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.