Definition
- Wild type IDH
- H3-wildtype
- The presence of one of the following
- Microvascular proliferation
- Necrosis
- TERT promoter mutation
- EGFR gene amplification
- + 7/ − 10 chromosome copy-number changes
General
- The new classification seems not to have Grade 2-3 astrocytomas IDH wild type
- Arises de novo
- Most common malignant brain tumour occurring in adults, accounting for up to half of all primary malignant tumours
- Astrocytic tumours, which do not fulfil the light microscopic criteria for CNS WHO grade 4 (i.e. microvascular proliferation and necrosis) but share typical molecular aberrations of GBM exhibit, in most cases, a similarly malignant clinical course
- Old name
- GBM
Numbers
- 45-50% of all primary malignant brain tumours
- 15% of all intracranial neoplasm
- Incidence of these tumours is often reported as approximately 5/ 100 000 person- years in Europe and North America
- Similar overall national age standardized incidence of 4.64/ 100 000/ year, with an average of over 2100 cases per year
- Mean age of diagnosis 62 yrs
- Rare < 40
- Incidence of glioblastomas increases with age, with a peak between 65 and 75 years of age
- Male to female: 1.35:1
Aetiology
- No causative factors
- Exposure to ionizing radiation
- FHx
- No clear guidelines on screening for familial gliomas
- Schwartzbaum 2006.pdf: Family with GBM 2x risk vs no FHx of GBM
- Bondy et al., 1994: 5% of patients with HGG have a family history of gliomas
- Genetic syndromes
- NF1
- SPS (NF2)
- Li- Fraumeni syndrome
- Turcot’s syndrome
- Studies have also shown links between DNA repair genes and tumour aggressiveness
- Familial glioma syndromes
- Mutations of the telomere shelterin gene complex, in particular POT1
- CMV
- Controversial if Viral infections are involved in the multistep development of gliomas.
- Dziurzynski et al., 2012
- Currently the consensus statement concluded that current literature supports an oncomodulatory role for CMV in malignant gliomas.
- No a direct cause
- Support for virus
- Cobbs et al., 2002
- Found CMV gene products in 100% of glioblastoma samples but failed to identify it in normal tissues
- Against
- Dey et al., 2015
- Failed to replicate these results
- Stragliotto et al., 2013 (the VIGAS Study),
- A randomized, double- blind trial of valganciclovir, an anti- CMV therapy used in addition to chemoradiotherapy failed to show any survival benefit
- Atopic diseases may be protective
- One unusual finding is that atopic diseases (e.g. asthma, eczema, or allergies) are ‘protective’ factors for developing gliomas.
- Patients with gliomas have fewer atopic symptoms compared to control subjects.
- As atopy may be a marker of immune dysfunction it may indicate a role for immunologic factors in glioma causation.
Pathology and pathogenesis of high- grade glioma
- Mutations that do occur tend to converge upon three intracellular signalling pathways:
- Spread and progression in high- grade gliomas
- Tumour invasion Local white matter invasion is a key pathological hallmark of gliomas, and a major cause of treatment failure.
- This extent of invasion varies between individuals.
- Histological studies looking at the extremes of invasion show that
- 20% -27% of GBM have limited invasion defined as less than 1 cm spread (Scherer, 1940; Burger et al., 1988)
- 20% have diffuse invasion defined as greater than 3 cm spread (Burger et al., 1988).
- Invading cells show changes in gene expression with upregulation of genes that promote migration and reduced expression of proapoptotic genes
- 3 stages of the invasion process
- Expression of cell adhesion molecules allowing glioma cells to attach to components of the extracellular matrix (especially tenascin- C),
- Production of proteases (e.g. metalloproteinases) which degrade the matrix removing the barriers to cell movement.
- In gliomas the production of metalloproteinases (MMP)— especially the secreted MMP- 2, MMP- 9 and the tissue bound MT1- MMP
- The secreted MMPs are regulated by their tissue inhibitors TIMP- 1 and TIMP- 2 which are down regulated in gliomas
- Cells migrate into the region of the matrix degraded by protease activity.
- This is promoted by the increased secretion of the chemokine CXCL12 (Zhang et al., 2005) that binds to the CXCR4 receptor that is upregulated in invasive glioma cells.
- Glioma stem cell: small population of cells capable of self- renewal and tumour formation.
- The cells have been shown to be representative of the parent tumour at the molecular genetic level.
