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FRCS Part 1 > Ch 36 Diffuse Astrocytic and oligodendroglial tumours > Flashcards

Ch 36 Diffuse Astrocytic and oligodendroglial tumours Flashcards

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1
Q

What are the risk factors for diffuse glioma?

A

Syndromic (familial diseases e.g. Li Fraumeni, Turcots, NF etc)

Post radiation therapy

*Not mobile phone use!*

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2
Q

What is the main division in astrocytic tumours according to 2016 WHO grading?

A

Diffuse vs ‘other’ Other astrocytic tumors - astrocytomas that are more circumscribed, that lack IDH gene mutations, and frequently have BRAF alterations (pilocytic astrocytoma, pleomorphic xanthoastrocytoma) or TSC1/TSC2 mutations - (SEGA)

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3
Q

How do you differentiate between grade 2 and 3 astrocytoma on histology?

A

anaplasia and mitotic activity seen in grade 3 and not in grade 2. Cellular atypia seen in grade 2. Ki67 proliferation index can also be used to differentiate between 2, 3 and 4

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4
Q

What is IDH wild-type and what does it do?

A

IDH-wildtype is a normal enzyme in the Krebs cycle, catalyzing isocitrate → α-ketoglutarate

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5
Q

What is the commonest IDH mutation?

A

IDH1 is the most common mutation. One metabolite is 2-hydroxyglutarate which may participate in tumorigenesis

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6
Q

Mutually exclusive of ATRX and TP53 mutation

A

1p19q codeletion

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7
Q

What is the significance of loss of heterozygosity with regards to oligodendrogliomas?

A

LOH in 1p & 19q (loss of one arm only in a hybrid chromosome) occurs as a result of unbalanced whole-arm translocations between chromosomes 1 & 19, which occurs early in the pathogenesis of oligodendrogliomas.

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8
Q

What is the ATRX gene?

A

The ATRX gene codes for ATRX (alpha-thalassemia/mental retardation syndrome, nondeletion type, X-linked) protein which is involved in silencing certain gene sites in humans. ATRX gene mutations are strongly coupled to IDH & TP53 mutations, and occur in a number of human cancers (in the CNS: in secondary GBM and its precursors, grade II & grade III gliomas). Uncommon in oligodendrogliomas and secondary GBMs.

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9
Q

What is TP53?

A

The TP53 gene encodes TP53 (tumor protein 53), which is a tumor suppressor that prevents cells from dividing and signals them to undergo apoptosis if they sustain irreparable DNA damage. TP53 gene mutations are very common in human cancers, and are the underlying cause of Li-Fraumeni syndrome.

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10
Q

Which mutations do TERTp mutations commonly occur with?

A

1p19q

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11
Q

How could you differentiate grade 2 gliomas from grade 3 on imaging?

A

PET - Grade 2 cold on FDG, whereas 3 and 4 hot. MRI - no Mass effect in grade 2, Some enhancement occasionally seen in Grade 3.

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12
Q

Name 3 molecular pathways identified in the development of glioblastomas

A

1st pathway: dysregulation of growth factor signalling through amplification and mutational activation of receptor tyrosine kinase (RTK) genes. RTKs are transmembrane proteins that act as receptors for epithelial growth factor (EGF), vascular endothelial growth factor (VEGF) & platelet-derived growth factor (PDGF). They can also act as receptors for cytokines, hormones, and other signalling pathways

2nd pathway: activation of the phosphatidylinositol-3-OH kinase (PI3K)/AKT/mTOR, which is an intracellular signalling pathway that is essential in regulating cell survival

3rd pathway: inactivation of the p53 and retinoblastoma (Rb) tumor suppressor pathways

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13
Q

What grade is a diffuse astrocytoma?

A

Grade 2

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14
Q

What are the imaging findings of a diffuse astrocytoma?

A

Usually hypodense on CT as well as hypointense on T1, and hyper intense on T2 beyond margins of tumour Do not enhance with contrast (although 40% do and have a worse prognosis)

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15
Q

What is the prognosis of a diffuse astrocytoma?

A

UCSF pre-op grading system has 4 prognostic features to give a score that predicts 5 year mortality and progression free survival. Age >50 KPS<80 Eloquent brain? (Primary sensory, motor, Broca or Wernicke’s) Maximal diameter >4cm (0-1) 97% survival 76% progression free (2) 81% ‘’ 49% progression free (3-4) 56% “ 18” progression free

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16
Q

What feature on MRI can help differentiate primary (IDH wildtype) from secondary (IDH mutant) GBM?

A

Central necrosis usually more abundant in primary GBM

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17
Q

How do oligodendrogliomas normally present?

A

Seizures (50-80%)

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18
Q

What evidence is there that surgery (maximal resection) for Grade 2 diffuse astrocytomas is better than biopsy and surveillance?

A

Jakola 2012, JAMA “Early surgical resection vs watchful waiting in LGG”.

Norwegian cohort study of outcomes from 2 different neurosurgical centres. Showed significant improvement in overall survival. 5 year survival was 60% with biopsy and 75% with early surgery.

