CNS Flashcards
What type of brain tumour is an ependymoma (based on cell type)
A glioma
What distinguishes grade 4 astrocytoma and glioblastoma
Glioblastoma are IDH1 and IDH2 wildtype, associated with worse prognosis.
Low grade gliomas that ‘transform’ into higher grade are transforming from what to what
From a low grade IDH mutant glioma (ie astrocytoma) to a high grade IDH mutant grade IV astrocytoma.
Ie, they can’t get rid of the IDH mutation to become a glioblastoma
What are common genetic mutations of grade 4 glioblastoma, IDH wt
Gain of chromosome 7, loss of chromosome 10.
EGFR amplification
TERT promoter mutations
What is the pallisading pattern seen in glioblastoma
Serpentine areas of necrosis, surrounded by hypercellularity around the edges of the necrosis.
See picture Robbins pg 1295
Why do high grade gliomas demonstrate a ring of contrast enhancement on imaging
Because they produce abnormal blood vessels which are leaky (ie disrupted blood brain barrier
What is the function of MGMT
It is a DNA repair enzyme
Why does MGMT promoter methylation predict for better response to alkylation agents
Because MGMT is a key component to the repair of chemotherapy induced DNA modification.
Promoter methylation results in lower levels of MGMT, and therefore less repair of chemo induced DNA damage, and more tumour cell kill
What type of genetic alteration is involved with 1p/19q co-deletion
Whole arm deletion of chromosomes 1 and 19
What is the typical microscopic appearance of oligodendrogliomas
Fried egg appearance: Round nuclei with cleared cytoplasm causing halos.
Chicken wire vasculature: Thin walled capillaries (myxoid liposarcoma is the other with chicken wire)
Calcification
What is the molecular profile of a Oligodendroglioma, WHO grade 2 or 3
IDH mutant
Nuclear ATRX retained
1p/19q co-deleted
What is the molecular profile of an Astrocytoma WHO grade 2 or 3
IDH mutant
(Nuclear ATRX retained AND 1p/19q non-codeleted) OR Nuclear ATRX lost
CDKN2A/B retained
No necrosis or microvascular proliferation
What is the molecular profile of an Astrocytoma, WHO grade 4
IDH mutant
(Nuclear ATRX retained AND 1p/19q non-codeleted) OR Nuclear ATRX lost
CDKN2A/B homozygously deleted AND/OR necrosis/microvascular proliferation
What is the molecular profile of glioblastoma WHO grade 4
IDH1/2 wild type
Nuclear ATRX retained
H3.3 G34R/V wild type
Any of:
-necrosis
-microvascular proliferation
-TERT promoter methylation
-EGFR amplification
-chromosome 7 gain or 10 loss
What WHO grade are pilocytic astrocytoma. What is the relevance of tumour necrosis
WHO grade 1.
No relevance of tumour necrosis. Ie, doesn’t make it higher grade
What kind of glioma is commonly associated with NF2 mutation
Spinal ependymomas
Where do ependymomas usually arise
In proximity to the ependyma lined ventricles or central canal of spinal cord
Often different sites are associated with different driver mutations
Where do ependymomas typically arise in the first two decades of life
The 4th ventricle
Where do ependymomas typically arise in adults
Spinal cord, commonly associated with NF2 mutation
What is an example of a WHO grade I ependymoma
Subependymomas: usually small incidentally identified lesions growing under the ependymal layer in the 4th or lateral ventricles.
