Perspectives on CNS Malignancies

1
Perspectives on CNS Malignancies

• Susan M. Staugaitis, M.D., Ph.D.
• Cleveland Clinic Foundation

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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

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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

4
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
• Doesnt 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

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CNS Parenchymal Neoplasms -"Glial phenotype"

• Astrocytoma
• Fibrillary astrocytoma,
• including glioblastoma multiforme
• Pilocytic astrocytoma
• Pleomorphic xanthoastrocytoma
• Oligodendroglioma
• Ependymoma
• Subependymoma

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CNS Parenchymal Neoplasms -"Neuronal and
glial/neuronal Phenotype"

• Ganglioglioma/gangliocytoma
• Central neurocytoma
• Dysembryoplastic neuroepithelial tumor
• Desmoplastic infantile astrocytoma/ganglioglioma

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CNS Parenchymal Neoplasms - "Embryonal phenotype"

• Primitive Neuroectodermal Tumors (PNET)
• Medulloblastoma
• Supratentorial PNET/cerebral neuroblastoma
• Atypical teratoid/rhabdoid tumor

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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

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Neoplasms Arising in CNS Coverings

• Leptomeninges
• Meningioma
• Hemangiopericytoma
• Other sarcomas
• Melanocytic neoplasms
• Intradural peripheral nerve sheath
• Schwannoma
• Neurofibroma

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CNS Neoplasms Age of Patients Affected

• Adult gtgt Pediatric
• Pediatric gtgt Adult
• Pediatric (nearly exclusively)

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Incidence of CNS neoplasms Adult gtgt Pediatric

• Most Gliomas
• Fibrillary Astrocytoma, including GBM
• Oligodendroglioma
• Spinal ependymoma
• Pineal Parenchymal Neoplasms
• Meningioma
• Nerve sheath neoplasms
• Melanocytic neoplasms

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Incidence of CNS neoplasms Pediatric gtgtAdult

• Low Grade Astrocytomas
• Pilocytic astrocytoma
• Pleomorphic xanthoastrocytoma
• Intraventricular Ependymoma
• Neuronal and glial/neuronal neoplasms
• Ganglioglioma, DNET
• Medulloblastoma
• Choroid Plexus Neoplasms
• Germ Cell Neoplasms
• Craniopharyngioma

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Incidence of CNS neoplasms Pediatric (nearly
exclusively)

• Desmoplastic infantile astrocytoma/ganglioglioma
• Atypical teratoid/rhabdoid tumor
• Cerebral PNET

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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.

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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

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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?

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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?

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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

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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?

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Rapidly Proliferating Neoplasms - Kill dividing
cells

• Medulloblastoma
• Supratentorial PNET
• Atypical teratoid/rhabdoid tumor
• Pineoblastoma
• High Grade Glioma
• Choroid Plexus Carcinoma

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Infiltrating Neoplasms - Inhibit migration

• Fibrillary astrocytoma
• Oligodendroglioma

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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?

23
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?

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Inhibit function of oncogenic signal transduction
pathways

• PDGFR-alpha - over expressed in many gliomas
• fibrillary astrocytoma
• oligodendroglioma
• ependymoma
• pilocytic astrocytoma

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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?

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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 gtgt
• Wnt pathway
• Sonic Hedgehog Patched Smoothened gtgt
• transcription of growth regulating genes

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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.