CNS neoplasms Flashcards
Gliomas are classified based off of what?
• Their resemblance to normal, non-neoplastic glial cells
What are the common gliomas and their WHO grade by definition?
• Pilocytic astrocytoma ○ Grade I • Diffuse astrocytoma ○ Grade II • Anaplastic astrocytoma ○ Grade III • Oligodendroglioma ○ Grade II • Anaplastic oligodendroglioma ○ Grade III • Glioblastoma ○ Grade IV
What makes a grade I glioma “not so bad”?
- Well demarcated
- Generally do not upgrade over time
- Can be surgically-excised if in an anatomically favorable location
- Treated with surgery alone
- Usually doesn’t require adjuvant therapies like radiation/chemo
What are the characteristics of pilocytic astrocytoma?
• Most common CNS neoplasm of childhood
• found also in young adults
• Cerebellum, optic pathway, hypothalamus, thalamus, spinal cord, temporal lobe
• WHO grade I, does not progress to higher grades (usually)
• Different genetic origins in different anatomical sites
• Histopathology
○ Bipolar neoplastic cells with elongated hairlike processes in parallel bundels
○ Rosenthal fibers, eosinophilic granular bodies
○ May be vascular with calcifications
in what population would you expect a pilocytic astrocytoma to be found?
- Most common CNS neoplasm of childhood
* found also in young adults
What is the histopathology of a pilocytic astrocytoma?
• Histopathology
○ Bipolar neoplastic cells with elongated hairlike processes in parallel bundels
○ Rosenthal fibers, eosinophilic granular bodies
○ May be vascular with calcifications
When you see pilocytic astrocytoma, what genetic underpinnings must you think of?
- BRAF:KIAA fusion
- BRAF fusion
- The grade I pilocytic astrocytomas by definition have the BRAF fusion
What does the BRAF gene product do?
- Mitogen-activated protein kinase
- MAPK
- In the RAS/RAF/MEK/ERK pathway
- Key in cell proliferation, survival, differentiation and apoptosis
- Ends up making cyclin D1
What makes the BRAF:KIAA fusion such an advantage for the tumor cell?
- Don’t know what KIAA does alone but fusion leads to ablation of BRAF N-terminal domain
- Renders BRAF constitutively active and leads to oncogene-induced senescence (OIS)
- Favorable feature in a slowly growing tumor
What’s up with diffuse astrocytoma?
• Mean age 30s-40s
• WHO grade II, may progress to higher grade
• Cerebral hemispheres, rarely posterior fossa
• Histopathology
○ Discohesive monotonous cellular infiltrate in patternless array
○ Fibrillary, protoplasmic, gemistocytic subtypes
○ Occasional microcystic change
○ Rare mitoses, two or more on small stereotactic biopsies = WHO grade III
○ No microvascular proliferation or necrosis
○ Ki67/MIB1 less than 4%
§ Marker of cell cycle
○ Often nuclear p53 IHC+
§ This is unlike oligodendrogliomas
What is the histopathology of diffuse astrocytoma?
• Histopathology
○ Discohesive monotonous cellular infiltrate in patternless array
○ Fibrillary, protoplasmic, gemistocytic subtypes
○ Occasional microcystic change
○ Rare mitoses, two or more on small stereotactic biopsies = WHO grade III
○ No microvascular proliferation or necrosis
○ Ki67/MIB1 less than 4%
§ Marker of cell cycle
○ Often nuclear p53 IHC+
§ This is unlike oligodendrogliomas
What are the important IHC markers in diffuse astrocytoma?
○ Ki67/MIB1 less than 4%
§ Marker of cell cycle
○ Often nuclear p53 IHC+
§ This is unlike oligodendrogliomas
What makes diffuse astrocytoma a difficult tumor to treat surgically?
- Microcysts and ill-defined borders
- Surgeon can’t tell where the tumor starts and stops
- Radiologist can’t tell…you can’t operate on this lesion
What’s up with anaplastic astrocytoma?
• Mean age is 45 years
• WHO grade III
• Cerebral hemispheres in adults
• Histopathology
○ Higher cellularity, increased nuclear pleomorphism, hyperchromasia, mitoses compared to WHO grade II astrocytomas
○ No necrosis or microvascular proliferation
○ Ki-67/MIB1 higher than WHO grade II, 5-15%
○ MOST IMPORTANT USE OF MIB1 is in distinguishing WHO grade II astrocytoma from WHO grade III anaplastic astrocytoma
What is the MOST IMPORTANT USE OF MIB1?
