Neuro oncology Flashcards
What’s the difference between a primary and secondary CNS tumour?
PRIMARY Tumours that originated within the CNS
SECONDARY (Metastases): 10x more frequent than primary tumours in adults
How common are CNS tumours?
Primary CNS tumours are rare in adults (1-2%)
Second most common cancer in children (25%)
What is the classification of CNS tumours by location?
EXTRA-AXIAL (COVERINGS)
Tumours of bone, cranial soft tissue, meninges and nerves
INTRA-AXIAL (PARENCHYMA)
Derived from the major normal cell populations of the CNS glia, neurons, vessels, connective tissue..
Derived from other cells types metastases, lymphomas (same name as extra-CNS tumours), germ cell tumours
What is the classification of CNS tumours by histology?
Neurons
Astrocytes
Oligodendrocytes
Ependyma
Choroid plexus epithelium
Meningothelial cells
Embryonal cells
What genes predispose to CNS tumours?
Neurofibromatosis 1 (17q11)
Neurofibromatosis 2 (22q12)
Tuberous Sclerosis 1 (9q34)
Tuberous Sclerosis 2 (16p13)
Turcot’s syndrome (APC 5q21) (PMS2 7p22) (MHL1 Chr3 & 2 Chr2)
Li-Fraumeni (p53 17p13)
Cowden syndrome PTEN (10q23.3)
Gorlin syndrome PTCH1 (9q31)
Von Hippel Lindau (3q25)
How may CNS tumours be inherited?
<5% of primary BT
Autosomal dominant inheritance
Clinical/family history
Adequate genetic screening
Surveillance and early diagnosis
NF1: NEUROFIBROMA, PILOCYTIC ASTROCYTOMA
NF2: SCHWANNOMA, MENINGIOMA
TS: HAMARTOMAS, SEGA
VHL: HEMANGIOBLASTOMA
What are the supratentorial S/S of CNS tumours?
Focal neurological deficit
Seizure
Headache
Change in mental status
Personality changes
What are the subtentorial S/S of CNS tumours?
Cerebellar Ataxia
Long tract signs
Cranial nerve palsy
What imaging can you use for CNS tumours?
How do you use these?
CT-SCAN
MR-SCAN
PET-SCAN (tracer compounds - research)
Multiparametric MRI:
MR-SPECTROSCOPY (metabolism)
Perfusion MRI
Functional MRI
Assess tumour type
Guide resection and biopsies
Assess post-surgery
Assess response to treatment
Follow up recurrence and progression
What is the management of a CNS tumours?
A. SURGERY
Maximal safe resection aims to obtain an extensive excision
with minimal damage to the patient
Age and performance status
Resectability: location, size, number of lesions
Histology (intraoperative diagnosis)
B. RADIOTHERAPY
Fractionated RT, stereotactic radiosurgery, whole brain
C. CHEMOTHERAPY
Mainly for high-grade gliomas (temozolomide)
What happens in neurosurgery?
Stereotactic biopsy – inoperable tumours (about 0.5cm tissue) – tissue may not be representative
Open biopsy – inoperable but approachable tumours (about 1cm) – more accurate
Craniotomy for debulking (as much tissue as possible)
- To provide a definitive and complete diagnosis
- To guide treatment: predictive tests assays for target therapy
- To assess treatment response
What is the WHO classification of CNS tumours?
- Tumour type: putative cell of origin or lineage of differentiation
- Tumour grade: tumour aggressiveness
- Molecular profile: expanded compared to previous 4th edition (genetics, methylome), most tumour types have molecular markers
INTEGRATED HISTOLOGICAL AND
MOLECULAR DIAGNOSIS
•No staging (TNM)
(exception: medulloblastoma)
How are tumours named?
Descriptive: tumour defined by histology
Names derive from putative cell of origin
Tumour type = histological type
What is grading?
The grading system is an attempt to stratify tumours by outcome:
“ Degree of malignancy”
It is based on histopathological criteria (proliferative activity, differentiation, necrosis, genetic profile)
It is based on their natural history = Grading does not consider tumour morbidity/ response to treatment (difference between “biological” and “clinical” outcome)
What is WHO grading?
