Glioblastoma, IDH-wildtype

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. 

This will therefore mean that the term "primary" and "secondary" will no longer be meaningful, representing glioblastoma IDH-wildtype and astrocytoma IDH mutant WHO grade 4 respectively under the new classification. 

Variants

In the current (2016) 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:

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

The remainder of this article concerns itself with primary (IDH wild-type) glioblastoma. 

Epidemiology

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 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.

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 (see WHO grading of astrocytomas).

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 the one tumour. In addition to the three recognised variants (giant cell glioblastoma, gliosarcoma, and epithelioid glioblastoma) additional histological features are sometimes encountered which impact imaging appearance and biological behaviour. Most of these are seen predominantly in primary IDH wild-type glioblastomas. These include ¹⁶:

• gemistocytes
  • more commonly seen in secondary IDH mutant glioblastoma arising from a pre-existing 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
• oligodendroglioma component
  • must be either IDH wild-type or IDH mutant but 1p19q intact
  • if IDH mutant and 1p19q co-deleted then regardless of other histological features it represents an anaplastic oligodendroglioma (WHO grade III)
• 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 are IDH wild-type and commonly 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 a secondary IDH mutant tumour) ¹⁶
• H3 K27M mutation: negative (if positive then diffuse midline glioma H3 K27M-mutant)

Genetics

As discussed above, the vast majority of glioblastomas are primary and are IDH wild-type. IDH mutations are more common, and perhaps synonymous of, secondary glioblastomas (those arising from a pre-existing lower grade diffuse astrocytoma) ^8,16.

TERT promoter mutations are frequently encountered and have a negative impact on prognosis, not as pronounced, however, as on lower grade diffuse astrocytomas¹⁴. 

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. 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 is 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 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 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 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 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 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

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:

• 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 assessment may be difficult 
  • presence of smooth and complete SWI low-intensity rim ⁶
  • presence of dual rim sign⁶
• 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

Primary

Primary glioblastomas are those that arise de novo, without a pre-existing lower grade diffuse astrocytoma. They account for 90% of all glioblastomas and are more aggressive than secondary glioblastomas and they tend to occur in older individuals.

Primary glioblastomas are almost invariably IDH wild-type. They tend to have amplification of EGFR and overexpression of MDM2, PTEN mutation and/or loss of heterozygosity of chromosome 10p ⁷.

Secondary

Secondary glioblastomas, in contrast, are those which arise from a pre-existing lower grade diffuse astrocytoma. They are relatively uncommon, only accounting for approximately 10% of all glioblastomas. These tumours tend to be less aggressive than primary glioblastomas and they tend to occur in younger patients ^7,16. Interestingly, and of uncertain significance, they have a predilection for the frontal lobes ¹⁶. 

Characteristically, and unlike primary tumours, secondary glioblastomas tend to be IDH mutant (positive), a mutation shared by over 80% of grade II and III astrocytomas^7,8. Secondary glioblastomas also 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.

Variants

In the current (2016) 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:

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

The remainder of this article concerns itself with primary (IDH wild-type) glioblastoma. 

Epidemiology

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 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.

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 (see WHO grading of astrocytomas).

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 the one tumour. In addition to the three recognised variants (giant cell glioblastoma, gliosarcoma, and epithelioid glioblastoma) additional histological features are sometimes encountered which impact imaging appearance and biological behaviour. Most of these are seen predominantly in primary IDH wild-type glioblastomas. These include ¹⁶:

• gemistocytes
  • more commonly seen in secondary IDH mutant glioblastoma arising from a pre-existing 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
• oligodendroglioma component
  • must be either IDH wild-type or IDH mutant but 1p19q intact
  • if IDH mutant and 1p19q co-deleted then regardless of other histological features it represents an anaplastic oligodendroglioma (WHO grade III)
• 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 are IDH wild-type and commonly 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 a secondary IDH mutant tumour) ¹⁶
• H3 K27M mutation: negative (if positive then diffuse midline glioma H3 K27M-mutant)

Genetics

As discussed above, the vast majority of glioblastomas are primary and are IDH wild-type. IDH mutations are more common, and perhaps synonymous of, secondary glioblastomas (those arising from a pre-existing lower grade diffuse astrocytoma) ^8,16.

TERT promoter mutations are frequently encountered and have a negative impact on prognosis, not as pronounced, however, as on lower grade diffuse astrocytomas¹⁴. 

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. 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 is 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 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 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 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 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 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

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:

• 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 assessment may be difficult 
  • presence of smooth and complete SWI low-intensity rim ⁶
  • presence of dual rim sign⁶
• 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