Tumors of the Central Nervous System
Tumors of the Central Nervous System Volume 3
For other titles published in this series, go to www.springer.com/series/8812
Tumors of the Central Nervous System Volume 3
Tumors of the Central Nervous System Brain Tumors (Part 1) Edited by
M.A. Hayat Distinguished Professor Department of Biological Sciences, Kean University, Union, NJ, USA
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Editor M.A. Hayat Department of Biological Sciences Kean University Union, NJ, USA
[email protected] ISBN 978-94-007-1398-7 e-ISBN 978-94-007-1399-4 DOI 10.1007/978-94-007-1399-4 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2011923069 © Springer Science+Business Media B.V. 2011 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
“Although touched by technology, surgical pathology always has been, and remains, an art. Surgical pathologists, like all artists, depict in their artwork (surgical pathology reports) their interactions with nature: emotions, observations, and knowledge are all integrated. The resulting artwork is a poor record of complex phenomena.” Richard J. Reed MD
Preface
In this volume, as in volumes 1 and 2, the emphasis is on the diagnosis, therapy, and prognosis of brain tumors. In addition to describing strategies for advanced brain tumor treatment, this volume presents information on understanding the unique biology of the brain and its tumors. The information contained in this volume should aid in the development of tools for better diagnosis and effective treatment of brain malignancy. The application of various imaging techniques, including MRI, MRSI, PET, and CT, for diagnosing brain tumors including peripheral nerve sheath tumors is detailed. The use of MRS modality for classifying brain tumors is presented. This volume also contains information on the passage of malignancy to brain from tumors of other organs such as female breast and lung (tumor to tumor). The inception of both primary and secondary brain tumors is discussed. Also is included the delivery of drugs into brain tumors, considering the presence of blood brain barrier. A wide variety of treatments, such as conventional chemotherapy, electrochemotherapy, conventional resection, stereotactic radiosurgery, and magnetic resonance-guided focused ultrasound surgery in clinical practice, are explained in detail. The use of radioresponsive gene therapy for malignant brain tumors is included in this volume. The use of molecular markers as predictive and prognostic indicators in treatment decisions for individual cases are already beginning to have a significant positive effect on the clinical practice. A number of such markers are discussed in the volume. This volume also discusses pain management following craniotomy, antiepileptic drugs, and quality of life after brain tumor therapy and follow-up. By bringing together a large number of experts (oncologists, neurosurgeons, physicians, research scientists, and pathologists) in various aspects of this medical field, it is my hope that substantial progress will be made against this terrible disease. It would be difficult for a single author to discuss effectively the complexity of diagnosis, therapy, and prognosis of any type of tumor in one volume. This volume was written by 69 authors representing 12 countries. I am grateful to contributors for their promptness in accepting my suggestions. Their practical experience highlights their writings, which should build and further the endeavors of the readers in this important area of disease. I respect and appreciate the hard work and exceptional insight into the nature of cancer provided by these contributors. The contents of the volume are divided into subgroups: Introduction, Diagnosis and Biomarkers, Therapy, and Prognosis for the convenience of the readers. It is my hope that the current volume will join the preceding volumes of this series for assisting in the more complete understanding of globally relevant cancer vii
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Preface
syndromes. There exists a tremendous, urgent demand by the public and the scientific community to address to cancer prevention, diagnosis, treatment, and hopefully cure. I am thankful to Dr. Dawood Farahi, Dr. Kristie Reilly, and Mr. Philip Connelly for recognizing the importance of medical research and publishing in an institution of higher education, and providing the resources for completing this project. Union, New Jersey December 2010
M.A. Hayat
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M.A. Hayat 2 Brain Tumor Classification Using Magnetic Resonance Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Juan M. García-Gómez 3 Cellular Immortality in Brain Tumors: An Overview . . . . . . . . . Ruman Rahman and Richard G. Grundy Part I
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Tumor to Tumor Passage of Malignancy . . . . . . . . . . . . .
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4 Tumor-to-Tumor Metastasis: Extracranial Tumor Metastatic to Intracranial Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . Jian-Qiang Lu and Arthur W. Clark
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5 Brain Metastases from Breast Cancer: Treatment and Prognosis . . Kazuhiko Ogawa, Shogo Ishiuchi, and Sadayuki Murayama
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6 Brain Metastasis in Renal Cell Carcinoma Patients . . . . . . . . . . Aida Loudyi and Wolfram E. Samlowski
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7 Coexsistence of Inflammatory Myofibroblastic Tumor in the Lung and Brain . . . . . . . . . . . . . . . . . . . . . . . . . . Naveen Sankhyan, Suvasini Sharma, and Sheffali Gulati 8 Breast Cancer and Renal Cell Cancer Metastases to the Brain . . . . Jonas M. Sheehan and Akshal S. Patel
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9 Breast Cancer Brain Metastases: Genetic Profiling and Neurosurgical Therapy . . . . . . . . . . . . . . . . . . . . . . . Andreas M. Stark
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10 Central Nervous System Tumours in Women Who Received Capecitabine and Lapatinib Therapy for Metastatic Breast Cancer . Stephanie Sutherland and Stephen Johnston
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Part II
Biomarkers and Diagnosis . . . . . . . . . . . . . . . . . . . . .
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11 Functional Role of the Novel NRP/B Tumor Suppressor Gene . . . . Theri Leica Degaki, Marcos Angelo Almeida Demasi, and Mari Cleide Sogayar
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Contents
Brain Tumors: Diagnostic Impact of PET Using Radiolabelled Amino Acids . . . . . . . . . . . . . . . . . . . . . . . Karl-Josef Langen, Matthias Weckesser, and Frank Floeth
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Malignant Peripheral Nerve Sheath Tumors: Use of 18FDG-PET/CT . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andre A. le Roux and Abhijit Guha
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Brain Tumors: Evaluation of Perfusion Using 3D-FSE-Pseudo-Continuous Arterial Spin Labeling . . . . . . . . . . Hanna Järnum, Linda Knutsson, and Elna-Marie Larsson
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Cerebral Cavernous Malformations: Advanced Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert Shenkar, Sameer A. Ansari, and Issam A. Awad
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Nosologic Imaging of Brain Tumors Using MRI and MRSI . . . . . . Jan Luts, Teresa Laudadio, Albert J. Idema, Arjan W. Simonetti, Arend Heerschap, Dirk Vandermeulen, Johan A.K. Suykens, and Sabine Van Huffel
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Brain Tumor Diagnosis Using PET with Angiogenic Vessel-Targeting Liposomes . . . . . . . . . . . . . . . . . . . . . . . Kosuke Shimizu and Naoto Oku
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Frozen Section Evaluation of Central Nervous System Lesions . . . . Richard Prayson
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Clinical Role of MicroRNAs in Different Brain Tumors . . . . . . . . Richard Hummel, Jessica Maurer, and Joerg Haier
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Part III Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Electrochemotherapy for Primary and Secondary Brain Tumors . . Mette Linnert, Birgit Agerholm-Larsen, Faisal Mahmood, Helle K. Iversen, and Julie Gehl
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Brain Tumors: Convection-Enhanced Delivery of Drugs (Method) . Anne-Laure Laine, Emilie Allard, Philippe Menei, and Catherine Passirani
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Brain Metastases: Clinical Outcomes for Stereotactic Radiosurgery (Method) . . . . . . . . . . . . . . . . . . . . . . . . . Ameer L. Elaimy, Alexander R. MacKay, Wayne T. Lamoreaux, Robert K. Fairbanks, John J. Demakas, Barton S. Cooke, Benjamin J. Arthurs, and Christopher M. Lee
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Noninvasive Treatment for Brain Tumors: Magnetic Resonance-Guided Focused Ultrasound Surgery . . . . . . . . . . . Ernst Martin and Ferenc A. Jolesz Radioguided Surgery of Brain Tumors . . . . . . . . . . . . . . . . . Laurent Menard
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Contents
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25 Implications of Mutant Epidermal Growth Factor Variant III in Brain Tumor Development and Novel Targeted Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Murielle Mimeault and Surinder K. Batra 26 Endoscopic Port Surgery for Intraparenchymal Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pawel G. Ochalski and Johnathan A. Engh
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27 Intracranial Tumor Surgery in Elderly Patients . . . . . . . . . . . . Paul Ronning, Torstein Meling, Siril Rogne, and Eirik Helseth
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28 Intracranial Hemangiopericytoma: Gamma Knife Surgery . . . . . Jason P. Sheehan and Edward M. Marchan
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29 Stereotactic Radiosurgery for Cerebral Metastases of Digestive Tract Tumors . . . . . . . . . . . . . . . . . . . . . . . . Jesse J. Savage and Jason P. Sheehan
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30 Malignant Brain Tumors: Role of Radioresponsive Gene Therapy . . Hideo Tsurushima and Akira Matsumura
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Part IV Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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31 Brain Tumors: Quality of Life . . . . . . . . . . . . . . . . . . . . . . Cristina D’Angelo, Antonio Mirijello, Giovanni Addolorato, and Vincenzo Antonio D’Angelo
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32 Health-Related Quality of Life in Patients with High Grade Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eefje M. Sizoo and Martin J.B. Taphoorn
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33 Epilepsy and Brain Tumours and Antiepileptic Drugs . . . . . . . . Sophie Dupont
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34 Familial Caregivers of Patients with Brain Cancer . . . . . . . . . . Youngmee Kim
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35 Pain Management Following Craniotomy . . . . . . . . . . . . . . . Doug Hughes and Scott Y. Rahimi
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36 Air Transportation of Patients with Brain Tumours . . . . . . . . . . Peter Lindvall and Tommy Bergenheim
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Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Contents of Volume 1
1 Introduction 2 Molecular Classification of Gliomas 3 Glioblastoma: Endosialin Marker for Pericytes 4 Glioma Grading Using Cerebral Blood Volume Heterogeneity 5 The Role of Ectonucleotidases in Glioma Cell Proliferation 6 Gliomas: Role of Monoamine Oxidase B in Diagnosis 7 Glioma: Role of Integrin in Pathogenesis and Therapy 8 Proton Magnetic Resonance Spectroscopy in Intracranial Gliomas 9 Infiltration Zone in Glioma: Proton Magnetic Resonance Spectroscopic Imaging 10 Malignant Gliomas: Role of E2F1 Transcription Factor 11 The Role of Glucose Transporter-1 (GLUT-1) in Malignant Gliomas 12 Malignant Gliomas: Role of Platelet-Derived Growth Factor Receptor A (PDGFRA) 13 Molecular Methods for Detection of Tumor Markers in Glioblastomas 14 Role of MGMT in Glioblastomas 15 Glioblastomas: Role of CXCL12 Chemokine 16 Cell Death Signaling in Glioblastoma Multiforme: Role of the Bcl2L12 Oncoprotein 17 Glioblastoma Multiforme: Role of Polycomb Group Proteins 18 Glioblastoma Multiforme: Role of Cell Cycle-Related Kinase Protein (Method) 19 Markers of Stem Cells in Gliomas 20 Efficient Derivation and Propagation of Glioblastoma Stem-Like Cells Under Serum-Free Conditions Using the Cambridge Protocol
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Contents of Volume 1
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Glioma Cell Lines: Role of Cancer Stem Cells
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Glioblastoma Cancer Stem Cells: Response to Epidermal Growth Factor Receptor Kinase Inhibitors
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Low- and High-Grade Gliomas: Extensive Surgical Resection
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Brainstem Gangliogliomas: Total Resection and Close Follow-Up
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Glioblastoma: Temozolomide-Based Chemotherapy
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Drug-Resistant Glioma: Treatment with Imatinib Mesylate and Chlorimipramine
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Glioblastoma Multiforme: Molecular Basis of Resistance to Erlotinib
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Enhanced Glioma Chemosensitivity
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Malignant Glioma Patients: Anti-Vascular Endothelial Growth Factor Monoclonal Antibody, Bevacizumab
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Aggravating Endoplasmic Reticulum Stress by Combined Application of Bortezomib and Celecoxib as a Novel Therapeutic Strategy for Glioblastoma
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Targeted Therapy for Malignant Gliomas
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Glioblastomas: HER1/EGFR-Targeted Therapeutics
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Epidermal Growth Factor Receptor Inhibition as a Therapeutic Strategy for Glioblastoma Multiforme
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Role of Acyl-CoA Synthetases in Glioma Cell Survival and Its Therapeutic Implication
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Malignant Glioma Patients: Combined Treatment with Radiation and Fotemustine
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Malignant Glioma Immunotherapy: A Peptide Vaccine from Bench to Bedside
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Malignant Glioma: Chemovirotherapy
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Intracranial Glioma: Delivery of an Oncolytic Adenovirus
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Use of Magnetic Resonance Spectroscopy Imaging (MRSI) in the Treatment Planning of Gliomas
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Malignant Glioma Cells: Role of Trail-Induced Apoptosis
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Long-Term Survivors of Glioblastoma
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Glioblastoma Patients: p15 Methylation as a Prognostic Factor
Contents of Volume 2
1 Introduction 2 Gliomagenesis: Advantages and Limitations of Biomarkers 3 Molecular Subtypes of Gliomas 4 Glioblastoma: Germline Mutation of TP53 5 Familial Gliomas: Role of TP53 Gene 6 The Role of IDH1 and IDH2 Mutations in Malignant Gliomas 7 Malignant Glioma: Isocitrate Dehydrogenases 1 and 2 Mutations 8 Metabolic Differences in Different Regions of Glioma Samples 9
Glioblastoma Patients: Role of Methylated MGMT
10 Brain Tumor Angiogenesis and Glioma Grading: Role of Tumor Blood Volume and Permeability Estimates Using Perfusion CT 11 Vasculogenic Mimicry in Glioma 12 Newly Diagnosed Glioma: Diagnosis Using Positron Emission Tomography with Methionine and Fluorothymidine 13 Role of Diffusion Tensor Imaging in Differentiation of Glioblastomas from Solitary Brain Metastases 14
131 I-TM-601
SPECT imaging of Human Glioma
15 Assessment of Biological Target Volume Using Positron Emission Tomography in High-Grade Glioma Patients 16 Skin Metastases of Glioblastoma 17 Diffuse Low-Grade Gliomas: What Does “Complete Resection” Mean? 18 Quantitative Approach of the Natural Course of Diffuse Low-Grade Gliomas 19 Impact of Extent of Resection on Outcomes in Patients with High-Grade Gliomas
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Glioma Surgery: Intraoperative Low Field Magnetic Resonance Imaging
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Low-Grade Gliomas: Intraoperative Electrical Stimulations
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Malignant Gliomas: Present and Future Therapeutic Drugs
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Recurrent Malignant Glioma Patients: Treatment with Conformal Radiotherapy and Systemic Therapy
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Glioblastoma: Boron Neutron Capture Therapy
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Glioblastoma: Anti-tumor Action of Cyclosporin A and Functionally Related Drugs
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Glioblastoma Patients: Chemotherapy with Cisplatin, Temozolomide and Thalidomide
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Glioblastoma: Role of Galectin-1 in Chemoresistance
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Glioma-Initiating Cells: Interferon Treatment
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Glioblastoma: Anti-tumor Action of Natural and Synthetic Cannabinoids
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Patients with Recurrent High-Grade Glioma: Therapy with Combination of Bevacizumab and Irinotecan
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Monitoring Gliomas In Vivo Using Diffusion-Weighted MRI During Gene Therapy-Induced Apoptosis
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High-Grade Gliomas: Dendritic Cell Therapy
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Glioblastoma Multiforme: Use of Adenoviral Vectors
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Fischer/F98 Glioma Model: Methodology
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Cellular and Molecular Characterization of Anti-VEGF and IL-6 Therapy in Experimental Glioma
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Adult Brainstem Gliomas: Diagnosis and Treatment
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The Use of Low Molecular Weight Heparin in the Treatment and Prevention of Thromboembolic Disease in Glioma Patients
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Brainstem Gliomas: An Overview
39
Tumor-Associated Epilepsy in Patients with Glioma
40
Brain Tumors Arising in the Setting of Chronic Epilepsy
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Low-Grade Gliomas: Role of Relative Cerebral Blood Volume in Malignant Transformation
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Angiocentric Glioma-Induced Seizures: Lesionectomy
Contributors
Giovanni Addolorato Department of Internal Medicine, Catholic University of Rome, 8 – 00168 Rome, Italy,
[email protected] Birgit Agerholm-Larsen Glostrup Research Institute, Copenhagen University Hospital Glostrup, 2600, Glostrup, Denmark,
[email protected] Emilie Allard INSERM, U646, Universite d’Angers, Angers F-491000, France,
[email protected] Sameer A. Ansari Section of Neuroradiology, Northwestern University Feinberg School of Medicine and the University of Chicago Pritzker School of Medicine, 5841 S. Maryland Ave., Chicago, IL 60637, USA,
[email protected] Benjamin J. Arthurs Department of Oncology, Cancer Care Northwest and Gamma Knife of Spokane, Spokane, WA 99204, USA,
[email protected] Issam A. Awad Neurovascular Surgery Program, Section of Neurosurgery, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Ave., Chicago, IL 60637, USA,
[email protected] Surinder K. Batra Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Cancer Institute, 7052 DRC, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA,
[email protected] Tommy Bergenheim Umea University Hospital, Umea, Sweden Arthur W. Clark Department of Pathology and Laboratory Medicine, Foothills Medical Centre, Calgary, AB, Canada T2N 2T9,
[email protected] Barton S. Cooke Department of Oncology, Cancer Care Northwest and Gamma Knife of Spokane, Spokane, WA 99204, USA,
[email protected] Cristina D’Angelo Department of Internal Medicine, Catholic University of Rome, Gemelli Hospital, l.go Gemelli, 8, 00168 Rome, Italy,
[email protected] Vincenzo Antonio D’Angelo Department of Neurosurgery, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy,
[email protected] xvii
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Theri Leica Degaki Department of Biochemistry, Chemistry Institute, NUCEL-Cell and Molecular Therapy Center, University of Sao Paulo, Sao Paulo 05508-900 SP, Brazil,
[email protected] John J. Demakas Department of Oncology, Cancer Care Northwest and Gamma Knife of Spokane, Spokane, WA 99204, USA,
[email protected] Marcos Angelo Almeida Demasi Department of Biochemistry, Chemistry Institute, NUCEL-Cell and Molecular Therapy Center, University of Sao Paulo, Sao Paulo 05508-900 SP, Brazil,
[email protected] Sophie Dupont Epilepsy Unit, Clinique Neurologique Paul Castaigne, Hopital de la Salpetriere, 75651 Paris cedex 13, France,
[email protected] Ameer L. Elaimy Department of Oncology, Cancer Care Northwest and Gamma Knife of Spokane, Spokane, WA 99204, USA,
[email protected] Johnathan A. Engh Department of Neurological Surgery, University of Pittsburgh Medical Center, UPMC Presbyterian, Pittsburg, PA 15213, USA,
[email protected] Robert K. Fairbanks Department of Oncology, Cancer Care Northwest and Gamma Knife of Spokane, Spokane, WA 99204, USA,
[email protected] Frank Floeth Department of Neurosurgery, Heinrich-Heine-University Düsseldorf, D-40225 Düsseldorf, Moorenstr. 5,
[email protected] Juan M. García-Gómez Informatica Biomedica, Institudo de Aplicaciones de las Technologias de la Informacion y de las Comunicaciones Avanzadas, Universidad Politecnica de Valencia, Valencia, Spain,
[email protected] Julie Gehl Department of Oncology, Copenhagen University Hospital Herlev, 2730 Herlev, Denmark,
[email protected] Richard G. Grundy Children’s Brain Tumor Research Center, Medical School D Floor, School of Clinical Sciences, Queen’s Medical Centre, Nottingham, NG7 2UH, UK,
[email protected] Abhijit Guha Division of Neurosurgery, Toronto Western Hospital, Toronto, ON, Canada,
[email protected] Sheffali Gulati Division of Pediatric Neurology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India,
[email protected] Joerg Haier Comprehensive Cancer Centre Muenster, International Patient Management, University Hospital Muenster, 48149 Muenster, Germany,
[email protected] M.A. Hayat Department of Biological Sciences, Kean University, Union, NJ 07083, USA,
[email protected] Arend Heerschap Department of Electrical Engineering (ESAT/SISTA), K.U. Leuven, Leuven, Belgium,
[email protected] Eirik Helseth Department of Neurosurgery, OSLO University Hospital, Oslo, Norway,
[email protected] Doug Hughes Department of Neurosurgery, Medical College of Georgia, Augusta, GA 30912, USA,
[email protected] Contributors
Contributors
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Richard Hummel Department of General and Visceral Surgery, University Hospital Muenster, 48149 Muenster, Germany,
[email protected] Albert J. Idema Department of Electrical Engineering (ESAT/SISTA), K.U. Leuven, Leuven, Belgium,
[email protected] Shogo Ishiuchi Department of Radiology, University of the Ryukyus, Nishihara-cho, Okinawa 903-0215, Japan,
[email protected] Helle K. Iversen Glostrup Research Institute, Copenhagen University Hospital Glostrup, 2600, Glostrup, Denmark,
[email protected] Hanna Järnum Department of Radiology, Aalborg Hospital, Arhus University Hospital, 9000 Aalborg, Denmark,
[email protected] Stephen Johnston Breast Unit, Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT, UK,
[email protected] Ferenc A. Jolesz Brigham and Women’s Hospital, Harvard Medical School, Boston, USA,
[email protected] Youngmee Kim Department of Psychology, University of Miami, Coral Gables, FL 33146, USA,
[email protected] Linda Knutsson Department of Medical Radiation Physics, Lund University, Lund, Sweden,
[email protected] Anne-Laure Laine INSERM, U646, Universite d’Angers, Angers F-491000, France,
[email protected] Wayne T. Lamoreaux Department of Oncology, Cancer Care Northwest and Gamma Knife of Spokane, Spokane, WA 99204, USA,
[email protected] Karl-Josef Langen Institute of Neuroscience and Medicine, Forschungszentrum Jülich, D-52425 Jülich, Germany,
[email protected] Elna-Marie Larsson Department of Radiology, Uppsala University, Uppsala University Hospital, SE 751 85 Uppsala, Sweden,
[email protected] Teresa Laudadio Department of Electrical Engineering (ESAT/SISTA), K.U. Leuven, Leuven, Belgium,
[email protected] Andre A. le Roux Division of Neurosurgery, Toronto Western Hospital, Toronto, ON, Canada,
[email protected] Christopher M. Lee Department of Oncology, Cancer Care Northwest and Gamma Knife of Spokane, Spokane, WA 99204, USA,
[email protected] Peter Lindvall Umea University Hospital, Umea, Sweden,
[email protected] Mette Linnert Department of Oncology, Copenhagen University Hospital Herlev, 2730 Herlev, Denmark,
[email protected] Aida Loudyi Section of Melanoma, Renal Cancer and Immunotherapy, Nevada Cancer Institute, Las Vegas, NV 89135, USA,
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Jian-Qiang Lu Department of Lab Medicine and Pathology, 5B2.24 WCM Health Sciences Centre, University of Alberta Hospital, Edmonton, AB, Canada TG6 2B7,
[email protected] Jan Luts Department of Electrical Engineering (ESAT/SISTA), K.U. Leuven, Leuven, Belgium,
[email protected] Alexander R. MacKay Department of Oncology, Cancer Care Northwest and Gamma Knife of Spokane, Spokane, WA 99204, USA,
[email protected] Faisal Mahmood Department of Oncology, Copenhagen University Hospital Herlev, 2730 Herlev, Denmark,
[email protected] Edward M. Marchan Department of Neurological Surgery, Health Sciences Center, Charlottesville, VA 22908, USA,
[email protected] Ernst Martin University Children’s Hospital, CH-8032 Zurich, Switzerland,
[email protected] Akira Matsumura Department of Neurosurgery, Clinical Medicine, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki 305-8565, Japan,
[email protected] Jessica Maurer Department of General and Visceral Surgery, University Hospital Muenster, 48149 Muenster, Germany,
[email protected] Torstein Meling Department of Neurosurgery, OSLO University Hospital, Oslo, Norway,
[email protected] Laurent Menard Laboratoire Imagerie et Modelisation en Neurobiologie et Cancerologie, IMNC- UMR 8165, Universita Paris Diderot 7, Paris, France,
[email protected] Philippe Menei INSERM, U646, Universite d’Angers, Angers, F-491000, France; Centre Hospitalier Universitaire d’Angers, Angers cedex 9, F-49933, France,
[email protected] Murielle Mimeault Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Cancer Institute, 7052 DRC, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA,
[email protected] Antonio Mirijello Department of Internal Medicine, Catholic University of Rome, 8 – 00168 Rome, Italy,
[email protected] Sadayuki Murayama Department of Radiology, University of the Ryukyus, Nishihara-cho, Okinawa 903-0215, Japan,
[email protected] Pawel G. Ochalski Department of Neurological Surgery, University of Pittsburgh Medical Center, UPMC Presbyterian, Pittsburg, PA 15213, USA,
[email protected] Kazuhiko Ogawa Department of Radiology, University of the Ryukyus, Nishihara-cho, Okinawa 903-0215, Japan,
[email protected] Naoto Oku Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526 Japan,
[email protected] Contributors
Contributors
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Catherine Passirani INSERM, U646, Universite d’Angers, Angers F-491000, France,
[email protected] Akshal S. Patel Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA,
[email protected] Richard Prayson Department of Anatomic Pathology, Cleveland Clinic Foundation, CCLCM, Cleveland, OH 44195, USA,
[email protected] Scott Y. Rahimi Department of Neurosurgery, Medical College of Georgia, Augusta, GA 30912, USA,
[email protected] Ruman Rahman Children’s Brain Tumor Research Center, Medical School D Floor, School of Clinical Sciences, Queen’s Medical Centre, Nottingham, NG7 2UH, UK,
[email protected] Siril Rogne Department of Neurosurgery, OSLO University Hospital, Oslo, Norway,
[email protected] Paul Ronning Department of Neurosurgery, OSLO University Hospital, Oslo, Norway,
[email protected] Wolfram E. Samlowski 2435 Grassy Spring Pl, Las Vegas, NV 89135, USA,
[email protected] Naveen Sankhyan Division of Pediatric Neurology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India,
[email protected] Jesse J. Savage Department of Neurological Surgery, Health Sciences Center, Charlottesville, VA 22908, USA,
[email protected] Suvasini Sharma Division of Pediatric Neurology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India,
[email protected] Jason P. Sheehan Department of Neurological Surgery, Health Sciences Center, Charlottesville, VA 22908, USA,
[email protected] Jonas M. Sheehan Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA,
[email protected] Robert Shenkar Neurovascular Surgery Program, Section of Neurosurgery, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Ave., Chicago, IL, 60637, USA,
[email protected] Kosuke Shimizu Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526 Japan,
[email protected] Arjan W. Simonetti Department of Electrical Engineering (ESAT/SISTA), K.U. Leuven, Leuven, Belgium,
[email protected] Eefje M. Sizoo Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands,
[email protected] Mari Cleide Sogayar Department of Biochemistry, Chemistry Institute, NUCEL-Cell and Molecular Therapy Center, University of Sao Paulo, Sao Paulo 05508-900 SP, Brazil,
[email protected] xxii
Andreas M. Stark Department of Neurosurgery, Schleswig-Holstein University Medical Center, Campus Kiel, 24105 Kiel, Germany,
[email protected] Stephanie Sutherland Breast Unit, Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT, UK,
[email protected] Johan A.K. Suykens Department of Electrical Engineering (ESAT/SISTA), K.U. Leuven, Leuven, Belgium,
[email protected] Martin J.B. Taphoorn Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Neurology, Medical Center Haaglanden, The Hague, The Netherlands,
[email protected] Hideo Tsurushima Department of Neurosurgery, Clinical Medicine, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki 305-8565, Japan,
[email protected] Sabine Van Huffel Department of Electrical Engineering (ESAT/SISTA), K.U. Leuven, Leuven, Belgium,
[email protected] Dirk Vandermeulen Department of Electrical Engineering (ESAT/SISTA), K.U. Leuven, Leuven, Belgium,
[email protected] Matthias Weckesser Department of Nuclear Medicine, Münster University, D-48149 Münster, Albert-Schweitzer-Strasse 33, Germany,
[email protected] Contributors
Chapter 1
Introduction M.A. Hayat
Keywords Tumor · CNS · Survival rate · Prognosis · Radiation · Dose Each year malignant tumors take a devastating toll on people, and among the most feared are brain tumors. Five-year survival rates per adults are disappointing, and mortality rates have not improved during the last 3 decades. Although overall 5-year survival rates have reached to 70% in children and mortality rates have declined 25% since 1970, prognosis is still poor for those inflicted with certain types of malignant tumors. There are manifold reasons, known and unknown, for lack of improved rates of survival. One of the main reasons is the difficulty encountered by drugs to cross the blood brain barrier that is a defense mechanism, protecting the brain from blood-born pathogens. Even when therapy is effective, its side-effects can cause serious disabilities. Another reason is that the diffuse infiltration of this neoplasm does not allow even the smallest surgical instruments to resect only the tumor cells bypassing the healthy neurons. In addition, these malignant cells are highly resistant to external radiation or systemic chemotherapy. Both radiation and chemotherapy can also have toxic effects not only on the tumor they are intended to treat but also on brain function. In other words, these treatments also kill normal brain cells. Functional deficits in patients after radiotherapy are probably more common than is currently reported. These deficits include mental retardation in patients and memory or cognitive deficits
M.A. Hayat () Department of Biological Sciences, Kean University, Union, NJ 07083, USA e-mail:
[email protected] in adults. Nevertheless, radiation therapy is a major component of the treatment of many primary and metastatic brain tumors. Doses higher than 60 Gy may produce vasogenic edema and necrosis in some patients. The 5-year relative survival rate following diagnosis of a primary malignant CNS tumor based on age is given below (CBTRUS): Age 0–19 years: 72.1% Age 20–44 years: 55.9% Age 45–54 years: 30.7% Age 55–64 years: 16.7% Age 65–74 years: 9.6% Age 75 or older: 5.2% From birth, males have a 0.67% lifetime risk of being diagnosed with a primary malignant CNS tumor, and 0.48% chance of dying from this cancer (excluding lymphomas, leukemias, and tumors of pituitary and pineal glands and olfactory tumors of the nasal cavity). From birth, females have a 0.54% lifetime risk of being diagnosed with this tumor, and a 0.38% chance of dying from this cancer. The 5-year relative survival rate following diagnosis of a primary malignant CNS tumor (including lymphomas and leukemias and tumors of pituitary and pineal glands, and olfactory tumors of the nasal cavity) is 33% for males and 37% for females. The estimated prevalence rate for all primary CNS tumors is 209/100.000. Approximately, more than 612,000 persons are living with this caner in the United States (malignant tumor: >124,000 and nonmalignant tumor: >488,000). The prevalence rate for all pediatric CNS tumors is estimated at 35.4/100,000, with more than 28,000 children living with this cancer in the United States.