○ MOST IMPORTANT USE OF MIB1 is in distinguishing WHO grade II astrocytoma from WHO grade III anaplastic astrocytoma
- less than 4% for grade II
- 5-15% for grade III
In terms of IDH, what do each of the tumors we discussed have?
- All pilocytic astrocytomas are IDH wildtype
- All oligodendrogliomas are IDH mutant AND show 1p/19q deletion
- Diffuse astrocytoma, anaplastic astrocytoma, GBM today SEPARATED into/DEFINED BY IDH mutant and IDH wildtype status
- GBM - glioblastoma multiformans
What is IDH?
• IDH - isocitrate dehydrogenase
• Absolutely essential to know that this is a CNS neoplasm diagnostic marker and it defines certain tumors
*normal function is protection against oxidative damage
If there is a problem in IDH, what is the result?
• IDH mutation can lead to too little alpha-ketoglutarate, which is protective against oxidative damage
• If there is too little alpha-ketoglutarate there is a release of HIF1
○ Hypoxia inducible factor
• Leads to angiogenesis really, and promotes the tumor invasion, survival and angiogenesis
What is the utility of the IDH1/2 mutations?
• Determining if the lesion is neoplastic vs. non-neoplastic
• Primary CNS tumor vs. non-CNS tumor (metastasis)
○ Remember that metastatic brain lesions are more common than primary
• Marker of astrocytic and oligodendroglial tumors
What is the IDH1 mutation important for?
- Diffuse astrocytomas, anaplastic astrocytomas, GBMs today DEFINED by IDH-mutant or wildtype status
- All adult oligodendrogliomas defined by presence of LOH 1p,19q AND IDH mutation (either IDH1 or 2)
- 90% of IDH1 mutations are at position R132H
Where do you find IDH2 mutations?
• These are less common and mostly are found in oligodendroglial tumors
What is the utility of an antibody against IDH1 R132H?
- This is 90% of all IDH mutations
- You would see lots of IDH problems and thus would see oligodendrogliomas well
- There is a small percentage of gliomas you could miss like the ones with sporadic mutations somewhere else or the rare IDH2 mutations
What does IDH1 mutation status have to do with prognosis?
- Strong evidence that negative IDH1 anaplastic astrocytomas do more poorly than those with IDH1 mutation
- Studies that have stratified IDH1 mutation assessment suggest that IDH is more powerful predictor in high grade gliomas than is grade
What are the genetics of diffuse astrocytomas?
- IDH1 mutation
- No LOH 1p, 19q
- p53/ATRX mutation
What tumors have ATRX gene and what have a loss of it?
• ATRX is lost in diffuse astrocytomas
○ Grade II and III
• Retained in oligodendrogliomas, primary GBMs and special glioma types
What’s up with oligodendrogliomas?
• 5-15% of all gliomas
• Mean age of onset is 42 years
• WHO grade II
• Usually arises in cerebral white matter
• Histopathology
○ Low to moderate cellularity occasional mitosis
○ Regular round nuclei with artifactual perinuclear halo
○ Fine capillary network and focal calcification
○ Perineuronal satellitosis, often extensive cortcal infiltration correlating with seizure activity clinically
○ Many cases have intermdiate or mixed oligodendroglial/astrocytic phenotype
○ Both tumor types now know to share common IDH1 mutational lineage, followed by later different and distinctive genetic mutations leading to oligo vs. atrocytic lineage
§ P53 vs LOH 1p, 19q
What is the histopathology common to oligodendrogliomas?
• Histopathology
○ Low to moderate cellularity occasional mitosis
○ Regular round nuclei with artifactual perinuclear halo
○ Fine capillary network and focal calcification
○ Perineuronal satellitosis, often extensive cortcal infiltration correlating with seizure activity clinically
○ Many cases have intermdiate or mixed oligodendroglial/astrocytic phenotype
○ Both tumor types now know to share common IDH1 mutational lineage, followed by later different and distinctive genetic mutations leading to oligo vs. atrocytic lineage
§ P53 vs LOH 1p, 19q
Why do oligodendrogliomas tend to have a mixed astrocytic/oligodendroglial phenotype?
