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 characterizing CNS 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.