Challenges and Considerations in Linking Adult and Pediatric CNS Malignancies Henry S. Friedman, MD The Brain Tumor Center at Duke

What is the relationship between adult and pediatric CNS tumors? Are there compelling similarities or differences in pediatric and adult CNS tumors which can guide application of the Pediatric Rule of 1998.

Histologic Classification of Tumors of the CNS Tumors of neuroepithelial tissue Astrocytic tumors –Astrocytoma –Anaplastic astrocytoma –Glioblastoma multiforme –Pilocytic astrocytoma –Pleomorphic xanthroastrocytoma –Subependymal giant-cell- astrocytoma Oligodendroglial tumors –Oligodendroglioma –Anaplastic oligodendroglioma Mixed glioma –Oligoastrocytoma –Anaplastic oligoastrocytoma Embryonal tumors –Medulloblastoma –Primitive neuroectodermal tumor Ependymal tumors –Ependymoma –Anaplastic ependymoma –Myxopapillary ependymoma –Subependymoma Choroid-plexus tumors –Choroid-plexus papilloma –Choroid-plexus carcinoma Neuronal and mixed neuronal-glial tumors –Gangliocytoma –Dysembryoplastic neuroepithelial tumor –Ganglioglioma –Anaplastic gangliglioma –Central neurocytoma Pineal parenchymal tumors –Pineocytoma –Pineoblastoma

Histologic Classification of Tumors of the CNS Meningeal tumors Meningioma Hemangiopericytoma Melanocytic tumor Hemangioblastoma Primary Central nervous system lymphomas Germ-cell tumors Germinoma Embryonal carcinoma Yolk-sac tumor (endodermal-sinus tumor) Choriocarcinoma Teratoma Mixed-germ cell tumors Tumors of the sellar region Pituitary adenoma Pituitary carcinoma Craniopharyngioma Metastatic tumors

Distribution of CNS Tumors Malignant gliomas, meningiomas, Schwann cell and pituitary tumors are most common primary adult brain tumors Benign gliomas, medulloblastomas/PNETs and craniopharyngiomas are most common primary pediatric brain tumors

Location of CNS Tumors Adult –cerebral hemispheres Pediatric –50% of tumors in children > 1 year of age are infratentorial –although majority of tumors in children < 1 year of age are supratentorial, these are chiasmatic- hypothalamic gliomas, medulloblastomas and choroid plexus tumors which are rare in adults

Are there differences between adult and pediatric non-glial CNS tumors? Neuroepithelial (non-glial) Nerve sheath Meningeal Germ cell Primary CNS lymphoma Sellar tumors No data supports a meaningful (if any) difference between these tumors in adults and children

Are there differences between adult and pediatric gliomas? Ependymomas Pilocytic astrocytoma Oligodendroglioma Subependymoma Diffuse fibrillary astrocytoma No data supports a meaningful (if any) difference between these tumors in adults and children

Are there differences between adult and pediatric malignant astrocytomas? Anaplastic astrocytoma Glioblastoma multiforme

Precursor Pilocytic astrocytomas Precursor Astrocytoma Astrocytoma III Secondary GBM Precursor Primary GBM LOH 17q (NF1) PDGF overexpression LOH 17q (p53) LOH 22q CDK4 gene amplification LOH 10 LOH 13q (Rb) LOH 9p (p15, p16) LOH 19q MDM2 gene amplification EGFR gene amplification LOH 10

Are there molecular distinctions between adult and pediatric malignant astrocytoma? Compared with adult tumors, + 1p, + 2Q, + 21Q, - 6Q, - 11Q, and - 16Q were more frequent in pediatric malignant glioma. Rickert et al Am J Path 158:1525, 2001

Are there differences between adult and pediatric malignant astrocytomas? Pediatric malignant astrocytoma show preferential p53 pathway inactivation (95%), moderate Rb pathway inactivation (25%), and no EGFR amplification. Sung et al Brain Pathology 10:249, 2000

Are there differences between adult and pediatric malignant astrocytomas? Peds malignant glioma have moderate rate of p53 mutation (38%), lack of EGFR amplification, a low rate of PTEN mutation (8%), and moderate rate of microsatelite instability (25%). Cheng et al Human Path 30:1284, 1999

Are there differences between adult and pediatric malignant astrocytomas? Pediatric malignant astrocytomas rarely display EGFR amplification (7%) but frequently display increased EGFR expression (80%). Bredel et al Clin Cancer Res 5:1786, 1999

Are there differences between adult and pediatric malignant astrocytomas? Malignant astrocytomas in children > 4 years old display TP53 mutations (50%) and p53 overexpression (77%) similar to adult tumors. Both TP53 mutations (0%) and p53 overexpression (14%) were much lower in children < 4 years of age. Pollock et al Cancer Res 57:304, 1997

How do the similarities and differences between adult and pediatric malignant astrocytoma guide the use of the pediatric rule? Malignant astrocytomas are more similar than distinct in adults vs. children > 4 years of age

Recommendation The Pediatric Rule applies to all adult brain tumors, including malignant astrocytoma

Advantages to joint adult and pediatric malignant gliomas New and improved therapies for our patients Better understanding of the underlying biology of these diseases Development of common, comprehensive prospective biological studies Better understanding of the effects of therapy in both poor and good prognosis groups Evolution of new study paradigms More efficient study accrual and use of resources

Challenges and disadvantages to joint adult and pediatric malignant gliomas Assumptions may be in error and children are exposed to inactive therapy Adverse events in children may result in sponsor concerns Requirement for cooperation and sharing of resources that may delay or confound study implementation Potential need for complex stratification and analysis