Glioma general
- Express GFAP
- Ki67 index is better than hunting for mitosis
- Microvascular proliferation: multi layering off endothelium or glomeruloid vasculature
- Atypia: Variation in nuclear shape or size with accompanying hyperchromasia
Numbers
- 85% of all newly diagnosed primary malignant brain tumours
- Breakdown
- Glioblastomas account for 60– 70%,
- Anaplastic astrocytomas for 10– 15%
- Anaplastic oligodendrogliomas for about 10%,
- Anaplastic ependymoma and anaplastic ganglioglioma make up the rest.
Grading
Molecular (new WHO CNS 2021)
Histopathology (old WHO CNS 2016)
Features | Grade 2 | Grade 3 | Grade 4 |
Microscopic | Tumours with cytological atypia | Anaplasia and mitosis activity | Microvascular proliferation and/or necrosis |
Mitotic rate | Ki67 index <4% | Ki67% index 5-10% | |
Radiological | Non-enhancing | Enhancing | Irregular-enhancing margins and a central necrotic core |
ㅤ | Primary GBM (IDH-wildtype) | Gliosarcoma | Giant cell GBM | Secondary GBM (IDH-mutant) |
Age at GBM diagnosis | 59 years | 56 years | 44 years | 43 years |
Male-to-female ratio | 1.4 | 1.4 | 1.6 | 1.0 |
Length of clinical history | 3.9 months | 3.0 months | 1.6 months | 15.2 months |
IDH1/2 mutation | 0% | 0% | 5% | 100% |
PTEN mutation | 24% | 41% | 33% | 5% |
ATRX expression loss | 0% | 0% | 19% | 100% |
TERT mutation | 72% | 83% | 25% | 26% |
TP53 mutation | 23% | 25% | 84% | 74% |
Loss of 19q | 4% | 18% | 42% | 32% |
EGFR amplification | 42% | 5% | 6% | 4% |
- Light blue, typical for IDH-wildtype GBMs; yellow, typical for IDH-mutant GBMs; Giant cell GBM shares characteristics with both GBM types.
- Key characteristics of IDH-wildtype and IDH-mutant glioblastoma in adults
ㅤ | IDH-wildtype glioblastoma | IDH-mutant glioblastoma |
Synonym | Primary glioblastoma, IDH-wildtype | Secondary glioblastoma, IDH-mutant |
Precursor lesion | Not identifiable, develops de novo | Diffuse astrocytoma Anaplastic astrocytoma |
Proportion of glioblastomas | -90% | -10% |
Median age at diagnosis | -62 years | -44 years |
Male-to-female ratio | 1.42:1 | 1.05:1 |
Location | Temporal | Frontal |
Mean length of clinical history | 4 months | 15 months |
Median overall survival: | ㅤ | ㅤ |
Surgery + radiotherapy | 9.9 months | 24 months |
Surgery + radiotherapy + chemotherapy | 15 months | 31 months |
Location | Supratentorial | Preferentially frontal |
Necrosis | Extensive | Limited |
TERT promoter mutations | 72% | 26% |
TP53 mutations | 27% | 81% |
ATRX mutations | Exceptional | 71% |
EGFR amplification | 35% | Exceptional |
PTEN mutations | 24% | Exceptional |
Future non invasive methods of grading
Cortical excitatory score
- iRMT stands for "individual Resting Motor Threshold,"
- A neurophysiological measure used in transcranial magnetic stimulation (TMS) or intraoperative neurophysiological monitoring to assess the excitability of the motor cortex.
- It reflects the minimum stimulus intensity (often delivered as a percentage of maximum stimulator output) required to elicit a motor evoked potential (MEP) of a defined amplitude in a target muscle at rest.
- Pathological iRMT means that this threshold is abnormally high, indicating impaired cortical excitability, which may be present in various neurological conditions and is relevant for scoring cortical excitatory status.
- Cortical excitatory score
- 0: no pathological iRMT
- 1: 1 pathological iRMT present (either upper or lower limb)
- 2: 2 pathological iRMT present (both upper and lower limb)
- Higher grade gliomas located in motor eloquent areas are related with decreased RMT, increased latency and decrease amplitude of motor responses, for the lower limb.
- The cortical excitability score provides a biological correlate between the WHO grading of gliomas and pre-operative nTMS motor mapping.
