Central Nervous System Tumors - Brain Tumors

Diagnosis

Indications for Testing

• Central nervous system (CNS) tumors cause either focal or generalized neurologic symptoms
  • Focal neurologic 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 neurologic 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
  • See Classification in Background and table in Pediatrics
• 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 ATRX mutations 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

• Metastatic cancer
• Infections
  • Meningitis
  • Encephalitis
  • Brain abscess
  • Parasites
    • Toxoplasma gondii
    • Toxocara spp
• Seizure disorder
• Migraine headache
• Stroke
• Vasculitis
• Autoimmune CNS syndrome (eg, systemic lupus erythematosus​ cerebritis, multiple sclerosis, sarcoidosis, autoimmune encephalitis, neuromyelitis optica)
• Progressive multifocal leukoencephalopathy (see JC Virus topic)
• Subacute sclerosing panencephalitis (see Rubeola topic)

Background

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
        • More than four mitoses or
        • Three of five histologic 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
  • 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
    • B-cell lymphomas
    • T-cell/NK-cell lymphomas

Genetics

Pediatrics

Epidemiology

Incidence – 2-5/100,000

Risk Factors

• Irradiation
• Familial syndromes (refer to Background)

Indications

• See Indications for Testing in Diagnosis
• 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