Glioblastoma multiforme

Glioblastoma multiforme (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 often cross white matter commisural tracts such as the corpus collosum  and can give rise to the so called butterfly glioma, to involve the contralateral hemisphere.  GBM's rarely involve the meninges.  These tumours are multifocal in 20% of patients and are rarely multicentric.

Epidemiology

A GBM may occur at any age, however they usually occur after the age of 40 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. 

Clinical presentation

Typically patients present in one of three ways

1. focal neurological deficit
2. symptoms of increased ICP
3. seizures

Pathology

Aetiology 

Usually unknown. Rarely related to radiation exposure. It can also occur sporadically as part of rare heritable tumour syndromes. Such examples include p53 mutation related syndromes such as NF1 and Li-Fraumeni syndrome.  Also Turcot syndrome, Ollier disease and Maffucci syndrome can also be complicated by GBM.

Classification

GBM's can be divided into primary and secondary.

Primary

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

Primary GBM tumours can have amplification of EGFR and overexpression of MDM2, mutation of PTEN and/or loss of heterozygosity of chromosome 10p.

Secondary

Cells degenerated from a lower grade astrocytoma. These tumours are less aggressive than primary GBMs and they tend to occur in younger patients.

Secondary GBM tumours can have p53 mutations, amplification of PDGF-A, loss of heterozygosity of chromosomes 10q and 17p, and increased telomerase activity and hTERT expression.

Gross appearance

GBM's are typically poorly-marginated, diffusely infiltrating necrotic masses localized to the cerebral hemispheres. 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 large 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 GBM.

Variants

• giant cell glioblastoma : accounting for 5% of GBM's, this histological variant has a mildly improved prognosis.
• gliosarcoma

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 infact usually contatins infiltration by neoplastic cells. 

CT

• irregular thick margins : iso to slightly hyper attenuating (high cellularity)
• irregular hypodense centre representing necrosis
• marked mass effect
• surrounding vasogenic oedema
• haemorrhage occasionally seen
• calcification is uncommon
• intense irregular, heterogenous enhancement  of the margins is almost always present.

MRI

• T1
  • hypo to isointense mass within white matter
  • central heterogenous signal (necrosis, intratumoural hemorrhage)
  • enhancement is variable, typically peripheral and irregular

• T2 / FLAIR
  • hyper intense
  • surrounded by vasogenic oedema
  • flow voids occasionally seen
• GE (gradient echo) / SWI - susceptability artifact on T2* from blood products (or occasionally calcification)
• DWI - no diffusion restriction, however, lower measured ADC than low grade gliomas.
• MR perfusion - rCBV elevated compared to lower grade tumours and normal brain
• MR spectroscopy
  • typical spectrocopic characteristics include
    • choline - increased
    • lactate - increased
    • lipids - increased
    • NAA - decreased
    • myo-inositol - decreased

PET

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

Treatment and prognosis

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

Differential diagnosis

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
  • haemorragic then assessment may be difficult 
• 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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