Central Nervous System Tumors - Brain Tumors

Diagnosis

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

  • CBC, chemistry profile, erythrocyte sedimentation rate (ESR)
    • Few abnormalities – except for possible increased ESR
    • Not used to make diagnosis

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 by FISH
      • Presence of codeletion establishes diagnosis of oligodendroglioma
      • Gain of chromosome 19 supports diagnosis of high-grade astrocytoma

Imaging Studies

  • CT, MRI – MRI is more sensitive than CT for diagnosis and for identifying tumor type
  • PET – used in assessing 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

  • 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
      • 1p/19q codeletion – frequently associated with IDH1 or IDH2 mutations
    • IDH1/IDH2 mutations – favorable outcomes in WHO grade I and II gliomas
      • SNP rs11554137 associated with unfavorable prognosis
    • MGMT promoter methylation
      • Prognostic in glioma
      • Methylation associated with significantly increased overall and progression-free survival
        • Improved survival in those treated with alkylating agents
    • Immunohistochemistry – p53

Differential Diagnosis

Clinical Background

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

Epidemiology

  • Incidence – 18/100,000 for both benign and malignant brain tumors
    • ~50% are histologically benign
    • Small percentage are hereditary
  • Sex – M<F (minimal)
    • Higher meningioma incidence in females
  • Age – highest increased incidence in patients >70 years
    • Peak incidence for anaplastic glioma/glioblastoma is 45-55 years

Risk Factors

  • Viral infection
    • HIV infection is associated with an increased risk of 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 gliomas
      • Ependymomas
    • Non-gliomas
      • Meningiomas – usually benign
      • Pituitary adenomas – often benign
      • Primary CNS lymphoma
      • Medulloblastoma – childhood cerebellar tumor
      • Brain metastases – neoplasm of lung, breast, or skin (melanoma) most common

Genetics

  • Associated CNS tumors/syndromes by gene

    Gene

    Symbol

    Associated CNS Tumors/Syndromes

    ALK

    Neuroblastoma; ganglioneuroblastoma; ganglioneuroma (typically infancy to early childhood)

    APC

    CNS medulloblastoma

    BAP1

    Meningioma

    BRCA2

    Medulloblastoma

    LZTR1

    Schwannoma

    MEN1

    MEN1 syndrome (pituitary adenoma)

    MLH1

    CNS glioblastoma; medulloblastoma; Turcot syndrome; constitutional mismatch repair-deficiency syndrome

    MSH2

    CNS glioblastoma;  medulloblastoma; Turcot syndrome; constitutional mismatch repair-deficiency syndrome

    MSH6

    CNS glioblastoma; medulloblastoma; Turcot syndrome; constitutional mismatch repair-deficiency syndrome

    NF1

    CNS, glioma

    NF2

    Bilateral vestibular schwannoma; meningioma; ependymoma; glioma; rarely astrocytoma

    PHOX2B

    Neuroblastoma; ganglioma

    PMS2

    Glioblastoma

    PRKAR1A

    Carney complex (pituitary adenoma, schwannoma)

    PTCH1

    Nevoid basal cell carcinoma syndrome (Gorlin syndrome); medulloblastoma

    PTCH2

    Medulloblastoma

    PTEN

    Occasionally brain tumor; Lhermitte-Duclos syndrome and Cowden syndrome type I (cerebellar dysplastic gangliocytoma)

    RB1

    Pinealoblastoma; retinoblastoma

    SMARCB1

    Choroid plexus carcinoma; medulloblastoma; central primitive neuroectodermal; schwannomatosis; meningioma; malignant rhabdoid tumor predisposition

    STK11

    Occasional brain tumor

    SUFU

    Desmoplastic medulloblastoma; meningioma

    SWNTS1

    Schwannomatosis (spinal schwannomas, meningioma)

    TP53

    Tuberous sclerosis complex (astrocytoma, glioma); brain; Li-Fraumeni syndrome (medulloblastoma) 

    TSC1

    Tuberous sclerosis type I (astrocytoma)

    VHL

    Retinal; spinal; cerebellar; hemangioblastoma; CNS 

Clinical Presentation

  • Neurological deficits
    • Seizures – more common with gliomas
    • Focal deficits
    • Executive/cognitive dysfunction
    • Tremors
  • Visual deficits
    • Visual field deficits
    • Paresis of upgaze (setting sun sign)
  • Papilledema

Pediatrics

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

  • Glioma
    • Incidence – 60% of childhood CNS tumors
    • Age – 5-10 years; peak is 6 years
    • Seizures more common with this tumor
  • Medulloblastoma
    • Incidence – 6/100,000
      • Most common childhood malignant CNS tumor
    • Age – peak is 6 years
    • Sex – M>F; 1.6:1
    • Ethnicity – more common in Caucasians
  • Ependymomas
    • Incidence – 10% of childhood tumors
    • Clinical presentation – predilection for 6th and 7th nerve palsies, loss of hearing and swallowing
  • Craniopharyngiomas
    • Incidence – 5-10% of all childhood CNS tumors
    • Age – bimodal peaks: 6-10 years, 11-15 years
    • Clinical presentation – visual signs and symptoms and endocrine abnormalities
  • Teratoma
    • Astrocytoma, primitive neuroectodermal and choroid plexus papillomas
    • Incidence – rare (1-3/1,000,000 live births)
    • Age – neonate (usually <1 year)
    • 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
Test Name and Number Recommended Use Limitations Follow Up
1p/19q Deletion by FISH 2008604
Method: Fluorescence in situ Hybridization

Use to diagnose oligodendrogliomas

Predict response to therapy in oligodendrogliomas

Fix in formalin for optimal results

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

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

Use to determine risk group of individuals with glioma

Analytical sensitivity – 40% mutated cells

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

Use in patients suspected of having a diagnosis of glioma based on morphology

Use to differentiate tumors from reactive gliosis

Stained and returned to client pathologist for interpretation; consultation available if needed

   
MGMT Methylation Detection by PCR 2009310
Method: Real-Time Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer

Use for individuals with glioma being treated or considered for treatment with alkylating agents (eg, Temozolomide)

Recommended for WHO grade III-IV astrocytic, oligodendroglial, and oligoastrocytic brain tumors

Analytical sensitivity – limit of detection is methylation levels ≥1%

Analytical specificity – 100%

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 diagnosing CNS tumor

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

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

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

Not indicated for individuals with suspected metastatic tumors

Genes included – ALK, APC, BAP1, MLH1, MSH2, MSH6, NF2, PHOX2B, PTEN, RB1, SMARCB1, SUFU, TP53, VHL

Clinical sensitivity 5% of primary CNS tumors are caused by germ line mutations

Analytical sensitivity/specificity – 99%

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