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The above-mentioned sobering statistics clearly indicate a considerable challenge to overcome brain tumors. To respond to this challenge, various experimental therapies have been administered, including gene therepy, antisense treatment, boron neutron capture, locoregional redioimmunotherapy, ligand-toxin conjugate administration and 5-aminolevulinic acid photodynamic therapy. Methods for sensitizing glioma cells to apoptosis induction and aiming at different targets such as the coagulation system have also been tried. These efforts have failed to significantly increase the overall survival of patients. Recently, Samnick et al. (2009) have tested the efficacy of 131 I-IPA combined with external beam photon radiotherapy as a new therapeutic approach against malignant glioma cells. This approach is based on the finding that malignant brain tumors accumulate amino acids more avidly than do healthy brains, using PET or SPECT (Hellwig et al., 2005). This finding led to the development of amino acid-based radiopharmaceuticals for detecting brain neoplasms. The use of this approach seems to merit a clinical trial to ascertain its potential in malignant glioma patients.
Causes of Developing Brain Tumors Although little is known regarding the causes of developing brain tumors, the following conditions may increase the risk of developing this neoplasm. Exposure to certain chemicals (e.g., vinyl chloride) and mutation of relevant genes are risk factors. Brain tumors can develop after medical radiation to the scalp or brain. Brain metastatic tumors can develop from cancer of other organs such as lung and breast. Certain viruses (Epstein-Barr virus and human cytomegalovirus) can also cause brain tumors. Diseased organ transplant can lead to primary CNS lymphoma. Genetic syndromes, such as neurofibromatosis types 1 or 2 and tuberous sclerosis, may increase the risk of developing brain tumors. Immune system disorders may also play a direct or indirect roe in developing these tumors. Some types of brain tumors tend to run in families. Although smoking, alcohol consumption, and certain dietary habits are associated with some types of cancer, they have not been directly linked to primary CNS tumors. Brain and spinal cord tumors are not contagious, and presently
M.A. Hayat
are not preventable. CNS tumors rarely spread outside the nervous system.
Distribution of Types of CNS Tumors There are many types of brain and spinal cord tumors (NCI): astrocytic tumors, embryonal tumors, ependymal tumors, germ cell tumors, meningeal tumors, mixed gliomas, oligodendroglial tumors, pineal parenchymal tumors, pituitary tumors, CNS lymphomas, tumors of the seller region, and other adult brain tumors. Anaplastic astrocytomas and glioblastoma account for ∼27% of brain tumors. Tumors that start in the brain are called primary brain tumors. Often tumors found in the brain are initiated somewhere else in the body and spread to one or more parts of the brain, and are called metastatic brain tumors. Brain metastases outnumber primary neoplasms by at least 10 to 1; the latter occur in 20–40% of cancer patients. The most common primary cancers metastasizing to the brain (tumor to tumor) are lung cancer (50%), breast cancer (15–20%), melanoma (10%), colon cancer (5%), and unknown primary cancers (10–15%). Approximately, 80% of brain metastases occur in the cerebral hemispheres, 15% occur in the cerebellum, and 5% occur in the brain stem. Metastases to the brain are multiple in >70% of cases, but solitary metastases also occur. Many brain tumors recur after they have been treated, and the recurrence may occur at the same cite or in other parts of the brain.
Tumor Grading Grading is based on the cellular make-up and location of the tumors. Tumors are graded in biopsy tissue or during surgery. The grade of a tumor can be used to indicate the difference between slow- and fastgrowing types of the tumor. Grade I tumors (e.g., pilocytic astrocytoma) grow slowly, do not spread into nearby tissues, and look like normal cells. It is possible to entirely remove this type of tumor by surgery. Grade II tumors (e.g., diffuse astrocytomas) also grow slowly, but may spread into nearby tissues, may recur after treatment, and may become a higher-grade tumor.
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Grade III tumors (e.g., annaplastic astrocytomas) grow rapidly, spread into nearby tissues, appear very different from normal cells, and may progress to a higher grade and become glioblastoma. Grade IV tumors (e.g., glioblastoma) grow and spread very quickly; the cells do not look like normal cells, and may show areas of dead cells.
Symptoms The symptoms caused by a brain tumor depend on its location in the brain, functions controlled by that part of the brain, and the size and grade of the tumor (NCI). Although the following symptoms are seen in brain tumor patients, other conditions may show the same symptoms. Headaches in the morning, which go away after vomiting. Frequent nausea and vomiting are not uncommon. Problems in normal speech, vision, and hearing are common. Trouble in walking and loss of balance may also be present. Depending on the location of the tumor in the brain, weakness on one side of the body may be found. Other symptoms include seizure, and unusual sleepiness and personal behavior.
Diagnosis Early Symptoms (mentioned elsewhere in this chapter and other chapters in this volume and in volume 1) necessitate immediate consultation with a physician. If the doctor suspects a brain tumor, a biopsy can be done to remove a sample of the tissue from the brain by removing a small part of the skull and using a needle. If a cancer is diagnosed under the microscope, the surgeon may remove as much tumor as safely possible during the same surgery or later, after detailed examination of the biopsy sample. A pathologist may check the cancer cells in the biopsy to find out the type and grade of the brain tumor and if the tumor is
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likely to grow and spread. An imaging modality such as computed tomography (CT) or magnetic resonance imaging (MRI) can be used to find out if any cancer cells remain after surgery. These and other imaging procedures are also used to diagnose spinal tumors.
Prognosis Prognosis (chance of recovery) and treatment depend on a large number of factors, most of which are enumerated below (NCI). 1. The Type, grade, and location of the tumor in the brain. 2. Whether the tumor can be removed by surgery; if not, radiotherapy or chemotherapy, or both are alternate treatments. 3. Prognosis also depends on whether cancer cells remain after surgery. 4. Late or early diagnosis and whether the cancer has recurred. 5. The health and age of the patient. 6. The presence or absence of relevant gene mutations. 7. Whether there is a single tumor or more than one tumor in the brain. 8. Use of an imaging procedure to determine whether the tumor is responding to the treatment or is continuing to grow and spread.
References Hellwig D, Ketter R, Romieke BF, Sell N, Schaefer A, Moringlane JR, Krisch G, Samnick S (2005) Validation of brain tumor imaging with p-[123 I] iodo-L- phenylalanine and SPECT. Eur J Nucl Med Mol Imag 32:1041–1049 Samnick S, Romeike BF, Lehmann T, Israel I, Rube C, Mautes A, Reimers C, Kirsch C-M (2009) Efficacy of systemic radionuclide therapy with p-131 I-iodo- L -phenylalanine combined with external beam photon irradiation in treating malignant gliomas. J Nucl Med 50:2025–2032
Chapter 2
Brain Tumor Classification Using Magnetic Resonance Spectroscopy Juan M. García-Gómez
Abstract The systematic compilation of Magnetic Resonance Spectroscopy (MRS) has allowed the application of statistical and signal processing techniques to analyze the contribution of metabolites and other compounds in the brain tissues. The complex nature of the MR spectra and the intrinsic difficulty of the Brain Tumor (BT) classification has led researchers towards the Machine Learning discipline, as an objective, as well as practical, methodology for discovering common patterns in the MR spectra acquired from the tumor tissues. This chapter tries to introduce the reader in the classification of brain tumor using MRS. The classification of the most prevalent types of brain tumors using MRS has been largely studied by several authors. Recently, classifiers for the childhood and for a wider range of types of tumors have been also obtained. Furthermore, incremental learning is a promising solution for the dynamism of the clinical environments. During the text we will justify the necessity of agreed acquisition protocols and prospective evaluation of the automatic classifiers to improve the predictive power of the classifiers. The aim of this chapter is to give a practical perspective of the automatic classification of brain tumors using magnetic resonance spectroscopy through the development of Clinical Decision Support Systems (CDSSs) and multicenter studies.
J.M. García-Gómez () Informatica Biomedica, Institudo de Aplicaciones de las Technologias de la Informacion y de las Comunicaciones Avanzadas, Universidad Politecnica de Valencia, Valencia, Spain e-mail:
[email protected] Keywords Magnetic resonance spectroscopy · Pattern classification · Brain tumors · Decision support systems · Multicenter evaluation study
Introduction MRS is an in-vivo noninvasive methodology requiring no ionizing radiation that allows a profile of the metabolites within a tissue to be obtained. The systematic compilation of MRS following agreed acquisition protocols has allowed the application of statistical and signal processing techniques to analyze the contribution of metabolites and other compounds in the brain tissues. Since the publication of the seminal paper by Preul et al. (1996), one major challenge during the last 2 decades has been the development of objective procedures to assist radiologists in the diagnosis of brain tumors by means of automatic classification of MRS signals from the patients. The complex nature of the MR spectra and the intrinsic difficulty of the BT classification has led researchers towards the Machine Learning discipline, as an objective, as well as practical, methodology for discovering common patterns in the MR spectra acquired from the tumor tissues. This chapter tries to introduce the reader in the classification of brain tumor using MRS. The application of the machine learning methodology will guide the exposition of the subject, illustrating the text through examples involving multicenter datasets. Along the chapter, we will try to range the next learning objectives:
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1. The first learning objective of the chapter will be to design of a brain tumor classification study with MRS based on the machine learning methodology. This general framework will lead us through the different steps to solve the automatic classification. 2. To enumerate the pre-processing steps needed to prepare the MR spectra for a correct classification study. 3. To summarize the feature extraction techniques applied to brain tumor diagnosis with MRS and to review relevant results in multicenter studies. 4. To summarize the classification techniques applied to brain tumor diagnosis with MRS and to review relevant results in multicenter studies and trends. 5. To justify the necessity of a correct evaluation of the classification results and to review a comparative evaluation with retrospective and prospective datasets. 6. To cite secondary outcomes of the automatic classification of brain tumors to analyze the contribution of metabolites, discover heterogeneous patterns, and detect outliers in the MRS datasets. 7. To cite Clinical Decision Support Systems (CDSSs) for brain tumor diagnosis using MRS.
MRS Classification Overview The life cycle of a Brain Tumor classification study based on MR spectroscopy mainly follows the Machine Learning methodology for solving a Pattern Recognition problem. It is composed of two main phases: the Training phase and the Recognition phase (see Fig. 2.1). During the Training phase, a set of signals following (the training corpus) a acquisition protocol is used to adapt a classification function. In this phase, a preprocessing and a features extracted from the signals are established. Afterwards, an adaptive model is fitted, selected and evaluated trying to obtain
Fig. 2.1 Design of a brain tumor classification with MR spectroscopy based on the machine learning approach
J.M. García-Gómez
the optimal generalization for predicting new cases. Once the model is ready, it can be incorporated into a CDSS to be used for the prediction of new cases, where the preprocessing and feature extraction steps will be carried out before applying the classification function. The rest of the chapter reviews the main techniques of each step of the Machine Learning methodology applied to Brain Tumor classification with MRS. Section “MRS Classification Overview” specifies the well-established pre-processing pipeline agreed in the eTUMOR project for normalizing MR spectra. In section “Preprocessing Magnetic Resonance Spectroscopy” the main pattern recognition techniques for extracting relevant features from MR spectra are studied. That section ends with a review of the effect of feature extraction from MRS in brain tumor classification. Section “Feature Extraction” studies the Machine Learning approach for classification, its techniques and its application to different problems of brain tumor diagnosis. The relevance of an accurate evaluation is studied in section “Peak Integration” by comparing retrospective and prospective evaluations of brain tumor classifiers. The use of the classification results to interpret of signal patterns, detect outliers, and perform quality control of MRS biobanks is presented in section “Stepwise Algorithm for Feature Selection in Classification”. Before conclusions, section “Relieff Feature Selection” provides an enumeration of CDSS for brain tumor diagnosis using MRS.
Preprocessing Magnetic Resonance Spectroscopy A spectrum acquired with a Time Echo (TE) 5 new lesions, WBRT was added. Palliative surgery was performed if there was a surgically accessible dominant or symptomatic lesion. The GK/SRS treatment dose was prescribed to the isodose line covering 95% of the target volume (range, 80–97%), with a planned dose based on the maximal diameter of each metastatic lesion: 3 years) of renal cancer patients with brain metastases may currently be achievable in ∼15% of patients by use of GK/SRS, followed by systemic immunotherapy. It is likely that broader application of combined modality treatment will result in further improvements in the outcome of RCC metastatic to the brain.
References Alexander E 3rd, Moriarty TM, Davis RB, Wen PY, Fine HA, Black PM, Kooy HM, Loeffler JS (1995) Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 87:34–40 Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik M, Demas W, Ryu J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran WJ Jr. (2004) Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363:1665–1672 Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G (2006) Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. J Am Med Assoc 295:2483–2491 Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 22: 2865–2872 Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP (2010) Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res 16:269–278 Bukowski RM, Negrier S, Elson P (2004) Prognostic factors in patients with advanced renal cell carcinoma: development of an international kidney cancer working group. Clin Cancer Res 10:6310S–6314S Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH, Meyers CA (2009) Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus wholebrain irradiation: a randomised controlled trial. Lancet Oncol 10:1037–1044 Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R (1997) Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745–751 Harada Y, Nonomura N, Kondo M, Nishimura K, Takahara S, Miki T, Okuyama A (1999) Clinical study of brain metastasis of renal cell carcinoma. Eur Urol 36:230–235 Hwang SW, Abozed MM, Hale A, Eisenberg RL, Dvorak T, Yao K, Pfannl R, Mignano J, Zhu JJ, Price LL, Strauss GM, Wu JK (2009) Adjuvant Gamma Knife radiosurgery following
A. Loudyi and W.E. Samlowski surgical resection of brain metastases: a 9-year retrospective cohort study. J Neurooncol 98:77–82 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009 CA Cancer J Clin 59:225–249 Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC (1999) Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45:427–434 Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS (2005) Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol 174:466–472; discussion 472; quiz 801 Leksell DG (1987) Stereotactic radiosurgery. Present status and future trends. Neurol Res 9:60–68 Levy DA, Slaton JW, Swanson DA, Dinney CP (1998) Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol 159:1163–1167 Loeffler JS (2004) Can combined whole brain radiation therapy and radiosurgery improve the treatment of single brain metastases? Nat Clin Pract Oncol 1:12–13 Manon R, O‘Neill A, Knisely J, Werner-Wasik M, Lazarus HM, Wagner H, Gilbert M, Mehta M (2005) Phase II trial of radiosurgery for one to three newly diagnosed brain metastases from renal cell carcinoma, melanoma, and sarcoma: an Eastern Cooperative Oncology Group study (E6397). J Clin Oncol 23:8870–8876 Maor MH, Frias AE, Oswald MJ (1988) Palliative radiotherapy for brain metastases in renal carcinoma. Cancer 62:1912– 1917 Mathieu D, Kondziolka D, Cooper PB, Flickinger JC, Niranjan A, Agarwala S, Kirkwood J, Lunsford LD (2007) Gamma knife radiosurgery in the management of malignant melanoma brain metastases. Neurosurgery 60:471–481; discussion 481–472 Mehta M, Noyes W, Craig B, Lamond J, Auchter R, French M, Johnson M, Levin A, Badie B, Robbins I, Kinsella T (1997) A cost-effectiveness and cost-utility analysis of radiosurgery vs. resection for single-brain metastases. Int J Radiat Oncol Biol Phys 39:445–454 Mori Y, Kondziolka D, Flickinger JC, Logan T, Lunsford LD (1998) Stereotactic radiosurgery for brain metastasis from renal cell carcinoma. Cancer 83:344–353 Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J (1999) Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17:2530–2540 O‘Neill BP, Iturria NJ, Link MJ, Pollock BE, Ballman KV, O‘Fallon JR (2003) A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys 55:1169–1176 Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, Markesbery WR, Foon KA, Young B (1998) Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. J Am Med Assoc 280:1485–1489 Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, Markesbery WR, Macdonald JS, Young B (1990) A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494–500
6 Brain Metastasis in Renal Cell Carcinoma Patients Pouessel D, Culine S 2007. High Frequency of Intracerebral Hemorrhage in Metastatic Renal Carcinoma Patients with Brain Metastases Treated with Tyrosine Kinase Inhibitors Targeting the Vascular Endothelial Growth Factor Receptor. Eur Urol Samlowski WE, Majer M, Boucher KM, Shrieve AF, Dechet C, Jensen RL, Shrieve DC (2008) Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating stereotactic radiosurgery. Cancer 113: 2539–2548 Sawaya R, Hammoud M, Schoppa D, Hess KR, Wu SZ, Shi WM, Wildrick DM (1998) Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery 42:1044–1055; discussion 1055–1046 Serizawa T, Hirai T, Nagano O, Higuchi Y, Matsuda S, Ono J, Saeki N (2010) Gamma knife surgery for 1–10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multiinstitute study (JLGK0901) inclusion criteria. J Neurooncol 93:163–167 Shiau CY, Sneed PK, Shu HK, Lamborn KR, McDermott MW, Chang S, Nowak P, Petti PL, Smith V, Verhey LJ, Ho M, Park E, Wara WM, Gutin PH, Larson DA (1997) Radiosurgery for brain metastases: relationship of dose and pattern of
61 enhancement to local control. Int J Radiat Oncol Biol Phys 37:375–383 Shuch B, La Rochelle JC, Klatte T, Riggs SB, Liu W, Kabbinavar FF, Pantuck AJ, Belldegrun AS (2008) Brain metastasis from renal cell carcinoma: presentation, recurrence, and survival. Cancer 113:1641–1648 Shuto T, Matsunaga S, Suenaga J, Inomori S, Fujino H (2010) Treatment strategy for metastatic brain tumors from renal cell carcinoma: selection of gamma knife surgery or craniotomy for control of growth and peritumoral edema. J Neurooncol Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, Tans JT, Lambooij N, Metsaars JA, Wattendorff AR et al. (1993) Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 33:583–590 Wowra B, Siebels M, Muacevic A, Kreth FW, Mack A, Hofstetter A (2002) Repeated gamma knife surgery for multiple brain metastases from renal cell carcinoma. J Neurosurg 97:785–793 Wronski M, Maor MH, Davis BJ, Sawaya R, Levin VA (1997) External radiation of brain metastases from renal carcinoma: a retrospective study of 119 patients from the M. D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 37:753–759
Chapter 7
Coexsistence of Inflammatory Myofibroblastic Tumor in the Lung and Brain Naveen Sankhyan, Suvasini Sharma, and Sheffali Gulati
Abstract Inflammatory myofibroblastic tumors (IMT) are rare tumors of unknown etiology, composed of proliferating myofibroblasts and accompanying lymphoplasmacytic infiltration. They are most commonly seen in the lung, but may rarely occur in other organs. The authors review the current literature of coexisting inflammatory myofibroblastic tumors of lung and brain. Keywords Plasma cell granuloma · Inflammatory granuloma · Anaplastic lymphoma kinase · Pseudotumor · ALK
Introduction Inflammatory myofibroblastic tumor is a quasineoplastic lesion consisting of inflammatory cells and myofibroblastic spindle cells (Scott et al., 1988). The myofibroblast is ubiquitous in soft tissues and its precise role in any given lesion may vary considerably, ranging from “innocent” bystander through being a reactive stromal component, to representing the primarily proliferating cell type (Petridis et al., 2004). Myofibroblastic tumors can be broadly classified into 4 main groups: reactive lesions, benign tumors (neoplastic, reactive, hamartomatous), the locally aggressive fibromatosis and sarcomas showing myofibroblastic differentiation (Fletcher, 1998). Inflammatory
N. Sankhyan () Division of Pediatric Neurology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India e-mail:
[email protected] myofibroblastic tumor was first described in the lungs by Brunn in 1939. It mainly affects children and young adults. Lungs or the upper respiratory tract are the most common sites of these tumors (Bahadori and Liebow, 1973; Lawson et al., 2010). However they have also been reported to occur in other areas like the skin (Vadmal and Pellegrini, 1999), spleen (Herman et al., 1994) thyroid (Kojima et al., 2009), breast (Chetty and Govender, 1997), uterus (Rabban et al., 2005), kidney (Dogra and Bhatt, 2009), heart (Hartyánszky et al., 2000), liver (Tang et al., 2010), pancreas (Dagash et al., 2009) retroperitoneum (Koirala et al., 2010), gastrointestinal tract (Sanders et al., 2001), mediastinum (Sugiyama and Nakajima, 2008) and central nervous system (Trojan et al., 2001). Other terms which have been used to describe this entity include plasma cell granuloma, fibroxanthoma, xanthogranuloma, pseudolymphoma, inflammatory pseudotumor, and inflammatory myofibrohistiocytic proliferation. The term inflammatory myofibrohistiocytic proliferation was suggested by Tang et al. (1990) to overcome the inadequacy and inaccuracy of the conventional designations of plasma cell granuloma and inflammatory pseudotumor; especially as plasma cells are not always a major feature of this lesion.
