Glioblastoma, IDH-wildtype
Updates to Article Attributes
Glioblastomas (GBM) are the most common adult primary brain tumour and are, unfortunately, aggressive, relatively resistant to therapy, and have a corresponding poor prognosis.
They typically appear as heterogeneous masses centred in the white matter with irregular peripheral enhancement, central necrosis and are surrounded by vasogenic oedema.
Treatment primarily consists of surgery and concurrent radiotherapy and temozolomide.
Terminology
Since 1926 when the term Glioblastoma multiforme was coined, the definition of this tumour has substantially changed, particularly over the past decade with an increasing reliance on molecular markers to define these tumours.
IDH-wildtype
In the 5th Edition (2021) of the WHO classification of CNS tumours, glioblastomas have been defined as diffuse astrocytic tumours in adults that must be IDH-wildtype and are now an entirely separate diagnosis from astrocytoma, IDH-mutant grade 2, 3 or 4 5.
Multiforme
Glioblastoma was previously known as glioblastoma multiforme; the multiforme referred to the tumour heterogeneity. In the revised 4th edition (2016) of the WHO classification, the term 'multiforme' was dropped, with these tumours referred to merely as glioblastomas. In the revised 4th edition, the abbreviation GBM was kept for disambiguation16 however it appears to have been deprecated in 5th edition summary 20.
Primary and secondary
Glioblastomas had traditionally been divided into primary and secondary; the former arising de novo (90%) whereas the latter developed from a pre-existing lower grade tumour (10%).
These historical terms now correlate closely to IDH-mutation status but should no longer be used.
Primary glioblastomas largely equate to glioblastoma, IDH wild-type, whereas secondary glioblastomas would now equate to astrocytoma, IDH mutant, WHO CNS grade 4.
Variants
In the 5th edition (2021) WHO classification of CNS tumours, three glioblastoma histological variants are recognised (which are discussed separately) as well as a number of histological patterns which are discussed below 16.
The three recognised variants are:
Epidemiology
Glioblastomas, now defined as IDH-wildtype tumours, are essentially tumours of adults, usually occurring 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 more frequently than other ethnicities: Europe and North America 3-4 per 100,000 whereas Asia 0.59 per 100,000 16.
The vast majority of glioblastomas are sporadic. 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 syndrome, Ollier disease and Maffucci syndrome.
Clinical presentation
Typically patients present in one of three ways:
- focal neurological deficit
- symptoms of increased intracranial pressure
- seizures
Rarely (<2%) intratumoral haemorrhage occurs and patients may present acutely with stroke-like symptoms and signs.
Diagnosis
Diagnostic criteria
The 5th edition (2021) of the WHO classification of CNS tumours incorporates molecular parameters into the diagnostic criteria. In this classification, to make the diagnosis of a glioblastoma the following are required 20:
- adult patient
- diffuse astrocytic tumour
- IDH-wildtype
- and at least one of the following
- necrosis
- microvascular proliferation
- TERT promoter mutation
- EGFR gene amplification
- combined gain of whole chromosome 7 and loss of chromosome 10 [+7/-10]
In the rare situation where these criteria are not met, it is likely the tumour will be denoted as not elsewhere classified (NEC) although a variety of pediatric-type diffuse gliomas may be worth considering 20.
Pathology
Although glioblastomas can arise anywhere within the brain, they have a predilection for the subcortical white matter and deep grey matter of the cerebral hemispheres, particularly the temporal lobe 16.
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, others are cystic with local haemorrhage. GBMs have significant variability in size from only a few centimetres to lesions that replace a hemisphere. Infiltration beyond the visible tumour margin is always present.
These tumours are multifocal in 20% of patients but are rarely truly multicentric.
Microscopic appearance
Pleomorphic astrocytes with marked atypia and numerous mitoses are seen. Necrosis and microvascular proliferation are hallmarks of glioblastomas.
Microvascular proliferation results in an abundance of new vessels with a 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.
