Glioblastoma

Glioblastoma (GBM) is the most common adult primary intracranial neoplasm (see brain tumours). It accounts for 12-15% of all intracranial neoplasms and ~50% of astrocytomas. Unfortunately, it also carries the worst prognosis (WHO grade IV).

They have a preferential spreading along the condensed white matter tracts such as corticospinal tracts and corpus callosum.  They often spread across white matter commissural tracts such as the corpus callosum and can give rise to the so called butterfly glioma, to involve the contralateral hemisphere. Glioblastomas rarely involve the meninges. These tumours are multifocal in 20% of patients and are rarely multicentric.

Glioblastoma was previously known as glioblastoma multiforme. The WHO classification has dropped the 'multiforme' and thus it is best to refer to these tumours merely as glioblastomas, or grade IV astrocytomas. Somewhat confusingly the abbreviation GBM is still appropriate.

The original term was coined in 1926 by Percival Bailey and Harvey Cushing, and the suffix multiforme was meant to describe the various appearances of haemorrhage, necrosis and cysts.

A glioblastoma may occur at any age, however, they usually occur after the age of 40 years with a peak incidence between 65 and 75 years of age. There is a slight male preponderance with a 3:2 M:F ratio 5. Caucasians are affected somewhat more frequently than other ethnicities.

Glioblastomas are usually sporadic, although a proportion evolve from lower grade astrocytomas (these are usually IDH mutant - see below). Rarely they are related to prior radiation exposure (radiation-induced GBM).

They can also occur as part of rare inherited tumour syndromes, such as p53 mutation related syndromes such as neurofibromatosis type1 (NF1) and Li-Fraumeni syndrome. Other syndromes in which GBMs are encountered include Turcot syndromeOllier disease and Maffucci syndrome.

Typically patients present in one of three ways:

  • focal neurological deficit
  • symptoms of increased intracranial pressure (ICP)
  • seizures

Rarely (<2%) intratumoral haemorrhage occurs and patients may present acutely with stroke-like symptoms and signs.

Glioblastomas have traditionally been divided into primary and secondary. 

Primary

De novo origin. These tumours are more aggressive than secondary glioblastomas and they tend to occur in older patients.

Primary glioblastomas tend to have amplification of EGFR and overexpression of MDM2, mutation of PTEN and/or loss of heterozygosity of chromosome 10p 7.

Secondary

Secondary glioblastomas are those which arise from pre-existing lower grade gliomas. These tumours tend to be less aggressive than primary glioblastomas and they tend to occur in younger patients 7.

Characteristically, and unlike primary tumours, secondary glioblastomas tend to be IDH-1 mutant (positive), and demonstrate p53 mutations, amplification of PDGF-A, loss of heterozygosity of chromosomes 10q and 17p, loss of 19q and increased telomerase activity and hTERT expression 7.

Of this IDH1 mutation is most important in allowing separation of primary and secondary glioblastomas, and is present in over 80% of grade II and III astrocytomas 7,8.

Macroscopic appearance

Glioblastomas are typically poorly-marginated, diffusely infiltrating necrotic masses localised to the cerebral hemispheres. The supratentorial white matter is the most common location.

These tumours may be firm or gelatinous. Considerable regional variation in appearance is characteristic. Some areas are firm and white, some are soft and yellow (secondary to necrosis), and still other are cystic with local haemorrhage. GBMs have a significant variability in size from only a few centimetres lesions that replace a hemisphere. Infiltration beyond the visible tumour margin is always present.

Microscopic appearance

Pleomorphic astrocytes with marked atypia and numerous mitoses are seen. Necrosis and microvascular proliferation are hallmarks of glioblastomas (see WHO grading of astrocytomas).

Microvascular proliferation results in and abundance of new vessels with poorly formed blood-brain barrier (BBB) permitting the leakage of iodinated CT contrast and gadolinium into the adjacent extracellular interstitium resulting in the observed enhancement on CT and MRI respectively 11.

Oedema and enhancement are however also seen in lower grade tumours that lack endovascular proliferation (anaplastic astrocytoma and other diffuse astrocytomas, for example, gemistocytic astrocytomas) and this is thought to be due to disruption of the normal blood-brain barrier by tumour produced factors. Vascular endothelial growth factor (VEGF) for example has been shown to both disrupt tight junctions between endothelial cells and increase the formation of fenestrations 12.

Variants
Immunophenotype

As with most other glial tumours, glioblastomas are positive for GFAP.

IDH1 is positive in many secondary GBMs 8.

Markers

Serum GFAP 4.

Radiographic features

GBM's are typically large tumours at diagnosis. They often have thick, irregular-enhancing margins and a central necrotic core, which may also have a haemorrhagic component. They are surrounded by vasogenic-type oedema, which in fact usually contains infiltration by neoplastic cells.