- They are highly motile in vitro and show extensive host invasion in vivo.
- Preliminary gene expression analysis shows that they express several markers associated with invasion and migration including membrane– bound proteins such as MT1- MMP, NG2, and B1- integrin, and soluble factors including plasminogen, MMP2, and MMP9.
- Glioma dissemination and metastasis
- High-grade gliomas mostly progress by
- Invasion of white matter tracts.
- Subpial growth along the pial surface
- Subependymal growth along the ventricular surface.
- Can lead to the occasional ‘drop metastasis’ into the spine.
- The invasive cells that are growing into white matter tracts have different biology and behaviour to central tumour cells.
- Cells are more motile,
- Cells do not divide
- Metastasis of HGG is very rare but has been described.
- Related to spread along
- VP shunts into the peritoneal cavity
- Into the scalp when the bone flap is missing.
- Transplanted organs from HGG patients
- Suggesting that suppression of the immune system is required for these cells to grow.
- The ‘hypoxic switch’ in glioma progression
- Hypoxia is central for the dichotomized behaviour of glioma stem cells where they either ‘go or grow’
- Go:
- In hypoxic conditions the tendency is to migrate and invade,
- Grow:
- At higher oxygen tensions proliferation is favoured
- As central tumour cell number increases, they challenge for the available metabolites. In the rapidly dividing areas of high- grade gliomas this competition will lead to the development of hypoxia.
- This ‘hypoxic switch’ leads to three major behavioural changes within these tumours:
- Promotes cancer stem cell division
- Promotes angiogenesis due to production of factors such as VEGF
- Promotes invasion by up regulating invasive factors
- As the degree of malignancy increases this hypoxia will lead to eventual necrosis and microvascular proliferation— both histological features of glioblastomas.
Location: cerebral hemisphere
- Subcortical white matter
- Deep gray matter
- Temporal (31%)>parietal(24%)>frontal(23%)
Spread
- Metastasis rare (0.5%)
Clinical presentation
- Raised intracranial pressure
- Due to
- Mass effect
- Oedema,
- Haemorrhage
- Manifest as
- Headaches
- Nausea
- Vomiting
- Reduced visual acuity
- Diplopia
- Drowsiness
- Confusion.
- Focal neurological deficits
- Dependent on the location of the tumour
- Aphasia,
- Limb weakness
- Altered sensation
- Neurocognitive
- Esp in elderly
- Disinhibition
- Personality changes
- Seizures (50%)
- 50% of grade III
- 25% of Grade IV
- 80% of low- grade gliomas
- Time from symptom onset to diagnosis is
< 3 months | 68% |
< 6 months | 84% |
Imaging
General
- Large tumours
- Thick, irregular-enhancing margins and a central necrotic core (haemorrhagic component)
- Surrounded by vasogenic-type oedema, which in fact usually contains infiltration by neoplastic cells.
CT
- Margin:
- Irregular thick
- Iso- to slightly hyperattenuating (high cellularity)
- Centre:
- Irregular hypodense
- Representing necrosis
- Marked mass effect
- Surrounding vasogenic oedema
- Haemorrhage is occasionally seen
- Calcification is uncommon
- Enhancement:
- Intense irregular
- Heterogeneous enhancement of the margins is almost always present
Images
CT
CTC
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
- Abd-elghany 2019 1.9% of GBM do not enhance
- Chamberlain et al., 1988:
- 4% of 93 patients with glioblastoma multiforme (GM),
- 30% - 50% of anaplastic tumours fail to enhance on CT
- Al Okaili 2007.pdf: 16% fail to enhance on MRI
- Vs low grade
- Chamberlain et al., 1988: 20% of low- grade gliomas (typically oligodendrogliomas) enhance on CT
- Al Okaili 2007.pdf: 35% enhance on MRI
- 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 artefact 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
- Hyperintense 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 WHO 2016 grade
- 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
- 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
- rCBV can be increased up to 18months before transformation
MR spectroscopy
- Typical spectroscopic characteristics include
- Choline: increased
- Lactate: increased
- Lipids: increased
- NAA: decreased
- Myoinositol: decreased
Images
T1
T1+C
T2
FLAIR
ADC
DWI
Examples: Adult-type gliomas: Glioblastoma, IDH-wildtype. MRI of three different patients with CNS WHO grade 4 tumours, previously classified as grades II, III, and IV according to WHO 2016.
