CNS neoplasms

Question 1

Most common site of pediatric vs adult brain tumors

Answer 1

pediatric: 2/3 are in infratentorial space (iie. Cerebellum, brainstem and below). Adult: supratentorial space (cerebrum)

Question 2

1. Know the World Health Organization (WHO) grading system for selected examples of primary CNS neoplasms

Answer 2

Grade 1: low proliferative potential and possibility of cure following surgical resection alone. Grade II: generally infiltrative in nature, and, despite low level proliferative (ie., mitotic) activity, often recur. Grade III: lesions with histological evidence of malignancy, including nuclear atypia and brisk mitotic activity. Grade IV: cytologically malignant, mitotically active, necrosis-prone neoplasms often associated with rapid pre- and post operative disease evolution and fatal outcome

Question 3

Treatment for grade II tumors

Answer 3

watchful waiting (ie., close-interval neuroimaging scans to detect upgrading) or external beam cranial irradiation, depending on location, clinical features, type and size of lesion

Question 4

Treatment for grade III tumors

Answer 4

adjuvant radiation and/or chemotherapy

Question 5

Infiltrative tumors and less infiltrative tumors

Answer 5

Infiltrative: Diffuse astrocytomas of all grades, oligodendrogliomas, neuronal neoplasms, and to a lesser extent ependymomas. Less infiltrative: meningiomas and schwannomas

Question 6

List types of neuroectodermal tumors

Answer 6

aka. Gliomas: Astrocytoma, Oligodendroglioma, Ependymoma, Ganglioglioma, Medulloblastoma

Question 7

List types of meningeal and mesenchymal tumors

Answer 7

Meningioma, Schwannoma, Neurofibroma

Question 8

list types of metastatic tumors to the brain

Answer 8

Breast, Lung, Kidney, GI Tract, Melanoma

Question 9

WHO grades for pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma and glioblastoma

Answer 9

Pilocytic astrocytoma: WHO grade I
Diffuse astrocytoma: WHO grade II
Anaplastic astrocytoma: WHO grade III
Oligodendroglioma: WHO grade II
Anaplastic oligodendroglioma: WHO grade III
Glioblastoma: WHO grade IVPilocytic astrocytoma: WHO grade I
Diffuse astrocytoma: WHO grade II
Anaplastic astrocytoma: WHO grade III
Oligodendroglioma: WHO grade II
Anaplastic oligodendroglioma: WHO grade III
Glioblastoma: WHO grade IVPilocytic astrocytoma: WHO grade I
Diffuse astrocytoma: WHO grade II
Anaplastic astrocytoma: WHO grade III
Oligodendroglioma: WHO grade II
Anaplastic oligodendroglioma: WHO grade III
Glioblastoma: WHO grade IVPilocytic astrocytoma: WHO grade I
Diffuse astrocytoma: WHO grade II
Anaplastic astrocytoma: WHO grade III
Oligodendroglioma: WHO grade II
Anaplastic oligodendroglioma: WHO grade III
Glioblastoma: WHO grade IV

Question 10

Pilocytic astrocytoma population, sites, progression,

Answer 10

Most common CNS neoplasm of childhood but not infrequently found also in young adults. Usual sites: cerebellum, optic pathway, hypothalamus, also thalamus, spinal cord, temporal lobe. minimal tendency to progress to higher grades.

Question 11

Which pilocytic astrocytomas can be completely surgically resected

Answer 11

Gross total resection of a cerebellar lesion can often be achieved whereas it is impossible to achieve gross total resection in the optic chiasm or hypothalamus. Tumors in these locations often require additional therapy beyond surgery, simply because they will slowly continue to grow and cause dysfunction of vital brain areas

Question 12

Pilocytic astrocytoma pathology

Answer 12

Pathology: Bipolar neoplastic cells with elongated hairlike processes in parallel bundles, Rosenthal fibers (eosinophilic accumulation of intracytoplasmic glial filaments), eosinophilic granular bodies, May be vascular with calcifications. Mass appear well demarcated and cystic

Question 13

Pilocytic astrocytoma genetics

Answer 13

BRAF fusion with KIAA leads to constitutive activation of BRAF. BRAF is mitogen-activated protein kinase (MAPK) in RAS/RAF/MEK/ERK pathway. Plays key role in cell proliferation, cell survival, differentiation, apoptosis. Oncogene-induced senescence occurs which is favorable for slow growing tumors.