Multifocal disease, which is found in ~20% of cases, is that where multiple areas of enhancement are connected to each other by abnormal white matter signal, which represents microscopic spread to tumour cells. Multicentric disease, on the other hand, is where no such connection can be seen.

CT
  • irregular thick margins: iso to slightly hyperattenuating (high cellularity)
  • irregular hypodense centre representing necrosis
  • marked mass effect
  • surrounding vasogenic oedema
  • haemorrhage occasionally seen
  • calcification is uncommon
  • intense irregular, heterogeneous enhancement of the margins is almost always present
MRI
  • T1
    • hypo to isointense mass within white matter
    • central heterogeneous signal (necrosis, intratumoural haemorrhage)
  • T1 C+ (Gd)
    • enhancement is variable but is almost always present
    • typically peripheral and irregular with nodular components
    • usually surrounds necrosis
  • T2/FLAIR
    • hyperintense
    • surrounded by vasogenic oedema
    • flow voids occasionally seen
  • GE/SWI
    • susceptibility artefact on T2* from blood products (or occasionally calcification)
    • Low-intensity rim from blood product 6
      • incomplete and irregular in 85% when present
      • mostly located inside the peripheral enhancing component
      • absent dual rim sign
  • DWI/ADC
    • solid component
      • elevated signal on DWI is common in solid/enhancing component
      • diffusion restriction is typically intermediate similar to normal white matter, but significantly elevated compared to surrounding vasogenic oedema (which has facilitated diffusion)
      • ADC values correlate with grade 13
        • WHO IV (GBM) = 745 ± 135 x 10-6 mm2/s
        • WHO III (anaplastic) = 1067 ± 276 x 10-6 mm2/s
        • WHO II (low grade) = 1273 ± 293 x 10-6 mm2/s
        • ADC threshold value of 1185 x 10-6 mm2/s sensitivity (97.6%) and specificity (53.1%) in the discrimination of high-grade (WHO grade III & IV) and low-grade (WHO grade II) gliomas 13
    • non-enhancing necrotic / cystic component
      • the vast majority (>90%) have facilitated diffusion (ADC values >1000 x 10-6 mm2/s)
      • care must be taken in interpreting cavities with blood product
  • MR perfusion: rCBV elevated compared to lower grade tumours and normal brain
  • MR spectroscopy
    • typical spectroscopic characteristics include
      • choline: increased
      • lactate: increased
      • lipids: increased
      • NAA: decreased
      • myoinositol: decreased
PET

PET demonstrates accumulation of FDG (representing increased glucose metabolism) which typically is greater than or similar to metabolism in grey matter.

Biopsy and tumour debulking with post-operative adjuvant radiotherapy and chemotherapy (temozolomide) are the most commonly carried out treatment. Despite this, it carries a poor prognosis with an average survival of ~12 months 3.

Negative prognostic factors include:

  • the degree of necrosis 10
  • the degree of enhancement 10
  • deep location (e.g. thalamus)
Response assessment criteria

Glioblastomas have been the subject of close trial scrutiny with many new chemotherapeutic agents showing promise. As such a number of criteria have been created over the years to assess response to treatment. Currently, the RANO criteria are most widely used. Other historical systems are worth knowing to allow interpretation of older data. These systems for response criteria for first-line treatment of glioblastomas include 9:

General imaging differential considerations include:

  • cerebral metastasis
    • may look identical
    • both may appear multifocal
    • metastases usually are centred on grey-white matter junction and spare the overlying cortex
    • rCBV in the 'oedema' will be reduced 
  • primary CNS lymphoma
    • should be considered especially in patients with AIDS, as in this setting central necrosis is more common
    • otherwise usually homogeneously enhancing 
  • cerebral abscess
    • central restricted diffusion is helpful
    • hemorrhagic then assessment may be difficult 
    • presence of smooth and complete SWI low-intensity rim 6
    • presence of dual rim sign 6
  • anaplastic astrocytoma
    • should not have central necrosis
    • consider histology sampling bias 
  • tumefactive demyelination
    • can appear similar
    • often has an open ring pattern of enhancement
    • usually younger patients
  • subacute cerebral infarction
    • history is essential in suggesting the diagnosis
    • should not have elevated choline
    • should not have elevated rCBV
  • cerebral toxoplasmosis
    • especially in patients with AIDS

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Article Information

rID: 4910
Section: Pathology
Synonyms or Alternate Spellings:
  • Glioblastoma multiforme (GBM)
  • GBM
  • GBM's
  • Glioblastoma multiforme
  • Glioblastomas
  • GBMs

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