Bone Cancer: Primary Bone Cancers and Bone Metastases

Bone Cancer, Second Edition comprehensively investigates key discoveries in the field of bone biology over the last five years that have led to the development of entirely new areas for investigation, such as therapies which combine surgery and biological approaches. The Second Edition expands on the original overview of bone cancer development (physiology and pathophysiology), with key chapters from the first edition, and offers numerous new chapters describing the new concepts of bone cancer biology and therapy, for both primary bone tumors as well as bone metastases. Each chapter has been written by internationally recognized specialists on the bone cancer microenvironment, bone metastases, osteoclast biology in bone cancer, proteomics, bone niche, circulating tumor cells, and clinical trials.

Given the global prevalence of breast and prostate cancers, knowledge of bone biology has become essential for everyone within the medical and cancer research communities. Bone Cancer continues to offer the only translational reference to cover all aspects of primary bone cancer and bone metastases – from bench to bedside: development (cellular and molecular mechanisms), genomic and proteomic analyses, clinical analyses (histopathology, imaging, pain monitoring), as well as new therapeutic approaches and clinical trials for primary bone tumors and bone metastases.

• Presents a comprehensive, translational source for all aspects of primary bone cancer and bone metastases in one reference work
• Provides a common language for cancer researchers, bone biologists, oncologists, and radiologists to discuss bone tumors and how bone cancer metastases affects each major organ system
• Offers insights to research clinicians (oncologists and radiologists) into understanding the molecular basis of bone cancer, leading to more well-informed diagnoses and treatment of tumors and metastases
• Offers insights to bone biologists into how clinical observations and practices can feed back into the research cycle and, therefore, can contribute to the development of more targeted genomic and proteomic assays

• Language: English
• Publisher: Academic Press
• Release date: Sep 4, 2014
• ISBN: 9780124167285

Book preview

Bone Cancer

Primary Bone Cancers and Bone Metastases

Second edition

Edited by

Dominique Heymann, PhD

Professor, Faculty of Medicine, University of Nantes

Head of Pathophysiology of Bone Resorption and Therapy of Primitive Bone Tumors, INSERM, Nantes, France

Table of Contents

Cover

Title page

Copyright Page

List of Contributors

Foreword

Preface

I: Basic aspects of bone cancers

Section 1: Epidemiology of bone cancer

Chapter 1: Epidemiology of primary bone tumors and economical aspects of bone metastases

Abstract

Introduction

Incidence of primary bone tumors

Pathology of bone metastases

Cost of illness

Economical burden of bone metastasis

Conclusions

Section 2: Bone microenvironment and bone cancer

Chapter 2: Tumor–bone interactions: there is no place like bone

Abstract

Introduction

Making its way to bone

Disseminated tumor cells and dormancy in bone

Induction of osteolysis by cancer cells in bone

Induction of bone formation by cancer cells in bone

Suppression of bone formation

The bone microenvironment support cancer cell growth

Conclusion

Chapter 3: Stem cell niches in the bone–bone marrow organ and their significance for hematopoietic and non-hematopoietic cancer

Abstract

Introduction

The concept of a niche

Niche and microenvironment

Osteoblastic and endothelial niches

Bone marrow stromal cells and the niche

The heterotopic transplantation system

An adaptive niche

Modeling the niche and probing its significance in disease

The niche in early metastatic growth

Acknowledgments

Chapter 4: Deregulation of osteoblast differentiation in primary bone cancers

Abstract

Introduction

Normal osteoblastogenesis: general process and major regulatory mechanisms

Deregulated genes in bone tumors

Deregulated signaling pathways in bone tumors

Deregulation of local regulatory mechanisms in bone tumors

Conclusions and perspectives

Acknowledgments

Chapter 5: Contribution of osteoclasts to the bone–tumor niche

Abstract

Introduction

Osteoclastogenesis

Bone resorption

The vicious cycle of tumor–bone metastases

Other ways osteoclasts contribute to the bone-tumor niche

Chapter 6: Involvement of osteocytes in cancer bone niche

Abstract

Introduction

Osteocytes: a multifunctional bone cell

Short overview of RANK/RANKL/osteoprotegerin and canonical Wnt signaling pathways

Central role of osteocytes in bone remodeling through RANKL and sclerostin regulation

Deregulation of RANK/RANKL and Wnt pathways in malignancy

Is there a direct link between malignant cells and osteocytes?