○ Both tumor types now know to share common IDH1 mutational lineage, followed by later different and distinctive genetic mutations leading to oligo vs. atrocytic lineage
§ P53 vs LOH 1p, 19q
A surgical pathology sample (gross) shows a loss of the gray white interface in the cortex. What is the likely culprit?
• Low grade oligodendroglioma will obscure the gray-white interface of the cortex
What’s up with the anaplastic oligodendroglioma subtype?
• 3.5% of adult supratentorial malignant gliomas
• Mean age of onset is 48 years
• WHO grade III
*expect to see elevated MIB1 presence (more mitoses)
• Histopathology
○ Same as classic oligodendroglioma but with incrased cellularity, nuclear atypia and mitoses
○ Occasional vascular proliferation and geographic necrosis is allowed
○ There is a bit more lee-way in the oligodendroglial lineage tumors with necrosis and vascular proliferation
○ IF IT IS ASTROCYTIC, necrosis and vascular proliferation would change the dx to GBM
In terms of geographical necrosis and vascular proliferation what is the difference in dx between a tumor of oligodendrocytic and astrocytic lineage?
○ There is a bit more lee-way in the oligodendroglial lineage tumors with necrosis and vascular proliferation
○ IF IT IS ASTROCYTIC, necrosis and vascular proliferation would change the dx to GBM
○ Occasional vascular proliferation and geographic necrosis is allowed in dx of anaplastic oligodendroglioma
Oligodendroglial tumors are associated with what particular genetic anomaly?
• 1p and 19q codeletions
• Established genetic marker of oligodendroglial tumors
• 60-80% of oligodendrogliomas have this
• More than 60% of anaplastic oligodendrogliomas have this
• Results from unbalanced translocation t(1;19)(q10;10)
○ Lose 1p/19q
○ Preservation of a 1q/19p chromosome
○ Entire chromosome arms typically lost
In terms of 1p,19q deletions, what CNS tumors have what abnormalities?
- All pilocytic astrocytomas are IDH wildtype and do NOT have 1p,19q deletions
- All oligodendrogliomas are IDH mutant AND show 1p/19q deletion
- Diffuse astrocytoma, anaplastic astrocytoma, GBM today SEPARATED into/DEFINED BY IDH mutant and IDH wildtype status
- GBM - glioblastoma multiformans
What is the utility of discovering a 1p/19q deletion presence/absence?
• Diagnostic: almost never seen in non-oligodendrogliomas
○ Excepting pediatric cases which have different genetics
• Prognostic - better survival if deletion is present
• Predicitive
○ Better response to procarbazine-lomustine-vincristine (PCV) treatment originally
○ Newer treatment is temozolomide plus radiotherapy and deletion presence predicts better response to this treatment
What’s up with GBM?
• GBM - glioblastoma multiformans
• 15% of all intracranial neoplasms
• Mean age of onset primary = 62 years
• Mean age of onset secondary = 45 years
• Usually involves cerebral hemispheres
• WHO grade IV
• Histopathology
○ Highly cellular and mitotically active
○ Dedifferentiated elemtns
○ Microvascular hyperplasia - glomeruloid/solid tufts
○ Necrosis
○ Ki-67/MIB1 is over 15%
○ Once diagnsis of GBM is established, controversial as to wheter mitotic rate/MIB1 index provides further diagnostic value
○ Probably due to overwhelming influence of necrosis on prognosis
What is the histopathology of GBM?
• Histopathology
○ Highly cellular and mitotically active
○ Dedifferentiated elemtns
○ Microvascular hyperplasia - glomeruloid/solid tufts
○ Necrosis
○ Ki-67/MIB1 is over 15%
○ Once diagnsis of GBM is established, controversial as to wheter mitotic rate/MIB1 index provides further diagnostic value
○ Probably due to overwhelming influence of necrosis on prognosis
How do you genetically arrive at secondary glioblastoma?
- IDH (must start out with this)
- TP53 mutation/17p loss
- (now diffuse astrocytoma)
- 9p loss
- (now anaplastic astrocytoma)
- 10q loss
- (now secondary GBM)
What are the genetic losses that make a primary GBM?
- 10q loss
- PTEN mutation
- EGFR amplification
- CDKN2A/B deletion
What is EGFRvIII?
