Intrinsic Tumour Flashcards
Def: Low-grade glioma
Generally means a glioma of a grade lower than anaplastic.
Subdivision of DLGG
Astrocytic low-grade glioma
Oligondendroglial LGG
Epidemiology of DLGG
1-1.5/100,000 patients/ years
Astrocytic > Oligodendrocytic.
Account for 10-15% of all primary brain tumours
Clinical presentation of DLGG
80% with seizures
Focal deficits, altered mental state, increased ICP
Epileptic seizures more frequently associated with cortically based tumours, particularly in frontal, temporal, insular and central locations.
DLGG show a predilection for eloquent briain.
How do DLGG exist for years in the eloquent brain without causing focal motor deficits or presenting with seizures?
Due to slow-growing, invasive nature allows for remapping of cerebral function through neural plasticity. In stark contrast to high-grade tumours/GBM
Neurological deficits in patients presenting with DLGG
Gross deficits such as dysphasia or limb weakness rare but disorders of executive function are more frequently detected.
Use of neuropsychological assessment before treatment of DLGG
Detection of subtle deficits
Tailor individual therapeutic strategy (e.g. CTx)
Devising surgical strategy
Establishing pre-treatment baseline.
MRI features of DLGG
Hypointense on T1
Hyperintense on T2
Extent corresponds best to FLAIR hyperintensity (though histologically may extend beyond this)
[Non-ehancing]
Contrast enhancement in DLGG
More than 30% of DLGG with no contrast enhancement will be reclassified as high grade histologically.
Conversely, 15-30% of DLGG enhance
The likelihood of histological grade being higher than 2 in non-enhancing glioma increases with age.
Enhancement is more common in oligodendrogliomas
MRI features of oligodendrogliomas
May contrast enhance
Have areas of haemorrhage
Have areas of calcification (which are best appreciated on CT, though twice as common in anaplastic oligodendrogliomas)
Range of MRI appearances of glioma
Can be relatively circumscribed
More diffuse
Spread into adjacent lobes
or Gliomatosis cerebri
Radiological Ddx for DLGG
Encephalitis
Ischaemia/infarction
Other intrinsic low-grade tumours (e.g. DNET, ganglioglioma)
Gliomas of higher grades.
Use of additional radiological Ix in DLGG
Interval MRI to determine disease progression
MR spectroscopy
PET scan can be used to identify areas of anaplastic loci.
The normal interval for MRI monitoring of DLGG?
3/12.
Clinical course of DLGG
Remain incurable
Over several years they relentlessly progress via serial anaplastic transformations towards the unequivocal endpoint- mortality.
Clinical prognostic parameters in DLGG?
Patient age
Kanofsky performance status
Presence of neurological deficits
Radiological prognostic parameters in DLGG?
Tumour volume
Tumour crossing midline
Frontal tumour
Speed of growth (velocity of diametric expansion)
High cerebral blood volume (an indicator of malignant transformation)
Examples of grade I astrocytomas
Pilocytic astrocytomas
Giant cell astrocytomas
5ys diffuse astrocytoma
79.5%
5ys anaplastic oligodendroglioma
52.2%
5ys Astrocytoma
47.4%
5ys anaplastic astrocytoma
27.3%
5ys glioblastoma
5%
What are the principle glioma relevant molecular markers
IDH1 or 2
ATRX
TERT
Loss of 1p/19q chromosomal arms
IDH
Isocitrate dehydrogenase
Deactivatin occurs in 75% of Grade 2 and 3 diffuse gliomas and 80% of secondary GBM
What is the gold standard for post-operative residual volume post DLGG resection?
FLAIR MRI
Total resection vs incomplete resection in DLGG
Incomplete resection patients have 4.9x risk of death
RTx in DLGG
No benefit to high vs low
More likely to result in impaired cognition and executive functioning.
Imrpoved OS when upfront RTx and PCV given vs RTx alone.
Characteristics in DLGG patients that favour adjuvant therapy
>40y/o
Partial resection/residual >10mL
Astrocytoma histology
Triple negative or TERT mutation status
Rapid growth
Difficult to control seizures
CTx options for DLGG
PCV
Temozolamide
TMZ MOA
Temozolomide (TMZ) is an oral alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma (GBM). Despite that high TMZ potential, progression of disease and recurrence are still observed.
