primary brain tumours

see also:

• neoplasia / cancer / tumours
• brain evolution and development
• arachnoid cysts
• CT brain

• most primary brain tumours are meningiomas or gliomas
• 6% of all malignant primary brain tumours are lymphomas

• tumours arising from arachnoidal cap cells in the meninges
• usually slow growing
• 92% are benign (“Grade I”), although may recur after surgery but still have benign histology
  • although usually benign a “petro-clival” meningioma being deep within the skull base near the brainstem is typically fatal without treatment due to its location and Rx can be challenging, often with poor outcomes
• are usually well-circumscribed, and takes on the form of the space it occupies
• accounts for 30% of adult brain tumours and affects ~1 in 1000 adults
• women 2x men (although malignant ones are more likely in men)
• becoming more likely with age, most are found in those over age 50yrs
• 25% are in falx cerebri, 19% are in the convexity of the brain, 17% are on the sphenoid ridge, 9% are suprasellar, 8% are in post fossa, 8% are in olfactory groove
• ~7% are atypical meningiomas (“Grade II”) with mean survival of ~12 yrs
• 2% are malignant anaplastic meningioma (“Grade III”) which are aggressive with mean survival of ~3 yrs
• risk factors:
  • most are sporadic rather than familial
  • FH meningioma
  • neurofibromatosis type 2 - 50% develop one or more meningiomas
  • ionizing radiation - frequent dental xrays (esp. older higher dose ones);
  • long-acting injectable contraceptive depot medroxyprogesterone acetate (Depo-Provera)
  • high doses of cyproterone acetate
• clinical features:
  • most are asymptomatic, esp. if < 2cm
  • symptoms depend on the location and occur as a result of the tumor pressing on nearby tissue
    • may cause focal seizures
• Mx:
  • select asymptomatic cases can be Mx by watchful waiting and repeat scanning as over half have no growth on repeat scans and only 6% develop symptoms
  • younger adults are more likely to have growth and should be considered for neurosurgical referral
  • can usually be surgically resected if location is amenable to surgery but 6-9% have ongoing symptoms from either the tumour or the surgery
  • if invasion of the adjacent bone occurs, total removal is nearly impossible
  • transarterial embolization has become a standard procedure in preoperative management of meningiomas
  • 10yr recurrence rates after surgery are quite high (based on Simpson grading of resection: 40% with subtotal resection, 29% with complete resection but no dura resected, 19% with dura resected as well)