Cellular variants
Glioblastomas are capable of demonstrating varied patterns, sometimes within one tumour. In addition giant cell glioblastoma, gliosarcoma, and epithelioid glioblastoma, other histological features are sometimes encountered which impact imaging appearance and biological behaviour. These include 16:
- gemistocytes
- more commonly seen in grade 4 gemistocytic astrocytoma
- granular cells
- histologically mimic macrophages and thus can lead to a misdiagnosis of macrophage-rich demyelination
- lipidized cells
- metaplasia
- most commonly squamous epithelium
- if dominant feature then a diagnosis of gliosarcoma should be considered
- multinucleated giant cells
- a common feature of glioblastoma
- if they are the dominant feature then a diagnosis of giant cell glioblastoma should be considered
- primitive neuronal cells
- previously known as glioblastoma with PNET-like component
- more frequently has CSF spread
- MYC or MYCN amplification common
- IDH mutant in 15-20% of cases
- small cell glioblastoma
- histologically appears similar to oligodendroglioma cell, but usually demonstrate EGFR amplification
- like oligodendrogliomas, they have a predilection for extensive cortical involvement
Immunophenotype
- GFAP: positive but of variable intensity
- S100: positive
- nestin: positive
- p53 protein: positive if TP53 mutated
- EGFR: positive in 40-98% of cases 16
- IDH-1 R132H: negative (by definition, otherwise not an IDH wild-type GBM, but rather an astrocytoma, IDH-mutant WHO CNS grade 4) 16
- H3 K27M mutation: negative (if positive then diffuse midline glioma H3 K27M-mutant)
Genetics
- EGFR gene amplification
- TERT promoter mutations
- combined gain of whole chromosome 7, loss of chromosome 10 [+7/-10]
Radiographic features
Glioblastomas 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. Multi-centric 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 is occasionally seen
- calcification is uncommon
- intense irregular, heterogeneous enhancement of the margins is almost always present
MRI
-
T1
- hypo to isointense mass within the 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 are occasionally seen
-
GE/SWI
- susceptibility artifact 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 in the solid component tend to be similar to normal white matter 745 ± 135 x 10-6 mm2/s 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
- solid component
- 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
- typical spectroscopic characteristics include
PET
PET demonstrates the accumulation of FDG (representing increased glucose metabolism) which typically is greater than or similar to metabolism in grey matter.
Radiogenomics
A number of features are seen to correlate with molecular marker status.
- high ADC values, limited surrounding oedema, low CBV is correlated with MGMT promoter methylation - sensitivity 79% (95% CI, 72%–85%), specificity 78% (95% CI, 71%–84%) 19
Radiology report
When reporting a new diagnosis of a mass that is likely a glioblastoma, it is useful to include:
- morphology
- size in three dimensions
- degree of central necrosis
- non-enhancing tumour involving cortex, deep grey or white matter: look at ADC for lower values
- presence of necrosis
- relationship to/involvement of
- eloquent areas
- major white matter tract
- large vessels
- extension
- across midline
- into brainstem
- subependymal spread
- CSF dissemination
Treatment and prognosis
Biopsy and tumour debulking with postoperative adjuvant radiotherapy and chemotherapy (temozolomide) are the most commonly carried out treatment. Newer therapies include antiangiogenesis (e.g. bevacizumab) and immunotherapy.
In individuals 70 years of age or younger a standard Stupp protocol is usual. In older individuals, radiotherapy is usually administered as a shorter course, but even in this setting adding temozolomide significantly increases survival, especially in MGMT methylated (inactive) tumours 15.
Despite this, it carries a poor prognosis with a median survival of fewer than 2 years 15.
Negative prognostic factors include:
- the degree of necrosis 10
- the degree of enhancement 10
- deep location (e.g. thalamus)
- MGMT not-methylated
- increased age
- lower pre-diagnosis functional status (e.g. ECOG performance status)
Followup
Glioblastomas are generally followed up fairly closely with MRI. Although timing and frequency will vary between institutions and treating surgeons/oncologists, generally a scan is obtained within 24-48 hours of surgery to assess residual disease (before postoperative enhancement develops) and thereafter every 8 to 12 weeks. In individuals who have no residual macroscopic disease and remain stable for a protracted time, the frequency of follow-up imaging can be decreased.
The primary aims of follow up are:
- identify tumour progression and complications thereof
- distinguish tumour progression from pseudoprogression
- distinguish pseudoresponse from tumour progression
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 the interpretation of older data. These systems for response criteria for first-line treatment of glioblastomas include 9:
- RANO criteria (most commonly used today)
- Macdonald criteria
- AVAglio criteria
- RTOG 0825 criteria
- BT-RADS
History and etymology
The original term glioblastoma multiforme was coined in 1926 by Percival Bailey and Harvey Cushing; the suffix multiform was meant to describe the various appearances of haemorrhage, necrosis, and cysts.
Differential diagnosis
General imaging differential considerations include:
-
astrocytoma, IDH mutant WHO CNS grade 4
- may appear very similar/indistinguishable
- generally younger patients
-
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, however, if GBM is hemorrhagic then the assessment may be difficult
- presence of smooth and complete SWI low-intensity rim 6
- presence of dual rim sign 6
-
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
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