Histopathology It is a benign solid tumor composed mainly of spindleshaped cells and has a chronic inflammatory component consisting of plasma cells, lymphocytes and occasional histiocytes. Absence of anaplasia, intermixture of lymphocytes and plasma cells among spindle cells, and paucity of mitotic cells leads to the diagnosis
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of inflammatory myofibroblastic tumor (Karnak et al., 2001). Major subgroups have been identified among inflammatory tumors not affecting the CNS, including a predominant myxoid/vascular pattern resembling granulation tissue, a compact spindle cellular and a hypocellular fibrotic pattern in nonpulmonary, and an organizing pneumonia pattern with central hyalinization, a fibrous histiocytoma-like pattern, and a lymphoplasmacytic pattern in pulmonary inflammatory tumors (Coffin et al., 1995; Matsubara et al., 1988). Inflammatory myofibroblastic tumor in the CNS is a neoplasm similar to its soft tissue counterpart and should be distinguished from the histologically similar, nonneoplastic inflammatory pseudotumors. Inflammatory pseudotumor, a term used in the past interchangeably with IMT is now best considered a separate entity. Inflammatory pseudotumor, a term synonymous with plasma cell granuloma and lymphoid hyperplasia, is a chronic inflammatory lesion of uncertain etiology that more often affects the central than the peripheral nervous system. Recent studies with stringent diagnostic criteria indicate that inflammatory pseudotumors lack anaplastic lymphoma kinase expression, with such expression being a feature of inflammatory myofibroblastic tumors (Swain et al., 2008).
Etiopathogenesis The myofibroblasts, fibroblasts, and histiocytes in inflammatory myofibroblastic tumor are probably derivatives of primitive mesenchymal cells which are widely distributed in the body and thus may contribute to the ubiquitous occurrence of inflammatory myofibroblastic tumor (Tang et al., 1990). The true etiology of inflammatory myofibroblastic tumors remains unknown. Some authors believed this tumor was a low grade fibrosarcoma with inflammatory cells. The propensity of these tumors to be locally aggressive, sometimes multifocal, and to progress occasionally to a true malignant tumor supported the idea (Narla et al., 2003). Others hypothesized that inflammatory myofibroblastic tumor represented an immunological response to an infectious or non-infectious agent. This idea was supported by the presence of clinical and laboratory signs of systemic inflammation in 15–30% of previous cases (Coffin et al., 1998). In part the
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confusion arose because; historically both neoplastic and nonneoplastic processes were combined as inflammatory pseudotumors. Recent reports suggest that inflammatory myofibroblastic tumors are neoplastic (Swain et al., 2008). Evidence favouring the neoplastic nature was presented by demonstrating a clonal population harboring the abnormal Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase expression due to aberrations on chromosomal locus 2p23 (Clarke et al., 2005; Su et al., 1998; Griffin et al., 1999). Hence, it may be reasonable to classify a lesion as inflammatory myofibroblastic tumor in the presence of typical histopathological features and ALK expression. But the nosology of lesions with similar morphology but absent ALK expression or those with unclear morphology but ALK expression remains unsettled. Human herpesvirus 8 (HHV-8) DNA sequences have been found in adult pulmonary inflammatory myofibroblastic tumors and presence of Ebstein-Barr Virus (EBV) has been reported in splenic and hepatic inflammatory myofibroblastic tumors, suggesting the role of these viruses in inflammatory myofibroblastic tumor pathophysiology (Gomez et al., 2000; Arber et al., 1998). However, Tavora et al. (2007), in a study of 20 patients with pulmonary inflammatory myofibroblastic tumors did not find HHV-8 related transcripts. Similar was the experience of Swain et al., in six patients with central nervous system inflammatory myofibroblastic tumors (Swain et al., 2008). It is clear that a lot remains to be known about the pathogenesis of this tumor.
Clinical Features The clinical presentation depends on the site, extent and spread of the tumor. Virtually any organ may be involved and exceptionally, even bone marrow spread has been described (Hagenstad et al., 2003). Extrapulmonary inflammatory myofibroblastic tumor affects a younger population of patients, with a predilection for the first and second decades; this is in contrast to a peak incidence in mid-adulthood for the pulmonary form (Coffin et al., 1995). Cough, dyspnea and hemoptysis are the usual presenting features of pulmonary inflammatory myofibroblastic tumors (Kim et al., 2002). Patients with inflammatory myofibroblastic tumors may also have systemic features
7 Coexsistence of Inflammatory Myofibroblastic Tumor in the Lung and Brain
including fever, growth impairment, iron deficiency anemia, thrombocytosis, elevated erythrocyte sedimentation rate and hypergammaglobulinemia (Coffin et al., 1998).
Intracranial Inflammatory Myofibroblastic Tumors Intracranial inflammatory myofibroblastic tumors may be either isolated or associated with a primary inflammatory myofibroblastic tumor in another organ, usually lung, mesentery or mediastinum. Intracranial inflammatory myofibroblastic tumor may present with seizures, focal neurological deficits, features of raised intracranial pressure (headache, vomiting, papilledema), cranial nerve deficits and in case of sellar/suprasellar location, with endocrine dysfunction (Makino et al., 1995). Spinal cord and meningeal involvement, suggesting hematogenous spread have also been described (Narla et al., 2003). Greiner et al. reviewed 38 published cases (16 female, 22 male, mean age 34 years) of intracranial inflammatory myofibroblastic tumor. The major complaints were headache (52.6%), seizures (26.3%), visual disturbance (36.8%), ataxia (13.2%), paresis (15.8%) and diabetes insipidus (7.9%). Intracranial inflammatory myofibroblastic tumor was found incidentally on cranial imaging in 5.3% of the patients (Greiner et al., 2003).
Co-existence of Pulmonary and Brain Inflammatory Myofibroblastic Tumor On reviewing the literature we found only eight case reports of combined pulmonary and intracranial inflammatory myofibroblastic tumors (Tang et al., 1990; Chan et al., 1994; Le Marc’hadour et al., 1995; Malhotra et al., 1991; Greiner et al., 2003; Petridis et al., 2004; Jeba et al., 2008; Sharma et al., 2009) (Table 7.1). The most frequent pulmonary symptoms in these patients included cough and hemoptysis. The intracranial symptoms included headache, seizures and vomiting (Table 7.1). Four of the reported cases had multifocal brain lesions (Chan et al., 1994; Sharma et al., 2009; Malhotra et al., 1991; Jeba et al., 2008). Five of these eight patients were children. Interestingly, though the lung lesions in these cases
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were solitary large masses, the brain lesions were small, multifocal and discrete, suggesting the possibility of hematogenous dissemination. In all but one (Petridis et al., 2004), the discovery of the lung lesion either preceded the brain lesion (duration ranging from 5 months to 5 years) or was simultaneous; suggesting that the primary pathology originated in the lung. The case described by Petridis et al. (2004) was unusual for two other aspects as well: the brain lesions were hemorrhagic, resembling cavernous hemangiomas; and secondly unlike all the other patients who had a benign course, this patient had a fulminant course and died. It is unclear whether these co-occurring lesions represent a metastasis or a multifocal, exaggerated inflammatory response to some unidentified etiological agent(s). The metastasis hypothesis would also have to account for selective predilection for brain involvement, and the slow growth and overall indolent nature of these tumors. Also, no nuclear atypia or abnormal mitoses have been seen. Demonstration of ALK expression at both sites would favor a metastatic etiology; however this has not been performed in any of the reported cases to date.
Cranial Imaging Findings in Inflammatory Myofibroblastic Tumor Both CT and MRI demonstrate well-circumscribed, solid, homogenous masses with mild-to-moderate enhancement (Makino et al., 1995). In the brain, both solitary and multifocal brain lesions have been reported. MRI reveals iso-to-hypointense T2 lesions which have occasionally demonstrated hemorrhage within the tumors. Calcification and necrosis are rare. A lack of mobile protons, due to the densely fibrotic background of these lesions, may account for the T2 hypointensity and weaker enhancement on MR images (Makino et al., 1995). T2 weighted MRI sometimes reveal interdigitation with the adjacent cortex which is in line with observation of pathological changes in the neighboring cerebral tissue (Greiner et al., 2003). Although inflammatory myofibroblastic tumors are well circumscribed lesions, lymphoplasmacytic inflammation, neuronal loss, and reactive gliosis can be found within the adjacent cortex (Tekkök et al., 2000).
8
30
13
Le Marc’hadour et al. (1995)
Greiner et al. (2003)
20
M
M
M
M
Age (year) Sex 13 M
Chan et al. (1994)
Malhotra et al. (1991)
Author, year Tang et al. (1990)
Cough
Asymptomatic
Cough
Pulmonary symptoms/ signs Asymptomatic, Examinationdull percussion note Hemoptysis
Seizure
Recurrent headaches
Seizure
Seizures
Intracranial symptoms Intermittent throbbing headache
4 years
Simultaneous
2 years
5 years
Interval between detection of lung & brain lesion Simultaneous
Solid lesion in Lt lower lobe
3 masses in Rt lower lobe
Night sweats, malaise
Nil
Developed lesion in opposite lung, and in pneumonectomy space NA
No progression on 9 year follow up
Remarks No regression, but no progession on 3 year follow up.
Both lung & brain No recurrence on lesions 4.5 year follow successfully up resected
NA
Lung: lesion resection Brain: conservative Lung: pneumonectomy Brain: conservative
Systemic features Treatment Anemia, Hyper- Radiotherapy gamma globulinemia
Mass extending NA from lateral aspect of the left cavernous sinus to the tentorium cerebelli and the infratemporal fossa Round lesion in Rt Fever frontal lobe
Chest imaging Brain imaging findings findings large mass with Single 1.5 cm dense enhancing calcification in lesion in Lt Rt lung parietooccipital region Circumscribed 3 lesions in Lt mass in Rt temporal, Rt & upper lobe Lt parietal regions Large calcified 3 round lesions in mass in Rt Rt frontal, Lt lower lobe parietal, & Lt frontal
Table 7.1 Summary of cases reported with co-existing inflammatory myofibroblastic tumors of lung and brain
66 N. Sankhyan et al.
M
Sharma et al. (2009)
Headache, vomiting
Intracranial symptoms Headache, vomiting, diplopia, seizures
Cough, dyspnea Seizure
Cough
Pulmonary symptoms/ signs Hemoptysis, cough
M-Male, NA-Not available, Lt-Left, Rt-Right
10
M
Age (year) Sex 29 M
Jeba et al. (2008) 12
Author, year Petridis et al. (2004)
Table 7.1 (continued)
1 year
5 months
Interval between detection of lung & brain lesion Brain lesion preceded ling lesion by 8 months
Large, lobulated, calcified mass in Lt Lung
Fever
Lung lesionpneumonectomy Brain lesion-surgery, radiotherapy, single agent chemotherapy (doxorubicin) Lung lesioninoperable Brain lesionchemotherapy (Methotrexate, 6-Mercaptopurine)
Systemic features Treatment Fever Lung & brain lesions resected
2 round lesions in Anemia Rt occipital lobe
Brain imaging findings Hemorrhagic lesions mimicking cavernomas in Lt frontal, Rt occipital, Lt parietal region Well defined mass 2 solid enhancing lesion with irregular mass central lesions in Rt & calcification in Lt frontal lobes Lt lower lobe
Chest imaging findings Cystic lesion with central calcification in Lt lung
Brain lesions reduced in size, Lung lesion static at 2 year follow up
NA
Remarks Had metastasis in spinal cord. Died due to pulmonary complications
7 Coexsistence of Inflammatory Myofibroblastic Tumor in the Lung and Brain 67
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Differential Diagnosis The differential diagnosis is broad because of the contrast-enhancing and sometimes multifocal pattern of CNS involvement by inflammatory myofibroblastic tumor. It includes infections as well as neoplasms. Because of the similar appearance on brain imaging infective granulomas particularly tuberculomas are important differentials. This is particularly true in asian countries where tuberculomas are common causes of enhancing ring lesions in the brain. CNS tumors, like plasmacytoma and meningioma containing plasma cells and lymphocytic infiltration may mimic CNS inflammatory myofibroblastic tumor (Le Marc’hadour et al., 1995). Both these tumors occur in older individuals. The presence of Bence-Jones proteins in the urine and the M spike on serum electrophoresis confirms the diagnosis of plasmacytoma. Histopathologically, meningiomas may be differentiated from inflammatory myofibroblastic tumor by the presence of meningeal whorls and positive epithelial membrane antigen (EMA) staining in the former (Greiner et al., 2003). Rarely, Histiocytosis X and Wegener’s granulomatosis may cause central nervous system involvement mimicking inflammatory myofibroblastic tumor. Multifocal central nervous system inflammatory myofibroblastic tumor may also mimic metastasis or CNS lymphoma.
Treatment and Prognosis The biological potential of inflammatory myofibroblastic tumors is highly variable. Complete surgical resection, if possible, is the treatment of choice for most inflammatory myofibroblastic tumors. Radiation therapy has been tried in unresectable cases but it is associated with significant morbidity. Response to steroids is unpredictable, some patients have shown improvement while some have even shown tumor progression (Narla et al., 2003). The other treatment modalities include immunomodulation (Cyclosporin A) and combination chemotherapy. Chemotherapeutic agents like methotrxate, azathioprine, chlorambucil, cyclophosphamide, ifosfamide, vincristine and dactinomycin have been tried in these patients without much success (Karnak et al., 2001). Anti-inflammatory agents including non-steroidal
N. Sankhyan et al.
anti-inflammatory drugs and infliximab (anti-TNF alpha binding antibody) have also been tried with variable success (Su et al., 2000; Germanidis et al., 2005). Shah and McClain described a 14-year old girl with recurrence of intracranial inflammatory myofibroblastic tumor after radiotherapy and steroids. This patient was treated successfully with a combination of methotrexate and 6-mercaptopurine, given for 2 years (Shah and McClain, 2005). This therpay was also successful in the case reported by Sharma et al. (2009). Till further specific therapy emerges this possibly beneficial simple anti-metabolite regimen can be used in children with in-operable IMT affecting the brain (Shah and McClain, 2005).
Illustrative Case A 10-year-old boy was symptomatic since the age of five. He was first seen at age of seven with history of recurrent episodes of cough and breathlessness. These episodes were occasionally associated with fever and wheeze. He had received multiple courses of oral antibiotics, bronchodilators and steroids; on which he would show improvement for a few days. He had received antitubercular treatment without any symptomatic relief for 1 year prior to presentation. Examination revealed a thin built, afebrile child with mild pallor. Chest examination revealed tracheal shift to left, vesicular breath sounds with reduced intensity and dull percussion noted on left side. Chest X-ray revealed left opaque hemithorax with ipsilateral mediastinal shift. Pleural tap was dry. Contrast enhanced CT of the chest showed a large (6×6×7 cm) lobulated mass with large chunks of calcification closely abutting diaphragm, left heart border, and left hilum with narrowing of left lower lobe bronchus (Fig. 7.1). A few enlarged pretracheal and precarinal lymph nodes were also noted. The patient underwent left thoracotomy which revealed opaque appearance of left lung. Only the upper lobe and upper part of lower lobe were inflatable. A large calcified mass involving hilum of left lung, adherent to pulmonary artery, pericardium and left dome of diaphragm was noted. The mass was non-resectable and a wedge biopsy was taken. Biopsy showed fascicles of spindle cells with variable collagenized and myxoid regions and variable density of chronic inflammatory cells. There were abundant
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thin walled curvilinear blood vessels. Proliferation of fibroblastic and myofibroblastic cells with collagen production and interspersed infiltrate of lymphocytes and plasma cells was evident. The spindle cells were immunopositive for vimentin and smooth muscle actin
and were negative for CD 34 immunostain (Fig. 7.2). Findings were consistent with inflammatory myofibroblastic tumor. A trial of oral prednisolone was given for 2 months but the patient did not show any improvement. Parents refused the options of radiotherapy and chemotherapy. The child continued to be in follow up, receiving conservative treatment including antibiotics for chest infections and bronchodilators and inhaled steroids for wheeze. One year after diagnosis, he developed one episode of afebrile generalized tonic clonic seizure. There was no history of headache, vomiting, limb weakness, cranial nerve deficits, personality or behavior changes. CECT and MR scan showed two well-defined rounded enhancing lesion in right occipital region with minimal perifocal edema (Fig. 7.3). He was given antitubercular treatment for 1 year and phenytoin. He remained well for the next 1 year then he had an episode of breakthrough seizure. A follow up MRI of brain was obtained which revealed persistence of lesions (Fig. 7.4 A & B). CT abdomen and bone marrow aspirate did not show further systemic spread. The chest pathology and the nature of the brain imaging findings suggested a diagnosis of multifocal
Fig. 7.2 Low power photomicrographs showing fascicles of spindle cells with variable collagenized and myxoid regions and variable density of chronic inflammatory cells. Abundant thin walled curvilinear blood vessels are identified (a & b, H & E × 40). There is proliferation of fibroblastic and myofibroblastic
cells with collagen production and interspersed infiltrate of lymphocytes and plasma cells (c, H & E × 400). The spindle cells are immunopositive for vimentin (d, IHC; DAKO × 100) and smooth muscle actin (e, IHC; DAKO × 100) and are negative for CD 34 immunostain (f, IHC; DAKO × 40)
Fig. 7.1 CECT thorax – Axial section at mid-thorax level shows a mixed-density mass lesion with area of calcification in left hemithorax
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N. Sankhyan et al.
Fig. 7.3 CECT scan (a) show well-defined enhancing lesion in right occipital region with minimal perifocal edema. On MR scan, the lesion is cortical-subcortical in location, isointense on T1-weighted (b) and T2-weighted images (c) with mild perilesional edema and shows homogenous enhancement
following gadolinium administration (e, f). Another smaller T2-isointense lesion (d) with moderate perifocal edema is seen in right postcentral gyrus, which also shows homogenous enhancement (e)
inflammatory myofibroblastic tumor. The child was started on oral methotrexate and 6-mercaptopurine. At 2 years follow up, he was asymptomatic and tolerated the therapy well. A magnetic resonance imaging of brain obtained at the end of 2 years shows significant reduction in the size of the lesions (Fig. 7.4 C & D). Comment: Successful treatment of recurrent of intracranial IMT with a combination of methotrexate and 6-mercaptopurine has been reported in the past. This treatment was based on the premise that IMT’s form a histopathological spectrum with Rosai-Dorfman disease (inflammatory sinus histiocytosis with massive lymphadenopathy) (Govender and
Chetty, 1997). Horneff et al. (1996) recommended this regimen for Rosai-Dorfman disease. Our case emphasizes the possible beneficial therapeutic effect of this simple anti-metabolite regimen in children with inoperable IMT affecting the brain. Spontaneous reduction in size cannot be excluded, however, the fact the lesions persisted the same for 2 years before starting treatment makes this unlikely. [The definitive version of this case was published in J. Child Neurol.; 24(10): Oct/2009: 1302–1306. SAGE Publications Ltd. SAGE Publications, Inc. 2010, All rights reserved. ©] In conclusion, the co-occurrence of intracranial and pulmonary inflammatory fibroblastic tumors is
7 Coexsistence of Inflammatory Myofibroblastic Tumor in the Lung and Brain
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Fig. 7.4 T1 weighted post contrast axial MRI images of the brain at the time of initial presentation (a and b) shows focal enhancing lesions representing metastases in the right temporooccipital region (a) and in right frontal and paritel lobes (b).
Follow up T1 weighted post contrast MRI images at the same levels after 2 years of antimetabolite therapy (c and d) shows marked regression in the size and enhancement of the lesions with minimal residual lesions
a very rare phenomenon. It is unclear whether these lesions represent a metastasis or a multifocal, exaggerated inflammatory response to some unidentified etiological agent(s). Diagnosis is suggested by magnetic resonance imaging and confirmed by
histopathology. ALK expression needs to be studied in these patients to understand the tumor biology better. Treatment of choice remains surgery. When this is not feasible, simple anti-metabolite regimens may benefit.