- A 66-year-old male
- WHO 2016:
- Grade II diffuse astrocytoma.
- WHO 2021 integrated diagnosis
- Molecular: IDHwt, TERTmut, EGFRwt CDKN2A/B no loss
- Diffuse glioma, IDH-wildtype with molecular profile favouring glioblastoma.*
- The left temporal, moderately well-marginated,
- Homogenous high T2w signal lesion (A)
- Demonstrates partial suppression on FLAIR (B),
- Increased intra-sulcal vascular enhancement, but no pathological parenchymal enhancement or necrosis (C).
- A 70-year-old man
- WHO 2016
- Grade III anaplastic astrocytoma.
- WHO 2021 integrated diagnosis
- Molecular: IDHwt, TERTwt, EGFR amplification, PTENmut
- Glioblastoma, IDH-wildtype (CNS WHO grade 4).
- The moderately heterogenous right temporal and occipital tumour
- High signal on T2w (D)
- High signal on FLAIR (E) and demonstrates ill-defined, multifocal enhancement without radiological evidence of necrosis (F).
- A 35-year-old man
- WHO 2016
- Grade IV glioblastoma.
- WHO 2021 integrated diagnosis
- Molecular: IDHwt, TERTmut, EGFR amplification, PTENmut, CDKN2A/B loss
- Glioblastoma, IDH-wildtype (CNS WHO grade 4).
- The left temporal,
- Heterogenous mixed T2w signal mass (G,H)
- Demonstrates peripheral irregular enhancement with central necrosis (I).
- Note: While in WHO CNS5 the presence of a TERT promoter mutation in an IDH wild-type glioma allows for the diagnosis of glioblastoma, it is important to be aware that grade II IDH wild-type gliomas with isolated TERT promoter mutations behave less aggressively than other molecular glioblastomas with a median overall survival of 88 months
- Unmetlylated Grade 4 Glioblastoma: left-sided arm and leg weakness, and poor balance. A scan was done showing a right-sided corpus callosum lesion.
PET imaging of HGG
- HGG tend to be hypermetabolic compared to normal cortex.
- FDG PET
- The tumour may be difficult to differentiate from functioning cortex.
- Increased FDG uptake is not specific to tumour and can be seen in inflammatory regions.
- Amino acid PET using either [11C]- methionine (MET PET) or [18F]- ethyl tyrosine (FET PET)
- More specific for tumour
- Appears to better delineate the tumour extent (Pirotte et al., 2006).
- Studies that have used PET to direct image- guided biopsies have shown that it improves diagnostic yield from biopsies (Levivier et al., 1995) and can help identify the region for surgical resection (Pirotte et al., 2009)
Histopathology
- Macroscopic
- Microscopy
- Does not invade the vessel intraluminally
- Do not use old term glioblastoma multiforme (multiforme: variability of tumour)
Prognosis
- Median survival: 15-18 months after therapy with chemoradiation
- 5 year survival: 6.8%
- Good prognostic indicator
- Younger age (< 50 years),
- High performance status,
- Complete tumour resection
- MGMT promoter methylation
WHO grading
- WHO grading: Histological
- Diffuse astrocytoma
- WHO 2016: grade 2
- Often lacks mutations in p53 and ATRX
- Anaplastic astrocytoma
- WHO 2016: grade 3
Examples: Adult-type gliomas: Glioblastoma, IDH-wildtype. MRI of three different patients with CNS WHO grade 4 tumours, previously classified as grades II, III, and IV according to WHO 2016.
- A 66-year-old male
- WHO 2016:
- Grade II diffuse astrocytoma.
- WHO 2021 integrated diagnosis
- Molecular: IDHwt, TERTmut, EGFRwt CDKN2A/B no loss
- Diffuse glioma, IDH-wildtype with molecular profile favouring glioblastoma.*
- The left temporal, moderately well-marginated,
- Homogenous high T2w signal lesion (A)
- Demonstrates partial suppression on FLAIR (B),
- Increased intra-sulcal vascular enhancement, but no pathological parenchymal enhancement or necrosis (C).
- A 70-year-old man
- WHO 2016
- Grade III anaplastic astrocytoma.
- WHO 2021 integrated diagnosis
- Molecular: IDHwt, TERTwt, EGFR amplification, PTENmut
- Glioblastoma, IDH-wildtype (CNS WHO grade 4).