Hindrance modulated orientational anisotropy (HMOA)
- Significant correlation between HMOA and RMT
- HMOA correlates with pathological RMT in glioma patients (rₛ(7)=-0.683, p=0.042)
- Normal HMOA asymmetry does not correlate to RMT asymmetry in healthy subjects (rₛ(7)=-0.383, p=0.309)
- This is because
- Disruption to CST microstructure correlates with pathological excitability → pathological RMT
- Advanced tractography: enables visualisation of microstructural changes to CST in a series of low grade gliomas
- Traditional tractography:
- No difference due to glioma (p>0.05)
MD: average displacement during diffusion
Da: average displacement in axial axis
Dr: average displacement in radial axis
- Advanced tractography:
- Pathological difference (p=0.028)
- HMOA: tract specific, individual fibre density
- HMOA: 5.2% lower in glioma hemisphere
Radiological: imprecise
Glioma | CT | MRI | MRS/Perfusion | PET |
Diffuse (infiltrative) astrocytoma (WHO grade II) | - Hyperdense - No enhancement (possibly wispy in gemistocytic)May be cystic | - T1 iso-hypointense, T2/FLAIR hyperintense white matter lesion expanding cortex - No enhancement | - No restricted diffusion (unlike infarct). - Elevated choline, low NAA, elevated Ch/Cr ratio, myoinositol and ml/Cr ratio. - Increased 2-hydroxyglutarate in LGG if mutant IDH1/2 | - FDG uptake similar to white matter. - Most hypermetabolic area on FDG, 18F-Chlorine and 11C-Chlorine PET useful for biopsy |
Anaplastic astrocytoma (WHO grade III) | - Heterogeneous low density - Intense and heterogeneous enhancement | - Heterogeneous signal intensities—predominantly T1 isointense, T2 hyperintense, ring-like enhancement, mass effect | Reduced NAA, reduced creatinine, increasing choline, lipids and lactate, increased rCBV | FDG uptake greater than white matter |
Oligodendroglioma (WHO grade II) | - Hypodense - Calcification (central, peripheral or ribbon-like) - No enhancement in 50%, rest variable - Cysts uncommon | - Hypointense T1, hyperintense T2/FLAIR Minimal/no edema - None or dot-like, lacy enhancement | - Increased regional TBV (?only if 1p19q loss) - Elevated rCBV compared to anaplastic oligodendroglioma (due to chicken wire capillaries). - Increased 2-hydroxyglutarate in LGG if mutant IDH1/2 | - FDG uptake similar to normal white matter. - 11C-Methionine studies can be used to differentiate ODs from anaplastic oligodendrogliomas |
Anaplastic oligodendroglioma (WHO grade III) | - Similar to grade II oligodendroglioma | - Similar to grade II oligodendroglioma | - More diffusion restriction (low ADC) than grade II oligo. - Lower rCBV compared to grade II oligodendroglioma | - FDG uptake similar to normal grey matter. - 11C-Methionine studies can be used to differentiate ODs from anaplastic oligodendrogliomas |
Primary or secondary glioblastoma multiforme (WHO grade IV) | - Iso to hyperdense (cellularity) ± hypodense (necrotic) center. Marked edema and mass effect. Intense, irregular, heterogeneous enhancement of margins | - Within white matter, T1 hypo-isointense with heterogeneous center (bleed, necrosis). T2/FLAIR hyperintense, edema, flow voids. Enhancement present but heterogeneous, ring-like but nodules. | - GRE/SWI may show blood products inside necrotic pockets. - Heterogeneous DWI pattern—restricted in solid component, facilitated in edematous and cystic. Low ADC = GBM, high ADC = low-grade. - Elevated rCBV. NAA and myoinositol decreased, increased choline/lipid/lactate | FDG uptake similar or higher than normal grey matter |
- Glioblatoma enhancement on MRI + C: some may not enhance. Most glioblastomas enhance, but some rare ones do not.
- The nonenhancing center may represent necrosis or associated cyst. The enhancing ring is cellular tumor; however, tumor cells also extend ≥ 15 mm beyond the ring.
Clinical features
- Headache
- HCP (rare)
- Large exophytic astrocytoma can
- Block foramen of Monro, or cut-off the posterior lateral ventricle and cause obstructive hydrocephalus for the whole ventricle
- Cause enlargement of the trapped posterior part of the ventricle (encysted ventricle).
Spread
- Mechanism
- Tracking through white matter:
- Corpus callosum: through genu/body → bilateral frontal lobe "butterfly glioma"
- Cerebral peduncles → midbrain
- Internal capsule → encroachment of basal ganglion tumours in centrum semiovale
- Uncinate fasciculus
- Interthalamic adhesion → bilateral thalamic gliomas
- CSF pathways (subarachnoid seeding):
- 10-25% freq of meningeal/ventricular seeding by high grade gliomas
- Rarely can spread systemically
- Gliomatosis cerebri growth pattern
- Extensive involvement of one hemisphere (>3 lobes)
- Most common in anaplastic astrocytomas
Glioma stem cells
- Stem cells are defined by their ability to self-renew:
- Have multipotency: the capacity to differentiate into multiple lineages,
- Can generate tumours
- Tumours with a stem cell fraction
- GBM
- Medulloblastoma
- Cancer stem cells and bulk tumour progeny share the same mutations, so it follows that these mutations are necessary but not sufficient to specify stem cell identity, with gene expression and genome configuration (epigenomics) as well as microenvironment also playing key roles.
- Seminal experiments demonstrated that surface markers of neural stem cells including CD133 and CD15/ SSEA- 1 also select for brain tumour stem cells (Singh et al., 2004).
- These brain tumour stem cells may be selectively resistant to radiotherapy and chemotherapy (Bao et al., 2006).
- The proneural group showed improved survival, but interestingly showed no survival advantage with chemoradiotherapy vs. radiotherapy alone. Further work is underway to understand the significance of this classification for individual patients. Analysis of trials of antiangiogenic drugs suggest that this proneural group may gain benefit from antiangiogenic therapy (Sandmann et al., 2015)
- Cancer genome atlas classification of GBM subtypes
Subtype | Characteristic mutations | Expression signature |
Proneural | TP53, PDGFRA, PI3K, IDH1 | OLIG2, NKX2-2 |
Neural | TP53, EGFR | MBP, SYT1 |
Classical | EGFR, Chr10, PDGFRA | EGFR, AKT2 |
Mesenchymal | NFkB, NF1 | CD44, YKL40 |
DDX for different MRI enhancing lesions
Differentiating | MRI | MRS | MR perfusion |
Tumefactive demyelination | 50% show enhancement, usually an open ring with in complete portion facing grey matter Mildy increased diffusion (unlike abscess) | Elevation glutamate/glutamine peaks reduced NAA Inc cho, lipis, 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. Lipid, choline and lactate | Marked elevation rCBV |
Primary CNS lymphoma | Homogenous enhancement common Ring enhancing in HIV/immunocompromise Restricted diffusion (lower ADC then metastasis or HGG) | Large Choline peak Reversed Cho/Cr Ratio Markedly reduced NAA Lactate peak possible | Modest elevation rCBV |
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