CNS neoplasms Flashcards
Most common site of pediatric vs adult brain tumors
pediatric: 2/3 are in infratentorial space (iie. Cerebellum, brainstem and below). Adult: supratentorial space (cerebrum)
- Know the World Health Organization (WHO) grading system for selected examples of primary CNS neoplasms
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
Treatment for grade II tumors
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
Treatment for grade III tumors
adjuvant radiation and/or chemotherapy
Infiltrative tumors and less infiltrative tumors
Infiltrative: Diffuse astrocytomas of all grades, oligodendrogliomas, neuronal neoplasms, and to a lesser extent ependymomas. Less infiltrative: meningiomas and schwannomas
List types of neuroectodermal tumors
aka. Gliomas: Astrocytoma, Oligodendroglioma, Ependymoma, Ganglioglioma, Medulloblastoma
List types of meningeal and mesenchymal tumors
Meningioma, Schwannoma, Neurofibroma
list types of metastatic tumors to the brain
Breast, Lung, Kidney, GI Tract, Melanoma
WHO grades for pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma and glioblastoma
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
Pilocytic astrocytoma population, sites, progression,
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.
Which pilocytic astrocytomas can be completely surgically resected
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
Pilocytic astrocytoma pathology
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
Pilocytic astrocytoma genetics
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.
Diffuse astrocytoma population, progression, location
Mean age 30-40s, WHO grade II, may progress to higher grade, Cerebral hemispheres (white matter), rarely posterior fossa
Diffuse astrocytoma pathology
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+
Diffuse astrocytoma surgically resectable?
No, ill defined borders. Surgery can be used to debulk tumor, but not totally excise the tumor
diffuse astrocytoma genetics
p53 or ATRX mutation, IDH1/2 mutation
Anaplastic astrocytoma population, grade, location
Mean age 45 years, WHO grade III, Cerebral hemispheres in adults
Anaplastic astrocytoma pathology
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% •
MOST IMPORTANT USE OF MIB1
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
Anaplastic astrocytoma genetics
IDH mutation, p53 mutation and 9p loss
Oligodendroglioma population, grade, location
Mean age of onset is 42 years, WHO grade II, Usually arises in cerebral white matter (frontal > parietal > temporal > occipital)
Oligodendroglioma presentation
seizures- tumor infiltrates cortex
Oligodendroglioma pathology
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
Oligodendroglioma genetics
IDH mutation, 1p/19q co-deletion (loss of heterozygosityP
oligodendroglioma surgically resectable?
is an infiltrative neoplasm which is usually not surgically curable by resection alone
Anaplastic oligodendroglioma population, grade
3.5% of adult supratentorial malignant gliomas, Mean age of onset is 48 years, WHO grade III
Anaplastic oligodendroglioma pathology
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.
compare astrocytic vs oligodendroglial features
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
Anaplastic oligodendroglioma genetics
IDH mutation, 1p/19q co-deletion and 9p loss/10q loss
1p/19q deletion utility
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.
Glioblastoma population, location, grade
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
glioblastoma pathology
Highly cellular and mitotically active • Dedifferentiated elements • Microvascular hyperplasia – glomeruloid/solid tufts • Necrosis • Ki-67 / MIB1 of >15%
compare primary and secondary glioblastomas
Primary: occurs de-novo. Mean 55 yrs. <1% IDH-1 postive. These are indistinguishable radiographically
Glioblastoma genetics
Primary: 10q loss, PTEN mutation, EGFR amplification, CDKN2A/B deletion. Secodary: IDH mutation, p53 mutation, 9p loss, 10q loss
Utility of IDH 1/2 mutation analysis
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
Are most glioblastomas primary or secondary
primary
Testing for IDH 1/2
Sanger sequencing, real time PCR, pyrosequencing, IDH1 antibody immunohistochemistry (R132H, will miss small % of gliomas with less common mutations, including IDH2)
does the IDH1 R132H antibody bind to tumor mimics?
NO. Reactive gliosis and other morphological mimics of tumors such as stroke or infectious disorders are negative for IDH1 immunostaining/IDH1/2 mutation
IDH1 and prognosis
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
Ependymoma origin, population, location, presentation
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
ependymoma pathology
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.
ependymoma grade
grade II
ependymoma surgical resection?
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
Anaplastic ependymoma grade, location, pathology
Grade III. Seen in children, in 4th ventricle. Often recur over several years
Choroid plexus papilloma location, grade, features
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
Medulloblastoma population, prognosis, cell of origin, genetics
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
Medulloblastoma pathology and grade
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
What signaling molecule is involved in external granule layer migration
sonic hedgehog
Large cell medulloblastoma prognosis
grade IV but has even worse prognosis than standard medulloblastoma
Meningioma grade, population, location,
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
Hemangiopericytoma
another meningeal based tumor with a worse prognosis and recurrence rate than meningioma
Meningioma pathology
arise from meninges/dura and usually push & distort the underlying brain or cord, rather than invading it
WHO grade II meningiomas
atypical types, more prone to rapid recurrence
Meningioma genetics
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
Schwannoma location progression
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
List familial tumor syndromes
NF-1 (neurofibromatosis type I), NF-2 (neurofibromatosis type II), Tuberous Sclerosis, Von Hippel Lindau Disease, Cowden disease, Turcot’s Syndrome
Metastasis in children
Solid neoplasms of childhood rarely metastasize to the brain
How do primary brain tumors kill patients
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
Which brain tumors break off into CSF and disseminate through the CSF
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.
Symptoms of brain tumor
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
Ganglioglioma grade, location, pathology
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
ganglioglioma genetics
Never IDH1/2 mutated. BRAF V600E mutations do occur
General features of WHO grade II gliomas
mitotic activity is minimal to absent. Necrosis and microvascular proliferation are completely absent. MIB <3-4%