No Class 1 evidence available.

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19
Q

What are the histological features of astrocytoma?

A

Gr2 = nuclear atypia / increased cellularity Gr3 = above + anaplasia and increased mitotic activity Gr4 = above + microvascular proliferation and necrosis

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20
Q

What stain can be used to differentiate glial tumours from ets?

A

GFAP!

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21
Q

What is the difference between IDH-1 and IDH-2 mutations?

A

IDH-1 Arg132 = cytoplasmic mutation IDH-2 Arg140 or Arg172 = mitochondrial mutation

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22
Q

Which diffuse (WHO 2) astrocytomas rarely undergo malignant transformation?

A

Paediatric diffuse astrocytomas (Age <20 y)

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23
Q

What % of GBMs have ventricular seeding?

A

10-25%

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24
Q

What proportion of GBMs are IDH-WT?

A

90%

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25
What does MGMT promoter methylation cause?
Reduced activity of MGMT which normally removes methyl groups on guanine bases. This means that Temozolamide is more effective.
26
What are gemistocytes?
Astrocytes with glassy plump angular eosinophilic cell bodies that contain GFAP+ cell processes
27
What is the TERT gene?
Telomerase reverse transcriptase
28
How would you plan surgery for a low grade glioma?
Ideally awake with intra-operative stimulation mapping. Meta Analysis published by Duffau and Berger (De Witt Hamer et al. 2012) shows that intraoperative mapping with fewer late neurological deficits and greater extent of resection
29
What is the evidence for the use of radiotherapy in Grade 2 astrocytomas?
In complete resection Radiotherapy makes no difference and should be reserved for recurrence. If partial resection then radiotherapy does prolong OS and PFS. Hanzely et al 2003 J Neurooncol. There is no difference between 45 Gy and 60 Gy (EORTC trial).
30
What is the role for chemotherapy in the treatment of grade 2 astrocytomas?
Usually reserved for tumor progression. Temozolomide (Temodar®) may be effective in progressive WHO grade II astrocytomas. Effectiveness of PCV+RT vs RT alone was assessed by RTOG 9802 - no difference in 5 year overall survival but some benefit in overall survival for those that survived \>2 years on post-hoc analysis.
31
How does gliolan work?
5-aminolevulinic-acid (5-ALA). 5-ALA is metabolized into fluorescent porphyrins, which accumulate in malignant glioma cells.
32
What is the benefit of gliolan?
use of 5-ALA leads to more complete resection (65% vs. 36%, p \< 0.0001), which translates into a higher 6-month progression free survival (41% vs. 21.1%, p = 0.0003) but no effect on OS Stummer 2006 Lancet oncology
33
What is the Stupp protocol?
Started within 6 weeks after surgery Fractionated focal radiation at a dose of 2 Gy per fraction once daily five days per week over a period of six weeks, for a total dose of 60 Gy, with a 2–3 cm margin of clinical target volume. Concomitant temozolomide 75mg/sqM given every day for 6 weeks whilst having radiotherapy. Then 4 week break and then 6 cycles of adjuvant Temozolomide 150-200 mg/SqM 1 cycle = 5 days at the start of the month so 6 cycles lasts 6 months. This improved median survival by 2 months (12 months RT alone vs 14 months with Stupp median survival.) Temozolomide is an oral alkylating agent.
34
What is the active metabolite of Temozolomide?
MTIC (Monomethyl Triazenoimidazole carboxamide). This adds methyl groups to guanine bases to induce apoptosis.
35
What difference to prognosis does having MGMT methylation make?
MGMT methylated group had median survival of 23.4 months vs 12.6 months in the unmethylated group
36
When does pseudoprogression occur? and in which specific group is it most common?
Typically occurs 3-6 months after radiotherapy and temozolomide treatment. More common in MGMT promoter methylated group (91% vs 41% in unmethylated)
37
What is RANO?
Response assessment in Neuro-Oncology. Has superceded the Macdonald criteria (which relied on contrast enhancement in CT). Splits outcome into complete response (complete disappearance of all disease), partial response (\>50% reduction in volume), stable (no change in volume) and progression
38
What mutation is specific for diffuse midline glioma?
Histone mutation H3 M27K
39
What is the PI3K pathway?
Tyrosine kinase R activation causes PIP2 to PIP3 conversion. The PIP3 activates Akt which activates mTOR. mTOR causes expression of transcription factors for cell survivial, proliferation and angiogenesis
40
What are the differences between primary and secondary GBMs?
Primary - mean age 62 years, no precursor lesion. Stupp survival 15 months. TERT promotor mutation more common. Secondary - mean age 44 years, transformation of LGG. Stupp survival 31 months. p53/ATRX/MGMT mutations more common.
41
How do DIPGs present?
Multiple cranial nerve palsies, long tract signs and ataxia. Obstructive hydrocephalus.
42
