Perspectives on CNS Malignancies

1. Perspectives on CNS Malignancies • Susan M. Staugaitis, M.D., Ph.D. • Cleveland Clinic Foundation

2. 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

3. 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 • 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

5. CNS Parenchymal Neoplasms -"Glial phenotype" • Astrocytoma • Fibrillary astrocytoma, • including glioblastoma multiforme • Pilocytic astrocytoma • Pleomorphic xanthoastrocytoma • Oligodendroglioma • Ependymoma • Subependymoma

6. CNS Parenchymal Neoplasms -"Neuronal and glial/neuronal Phenotype" • Ganglioglioma/gangliocytoma • Central neurocytoma • Dysembryoplastic neuroepithelial tumor • Desmoplastic infantile astrocytoma/ganglioglioma

7. CNS Parenchymal Neoplasms -"Embryonal phenotype" • Primitive Neuroectodermal Tumors (PNET) • Medulloblastoma • Supratentorial PNET/cerebral neuroblastoma • Atypical teratoid/rhabdoid tumor

8. 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

9. Neoplasms Arising in CNS Coverings • Leptomeninges • Meningioma • Hemangiopericytoma • Other sarcomas • Melanocytic neoplasms • Intradural peripheral nerve sheath • Schwannoma • Neurofibroma

10. CNS Neoplasms – Age of Patients Affected • Adult >> Pediatric • Pediatric >> Adult • Pediatric (nearly exclusively)

11. Incidence of CNS neoplasms – Adult >> Pediatric • Most Gliomas • Fibrillary Astrocytoma, including GBM • Oligodendroglioma • Spinal ependymoma • Pineal Parenchymal Neoplasms • Meningioma • Nerve sheath neoplasms • Melanocytic neoplasms

12. 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

13. Incidence of CNS neoplasms – Pediatric (nearly exclusively) • Desmoplastic infantile astrocytoma/ganglioglioma • Atypical teratoid/rhabdoid tumor • Cerebral PNET

14. 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.

15. 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

16. 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?

17. 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?

18. 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

19. 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?

20. Rapidly Proliferating Neoplasms - Kill dividing cells • Medulloblastoma • Supratentorial PNET • Atypical teratoid/rhabdoid tumor • Pineoblastoma • High Grade Glioma • Choroid Plexus Carcinoma

21. Infiltrating Neoplasms - Inhibit migration • Fibrillary astrocytoma • Oligodendroglioma

22. 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?

24. Inhibit function of oncogenic signal transduction pathways • PDGFR-alpha - over expressed in many gliomas • fibrillary astrocytoma • oligodendroglioma • ependymoma • pilocytic astrocytoma

25. 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?

26. 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

27. 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.