Glioblastoma, IDH-wildtype

Last revised by Assoc Prof Frank Gaillard on 19 Oct 2021

Glioblastomas (GBM) are the most common adult primary brain tumor and are, unfortunately, aggressive, relatively resistant to therapy, and have a corresponding poor prognosis.

They typically appear as heterogeneous masses centered in the white matter with irregular peripheral enhancement, central necrosis and are surrounded by vasogenic edema. 

Treatment primarily consists of surgery and concurrent radiotherapy and Temozolomide. 

Since 1926 when the term Glioblastoma multiforme was coined, the definition of this tumor has substantially changed, particularly over the past decade with an increasing reliance on molecular markers to define these tumors. 

In the 5th Edition (2021) of the WHO classification of CNS tumors, glioblastomas have been defined as diffuse astrocytic tumors in adults that must be IDH-wildtype and are now an entirely separate diagnosis from astrocytoma, IDH-mutant grade 2, 3 or 4 5

Glioblastoma was previously known as glioblastoma multiforme; the multiforme referred to the tumor heterogeneity. In the revised 4th edition (2016) of the WHO classification, the term 'multiforme' was dropped, with these tumors 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.

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 tumor (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.

In the 5th edition (2021) WHO classification of CNS tumors, three glioblastoma histological variants are recognized (which are discussed separately) as well as a number of histological patterns which are discussed below 16.

The three recognized variants are:

  1. giant cell glioblastoma
  2. gliosarcoma
  3. epithelioid glioblastoma

Glioblastomas, now defined as IDH-wildtype tumors, are essentially tumors 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 tumor 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
  • seizures

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

The 5th edition (2021) of the WHO classification of CNS tumors 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 tumor
  • 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 tumor will be denoted as not elsewhere classified (NEC) although a variety of pediatric-type diffuse gliomas may be worth considering 20.  

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

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

These tumors 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 hemorrhage. GBMs have significant variability in size from only a few centimeters to lesions that replace a hemisphere. Infiltration beyond the visible tumor margin is always present.

These tumors are multifocal in 20% of patients but are rarely truly multicentric.

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.

Edema and enhancement are however also seen in lower grade tumors 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 tumor 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.

Glioblastomas are capable of demonstrating varied patterns, sometimes within one tumor. In addition giant cell glioblastoma, gliosarcoma, and epithelioid glioblastoma, other histological features are sometimes encountered which impact imaging appearance and biological behavior. These include 16:

  • gemistocytes
  • 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

Glioblastomas are typically large tumors at diagnosis. They often have thick, irregular-enhancing margins and a central necrotic core, which may also have a hemorrhagic component. They are surrounded by vasogenic-type edema, 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 tumor cells. Multicentric disease, on the other hand, is where no such connection can be seen.

  • irregular thick margins: iso- to slightly hyperattenuating (high cellularity)
  • irregular hypodense center representing necrosis
  • marked mass effect
  • surrounding vasogenic edema
  • hemorrhage is occasionally seen
  • calcification is uncommon
  • intense irregular, heterogeneous enhancement of the margins is almost always present
  • T1
    • hypo to isointense mass within the white matter
    • central heterogeneous signal (necrosis, intratumoral hemorrhage)
  • 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 edema
    • 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 edema (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
  • MR perfusion: rCBV elevated compared to lower grade tumors and normal brain
  • MR spectroscopy
    • typical spectroscopic characteristics include
      • choline: increased
      • lactate: increased
      • lipids: increased
      • NAA: decreased
      • myoinositol: decreased

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

A number of features are seen to correlate with molecular marker status. 

  • high ADC values, limited surrounding edema, low CBV is correlated with MGMT promoter methylation - sensitivity 79% (95% CI, 72%–85%), specificity 78% (95% CI, 71%–84%) 19

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 tumor 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

Biopsy and tumor 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) tumors 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)

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 tumor progression and complications thereof
  • distinguish tumor progression from pseudoprogression
  • distinguish pseudoresponse from tumor progression

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:

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 hemorrhage, necrosis, and cysts.

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 centered on grey-white matter junction and spare the overlying cortex
    • rCBV in the 'edema' 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
    • especially in patients with AIDS

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Cases and figures

  • Figure 1: gross pathology
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  • Case 1
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  • Case 2
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  • Case 3
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  • Case 4
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  • Case 5: GBM perfusion
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  • Case 6
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  • Case 7: "gliosarcoma"
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  • Case 8: mulifocal glioblastoma multiforme
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  • Case 9: with periventricular extension
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  • Case 10
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  • Case 11: with subependymal spread
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  • Case 12
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  • Case 13
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  • Case 14: hemorrhagic : T2 GRE
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  • Case 15
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  • Case 16: multifocal
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  • Case 17
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  • Case 18
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  • Case 19: transependymal spread
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  • Case 21
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  • Case 22
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  • Case 23
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  • Case 24
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  • Case 25: with intraventricular extension
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  • Case 26
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  • Case 27
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  • Case 32
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  • Case 33
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  • Case 34: involving the corpus callosum
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  • Case 36: with cystic component
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  • Case 35
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  • Case 37: with hemorrhage
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  • Case 38: involving splenium of corpus callosum
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  • Case 39: involving the brainstem
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  • Case 40: spreading along the corticospinal tract and corpus callosum
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