Primary Central Nervous System Tumors - Pathogenesis and Therapy

Preface

Contents

Contributors

Part I General Principles

1 Epidemiology and Risk Factors

Introduction

Gliomas

Population Epidemiology

Survival and Prognosis

Risk Factors

Hormonal and Reproductive Factors

Ionizing Radiation

Cellular Telephone Usage

Other Possible Environmental or Behavioral Risk Factors

Genetic Factors

Familial Aggregation

Polymorphisms in Genes Relevant to Cancer

Infections and Immunologic Factors

Meningiomas

Population Epidemiology

Exogenous Risk Factors

Ionizing Radiation

Hormones

Association with Breast Cancer

Head Trauma

Family History

Genetic Polymorphisms

Conclusion

References

2 Molecular Pathogenesis

Introduction

Gliomas

Low-Grade and Intermediate-Grade Gliomas

Diffuse Astrocytoma, WHO Grade II

Anaplastic Astrocytoma

Oligodendroglioma and Anaplastic Oligodendroglioma

Glioblastoma

Secondary GBM

Primary GBM

Key Functional Pathways in Glioma Pathogenesis

Molecular Classification and Clinically Relevant Subtypes of Glioblastoma

Prognostic and Predictive Markers

Cell of Origin and the Tumor Stem Cell Hypothesis

Mouse Models

Tumor Stem Cells

References

3 Cellular Origins of Malignant Glioma: The Cancer Stem Cell Polemic

Introduction

Glioma Stem Cells

Glioma Stem Cell Caveats

Astrocytes or Astrocyte Progenitors as Cell of Origin for Glioma

''Restricted'' Neural Progenitors as Cell of Origin for Glioma

Multipotent Neural Progenitors as Cell of Origin

Conclusion

References

4 Principles of Supportive Care

Cerebral Edema

Complications of Corticosteroids

Gastrointestinal Complications

Musculoskeletal Complications

Psychiatric Complications

Immunosuppressive Effects and Infectious Complications of Corticosteroids

Other Steroid Side Effects

Novel Therapies for Cerebral Edema

Seizures

Epidemiology and Pathophysiology

Prophylactic Treatment

AED Interactions with Antineoplastic Agents

Surgical Management of Seizures

Thromboembolic Complications

Epidemiology and Pathophysiology

Diagnosis

Prophylactic Treatment

Symptomatic Treatment

Intracranial Hemorrhage

Neurocognitive Symptoms

Fatigue

Cognitive Impairment

Depression and Anxiety

Summary

References

5 Principles of Clinical Trial Design and Response Assessment

Introduction

Phase 0 Trials

Phase I Trials

Cytotoxic Agents

Novel Agents

Limitations

Phase II Trials

Cytotoxic Agents

Novel Agents

Secondary Evaluations

Limitations

Phase III Clinical Trials

Special Challenges of Brain Tumor Trials

Drug Selection

Neuropathology

Response Assessment and Endpoints

Historical Controls

Conclusion

References

6 Complications of Therapy

Pharmaceutical Therapy

Systemic Therapies

Conventional Chemotherapeutic Agents

Molecularly Targeted Agents

Anti-epileptic Therapy Issues

Local/Regional Therapies

Complications After Radiation Therapy for CNS Neoplasms

Introduction

Acute Toxicities

Fatigue

Local Symptoms

Craniospinal Axis Radiation

Subacute Toxicity

Pseudoprogression

Somnolence Syndrome

Lhermitte's Sign

Neurologic Late Toxicity

Brain Necrosis

Spinal Cord Myelopathy

Optic Neuropathy

Ototoxicity

Other Cranial Nerve Injury

Stroke-Like Migraine Attacks

Multiple Sclerosis-Related Toxicity

Non-neurologic Late Toxicity

Endocrinopathy

Vasculopathy

Secondary Neoplasm

Conclusion

References

7 Neuropsychological Function and Quality of Life

Neurocognitive Function

Impact of the Tumor on Neurocognitive Function

Treatment Effects

Effects of Adjuvant Medications and Medical Complications

Patient Care and Management

Neurocognitive Interventions and Pharmacotherapy

Neurocognitive Interventions

Pharmacotherapy

Methylphenidate

Modafinil

Donepezil

Alpha-Tocopherol (Vitamin E)

