CNS Tumors Flashcards
Basic principles
o Can be metastatic (50%) or primary (50%)
o Metastatic tumors characteristically present as multiple, well circumscribed lesions at the gray-white junction –> lung, breast and kidney are common sources
o Primary tumors are classified according to cell type of origin –> e.g. astrocytes, meningothelial cells, ependymal cells, oligodendrocytes or neuroectoderm
o In adults, primary tumors are usually supratentorial (cerebral hemispheres)
—> Most common tumors in adults are glioblastoma multiforme, meningioma and schwannoma
o In children, primary tumors are usually infratentorial (posterior fossa)
—> Most common tumors in children are pilocytic astrocytoma, ependymoma and medulloblastoma
o Primary malignant CNS tumors are locally destructive, but rarely metastasize
Diffuse astrocytoma
o Astrocytoma grade II = low grade astrocytoma –> lacks additional features of malignancy
o Anaplastic astrocytoma = astrocytoma, grade III
—> Increased cellularity, pleomorphism + mitotic activity
—> Vascular proliferation and necrosis are absent
o Glioblastoma = grade IV astrocytoma –> high cellularity, pleomorphism + mitotic activity
—> Prominent vascular proliferation and/or necrosis
Glioblastoma multiforme
Malignant, high grade tumors of astrocytes
o Most common primary malignant CNS tumor in adults –> usually in elderly
o Usually arises in the cerebral hemisphere –> characteristically crosses the corpus callosum = “butterfly” lesion
o Characterized by regions of necrosis surrounded by tumor cells (pseudopalisading) + endothelial cell proliferation
o Tumors cells are GFAP positive
o Poor prognosis –> rapid progression
2 pathways 1. Primary/de novo glioblastoma typically older patients, no prior progression from a lower grade lesions • LOH 10q • EGFR gene amplification • P16INK4a deletion • PTEN mutations
- Secondary glioblastoma typically younger patients, early TP53 mutation, progression from low grade to high grade
• More frequent IDH1 mutations
Additional molecular advances in gliomas
- Isocitrate dehydrogenase 1 (IDH-1) –> Most frequent mutation in Grade II and Grade III gliomas; mutated in “secondary” glioblastoma
• Possible prognostic marker
• R132H –> mutated segment in IDH1 present in low grade gliomas = favorable prognostic marker - Epigenetic silencing/methylation of the MGMT –> O6-methylguanine–DNA methyltransferase DNA repair gene; confers improved progression free survival in patients treated with radiation and alkylating agent temozolomide
- 1p/19q deletion –> Associated with
i) oligodendroglial differentation;
ii) improved progression free survival
iii) in high grade oligodendrogliomas, sensitivity to chemoradiation
• May be related in part to FUBP1 (far-upstream element (FUSE) binding protein 1) mutations on 1p, and/or CIC (homolog of drosophila gene capicua) mutations on 19q - 7q34 duplication –> produces BRAF fusion gene in pilocytic astrocytoma
Glioblastoma - treatment
- GTR almost impossible
- Extent of resection need tissue confirmation
• Controversy regarding the benefit of greater extent of resection in high grade gliomas - External beam radiotherapy –> mean survival without RT = 3-6 months, with RT = 9-12 months
- Radiation +/- temozolomide (alkylating agent) improved survival
• Issue with temozolomide is that our body has DNA repair mechanism via MGMT removes alkyl group counteracting the effect of treatment
• Patients whose tumor had a mutation in MGMT rendering it ineffective have much higher survival rates following this therapy this mutation is a positive prognostic marker
Oligodendroglioma
Malignant tumor of oligodendrocytes
o Adult patients
o WHO grade II or III –> generally more slowly growing and treatment responsive than astrocytomas
o Associated with loss of chromosomes 1p and 19Q –> 1p/19q loss used as marker of…
—> Oligodendoglial differentiation
—> Long progression free survival
—> Chemosensitivity, particularly in grade III tumors
—> Positive prognostic and predictive marker
o Imaging reveals a calcified tumor in the white matter, usually involving the frontal lobe
o May present with seizures
o “fried egg” appearance of cells on biopsy
Ependymoma
Malignant tumor of ependymal cells –> intraventricular
o Usually seen in children
—> In children –> 4th ventricle most common; may cause hydrocephalus
—> Adults –> spinal cord most common
o Better demarcated than astrocytomas
o Microscopic hallmarks = true ependymal rosettes and perivascular pseudorosettes
o Deletion of chromosome 22
o Ependymoma is WHO grade II tumor by definition
o Anaplastic ependymoma = WHO grade III ependymoma –> very subjective differences between grades 2 and 3
o Myxopapillary ependymoma –> occurs in filum terminale, WHO grade I = benign
Choroid plexus papilloma/carcinoma
Central neurocytoma
Ganglioma
Dysembryoplastic neuroepithelial tumor
Choroid plexus papilloma/carcinoma –> young patients, intraventricular
Central neurocytoma –> slow growing, usually intraventricular, neuronal differentiation (synaptophysin immunoreactive)
