perspectives on cns malignancies susan m. staugaitis, m.d., ph.d. cleveland clinic foundation
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Perspectives on CNS Malignancies
Susan M. Staugaitis, M.D., Ph.D.
Cleveland Clinic Foundation
Introduction and Outline
Neoplasia and the Pediatric Rule of 1998
Evolution in Tumor Classification
Classification and Incidence of CNS Neoplasms
Dogma:
Indications defined by histology
Speculation:
Indications defined by physiology of neoplastic cell
Diagnosis of CNS Malignancies – Current Practice and Possibilities
Clinical Diagnosis - Advances in in vivo imaging Improved sensitivity clinical diagnosis and disease monitoring Image-guided surgical techniques -
Larger resections, but smaller biopsies
Tissue Diagnosis - Role of Pathologist Adequacy of specimen
Is lesional tissue present? Does the tissue represent the highest grade portion of the lesion? Is there sufficient lesional tissue for all desired analyses?
Classification Histologic phenotype Cytologic grade
Gene expression Genomic alterations
Morphologic Classification of CNS Neoplasms
Based upon the cytologic resemblance of neoplastic cells to normal cells
Often used to infer cell of origin
Become basis of in vitro experimental models
Doesn’t predict the behavior of the neoplastic cells
Site of origin
Neoplasms Arising within CNS Parenchyma
Neoplasms Arising in Accessory CNS Structures
Neoplasms Arising in CNS Coverings
CNS Parenchymal Neoplasms -"Glial phenotype"
Astrocytoma Fibrillary astrocytoma,
including glioblastoma multiforme Pilocytic astrocytoma Pleomorphic xanthoastrocytoma
Oligodendroglioma Ependymoma Subependymoma
CNS Parenchymal Neoplasms -"Neuronal and glial/neuronal Phenotype"
Ganglioglioma/gangliocytoma Central neurocytoma Dysembryoplastic neuroepithelial tumor Desmoplastic infantile astrocytoma/ganglioglioma
CNS Parenchymal Neoplasms - "Embryonal phenotype"
Primitive Neuroectodermal Tumors (PNET)
Medulloblastoma Supratentorial PNET/cerebral neuroblastoma Atypical teratoid/rhabdoid tumor
Neoplasms Arising in Accessory CNS structures
Choroid plexus
Papilloma, carcinoma
Pineal gland
Pineal parenchymal neoplasms
Germ cell neoplasms
Pituitary gland
Adenoma
Neurohypophyseal gliomas/hamartoma
Craniopharyngioma
Neoplasms Arising in CNS Coverings
Leptomeninges
Meningioma
Hemangiopericytoma
Other sarcomas
Melanocytic neoplasms
Intradural peripheral nerve sheath
Schwannoma
Neurofibroma
CNS Neoplasms – Age of Patients Affected
Adult >> Pediatric
Pediatric >> Adult
Pediatric (nearly exclusively)
Incidence of CNS neoplasms – Adult >> Pediatric
Most Gliomas
Fibrillary Astrocytoma, including GBM
Oligodendroglioma
Spinal ependymoma
Pineal Parenchymal Neoplasms
Meningioma
Nerve sheath neoplasms
Melanocytic neoplasms
Incidence of CNS neoplasms – Pediatric >>Adult
Low Grade Astrocytomas
Pilocytic astrocytoma
Pleomorphic xanthoastrocytoma
Intraventricular Ependymoma
Neuronal and glial/neuronal neoplasms
Ganglioglioma, DNET
Medulloblastoma
Choroid Plexus Neoplasms
Germ Cell Neoplasms
Craniopharyngioma
Incidence of CNS neoplasms – Pediatric (nearly exclusively)
Desmoplastic infantile astrocytoma/ganglioglioma
Atypical teratoid/rhabdoid tumor
Cerebral PNET
Pathobiology of Neoplasia
Cell acquire a genetic alteration.
This alteration results in change in gene expression that provides
a growth or survival advantage to the cell.
Genetic alteration is passed onto progeny.
Additional alterations are acquired and passed on.
