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Flashcards in CNS neoplasms Deck (54):
1

Gliomas are classified based off of what?

• Their resemblance to normal, non-neoplastic glial cells

2

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

3

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

4

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

5

in what population would you expect a pilocytic astrocytoma to be found?

• Most common CNS neoplasm of childhood
• found also in young adults

6

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

7

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

8

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

9

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

10

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

11

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

12

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

13

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

14

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

15

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

16

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

17

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

18

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

19

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

20

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

21

Where do you find IDH2 mutations?

• These are less common and mostly are found in oligodendroglial tumors

22

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

23

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

24

What are the genetics of diffuse astrocytomas?

• IDH1 mutation
• No LOH 1p, 19q
• + p53/ATRX mutation

25

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

26

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

27

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

28

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

29

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

30

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

31

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

32

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

33

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

34

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

35

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

36

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

37

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)

38

What are the genetic losses that make a primary GBM?

• 10q loss
• PTEN mutation
• EGFR amplification
• CDKN2A/B deletion

39

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

40

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

41

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

42

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

43

When you see synaptophysin you think…?

• Ganglioglioma
• Neoplastic neurons express synaptophysin and NeuN (nuclear neurofilament)

44

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%

45

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

46

What are the two ways that medulloblastomas are classified by the WHO?

• Genetically defined
○ In particular shh and wnt
• Histopathologically defined

47

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

48

What grade are all medulloblastomas?

• WHO grade IV
• They can subclassify by moleuclar criteria: radiation and chemotherapy protocols being modified based on subtype

49

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

50

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)

51

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)

52

The 8th cranial nerve is an unfortunately common site of what tumor's growth?

• Schwannoma
• Vestibular schwannomas or acoustic neuromas

53

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

54

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

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