PCV
Procarbazine
Lomustine
Vincristine
Procarbazine MOA
Alkylating agent
Vincristine MOA
Microtubule inhibitor
Lomustine
Alkylating agent
MGMT promoter methylation
Results in reduced expression of this DNA repair gene thus conferring increased sensitivity to alkylating CTx
Characteristic gene mutations in medulloblastoma subgroups
Hedgehog or Wnt/Beta-catenin pathway
High-grade glioma
Grade III or IV glioma
Classification of high grade glioma
Based on the predominant cell type
Grade based on appearances under light microscopy
Grade III glioma
Anaplastic astrocytoma
Anaplastic oligodendrolgioma
Grade IV glioma
Glioblastoma
Gliosarcoma
Glioblastoma with oligodendrocyte component
Histological features of Grade III tumours
Diffusely infiltrating gliomas with focal or dispersed anaplasia
Marked proliferative potential with increased cellularity, distinct nuclear atypia and high mitotic activity
Histological features of Grade IV tumours
Cellular polymorphism
Nuclear atypia
Brisk mitotic acitivity
Vascular thrombosis
Microvascular proliferation and necrosis
What is the commonest primary intrinsic brain tumour?
High-grade glioma (account for 85% of all newly diagnosed primary malignant brain tumours)
Types of high grade glioma
Glioblastoma (60-70%)
Amnaplastic astrocytomas (10-15%)
Anaplastic oligodendrogliomas (10%)
Anaplastic ependymoma and anaplastic ganglioglioma make up the rest
Peak incidence of GBM
65-75y/o
Risk factors for high grade glioma
Ionising radiation
Genetics (5% of patients with HGG have a FHx of glioma)
Li-Fraumeni syndrome
Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder[1] that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni, Jr., who first recognized the syndrome after reviewing the medical records and death certificates of 648 childhood rhabdomyosarcoma patients.[2] This syndrome is also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.
The syndrome is linked to germline mutations of the p53 tumor suppressor gene,[3] which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The mutations can be inherited, or can arise from mutations early in embryogenesis, or in one of the parent’s germ cells.
The classical LFS malignancies - sarcoma, cancers of the breast, brain, and adrenal glands - comprise about 80% of all cancers that occur in this syndrome.
Turcot syndrome
Mismatch repair cancer syndrome (MMRCS) is a cancer syndrome associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome (after Jacques Turcot, who described the condition in 1959) and by several other names.
In MMRCS, neoplasia typically occurs in both the gut and the central nervous system (CNS). In the large intestine, multiple colonic polyps develop; in the CNS, brain tumors.
Virus implicated in HGG?
CMV thought to have an oncomodulatory role.
Treatment with valganciclovir in an RCT showed no benefit
Gross divisions of glial-origin tumours
IDH WT
IDH mutated
IDH NOS
Within this classification, 1pq19 codeletion for oligodendroglioma has also been included
Signalling pathways implicated in glioma tumourigenesis
P13K
TP53
Rb
Activating mutations of EGFR, PDGFR and MET
LOF in PTEN, NF-1, RB1 and TP53
Primary vs Secodnary GBM
Develop either as primary tumours or arise from pre-existing low-grade gliomas
These are separate and distinct disease entities.
GBM are usually de novo manifestations in older patients with short clinical history, in contrast to secondary where they represent a malignant progression from LGG to HGG with a variable interval.
Tumour invasion in GBM
Local WM invasion is a key pathological hallmark of gliomas and a major cause of treatment failure.
Mostly progress by the invasion of WM tracts,
They can also grow along the pial surface (subpially)
Subependymally along the ventricular surface. This can result in drop metastasis to the spine.
Metastases of HGG is very rare and is mostly related to spreading down VP shunts to the peritoneal cavity.
There are cases of HGG metastases developing in patients receiving transplants from HGG patients.
What is the ‘hypoxic switch” in glioma development
In rapidly dividing areas of high-grade glioma, due to competition for metabolites, there will be the development of hypoxia.
This causes three major behavioural changes:
Stem cell division
Angiogenesis due to VEGF expression
Upregulation of invasive factors.