Question 14

Diffuse astrocytoma population, progression, location

Answer 14

Mean age 30-40s, WHO grade II, may progress to higher grade, Cerebral hemispheres (white matter), rarely posterior fossa

Question 15

Diffuse astrocytoma pathology

Answer 15

Discohesive monotonous cellular infiltrate in patternless array. Mild hypercellularity, mild nuclear pleomorphism. • 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 <4% • Often nuclear p53 IHC+

Question 16

Diffuse astrocytoma surgically resectable?

Answer 16

No, ill defined borders. Surgery can be used to debulk tumor, but not totally excise the tumor

Question 17

diffuse astrocytoma genetics

Answer 17

p53 or ATRX mutation, IDH1/2 mutation

Question 18

Anaplastic astrocytoma population, grade, location

Answer 18

Mean age 45 years, WHO grade III, Cerebral hemispheres in adults

Question 19

Anaplastic astrocytoma pathology

Answer 19

Higher cellularity, increased nuclear pleomorphism, hyperchromasia, and mitoses compared to WHO grade II astrocytomas • No necrosis or microvascular proliferation • Ki-67 / MIB1 higher than WHO grade II, usually 5-15% •

Question 20

MOST IMPORTANT USE OF MIB1

Answer 20

is in distinguishing WHO grade II astrocytoma from WHO grade III anaplastic astrocytoma. MIB1 is higher in anaplastic astrocytoma, MIB-1 is present in nucleus of cells in all phases of cell cycle except G0, thus cells with higher mitotic activity have more MIB1

Question 21

Anaplastic astrocytoma genetics

Answer 21

IDH mutation, p53 mutation and 9p loss

Question 22

Oligodendroglioma population, grade, location

Answer 22

Mean age of onset is 42 years, WHO grade II, Usually arises in cerebral white matter (frontal > parietal > temporal > occipital)

Question 23

Oligodendroglioma presentation

Answer 23

seizures- tumor infiltrates cortex

Question 24

Oligodendroglioma pathology

Answer 24

Low to moderate cellularity occasional mitosis • Regular round nuclei with artifactual perinuclear halo (appear like a fried egg) • Fine capillary network (chicken wire pattern) and focal calcification • Perineuronal satellitosis, often extensive cortical infiltration correlating with seizure activity clinically • Many cases have intermediate or mixed oligodendroglial/astrocytic phenotype

Question 25

Oligodendroglioma genetics

Answer 25

IDH mutation, 1p/19q co-deletion (loss of heterozygosityP

Question 26

oligodendroglioma surgically resectable?

Answer 26

is an infiltrative neoplasm which is usually not surgically curable by resection alone

Question 27

Anaplastic oligodendroglioma population, grade

Answer 27

3.5% of adult supratentorial malignant gliomas, Mean age of onset is 48 years, WHO grade III

Question 28

Anaplastic oligodendroglioma pathology

Answer 28

Same as classic but with increased cellularity, nuclear atypia, mitoses • Occasional vascular proliferation (enhancement on imaging studies) and geographic necrosis. Elevated MIB-1. Cells have fried egg appearance.

Question 29

compare astrocytic vs oligodendroglial features

Answer 29

different criteria (“more lenient”) used for oligodendroglial lineage tumors versus astrocytic tumors. Necrosis and vascular proliferation in an anaplastic astrocytic tumor would be a glioblastoma

Question 30

Anaplastic oligodendroglioma genetics

Answer 30

IDH mutation, 1p/19q co-deletion and 9p loss/10q loss

Question 31

1p/19q deletion utility

Answer 31

Seen in oligodendroglial histology. Prognostic of better survival. When positive for this deletion, patients have better response to procarbazine-lomustine-vincristine (PCV) and temozolomide plus radiotherapy.