Conclusions and perspectives

Chapter 7: Role of mesenchymal stem cells in bone cancer; initiation, propagation and metastasis

Abstract

Introduction to the mesenchymal stem cell

Initiation: MSCs as progenitors of bone tumors

Cartilaginous tumors

Ewing sarcomas

Osteosarcomas

Propagation: cancer stem cells in bone sarcoma

Metastasis: MSCs prepare the road for metastasis

Conclusion

Chapter 8: Gap junction in bone remodeling and in primary bone tumors: osteosarcoma and Ewing sarcoma

Abstract

Introduction

Gap junction channels

Role of gap junctions in bone remodeling

Gap junction in primary bone cancers

Conclusion and perspectives

Chapter 9: Macrophages and pathophysiology of bone cancers

Abstract

Introduction

Macrophage differentiation, polarization and activation status

Tumor associated macrophages

Macrophages in intravasation

Macrophages in extravasation

Macrophages in metastasis formation

Therapeutic interests on macrophages in bone cancer

Conclusion

Acknowledgment

Chapter 10: Cytokines and bone cancers

Abstract

Introduction

Clinical observational studies on cytokines and bone cancer development

Cytokines in cancer cell metastasis to bone

Cytokines and primary bone cancers

Conclusions and perspectives

Chapter 11: Technical aspects: how do we best prepare bone samples for proper histological analysis?

Abstract

Introduction

Bone biopsy in humans or large animals

Bone fixation

Microcomputed tomography (MicroCT)

Dehydration and infiltration

Bone embedding

Staining methods

Acknowledgments

Section 3: Markers of bone cancer (cells, genes and proteins)

Chapter 12: Bone remodeling markers and bone cancer

Abstract

Introduction

Diagnostic use

Prognostic use

Monitoring of anti-tumor therapy

Conclusions and perspectives

Chapter 13: Cancer stem cells in representative bone tumors: osteosarcoma, Ewing sarcoma and metastases from breast and prostate carcinomas

Abstract

Introduction: the cancer stem cell theory and isolation assays

CSC evidence and origin in osteosarcoma

Stem cell features in Ewing tumor of bone

Bone metastasis stem cells

Conclusion: limits of CSC evidence and therapeutic implications

Chapter 14: Homeobox genes from the Dlx family and bone cancers

Abstract

Introduction

Dlx homeobox genes

Dlx homeoproteins

Dlx homeobox gene expressions and functions in skeleton

Dlx homeobox genes and cancers

Conclusions

Chapter 15: MicroRNA implication in therapeutic resistance and metastatic dissemination of bone-associated tumors

Abstract

Introduction

MicroRNAs and metastasis

MicroRNAs and chemoresistance

Conclusion and perspectives

Chapter 16: Hypoxia and angiogenesis: from primary tumor to bone metastasis

Abstract

Introduction

Angiogenesis

Hypoxia

Angiogenesis and tumor progression

Angiogenesis in metastatic bone cancer

Models to study angiogenesis

Anti-angiogenic treatments for bone cancer

Conclusion and perspectives

II: Primary bone tumors

Section 1: Specific biological aspects

Chapter 17: Modeling osteosarcoma: in vitro and in vivo approaches

Abstract

Introduction

In vitro approaches

In vivo approaches

Additional models to consider

Conclusions

Acknowledgments

Chapter 18: Stemness markers of osteosarcoma

Abstract

Introduction

Cancer stem cells

Stemness markers of osteosarcoma

Conclusions

Chapter 19: Molecular pathology of osteosarcoma

Abstract

Introduction

Genomic instability and genetic changes

Tumor suppressor gene dysfunction in osteosarcoma

Oncogenes in osteosarcoma

RECQ helicases

MicroRNA involvement

Genes involved in osteosarcoma metastasis

Molecular insights into therapeutics

Conclusion

Acknowledgments

Chapter 20: Gene and proteomic profiling of osteosarcoma

Abstract

Introduction

Genetic alterations: classical oncogenes and tumor suppressors

Other oncogenic alterations

Classical signaling pathways

Markers of disease progression

Markers derived from proteomics

Other markers influencing the phenotype

Conclusions and future perspectives

Chapter 21: Ewing sarcoma family of tumors

Abstract

Introduction

Clinical features and pathogenesis

Diagnosis and staging

Treatment

Conclusion

Chapter 22: Biology of Ewing sarcoma

Abstract

Introduction

Ewing sarcoma’s oncogenes

The cell of origin of Ewing sarcoma

Other genetic events

Roles of EWS-ETS fusions

Interaction with microenvironment

Understanding metastatic disease

Conclusion

Chapter 23: Osteoclast-rich lesions of bone: a clinical and molecular overview

Abstract

Osteoclast-rich neoplasms of bone

The cherubism phenotype: cherubism, noonan-like/multiple giant cell lesion of the jaw and neurofibromatosis

