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Neurosurgical Training > Intrinsic Tumour > Flashcards

Intrinsic Tumour Flashcards

1
Q

Def: Low-grade glioma

A

Generally means a glioma of a grade lower than anaplastic.

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2
Q

Subdivision of DLGG

A

Astrocytic low-grade glioma

Oligondendroglial LGG

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3
Q

Epidemiology of DLGG

A

1-1.5/100,000 patients/ years

Astrocytic > Oligodendrocytic.

Account for 10-15% of all primary brain tumours

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4
Q

Clinical presentation of DLGG

A

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.

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5
Q

How do DLGG exist for years in the eloquent brain without causing focal motor deficits or presenting with seizures?

A

Due to slow-growing, invasive nature allows for remapping of cerebral function through neural plasticity. In stark contrast to high-grade tumours/GBM

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6
Q

Neurological deficits in patients presenting with DLGG

A

Gross deficits such as dysphasia or limb weakness rare but disorders of executive function are more frequently detected.

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7
Q

Use of neuropsychological assessment before treatment of DLGG

A

Detection of subtle deficits

Tailor individual therapeutic strategy (e.g. CTx)

Devising surgical strategy

Establishing pre-treatment baseline.

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8
Q

MRI features of DLGG

A

Hypointense on T1

Hyperintense on T2

Extent corresponds best to FLAIR hyperintensity (though histologically may extend beyond this)

[Non-ehancing]

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9
Q

Contrast enhancement in DLGG

A

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

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10
Q

MRI features of oligodendrogliomas

A

May contrast enhance

Have areas of haemorrhage

Have areas of calcification (which are best appreciated on CT, though twice as common in anaplastic oligodendrogliomas)

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11
Q

Range of MRI appearances of glioma

A

Can be relatively circumscribed

More diffuse

Spread into adjacent lobes

or Gliomatosis cerebri

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12
Q

Radiological Ddx for DLGG

A

Encephalitis

Ischaemia/infarction

Other intrinsic low-grade tumours (e.g. DNET, ganglioglioma)

Gliomas of higher grades.

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13
Q

Use of additional radiological Ix in DLGG

A

Interval MRI to determine disease progression

MR spectroscopy

PET scan can be used to identify areas of anaplastic loci.

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14
Q

The normal interval for MRI monitoring of DLGG?

A

3/12.

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15
Q

Clinical course of DLGG

A

Remain incurable

Over several years they relentlessly progress via serial anaplastic transformations towards the unequivocal endpoint- mortality.

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16
Q

Clinical prognostic parameters in DLGG?

A

Patient age

Kanofsky performance status

Presence of neurological deficits

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17
Q

Radiological prognostic parameters in DLGG?

A

Tumour volume

Tumour crossing midline

Frontal tumour

Speed of growth (velocity of diametric expansion)

High cerebral blood volume (an indicator of malignant transformation)

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18
Q

Examples of grade I astrocytomas

A

Pilocytic astrocytomas

Giant cell astrocytomas

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19
Q

5ys diffuse astrocytoma

A

79.5%

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20
Q

5ys anaplastic oligodendroglioma

A

52.2%

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21
Q

5ys Astrocytoma

A

47.4%

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22
Q

5ys anaplastic astrocytoma

A

27.3%

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23
Q

5ys glioblastoma

A

5%

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24
Q

What are the principle glioma relevant molecular markers

A

IDH1 or 2

ATRX

TERT

Loss of 1p/19q chromosomal arms

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25
Q

IDH

A

Isocitrate dehydrogenase

Deactivatin occurs in 75% of Grade 2 and 3 diffuse gliomas and 80% of secondary GBM

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26
Q

What is the gold standard for post-operative residual volume post DLGG resection?

A

FLAIR MRI

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27
Q

Total resection vs incomplete resection in DLGG

A

Incomplete resection patients have 4.9x risk of death

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28
Q

RTx in DLGG

A

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.

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29
Q

Characteristics in DLGG patients that favour adjuvant therapy

A

>40y/o

Partial resection/residual >10mL

Astrocytoma histology

Triple negative or TERT mutation status

Rapid growth

Difficult to control seizures

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30
Q

CTx options for DLGG

A

PCV

Temozolamide

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31
Q

TMZ MOA

A

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.