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N. Sankhyan et al. Herman TE, Shackelford GD, Ternberg JL, Dehner LP (1994) Inflammatory myofibroblastic tumor of the spleen: report of a case in an adolescent. Pediatr Radiol 24:280–282 Horneff G, Jürgens H, Hort W, Karitzky D, Göbel U (1996) Sinus histiocytosis with massive lymphadenopathy (RosaiDorfman disease): response to methotrexate and mercaptopurine. Med Pediatr Oncol 27:187–192 Jeba J, John S, Backiyanathan S, Christopher DJ, Kurian S (2008) Inflammatory pseudotumour of the lung with sarcomatous brain metastasis. Eur J Cancer Care 17: 412–414 Karnak I, Senocak ME, Ciftci AO, Ca˘glar M, Bingöl-Kolo˘glu M, Tanyel FC, Büyükpamukçu N (2001) Inflammatory myofibroblastic tumor in children: diagnosis and treatment. J Pediatr Surg 36:908–912 Kim JH, Cho JH, Park MS, Chung JH, Lee JG, Kim YS, Kim SK, Shin DH, Choi BW, Choe KO, Chang J (2002) Pulmonary inflammatory pseudotumor – a report of 28 cases. Korean J Intern Med 17:252–258 Koirala R, Shakya VC, Agrawal CS, Khaniya S, Pandey SR, Adhikary S, Pathania OP (2010) Retroperitoneal inflammatory myofibroblastic tumor. Am J Surg 199:e17–e19 Kojima M, Suzuki M, Shimizu K, Masawa N (2009) Inflammatory pseudotumor of the thyroid gland showing prominent fibrohistiocytic proliferation. A case report. Endocr Pathol 20:186–190 Lawson SL, Azoumah DK, Lawson-Evi K, N’Timon B, Savi de Tove HM, Yehouessi-Vignikin B, Kpemissi E (2010) Inflammatory myofibroblastic tumour of nose and paranasal sinuses in a little girl of 7-year-old. Arch Pediatr 17:34–37 Le Marc’hadour F, Lavielle JP, Guilcher C, Brambilla E, Brichon PY, Lebas JF, Charachon R, Pasquier B (1995) Coexistence of plasma cell granulomas of lung and central nervous system. Pathol Res Pract 191:1038–1045 Makino K, Murukami M, Kitano Y, Ushio Y (1995) Primary intracranial plasma-cell granuloma. A case report and review of the literature. Surg Neurol 43:374–378 Malhotra V, Tatke M, Malik R, Gondal R, Beohar PC, Kumar S, Puri V (1991) An unusual case of Plasma cell granuloma involving lung and brain. Ind J Cancer 28:223–227 Matsubara O, Tan-Liu NS, Kenney RM, Mark EJ (1988) Inflammatory pseudotumors of the lung: progression from organizing pneumonia to fibrous histiocytoma or to plasma cell granuloma in 32 cases. Hum Pathol 19:807–814 Narla LD, Newman B, Spottswood SS, Narla S, Kolli R (2003) Inflammatory pseudotumor. Radiographics 3:719–729 Petridis AK, Hempelmann RG, Hugo HH, Eichmann T, Mehdorn HM (2004) Metastatic low-grade inflammatory myofibroblastic tumor in the central nervous system of a 29-year old male patient. Clin Neuropathol 23:158–166 Rabban JT, Zaloudek CJ, Shekitka KM, Tavassoli FA (2005) Inflammatory myofibroblastic tumor of the uterus: a clinicopathologic study of 6 cases emphasizing distinction from aggressive mesenchymal tumors. Surg Pathol 29:1348–1355 Sanders BM, West KW, Gingalewski C, Engum S, Davis M, Grosfeld JL (2001) Inflammatory pseudotumor of the alimentary tract: clinical and surgical experience. J Pediatr Surg 36:169–173 Scott L, Blair G, Taylor G, Dimmick J, Fraser G (1988) Inflammatory pseudotumors in children. J Pediatr Surg 23:755–758
7 Coexsistence of Inflammatory Myofibroblastic Tumor in the Lung and Brain Shah MD, McClain KL (2005) Intracranial plasma cell granuloma: case report and treatment of recurrence with methotrexate and 6-mercaptopurine. J Pediatr Hematol Oncol 27:599–603 Sharma S, Sankhyan N, Kalra V, Garg A, Gupta SD, Agarwala S, Das P (2009) Inflammatory myofibroblastic tumor involving lung and brain in a 10-year-old boy: a case report. J Child Neurol 24:1302–1306 Su LD, Atayde-Perez A, Sheldon S, Fletcher JA, Weiss SW (1998) Inflammatory myofibroblastic tumor: cytogenetic evidence supporting clonal origin. Mod Pathol 11:364–368 Su W, Ko A, O’Connell TX, Applebaum H (2000) Treatment of pseudotumors with nonsteroidal anti-inflammatory drugs. J Pediatr Surg 35:1635–1637 Sugiyama K, Nakajima Y (2008) Inflammatory myofibroblastic tumor in the mediastinum mimicking a malignant tumor. Diagn Interv Radiol 14:197–199 Swain RS, Tihan T, Horvai AE, Di Vizio D, Loda M, Burger PC, Scheithauer BW, Kim GE (2008) Inflammatory myofibroblastic tumor of the central nervous system and its relationship to inflammatory pseudotumor. Hum Pathol 39:410–419
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Tang L, Lai EC, Cong WM, Li AJ, Fu SY, Pan ZY, Zhou WP, Lau WY, Wu MC (2010) Inflammatory myofibroblastic tumor of the liver: a cohort study. World J Surg 34:309–313 Tang TT, Segura AD, Oechler HW, Harb JM, Adair SE, Gregg DC, Camitta BM, Franciosi RA (1990) Inflammatory myofibrohistiocytic proliferation simulating sarcoma in children. Cancer 65:1626–1634 Tavora F, Shilo K, Ozbudak IH, Przybocki JM, Wang G, Travis WD, Frank TJ (2007) Absence of human herpesvirus-8 in pulmonary inflammatory myofibroblastic tumor: immunohistochemical and molecular analysis of 20 cases. Mod Pathol 20:995–999 Tekkök IH, Ventureyra EC, Jimenez CL (2000) Intracranial plasma cell granuloma. Brain Tumor Pathol 17:97–103 Trojan A, Stallmach T, Kollias S, Pestalozzi BC (2001) Inflammatory myofibroblastic tumor with CNS involvement. Onkologie 24:368–372 Vadmal MS, Pellegrini AE (1999) Inflammatory myofibroblastic tumor of the skin. Am J Dermatopathol 21:449–453
Chapter 8
Breast Cancer and Renal Cell Cancer Metastases to the Brain Jonas M. Sheehan and Akshal S. Patel
Abstract Metastatic tumors from systemic cancers comprise the majority of brain tumors. These tumors most commonly originate from the lung and breast skin or kidney cancers. There are numerous similarities regarding the pathophysiology of these entities. Primary tumors spread to the central nervous system in a stepwise and highly concerted fashion. Tumor particles must breach the containment organ and subsequently travel via the blood stream to lodge within the brain. Trans-endothelial migration allows cells to penetrate the blood brain barrier. Tumor emboli must then survive and grow within the brain microenvironment with local nutrient supply and glial support. Breast and renal tumors utilize an array of similar molecular signals to accomplish these tasks: such as the Ras/MEK/MAPK and PI-3K/Akt pathways. This may explain why these primaries have a preponderance to metastasize to the brain. As antioncogenic therapies become more effective and patients with systemic cancers are afforded longer survival, cerebral invasion becomes more common and more important to overall management. Based on recent scientific data, emerging therapeutic targets for brain metastasis include vascular endothelial growth factor (VEGF), the epidermal growth factor receptor (EGFR) family, chemokines and mTOR. Keywords Tumor · Metastasis · BBB · Chemokines · VEGF · EGFR · mTOR
J.M. Sheehan () Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA e-mail:
[email protected] Introduction Brain metastases are common entities, comprising more than half of all brain tumors. (Ranasinghe and Sheehan, 2007). As systemic therapies improve, patients with cancer are living longer, and the number of cancer patients with metastatic tumors to brain is increasing. By the time of death, nearly 40% of all patients with cancer will have involvement of the central nervous system with metastases (Schouten et al., 2002). Metastases are either discovered on a staging evaluation of a patient with a known primary disease or less commonly during investigation of new neurologic deficits with occult tumor. The incidence of metastatic disease is not accurately known due to underreporting or inaccurate diagnoses. Epidemiological studies estimate the incidence of brain metastases up to 11 per 100,000 of the population (Sawaya, 2004). However autopsy data places the incidence even higher. The largest and most comprehensive study from the Memorial Sloan-Kettering Cancer Center found an intradural involvement rate of 20% (Gavrilovic and Posner, 2005). After age 60, the incidence appears to climb greater than 30 per 100,000 population (Sawaya, 2004). Though breast cancer has an obvious sex predilection in regards to primary tumor, renal cell cancer does not. Gender does not seem to affect independently the occurrence of cerebral metastases. The cumulative incidence of cerebral metastases from breast cancer at 1 and 5 years after initial diagnosis of primary is 1 and 5% respectively. For renal cell cancer at 1 and 5 years the cumulative incidence is 5.2 and 9.8%, respectively (Schouten et al., 2002). The cerebral hemispheres are involved in 80–85% of cases of metastases, and the cerebellum or
M.A. Hayat (ed.), Tumors of the Central Nervous System, Volume 3, DOI 10.1007/978-94-007-1399-4_8, © Springer Science+Business Media B.V. 2011
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posterior-fossa in 15% of the time. Metastases to the brain stem comprise only 1–5% of cases of all cancers. The location of metastatic disease in the brain seems to follow brain mass and blood distribution. However, renal cell cancer metastasized disproportionately to the posterior fossa. In more than half of the cases, multiple metastatic lesions are present on initial imaging. When single metastases are found, they are rarely “solitary,” i.e. the only detectable cancer in the body. There has been renewed focus on the treatment of brain metastases in recent years. Systemic therapies have increased patient longevity and thus increased the likelihood of late tumor occurrence and growth in the brain. Advances in neuroimaging have permitted more accurate surveys of the CNS so that smaller lesions earlier in their growth can be detected and addressed. Accounting for 10–15% of metastatic brain tumors, breast cancer is the second most common tumor likely to metastasize to brain, following lung cancer. Renal cell cancer is the fourth most common and comprises 7–10% of CNS metastases (Eichler and Plotkin, 2008). Why these entities possess an affinity for the central nervous system is a topic of intense investigation. Although simplistic, if one were to think of tumor cells as parasites, the brain provides a perfect nesting ground. The blood-brain-barrier (BBB) excludes most of our current systemic therapies and thus affords a “sanctuary” to treatment. Although not “tight” enough to exclude invasion of tumor cells, the BBB manages to successfully block entry of potential therapeutic agents into the CNS. There have been many allegories to falsely suggest that invasion of brain tissue occurs via penetration of the blood brain barrier by tumor cells. Recently the paradigm has shifted and it appears that the CNS may preferentially sustain tumor cells within this sanctuary. We will discuss the pathobiology of breast cancer and renal cell cancer in this regard.
Presenting Signs and Symptoms Cerebral metastases present with either focal or diffuse signs. Cancer staging, with neuroimaging workup, will detect asymptomatic lesions in up to 50% of patients with locally metastatic disease. The two major determinants of clinical presentation are size and anatomic location of the tumor. It is often telling whether there is torpid progression or rapid neurologic decline.
J.M. Sheehan and A.S. Patel
Although many brain tumors may hemorrhage, renal cell metastases have a greater tendency to hemorrhage and rapidly compress and affect the surrounding parenchyma. The hemorrhage event often produces sharp neurologic deterioration or a severe sudden headache. Of the common general complaints, headache and focal neurological deficit (such as weakness) are the foremost, each being present in 50% of patients. Seizures are the initial presenting event in 15% of patients. More subtly, metastases may present with cognitive or behavioral changes. Localizing symptoms such as hemiparesis, aphasias and visual disturbances will initially broaden a clinician’s differential to include stroke. If we combine three studies on this topic and collect information from over one thousand patients: 31% presented with headaches, 24% with weakness, 19% with seizures, 5% with visual changes and 9% were asymptomatic (Nussbaum et al., 1996; Zimm et al., 1981). Stephen Paget (1855–1926), an English surgeon, presented a paper analyzing 735 autopsy cases of breast cancer, with the addition of additional cases from the literature, and argued that the distribution of metastases was not due to chance, but rather suggested “the best work in pathology of cancer is done by those who. . . are studying the nature of the seed. . .” (micrometastases), and the “observations of the properties of the soilmay also be useful”. Thus the “seed-soil” paradigm of metastases was born. In apparent contrast to this came a slightly later theory proposed by James Ewing (1846–1943). This American pathologist believed that cancer cells migrated across the body based on the fluid mechanics of blood circulation. Breast cancer, for example, can burst into the arterial circulation and be filtered by the lung were it can flourish before making an onward journey to other organs. Renal cell cancer, on the other hand, can slip into Batson’s venous plexus and make its way directly to the brain. A persistently patent foramen ovale between the right and left atrium of the heart would change the dynamics of spread.
Imaging This century has seen tremendous progress in imaging technology. From an inauspicious beginning in skull
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Breast Cancer and Renal Cell Cancer Metastases to the Brain
plain X-ray films and pneumoencephalograms, modern neuroimaging modalities such as Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), and MR Spectroscopyhave become useful adjuncts the clinical history and neurologic exam. The subtle and insipid growths of micro-metastases are impossible to detect with physical assessment alone. Current state-of-the-art magnetic resonance technology, along with its sub-modalities (such as spectroscopy, perfusion, and diffusion techniques), is the neuroimaging modality of choice for metastatic CNS disease. The classic imaging findings for cerebral metastases include: a well-circumscribed round lesion in the region of the gray-white junction and significant vasogenic edema (Fig. 8.1). If lesions are multiple this may also hint at metastatic disease versus a primary neoplasm. Renal cell cancer metastases are highly cellular and will tend to bleed, or in other words present as hemorrhagic metastases. In differentiating metastases versus primary neoplasms of the brain, imaging of the peritumoral tissue provides the most useful diagnostic information. Magnetic resonance spectroscopy (MR SPECT) patterns for metastatic lesions usually display elevated signals for lipid (products of brain destruction), choline (cell membrane marker) and lactate (product of anaerobic glycolysis), with a decreased N-aceyl-aspartate or NAA (neuronal marker) peak. Primary brain tumors are more likely to infiltrate surrounding brain compared to metastatic lesions. Voxel calculations of the peritumoral region can thus aid in differentiating primary glioma versus metastases (Law et al., 2002). More recently, radiologists have begun to examine the relative cerebral blood volume of the edema that surrounds tumor and use this calculated property to again differentiate between high-grade glioma and metastatic disease (Hakyemez et al., 2010).
General Tumor Biology The etymology of metastases derives from the Greek word for displacement. There are two theories, as mentioned above, that explain how this displacement or spillage of tumor particles results in cerebral involvement. Both breast and renal cell cancer utilize similar
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Fig. 8.1 Gadolinium enhanced T1 weighted MRI axial images. Above: Metastatic Breast Carcinoma. Bottom: Metastatic Renal Carcinoma
mechanisms to leave the primary site, spread and settle within the brain in a metachronous fashion. Metastatic emboli often wedge near the temporoparieto-occiptal junction, in the distribution of the middle cerebral artery. This distribution correlates with blood flow and mirrors the location of other embolic events in the CNS such as ischemic strokes. They rarely involve the cortical surface but rather embed at the junction where arterioles transition into capillaries.
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This wedging concept is rather simplistic given that we now know that there is a complex interaction between cancer cells and the endothelium. Trans-endothelial migration of tumor particles involves cell adhesion molecules (CAMs) such as integrin and destructive cytokines. Regulators of the cell cytoskeleton such as Rho GTPases facilitate integrin based trans-endothelial migration of cancer cells. Therapies that inhibit this extravasation process may slow the development of metastases (Miles et al., 2008).
Blood Brain Barrier Physiology The blood brain barrier (BBB) is perhaps the most complex biologic interface in nature. It invests 99% of the CNS and acts like a gatekeeper to ensure highly specific flow in and out of the CNS cellular environment. The “Rule of Five” highlights favorable characteristics for permeability through the BBB: a molecular weight =240 keV) placed in contact. As a consequence, the overall sensitivity of beta detection probes is roughly one order of magnitude higher than that of gamma detection probes. The sensitivity of commercially available gamma counting
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probes ranges from 1 to 40 cps/MBq in contact of a point source (122 keV) depending on the geometry of the collimation (Mariani et al., 2008). For a beta probe, the sensitivity is usually higher than 200 cps/MBq for a contact 18 F source. These probes can therefore be used to detect few milligram quantities of tumor when they are placed on the lesion. However, the short range of beta particles in soft tissue also constrains the detector to operate within less than 1 mm of the tumor. This shallow detection makes a beta probe of no value for the localization of deep-seated tumors. Otherwise, this method is particularly suited to radioguided protocols, such as brain tumor surgery, where the main issue is to detect the presence of residual lesion in the resection bed of the gross tumor mass. The first intraoperative beta probe was used in 1949 by Selverstone et al. to localize brain tumors labeled with 32 P. The detector was a miniature Geiger Müller tube. This kind of gas-filled detector is no more used today and the beta probes currently available or under development are based on, schematically, two detection designs. The first one consists of plastic scintillators directly coupled or by means of a fiber light guide to a photosensor, such as a photomultiplier tube, an avalanche photodiode or a CCD, in order to be detected and counted (Daghighian et al., 1994; Tipnis et al., 2004; Yamamoto et al., 2005). The second design is based on direct interaction of charged particles within semiconductor material, such as silicon photodiodes (Raylman, 2000; Lauria et al., 2007). To ensure the detection of positrons in the operative wound, most of imaging or non-imaging beta probes utilizing scintillator detectors or solid-state devices are able to reject the background 511 keV gamma rays. In fact, despite the low intrinsic sensitivity of beta probes to gamma photons, the high flux of 511 keV photons coming from physiological radiotracer accumulation areas can still produce a significant noise. This noise may reduce the in vivo tumor–to-normal tissue ratio relative to the true radiotracer uptake and strongly hampers the intraoperative detection of small tumor lesions (Piert et al., 2007). Various background rejection set-ups can be implemented to eliminate the gamma photon contamination. Some groups proposed phoswich detector configurations for coincidence detection of positron and one of the two associated annihilation gamma rays (Yamamoto et al., 2005; Tornai et al., 1998). To minimize the reduction in sensitivity due to the coincidence rejection scheme, these positron probes 57 Co
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use bulky high-Z scintillators such as BGO or GSO to detect the 511 keV gamma photons. Other beta probes use real-time subtraction methods between two detectors (Raylman, 2000; Daghighian et al., 1994; Bogalhas et al., 2008). The first one predominantly detects positrons and the second one is made sensitive only to gamma rays by using a beta shielding. By subtracting count rates measured by the second detector from that counted with the first detector, one obtains an estimate of the pure beta signal. When coupled to a background rejection system, positrons probes enable the detection of small lesions even in a noisy environment (Raylman, 2000; Bogalhas et al., 2008). Background compensated probes can also be used as dual probes detecting both beta-emitting and gammaemitting radiotracers simultaneously (e.g. 18 F-FDG and 99m T-Tc) (Raylman, 2001; Tipnis et al., 2004). In that context, Bogalhas et al. (2008, 2009) have developed an intraoperative positron imaging probe specifically dedicated to the real-time localization of residual brain tumors after the bulk has been excised. The probe was designed to be directly coupled to the excision tool leading to simultaneous detection and removal of radiolabeled tumors. This association should help to overcome localization errors due to brain shift or to bad correlations between the intraoperative mapping of radiotracer distribution and the true and precise position of the tumor in the operative wound, especially when no anatomical reference marker is available. The probe, built around clear and plastic scintillating fibers, was also designed to detect positrons emitted from radiolabeled brain tissue and laser induced fluorescence simultaneously. This association should allow one to discriminate more specifically neoplastic from normal tissues due to the complementarity of the biological information coming from radiolabeled radioactive tracers and endogenous fluorophores. A first prototype of the positron probe has been built and evaluated (Bogalhas et al., 2009) (Fig. 24.1). It consists of a detection head composed of detection elements held around the excision tool in a closed packed annular arrangement. Each detection element was composed of a thin piece of scintillating fiber of 1.5 mm diameter thermally fused to a 10 cm long clear fiber. The detection head is coupled to a fiber light guide that exports the scintillating light to an external detection and processing module based on a multi-channel photomultiplier tube. The data are visualized as a two-dimensional image showing the count
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Fig. 24.1 An intraoperative positron imaging probe specifically dedicated to radioguided resection of brain tumors (Bogalhas et al., 2009)
rate on each detection fiber placed around the surgical tool. The tip of the probe has outer diameters ranging from 8.6 to 12.7 mm, depending on the geometry of the exchangeable detection heads. The gamma ray background is eliminated by a real-time subtraction method. More precisely, the amount of gamma contamination is measured by several detection elements shielded to beta particles by a 400-μm thick sheet of stainless steel. The detector exhibits a beta sensitivity of 217 cps/kBq (3.4 cps/kBq/ml) and 70 cps/Mbq (1.1 cps/kBq/ml) for the large and small head configurations, respectively. The gamma ray rejection efficiency measured by realistic brain phantom modeling of the surgical cavity and the boundaries of the tumor was 99.4%. This good rejection ability allows the true tumor-to-normal tissue uptake ratio to be recovered during phantom measurements (Bogalhas et al., 2009). Phantom studies also demonstrated that tumor tissue blocks as small as 5 mm in diameter and 1 mm thick (20 mg) can confidently be detected, with spatial accuracy better than 2 mm, for tumor-to-normal tissue uptake ratios of fluorinated tracers greater than 3:1. This ratio is achieved with radiopharmaceuticals like 18 F-Fluoroethyl-L-Tyrosine or 18 F-choline. The minimal amount of detectable tumor tissue measured with this positron probe can favorably be compared to the detection threshold of PET systems. For example, the minimal diameter of tumor tissue that can be detected during whole-body 18 F-FDG scans of torso lesions is about 8 mm (equivalent to 300 mg) for radiotracer uptake ratio greater than 10:1 (Piert et al., 2007; Raylman et al., 1999).
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Radioguided Surgery of Brain Tumors Clinical Experiences with Gamma Probes The clinical concept of intraoperative detection of brain tumor with a gamma counting probe was first introduced by the neurosurgeon William Sweet in 1951 (Sweet, 1951). 50 years later, in 2002, Vileha Filho and Carneiro Filho described the first radio-guided microsurgical resection of a metastatic renal cell carcinoma to the right parietal lobe with a gamma probe. Five hours before the operation, a dose of 30 mCi of 99m Tc-MIBI was intravenously injected to the patient. Accumulation of the radiotracer in the brain tumor was controlled by a preoperative SPECT. At surgery, the gamma probe based on a CdTe crystal (Europrobe, Eurorad) was used to measure radioactive counts from the expected tumor site, as identified on the preoperative MIBI SPECT, and from the adjacent normal tissue. A signal-to-background activity ratio equal or greater than 2:1 was set as a reliable indicator of the pathological nature of the target tissue, as commonly used in radioguided protocols (Gulec et al., 2006). The subcortical area with the highest counting rate corresponding to the highest MIBI uptake was chosen as the best place to perform corticotomy, respecting eloquent areas. Once gross total tumor resection was done, the completeness of removal was controlled by using again the gamma probe to scan the bed of resection in order to ascertain that no radiolabeled residual tissue was left behind. At that time, a 3 mm diameter piece of tumor with tumor-to-normal tissue ratio of 5:1 was detected and removed. This residual tumor was not visually identified during the first survey. A post-operative CT confirmed complete tumor resection and a follow-up of 3 months showed no evidence of tumor recurrence. This single-case study indicates the feasibility of radio-guided brain tumorectomy that may facilitate localization of superficial tumors before the excision to restrict the size of the craniotomy, but above all, to assure completeness of its removal in real time. Following a similar protocol, Bhanot et al. (2007) reported on the use of 99m Tc-MIBI in a dose of 10 mCi, for gamma-probe assisted resection in 13 patients with high-grade supratentorial gliomas. The radiotracer was administered 2 h before surgery. In accordance to Vileha Filho and Carneiro Filho (2002),
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the intraoperative probe (Euro 4 probe, Euro Medical Instruments) was used to guide the location of craniotomy by picking up radioactivity through the scalp, to visually identify indistinct tumor from normal tissue near or in eloquent areas during the excision and to provide assessment of completeness of tumor resection. In 9 patients, the post-operative CT/MRI showed no enhancing area and in 4 patients, only small residual enhancing areas. These cases were associated to doubtful positive readings from the probe inside the cavity (signal-to-background activity ratio less than 2:1). The authors concluded that the radio-guided resection of brain tumor with a gamma counting probe is an inexpensive and easy to use technique that provides realtime intraoperative information about the tissue that is being excised and thus, a reliable proof to confirm the presence or absence of residual tumors. They also emphasized several limits of the method. First of all, the retention of MIBI in gliomas is dependant on the damage of the blood-brain barrier and thus, has no value for the localization of low-grade lesions where new methodologies to monitor the resection margins might be particularly helpful. The intraoperative detection of radiolabed tissue was also hampered by the radioactivity in the blood that contaminates the probe readings in the vicinity of large veins, venous sinuses or pools of blood in the surgical cavity. Finally, the large size of the gamma counting probe restricted the probe manipulation in the resection bed and prevented to perform a detailed search for tumor remnants (oversampled exploration). In 2008, Serrano et al. reported on the use of a different radiotracer, 201 Tl, for radioguided resection of high-grade astrocytomas in 6 patients (Serrano et al. 2008). In all cases, residual activity uptake was found with a scintillating gamma probe (Scintiprobe MR100, Pol.Hi.tech) in the surgical bed after visual resection. These areas were confirmed as pathological by examination of biopsy samples. In 3 cases, the suspicious tissue was removed and the final activity was similar to the activity found in the normal brain. In the other 3 patients, the removal of all the residual activity was impossible due to eloquent structures involved. Despite these encouraging results that showed the feasibility of radioguided surgery of highgrade astrocytomas with 201 Tl, authors also underline the limitation of this radiotracer compared to 99m TcMIBI, in terms of detectability, signal-to-background ratio and availability. Because the high background activity in the normal brain can make difficult to
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discriminate residual tumors from surrounding normal tissue with the gamma probe, they concluded that this technique requires a good expertise of the medical staff in both radioguided surgery and neuroimaging. To improve the accuracy of the intraoperative detection of radiolabeled brain tissue, Kojima et al. (2004) reported on the use of a mobile gamma camera during radioguided surgery of brain tumors, as a complementary tool to a conventional gamma counting probe. Thirteen patients with primary or recurrent high-grade astrocytomas or metastatic brain lesions received an intravenous dose of 99m Tc-MIBI just before surgery. During the operation, the tumor was localized with a semiconductor counting probe (Navigator, United State Surgical Corporation) and the mobile gamma camera (2020tc imager, Digirad). The camera was placed in close proximity with the brain surface to acquire scintigraphic images for 5 min. The probe was also coupled to an optical stereotactic navigation system in order to provide real-time indication on its location relative to the target tumor and other eloquent brain structures based on preoperative MRI scan. The probe and the gamma camera correctly identified tumors in all patients, according both to the preoperative MRI and 99m Tc-MIBI SPECT. The tumors ranged in size from 12 to 70 mm. The tumor-to-background activity ratio measured with the mobile gamma camera showed a significant correlation with values found in the pre-operative 99m Tc-MIBI-SPECT images (mean value of 6.9:1). After tumor resection was considered to be finished, residual tumors were seeked with the mobile gamma camera. In 9 out of 13 patients, scintigraphy images showed no accumulation of radioactivity in the tumor sites. The absence of residual tumors was confirmed by histologic results of tissue samples taken around the resection bed. Residual tumor tissue was found in 4 patients with high-grade primary gliomas (astrocytoma and glioblastoma). This study indicates the potential impact of intraoperative scintigraphy imaging for monitoring in real time the extent of brain tumor resection. Compared to open intraoperative MRI or ultrasound, scintigraphy images are not affected by artifacts due to postoperative bleeding that can hamper the detection of residual tumor during surgery. The technique can also be easily implemented in any operating room and only slightly prolongs the operation duration (less than 10 min for the whole imaging procedure). Authors also underline the difficulty to discriminate target signal from background
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activity with the counting probe when the tumor uptake is low and located close to physiological area of MIBI accumulation in the scalp, choroid plexus or base of the skull. As expected, the better spatial selectivity of the mobile gamma camera allows one to overcome this limitation. If most clinical experiences with gamma-probe assisted resection was focused on high grade gliomas, Gay et al. (2005) also investigated the use of a handheld gamma probe to guide the resection of bone invasive or “en plaque” meningiomas labeled with 111 In(DTPA)-octreotide. Ten patients with sphenoid wing meningiomas without any cavernous sinus involvement and meningiomas with invasion of the skull convexity or into the mastoid process were enrolled. A dose of 3 mCi of 111 In-(DTPA)-octreotide was injected the day before surgery and its good accumulation in the tumor was controlled with a pre-operative scintigraphy. During the surgery, the scintillating-based gamma probe (Tec probe 2000, Stratec electronic) was used to compare the counting rates of the invaded bone and of adjacent normal skull in order to help define the tumor margins. In all patients, intraoperative detection was able to identify radiolabeled tumor invasion on bone, dura matter and periorbital involvement of sphenoid wing meningiomas. The high affinity of octreotide for somatostatin receptors of meningiomas provided high in vivo tumor-to-background ratio ranging from 2:1 to 12:1 with a mean value of 4.4:1. In 6 patients, the high level of radiotracer uptake measured with the probe demonstrated good correlation with the margins of the invaded bone defined with a computer-aided navigation system using CT images. This led to assist the delineation of bone and dural resection. The post-operative control of the counting rates of the bony margins with the gamma probe was used again to assess the accuracy of the resection. The absence of residual radioactivity confirmed the complete removal of meningiomas of the skull convexity, but was more difficult to implement for sphenoid wing tumors due to the size of the probe and the background contamination from the pituitary gland that also binds the 111 In-(DTPA)-octreotide. Post-operative somatostatin receptor scintigraphies performed during the follow-up period showed no sign of recurrence in all patients. This study demonstrates the feasibility of intraoperative detection of somatostatin receptors in meningiomas. The high specificity of radiolabeled somatostatin analogues offers the benefit of high
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tumor-to-background ratio, which is a critical issue for radioguided resection of tumors, and low radiation exposure to patient. The method was more efficient for bone invasive meningiomas of the skull convexity and may increase the probability of complete resection of these tumors that are difficult to control surgically. In 2009, Dammers et al. (2009) conducted successfully a similar study on a patient with a left sphenoid wing meningioma labeled with 111 In-(DTPA)-D-Phe1 pentetreotide.