Low Grade (longer survival)
- Grade I - Long-term survival / cured
- Grade II - Cause death in more than 5 yrs
High Grade (shorter survival)
- Grade III - Cause death within 5 yrs
- Grade IV - Cause death within 1yr
Grading less accurate than typing: limited by size of biopsies
Some tumour types have only one possible grade, some have 2 or 3
Evolving concept
What are glial tumours?
Diffuse infiltration - grades ≥ II
- adults
Astrocytoma (grades II-IV)
Oligodendroglioma (grades II-III)
Compressive margins - grades I-II
- children
- rare malignant transformation
Pilocytic astrocytoma (grade I)
Pleomorphic xantoastrocytoma
Subependymal astrocytoma
Ganglioglioma
What are the genetics of glial tumours?
DIFFUSE GLIOMAS- IDH mutations (IDJ 1/2 mutations- 30%, H3-1%)
CIRCUMSCRIBED GLIOMAS- MAPK pathway mutations (BRAF, NF1, FGFR)
What is pilocytic astrocytoma?
Usually 1st and 2nd decade - 20% of CNS tumours below 14 years
Often cerebellar, optic-hypothalamic, brain stem
MRI: always contrast enhancement and circumscribed
(never diffuse infiltration)
Hallmark: Piloid “hairy” cell
Very often Rosenthal fibres and granular bodies
Slowly growing: low mitotic activity
Genetic profile: BRAF mutation (KIAA1549-BRAF fusion) in 70% of PA
What is this?
What are diffuse gliomas?
- ASTROCYTOMA, IDH MUTANT
- OLIGODENDROGLIOMA, IDH MUTANT
Patients usually 20-40 years
Pathogenic point mutation in the IDH1/2 gene
IDH mutation is associated with longer survival and a better response to
chemotherapy and radiotherapy
Cerebral hemispheres most common site
Progression to higher grade is the rule: astrocytomas become eventually glioblastoma (in 5-7 years)
Most aggressive and most frequent: de novo glioblastoma (grade IV), IDH wildtype
What is a diffuse astrocytoma?
- Occur more commonly between 20-40 years
- MRI: T1 hypointense, T2 hyperintense, non-enhancing lesion.
Low choline / creatinine ratio at MRSpec.
•Low to moderate cellularity.
Mitotic activity is negligible or absent.
Vascular proliferation and necrosis are absent
Genetic: Mutation of IDH1/2: WHO Definition “A diffuse infiltrating astrocytoma with a mutation in the IDH1 or IDH2 gene”
What is this?
Diffuse Astrocytoma
What is glioblastoma multiforme?
Most aggressive and common glioma which increases with age (Med survival 8mo)
- Most patients >50 years
- MRI: T1 enhancing post-contrast
- High cellularity and high mitotic activity
Endothelial proliferation and/or necrosis
•90% de novo GBM
IDH wildtype
•10% secondary GBM (progression)
IDH mutant
What is this?
Neoangiogenesis and high cellularity
What is an oligodendroglioma?
- 5% of all primary brain tumours
- Patients usually 20-40 years
- Presents with long history of neurological signs – seizure
- MRI: no or patchy contrast enhancement; MRI and MRSpec are not predictive of transformation
- Round cells with clear cytoplasm (fried eggs)
- Mutation of IDH1/2 + codeletion 1p/19q: “a diffusely infiltrating, slow growing glioma with IDH1/2 mutation and 1p/19q codeletion”
Better prognosis than astrocytomas
Slow growth – resection is important
Better response to chemo and radiotherapy
What is this?
What is an oligodendroglioma?
What is the most frequent brain tumour in adults?
Mets (Secondary)
What is the most frequent brain tumour in children?
Pilocytic astrocytoma
What is the major change in the last (2016) CNS tumour classification?
f
What does tumour grade tell us?
v
What is a meningioma?
•25-30% primary intracranial tumours – second after gliomas
Incidental in up to 10% of post-mortem
- Rare in patients < 40
- Any site of craniospinal axis
- Focal symptoms (seizure, compression)
- MRI: extraxial, isodense, contrast-enhancing
- 80% Grade I: benign, recurrence <25%
20% Grade II: atypical, recurrence 25-50%
1% Grade III: malignant, recurrence 50-90%
What is this?