Symptoms and Quality of Life in Brain Tumor Patients

Overview of QOL and Symptoms

Overview of Common Symptoms

Fatigue

Pathophysiology/Etiologic Contributors and Assessment

Interventions

Mood Disturbance

Pathophysiology/Etiology and Assessment

Interventions

New Paradigms: Sleep--Wake Cycle Disturbance and Symptom Clusters

Impact on the Patient and Family

Conclusions

References

Part II Gliomas

8 Low-Grade Gliomas

Epidemiology

Pathology and Pathogenesis

Astrocytic Tumors

Molecular Genetics of Low-Grade Gliomas

Clinical Presentations

Imaging

Prognostic Factors

Surgical Management

Innovations in Surgical Management of Gliomas

Radiation Therapy

Chemotherapy

Conclusions

References

9 High-Grade Astrocytomas

Introduction

Epidemiology

Pathology and Pathogenesis

Management of Newly Diagnosed High-Grade Astrocytomas

Surgical Management

Carmustine Wafers

Radiation Therapy

Chemotherapy

Temozolomide

HGA in the Elderly

Management of Recurrent HGA

Diagnosis of Recurrence

Surgical Resection

Locoregional Therapy

Re-irradiation

Salvage Chemotherapy

Novel Treatment Approaches

Molecularly Targeted Therapy

Anti-angiogenic Therapy

Other Molecular Targets

Other New Treatment Approaches

Conclusions

References

10 Anaplastic Oligodendrogliomas and Mixed Gliomas

Introduction

Incidence, Clinical Presentation, Localization

Pathology and Genetics

Histology

Genetics

Diagnosis

Prognosis

Histology

Genotype

Clinical Characteristics

Treatment

Surgery

Radiotherapy

Chemotherapy

Chemotherapy at Recurrence

Adjuvant Chemotherapy in Newly Diagnosed AOT

Upfront Chemotherapy in Newly Diagnosed AOT

References

11 Ependymomas

Introduction

Pathology and Classification

Prognostic Factors

Incidence and Epidemiology

Molecular Profiles

Chromosomal Abnormalities

Molecular Pathway Abnormalities

Gene Array-Based Profiles

Epigenetic Studies

Ependymoma Stem Cells

Implications for Prognosis and Treatment

Treatment

Intracranial Tumors

Spinal Cord Ependymomas

Future Directions

Conclusions

References

12 Uncommon Gliomas in Adults: Brainstem Gliomas, Pilocytic Astrocytomas, and Pleomorphic Xanthoastrocytomas

Introduction

Epidemiology

Clinical Presentation/Diagnosis

Pathology/Classification

Prognostic Factors

Treatment

Diffuse Tumors

Focal Tumors

Pilocytic Astrocytoma

Introduction

Epidemiology

Clinical Presentation/Diagnosis

Pathology/Classification

Prognostic Factors

Treatment

Pleomorphic Xanthoastrocytoma

Introduction

Epidemiology

Clinical Manifestations/Diagnosis

Pathology/Classification

Prognostic Factors

Treatment

References

Part III Other Tumor Types

13 Pediatric Tumors

Epidemiology

Pediatric Brain Tumors and Genetic Syndromes

Presentation of Pediatric Central Nervous System Tumors

Direct Compression of Brain Tissue

Obstructive Hydrocephalus Causing Increased Intracranial Pressure

Gliomas

Glioma Location Often Predicts Presentation

Supratentorial and Cerebellar Astrocytomas

Optic Pathway/Hypothalamic Gliomas

Thalamic Gliomas

Midbrain and Brainstem Astrocytomas

Glioma Grade Often Predicts Prognosis and Treatment

Low-Grade Astrocytomas

High-Grade Astrocytomas

Imaging

Histology

Treatment

Ependymoma