Pathobiology of Neoplasia
Genomic alterations - mutation rearrangement loss or gain of genetic material
Gene expression - intrinsic metabolic pathways
proliferation, survival, motility response to environment
endogenous signals, drugs
Pathobiology of Neoplasia
Influence of the precursor cell on the behavior of the neoplasm?
Do different alterations in the same precursor cell result in different neoplasms?
Is there a different precursor for each neoplasm?
Once a precursor cell is transformed by a genetic alteration, does its normal physiologic processes influence the behavior of the neoplasm?
Pediatric Neoplasms
Some “pediatric” malignancies are low grade and some are high grade.
Time of rapid cell division and growth
Impact on repair mechanisms?
Intrinsic versus extrinsic factors
Cells are proliferating within an environment
bathed by growth factors
What is the role of the environment?
Does it play an active part in promoting growth
in the mature organism?
Does it play a role in restricting growth in the developing organism?
Familial Syndromes Associated with CNS Neoplasms
Neurofibromatosis Type 1 - neurofibromin -
neurofibroma, pilocytic astrocytoma, fibrillary astrocytoma
Neurofibromatosis Type 2 - merlin -
schwannoma, meningioma, fibrillary astrocytoma, ependymoma
Von Hippel Lindau - VHL - hemangioblastoma
Tuberous Sclerosis Complex - hamartin, tuberin - SEGA
Li-Fraumeni Syndrome - TP53 - astrocytoma, medulloblastoma
Turcot Syndrome - mismatch repair, APC - astrocytoma, medulloblastoma
Nevoid Basal Cell Carcinoma Syndrome - PTCH - medulloblastoma
Cowden Syndrome - PTEN - dysplastic gangliocytoma of cerebellum
Other ways of characterizingCNS malignancies
Histopathology perspective
Where do tumors arise? What do they look like?
Growth properties of the transformed cells
Proliferation/survival
Migration/motility
Angiogenesis
Growth properties of cell of origin
Can precursor cell be identified?
What are the molecular pathways that regulate the normal
phenotype of this cell?
Rapidly Proliferating Neoplasms - Kill dividing cells
Medulloblastoma
Supratentorial PNET
Atypical teratoid/rhabdoid tumor
Pineoblastoma
High Grade Glioma
Choroid Plexus Carcinoma
Infiltrating Neoplasms - Inhibit migration
Fibrillary astrocytoma
Oligodendroglioma
Angiogenesis
Both high grade astrocytomas and low grade pilocytic astrocytomas show histologically similar vascular proliferation.
Do the same mechanisms promote this proliferation?
If so, can drugs designed to target vasculature in high grade astrocytomas be effective in unresectable pilocytic astrocytomas?
TP53 mutations
Most common mutation in human cancer
Stimulate p53 function in tumor cells.
If an agents were available, might it be applied to histologically disparate neoplasms?
Inhibit p53 function in normal cells.
Protect normal tissues against genotoxic stress during therapy.
Could this be one indication for all neoplasms with p53 mutations?
Inhibit function of oncogenic signal transduction pathways
PDGFR-alpha - over expressed in many gliomas
fibrillary astrocytoma
oligodendroglioma
ependymoma
pilocytic astrocytoma
Inhibit function of oncogenic signal transduction pathways
EGFR
amplified in de novo glioblastoma
typically not amplified in glioblastoma that arise within low grade astrocytoma
How to define indication?
Will this limit testing of new drugs?
Look at entire pathway - not just single component
In a single pathway,
some genes may acquire
activating “oncogenic” mutations or
inactivating “tumor suppressor” mutations.
Both may lead to the same tumor phenotype.
APC + beta-catenin >>
Wnt pathway
Sonic Hedgehog + Patched + Smoothened >>
transcription of growth regulating genes
Cautions
• Necrosis and swelling associated with rapid efficient cell killing may
have adverse effects within the confines of the CNS.
• Environmental signals, that may effect the behavior of neoplastic cells,
may change during development.
• Specific targeted therapies will work only is the inhibited pathway is
intact in the particular tumor being treated.
• Neoplasms accumulate alterations that may lead to specific drug
resistance.
• Therapies that target specific functions, e.g., proliferation, migration,
may adversely affect normal developing cells that may also depend
upon those functions.
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