Clinical Experiences with Beta Probes Although Vilela Filho and Carneiro Filho (2002) reported the first radioguided surgery of brain tumor using a gamma probe in 2002, many attempts have been performed in the 1950s with 32 P-labeled sodium phosphate. Selverstone et al. (1949) first used this radioactive phosphorus to define the localization and demarcation of brain tumors during surgery. The radiotracer was intravenously injected 1 day before the surgery, as a buffered phosphate solution of 0.5–2 mCi, to 33 patients with various types of cerebral tumors (meningiomas, astrocytomas, glioblastomas. . .). During the operation, a miniature Geiger-Müller counter in the end of a needle probe with external diameter of 2 mm was sunk into the brain and counting rates were obtained at several areas and depths beneath the cerebral cortex. The position and extend of tumors were estimated from the regions showing an increased counting rate when the probe is inserted into or very close to the lesion. Tumors were localized in 29 of 33 cases. In 23 patients, the tumor was subcortical. In 12 patients, the operative mapping with the probing counter was used to estimate the gross delineation of the tumor boundary margins in order to facilitate its complete resection. Three falsenegative detections were reported. Two of them were reported obtained when the Geiger-Müller counter could not be placed close enough to the tumor to detect it. Finally, one additional case gave a false-positive response, which was attributed to a diffuse gliomatosis. Morley and Jefferson (1952) demonstrated similar results in 32 cases of brain tumor following the protocol laid down by Selverstone et al. (1949). Both studies underline the potential value of the intraoperative detection of brain tumors labeled with 32 P for two
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main purposes: to map the gross extend of tumors in order to plan the excision into the brain (accessibility of the tumor and potential extensions in eloquent areas) and to pin-point the tumor location in order to obtain a valid biopsy specimen from the active portion of a tumor along a cannula introduced through a solitary burr hole. However, these studies also highlight the intrinsic limitations of 32 P as a tumor-seeking radiotracer. First, the unspecific accumulation of 32 P in tissue with increased metabolic activity, such as cerebral inflammatory lesion, can cause false-positive detections. Second, its short beta range in white or grey matters can also strongly prevent the detection of small deeply situated tumors. This requires that their locations are known by other tools before the beta probe is used. In the 1950s, ventriculography and angiography were the main techniques for imaging the central nervous system. Nowadays anatomical or functional MRI and stereotactic navigation systems enable the accurate localization of tumors relative to eloquent brain structures. Therefore, the main current application of radioguided brain tumorectomy is no longer to locate the lesion prior to the excision, but to detect the presence of residual tumor tissue in the resection bed of the gross tumor mass identified on preoperative scans. In that context, the shallow detection achieved with betaemitting radionuclides is not a limitation, but rather an advantage. However, the assessment of surgical resection margins requires a degree of sensitivity far beyond that of the Geiger-Müller counter employed in these studies could provide. More recently, Reinhardt (1989) reported the use of a more suitable beta probe based on a solid-state technology and demonstrated its benefit for intraoperative detection of radiolabeled brain tumors after 32 P infusion (1.5 mCi). A reliable discrimination between tumor and normal tissue was achieved, especially in the border area of meningiomas, where high accumulation of 32 P was found within the matrix zone. The intraoperative detection of tumor remnants was also possible in brain metastases and high-grade gliomas. In accordance to Morley and Jefferson (1952), the contrast between tumors and normal brain tissue was only insufficient for low-grade gliomas. The recent emergence of promising specific tumorseeking agents labeled with positron emitters for glioma delineation is giving rise to a renewed interest for radioguided brain surgery using beta probes. In that context, Leston et al. (2009) investigated the feasibility
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of using their positron-sensitive intraoperative imaging probe to guide detection and excision of brain tumors in a primate model (Bogalhas et al., 2009). The main purposes were to test the ability of the probe to localize radiolabeled tissue in vivo and to evaluate the direct coupling between the probe and the excision tool to detect and remove the target tissue at once. Because no model of gliomas is currently available in primate, they chose to mimic a brain tumor surgery by using the accumulation of 18 F-FDOPA in the striatum and the globus pallidus of a rhesus monkey’s brain and by implementing the beta probe to accurately remove the left part of this cerebral structure. A dose of 3 mCi of 18 F-FDOPA was injected after the craniotomy and 40 min before the excision. The beta probe was coupled to an ultrasonic aspirator (Dissectron, Integra) and used to map the radioactivity distribution in the brain (Fig. 24.2). A first counting rate was obtained from the cerebellum to determine the threshold signal. Once the left lobe of the striatum has been exposed, all cerebral tissue showing a signal-to-background activity ratio equal or greater than 1.5:1 was removed. After gross total removal was thought to be complete, the bed of resection was probed again in order to seek any residual tissue. The accuracy of the resection was controlled by post-mortem histological examination of the brain. All targeted cerebral structures labeled with 18 F-FDOPA were correctly removed, including putamen and globus pallidus, without significant damage to the surrounding tissues. The caudate nucleus was left behind due to its bad accessibility. Small residual
Fig. 24.2 Evaluation on a primate model of the association between the intraoperative positron probe developed by Bogalhas et al. (2009) and an ultrasonic aspirator (Leston et al., 2009)
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regions in the putamen were attributed to the difficulty to move the probe inside the small surgical cavity. This preliminary study indicates that the ability to map the distribution of residual radiolabeled lesions in the close vicinity of the excision tool should facilitate and improve brain tumor removal when associated with a specific tumor-seeking agent labeled with positron emitters.
Radiation Exposure During Radioguided Brain Surgery An important issue when studying the clinical potential of radioguided surgery for brain tumor relative to nonradioisotopic monitoring techniques is the additional radiation exposure to the surgical team. The annual occupational exposure limits for radiation workers set by the International Commission on Radiological Protection (ICRP) is a total effective dose equivalent to 20 mSv per year for the whole body (100 mSv averaged over a 5-year period) and 500 mSv per year for the hands. Due to the small number of clinical experiences, data on radiation exposure from radiotracers used during radioguided brain surgery surgical is currently very limited. Kojima et al. (2004) evaluated the whole body dose to surgical personnel during radioguided brain tumorectomy using 99m TcMIBI. The radiotracer was administered on the day of surgery. The radiation dose to the hands was not reported. The mean exposure time was 6.1 h. The mean whole body dose per operation was 27.9 μSv for the surgeon, 25.8 μSv for the nurse and 14.9 μSv for the anesthetist. Bhanot et al. (2007) reported a similar value (22.9 μSv), 2 h after injection of 99m Tc-MIBI, in a dose of 10 mCi. These values are quite below the allowable limit. However, the radiation exposition to the operating team is strongly dependant on the features of the radiopharmaceutical agent (gamma or beta emitters, biological distribution in the human body, physical half-life of the radionuclide) and higher absorbed doses of radiation are expected with beta-emitting radiopharmaceuticals. Bogalhas et al. (2009) investigated the radiation exposure to the surgeon’s hand during brain phantom experiments with their positron-sensitive intraoperative probe. Lithium fluoride thermoluminescent dosimeters were placed around the probe. The radiation dose to the surgeon’s
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hand was assumed to be mainly due to the radiotracer accumulation in the brain. The measurements were scaled to extrapolate the radiation dose received by the hands of the surgeon due to the accumulation of 18 F-FDG, 18 F-FET or 18 F-Choline in tumor and normal brain tissue, 1 h after injection of a typical injected dose of 300 MBq. The dose rate to the surgeon’s hand was significant (300, 60 and 12 μSv per hour for 18 F-FDG, 18 F-FET and 18 F-Choline, respectively), but well within the exposure limits. Moreover, several recent studies have also demonstrated that the mean body dose received by the surgical staff involved in radio-guided cancer surgery using 18 F-FDG and high-energy gamma probes was small compared to the ICRP recommendations (range 20–80 μSv per hour) (Povoski et al., 2009). As a conclusion, although additional comprehensive evaluations of occupational radiation exposure to intraoperative and perioperative personnel are required, the absorbed radiation dose appears to present no serious limitation to the development and the repetition of radioguided brain tumor surgical procedures.
Discussion Radical removal of brain tumors, such as gliomas and meningiomas, remains the best mean of providing increased survival, lesser morbidity and better quality of life. Intraoperative surgical techniques have been developed to improve the completeness of local tumor removal while sparing normal tissue. At this time, neurosurgical navigation systems and intraoperative MRI or ultrasound are the standard of care to guide the neurosurgeon in the operative room. However, there is a need for novel intraoperative tools that could provide a more specific discrimination between tumor and normal brain tissue during operations in order to facilitate tumor detection and its complete removal, especially for invasive lesions. Some feasibility studies demonstrated that radioguided resection using gamma or beta-sensitive probes is a safe, easy to use and reliable technique to enhance the ability of the surgeon to delineate more accurately the brain tumor extend and to confirm in real time the presence or absence of residual tumor in the surgical resection margins. Despite these preliminary encouraging results that must be completed on large cohorts of patients, several
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issues have to be addressed in order to increase the impact of radioguided surgery on the surgical management of brain tumors. First of all, future efforts should aim to increase the specificity of brain tumor markers. New positron-emitting radiopharmaceuticals, preliminary developed for PET, such as 18 F-Choline or 18 FFluorothymidine, or radiolabeled analogues of tumor specific receptors have the potential to fulfill this goal and to extend the application field of radioguided brain cancer surgery beyond meningiomas and high-grade gliomas. From a technological point of view, the detection of brain tumor remnants in the resection margin of the gross tumor mass requires dedicated miniaturized probes with high sensitivity and background noise rejection capabilities. In that context, miniaturized beta imaging probes are very attractive to map the distribution of small and weak radioactive sources and to spatially resolve target signal from background noise (Bogalhas et al., 2009; Lauria et al., 2007; Tipnis et al., 2004; Tornai et al., 1998). Background compensated imaging probes used as dual probes detecting both positrons arising from the decay of positron-emitting radiotracers and the associated 511 keV annihilation γ-rays simultaneously seem also very promising to further improve the detection accuracy (Raylman, 2001; Tipnis et al., 2004; Tornai et al., 1998). The gamma signal could be used to rapidly identify residual uptake within the boundaries of the tumor, even for deepseated lesions, and the beta signal to evaluate surgical margins of these tumor remnants. Another important issue to improve the accuracy of brain tissue removal is to combine the various surgical and monitoring devices used during brain tumorectomy. This may include the direct coupling between the intraoperative probe and the excision tool (Bogalhas et al., 2009) and the convergence of the information provided by radiation-sensitive probes, neuronavigation systems and intraoperative MRI, when available (Yamamoto et al., 2004). For example, the complete exploration of the tumor boundaries could be facilitated by coupling the probe to a frameless stereotaxic neuronavigation system to track its intraoperative location and thereby reconstruct the three-dimensional activity distribution in the cavity (Wendler et al., 2006). This could provide a reliable verification of the completeness of resection in real time. Bogalhas et al. (2008) also proposed an intraoperative bimodal probe, which will combine simultaneous localization of radiolabeled tissues with measurement of laser-induced fluorescence
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so as to discriminate neoplastic from normal tissues more specifically (Siebert et al., 2008).
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249 Mariani G, Giuliano AE, Strauss HW (2008) Radioguided surgery: a comprehensive team approach. Springer Science, New York, NY. ISBN: 978–0–387–33684–8 Morley TP, Jefferson G (1952) Use of radioactive phosphorus in mapping brain tumours at operation. Br Med J 2:575–578 Piert M, Burian M, Meisetschlager G, Stein HJ, Ziegler S, Nahrig J, Picchio M, Buck A, Siewert JR, Schwaiger M (2007) Positron detection for the intraoperative localisation of cancer deposits. Eur J Nucl Med Mol Imaging 34(10):1534–1544 Pitre S, Menard L, Ricard M, Solal M, Garbay JR, Charon Y (2003) A hand-held imaging probe for radio-guided surgery: physical performance and preliminary clinical experience. Eur J Nucl Med Mol Imaging 30(3):339–343 Pogue BW, Gibbs-Strauss S, Valdés PA, Samkoe K, Roberts DW, Paulsen KD (2010) Review of Neurosurgical Fluorescence Imaging Methodologies. IEEE J Sel Top Quantum Electron 16(3):493–505 Povoski SP, Neff RL, Mojzisik CM, O’Malley DM, Hinkle GH, Hall NC, Murrey DA Jr, Knopp MV, Martin EW Jr (2009) A comprehensive overview of radioguided surgery using gamma detection probe technology. World J Surg Oncol 7:11 Raylman RR (2000) A solid-state intraoperative beta probe system. IEEE Trans Nucl Sci 47(4):1696–1703 Raylman RR (2001) Performance of a dual solid state intraoperative probe system with 18 F, 99m Tc, and 111 In. J Nucl Med 42:352–360 Raylman RR, Kison PV, Wahl RL (1999) Capabilities of twoand three-dimensional FDG-PET for detecting small lesions and lymph nodes in the upper torso: a dynamic phantom study. Eur J Nucl Med 26(1):39–45 Reinhardt H (1989) Surgery of brain neoplasm using 32-P tumour marker. Acta Neurochir 97:89–94 Sanai N, Berger MS (2008) Glioma extent of resection and its impact on patient outcome. Neurosurgery 62(4):753–764. discussion 264–266 Schneider JP, Trantakis C, Rubach M, Schulz T, Dietrich J, Winkler D, Renner C, Schober R, Geiger K, Brosteanu O, Zimmer C, Kahn T (2005) Intraoperative MRI to guide the resection of primary supratentorial glioblastoma multiforme – a quantitative radiological analysis. Neuroradiology 47(7):489–500 Scopinaro F, Tofani A, di Santo G, Di Pietro B, Lombardi A, Lo Russo M, Soluri A, Massari R, Trotta C, Amanti C (2008) High-resolution, hand-held camera for sentinel-node detection. Cancer Biother Radiopharm 23(1):43–52 Selverstone B, Sweet WH, Robinson CV (1949) The clinical use of radioactive phosphorus in the surgery of brain tumors. Ann Surg 130(4):643–651 Serrano J, Rayo JI, Infante JR, Dominguez L, Garcia-Bernardo L, Duran C, Fernandez Portales I, Cabezudo JM (2008) Radioguided surgery in brain tumors with thallium-201. Clin Nucl Med 33(12):838–840 Siebert R, Vu Thi MH, Jean F, Charon Y, Collado-Hilly M, Duval MA, Mandat T, Menard L, Palfi S, Tordjmann T (2008) Development of a new autofluorescence probe for the analysis of normal and tumour brain tissues. Proc SPIE 2008 6991:699122 Sweet WH (1951) The uses of nuclear disintegration in the diagnosis and treatment of brain tumors. N Engl J Med 245(875):887
250 Tipnis SV, Nagarkar VV, Shestakova I, Gaysinskiy V, Entine G, Tornai MP, Stack BC (2004) Feasibility of a beta-gamma digital imaging probe for radioguided surgery. IEEE Trans Nucl Sci 51(1):110–116 Tornai MP, Levin CS, MacDonald LR, Holdsworth CH, Hoffman EJ (1998) A miniature phoswich detector for gamma ray localization and beta imaging. IEEE Trans Nucl Sci 45(3):1166–1173 Unsgaard G, Rygh OM, Selbekk T, Muller TB, Kolstad F, Lindseth F, Hernes TA (2006) Intra-operative 3D ultrasound in neurosurgery. Acta Neurochir (Wien) 148(3): 235–53 Vermeeren L, Valdes Olmos RA, Meinhardt W, Bex A, van der Poel HG, Vogel WV, Sivro F, Hoefnagel CA, Horenblas S (2009) Intraoperative radioguidance with a portable gamma camera: a novel technique for laparoscopic sentinel node localisation in urological malignancies. Eur J Nucl Med Mol Imaging 36(7): 1029–1036
L. Menard Vilela Filho O, Carneiro Filho O (2002) Gamma probe-assisted brain tumor microsurgical resection: a new technique. Arq Neuropsiquiatr 60(4):1042–1047 Wendler T, Traub J, Ziegler SI, Navab N (2006) Navigated three dimensional beta probe for optimal cancer resection. Med Image Comput Comput Assist Interv 9(Pt 1):561–569 Willems PW, van der Sprenkel JW, Tulleken CA, Viergever MA, Taphoorn MJ (2006) Neuronavigation and surgery of intracerebral tumours. J Neurol 253(9):1123–1136 Yamamoto S, Kuroda K, Senda M (2004) Development of an MR-compatible gamma probe for combined MR/RI guided surgery. Phys Med Biol 49(15):3379–3388 Yamamoto S, Matsumoto K, Sakamoto S, Tarutani K, Minato K, Senda M (2005) An intra-operative positron probe with background rejection capability for FDG-guided surgery. Ann Nucl Med 19(1):23–28 Zanzonico P, Heller S (2000) The intraoperative gamma probe: basic principles and choices available. Semin Nucl Med 30:30–48
Chapter 25
Implications of Mutant Epidermal Growth Factor Variant III in Brain Tumor Development and Novel Targeted Therapies Murielle Mimeault and Surinder K. Batra
Abstract The mutant epidermal growth factor receptor variant III (EGFRvIII) oncogene has attracted much attention due to its critical functions in primary brain cancer development, treatment resistance and disease relapse. The EGFRvIII mutant is frequently overexpressed during brain cancer initiation and progression in conjunction with the wild-type EGFR amplification while no expression level of its truncated receptor is detected in normal brain tissue specimens and any distant tissues. The constitutively activated EGFRvIII mutant can substantially contribute in cooperation with other receptor tyrosine kinases, including wild-type EGFR, to the sustained growth, migration and local metastases of brain cancer cells and resistance to current therapies. Therefore, the truncated EGFRvIII mutant represents a therapeutic target of great clinical interest for developing new effective treatments against primary brain tumors. In this chapter, we summarize the recent advancements on the characterization of key functions supplied by the EGFRvIII mutant and wild-type EGFR in brain tumor development and the most important findings about the novel therapeutic strategies developed for their effective molecular targeting. The emphasis is on the specific roles played by
M. Mimeault () Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Cancer Institute, 7052 DRC, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA e-mail:
[email protected] S.K. Batra () Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Cancer Institute, 7052 DRC, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA e-mail:
[email protected] the EGFRvIII mutant and its cooperative interactions with wild-type EGFR in brain tumor cells, treatment resistance and disease relapse. The implications of targeting the EGFRvIII mutant and/or wild-type EGFR to develop novel combination therapies for improving the current treatments against aggressive and recurrent medulloblastomas and glioblastoma multiforme are also discussed. Keywords EGFR · Mutant · Tyrosine kinase · Inhibitor · Antibody · Vaccination
Introduction Malignant primary brain tumors, including pediatric medulloblastomas and adult glioblastoma multiforme (GBMs), are among the most frequent, rapidly growing and lethal tumors of the central nervous system (CNS) (Furnari et al., 2007; Sampson et al., 2008; Stupp et al., 2005). The highly aggressive and locally invasive medulloblastomas and GBMs are generally refractory to current clinical therapies by tumor resection, radiotherapy and/or adjuvant chemotherapeutic treatments (Furnari et al., 2007; Halatsch et al., 2006; Stupp et al., 2005). Especially, the GBM patients treated with radiotherapy plus adjuvant temozolomide have a poor median survival time of about 14.6 months after diagnosis (Stupp et al., 2005). The inefficacy of current therapies for treating patients with medulloblastomas and gliomas has been associated with the accumulation of genetic and epigenetic alterations that can contribute to the acquisition of more malignant phenotypes and survival advantages by brain cancer cells.
M.A. Hayat (ed.), Tumors of the Central Nervous System, Volume 3, DOI 10.1007/978-94-007-1399-4_25, © Springer Science+Business Media B.V. 2011
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Fig. 25.1 Schematic structure of human wild-type EGFR protein and truncated EGFRvIII mutant. The scheme shows the extracellular domains divided in four subdomains I–IV, transmembrane region (TM), juxtamembrane segment (JM), tyrosine kinase domain and C-terminal tail. Moreover, the in-frame
deletion of the 6–273 amino acid segment of wild-type EGFR in the extracellular domain of truncated EGFRvIII mutant, which results in the generation of a novel glycine residue at the fusion point that is specific to the mutant receptor, is also indicated
Among the frequent genetic alterations that can contribute to primary brain tumor development, the wild-type EGFR (erbB1) transmembrane receptor tyrosine kinase (RTK) is amplified, overexpressed and/or mutated in approximately 40–60% of GBM patients (Fig. 25.1) (Aldape et al., 2004; Furnari et al., 2007; Halatsch et al., 2006). Moreover, the immunohistochemical and real-time PCR analyses have revealed that an enhanced expression of constitutively actived EGFRvIII mutant frequently occurs in approximately 30–60% of GBM patients while no expression of this mutant is observed in the normal adult brain and any other tissues (Fig. 25.1) (Aldape et al., 2004; Pelloski et al., 2007; Yoshimoto et al., 2008). Of particular interest, it has also been shown that the wild-type EGFR and/or EGFRvIII mutant can cooperate with other genetic alterations to the malignant transformation of neural stem cells (NSCs) or their early progenies during medulloblastomas and GBM development, treatment resistance and disease relapse (Batra et al., 1995; Lammering et al., 2004). Consequently, it appears that the development of multitargeted strategies directed against wild-type EGFR and/or EGFRvIII mutant with the current clinical treatments by radiation and chemotherapies, might represent promising therapies for treating the patients diagnosed with aggressive and recurrent primary brain tumors (Fig. 25.2). In this regard, we reviewed the specific functions of the wild-type EGFR and EGFRvIII mutant in cancer cells during the development of medulloblastomas and GBMs. Of clinical interest, recent studies supporting the therapeutic benefit of targeting the wild-type EGFR and EGFRvIII signaling pathways, alone or in combination, for improving the current treatments against highly aggressive and recurrent medulloblastomas and GBMs are also discussed.
Functions of the Wild-Type EGFR and EGFRvIII Mutant in Primary Brain Tumor Development Several investigations have revealed that the sustained activation of the wild-type EGFR and EGFRvIII mutant can cooperate for the malignant transformation of GBM cells, angiogenic process and tumor development. More specifically, the enhanced expression of wild-type EGFR may lead to its activation by its secreted ligands, including EGF and transforming growth factor-α (TGF-α), through an autocrine loop or in a juxtacrine or a paracrine manner and the stimulation of diverse intracellular signaling elements (Halatsch et al., 2006; Lo et al., 2008). These intracellular signaling components include phosphatidylinositol 3 kinase (PI3K)/Akt, Ras/mitogen-activated protein kinases (MAPKs), Janus-activated kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) and phospholipase-Cγ (PLC-γ) (Fig. 25.2) (Halatsch et al., 2006; Lo et al., 2008). The activation of these intracellular pathways might result in the induction of mitotic effects and promote the growth, migration and local invasion of GBM cells. In the case of the EGFRvIII mutant, which lacks a N-terminal 267 amino acid-portion of the full-length EGFR’s extracellular ligand-binding domain, this truncated receptor acts as a constitutively autophosphorylated and activated receptor that mediates its oncogenic effects in the absence of a ligand (Fig. 25.1) (Batra et al., 1995). The constitutively activated EGFRvIII mutant can stimulate in a persistent manner diverse intracellular cascades and up-regulate the expression of numerous target genes such as metalloproteinases (MMPs), tissue factor (TF) and TATA-binding protein
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Fig. 25.2 Schematic representation showing the signaling elements induced through the wild-type EGFR and EGFRvIII mutant involved in the malignant behavior of brain cancer cells and novel targeted strategies. This scheme shows the stimulatory effect induced through the activation of EGF/EGFR and constitutively activated EGFRvIII mutant on the Ras/mitogen activated protein kinases (MAPKs) and phosphatidyl 3 inositol (PI3K)/Akt which might lead to an mTOR, inhibition of cyclin-dependent kinase inhibitors p27kip1 and p21cip1 and enhanced expression of target gene products. In addition, the potential inhibitory effect induced by diverse pharmacological agents, such as a monoclonal antibody (mAb) or immunotoxins directed against EGF or TGF-α ligand, wild-type EGFR or EGFRvIII mutant, selective inhibitors of EGFR/EGFRvIII tyrosine kinase activity such as gefitinib and erlotinib and
vaccination based on the EGFRvIII-specific peptide are also indicated. Moreover, the therapeutic strategy consisting of using a mAb directed against HGF, a specific PI3K (LY294002), mTOR (rapamycin), dual inhibitor of PI3K/mTOR (PI-103), and SREBP-1 (25-HC) in combination therapies is also indicated. c-MET, hepatocyte growth factor receptor; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EGFRvIII, mutant epidermal growth factor receptor variant III; 25-HC, 25-hydroxycholesterol; HGF, hepatocyte growth factor; mAb, monoclonal antibody; MMPs, matrix metalloproteinases; mTOR, mammalian target of rapamycin; SREBP-1, serol regulatory element-binding protein 1; TBP, TATA-binding protein; TF, tissue factor; TGF-α, transforming growth factor-α and VEGF, vascular endothelial growth factor
(TBP), that can contribute to malignant behavior of GBM cells. The downstream signaling elements that can be induced through the EGFRvIII mutant in a cell type-dependent manner include PI3K/Akt, Ras/MAPK, JAK2/STAT3, protein kinase C-α (PKCα)/myristoylated alanine-rich protein kinase C substrate (MARCKS) and abnormal spindle-like microcephaly associated (ASPM) protein (Fig. 25.2) (Lal et al., 2002; Fan et al., 2006; Wang et al., 2006; Fromm et al., 2008; Micallef et al., 2009; Mukherjee et al., 2009a; Bikeye et al., 2010). Hence, the EGFRvIII mutant can play critical roles in the proliferation and migration of GBM cells, and enhanced tumorigenecity and angiogenic process, and cooperate with the wild-type EGFR and other oncogenic products for GBM tumor development. Moreover, the expression of the EGFRvIII mutant in the GBM patients has also been associated with a decreased expression level
of collapsing response mediator protein 1 (CRMP1), which in turn can promote the invasion of EGFRvIIIexpressing GBM cells (Mukherjee et al., 2009a). In addition, the co-expression and heterodimerization of the wild-type EGFR and EGFRvIII mutant in GBM cells might also contribute to their acquisition of a more malignant behavior (Johns et al., 2007; Martens et al., 2008; Patel et al., 2007).