- The moderately heterogenous right temporal and occipital tumour
- High signal on T2w (D)
- High signal on FLAIR (E) and demonstrates ill-defined, multifocal enhancement without radiological evidence of necrosis (F).
- A 35-year-old man
- WHO 2016
- Grade IV glioblastoma.
- WHO 2021 integrated diagnosis
- Molecular: IDHwt, TERTmut, EGFR amplification, PTENmut, CDKN2A/B loss
- Glioblastoma, IDH-wildtype (CNS WHO grade 4).
- The left temporal,
- Heterogenous mixed T2w signal mass (G,H)
- Demonstrates peripheral irregular enhancement with central necrosis (I).
- Note: While in WHO CNS5 the presence of a TERT promoter mutation in an IDH wild-type glioma allows for the diagnosis of glioblastoma, it is important to be aware that grade II IDH wild-type gliomas with isolated TERT promoter mutations behave less aggressively than other molecular glioblastomas with a median overall survival of 88 months
- Unmetlylated Grade 4 Glioblastoma: left-sided arm and leg weakness, and poor balance. A scan was done showing a right-sided corpus callosum lesion.
Histological subtypes wildtype glioblastoma (Old)
Giant cell
- Definition
- Rare histological variant of IDH wild-type glioblastoma
- Characterised by multinucleate giant cells and occasionally abundant reticulum
- Better circumscribed and better prognosis that regular glioblastoma
- More common in paeds
- <1% of all glioblastoma
- Cerebral hemisphere: temporal> parietal>frontal
- High connective tissue content
- More circumscribed
- Firm appearance
- Mulinodular appearance
- Can be mistaken for a met
Gliosarcoma
- Rare biphasic subtype of glioblastoma, with alternating glial and mesenchymal differentiation (glioblastoma and sarcoma)
- WHO grade IV
- Glial and sarcomatous component comes from the same cell lineage (monoclonal)
- May progress to pure sarcoma (GFAP-)
- Can spread systematically
- Radiology
- Sarcomatous tumors appear well demarcated with homogeneous contrast enhancement, may mimic meningioma.
- T1 Post contrast
Histopathology
- Firm, well circumscribed mass (resembling meningioma or metastasis)
- Rarely expresses epithelial markers or lipid
- Glioblastoma (occasionally oligodendroglioma, rarely ependymoma) plus regions of sarcoma resembling fibrosarcoma or malignant fibrous histiocytoma rich in reticulin (collagen+, GFAP-)
- High grade tumor with mesenchymal and glial components Mesenchymal features may be fibrosarcoma, rhabdoid, osteoclastic giant cell, undifferentiated or heterologous elements
- A) Portion of the tumor showing sarcomatous, spindle morphology. Other potential differentiation includes osseous, vascular, skeletal muscle, and adipose phenotypes.
- B) GFAP, 100×. The sarcomatous component is GFAP negative
- C) 400×. The basement membrane is highlighted by Laidlaw Reticulin impregnation in the sarcomatous component of the tumor. Reticulin shows thick uniform atypical appearance
Epithelioid glioblastoma
- High grade diffuse astrocytic tumour variant with a dominant population of closely packed epithelioid cells, some rhapsodic cells, mitotic activity, microvascular proliferation and necrosis
- Young adults and children
- Location:
- Cerebral cortex
- Temporal
- Frontal
- Midbrain
- Contain BRAF V600E point mutation is more common in epithelioid glioblastoma than any other glioblastoma
- Shared with Anaplastic pleiomorphic astrocytoma
DDx
Differentiating | MRI | MRS | MR perfusion |
Tumefactive demyelination | - 50% show enhancement, usually an open ring with in complete portion facing grey matter - Mildly increased diffusion (unlike abscess) | - Reduced NAA - Elevation glutamate/glutamine peaks - Inc choline, lipids, lactate | No elevation in rCBV |
High grade glioma | - Peripheral, heterogenous enhancement with nodules and necrosis - Can be ring enhancing Solid parts diffusion restriction | - Reduce NAA Myoinositol - Inc choline, lipids, lactate | Marked elevation rCBV |
Primary CNS lymphoma | - Homogenous enhancement common - Ring enhancing in HIV/immunocompromise - Restricted diffusion (lower ADC then metastasis or HGG) | - Reduced NAA (very) - Large Choline peak - Reversed Cho/Cr Ratio - Lactate peak possible | Modest elevation rCBV |
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