- 50% of GBMs with EGFR amplification contain EGFRvIII
- In-frame deletion of extracellular domain of EGFR, which makes it constitutively active
- Helpful for showing the high-grade evilness of GBM
Pediatric and adult GBMs are similar in all ways except:
- PTEN mutations and EGFR amplification
- These are way more rare in pediatric cases
- IDH1 mutations are also rare in children
What is the worst of all pediatric brain tumors?
• Pediatric diffuse gliomas
• Diffuse intrinsic pointine glioma (DIPG)
• Midline non-brainstem high grade glioma (mHGG)
• Almost ALL have H3 K27M mutations
○ Histone mutation
• Almost 100% fatality and medial survival is 9 months
What’s up with ganglioglioma?
- WHO grade I
- Younger patient population, 8-25 years
- Usually supratentorial - temporal lobe
- Calcified, cystica nd demarcated, usually little mass effect
- Present with seizures pretty often
When you see synaptophysin you think…?
- Ganglioglioma
* Neoplastic neurons express synaptophysin and NeuN (nuclear neurofilament)
What’s up with medulloblastoma?
- Tumor of cerebellum
- Peak age of 7 years, most are in children under 16 years old
- Male predominance
- Present with disturbances of gait, truncal ataxia, lethargy, headache, morning vomiting
- Radiation and chemotherapy regimens in treatment of medulloblastoma has improved the 5-year survival rate to 90%
You see the word rosette, or a slide with a nice circular clump of tumor cells that look like a blueberry you think…?
- Medduloblastoma
- Flexner’s rossette (1891)
- Wrights rosette (1911)
- Bailey’s pseudo-rosettes (1926)
- All are used to classify medulloblastoma
What are the two ways that medulloblastomas are classified by the WHO?
• Genetically defined
○ In particular shh and wnt
• Histopathologically defined
Can you suspect either a wnt-MB or shh-MB by imaging?
- MB = medulloblastoma
- Yes, wnt = cerebellar peduncle/CPA
- Lateral cerebellum = shh
- You still have to test but you can suspect based off of tumor location
What grade are all medulloblastomas?
- WHO grade IV
* They can subclassify by moleuclar criteria: radiation and chemotherapy protocols being modified based on subtype
What is important about a choroid plexus papilloma?
- Intraventricular tumor most often
- WHO grade I, surgically excisable quite often
- Can cause hydrocephalus by CSF overproduction, but that is rare.
- Hydrocephalus is usually caused by CSF blockage in this case
What’s up with the ependymoma?
- WHO grade II
- From ependymal cells that line the ventrical and most are found intraventricular
- Most are in first 20 years of life
- Most are in 4th ventricle
- Most present with hydrocephalus
- Commonly calcified tumors and protrude up from floor of 4th ventricle
- Should see some hairs on them to determine ependymal differentiation
- Some form canals or tubes (trying to form 4th ventricle aqueduct)
What is a common form of mesenchymal-based tumor that is in the cranial vault?
• Meningiomas
• Grade I mostly, but can push on stuff that can be harmful (mass effect)
• They may penetrate dura, occlude venous sinuses and invade bone, causing hyperostosis
You see hyperostosis in the cranial vault and you think…?
• Meningiomas have the ability to invade bone and make a large bony tumor (can’t really excise without super specialist help)
The 8th cranial nerve is an unfortunately common site of what tumor’s growth?
- Schwannoma
* Vestibular schwannomas or acoustic neuromas
What are the familial tumor syndromes that concern the CNS?
• Neurofibromatosis type 1 and 2
○ Type 1 - autosomal dominant
§ Intra and extracranial schwann cell tumors
§ Optic gliomas, astrocytomas and meningiomas also occur
§ Protein is neurofibromin, which inhibits RAS
§ Located at 17q11.2
○ Type 2
§ Bilateral vestibular schwannomas and multiple meningiomas
§ Gene on 22q12
§ Protein is merlin and regulates cell surface receptor signalling
• Tuberous sclerosis
○ Autosomal dominant
○ TSC1 and 2 genes
○ Hamartin and tuberin are gene products
○ Inhibit mTOR which regulates cell size and anabolic growth
○ Characterized by hamartomas and benign neoplasms of the brain and other tissues
○ Sub-ependymal giant cell astrocytoma
What are the 5 most common metastatic cancers to the CNS?
Lung, breast, melanoma, kidney and GI
Account for 80% of all metastases in CNS
Meninges are often a metastatic site as well
All are sharply demarcated and form at the gray-white junction
Treatment is treating primary tumor and surgical resection from brain
