Glioblastoma, IDH-wildtype
Updates to Article Attributes
Glioblastoma,also known as 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 have a preferential spreading along the condensed white matter tracts such as corticospinal tracts and corpus callosum. They often spread across white matter commisural tracts such as the corpus collosum and can give rise to the so called butterfly glioma, to involve the contralateral hemisphere. Glioblastomas rarely involve the meninges. These tumours are multifocal in 20% of patients and are rarely multicentric.
Terminology
The WHO classification has dropped the 'multiforme' and thus it is best to refer to these tumours merely as glioblastomas, or grade IV astrocytomas. Somewhat confusingly the abbreviation GBM is still appropriate.
The original term was coined in 1926 by Percival Bailey and Harvey Cushing, and the suffix multiforme was meant to describe the various appearances of haemorrhage, necrosis and cysts.
Epidemiology
A glioblastoma 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
- focal neurological deficit
- symptoms of increased ICP
- seizures
In less than 2% if intratumoral hemorrhage occurs they may present by stroke like manifestation.
Pathology
Aetiology
Usually unknown. Rarely related to radiation exposure (radiation-induced GBM). 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 glioblastomas.
Classification
Gliblastomas can be divided into primary and secondary.
Primary
De novo origin. These tumours are more aggressive than secondary glioblastomas and they tend to occur in older patients.
Primary glioblastomas tend to have amplification of EGFR and overexpression of MDM2, mutation of PTEN and/or loss of heterozygosity of chromosome 10p 7.
Secondary
Secondary glioblastomas are those which arise from pre-existing lower grade gliomas. These tumours tend to be less aggressive than primary glioblastomas and they tend to occur in younger patients 7.
Characteristically, and unlike primary tumours, secondary glioblastomas tend to be IDH1 positive, 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.
Of these IDH1 mutation is most important in allowing separation of primary and secondary glioblastomas, and is present in over 80% of grade II and III astrocytomas 7,8.
Gross appearance
Glioblastomas 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 glioblastomas (see WHO grading of astrocytomas).
Microvascular proliferation results in and abundance of new vessels with 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 which 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.
Variants
- giant cell glioblastoma: accounting for 5% of glioblastomas, this histological variant has a mildly improved prognosis.
- gliosarcoma
Markers
Serum GFAP 4
Immunohistochemistry
Shows positive GFAP. IDH1 is positive in secondary GBMs. 8
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)
-
T1 C+ (Gd)
- enhancement is variable but is almost always present
- typically peripheral and irregular with nodular components
- usually completely surrounds necrosis
-
T2/FLAIR
- hyperintense
- surrounded by vasogenic oedema
- flow voids occasionally seen
-
GE/SWI
- susceptability 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: 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
- typical spectrocopic characteristics include:
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.
Negative prognostic factors include:
- degree of necrosis 10
- degree of enhancement 10
- deep location (e.g. thalamus)
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
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
- presence of smooth and complete SWI low intensity rim 6
- presence of dual rim sign 6
-
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:
-</ol><p>In less than 2% if intratumoral hemorrhage occurs they may present by stroke like manifestation. </p><h4>Pathology</h4><h5>Aetiology </h5><p>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 <a href="/articles/neurofibromatosis-type-1">NF1</a> and <a href="/articles/li-fraumeni-syndrome">Li-Fraumeni syndrome</a>. Also <a href="/articles/turcot-syndrome">Turcot syndrome</a>, <a href="/articles/enchondromatosis">Ollier disease</a> and <a href="/articles/maffucci-syndrome">Maffucci syndrome</a> can also be complicated by glioblastomas.</p><h5>Classification</h5><p>Gliblastomas can be divided into primary and secondary.</p><h6>Primary</h6><p>De novo origin. These tumours are more aggressive than secondary glioblastomas and they tend to occur in older patients. </p><p>Primary glioblastomas tend to have amplification of EGFR and overexpression of MDM2, mutation of PTEN and/or loss of heterozygosity of chromosome 10p <sup>7</sup>.</p><h6>Secondary</h6><p>Secondary glioblastomas are those which arise from pre-existing lower grade gliomas. These tumours tend to be less aggressive than primary glioblastomas and they tend to occur in younger patients <sup>7</sup>.