Recent advances in molecular biology and genetics have revolutionized our understanding of the biology that underlies the clinical diversity of nervous system tumors. The majority of these data have emerged from a number of large-scale genomic profiling projects and groups, and facilitated by the availability of ever more powerful next-generation sequencing and molecular profiling technologies. At the same time, functional studies have begun to characterize the biology of many of the molecular genetic alterations identified, including novel oncogenic driver mutations. In parallel, the advances in stem cell biology have provided valuable insight into the evolution and progression of brain tumors, including glioblastoma. Functional and preclinical studies are also aided by an increasing number and sophistication of genetically engineered mouse models that recapitulate the development of specific tumor subtypes.A\Genomic profiling of disease entities that had been previously classified mainly through histomorphology and a limited set of immunohistochemical markers has revealed a diverse and complex biology of brain tumors. As a result, new molecular diagnostic tools are entering the field of neuropathology at a rapid pace. Newly defined sub-entities that are driven by divergent oncogenic pathways have been recognized to show distinctive clinical behavior and will likely require tailored risk- stratification and treatments. Molecular targeted therapies are increasingly entering clinical trials in neuro-oncology and hold promise for improving the outcome of patients with nervous system tumors, especially those that frequently recur despite aggressive multimodal therapy including surgery, radiotherapy, and chemotherapy. Molecular genetic testing that until very recently was limited to research labs is becoming increasingly available for routine clinical use.A\This book is intended to be used as a comprehensive guide to the rapidly evolving field of molecular neuropathology of nervous system tumors, as well as the underlying biology and emerging molecular targeted therapies. We hope that it will serve as a useful resource for physicians as well as clinical and laboratory scientists involved with or interested in the up-to-date diagnosis and treatment of patients with brain tumors. Accordingly, the target audience includes neuropathologists, neuro-oncologists, neurosurgeons, radiation oncologists, neurologists, neuroradiologists, as well as residents and fellows, who diagnose and treat patients with nervous system tumors including tumors of the brain, spine, leptomeninges, and peripheral nerves.A\Special emphasis was given to already established and emerging molecular diagnostic tests in neuropathology, as well as molecular targeted therapies. The book is organized by clinicopathologic disease entities, and each chapter has been prepared by a team of authors to cover a full spectrum of expertise including neuropathology, molecular biology, and clinical management, with a focus on practical diagnostic and clinical considerations. New York, NY, USA: Matthias A. Karajannis, M.D., M.S..,David Zagzag, M.D., Ph.D.

1 Hereditary Predisposition to Primary CNS Tumors 1

2 Brain Tumor Stem Cells 23

3 Molecular Pathology Techniques 35

4 Low-Grade Gliomas 45

5 Ependymoma 67

6 Adult High-Grade (Diffuse) Glioma 77

7 Pediatric High-Grade Gliomas and DIPG 95

8 Oligodendroglial Tumors 105

9 Medulloblastoma and CNS Primitive Neuroectodermal Tumors 121

10 Subependymal Giant Cell Astrocytoma 143

11 Germ Cell Tumors 153

12 Choroid Plexus Tumors 163

13 Atypical Teratoid Rhabdoid Tumors 177

14 Hemangioblastoma 191

15 Schwannomas 201

16 Malignant Peripheral Nerve Sheath Tumors 213

17 Meningiomas 225

Index 239

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