Question 32

Glioblastoma population, location, grade

Answer 32

15% of all intracranial neoplasms, Mean age of onset, Primary GBM =62 years, Secondary GBM =45 years, Usually involves cerebral hemispheres, WHO grade IV astrocytoma

Question 33

glioblastoma pathology

Answer 33

Highly cellular and mitotically active • Dedifferentiated elements • Microvascular hyperplasia – glomeruloid/solid tufts • Necrosis • Ki-67 / MIB1 of >15%

Question 34

compare primary and secondary glioblastomas

Answer 34

Primary: occurs de-novo. Mean 55 yrs. <1% IDH-1 postive. These are indistinguishable radiographically

Question 35

Glioblastoma genetics

Answer 35

Primary: 10q loss, PTEN mutation, EGFR amplification, CDKN2A/B deletion. Secodary: IDH mutation, p53 mutation, 9p loss, 10q loss

Question 36

Utility of IDH 1/2 mutation analysis

Answer 36

IDH1 mutation is positive in 60-80% of WHO grade II and III gliomas (astrocytic and oligodendroglial) and secondary GBMs, but rare in primary GBMs and absent in pilocytic astrocytomas. IDH2 mutations are mostly in oligodendroglial tumors. IDH1/2 mutations rare in non CNS tumors

Question 37

Are most glioblastomas primary or secondary

Answer 37

primary

Question 38

Testing for IDH 1/2

Answer 38

Sanger sequencing, real time PCR, pyrosequencing, IDH1 antibody immunohistochemistry (R132H, will miss small % of gliomas with less common mutations, including IDH2)

Question 39

does the IDH1 R132H antibody bind to tumor mimics?

Answer 39

NO. Reactive gliosis and other morphological mimics of tumors such as stroke or infectious disorders are negative for IDH1 immunostaining/IDH1/2 mutation

Question 40

IDH1 and prognosis

Answer 40

fairly strong evidence that negative IDH1 anaplastic astrocytomas do more poorly than those with IDH1 mutation. Studies that have stratified IDH1 mutation assessment suggest that it is more powerful predictor in high grade gliomas than is grade

Question 41

Ependymoma origin, population, location, presentation

Answer 41

Arises from ependymal cells that line the ventricles; most (not all) are in intraventricular locations • Most present during the first 2 decades of life • Most in the 4th ventricle, present with obstructive hydrocephalus • Commonly calcified, protrude up from floor of 4th ventricle • Spinal cord ependymomas are usually tumors of adults. 4th ventricle lesions have worse prognosis

Question 42

ependymoma pathology

Answer 42

cells form either true rosettes mimicking ependymal canals or perivascular pseudorosettes (a perpendicular arrangement of cells around blood vessels with the formation of elongate cell processes). Grade II show mild cell density, few mitotic figures, little necrosis or microvascular proliferation.

Question 43

ependymoma grade

Answer 43

grade II

Question 44

ependymoma surgical resection?

Answer 44

When they occur in the spinal cord they are usually fairly well demarcated from cord and total or near total excision may be possible. In the brainstem, not cured by gross excision due to important nuclei in floor of 4th ventricle

Question 45

Anaplastic ependymoma grade, location, pathology

Answer 45

Grade III. Seen in children, in 4th ventricle. Often recur over several years

Question 46

Choroid plexus papilloma location, grade, features

Answer 46

Occurs in ventricles (NOT ependymoma), WHO grade I. In children, usually occur in lateral ventricles. In adults, usually occur in 4th ventricle. Produce hydrocephalus by blocking CSF flow, NOT by producing excess CSF

Question 47

Medulloblastoma population, prognosis, cell of origin, genetics

Answer 47

Most common malignant brain tumor in children. Peak incidence 3-8 yrs old, slightly more males. 50% survival rate. Cells of origin are granule cell precursors from external granule layer. occurs in cerebellum/brainstem area. Cells undergo transformation and lack of differentiation, chrom 17 deletions/mutations