Meningioma
What are the histology and grading criteria?
Why is mitotic activity important?
- Crucial: determines grade
- Time consuming: cases must be thoroughly examined (even 100 fields or more)
•
•
mitoses / 10HPF (0.16mm2):
<4 = grade I
4-20 = grade II
> 20 = grade III
What is brain invasion?
What is a (grade IV) Medulloblastoma?
- EMBRYONAL TUMOUR: originates from neuroepithelial precursors of the cerebellum/dorsal brainstem
- Rare (2 per 1,000,000 year), but second most common brain tumour in children
- “Small blue round cell tumour”
- Molecular classification: WNT-activated, SHH-activated,
non-WNT/non-SHH
•Outcome considerably improved with radio-chemotherapy
What is this?
Medulloblastoma
What are CNS Mets?
- Most frequent CNS tumour (10 x intrinsic tumours)
- Increasing incidence due to longer survival
- Often multiple
- Any tumour can potentially give CNS metastases,
may be the first presentation of the disease
- Most frequent tumours are: lung ca, melanoma, breast ca, renal ca and colon ca.
- Origin can be challenging to determine
- Very poor prognosis
What is this?
Metastases
- 45 year old female
- History: pulmonary lobectomy
- 2 days of headache and vomiting
- Worsening headache
- CT: right frontoparietal SOL with minimal midline shift to the left
Dd: primary tumour, metastasis, abscess
Diagnosis?
f
70 year old male
Seizure following 2 weeks of left arm and leg weakness
MRI showing heterogeneous enhancing right frontal lesion, started on steroids
Partial response to steroids with improved dexterity of the left arm and leg
Diagnosis?
f
What is this?
f
Malignant tumours are less common but are often extra axial
Malignant tumours are less common but are often extra axial
What are the S/S of intercranial HTN?
Headache, vomiting
Change in mental status
What is tumour type?
Tumour type = histological type
Tumour defined by histological features
Tumour names often derive from putative cell of origin or differentiation
Histological type predicts tumour behaviour
What is a meningioma?
- 38% of primary CNS tumours
- Rare in patients < 40, incidence ↑ with age
- Originate from meningothelial cells of the arachnoid mater.
Any site of craniospinal axis, can be multiple (NF2)
- MRI: extraxial, isodense, contrast-enhancing
- 80% Grade 1: benign, recurrence <25%
20% Grade 2: atypical, recurrence 25-50%
1% Grade 3: malignant, recurrence 50-90%
What does this show?
Psammoma bodies: calcifications
(Meningioma)
What is subtype and grading?
Grading is the most useful predictor of recurrence. It is mainly based on histology, recently molecular markers (ex TERT mutation, methylome)
Complex histological assessment: proliferation, cell morphology, microscopic brain invasion…
15 morphological subtypes, 3 grades
What is mitotic activity?
Crucial: determines grade
mitoses / 10HPF (of 0.16mm2):
<4 = grade 1
4-20 = grade 2
> 20 = grade 3
What is microscopic brain invasion?
Interface between tumour and cortex should be carefully examined
What is a methylome profile?
- Most tumours have characteristic patterns of DNA methylation of CpG islands
- The methylation signature is stable and reflects the tumour cell of origin or early transformed cells
-> Gives information on tumour type not progression/grade
•The DNA methylation status of a subset of CpG islands is assessed with DNA arrays and compared to a reference dataset (“Classifier”)
What is methylation classifier?
Helpful for atypical cases, rare entities, small biopsies, and subtyping: ex medulloblastoma subtypes, meningiomas…
Not used for grade/progression or targeted therapy
True molecular classification: does not consider the histology
What does the tumour grade tell us?
survival
Which mutation identifies diffuse astrocytic tumours with a better prognosis?
IDH mutation
45F headache, previous lobectomy, CT shows frontal lesion and this histology:
Metastases
5 yr old, headache, vomiting, papilloedema. MRI shows cystic cerebellar lesion, histology:
Pilocytic astrocytoma
70 yo left arm and leg weakness, seizures. MRI shows heterogenous enhancing right frontal region with this histology:
Glioblastoma