Implications of Wild-Type EGFR and EGFRvIII Mutant in Treatment Resistane of Brain Tumor Cells The enhanced expression of the wild-type EGFR and EGFRvIII mutant has also been shown to contribute to radiation and chemotherapy resistance of GBM cells
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and has been associated with a poor survival of GBM patients (Golding et al., 2009; Halatsch et al., 2006; Kim et al., 2008; Lammering et al., 2004). The cytoprotective effects induced through the activation of these RTKs might be mediated, at least in part, by an up-regulation of the Ras/MAPK and PI3K/Akt survival pathways and anti-apoptotic factor expression such as Bcl-2 and Bcl-xL that leads to an inhibition of the apoptosis of GBM cells (Fig. 25.2). Moreover, it has also been reported that the expression of the wild-type EGFR and/or EGFRvIII mutant might promote the DNA double-strand break repair, and thereby contribute to the radioresistance of malignant gliomas (Golding et al., 2009). In addition, a growing body of experimental evidence has indicated that the wild-type EGFR and EGFRvIII mutant are expressed in brain tumor-initiating cells which can provide critical roles in tumor development, treatment resistance and disease relapse (Griffero et al., 2009; Mimeault and Batra, 2010). Hence, on the basis of these observations, it appears that the molecular targeting of the wild-type EGFR and EGFRvIII mutant, and other oncogenic products that are frequently deregulated during human primary brain cancer development might constitute more promising therapeutic strategies as monotherapies to eradicate total brain tumor cell mass and prevent disease relapse. In this matter, we are reporting the recent investigations supporting the therapeutic interest of targeting the wild-type EGFR and EGFRvIII mutant, and other oncogenic signaling elements, alone or in combination with current therapies, for overcoming the treatment resistance of GBM cells and preventing disease relapse.
Novel Therapeutic Strategies Against Primary Brain Cancers by Molecular Targeting of the Wild-Type EGFR and EGFRvIII Mutant Signaling Pathways Different therapeutic strategies have been designed to block the wild-type EGFR and/or EGFRvIII mutant cascades. Among them, there are the use of a specific tyrosine kinase activity inhibitor (TKI) such as gefitinib and erlotinib, monoclonal antibody (mAb) directed against these receptors or EGF and TGF-α ligands and their silencing by small interference (siRNA)
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or short hairpin RNA (shRNA) (Fig. 25.2) (Halatsch et al., 2006; Mimeault and Batra, 2010). Moreover, the inhibition of the downstream signaling elements, such as PI3K/Akt/mTOR, JAK2/STAT3, MARCKS and ASPM, also might constitute an alternative therapeutic approach for improving the antitumoral efficacy induced through the wild-type EGFR and EGFRvIII blockade (Lo et al., 2008; Mukherjee et al., 2009b; Bikeye et al., 2010). The data from numerous studies have revealed that the blockade of the wild-type EGFR and/or EGFRvIII pathways with these agent types, alone or in synergy with radiation and chemotherapeutic drugs, results in an inhibition of growth and invasion and/or the apoptotic death of the primary brain cancer cells in vitro and in vivo (Fig. 25.2) (Cemeus et al., 2008; Halatsch et al., 2006; Lal et al., 2002; Lo et al., 2008; Loew et al., 2009; Mukherjee et al., 2009b; Pillay et al., 2009).
Targeting of EGFR and/or EGFRvIII Using Specific Tyrosine Kinase Activity Inhibitors Numerous studies have been made to improve the current treatments of brain tumors by using specific inhibitors of EGFR and/or EGFRvIII tyrosine kinase activity, alone or in combination with other cytotoxic agents. In particular, the results from a recent investigation have indicated that the treatment of EGFRvIIIexpressing astrocytes with gefitinib or PI3K inhibitor, LY294002 improved the cytotoxic effects induced by radiation through the inhibition of DNA doublestrand break repair enzyme, DNA-dependent protein kinase catalytic subunit (DNA-PKsc) (Mukherjee et al., 2009b). Moreover, gefitinib plus a specific inhibitory agent of JAK2/STAT3 cascade, JSI-124 also inhibited the growth and induced the apoptosis in the GBM and medulloblastoma cell lines expressing the wild-type EGFR or EGFRvIII mutant in vivo (Lo et al., 2008). Importantly, it has also been reported that a combination of gefitinib plus a 3-hydroxy-3methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor, lovastatin synergistically induced the cytotoxic effects on U87MG human malignant glioma cells engineered to overexpress EGFRvIII (U87MGEGFRvIII) and PTEN irrespective of EGFRvIII and PTEN status (Cemeus et al., 2008). In the same way, a decreased expression of the cell-surface EGFRvIII mutant and certain target gene products involved in the
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invasion of GBM cells has also been observed after a long-term exposure of these cancer cells to erlotinib in vitro (Lal et al., 2002). It has however been observed that erlotinib as single agent did not significantly inhibit the tumor growth of U87MG overexpressing EGFRvIII mutant in vivo (Lal et al., 2002). In contrast, a combination of erlotinib with an anti-hepatocyte growth factor (HGF) antibody, L2G7 synergistically induced a marked reduction of the tumor growth and an increase of the survival of mice (Fig. 25.2) (Lal et al., 2002).
after short-term culture into the brains of nude mice (Martens et al., 2008). In contrast, all the unresponsive GBM tumors lacked amplified and/or mutated EGFR expression (Martens et al., 2008). Based on these observations, it has been proposed that the mAb528 or cetuximab treatment of GBM cells might prevent the heterodimer formation between the wild-type EGFR and EGFRvIII molecules by sterically impairing the adoption of an extended conformation by these receptors which is necessary for their dimerization (Fig. 25.2) (Martens et al., 2008; Patel et al., 2007).
Targeting of EGFR and/or EGFRvIII Using Specific Antibodies
Clinical Trials Involving the Molecular Targeting of Wild-Type EGFR and EGFRvIII Mutant
It has been reported that he treatment of U87MGEGFRvIII cell-derived xenografts with an anti-EGFR antibody, panitumumab partially inhibited the tumor growth whereas a combination of panitumumab and an anti-HGF antibody, AMG 102 substantially suppressed the tumor growth through the induction of the apoptotic death of glioma cells (Pillay et al., 2009). In addition, other mAbs specifically recognizing the wild-type EGFR and/or EGFRvIII mutant, including mAb528, chimeric IMC-C225 (cetuximab or Erbitux), mAb 806 and 3C10 have also been shown to induce antitumoral effects on GBM cells in vitro and/or in vivo (Halatsch et al., 2006; Martens et al., 2008; Patel et al., 2007). More specifically, it has been reported that cetuximab can induce its cytotoxic effects on GBM cells expressing the wild-type EGFR and/or EGFRvIII mutant by inhibiting the ligand binding to the wildtype EGFR and homodimerization as well as by causing the internalization of the cetuximab-EGFRvIII complexes (Patel et al., 2007). Moreover, it has also been observed that mAb528 inhibited the in vivo tumor growth of U87MG cells expressing endogenous EGFR, which have been engineered for also overexpressing EGFRvIII mutant while be this mAb does not suppress the tumor growth of xenografted fibroblasts overexpressing EGFRvIII alone (Johns et al., 2007). In the same way, the intracranial delivery of cetuximab also induced the tumor growth inhibitory, anti-invasive and apoptotic effects on three of seven cases of diffusely invasive xenografts established from different human GBM spheroids exhibiting EGFR amplification and EGFRvIII expression, which have been implanted
Several clinical trials undertaken to investigate the therapeutic interest of using the RTKs such as gefitinib and erlotinib or mAbs directed against wild-type EGFR and EGFRvIII murant for the treatment of GBM patients have also given promising results, and more particularly in combination with radiation or chemotherapies (Rich et al., 2004; Halatsch et al., 2006; Prados et al., 2009). In general, it has been observed that these agents used as monotherapy may be effective to control the disease, while their combination with the current treatments by radiation and/or chemotherapies, might lead to an improvement of the survival in certain GBM patients (Rich et al., 2004; Halatsch et al., 2006; Prados et al., 2009). It has also been noticed that the response to the RTK inhibitors was positively associated with the expression of EGFRvIII and PTEN in certain cases of GBM patients (Halatsch et al., 2006; Mellinghoff et al., 2005). For instance, the data from a recent phase II study have revealed that the inclusion of erlotinib plus temolomide during and after radiation therapy of newly diagnosed GBM patients improved median survival to 19.3 months as compared to 14.1 months observed for a treatment consisting of radiation plus temolomide without erlotinib (Prados et al., 2009). In this matter, it has also been observed that the gefitinib or erlotinib induced the anti-proliferative and cytotoxic effects on EGFR+ /CD133+ tumor-initiating cells from five patients with glioblastomas (GBM TICs) while two cases of GBM TICs with high Akt activation were insensitive to both drugs or only sensitive
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to high concentrations of erlotinib (Griffero et al., 2009). Altogether, these observations suggest then that the combined use of specific inhibitors of the wild-type EGFR, EGFRvIII mutant and other tumorigenic cascades, including PI3K/Akt, could be more effective in certain GBM patients than the single agents. Consistently, the data from several studies have revealed that the targeting of PI3K/Akt/mammalian target of rapamycin (mTOR) or SREBP-1 signaling components improved the cytotoxic effects induced by different antitumoral agents including the wild-type EGFR and mutant EGFRvIII inhibitors on GBM cells in vitro and in vivo (Fig. 25.2) (Fan et al., 2006; Guo et al., 2009; Wang et al., 2006). In addition to targeting PI3K/Akt pathway, diverse immunotherapies have also been designed to specifically target the EGFRvIII mutant.
EGFRvIII Mutant-Based Immunotherapies and Vaccination Distinct anti-EGFRvIII antibodies and EGFRvIIIspecific peptides have been developed, which may serve as potential carriers for radioconjugate- and immunotoxin-based therapies and therapeutic tools for vaccination of patients diagnosed with GBM tumors overexpressing the EGFRvIII mutant (Choi et al., 2009; Sampson et al., 2008). In fact, the EGFRvIII mutant, which is not expressed in normal tissues, constitutes an ideal and attractive tumor-specific target for vaccination due to its unique extracellular epitope that is formed subsequent to an in-frame genomic deletion creating a unique antigenic site that might be targeted using antibody-based antitumor vaccines (Fig. 25.2) (Beers et al., 2000; Choi et al., 2009; Sampson et al., 2008). Numerous preclinical and clinical studies aimed at the immunologic targeting of the tumor cell-expressing EGFRvIII mutant have been carried out with cultured cells engineered to overexpress EGFRvIII mutant, in animal models or selected cancer patients. The investigations consisting of the vaccination with dendritic cells and EGFRvIII-specific peptide or immunotoxins, have indicated that these therapeutic strategies might be effective to eradicate the brain cancer cells expressing EGFRvIII mutant and enhance the median survival time of GBM patients (Beers et al., 2000; Choi et al.,
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2009; Sampson et al., 2008). Different antibodies specifically reacting at the fusion junction of deletionmutant EGFRvIII have also been developed and in certain cases reached the clinical trials (Fig. 25.1) (Beers et al., 2000; Choi et al., 2009; Sampson et al., 2008). For instance, it has been observed that an immunotoxin MR1(Fv)-PE38 obtained from an antibody phage display library consisting of a single-chain antibody variable domain (scFv2 ), which specifically binds the EGFRvIII mutant, fusioned with a truncated form of Pseudomonas exotoxin induced the cytotoxic effects on GBM cells (Beers et al., 2000). More specifically, the treatment of U87MG cells and tumor spheres expressing EGFRvIII mutant and CD133 with BsAb and human CD16-expressing natural killer (NK) cells used as the effectors resulted in a greater lysis of the U87MG cells and tumor spheres expressing both antigens as compared to normal neurospheres expressing only CD133 (Wong et al., 2009). Hence, this strategy is of great therapeutic interest to specifically target CD133+ /EGFRvIII+ brain tumorinitiating cells, and thereby prevent the secondary effects on the normal CD133+ neural stem/progenitor cells. In addition, several EGFRvIII mutant-based immunotherapies and vaccine therapies have also given promising results in preclinical and clinical trials. For instance, several studies have been performed using an EGFRvIII mutant-based cancer vaccine designated as PEPvIII-KLH. The PEPvIII-KLH construct consists of an EGFRvIII-specific peptide PEPvIII (LEEKKGNYVVTDHC) which corresponds to a 13 amino acid sequence that spans the EGFRvIII fusion junction combined with an additional cystein residue to facilitate the chemical conjugation to a keyhole limpet hemocyanin (KLH). It has been reported that PEPvIII-KLH can generate EGFRvIII-specific antibodies in the patients with high grade gliomas (Choi et al., 2009; Sampson et al., 2008). It has also been observed that the brain tumor resection and sequential treatment of GBM patients with radiation plus TMZ followed by intradermal injections of the cancer vaccine PEPvIII-KLH was accompanied by a specific T- and B- cell-induced immune response and elimination of tumor cells expressing the EGFRvIII mutant (Choi et al., 2009). The overall survival of newly-diagnosed GBM patients overexpresing the EGFRvIII mutant after this treatment type was significantly enhanced to about 26.0 months as compared to 15 months observed for the patients treated with
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radiation plus temozolomide alone (Sampson et al., 2008). Importantly, it has also been noticed that the temozolomide-induced lymphopenia associated with this treatment improved the efficacy of the peptide vaccination by inhibiting regulatory T cells or their delayed recovery (Choi et al., 2009). In the same way, the results from a phase II multi-center trial with 22 cases of newly-diagnosed GBM patients overexpresing the EGFRvIII consisting of external beam radiation therapy followed by vaccinations with PEPvIII-KLH and granulocyte macrophage-colony stimulating factor (GM-CSF) have also indicated that the humoral and immune responses were manifested in patients. The median time-toprogression of these patients was of 14.2 months which is superior to only 7.1 months observed for the patients who have not been treated with temozollonide (Sampson et al., 2008). Although these are interesting results, it has been noticed that a down-regulation of the EGFRvIII mutant and stimulation of diverse tumorigenic cascades might occur in certain GBM patients during disease progression, and contribute to the disease recurrence (Sampson et al., 2008). These observations suggest that it is necessity to also include other potential tumor-specific antigens to immunotherapy such as interleukin-13 receptor α2 in addition to the EGFRvIII mutant-specific peptide in the future investigations in order to prevent treatment resistance and disease relapse.
brain-initiating cells versus their differentiated progenies during primary brain cancer development. Particularly, it will be important to further determine the specific functions supplied by homodimers and heterodimers formed by the wild-type EGFR and EGFRvIII mutant and interactive cross-talks between these RTKs and other growth factor pathways during primary brain cancer progression to locally advanced and invasive stages and their implications in the resistance to current therapies. Hence, these additional studies should lead to the development of more effective multi-targeted approaches to inhibit the wild-type EGFR and mutant EGFRvIII tumorigenic pathways and other key signaling elements that cooperate for the acquisition of a more malignant behavior and survival advantages by brain tumor-initiating cells and their progenies during disease progression. These multi-targeted strategies could be used to improve the current radiation and chemotherapeutic treatments against highly aggressive and lethal primary brain cancers, including pediatric medulloblastomas and adult GBMs, and thereby prevent disease relapse and the death of cancer patients.
Conclusions and Perspectives
References
Together these recent investigations suggest that the enhanced expression of the wild-type EGFR and truncated EGFRvIII mutant and up-regulation of PI3K/Akt represent frequent transforming events occurring during primary brain cancer development, and more particularly during GBM progression to aggressive and invasive disease stage. Especially, oncogenic pathways induced through EGFRvIII mutant can provide critical roles for the cell proliferation, survival and migration of cancer cells, and thereby cooperate with the wildtype EGFR for tumor formation and local invasion, treatment resistance and disease relapse. In spite of these important advancements, future studies are required to more precisely establish the specific intracellular pathways induced through the wild-type EGFR and EGFRvIII mutant in the
Aldape KD, Ballman K, Furth A, Buckner JC, Giannini C, Burger PC, Scheithauer BW, Jenkins RB, James CD (2004) Immunohistochemical detection of EGFRvIII in high malignancy grade astrocytomas and evaluation of prognostic significance. J Neuropathol Exp Neurol 63:700–707 Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS, Bigner DD (1995) Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ 6:1251–1259 Beers R, Chowdhury P, Bigner D, Pastan I (2000) Immunotoxins with increased activity against epidermal growth factor receptor VIII-expressing cells produced by antibody phage display. Clin Cancer Res 6:2835–2843 Bikeye SN, Colin C, Marie Y, Vampouille R, Ravassard P, Rousseau A, Boisselier B, Idbaih A, Calvo CF, Leuraud P, Lassalle M, El Hallani S, Delattre JY, Sanson M (2010) ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target. Cancer Cell Int 10:1
Acknowledgements The authors on this work are supported in part by U.S. Department of Defense grants PC04502 and PC074289 and the National Institutes of Health [Grants CA78590, CA111294, CA133774, CA131944 and CA138791].
258 Cemeus C, Zhao TT, Barrett GM, Lorimer IA, Dimitroulakos J (2008) Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status. J Neurooncol 90:9–17 Choi BD, Archer GE, Mitchell DA, Heimberger AB, McLendon RE, Bigner DD, Sampson JH (2009) EGFRvIII-targeted vaccination therapy of malignant glioma. Brain Pathol 19:713– 723 Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA (2006) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9:341–349 Fromm JA, Johnson SA, Johnson DL (2008) Epidermal growth factor receptor 1 (EGFR1) and its variant EGFRvIII regulate TATA-binding protein expression through distinct pathways. Mol Cell Biol 28:6483–6495 Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21:2683–2710 Golding SE, Morgan RN, Adams BR, Hawkins AJ, Povirk LF, Valerie K (2009) Pro-survival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells. Cancer Biol Ther 8: 730–738 Griffero F, Daga A, Marubbi D, Capra MC, Melotti A, Pattarozzi A, Gatti M, Bajetto A, Porcile C, Barbieri F, Favoni RE, Lo CM, Zona G, Spaziante R, Florio T, Corte G (2009) Different response of human glioma tumor-initiating cells to EGFR kinase inhibitors. J Biol Chem 284:7138–7148 Guo D, Prins RM, Dang J, Kuga D, Iwanami A, Soto H, Lin KY, Huang TT, Akhavan D, Hock MB, Zhu S, Kofman AA, Bensinger SJ, Yong WH, Vinters HV, Horvath S, Watson AD, Kuhn JG, Robins HI, Mehta MP, Wen PY, DeAngelis LM, Prados MD, Mellinghoff IK, Cloughesy TF, Mischel PS (2009) EGFR signaling through an Akt-SREBP-1dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci Signal 2:ra82 Halatsch ME, Schmidt U, Behnke-Mursch J, Unterberg A, Wirtz CR (2006) Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. Cancer Treat Rev 32:74–89 Johns TG, Perera RM, Vernes SC, Vitali AA, Cao DX, Cavenee WK, Scott AM, Furnari FB (2007) The efficacy of epidermal growth factor receptor-specific antibodies against glioma xenografts is influenced by receptor levels, activation status, and heterodimerization. Clin Cancer Res 13:1911–1925 Kim K, Brush JM, Watson PA, Cacalano NA, Iwamoto KS, McBride WH (2008) Epidermal growth factor receptor VIII expression in U87 glioblastoma cells alters their proteasome composition, function, and response to irradiation. Mol Cancer Res 6:426–434 Lal A, Glazer CA, Martinson HM, Friedman HS, Archer GE, Sampson JH, Riggins GJ (2002) Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Res 62:3335–3339 Lammering G, Valerie K, Lin PS, Hewit TH, Schmidt-Ullrich RK (2004) Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance. Radiother Oncol 72:267–273
M. Mimeault and S.K. Batra Lo HW, Cao X, Zhu H, li-Osman F (2008) Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Cancer Res 14:6042–6054 Loew S, Schmidt U, Unterberg A, Halatsch ME (2009) The epidermal growth factor receptor as a therapeutic target in glioblastoma multiforme and other malignant neoplasms. Anticancer Agents Med Chem 9:703–715 Martens T, Laabs Y, Gunther HS, Kemming D, Zhu Z, Witte L, Hagel C, Westphal M, Lamszus K (2008) Inhibition of glioblastoma growth in a highly invasive nude mouse model can be achieved by targeting epidermal growth factor receptor but not vascular endothelial growth factor receptor-2. Clin Cancer Res 14:5447–5458 Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024 Micallef J, Taccone M, Mukherjee J, Croul S, Busby J, Moran MF, Guha A (2009) Epidermal growth factor receptor variant III-induced glioma invasion is mediated through myristoylated alanine-rich protein kinase C substrate overexpression. Cancer Res 69:7548–7556 Mimeault M, Batra SK (2010) New promising drug targets in cancer- and metastasis-initiating cells. Drug Discov Today 15:354–364 Mukherjee J, DeSouza LV, Micallef J, Karim Z, Croul S, Siu KW, Guha A (2009a) Loss of collapsin response mediator protein1, as detected by ITRAQ analysis, promotes invasion of human gliomas expressing mutant EGFRvIII. Cancer Res 69:8545–8554 Mukherjee B, McEllin B, Camacho CV, Tomimatsu N, Sirasanagandala S, Nannepaga S, Hatanpaa KJ, Mickey B, Madden C, Maher E, Boothman DA, Furnari F, Cavenee WK, Bachoo RM, Burma S (2009b) EGFRvIII and DNA doublestrand break repair: a molecular mechanism for radioresistance in glioblastoma. Cancer Res 69:4252–4259 Patel D, Lahiji A, Patel S, Franklin M, Jimenez X, Hicklin DJ, Kang X (2007) Monoclonal antibody cetuximab binds to and down-regulates constitutively activated epidermal growth factor receptor vIII on the cell surface. Anticancer Res 27:3355–3366 Pelloski CE, Ballman KV, Furthm AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H, Woo SY, Heimberger AB, Suki D, Prados MD, Chang SM, Barker FG, Buckner JC, James CD, Aldape K (2007) Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 25:2288–2294 Pillay V, Allaf L, Wilding AL, Donoghue JF, Court NW, Greenall SA, Scott AM, Johns TG (2009) The plasticity of oncogene addiction: implications for targeted therapies directed to receptor tyrosine kinases. Neoplasia 11: 448–458 Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, Kabuubi P, yers-Ringler J, Rabbitt J, Page M, Fedoroff A, Sneed PK, Berger MS, McDermott MW, Parsa AT, Vandenberg S, James CD, Lamborn KR, Stokoe D,
25 Implications of Mutant Epidermal Growth Factor Variant III Haas-Kogan DA (2009) Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 27:579–584 Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed Rasheed BK, Tourt-Uhlig SE, Herndon JE, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142 Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD (2008) Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 20:267–275 Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff
259 RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996 Wang MY, Lu KV, Zhu S, Dia EQ, Vivanco I, Shackleford GM, Cavenee WK, Mellinghoff IK, Cloughesy TF, Sawyers CL, Mischel PS (2006) Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res 66:7864–7869 Wong A, Mitra S, Gupta P (2009) Targeting brain tumor stem cells using a bispecific antibody directed against CD133+ and EGFRvIII+. J Clin Oncol 27:15s Yoshimoto K, Dang J, Zhu S, Nathanson D, Huang T, Dumont R, Seligson DB, Yong WH, Xiong Z, Rao N, Winther H, Chakravarti A, Bigner DD, Mellinghoff IK, Horvath S, Cavenee WK, Cloughesy TF, Mischel PS (2008) Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples. Clin Cancer Res 14: 488–493
Chapter 26
Endoscopic Port Surgery for Intraparenchymal Brain Tumors Pawel G. Ochalski and Johnathan A. Engh
Abstract Intraparenchymal endoscopic port surgery (EPS) is a minimally-invasive technique for the removal of brain tumors and other mass lesions. The operation is made feasible through the combination of multiple technologies including imageguidance, parallel endoscopy, and cylindrical brain retraction. Tumors with an overlying cuff of normal brain parenchyma, soft consistency, and low or moderate vascularity are the ideal candidates. Techniques for tumor removal using the endoscopic port and prevention of peri-operative morbidity are discussed. In selected cases, EPS can provide superior visualization and decreased white matter manipulation during intraparenchymal tumor resection when compared with conventional approaches using the operating microscope. Keywords EPS · Brain tumor · Lesions · CNS · Neuroendoscopy · Hemostasis
Introduction Brain Tumor Demographics and Challenges Although brain tumors are not particularly common adult tumors, accounting for 2% of all cancer deaths
J.A. Engh () Department of Neurological Surgery, University of Pittsburgh Medical Center, UPMC Presbyterian, Pittsburg, PA 15213, USA e-mail:
[email protected] in the United States, they are among the most deadly. Most primary central nervous system (CNS) tumors in adult patients are malignant. The incidence of such tumors is approximately 22,000 cases/year in the United States, with approximately 13,000 deaths/year attributable to brain tumors (American Cancer Society, 2009). Brain metastases, all of which are malignant, have an incidence greater than 170,000 cases/year (Suh, 2010). Therapy for CNS primary and metastatic tumors is multi-modal, often beginning with surgical resection in selected cases followed by adjuvant radiation and/or chemotherapy. Neurological morbidity from brain tumors is often attributed to regional pressure (i.e. mass effect) from the lesion disrupting the normal function of surrounding neurons. Surgical removal of the tumor can facilitate relaxation of the surrounding brain, facilitating the subsequent return of improved neurologic function. However, surgical manipulation also requires dissection through surrounding brain, which often includes eloquent neurological tissue. As a result of such manipulation, patients may develop hemiparesis, dysphasia, cognitive impairment, seizures, or stroke. In an effort to facilitate the resection of intraparenchymal brain tumors with minimal injury to the surrounding brain, EPS was developed. This technique combines a minimally invasive cylindrical retraction system, light and magnification as delivered by parallel endoscopy, and frameless image-guidance. In selected cases, this method of brain tumor resection facilitates neurological recovery by minimizing the amount of normal tissue disruption required for tumor removal (Fig. 26.1).