As malignancy increases, this hypoxia will lead to necrosis and microvascular proliferation, histological hallmark features of GBM
Def: biomarker
Characteristic rthat is objectively measured and evaluated as an indicator of normal biological or pathogenic process or pharmaceutical response to a therapeutic intervention
IDH mutations in gliomas
Found in up to 12% of patients and seems to confer prognositc benefit for PFS
Absence of IDH mutation confers very poor prognosis in LGG
1p/19q deletion
Loss of heterogeneity of 1p19q in IDH mutated tumours is characteristic of oligodendroglioma or anaplastic oligodendroglioma in the WHO classification.
This mutation has improved survival with CTx and RTx
MGMT gene
Encodes O-6-methylguanine-DNA-methyltransferase enzyme.
MGMT methylation status can be used to prognosticate response to alkylating chemotherapeutic agents.
It is non-functional in its methylated state and is associated with significantly longer survival after TMZ + RTx vs RTx alone.
Which molecular markers can be used to classify HGG?
IDH mutations
1p19q codeletion
TERT mutaiton
TERT mutations
Gene that encodes for telomerase found in GBM and low grade gliomas.
Suggests telomere maintenance may be important for tumorgenesis
Histone H3 mutations
Identified in paediatric brain stem and midline GBM
What are the layers of diagnosis now incorportated into the WHo calssification system?
Layer 1: integrated diagnosis
Layer 2: Histological
Layer 3: WHO grade
Layer 4: Molecular information
What proportion of patients with HGG present with seizures?
50% in comparison to 80% of LGG
Radiological features of HGG?
Irregular, ill-defined intrinsic lesion with vasogenic oedema.
Oedema typicaaly around the rim with a central area of non-enhancing tissue.
Most commonly supratentorial (frontal lobe > temporal > parietal> occipital> cerebellum> brainstem)
What is a problem with radiology for HGG
Tumour extends beyond imaging margins
What is the most effective method of objectively evluating extent of resection?
Post-op MRI
Use of diffusion imaging
Examines the diffusion of protons within an image.
Areas where there are trapped protons, such as areas of ischaemic cytotoxic oedema, epidermoid cysts or abscesses appear bright on DWI. Not quantitative
MRI shows restricted diffusion
Use of apparent diffusion co-efficient
Used as a quantiative measure that relates to how far protons can diffuse.
In areas of free diffusion, the ADC is large.
Where there is retricted diffusion, the ADC is low.
ADC in HGG
In HGG, due to increased water from oedema, the ADC is larger than normal brain but as the cellularity increases, the ADC reduces.
DWI and ADC in HGG
DWI- dark, no restriction of diffusion
ADC- light, due to free diffusion.
Use of DTI
Extension of DWI imaging that is sensitive to the directional diffusion of water molecules.
Can be used to assess the disruption of WM tracts and the location of tracts close to the tumour
Use of perfusion MRI
Used to assess blood flow.
Higher grade tumours have higher blood flow and there is some evidence that perfusion may be able to identify anaplastic foci within LGG
Use of MRI spectroscopy in HGG
Can identify tumour metabolites in a volume of interest.
HGG have a particulary spectral pattern
HGG MRI spectroscopy markers
Reduced n-acetylaspartate (marker of WM integrity)
Increased total choline (marker of membrane turnover)
Lipid and lactate (necrosis)
Use of PET in HGG
HGG tend to be hypermetabolic though FDG PET may not be best for cortical imaging.
MET PET or FET PET is more specfiic for tumour
Failure of HGG to respond to steroids
Suggests radical surgical resection may cause a worsening neurological deficits
Aims of surgery in HGG
Obtain representative tissue sample
Safely remove the tumour to improve pressure symptoms
Improve the efficacy of adjuvant therapy
Delay deterioration and improve survival
Potential for delivery of surgically delivered treatments
Problem with studies looking at outcomes after surgical resection of HGG
Suffer resection bias in that selects for patients with better prognostic features
Most surgeons would now consider it unethical to randomise patients to partial resection
Methods for improving degree of resection
Image guidance
Intraoperative US
Intraoperateive MRI (most effective) 5-ALA
MOA 5-ALA
5-aminolevulinic acid is taken up and is converted in the normal haem biosynthesis pathway. In tumours there is a deficiency of the ferrochelatase enzyme that leads to the accumulation of the fluorophore protoporphyrin IX that fluoresces under blue light.