Excellent prognosis
What are the features that distinguish WHO grade 2 and 3 ependymomas
WHO grade 3: pallisading necrosis, increased cell density, high mitotic rates, microvascular proliferation
What are the key predictors of outcome for WHO grade 2-3 Ependymomas
Extent of resection
Molecular subtype
NOT WHO grade
What is a general term for higher grade gliomas
Diffuse gliomas
In gliomas which molecular markers are known to be homogenously expressed
IDH mutation
MGMT promoter methylation
1p/19q codeletion
What is the function of ATRX
Incompletely understood, but it is a regulator of gene expression very important for development
What is the initial testing that should be done on a diffuse glioma biopsy to check IDH status
Immunohistochemistry for IDH1 R132H protein. (Mutant protein product)
Under what circumstances can a WHO grade 4 glioma be classified at IDH wild type glioblastoma based on IHC for IDH1 R132H alone
Age >55
Histologically typical glioblastoma
No previous history of lower grade glioma
Non-midline location
ATRX nuclear expression retained
If IDH1 R132H IHC is negative and further testing is indicating, what testing should be performed
IDH1 and IDH2 DNA sequencing
What is an example of a neuronal brain tumour
Gangliogliomas. WHO grade 1
What is the most common embryonal brain tumour
Medulloblastoma. 20% of all paediatric brain tumours
Where are medulloblastomas located by definition, and what grade are they
Always cerebellum
WHO grade 4
Which two signalling pathways are frequently abnormal in medulloblastoma
Sonic hedgehog
WnT/B-catenin
What are some of the microscopic features of classical medulloblastoma
Small round blue cells
Synaptophysin IHC staining
Homer Wright rosettes
Abundant mitosis
High Ki-67
What are the histological subtypes of medulloblastoma
Classical
Desmoplastic/nodular
Large cell/anaplastic
What are risk factors for CNS lymphoma
Immunosuppression
Usually malignant B cells are infected by EBV
Which layer of the meninges do meningiomas arise from
The arachnoid mater
What type of genetic abnormality is common in meningiomas
Chromosomal loss, particularly part of 22
Higher grade meningiomas often have loss of several chromosomes
What gene is most commonly mutated/lost in sporadic meningioma
NF2
What are 4 types of WHO grade 1 meningioma
Psammomatous (psammoma bodies; see pg 1300)
Fibroblastic
Meningothelial
Transitional
How is WHO grade 2 (atypical) meningioma defined
Require either 1 major criteria, or 3/5 minor criteria
Major criteria:
-increased mitotic index (>3 mitosis per 10 HPF)
-brain invasion (tongue like protrusions)
Minor criteria:
-increased cellularity
-small cells with high N:C ratios
-sheet-like growth
-spontaneous tumour-type necrosis
-macronucleoli
What are the features of WHO grade 3 (anaplastic) meningiomas. What are examples
Markedly increased mitosis
Papillary and rhabdoid
Is it possible to have an IDHwt grade 2 astrocytoma
Yes, there are some heterogenous other tumours that behave is much more indolent pattern than glioblastoma. Usually these arise in childhood rather than adults.
These need further molecular classification to figure out where they fit
What are the criteria for grade 4 pathological features in glioma
Pseudo pallisading necrosis
OR
At least 3 of 4 MEAN criteria
high Mitotic index
Endothelial proliferation (ie microvascular proliferation)
nuclear Atypia
Necrosis
Are there currently any treatment implications for EGFR amplification or mutation in glioblastoma
No. Phase 1/2 trials so far of tyrosine kinase inhibitors in glioblastoma have not shown any significant results. Likely due to significant heterogeneity in EGFR abnormality in glioblastoma
What type of cell do vestibular schawannomas arise from.
Schwann cells (peripheral myelin sheath cells)
What IHC marker is usually positive in vestibular schwannoma
S100
What is the microscopic appearance of astrocytoma
Diffusely infiltrating tumour with oval to elongated nuclei. Variable cellular morphology
What is the typical radiological appearance of oligodendroglioma
Well demarcated
Usually no contrast enhancement
Calcification commonly present
What are the three main types of glial cells of the CNS, and what is their function
Oligodendrocytes: form myelin sheath. (Nerve conduction)
Astrocytes: blood brain barrier/regulate chemical environment
Ependymal cells: produce CSF
What is the radiological appearance of glioblastoma
Infiltrative
Rim enhancing with contrast
May cross midline via corpus callosum
Vasogenic oedema.
What are the important prognostic factors for a grade 2 glioma
Worse:
Age >40
Neurological deficit pre surgery
Size >6cm
Crossing midline
Astrocytoma
Extent of resection
What are 4 examples of grade 1 gliomas
Pilocytic astrocytoma
Pleomorphic Xanthroastrocytoma
Subependymal giant cell astrocytoma
Ganglioglioma
What are the key radiological/histological/mutation features of pilocytic astrocytoma
Enhancing on MRI
Often cystic
Commonly posterior fossa
Rosenthal fibres
BRAF driver mutations
What are two key IHC markers for glial tumours
Olig2
GFAP
In general, what are microscopic features associated with glial tumours
Fibrillary processes
“Naked nuclei”
Infiltrative growth into brain tissue (non glial tumours are usually well demarcated)
“Secondary structures”
Eosinophilic cytoplasm
Nuclear pleomorphism/hyperchromasia
What are the differences in microscopic appearance between WHO grade 2 and 3 astrocytoma
A bit subjective overall
Grade 3: subjectively increased nuclear atypia (pleomorphism, coarse chromatin, multinucleation), increased hypercellularity
1 mitosis in biopsy sample, or multiple in resection sample (exact number not defined) = grade 3
What is the histological appearance of glioma Roma
Biphasic: glial component and stromal component (spindle cells)
Similar clinical and prognostic characteristics to glioblastoma
What are some microscopic features that distinguish grade 2 and grade 3 oligodendroglioma
Marked atypia
Increased mitotic activity
Microvascular proliferation
Necrosis
Progression from grade 2 to grade three thought to take approx 6 years
What are the microscopic features of ependymoma
Uniform cells with speckled chromatin in fibrillary matrix: not really small round blue cell.
