Central Nervous System Tumors - Brain Tumors

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

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

Histology

  • 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)
  • 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

  • Confirm suspected hereditary tumor in individual with personal or family history of primary CNS tumors

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
        • Patients with 1p/19q codeletion have a better prognosis than those with a single or no deletion
        • 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
          • Mutually exclusive for TP53 and EGFR amplification
          • Frequently associated with IDH1 or IDH2 mutations
    • 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 – 18/100,000 (combined benign and malignant primary brain tumors)
    • ~50% are benign
    • 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 – F>M
  • 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

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)

    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

    • Gliomas
      • Incidence – 60% of childhood CNS tumors; 6/100,000
      • Age – 5-10 years; peak 6 years
      • Clinical presentation – seizures
    • Cranial PNETs – medulloblastoma and supratentorial PNETs
      • Incidence – <1/100,000 (NCCN, 2015)
        • Most common childhood malignant CNS tumor
      • Age – peak 6 years
      • Sex – M>F; 1.6:1
      • Ethnicity – more common in Caucasians
      • Supratentorial tumors include
        • Cerebral neuroblastoma
        • Pineal blastoma
        • Esthesioneuroblastoma
      • Clinical presentation – headache, ataxia, nausea due to increased intracranial pressure
    • Ependymomas
      • Incidence – 10% of childhood tumors
      • Clinical presentation – predilection for 6th and 7th nerve palsies, loss of hearing, and swallowing difficulties
    • Craniopharyngiomas
      • Incidence – 5-10% of all childhood CNS tumors
      • Age – bimodal peaks
        • 6-10 years
        • 11-15 years
      • Clinical presentation – visual defects and endocrine abnormalities
    • Teratomas
      • Incidence – rare (1-3/1,000,000 live births)
      • Age – neonate (usually <1 year)
      • Includes 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

    Diagnosis

    • Refer to Diagnosis tab

    Indications for Laboratory Testing

    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 on 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

    Additional Tests Available

    C-Reactive Protein 0050180
    Method: Quantitative Immunoturbidimetry

    Comments

    Preferred test to detect inflammatory processes

    Sedimentation Rate, Westergren (ESR) 0040325
    Method: Visual Identification

    Comments

    Nonspecific test to rule out other disease processes

    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]

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    General References

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

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    References from the ARUP Institute for Clinical and Experimental Pathology®

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    Medical Reviewers

    Last Update: February 2016