Embryonal Tumors

Medulloblastoma

Supratentorial PNET

Pineoblastoma

Choroid Plexus Tumors

Germ Cell Tumors

Craniopharyngioma

Late Effects

Surgery

Radiation Therapy

Chemotherapy

References

14 Primary Central Nervous System Lymphoma

Primary CNS Lymphoma

Pathobiology

Clinical Features

Diagnostic Evaluation

Neuroimaging

Prognostic Markers

Treatment of Immunocompetent Patients with PCNSL

Corticosteroids

Radiation

Combined Modality Therapy

Chemotherapy Alone

Intrathecal Chemotherapy

High-Dose Chemotherapy with Stem Cell Rescue

Salvage Therapy

Neurotoxicity

Treatment of HIV-Related PCNSL

References

15 Meningiomas

Historical Perspective and Epidemiology

Clinical Presentation

Neuroradiology

Pathology and Molecular Genetics

Natural History

Treatment

Surgery

Radiotherapy

Hormonal Therapy

Biochemotherapy

Targeted Therapy

Conclusions

References

16 Pituitary Adenomas

Epidemiology

Pathogenesis

Classification

Clinical Presentation

Functional Pituitary Tumors

Diagnosis

Endocrine Testing

Imaging

Medical Therapy

Pituitary Hormone Replacement

Surgical Treatment

Radiation Therapy and Radiosurgery

Prognosis

Quality of Life

Conclusions

References

17 Vestibular Schwannomas

Introduction

Observation

Surgical Resection

Radiotherapy

Chemotherapy

Conclusion

References

18 Medulloblastomas

Introduction

Incidence

Survival

Risk Factors

Pathology and Biology

Diagnosis

Staging

Prognosis

Treatment

Neurosurgery

Radiation Therapy

Quality of Radiation Therapy

Chemotherapy

Standard-Risk Medulloblastoma

High-Risk Medulloblastoma

General Recommendations for the Management of Medulloblastoma

Late Sequelae

Long-Term Sequelae

Follow-Up

References

19 Pineal Region Tumors

Introduction

Brief History of the Pineal Gland

Anatomy and Physiology of the Pineal Gland

Overview of Tumors of the Pineal Region

Presentation of Pineal Tumors

Germ Cell Tumors: Pathology and Diagnosis

Imaging

Pathology and Immunohistochemistry of Germ Cell Tumors

Germinomas

Teratomas

Yolk Sac Tumor

Embryonal Carcinomas

Choriocarcinomas

Genetics of Germ Cell Tumors

CSF and Serum Analysis of Germ Cell Tumors

Prognosis of Germ Cell Tumors

Pineal Parenchymal Tumors: Pathology and Diagnosis

Imaging

Pathology of PPTs

Pineocytomas

Pineoblastomas

Pineal Parenchymal Tumor of Intermediate Differentiation

Genetics of PPTs

Prognosis

Miscellaneous Tumor Types

Glioma

Meningioma

Papillary Tumor of the Pineal Region

Metastases to the Pineal Gland

Treatment of Pineal Region Tumors

Treatment of Hydrocephalus

Treatment of Germ Cell Tumors

Germinomas

Non-germinomatous Germ Cell Tumors

Treatment of Pineal Parenchymal Tumors

Pineocytomas

Pineoblastomas

Pineal Parenchymal Tumors of Intermediate Differentiation

Pineal Gliomas

Meningiomas

Ependymomas

Conclusion and Future Directions

References

20 Genetic Syndromes

Introduction

Neurofibromatosis

Overview

Epidemiology

Clinical Genetics

Molecular Genetics and Pathogenesis

NF1, Neurofibromin

Mutations

Genetic Testing

Clinical Features

Diagnostic Criteria

Developmental Expression of Phenotype

Associated Tumors

Neurofibromas

Malignant Peripheral Nerve Sheath Tumors (MPNSTs)