• malignant tumours arising from Glial Progenitor Cells (GPC)
• 30% of all brain and CNS tumours
• 80% of all brain malignant tumours
• more commonly diagnosed in men
• glioblastoma diagnoses increase at an exponential rate with age, whereas non-glioblastoma gliomas increase in a pattern that is approximately the square root of age¹⁾
• in the US 1 year mortality is ~50%, while 2 year mortality is ~75%²⁾
• 70% of gliomas in adults are supratentorial³⁾
• 70% of gliomas in children are infratentorial⁴⁾
• usually metastasize via the CSF and can drop metastases down the spinal cord
• high-grade gliomas are highly vascular tumors and have a tendency to infiltrate diffusely and may have areas of necrosis
• tumor growth causes a breakdown of the blood–brain barrier in the vicinity of the tumor
• most high-grade gliomas grow back even after complete surgical excision, so they are commonly called recurrent cancer of the brain
• low-grade gliomas grow slowly, often over many years, and can be followed without treatment unless they grow and cause symptoms, they do still tend to recur if surgically removed
• each glioma subtype has distinct properties and requires a tumour-specific Rx approach, however, nearly all treatments include some form of surgical resection.
• IDH1 mutations have been identified in approximately 80% of grade 2/3 gliomas
  • IDH-mutant gliomas are the most common malignant brain tumor among young adults under the age of 50 with two subtypes, oligodendroglioma with 1p/19q codeletion and astrocytoma that do not harbor the 1p/19q codeletion
• glioma survival is strongly associated with the IDH1/IDH2 mutation, with IDH1 wild-type typically being associated with poorer outcomes
• whole arm deletions of the 1p and 19q chromosomes are diagnostic for oligodendrogliomas, and confer a better prognosis
• several main groups by mutation types:⁵⁾
  • IDH1 mutated infiltrating gliomas
    • IDH mutant - begin in GPCs, including OPCs, after acquiring an initial IDH mutation followed by other driver mutations ⁶⁾
    • IDH wild type - poorer outcomes; arise from neural stem cells in the subventricular zone (SVZ)
  • paediatric anaplastic astrocytoma/GBM - mutations in H3F3a, DAXX, TP53, ATRX
  • primary adult GBM - mutations in EGFR, PTEN, CDKN2A/B, NF1, PDGFRA, TERT
  • pilocytic astrocytoma/PXA - BRAF mutation
• aetiology / risk factors
  • genetic
    • neurofibromatosis
    • tuberous sclerosis complex
    • oncogenes
      • polymorphisms of the DNA repair genes ERCC1, ERCC2 (XPD) and XRCC1
    • DNA damage
      • epigenetic repression of DNA repair genes is often found in progression to sporadic glioblastoma
      • tumor suppressor protein 53 (p53) is mutated early in the disease
      • phosphatase and tensin homolog (PTEN), another tumor suppressor gene, is itself lost or mutated
      • epidermal growth factor receptor, a growth factor that normally stimulates cells to divide, is amplified and stimulates cells to divide too much
      • IDH1 and IDH2
      • nitric oxidase synthase (NOS) mutation
        • the presence of NOS mutations is now used to further differentiate diffuse gliomas, anaplastic astrocytomas, glioblastomas, oligodendrogliomas, oligoastrocytomas, and anaplastic oligoastrocytomas
    • ionizing radiation such as CT scans
      • dose-response for the relationship between low-dose ionizing radiation and glioma risk is a risk increase of 55% per 100 milligray of radiation
    • infections
      • possible causative effect of cytomegalovirus (CMV) infections but this is controversial
    • pesticide exposure
      • the TRACTOR project study, including 1,017 brain tumors among 1,036,069 farm managers, published in 2022, showed an increased risk of glioma in pig farming (HR = 2.28), crop farming (HR = 1.28) and fruit arboriculture (HR = 1.72)

• arising from astrocytes
• 17% of all malignant primary brain tumours ⁷⁾

• 46% of all malignant primary brain tumours
• mainly in adults
• aggressive form of astrocytomas appear to originate from outer radial glia cells (oRG cells) ⁸⁾
  • normally, each outer radial glia cell in human fetuses normally generate 700-1000 upper and lower layer neurons (in mice, these cells only produce 20-40 neurons)
  • as with stem cells, oRG cells selectively express LIFR/STAT3 signalling which promotes self-renewal
  • “oRG cells in mice line the ventricles where they can receive trophic factors from the CSF, however, in primates, these cells have moved away from the ventricles and no longer able to access the CSF but instead created their own signalling pathways and their own growth factors, creating their own niche for self-renewal and expansion, and thus are able to undergo prolonged and massive proliferation” ⁹⁾

• arising from oligodendrocytes
• 4.8% of all malignant primary brain tumours

• 2.7% of all malignant primary brain tumours

• arising from ependymal cells that comprise the epithelial lining of the ventricles of the brain
• 3.6% of all malignant primary brain tumours
• are generally soft and may contain calcifications or cysts
• generally develop supratentorially
• in children 90% are found in the brain whereas, in adults, 60% are found in the spinal cord
• there is an association with neurofibromatosis type II

• arise in or around the optic nerve and may cause blindness

• lack any differentiating mutations and are described primarily on histologic and phenotypic features
• angiocentric gliomas, astroblastomas, and chordoid gliomas of the third ventricle

• 3.1% of all malignant primary brain tumours