndromes (refer to Clinical Background tab)

    Genetics

    • Refer to Background tab

    Clinical Presentation

    • Neurological deficits
      • Seizures
      • Focal deficits
      • Executive/cognitive dysfunction
      • Tremors
    • Visual deficits
      • Visual field deficits
      • Paresis of upgaze (setting sun sign)
    • Papilledema
      • Nausea, emesis, and headaches are much more common in children than in adults

    Specific tumors

    Diagnosis

    • Refer to Diagnosis tab

    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

    Absence of combined loss of 1p and 19q does not exclude diagnosis of oligodendroglioma

    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 the limit of detection and presence of mutations other than those detected by the test

    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

    Central Nervous System Hereditary Cancer Panel, Sequencing and Deletion/Duplication, 15 Genes 2010188
    Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

    Limitations

    Not determined or evaluated

    • Mutations in genes not included on the panel
    • Deep intronic and regulatory region mutations
    • Breakpoints for large deletions/duplications
    • Large deletions/duplications in exon 1 of BAP1 and MSH2 genes; exons 7 and 13 in NF2 gene; exon 8 in PTEN gene; exon 5 in SMARCB1 gene; exons 4, 6, and 7 in STK11 gene

    Diagnostic errors can occur due to rare sequence variations

    Individuals with hematological malignancy and/or a previous allogenic bone marrow transplant should not undergo molecular genetic testing on peripheral blood specimen

    Testing of cultured fibroblasts or buccal specimen is required for accurate interpretation of test results

    Lack of a detectable gene mutation does not exclude a diagnosis of hereditary CNS cancer syndrome; not all predisposing genes are analyzed

    Related Tests

    Guidelines

    American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

    Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG W, et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med. 2015; 372(26): 2481-98. PubMed

    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: June 2008; Protocol effective date: February 2009 . No AJCC/UICC TNM Staging System. Protocol web posting date: June 2008; Protocol effective date: February 2009. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

    General References

    Brain and Spinal Cord Tumors in Adults. American Cancer Society. Atlanta, GA [Accessed: Nov 2015]

    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 SAshok. 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®

    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

    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

    Last Update: May 2016