What is the prognosis for DIPG?
10% 2 year survival
43
What are the classical histological features of an oligodendroglioma?
Fried egg cytoplasm, chicken wire vasculature and calcifications.
44
How do most oligodendrogliomas present?
Seizures
45
What is gliomatosis cerebri?
Widespread GBM invasion involving \>3 lobes
46
Which conditions are associated with multifocal / multicentric gliomas?
NF and TSC
47
How do you manage grade 2 astrocytomas?
Base on RTOG 9802 (2016) phase 3 trial published in NEJM: Low risk = Age \<40 years and GTR should have radiological follow up. (unless IDH WT, then treat as a GBM!) High risk = Age \>40 or subtotal resection should have Chemo with PCV and radiotherapy. Chemo+RT increases progression-free survival from 4 years with RT alone to 10 years.
48
How do you manage high grade gliomas?
For GBM with good KPS 70 or above then Stupp protocol For anaplastic oligo PCV+RT For anaplastic astrocytoma TMZ+RT
49
What is the difference in survival with MGMT promotor methylation?
Promotor methylation improves the effectiveness of temozolomide to 23.4 months vs non-methylated 12.6 months
50
What is the main side effect of TMZ?
Myelosuppression. It should not be given if the WCC \<1.5 or Plt \<100. Pneumocystis carinii pneumonia prophylaxis should be given for the first 6 weeks.
51
What are gladel wafers?
Carmustine (BCNU). This improves survival from 11.6 to 13.8 months in primary resection but no benefit for recurrent disease. Reference Westphal et al 2006 Gliadel study group.
52
What is pseudoprogression histologically?
Radiation necrosis. More common with MGMT promotor methylation as the TMZ is more effective.
53
What are the management options for recurrent GBMs?
Surgery improves survival by 8 months for GBMs and 20 months for anaplastic astros. Complication rate is 3x higher with redos. Chemotherapy: Temozolomide limited benefit based on 2013 cochrane review. Avastin and Lomustine are other second line options.
54
What factors confer the best outcomes in GBM?
MGMT methylation IDH mutation GTR KPS\>90 Based on recursive partition analysis Wee et al 2017
55
Which calculator can be used for GBM survival?
The EORTC European Normogram GBM calculator. Based on treatment received e.g. Stupp protocol or RT alone, Age, Extent of surgery, MMSE \>27 and steroid dependence.
56
What is the survival advantage of 5ALA?
Stummer et al. (2006) RCT showed an increase in median survival from 11.8 to 16.8 months
57
What is the 2-year survival of GBM treated with Stupp protocol?
26.5%
58
When does pseudoprogression / radiation necrosis occur?
6-12 months Radiation necrosis has low rCBF and FDG-PET signal. ADC is lower in tumour recurrence compared to radiation necrosis reflecting the cellular density.
59
How do you assess radiological response to treatment with GBM?
Based on the RANO (response assessment neuro-oncology) criteria. Divided into: Complete response, Partial response, Stable disease and Progression based on the enhancing portion and FLAIR
60
Which PET tracer is worse for LGG?
FDG-PET
61
What is a good MR SPECT predictor for IDH status?
2-hydroxyglutarate peak. Remember that IDH-mutant results in an accumulation fo 2-hydroxyglutarate instead of alpha-ketoglutarate. The rest of the spectrum looks high grade with high choline peak, low NAA and visible lactate/lipid peaks so this is an IDH-mutant GBM!
62
What is the difference between RT or RT+ chemo for low grade glioma?
No difference between progression-free and overall survival if complete resection in low risk patients so reserve for disease recurrence. If high risk of residual disease then treat with RT+Chemo according to RTOG 9802 NEJM 2016 improves survival. Use PCV for oligodendrogliomas and temozolamide for astrocytomas or MGMT-promoter methylation.
63
What trial showed the prognostic benefit of MGMT methylation?
RTOG 0525 showed overall survival 21 months with MGMT-methylation vs 14 months without
64
What at TERT?
Telomerase reverse transcriptase. TERT promoter mutation causes overexpression which adds on nucleotides to the end of the chromosome allowing the cell to replicate more times before it dies. TERT promoter mutations are strongly associated with 1p19q mutations (oligodendrogliomas) BUT TERT mutation and IDH-WT has the worse prognosis.
65
What is the most important prognostic factor for survival in GBM?
IDH mutation!
66
How do you treat a low-grade 1p19q co-deleted oligodendroglioma after surgical resection?
First-line is with chemotherapy (PCV / Temozolomide). If no 1p19q co-deletion then first-line is radiotherapy.
67
What proportion of patients with PNETs have leptomeningeal dissemination?
1/3 and is associated with a worse prognosis
68
How do you treat PNETs in adults?
35Gy radiotherapy to the neuroaxis without chemotherapy. Adult prognosis is less than children. (Note children get 24 Gy radiotherapy)
69
Is PCNSL more common with immunocompetent or immunosuppressed patients?
Immunocompetent. PCNSL has a lower ADC and lower rCBF than high-grade gliomas but is higher on FDG-PET!

FRCS Part 1 (85 decks)

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