Question 48

Medulloblastoma pathology and grade

Answer 48

grade IV. Homer Wright rosettes (circular ring of nuclei with a central anuclear area filled with cell processes ), as well as hypercellularity and poor differentiation of small blue cells (small embryonic cells with scant cytoplasm) in tumor grade IV. Homer Wright rosettes (circular ring of nuclei with a central anuclear area filled with cell processes ), as well as hypercellularity and poor differentiation of small blue cells (small embryonic cells with scant cytoplasm) in tumor

Question 49

What signaling molecule is involved in external granule layer migration

Answer 49

sonic hedgehog

Question 50

Large cell medulloblastoma prognosis

Answer 50

grade IV but has even worse prognosis than standard medulloblastoma

Question 51

Meningioma grade, population, location,

Answer 51

Common intracranial neoplasm, vast majority are WHO grade I • Most become clinically evident after third decade, rare in childhood. PEAK INCIDENCE IS WOMEN IN THEIR 50’s • Usually solitary, may penetrate dura, occlude venous sinuses, invade bone and cause hyperostosis • Most variations in microscopic subtype do NOT reflect different prognosis

Question 52

Hemangiopericytoma

Answer 52

another meningeal based tumor with a worse prognosis and recurrence rate than meningioma

Question 53

Meningioma pathology

Answer 53

arise from meninges/dura and usually push & distort the underlying brain or cord, rather than invading it

Question 54

WHO grade II meningiomas

Answer 54

atypical types, more prone to rapid recurrence

Question 55

Meningioma genetics

Answer 55

Grade I: arachnoidal cells have NF2 gene mutation/chromosome 22q loss. Atypical meningioma Grade II: additional gains/losses. Anaplastic meningioma, grade III: additional losses, plus rare mutations or deletions

Question 56

Schwannoma location progression

Answer 56

Slow growing, little histological variability, Malignant transformation rare, Found on cranial nerve 8, can be found on other cranial nerves, Also found on spinal nerve roots

Question 57

List familial tumor syndromes

Answer 57

NF-1 (neurofibromatosis type I), NF-2 (neurofibromatosis type II), Tuberous Sclerosis, Von Hippel Lindau Disease, Cowden disease, Turcot’s Syndrome

Question 58

Metastasis in children

Answer 58

Solid neoplasms of childhood rarely metastasize to the brain

Question 59

How do primary brain tumors kill patients

Answer 59

They infiltrate as individual cells throughout widespread areas of the brain. Those that grow rapidly cause additional compression of vital structures, with mass effect, and eventually herniation and death. Tumors that grow in or into the ventricles can cause obstructive hydrocephalus

Question 60

Which brain tumors break off into CSF and disseminate through the CSF

Answer 60

Astrocytomas and oligodendrogliomas almost never/very rarely ‘break off’ into the CSF pathway and disseminate through the cerebrospinal fluid. In contrast, this does occur late in the course of some ependymomas, especially those in childhood and originating in the 4th ventricle, and CSF dissemination occurs in a significant percentage of medulloblastomas.

Question 61

Symptoms of brain tumor

Answer 61

Seizures, paresis of one side of the body, or other neurological deficits are usually present; headache alone for any length of time is not the way most brain tumor patients come to medical attention

Question 62

Ganglioglioma grade, location, pathology

Answer 62

WHO grade I. Occurs in temporal lobe usually, but may be found in cerebral hemispheres, brainstem/cerebellum/spinal cord. Cystic, well demarcated and calcifications. cytologically-abnormal neurons mixed into a low grade glial background

Question 63

ganglioglioma genetics

Answer 63

Never IDH1/2 mutated. BRAF V600E mutations do occur

Question 64

General features of WHO grade II gliomas

Answer 64

mitotic activity is minimal to absent. Necrosis and microvascular proliferation are completely absent. MIB <3-4%