Perivascular pseudorosettes (perivascular anucleate zones)
Can also get true ependymal rosettes (cudoidal cells surrounding a central lumen)
How are Ependymomas graded
WHO grade 2 or 3
Grade 2 is default. Grade 3 if dense cellularity and brisk mitotic activity
What type of ependymoma typically arises in the spinal cord, and where specifically
Myxopapillary ependymoma, WHO grade 2
Arises at the conus medullaris, cauda equine and filum terminale
What IHC stains are positive in medulloblastoma
Synaptophysin (not necessarily full range of neuroendocrine markers)
NeuN
What are the microscopic features of meningioma in general
Oval nuclei, delicate chromatin
Frequent intranuclear pseudoinclusions
Abundant eosinophilic cytoplasm
Numerous whorls
Occasional psammoma bodies
What is the common IHC findings of meningioma
Somatostatin receptor 2a (SSTR2A): most sensitive/specific
EMA, vimentin, PR.
S100 variable.
In keeping with somatostatin receptors being positive (with activation of Pi3K/Akt/mTOR pathways), there are trials assessing combined use of octreotide/everolimus. There is a phase 2 study supporting clinical benefit. Octreotide alone has demonstrated limited clinical benefit.
What are two WHO grade 2 (atypical) subtypes of meningioma
Chordoid
Clear cell
What are the two criteria that define grade 3 meningioma
Overtly malignant histology (resembling carcinoma, melanoma or sarcoma)
And/or
Markedly elevated mitotic rate >20/10 HPF
What is the difference between solitary fibrous tumour and haemangiopericytoma, and what are the microscopic features of each
They are histological variations of the same entity
SFT: alternating hyper and hypo cellular areas with thick collagen bands
Haemangiopericytoma: high cellularity, rich network of reticulin fibres
Both: staghorn vessels: large open branching vessels.
IHC: STAT6 IHC (NAB2-STAT6 fusion)
CD34 and CD99+
What are the grades of solitary fibrous tumour/haemangiopericytoma, and how does this affect treatment
Grade 1: solitary fibrous tumour. Considered benign: surgery only
Grade 2: haemangiopericytoma with <5 mitosis per 10 HPF
Grade 3: 5+ mitosis. Considered malignant and treated with surgery and radiation
What mesenchymal CNS tumour resembles metastatic clear cell RCC
Haemangioblastoma
Both VHL associated with similar microscopic appearance, but different IHC profiles
Where are CNS germ cell tumours most commonly located
Midline.
Usually arising from the 3rd ventricle and involving Pineal gland, hypothalamus, basal ganglia
What is the microscopic appearance of pituitary adenoma
Variety of growth patterns, but overall similar to other neuroendocrine tumours, eg papillary, diffuse, trabecular
Monomorphic neuroendocrine cells.
Might get perivascular orientation (ie rosettes)
What IHC is useful for pituitary adenoma
NE markers: synaptophysin, chromogranin
S100 negative
IHC panel for hormone secretion to determine cell type (usually still stain in non-functioning tumours)
-GH, prolactin, TSH-B, ACTH, FSH-B, LH-B, alpha subunit.
What is the most common functioning pituitary adenoma
Prolactinoma
Presents with amenorrhea, galactorrhoea in females, sexual dysfunction and mass effect in males
How is pituitary carcinoma defined
Defined by the presence of metastasis with a primary pituitary adenoma present.
IHC mostly resembles pituitary adenoma, but associated with more mitosis, higher Ki67
What is craniopharyngioma
Benign epithelial CNS tumours derived from rathkes pouch.
In differential diagnosis for a suprasellar tumour
What are differentials for a sellar region tumour
Benign:
Pituitary adenoma
Craniopharyngioma (1st and 5th decades)
Rathkes cleft cyst
Xanthogranuloma
Epidermoid cyst
Meningioma
Malignant:
Pituitary blastoma
Germ cell tumour
Metastasis
Glioma
What is the usual CT appearance of meningioma
Well circumscribed
Homogenously enhancing
-moderate-intense enhancement with with contrast
Dural tail= linear thickening and enhancement adjacent to extra-axial mass
What is the typical MRI appearance of meningioma
T1 isointense to grey matter
T2 hyper intense to grey matter
Intensely enhancing with gadolinium
Oedema uncommon
Describe the Simpson grading system for meningioma
Estimates risk of recurrence based on degree of resection. Recurrence risk approx 10x Simpson grade
0- GTR + dural attachment and bone plus stripping of 2-4cm of dura
1- GTR with resection of dural attachement and abnormal bone
2- GTR with coagulation of dural attachment
3- GTR without resection or coagulation of dural attachment
4- STR
5- biopsy only
In simple terms what are the recurrence rates for each grade of meningioma following GTR
Grade 1: up to a quarter
Grade 2: quarter to half
Grade 3: more that half