M.A. Hayat (ed.), Tumors of the Central Nervous System, Volume 3, DOI 10.1007/978-94-007-1399-4_26, © Springer Science+Business Media B.V. 2011
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Fig. 26.1 Comparison of the visualization corridor provided by the operating microscope (a) versus rod-lens endoscope (b). Post-contrast axial T1-weighted magnetic resonance imaging showing a large rim-enhancing lesion arising from the putamen
and extending into the deep cerebral white matter. Note the difference in the visualization corridor provided by the source light (white line) when using the operating microscope (a) versus the rod-lens endoscope (b)
History
for visualization of skull base pathology. Resection is performed in an air medium, and all scarring is invisible to the patient. More importantly, particularly for lesions of the sella, tuberculum, and clivus, this approach exploits a natural corridor which avoids critical blood vessels and cranial nerves. Starting with the demonstration of the feasibility of endoscopic pituitary surgery in 1996 (Carrau et al., 1996), the expanded endonasal approach has now become an accepted approach to a large variety of skull base lesions (Kassam et al., 2005). In addition, the endoscope has often been used as an adjunct to the operating microscope for seeing around corners and inspecting operative cavities following skull base tumor resection. In addition, the endoscope may be used as the sole source of light and magnification within the subarachnoid space, so-called “endoscope-assisted microsurgery” (Badie et al., 2004; Perneczky and Fries, 1998). Endoscopy has been much less widely applied to intra-axial brain tumors, mainly because the intraparenchymal space provides no natural medium for light dispersion, thus limiting visualization. However, there are scattered reports of pioneering attempts using an endoscope mounted on a stereotactic frame for biopsy and limited resection of brain tumors
Endoscopic Brain Surgery The endoscope was initially adapted for neurosurgical use by Lespinasse in 1910, who performed intraventricular choroid plexus fulguration in the treatment of two cases of infantile hydrocephalus (Grant, 1996; Prevedello et al., 2007). Subsequently, Dandy refined the technique of intraventricular endoscopy, mainly for choroid plexus extirpation in the treatment of hydrocephalus, and coined the term “neuroendoscopy” (Dandy, 1932). Subsequent modifications and technological improvements have facilitated the development of other common intraventricular endoscopic operations, such as endoscopic third ventriculostomy. The large fluid medium for visualization that is provided by the ventricular system makes neuroendoscopy an intuitive approach for the treatment of obstructive hydrocephalus and other ventricular lesions. More recently, the endoscope has become a critical component in the growth and development of endonasal surgery for lesions of the pituitary region and surrounding skull base. In the anterior and middle skull base, the sinuses provide a natural corridor
26 Endoscopic Port Surgery for Intraparenchymal Brain Tumors
through a tulip-shaped retractor, dating as far back as 1980 (Jacques et al., 1980; Shelden et al., 1980). A decade later, the use of a bullet-shaped dilator for stereotactic-guided endoscopic tumor resection was reported (Otsuki et al., 1990). However, these approaches remained limited in their ability to handle larger and more vascular tumors, as they lacked the versatility of the operating microscope as well as its ability to be dynamically manipulated to provide multiple angles of tumoral visualization.
Cylindrical Retractors for Brain Surgery The introduction of the operating microscope to the field of neurosurgery revolutionized the treatment of brain tumors as well as numerous other disorders. The illumination and magnification provided by the use of the operating microscope significantly improved the ability to visualize and dissect tissue planes. However, because the microscope uses a funneling cone of light for binocular visualization, removal of deep intraparenchymal lesions can require extensive dissection of the overlying brain. In order to minimize tissue trauma inherent to the dissection and resection of deep seated tumors, Dr. Patrick Kelly pioneered a 20-mm-diameter tubular retraction system for the stereotactically-guided microscopic resection of deep brain tumors (Kelly et al., 1986, 1988; Kelly et al., 1986). Dr. Kelly’s technique combined computer technology, frame-based stereotaxy, and microsurgical dissection to deploy a cylindrical retractor as a transcortical conduit into the tumor. Visualization was provided by the operating microscope, and retractor diameter was typically ~20 mm. His approach made the resection of deep subcortical brain tumors far more feasible and far less traumatic than it had been in the past.
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the challenges inherent to the removal of deep-seated brain tumors, both intraparenchymal and intraventricular. The technique is a combination of elements of traditional endoscopy and traditional microsurgery. Goals include minimization of tissue trauma, maximal precision, and the versatility to address a high variety of lesions. In addition, dynamic manipulation of the port is intended to facilitate resection of lesions larger than the port itself. Initially reported in 2005 (Harris et al., 2005), stereotactic-guided EPS was originally applied to intraventricular lesions alone. This technique was a modification of a previous application which consisted of rolling up a 1 cm vinyl tube, stereotactically placing it into the ventricle, and then unrolling the tube, creating a conduit into the ventricle (Jho and Alfieri, 2002). The ventricles provide a natural conduit for light and magnification, and they can be converted into an air medium for bimanual microsurgery by aspirating cerebrospinal fluid from the ventricle. Visualization is provided by parallel endoscopy through a rod-lens endoscope. Colloid cysts and intraventricular tumors are both quite amenable to this technique of resection (Engh et al., 2010). Application of EPS to intraparenchymal lesions appeared shortly thereafter (Kassam et al., 2009). By converting the endoscopic port itself into a cylindrical retractor, EPS can be performed quite similarly to the manner of Dr. Kelly’s pioneering work. Critical differences include the smaller port size (11.5 mm), completely endoscopic visualization, and the use of frameless image-guidance. Dynamic mobilization of the endoscopic port facilitates visualization and removal of lesions much larger than the port itself. Most importantly, although the working space is small, bimanual microsurgery is performed within the port, which allows for complex tumor resections to be possible.
Technique Endoscopic Port Surgery
Patient Selection
Despite the success with the cylindrical retractor system demonstrated by Dr. Kelly’s group, widespread adoption of this technology was limited. However, the marriage of parallel endoscopy with cylindrical retraction techniques led to the adoption of EPS to address
Careful patient selection is essential to identify those who may be suitable for EPS, based on clinical, radiographic and anatomical considerations. From a clinical perspective, EPS should generally be considered in those patients who develop evidence of a significant
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neurologic deficit combined with regional tumoral mass effect. In addition, one can consider EPS whenever tissue sampling is required for diagnosis, and when there is a need for neo-adjuvant surgical debulking for cytoreduction prior to the start of systemic therapy. The goals of EPS are similar to the goals of conventional microsurgical tumor resection: maximal tumor resection with functional neurologic preservation. Primary brain tumors, metastases, and cavernous malformations are often suitable candidates for this procedure. Radiographic features which favor EPS are related to the anatomic configuration of the tumoral mass relative to the skull and overlying cortex. A significant cortical cuff certainly favors using EPS for resection. In addition, if the long axis of the tumor is perpendicular to the skull, the port can be advantageous by limiting the amount of white matter dissection required for tumor removal. On the other hand, since cortical and subcortical tissue preservation is the paramount goal of EPS, tumors which feature a wide, shallow cortical component are poor candidates. In addition, tumors which cross a large pial surface, such as the Sylvian fissure are not favorable, and should be addressed with standard microsurgical techniques. Furthermore, tumors which can be removed piecemeal are far more favorable than tumors which require en bloc resection. Finally, for tumors which are amenable to a cisternal approach or a trans-sulcal dissection directly into tumor, EPS does not afford the same benefit of minimizing tissue trauma as for tumors which are completely surrounded by white matter.
Operative Planning and Surgical Technique Pre-operative evaluation and imaging consists of an image-guided fine-cut MRI or CT scan for the purposes of identifying the appropriate site of the craniotomy and a safe cortical entry. A CT angiogram can be particularly useful in delineating important cortical and subcortical vascular structures prior to surgical debulking. In selected cases, fiber tractography or functional MRI scans can further delineate the planned operative trajectory. All patients are placed under general anesthesia. The head is immobilized via three-point fixation using a standard rigid head holder. Surgical head positioning is such that the long
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axis of the tumor is elevated within the field, in order to maximize the surgeon’s comfort. Using image guidance, the tumor’s location and the best trajectory into the tumor are marked out on the patient’s scalp. A linear incision is typically performed (except for lesions anterior to the hairline), large enough to allow for a craniotomy of approximately 2.5 cm in diameter. A cruciate dural opening is performed, and the trajectory into the tumor is planned using image-guidance. The process of cannulation and the typical intraoperative view are demonstrated in Fig. 26.2. The decision to enter via a transgyral or trans-sulcal entry point is based on regional vascular anatomy, the location of the tumor, and the eloquence of the surrounding brain. Once the entry point is defined, a small cortisectomy is performed, and a 2 mm brain needle (Elekta, Inc., Stockholm, Sweden) is advanced through the cortical-pial surface. Then, a bullet-shaped dilator (Omni Services, Inc., Wilmerding, PA) is passed over the needle, using gentle rotation to facilitate cannulation of the brain. Directly overlying the dilator is a clear plastic tube, 11.5 mm in outer diameter with lengths varying from 5.0 to 8.5 cm, depending on lesional depth. The port length used during an operation is based on measurements performed using the pre-operative MRI scan. Typically the goal of cannulation is to arrive at approximately 2/3 the depth of the tumor from the pial surface. The brain needle and dilator are then removed, and the port is secured to the scalp using sutures. A 4 mm zero degree rodlens endoscope (Karl Storz, Inc., Tuttlingen, Germany) is brought into the port for visualization. Resection is performed using bimanual microsurgical technique facilitated by tear-drop suction, pituitary forceps, scissors, and bipolar electrocautery. In many cases, two suction devices are used at the same time to facilitate gentle tumoral aspiration. The scope and port angles are adjusted multiple times throughout the resection in order to facilitate dynamic lesion visualization. This technique facilitates removal of lesions much larger than the 11.5 mm port itself. Following resection, meticulous hemostasis is achieved, then the cavity is irrigated with warm saline and lined with Surgicel (Ethicon, Inc., Somerville, NJ). The port is removed, the cortical entry site is also lined with Surgicel, and the dura is then closed in watertight fashion, with or without a dural graft. The bone flap is plated and replaced, and the wound is closed in standard fashion, following copious antibiotic irrigation. Post-operative
26 Endoscopic Port Surgery for Intraparenchymal Brain Tumors
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Fig. 26.2 (a–c) Technique of cannulation during endoscopic port surgery via a small cortisectiomy. (d) Endoscopic view during resection of a high grade glioma demonstrating bimanual
microsurgical technique within the port. Note the transparent tube which provides an excellent view of the surrounding white matter
care is essentially identical to that for a standard craniotomy. Most patients stay in the intensive care unit overnight, then are discharged from the hospital approximately on post-operative day 3. Sutures are removed at approximately post-operative day 10.
delineate tissue planes and promote hemostasis. In selected cases, especially for larger tumors, intratumoral decompression is performed prior to extracapsular dissection. However, the philosophy is generally to work around the outside of the tumor whenever possible. In contrast, EPS represents an “inside-out” approach to tumor surgery. The regional mass effect of the tumor is exploited in order to facilitate delivery of the tumor into the port, and white matter planes are defined with minimal manipulation. Hemostasis is obtained in slightly more difficult fashion, but the dural opening and white matter manipulation are absolutely minimized. Except for the most vascular of brain tumors (e.g. renal cell carcinoma metastases, solid hemangioblastomas), blood loss does not tend to be excessive, and can be adequately managed through the port.
Discussion Philosophy of Endoscopic Port Surgery The most essential aspect of EPS which represents a departure from microscopic approaches to intraaxial tumors is intra-tumoral cannulation. Typical microsurgical approaches to brain tumors advocate extracapsular dissection whenever possible, both to
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The application of the operating microscope to neurosurgery was a landmark achievement (Yasargil, 2010). Improvements in the ability to visualize and dissect around brain tumors and other pathological entities have resulted in significant improvements in patient outcomes. Despite the advantages of the operating microscope, in selected cases, even this device can be associated with a high degree of tissue trauma for the sake of tumoral visualization. In contrast, EPS creates a constant corridor width at increasing depths, minimizing tissue dissection both because of the shape of the port and the “flashlight” effect of the
endoscope. This distinction is particularly relevant in an era in which the biological cost of brain surgery is of paramount interest to patients. No longer is the success of tumor surgery defined merely by the degree of resection alone; preservation of neurologic function is equally, if not more critical. Figure 26.3 provides a case illustration of a peri-ventricular high grade glioma which was resected using the endoscopic port with minimal brain manipulation, as well as a schematic of intra-tumoral cannulation. Despite the recent success with EPS, further research and developments in the field are necessary
Fig. 26.3 Schematic and radiographic overview of endoscopic port surgery. (a, b) Example of pre- and post-operative axial contrast-enhanced images of a high-grade glioma bordering the occipital horn of the left lateral ventricle which was resected
using EPS. (c) Schematic of endoscopic port surgery for a deep-seated tumor in the coronal plane, demonstrating intratumoral cannulation and the two-suction technique of tumor removal
26 Endoscopic Port Surgery for Intraparenchymal Brain Tumors
in order to overcome certain limitations with the technique. Improvements in instrumentation and port design are both in the midst of development. For example, a dilatable endoscopic port may be able to limit white matter disruption during cannulation to a greater degree than the current dilatation technique. Furthermore, the ability to differentially dilate the distal end of the port once it has been docked within lesional tissue may improve visualization and resection of tumors. One of the biggest advantages of the port is that it allows bimanual dissection with instruments working in parallel to the endoscope. However, at times there can be a limited working corridor within the port. A design that incorporates a camera into the port could significantly increase working space, thereby facilitating instrument manipulation during tumor resections. Further research is underway to compare the effects and structural footprint of the endoscopic port on the surrounding white matter versus the white matter trauma inherent to standard transcortical approaches using the operating microscope and blade retraction systems.
Conclusion In appropriately selected patients, EPS offers a viable option to achieve the goals of tumor surgery – that is, cytoreduction or complete tumor removal with avoidance of morbidity. Nevertheless, proficiency in microsurgical techniques is an essential component to performing these procedures. Furthermore, a stepwise and methodical introduction of endoscopic techniques in conjunction with conventional approaches can help inexperienced surgeons to gain familiarity with the technology and better understand its limitations. Most importantly, however, correct patient selection is paramount in ensuring good outcomes with EPS. In the senior author’s current practice, approximately one-third of brain tumors that are candidates for resection are approached via EPS; the remainder are treated with conventional approaches. The most advantageous tumors for EPS have a significant cortical cuff (> 1 cm), with significant regional mass effect on the surrounding brain, loose consistency, and low to moderate vascularity. In many such cases, the EPS approach allows a significant reduction to the amount of brain trauma inherent to tumoral resection.
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References American Cancer Society (2009) Cancer facts & figures. The Society, Atlanta, GA Badie B, Brooks N, Souweidane MM (2004) Endoscopic and minimally invasive microsurgical approaches for treating brain tumor patients. J Neurooncol 69:209–219 Carrau RL, Jho HD, Ko Y (1996) Transnasal-transsphenoidal endoscopic surgery of the pituitary gland. Laryngoscope 106: 914–918 Dandy W (1932) The brain. In: Lewis D (ed) Practive of surgery. WF Prior, Hagerstown, MD, pp 247–252 Engh JA, Lunsford LD, Amin DV, Ochalski PG, FernandezMiranda J, Prevedello DM, Kassam AB (2010) Stereotactically guided endoscopic port surgery for intraventricular tumor and colloid cyst resection. Neurosurgery 67:198–204. discussion 204–195 Grant JA (1996) Victor Darwin Lespinasse: a biographical sketch. Neurosurgery 39:1232–1233 Harris AE, Hadjipanayis CG, Lunsford LD, Lunsford AK, Kassam AB (2005) Microsurgical removal of intraventricular lesions using endoscopic visualization and stereotactic guidance. Neurosurgery 56:125–132. discussion 125–132 Jacques S, Shelden CH, McCann GD, Freshwater DB, Rand R (1980) Computerized three-dimensional stereotaxic removal of small central nervous system lesions in patients. J Neurosurg 53:816–820 Jho HD, Alfieri A (2002) Endoscopic removal of third ventricular tumors: a technical note. Minim Invasive Neurosurg 45:114–119 Kassam AB, Engh JA, Mintz AH, Prevedello DM (2009) Completely endoscopic resection of intraparenchymal brain tumors. J Neurosurg 110:116–123 Kassam AB, Snyderman CH, Mintz A, Gardner P, Carrau RL (2005) Expanded endonasal approach: the rostrocaudal axis. part I. crista galli to the sella turcica. Neurosurg Focus 19:E3 Kelly PJ, Goerss SJ, Kall BA (1988) The stereotaxic retractor in computer-assisted stereotaxic microsurgery. Technical note. J Neurosurg 69:301–306 Kelly PJ, Kall BA, Goerss S, Earnest F 4th (1986) Computerassisted stereotaxic laser resection of intra-axial brain neoplasms. J Neurosurg 64:427–439 Otsuki T, Jokura H, Yoshimoto T (1990) Stereotactic guiding tube for open-system endoscopy: a new approach for the stereotactic endoscopic resection of intra-axial brain tumors. Neurosurgery 27:326–330 Perneczky A, Fries G (1998) Endoscope-assisted brain surgery: part 1: evolution, basic concept, and current technique. Neurosurgery 42:219–224 Prevedello DM, Doglietto F, Jane JA Jr, Jagannathan J, Han J, Laws ER Jr (2007) History of endoscopic skull base surgery: its evolution and current reality. J Neurosurg 107:206–213 Shelden CH, McCann G, Jacques S, Lutes HR, Frazier RE, Katz R, Kuki R (1980) Development of a computerized microstereotaxic method for localization and removal of minute CNS lesions under direct 3-D vision. Technical report. J Neurosurg 52:21–27 Suh JH (2010) Stereotactic radiosurgery for the management of brain metastases. N Engl J Med 362:1119–1127 Yasargil MG (2010) Editorial. Personal considerations on the history of microneurosurgery. J Neurosurg 112:1347
Chapter 27
Intracranial Tumor Surgery in Elderly Patients Paul Ronning, Torstein Meling, Siril Rogne, and Eirik Helseth
Abstract The western world is facing an aging population and this will present challenges for the medical profession insofar as most studies regarding therapy has been undertaken in a younger population. In this chapter we present our experience with intracranial tumor surgery in patients aged more than 70 years old. We find that in our selected aging patients undergoing surgery the results are comparable to the results in younger patients given that the same adjuvant therapy is given. Hence, we believe that the indication for surgery should be based on the physiological age rather than the chronological age of the patient. This and the potential sources of surgical morbidity must always be weighted against the natural history of the disease. Keywords Meningiomas · Brain · Intracranial tumors · ECOG · Astrocytomas · Macroadenoma
Introduction “Primum non noncere”- All medical care is a matter of weighing positive vs. negative effects of treatment for the patient against the natural history of the disease. Applying this basic tenet to intracranial tumor surgery entails that the clinician must contrast the natural history of the tumor against whether the possible positive effects of symptom relief and cyto-reduction outweigh the risk of infection, hematomas, anesthesia and approach related morbidity.
There is an increasing incidence of intracranial tumors up until the age of 75, whereafter the incidence falls steeply (Johannesen et al., 2004). There is no biological rationale for this age-threshold and we suspect that it is due to a negative referral bias due to preconceptions about intracranial surgery in old patients, that old patients often suffer from multiple systemic diseases that increase the risk of surgery and due to reduced difference between the natural history of the disease and the remaining life years (the marginal effect of surgery will diminish as the patient grows older). In this chapter we present the results of surgery in patients aged above 70 years and discuss whether this practice is worthwhile, based on a recently published article by Rogne et al. (2009).
Methodology Data were retrieved from a prospectively collected tumor database containing information on all tumors operated in the department of neurosurgery, Oslo University Hospital, Norway, between 2003 and 2007. A subset of the database, comprising patients aged over 70 years, was further scrutinized by a retrospective systematic review of their medical records to supplement the information in the database. The data was analyzed using Kaplan-Meier curves and multivariate Cox regression models after verifying that the standard assumptions of the models were fulfilled.
Results P. Ronning () Department of Neurosurgery, OSLO University Hospital, Oslo, Norway e-mail:
[email protected] A total of 289 patients were included with a median age of 74.9 (range 70–89.1) years at the time of
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surgery. Ninety percent of the tumors could be categorized as meningioma (total n = 79, n = 70 WHO grade I, n = 8 WHO grade II, n = 1 WHO grade III), astrocytoma (total n = 87, n = 82 WHO grade IV, n = 4 WHO grade III, n = 1 WHO grade II), metastases (n = 20 lung cancer, n = 17 malignant melanoma, n = 9 GI cancer, n = 4 breast cancer, n = 12 others) or pituitary adenomas (n = 33). Eight patients died within 30 days of surgery (two patients with meningioma, four with astrocytoma and two with metastases) yielding a surgical mortality of 2.8% in this series. Overall survival rates at 6, 12, 24, and 60 months were 73, 57, 46 and 38% respectively. A multivariate Cox model was fitted with histology, preoperative ECOG score, age, sex, ASA score and resection as opposed to biopsy as independent variables. Increasing preoperative ECOG and biopsy, compared to resection, were significantly (p < 0.05) associated with increasing hazard ratio (1.33 and 1.94 respectively). Astrocytomas and brain metastases had a significantly (p < 0.01) worse prognosis than meningiomas (hazard ratio 17.7 and 12.7, respectively). Furthermore, with regard to functional status at 6 months, we found that 85% were still alive and that stable or improved ECOG scores were witnessed in all patients with pituitary adenomas, >90% of patients with meningiomas, >80% of patients with brain metastases and more than 70% of astrocytoma patients alive at 6 months. Both patients with astrocytomas and metastases showed a significantly decreased hazard ratio with adjuvant treatment (p < 0.01). The astrocytomas and metastases undergoing adjuvant treatment had a median survival of approx 14 and 10 months, respectively, compared to 4 and 5 months without adjuvant treatment.
