Central Nervous System Tumors - Brain Tumors

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: 5 Things Physicians and Patients Should Question, 2015; American Society for Clinical Pathology)
- Lumbar tap with CSF studies may be indicated

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

Infections
- Meningitis
- Encephalitis
- Brain abscess
- Parasites
  - Taenia solium
  - Toxocara spp
Seizure disorder
Migraine headache
Stroke
Vasculitis
Autoimmune CNS syndrome (eg, systemic lupus erythematosus cerebritis)

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

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, 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

Specific tumors in pediatrics
- 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

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

Recommended Use

Use to diagnose oligodendrogliomas; indicated in both low-grade and high-grade (anaplastic) oligodendrogliomas

Predict response to therapy in oligodendrogliomas

Fix in formalin for optimal results

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

Recommended Use

Prognostic testing for individuals with glioma

Refer to Additional Technical Information document for further content

Analytical sensitivity – 40% mutated cells

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

Recommended Use

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

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

Recommended Use

Aid in therapeutic decisions in individuals with gliomas

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

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

Analytical specificity – 100%

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

Recommended Use

Aid in diagnosing CNS tumor

Stained and resulted by ARUP

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

Recommended Use

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

Recommended Use

Aid in diagnosing CNS tumor

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

CD56 (NCAM) by Immunohistochemistry 2003589
Method: Immunohistochemistry

Recommended Use

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

Recommended Use

Aid in diagnosing and prognosing CNS tumor

Stained and resulted by ARUP

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

Recommended Use

Initial screening test in tumor that is morphologically and clinically suspicious for GIST

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

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

Recommended Use

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

Recommended Use

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

Recommended Use

Aid in diagnosing CNS tumor

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

Inhibin by Immunohistochemistry 2003969
Method: Immunohistochemistry

Recommended Use

Aid in diagnosing CNS tumor

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

D2-40 by Immunohistochemistry 2003857
Method: Immunohistochemistry

Recommended Use

Aid in diagnosing CNS tumor

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

Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

Recommended Use

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: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Recommended Use

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

Not indicated for individuals with suspected metastatic tumors

Pathogenic PHOX2B polyalanine expansions causative for congenital hypoventilation syndrome not detected

Genes included – ALK, APC, BAP1, MLH1, MSH2, MSH6, NF2, PHOX2B, PTEN, RB1, SMARCB1, STK11, SUFU, TP53, VHL

Refer to Additional Technical Information document for further content

Clinical sensitivity – 5% of primary CNS tumors are caused by germline mutations

Limitations

Not determined or evaluated

Pathogenic variants in genes not included on the panel
Deep intronic and regulatory region pathogenic variants
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

Polyalanine repeats of the PHOX2B gene are not analyzed

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 pathogenic gene variant does not exclude a diagnosis of hereditary CNS cancer syndrome; not all predisposing genes are analyzed

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, 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: Dec 2014. College of American Pathologists (CAP). Northfield, IL [Revised Dec 2014; 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 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

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