Ganglioma –> mixed neuronal and glial tumor, relatively benign
Dysembryoplastic neuroepithelial tumor –> mixed neuronal and glial tumor (hamartoma), benign
o Commonly presents with long history of partial complex seizures
Pilocytic astrocytoma
Benign tumor of astrocytes
o Most common CNS tumor in children –> usually arises in the cerebellum; also hypothalamus + optic pathways
o Gross –> cystic lesion with a mural nodule
o Micro –> Rosenthal fibers (thick eosinophilic processes of astrocytes), eosinophilic granular bodies + biphasic architecture
o Tumor cells are GFAP positive
o WHO grade I
o Surgery may be curative –> depends on where the tumor is located
o 7q34 duplication produces BRAF fusion gene
Medulloblastoma
Malignant tumor derived from the granular cells of the cerebellum (neuroectoderm)
o “Primitive neuroectodermal tumor” = PNET mostly roof of 4th ventricle, >90% infratentorial
o Most common in children median age 6-7 years
o Histology reveals small, round blue cells Homer-Wright rosettes may be present
o Malignant but responsive to therapy molecular pathways are a work in progress
o Poor prognosis tumor grows rapidly and spreads via CSF (33% at presentation, 50% ultimately)
—> Metastasis to the cauda equine = “drop metastasis”
—> mets rare, occurs more in this type than other CNS tumors
Treatment
- Standard of care = resection and external beam radiation therapy
- Chemo has become the defacto standard for both average and high risk
- Craniospinal radiation therapy is the gold standard
- > 50% of children with medulloblastoma can be cured
- 80-90% of those without disseminated disease can be cured
Meningioma
Benign tumor of arachnoid cells
o Most common benign CNS tumor in adults incidence increases with age
o More commonly seen in women, rare in children
o Dural attachment but derived from meningothelial cells (arachnoid)
o Well-circumscribed
o Many histologic variants majority are WHO grade I
o Loss of 22q12.1 including gene from Merlin/schwannomin tumor suppressor
o Often express hormone receptors estrogen and progesterone receptors; associated with breast cancer
o May present as seizures tumor compresses but does not invade the cortex
o Imaging reveals a round mass attached to the dura
o Histology shows a whorled pattern
o Psammoma bodies may be present
o Etiologic associations with radiation, neurofibromatosis, etc.
o Majority are benign have very low % relapse
Meningioma - treatment
- For small, asymptomatic meningiomas in a non-harmful location, it is perfectly reasonable to observe tumor on a regular basis and intervene when necessary
- Surgery –> Gross total resection (GTR) if medically operable
• GTR generally thought to give 90% recurrence free survival, but depends on the location of tumor
• STR still good option if GTR not possible –> tumors grow slowly so can buy the patients a lot of time
• Recommended for younger patients with surgically accessible lesions
• In general –> convexity lesions are managed with surgery; base of skull lesions and optic nerve sheath meningiomas are not - In general, GTR has much lower recurrence rate than STR –> however, when combined STR with external beam radiation therapy, patients had the same recurrence rates as GTR group
Summary –> most common benign brain tumor, generally slow growing and some can be observed, location and grade are crucial for outcomes, extent of resection predictive of failure, radiotherapy has major role
Schwannoma
Benign tumor of schwann cells
o Involves cranial or spinal nerves within the cranium most frequently involves cranial nerve VIII at the cerebellopontine angle = presents as loss of hearing + tinnitus (acoustic neuroma)
o Tumor cells are S-100 positive
o Bilateral tumors are seen in neurofibromatosis type 2
Vestibular schwannoma
Tumor of the vestibular nerve sheath
- Almost always unilateral and benign –> bilateral is pathognomonic feature of NF2
- Variable growth rate –> 40% show no growth or even spontaneous shrinkage
- Biology –> biallelic inactivating mutations of tumor suppressor gene NF2 on 22q12 seen in sporadic and NF2 associated VS
- NF2 –> encodes for merlin = a protein involved in cell proliferation
- Merlin downstream pathways may be targets for future therapies
Vestibular schwannoma - treatment
- Observation –> reasonable in some patients
• Elderly patients with slow growing tumors confirmed on serial scans, patients with a lesion in the dominant or sole side of hearing where an intervention would render hearing loss
• Risks hearing loss despite minimal growth, 75% of tumors grow within 1 year - Surgery –> 50% of patients are treated surgically, cure rates >95%
• Preservation of facial nerve and hearing is goal –> influenced significantly by tumor size and approach
• Facial nerve function is electrically monitored during surgery - Radiosurgery –> viable option for patients with tumors VEGF expressed in 100% of patients in a study
• Effective in reducing tumor size
