Glioblastoma multiforme (GBM)

Glioblastoma (GBM) is the most common primary intracranial neoplasm in adults, accounting for 12-15% of all intracranial neoplasms and 50-60% of astrocytomas.  Unfortunately, it also carries the worst prognosis (WHO grade IV/IV). 

GBM's are typically poorly-marginated, diffusely infiltrating necrotic masses localized to the cerebral hemispheres. Supratentorial white matter is the most common location. 

They often cross white matter commisural tracts such as the corpus collosum ("butterfly glioma", anterior and posterior commisures) to involve the contralateral hemisphere.  GBMs rarely involve the meninges.  These tumours are multifocal in 20% of patients and are rarely multicentric.

Demographics

GBM may occur at any age, however they usually occurs after age 40.  The peak age range is 45 to 70 years old and there is a 3:2 male:female preponderance.

Aetiology

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

Gross Appearance

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 microvascula proliferation are hallmarks of GBM.

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

Classification and molecular genetics

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 amplication of EGFR and overexpression of MDM2, mutation of PTEN and/or loss of heterozygosity of chromosome 10p.

Secondary

Cell degenerated from a lower grade astrocytoma.  These tumours are less aggressive than primary GBM 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.

NB. Both primary and secondary are WHO grade IV/IV.

Radiographic findings

DX CLUE: thick, irregular-enhancing ring of neoplastic tissue surrounding a necrotic core.

CT

NECT: Irregular isodense to hypodense mass with central hypodensity representing necrosis.  The tumour causes marked mass effect and surrounding edema.  Hemorrhage can be seen but calcification is rare.

CECT: Strong, irregular, heterogenous ring-enhancement is seen in 95% of cases.

MRI

TW1: Irregular hypointense to isointense white matter mass.  Heterogeneous with hypointensity secondary to necrosis and irregular enhancement and high signal that can be attributed to active mitoses and intratumoural hemorrhage respectively.

TW2: Heterogenous, hyperintense mass with adjacent vasogenic edema.  Flow voids, secondary to neovascularity, may be seen.

FLAIR: Heterogenous, hyperintense mass with adjacent vasogenic edema.

T2*GRE: Blood products cause susceptability artifact on T2*.

T1 C+: Enhancement may be solid, ring-shaped, nodular or patchy.  The typical pattern of enhancement is a thick, irregular rind surrounding central necrosis.

DWI: No diffusion restriction, however, lower measured ADC than low grade gliomas.

PWI: rCBV elevated compared to low grade tumours.

MRS: decreased NAA and myo-inositol.  Elevated choline, lactate and lipid levels.

Nuclear Medicine

PET: as with other malignant tumours, GBM's have elevated accumulation of FDG due to increased glucose metabolism (similar to or exceeding glucose metabolism in gray matter).

Clinical presentation and prognosis

The presentation varies with location.  However, seizures, mental status changes and focal neurologic deficits are common.  The duration of symptoms is relatively short due to the rapid growth of these tumours. 

Prognosis is horrible and patients generally die in 9-12 months from diagnosis.  Mean survival at 2 years is 10% [2].

Treatment

Biopsy and tumour debulking with post-operative adjuvant radiotherapy and chemotherapy. 

DDx

• Cerebral abscess: ring-enhancement is thinner than in GBM.  On T2, the abscess rim is hypointense. The MRS may show metabolites not in GBM such as succinate and amino acids.
• Cerebral metastasis: usually not solitary however if single, a met may be indistinguishable.  Typically multiple lesions located at the gray white junction.  More often rounded and infiltrating less likely. Primary often known from the history.
• Primary CNS lymphoma: tendancy to localize periventricularly and cross the corpus collosum.  Typically isointense to hypointense on T2W.  Necrosis is common in AIDS-related lymphoma
• Anaplastic Astrocytoma: It may be indistinguishable however it is often a non-enhancing white matter mass with far less vasogenic edema.  Any enhancement may indicate degeneration to a GBM.
• Tumefactive demyelination: may differ with incomplete, "horseshoe-shaped" enhancement.
• Subacute infarct: localized to a vascular territory (eg MCA, ACA, PCA) and may have mass effect and gyriform enhancement.  Follow-up imaging may be useful in differentiating.
• Status epilepticus: active seizures may cause diffuse enhancement which affects both the gray and white matter.  Signal abnormalities are also seen.  A clinical history of seizures is formative.

NB. Corpus Collosum involvement is seen in GBM, lymphoma, and rarely in metastasis and demyelination.