</p><p>Characteristically, and unlike primary tumours, secondary glioblastomas tend to be IDH1 positive, p53 mutations, amplification of PDGF-A, loss of heterozygosity of chromosomes 10q and 17p, loss of 19q and increased telomerase activity and hTERT expression <sup>7</sup>.</p><p>Of these IDH1 mutation is most important in allowing separation of primary and secondary glioblastomas, and is present in over 80% of <a href="/articles/diffuse-astrocytoma-grading">grade II and III astrocytomas</a> <sup>7,8</sup>. </p><h5>Gross appearance</h5><p>Glioblastomas are typically poorly-marginated, diffusely infiltrating necrotic masses localized to the cerebral hemispheres. Supratentorial white matter is the most common location. </p><p>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.</p><h5>Microscopic appearance</h5><p>Pleomorphic astrocytes with marked atypia and numerous mitoses are seen. Necrosis and microvascular proliferation are hallmarks of glioblastomas (see <a href="/articles/who-grading-system-for-diffuse-astrocytomas">WHO grading of astrocytomas</a>). </p><p>Microvascular proliferation results in and abundance of new vessels with poorly formed <a href="/articles/blood-brain-barrier">blood brain barrier (BBB)</a> permitting the leakage of iodinated CT contrast and gadolinium into the adjacent extracellular interstitium resulting in the observed enhancement on CT and MRI respectively <sup>11</sup>. </p><p>Oedema and enhancement are however also seen in lower grade tumours which 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 <sup>12</sup>. </p><h5>Variants</h5><ul>- +</ol><p>In less than 2% if intratumoral hemorrhage occurs they may present by stroke like manifestation. </p><h4>Pathology</h4><h5>Aetiology </h5><p>Usually unknown. Rarely related to radiation exposure (<a title="Radiation-induced glioma" href="/articles/radiation-induced-glioma">radiation-induced GBM</a>). It can also occur sporadically as part of rare heritable tumour syndromes. Such examples include p53 mutation related syndromes such as <a href="/articles/neurofibromatosis-type-1">NF1</a> and <a href="/articles/li-fraumeni-syndrome">Li-Fraumeni syndrome</a>. Also <a href="/articles/turcot-syndrome">Turcot syndrome</a>, <a href="/articles/enchondromatosis">Ollier disease</a> and <a href="/articles/maffucci-syndrome">Maffucci syndrome</a> can also be complicated by glioblastomas.</p><h5>Classification</h5><p>Gliblastomas can be divided into primary and secondary.</p><h6>Primary</h6><p>De novo origin. These tumours are more aggressive than secondary glioblastomas and they tend to occur in older patients. </p><p>Primary glioblastomas tend to have amplification of EGFR and overexpression of MDM2, mutation of PTEN and/or loss of heterozygosity of chromosome 10p <sup>7</sup>.</p><h6>Secondary</h6><p>Secondary glioblastomas are those which arise from pre-existing lower grade gliomas. These tumours tend to be less aggressive than primary glioblastomas and they tend to occur in younger patients <sup>7</sup>.</p><p>Characteristically, and unlike primary tumours, secondary glioblastomas tend to be IDH1 positive, p53 mutations, amplification of PDGF-A, loss of heterozygosity of chromosomes 10q and 17p, loss of 19q and increased telomerase activity and hTERT expression <sup>7</sup>.</p><p>Of these IDH1 mutation is most important in allowing separation of primary and secondary glioblastomas, and is present in over 80% of <a href="/articles/diffuse-astrocytoma-grading">grade II and III astrocytomas</a> <sup>7,8</sup>. </p><h5>Gross appearance</h5><p>Glioblastomas are typically poorly-marginated, diffusely infiltrating necrotic masses localized to the cerebral hemispheres. Supratentorial white matter is the most common location. </p><p>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.</p><h5>Microscopic appearance</h5><p>Pleomorphic astrocytes with marked atypia and numerous mitoses are seen. Necrosis and microvascular proliferation are hallmarks of glioblastomas (see <a href="/articles/who-grading-system-for-diffuse-astrocytomas">WHO grading of astrocytomas</a>). </p><p>Microvascular proliferation results in and abundance of new vessels with poorly formed <a href="/articles/blood-brain-barrier">blood brain barrier (BBB)</a> permitting the leakage of iodinated CT contrast and gadolinium into the adjacent extracellular interstitium resulting in the observed enhancement on CT and MRI respectively <sup>11</sup>. </p><p>Oedema and enhancement are however also seen in lower grade tumours which 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 <sup>12</sup>. </p><h5>Variants</h5><ul>
-<a href="/articles/cerebral-toxoplasmosis-2">cerebral toxoplasmosis</a>:<ul><li>especially in patients with <a href="/articles/hiv-aids-1">AID</a><a href="/articles/hiv-aids-1">S</a>- +<a href="/articles/cerebral-toxoplasmosis-2">cerebral toxoplasmosis</a>:<ul><li>especially in patients with <a href="/articles/hivaids">AID</a><a href="/articles/hivaids">S</a>
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