Gliomas

Management

Neurofibromas

MPNSTs

Glioma

Future Directions

Neurofibromatosis

Overview

Epidemiology

Clinical Genetics

Molecular Genetics and Pathogenesis

Mutations

Genetic Testing

Clinical Features

Diagnostic Criteria

Associated Tumors

Management

Initial Evaluation

Subsequent Evaluation

Future Directions

Tuberous Sclerosis Complex

Overview

Epidemiology and Clinical Genetics

Molecular Genetics and Pathogenesis

Clinical Features

Presentation

Diagnostic Criteria

Genetic Testing

Screening

Associated Tumors

Cortical Tubers

Subependymal Nodules

SEGAs

Other Malignancies

Prognosis and Future Directions

Von Hippel-Lindau Disease

Overview

Clinical Overview

Epidemiology and Clinical Genetics

Molecular Genetics and Pathogenesis

VHL, pVHL

Mutations

Clinical Features

Diagnostic Criteria

Genetic Testing

Screening

Associated Tumors

CNS Hemangioblastoma

Other Malignancies

Prognosis

Future Directions

Cowden Syndrome

Overview

Molecular Genetics and Pathogenesis

Clinical Features

Diagnostic Criteria

Associated Tumors: LDD

Management

Li-

485

Overview

Molecular Genetics and Pathogenesis

Clinical Features

Presentation

Diagnostic Criteria

Management

Turcot Syndrome

Overview

Clinical Presentation

Molecular Genetics and Pathogenesis

Diagnostic Criteria

Management

Gorlin Syndrome

Overview

Molecular Genetics and Pathogenesis

Clinical Features

Presentation

Diagnosis

Management

References

21 Rare Tumors

Introduction

Tumors of Neuroepithelial Tissue

Choroid Plexus Tumors

Choroid Plexus Papillomas

Choroid Plexus Carcinoma

Neuronal and Mixed Neuronal--Glial Tumors

Ganglioglioma and Gangliocytoma

Desmoplastic Infantile Astrocytoma and Desmoplastic Infantile Ganglioglioma

Dysplastic Gangliogliocytoma of the Cerebellum (Lhermitte--Duclos disease)

Cerebellar Liponeurocytoma

Central Neurocytoma and Extraventricular Neurocytoma

Papillary Glioneuronal Tumor

Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle

Dysembryoplastic Neuroepithelial Tumor

Intracranial and Intraspinal Paraganglioma

Embryonal Tumors

CNS Primitive Neuroectodermal Tumors

Supratentorial Primitive Neuroectodermal Tumor

Ependymoblastoma

Medulloepithelioma

CNS Ganglioneuroblastoma

CNS Atypical Teratoid/Rhabdoid Tumors

Other Neuroepithelial Tumors

Astroblastoma

Chordoid Glioma of the Third Ventricle

Angiocentric Glioma

Tumors of the Meninges

Mesenchymal Tumors

Tumors of Adipose Tissue

Intracranial Lipoma

Central Nervous System Angiolipoma

Central Nervous System Hibernoma

Liposarcoma

Fibrous Tumors

Solitary Fibrous Tumor

Fibrosarcoma

Malignant Fibrous Histiocytoma

Tumors of Cartilaginous Tissue: Chordoma, Chondrosarcoma

Primary Meningeal Hemangiopericytoma

Ewing--s Sarcoma -- Primitive Neuroectodermal Tumor

Primary Melanocytic Lesions

Primary Malignant Melanoma of the Central Nervous System

Melanocytoma

Melanocytosis and Melanomatosis

Cystic Lesions

Epidermoid Cyst

Dermoid Cyst

Colloid Cyst

Arachnoid Cyst

References

22 Spinal Tumors

Incidence and Prevalence of Primary Neoplasms of the Spine

Anatomical Distribution

Epidural Tumors

Intradural--Extramedullary Spinal Cord Tumors

Intramedullary Spinal Cord Tumors

Diagnostic Utilities

Imaging Studies

Biopsy

Laboratory Studies

Presentation, Diagnosis, and Management

Main Types of Epidural Spinal Cord Tumors

Chordomas

Chondrosarcomas

Osteosarcomas

Ewings Sarcoma and Peripheral Neuroectodermal Tumor

Multiple Myeloma and Plasmacytomas

Other Spinal Epidural Tumors

Intraspinal Extramedullary Spinal Cord Tumors

Presentation

Diagnosis

Types of Tumors

Prognosis and Management

Intramedullary Spinal Cord Tumors (ISCTs)

Presentation

Diagnosis

Main Types of Tumors

Prognosis and Management

References

Index