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32
Q

PCV

A

Procarbazine

Lomustine

Vincristine

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33
Q

Procarbazine MOA

A

Alkylating agent

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34
Q

Vincristine MOA

A

Microtubule inhibitor

35
Q

Lomustine

A

Alkylating agent

36
Q

MGMT promoter methylation

A

Results in reduced expression of this DNA repair gene thus conferring increased sensitivity to alkylating CTx

37
Q

Characteristic gene mutations in medulloblastoma subgroups

A

Hedgehog or Wnt/Beta-catenin pathway

38
Q

High-grade glioma

A

Grade III or IV glioma

39
Q

Classification of high grade glioma

A

Based on the predominant cell type

Grade based on appearances under light microscopy

40
Q

Grade III glioma

A

Anaplastic astrocytoma

Anaplastic oligodendrolgioma

41
Q

Grade IV glioma

A

Glioblastoma

Gliosarcoma

Glioblastoma with oligodendrocyte component

42
Q

Histological features of Grade III tumours

A

Diffusely infiltrating gliomas with focal or dispersed anaplasia

Marked proliferative potential with increased cellularity, distinct nuclear atypia and high mitotic activity

43
Q

Histological features of Grade IV tumours

A

Cellular polymorphism

Nuclear atypia

Brisk mitotic acitivity

Vascular thrombosis

Microvascular proliferation and necrosis

44
Q

What is the commonest primary intrinsic brain tumour?

A

High-grade glioma (account for 85% of all newly diagnosed primary malignant brain tumours)

45
Q

Types of high grade glioma

A

Glioblastoma (60-70%)

Amnaplastic astrocytomas (10-15%)

Anaplastic oligodendrogliomas (10%)

Anaplastic ependymoma and anaplastic ganglioglioma make up the rest

46
Q

Peak incidence of GBM

A

65-75y/o

47
Q

Risk factors for high grade glioma

A

Ionising radiation

Genetics (5% of patients with HGG have a FHx of glioma)

48
Q

Li-Fraumeni syndrome

A

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.

49
Q

Turcot syndrome

A

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.

50
Q

Virus implicated in HGG?

A

CMV thought to have an oncomodulatory role.

Treatment with valganciclovir in an RCT showed no benefit

51
Q

Gross divisions of glial-origin tumours

A

IDH WT

IDH mutated

IDH NOS

Within this classification, 1pq19 codeletion for oligodendroglioma has also been included

52
Q

Signalling pathways implicated in glioma tumourigenesis

A

P13K

TP53

Rb

Activating mutations of EGFR, PDGFR and MET

LOF in PTEN, NF-1, RB1 and TP53

53
Q

Primary vs Secodnary GBM

A

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.

54
Q

Tumour invasion in GBM

A

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.

55
Q

What is the ‘hypoxic switch” in glioma development

A

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

56
Q

Def: biomarker

A

Characteristic rthat is objectively measured and evaluated as an indicator of normal biological or pathogenic process or pharmaceutical response to a therapeutic intervention

57
Q

IDH mutations in gliomas

A

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

58
Q

1p/19q deletion

A

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

59
Q

MGMT gene

A

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.

60
Q

Which molecular markers can be used to classify HGG?

A

IDH mutations

1p19q codeletion

TERT mutaiton

61
Q

TERT mutations

A

Gene that encodes for telomerase found in GBM and low grade gliomas.
Suggests telomere maintenance may be important for tumorgenesis

62
Q

Histone H3 mutations

A

Identified in paediatric brain stem and midline GBM

63
Q

What are the layers of diagnosis now incorportated into the WHo calssification system?

A

Layer 1: integrated diagnosis

Layer 2: Histological

Layer 3: WHO grade

Layer 4: Molecular information

64
Q

What proportion of patients with HGG present with seizures?

A

50% in comparison to 80% of LGG

65
Q

Radiological features of HGG?

A

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)

66
Q

What is a problem with radiology for HGG

A

Tumour extends beyond imaging margins

67
Q

What is the most effective method of objectively evluating extent of resection?

A

Post-op MRI

68
Q

Use of diffusion imaging

A

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

69
Q
A

MRI shows restricted diffusion

70
Q

Use of apparent diffusion co-efficient

A

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.

71
Q

ADC in HGG

A

In HGG, due to increased water from oedema, the ADC is larger than normal brain but as the cellularity increases, the ADC reduces.

72
Q

DWI and ADC in HGG

A

DWI- dark, no restriction of diffusion

ADC- light, due to free diffusion.

73
Q

Use of DTI

A

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

74
Q

Use of perfusion MRI

A

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

75
Q

Use of MRI spectroscopy in HGG

A

Can identify tumour metabolites in a volume of interest.

HGG have a particulary spectral pattern

76
Q

HGG MRI spectroscopy markers

A

Reduced n-acetylaspartate (marker of WM integrity)

Increased total choline (marker of membrane turnover)

Lipid and lactate (necrosis)

77
Q

Use of PET in HGG

A

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

78
Q

Failure of HGG to respond to steroids

A

Suggests radical surgical resection may cause a worsening neurological deficits

79
Q

Aims of surgery in HGG

A

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

80
Q

Problem with studies looking at outcomes after surgical resection of HGG

A

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

81
Q

Methods for improving degree of resection

A

Image guidance

Intraoperative US

Intraoperateive MRI (most effective)
5-ALA
82
Q

MOA 5-ALA

A

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.

83
Q
A

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