Discussion In selected patients we find that surgery clearly is worthwhile, in that it offers prolonged survival compared to the natural history of the disease. Furthermore we find that patients respond to adjuvant therapy to a similar extent as younger patients. The main limitation of our data, that must be kept in mind, is the nonrandomized nature of this series, i.e. there is a strong selection bias towards older patients that are good candidates for surgery: patients with good neurological
P. Ronning et al.
function, non-eloquent location and low co-morbidity. Hence, our results are not generalizable to the entire geriatric population, but only to a restricted subset of patients demonstrating these favorable preoperative conditions. Age is a well-known risk factor for poor outcome in glioblastoma patients as detailed by multiple authors (Antonio, 2008; Barnholtz-Sloan et al., 2008; Carson et al., 2007; de Robles and Cairncross, 2008; Iwamoto et al., 2009, 2008; Kurimoto et al., 2007; Lutterbach et al., 2005; Mukerji et al., 2008; Piccirilli et al., 2006). At the same time geriatric glioblastoma patients are known to receive limited treatment due to the preconception that the marginal effect of treatment is low compared to the effect in younger patients. In our series only 18% of our elderly glioblastoma patient underwent both radiation and chemotherapy. However, in our glioblastoma patients undergoing both temodal and radiation therapy we find survival close to what was reported by Stupp et al. (2005), despite the patients in the Stupp trial being limited to an age interval between 18 and 70 years old. Furthermore, in another analysis not yet published, we do not find evidence of a significant interaction between age and treatment. This further supports the notion that elderly patients can benefit from radiation and chemotherapy to a similar extent as younger patients. Similar findings have been published by other authors (Mukerji et al., 2008; Piccirilli et al., 2006). Toxicity can be reduced by offering 40 Gy radiotherapy concurrent with temodal instead of 60 Gy with a marginal effect on survival and with 2 weeks less radiotherapy (Minniti et al., 2008, 2009; Roa et al., 2004). EORTC trial 26062 (http://www.eortc. be/protoc/details.asp?protocol=26062) started accruing patients in 2009 specifically investigating the effect of temodal in patients aged above 70 receiving short course radiation EORTC (2009). Pending the publication of this trial we advocate that biological, instead of chronological age, should be the criterion for offering adjuvant therapy. Due to improved treatment for many common cancers, increased availability of CT and MRI scanners and an aging population there is an increasing trend in overall incidence of brain metastases. The treatment modalities available for brain metastases are surgery, whole brain radiation, chemotherapy (in certain cancers) and radio-surgery. The general consensus is that single, large lesions not amenable to radiosurgery (>3 cm), and lesions of unknown origin with
27 Intracranial Tumor Surgery in the Elderly Patients
negative work-up (approx 10%) should be considered for surgery if the patient has a favorable physiological status and limited systemic disease. Since metastatic disease often confers limited survival time (median survival 8–16 months) patients undergoing surgery should have a short postoperative course and incur limited need for rehabilitation. Hence, deep seated lesions in the basal ganglia, thalamus and brain stem are less than ideal candidates for surgery. Our results indicate again that biological age should not in itself be a limiting factor in offering treatment for metastatic brain disease, but that the general consensus should be followed irrespective of age. Both meningiomas and pituitary adenomas are usually benign slow growing tumors that can create neurological symptoms due to compressive effects and edema. Whether surgery is indicated is a balance between the tumors’ potential for growth, nature of the symptoms and potential morbidity of surgical approach against expected survival. Surgical outcome in the geriatric population has also been reported by other groups claiming good outcomes in the majority of elderly meningioma patients (Black et al., 1998; Cohen-Inbar et al., 2010; D’Andrea et al., 2005; Nakamura et al., 2005; Proust et al., 1997; Riffaud et al., 2007; Roser et al., 2007). We also find that surgery is well tolerated both with regard to survival and functional outcome. However, we believe that these tumors should be symptomatic before surgery is contemplated in this age group. Old asymptomatic patients with radiological growth probably should be referred for radio-surgery (Sonoda et al., 2005). Pituitary adenomas in elderly patients are most often non-secreting macroadenomas (80%), followed by GH- and prolactin secreting tumors (Minniti et al., 2005). A decision to offer surgery should be based on weighing local compressive effects and endocrine disturbances against approach related morbidity. Transsphenoidal surgery has proved to be safe and effective in pituitary surgery (Ferrante et al., 2002; Hong et al., 2008; Nakamura et al., 2007). Macroadenomas and intrasellar GH secreting adenomas are usually well controlled by transsphenoidal surgery (Minniti et al., 2005), whilst the rare prolactin secreting macroadenoma in this population can be controlled by dopamine agonists (Minniti et al., 2005). In our material, we found the life expectancy of elderly patients with pituitary adenomas to be almost identical with the age adjusted survival curves of the
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general population. Hence, we advocate that patients with symptoms that can be attributed to the pituitary adenoma should undergo transsphenoidal surgery irrespective of their age as long as their physiological reserve is adequate. In conclusion we believe that the indication for surgery should be based on the physiological age rather than the chronological age of the patient. This and the potential sources of surgical morbidity must always be weighted against the natural history of the disease.
References Antonio E (2008) Being old is no fun: treatment of glioblastoma multiforme in the elderly. J Neurosurg 108:639–640 Barnholtz-Sloan JS, Williams VL, Maldonado JL, Shahani D, Stockwell HG, Chamberlain M, Sloan AE (2008) Patterns of care and outcomes among elderly individuals with primary malignant astrocytoma. J Neurosurg 108:642–648 Black P, Kathiresan S, Chung W (1998) Meningioma surgery in the elderly: a case-control study assessing morbidity and mortality. Acta Neurochir 140:1013–1020 Carson KA, Grossman SA, Fisher JD, Shaw EG (2007) Prognostic factors for survival in adult patients with recurrent glioma enrolled onto the new approaches to brain tumor therapy CNS consortium phase I and II clinical trials. J Clin Oncol 25:2601–2606 Cohen-Inbar O, Soustiel JF, Zaaroor M (2010) Meningiomas in the elderly, the surgical benefit and a new scoring system. Acta Neurochir 152:87–97 D’Andrea G, Roperto R, Caroli E, Crispo F, Ferrante L (2005) Thirty-seven cases of intracranial meningiomas in the ninth decade of life: our experience and review of the literature. Neurosurgery 56:956–960 de Robles P, Cairncross G (2008) Glioblastoma in the elderly: an age-old problem. Ann Neurol 64:597–599 Ferrante L, Trillo G, Ramundo E, Celli P, Jaffrain-Rea ML, Salvati M, Esposito V, Roperto R, Osti MF, Minniti G (2002) Surgical treatment of pituitary tumors in the elderly: clinical outcome and long-term follow-up. J Neurooncol 60: 185–191 Hong JF, Ding XH, Lu YC (2008) Clinical analysis of 103 elderly patients with pituitary adenomas: transsphenoidal surgery and follow-up. J Clin Neurosci 15:1091–1095 Iwamoto FM, Cooper AR, Reiner AS, Nayak L, Abrey LE (2009) Glioblastoma in the elderly the memorial sloankettering cancer center experience (1997–2007). Cancer 115:3758–3766 Iwamoto FM, Reiner AS, Panageas KS, Elkin EB, Abrey LE (2008) Patterns of care in elderly glioblastoma patients. Ann Neurol 64:628–634 Johannesen TB, Angell-Andersen E, Tretli S, Langmark F, Lote K (2004) Trends in incidence of brain and central nervous system tumors in Norway, 1970–1999. Neuroepidemiology 23:101–109 Kurimoto M, Nagai S, Kamiyama H, Tsuboi Y, Kurosaki K, Hayashi N, Origasa H, Endo S (2007) Prognostic factors
272 in elderly patients with supratentorial malignant gliomas. Neurol Med-Chir 47:543–549 Lutterbach J, Bartelt S, Momm F, Becker G, Frommhold H, Ostertag C (2005) Is older age associated with a worse prognosis due to different patterns of care? A long-term study of 1346 patients with glioblastomas or brain metastases. Cancer 103:1234–1244 Minniti G, De Sanctis V, Muni R, Filippone F, Bozzao A, Valeriani M, Osti MF, De Paula U, Lanzetta G, Tombolini V, Enrici RM (2008) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. J Neurooncol 88:97–103 Minniti G, De Sanctis V, Muni R, Rasio D, Lanzetta G, Bozzao A, Osti MF, Salvati M, Valeriani M, Cantore GP, Enrici RM (2009) Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma. J Neurooncol 91:95–100 Minniti G, Esposito V, Piccirilli M, Fratticci A, Santoro A, Jaffrain-Rea ML (2005) Diagnosis and management of pituitary tumours in the elderly: a review based on personal experience and evidence of literature. Eur J Endocrinol 153:723–735 Mukerji N, Rodrigues D, Hendry G, Dunlop PRC, Warburton F, Kane PJ (2008) Treating high grade gliomas in the elderly: the end of ageism? J Neurooncol 86:329–336 Nakamura K, Iwai Y, Yamanaka K, Kawahara S, Ikeda H, Nagata R, Uda T, Ichinose T, Murata K, Sakaguchi M, Yasui T (2007) The surgical treatment of non-functioning pituitary adenomas in the ninth decade. Neurol Surg 35:371–375 Nakamura M, Roser F, Dormiani M, Vorkapic P, Samii M (2005) Surgical treatment of cerebellopontine angle meningiomas in elderly patients. Acta Neurochir 147:603–610 Piccirilli M, Bistazzoni S, Gagliardi FM, Landi A, Santoro A, Giangaspero F, Salvati M (2006) Treatment of glioblastoma
P. Ronning et al. multiforme in elderly patients. Clinico-therapeutic remarks in 22 patients older than 80 years. Tumori 92:98–103 Proust F, Verdure L, Toussaint P, Bellow F, Callonec F, Menard JF, Freger P (1997) Surgery of intracranial meningiomas in elderly patients. Prognosis factors: 39 cases. Neurochirurgie 43:15–20 Riffaud L, Mazzon A, Haegelen C, Hamlat A, Morandi X (2007) Surgery for intracranial meningiomas in patients older than 80 years. Pres Med 36:197–202 Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, Fisher B, Fulton D, Gulavita S, Hao C, Husain S, Murtha A, Petruk K, Stewart D, Tai P, Urtasun R, Cairncross JG, Forsyth P (2004) Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 22:1583–1588 Rogne SG, Konglund A, Meling TR, Scheie D, Johannesen TB, Ronning P, Helseth E (2009) Intracranial tumor surgery in patients >70 years of age: is clinical practice worthwhile or futile? Acta Neurol Scand 120:288–294 Roser F, Ebner FH, Ritz R, Samii M, Tatagiba MS, Nakamura M (2007) Management of skull based meningiomas in the elderly patient. J Clin Neurosci 14:224–228 Sonoda Y, Sakurada K, Saino M, Kondo R, Sato S, Kayama T (2005) Multimodal strategy for managing meningiomas in the elderly. Acta Neurochir 147:131–136 Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352: 987–996
Chapter 28
Intracranial Hemangiopericytoma: Gamma Knife Surgery Jason P. Sheehan and Edward M. Marchan
Abstract This review provides an overview of the biology of hemangiopericytomas as well as an overview of currently available treatment regimens for this highly vascular lesion. While extirpation is the gold standard for diagnosis, tumor control, and relief of mass effect, the high recurrence rate of this tumor type in addition to its proximity to venous channels or skull base locations, can makes resection much less re-resection less attractive. Therefore, stereotactic radiosurgery principally with the Gamma Knife has been used to deliver a steep dose gradient and minimizes the radiation delivered to the surrounding areas. Hence, it becomes possible to deliver a significantly larger and presumably more biologically effective dose to the tumor while limiting the side effects of radiation to normal brain tissue. These characteristics make Gamma Knife radiosurgery (GKS) a very useful tool in treating patients with recurrent hemangiopericytoma or tumors in surgically inaccessible locations. Keywords Hemangiopericytoma · GKS · Meningiomas · Embolization · Radiosurgery · Dose
Introduction Hemangiopericytomas (HPC) are highly vascular and rapidly growing lesions of the central nervous system (Bastin and Mehta, 1992). Embryologically they
J.P. Sheehan () Department of Neurological Surgery, Health Sciences Center, Charlottesville, VA 22908, USA e-mail:
[email protected] belong to the mesenchymal type of tumor class harboring pericytic differentiation (Stout and Murray, 1942). They represent a rare type of brain tumor, and they tend to be misdiagnosed as meningiomas (often mislabeled as angioblastic in the meningioma category) because they can share similar clinical and radiographic findings. It was Begg and Garret who recognized the similarity of the angioblastic meningioma described in 1938 to this soft tissue sarcoma in 1954 (Begg and Garret, 1954). However, more recent assessment of this issue has placed them in a separate category from meningiomas. They are recognized for their aggressive clinical behavior with high recurrence rates and distant metastases even after gross total resection (Goellner et al., 1978; Guthrie et al., 1989; Mena et al., 1991; Pitkethly et al., 1970). HPC and malignant meningioma patients share the potential to develop CNS or systemic metastases (Goellner et al., 1978; Guthrie et al., 1989; Mena et al., 1991). For instance, in Galanis et al.’s series (1998), 50% of patients (17/34) had extraneural recurrence: 14 in bones (82%), 7 in liver parenchymal areas (41%), and 5 had lung metastases (29%). Surgical resection is still considered to be the gold standard for accurate tissue diagnosis and control of mass effect (Fountas et al., 2006; Olson et al., 2010). Most HPCs can be totally removed in toto; however, local recurrence occurs often, with some series quoting as many as 91% of patients (Vuorinen et al., 1996). It is well established that lower cell proliferation indexes (e.g., a MIB-1 index) are associated with a better prognosis, longer intervals to recurrence, a lower rate of metastasis, and extended long term survival (Vuorinen et al., 1996). Those hemangiopericytomas which possess low-grade histology (i.e., Grade 2) usually have a lower MIB-1 index, while high proliferation indexes
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favor anaplastic WHO Grade 3 tumors (Vuorinen et al., 1996). It is well established that their proximity to venous sinuses or their highly aggressive, recurrent nature makes an initial gross total resection much less a reoperation difficult (Goellner et al., 1978; Guthrie et al., 1989; Sheehan et al., 2002) Because these tumor recurrences are often circumscribed and focal, stereotactic radiosurgery with the Gamma Knife has become a very attractive technique to achieve tumor control. This chapter focuses upon the current role of stereotactic radiosurgery for hemangiopericytomas.
Surgical Resection of Hemangiopericytomas As stated above, resection is usually the initial treatment for hemangiopericytomas (Olson et al., 2010). In surgery, grossly meningeal hemangiopericytomas are lobulated and have a firm consistency with a pinkgray to red color. They usually have a broad meningeal base but do not tend to spread en plaque or invade brain (Guthrie et al., 1989; Jaaskelainen et al., 1985). They are highly vascular but at surgery are usually separated from surrounding brain without difficulty. Nonetheless, it is this highly vascular nature of this lesion in addition to its origin from deep skull base regions that can make surgery a highly morbid undertaking. Thus, mortality rates can range from 9 to 24% (Guthrie et al., 1989; Jaaskelainen et al., 1985; Olson et al., 2010; Sheehan et al., 2002) Moreover, recurrence is the rule rather than the exception even after gross total resection. Furthermore, distant metastases have been noted to appear between a mean of 63 and 99 months after the first diagnosis (Dufour et al., 2001; Guthrie et al., 1989; Jaaskelainen et al., 1985; Pitkethly et al., 1970; Sheehan et al., 2002). The incidence of local recurrence has varied from 26 to 80%, depending on the quality of resection, the length of follow-up, and the delivery of postoperative RT (Mena et al., 1991; Guthrie et al., 1989). While multiple resections can be feasible, they are nevertheless not usually performed because of the known morbidity of re-operation. For instance, Guthrie et al. (1989) found that if microsurgery was the sole treatment for hemangiopericytoma, the tumor recurred after an average of 29 months. Moreover,
J.P. Sheehan and E.M. Marchan
subsequent recurrences following additional microsurgery occurred at progressively shorter intervals (Guthrie et al., 1989). Therefore, the added clinical setbacks caused by the emergence of iatrogenic neurological deficits in the pursuit of improved resection should therefore be discouraged (Payne et al., 2000). In many cases, preoperative embolization of the feeding vessels can be helpful in controlling bleeding during surgery. Nonetheless, its usefulness is not as evident as it is for meningiomas because of the propensity of hemangiopericytomas to invade cortical vessels. Payne et al. (2000) described how, in his series, one patient was embolized three times over the course of 3 years and the therapy was successful in postponing an additional craniotomy for 3 years after the last embolization. However, a Horner’s syndrome ensued from that procedure. Another patient had two simultaneous recurrences, both of which were embolized, but only one was surgically extirpated. Neither tumor was apparent at 1 year on surveillance MRIs. A third patient was embolized but the intervention was unable to prevent a recurrence and the lesion was treated with Gamma surgery 9 months following embolization. 2 years after the radiosurgical intervention, the tumor had decreased in volume by 35%. The incidence of metastasis increases with time and has been reported as 13%, 33 and 64% at 5, 10 and 15 years respectively (Guthrie et al., 1989; Sheehan et al., 2002) Thus, it is vital that long term follow-up be obtained in order to maximize available adjuvant therapies and to prevent tumor recurrence.
Conventional Radiotherapy in the Management of Hemangiopericytomas Conventional radiotherapy has been proposed for post-surgical treatment of hemangiopericytomas, even when a gross total resection is performed, due to the tumor’s propensity to recur. The purpose of radiation therapy is to delay recurrence of tumors. Dube and Paulson (1974) published the first account of postoperative control of a hemangiopericytoma, and they witnessed a complete radiologic response. Meanwhile, Dufour et al. (2001) showed that post-operative radiotherapy decreased the recurrence rate from 88% after surgical removal alone to 12.5% with adjuvant fractionated radiotherapy. The authors delivered a dose of 50–64 Gy to patients in this series. It has been
28 Intracranial Hemangiopericytoma: Gamma Knife Surgery
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established that a regional minimum of 50 Gy should be used to prevent early recurrence (Guthrie et al., 1989). Moreover, Mira et al. (1977) reported on a series of 11 patients where hemangiopericytomas were treated with around 29 courses of radiation, and they noticed a strong clinical response in 26 of the 29 courses with complete regression following 14 courses (Mira et al., 1977). Comparatively, a series from our institution published by Payne et al. (2000) described how three patients had received 54 Gy regional fractionated radiation therapy following the first hemangiopericytoma surgical procedure and five had not received any radiation therapy. Those who were not irradiated averaged 2.4 years between their 26 procedures while those that were irradiated post operatively averaged 7.5 years between their 9 procedures. Furthermore, no patient had died or developed systemic metastases in the latter group. This corroborates Guthrie et al.’s (1989) finding that radiotherapy after the first operation extends the mean time before first recurrence from 34 to 75 months while extending survival from 62 to 92 months. In their series, Jaaskelainen et al. (1985) concluded that radiation therapy should be only used after the initial resection. For instance, two patients irradiated after an initial gross total resection were disease free at 167 and 263 months respectively. In contrast, three patients who received conventional radiotherapy for recurrent non-resectable tumors had progression of disease. Interestingly, there have been studies such as from Uemura et al. (1992) who clearly have shown that
radiotherapy can provide a benefit if delivered prior to resection. He hypothesized that radiation can make this type of tumor less vascular while allowing the resection to proceed with less blood loss.
Role of Stereotactic Radiosurgery in the Management of Hemangiopericytomas With radiosurgery, one is able to maximize the efficacy that resection can achieve while using radiation to minimize the potential morbidity associated with re-operation. Radiosurgery can thus achieve a steep dose gradient that minimizes the radiation delivered to the surrounding areas. Consequently, it is possible to deliver a significantly larger and presumably more biologically effective dose to the tumor and minimize other undesired side effects of radiation to normal tissue (Olson et al., 2010). By performing surveillance MRIs, early detection of tumor recurrence or distant tumor formation is achieved. With early detection comes the potential to target smaller tumor volumes and make adjuvant treatment with radiosurgery a more efficient option. Coffey et al. (1993) has postulated that the highly vascular and focal component of the hemangiopericytoma makes it an excellent radiosurgical target Table 28.1. In his series he reported a small subset of five patients with eleven tumors treated with Gamma Knife radiosurgery. A marginal dose of 12–18 Gy
Table 28.1 Stereotactic radiosurgery (LINAC or gamma knife) for hemangiopericytoma
Author
Dosage (Gy) (range)
# of patients
# of lesions
Median F/U (mo)
Median survival after GKS (mo, %)
Coffey et al. (1993) Galanis et al. (1998)
12–18 12–18
5 10
11 20
14.8 36
n/a, 80 n/a, n/a
Payne et al. (2000)
14–37
10
12
25
28, n/a
Sheehan et al. (2002) Olson et al. (2010) Kano et al. (2008)
11–20 2.8–22 11–20
14 21 20
15 28 29
21 68 46
21, 93 68, 33 46, 60
Chang and Sakamoto (2003) n/a: not available
16–24
8
8
44
44, 88
Local control (complete regression or partial regression) 82% (9/11 lesions) 3 patients, no prior XRT: 100% at 36 months 7 patients, + prior XRT: 100% at 12 months 67% (8/12 lesions) at 22 months 80% (12/15 lesions) 46% (13/28 lesions) 72% (21/29 lesions) at 23.3 months 75% (6/8 lesions) at 44 months
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was used, and 3 patients had undergone prior radiotherapy with doses ranging from 50 to 53 Gy. Nine tumors had post-radiosurgery imaging for comparison. This cohort showed an impressive reduction of size after a mean follow-up of 14.8 months. It is interesting to note that in one of these patients, no tumor was visualized in the post radiosurgery neuro-imaging study. In another report, Galanis et al. (1998) described how in 10 patients with 20 hemangiopericytomas treated with doses ranging from 12 to 18 Gy, there was a dramatic reduction of 14 of them, and a complete eradication of the lesion in three of them. The effect however lasted less than a year. Most of the tumors had also received fractionated radiation therapy and averaged 32 mm in greatest dimension. A subgroup of three patients with solitary tumors less than 25 mm in greatest diameter that had not been treated with radiation therapy all showed complete imaging response that had persisted for a median of 36 months. Finally, he reported a 5-year HPC distant metastasis rate of 33%. Moreover, Payne et al. (2000) followed 10 hemangiopericytoma patients who had 12 stereotactic radiosurgery treatments for these lesions and monitored them for 24.8 months. A dose of 14–37 Gy was given to these tumors. Nine of these hemangiopericytomas initially decreased in size while three remained stable. Local control at a span of 22 months was 67% as four of the nine tumors that shrank later progressed. Two new tumors occurred in patients previously treated. Of the tumors that decreased in volume and did not progressed, the response had totaled 11 months at the time of publication. The follow-up for two tumors that remained unchanged was 10 and 34 months (average 22 months). There were no complications and the quality of life following the procedure was maintained or improved in every case. The senior author (Sheehan et al., 2002) has also obtained positive results in reduction of tumor size with the use of Gamma Knife Radiosurgery. In one study, a series of 14 patients with 15 hemangiopericytomas was analyzed. Seven patients had undergone prior radiotherapy (dose 30–61 Gy), while 27 had prior craniotomies conducted. Doses of 11–20 Gy were implemented with a mean follow-up of 31.3 months. On follow up MR data, 12 of 15 lesions showed reduction in size. Nonetheless, there was a 29% distal failure rate emphasizing the poor ability of radiosurgery to prevent distant metastases.
J.P. Sheehan and E.M. Marchan
In another study of a cohort of patients from the University of Virginia and published by the senior author (Olson et al., 2010), the tumor control rate was found to be lower compared to those of earlier published series, i.e., a 46.4% tumor control rate (13 out of 28 tumors). The mean prescription dose to the tumor was 16.8 Gy. A mean clinical and imaging followup period of 69 months was established (range 2–138 months). Of note, this mean follow-up period was significantly greater than previous series assessing the role of radiosurgery in the treatment of hemangiopericytomas (Chang and Sakamoto, 2003; Coffey et al., 1993; Galanis et al., 1998; Kano et al., 2008; Payne et al., 2000; Sheehan et al., 2002). Hence, it is conceivable that the longer follow-up period provided a greater chance for hemangiopericytoma recurrence or metastasis. Seventeen of the 28 tumors decreased after the first GKS. Six tumors later demonstrated re-growth. Thirteen cases were treated two times or more with GKS. Two of these tumors that underwent multiple GKS demonstrated regression below the initial tumor volume at the last imaging follow-up. The mean time to progression of the tumor after the first GKS was 48 months. The occurrence of new intracranial tumors was 19%; with only one of these tumors demonstrating tumor control after subsequent additional GKS. Nineteen percent of the patients (4 of 21 patients) developed extracranial metastases. These findings of local recurrence rate and extracranial metastases are comparable to previous studies (Chang and Sakamoto, 2003; Kano et al., 2008; Payne et al., 2000; Sheehan et al., 2002). Recently, Kano et al. (2008) demonstrated that a greater marginal dose (≥14 Gy) was significantly associated with better progression-free survival. In their series, 20 patients were reviewed who had undergone GKS for 29 tumors. They reported a median time to the development of intracranial or systemic metastasis at 79.2 months (range, 12.2–158.3 months) after the initial diagnosis. At last assessment, twelve patients (60%) were alive and eight (40%) had died at an average of 62.6 months (range, 13.8–99.4) after GKS and an average of 135.5 months (range, 40.6–255.7) after the initial diagnosis. Four patients (20%) died secondary to dissemination throughout the neuraxis and one (5%) died of liver and lung metastasis. Three patients (15%) developed local tumor progression and died. The follow-up imaging studies demonstrated tumor control in 21 (72.4%) of 29 tumors. However,
28 Intracranial Hemangiopericytoma: Gamma Knife Surgery
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in this report, the length of imaging follow-up was relative short with a median and mean of 23.3 and 37.9 months after GKS, respectively. Complete eradication was observed in five hemangiopericytomas (Kano et al., 2008). Of note, of the 29 tumors, 21 (72.4%) had received a marginal dose of ≥14 Gy and 8 (27.6%) had received