Conclusion

Chapter 24: Markers for bone sarcomas

Abstract

Introduction

Markers for osteogenic sarcomas

Markers for chondrogenic sarcomas

Markers for Ewing family sarcomas and small blue cell tumors

Markers in other primary bone sarcomas

Conclusion

Chapter 25: Margins and bone tumors – what are we talking about?

Abstract

Introduction

Margins, a mainstay in bone tumor management

Characterization of margins

What is an adequate margin?

Conclusion

Chapter 26: Cytogenetics of bone tumors

Abstract

Introduction

Cartilage tumors

Osteogenic tumors

Fibrogenic tumors

Fibrohistiocytic tumors

Ewing sarcoma/primitive neuroectodermal tumor

Giant cell tumor

Notochordal tumors

Vascular tumors

Myogenic, lipogenic, neuronal, and epithelial tumors

Tumors of undefined neoplastic nature

Conclusion

Chapter 27: Genetic aspects of bone tumors

Abstract

Introduction

Cartilaginous neoplasms

Bone-forming tumors

Conclusion and perspectives

Chapter 28: Cytogenetic and molecular genetic alterations in bone tumors

Abstract

Introduction

Techniques for detecting genetic alterations in bone tumors

Genetic alterations in bone tumor entities

Conclusions and perspectives

Chapter 29: Genetics of giant cell tumors of bone

Abstract

Introduction

Pathophysiology

Cytogenetic analyses of GCT

Molecular analysis of GCT

Conclusions

Section 2: Pre-clinical and clinical aspects

Animal models

Chapter 30: Mammalian models of bone sarcomas

Abstract

General considerations

Osteosarcoma models

Chondrosarcoma models

Ewing sarcoma models

Conclusions and outlook

Chapter 31: Zebrafish models for studying bone cancers: mutants, transgenic fish and embryos

Abstract

Advantages of zebrafish models for cancer research

Osteochondroma

Ewing sarcoma

Osteosarcoma

Imaging

Chapter 32: Imaging of bone sarcomas

Abstract

Introduction

Imaging techniques

Imaging characteristics and considerations of specific sarcoma types

Conclusion

New therapeutic approaches

Chapter 33: New therapeutic targets in Ewing sarcoma: from pre-clinical proof-of-concept to clinical trials

Abstract

Introduction

Therapeutic options for Ewing sarcoma (Table 33.1)

Chapter 34: Therapeutic approaches for bone sarcomas

Abstract

Introduction

Work-up and staging

Surgery

Reconstruction

Computer-assisted navigation

Chemotherapy

Radiation therapy

Therapeutic approaches for primary metastatic and recurrent disease

Conflict of interest statement

Chapter 35: Chondrosarcoma of bone: diagnosis and therapy

Abstract

Introduction

Classification

Difficulties in making the diagnosis of chondrosarcoma

Therapy and prognosis

Outlook for new therapeutic approaches

Chapter 36: Apoptosis and drug resistance in malignant bone tumors

Abstract

Introduction

Osteosarcoma

Apoptosis in Ewing sarcoma

Chapter 37: Giant cell tumors of bone

Abstract

Introduction

Epidemiology

Histology

Clinical presentation

Radiology (Figures 37.2–37.5)

Treatment

RANKL and GCTB: how understanding of pathogenesis drove development of highly active targeted therapy

Clinical studies of RANKL inhibitors

Denosumab

Conclusion

Acknowledgments

III: Bone metastases

Section 1: Specific biological aspects

Chapter 38: EMT process in bone metastasis

Abstract

Introduction

EMT in physiological processes and cancer

EMT in primary tumor and metastatic dissemination

EMT and metastasis to the bone

EMT and cancer stem cells

EMT, circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in the bone marrow

MET and outgrowth of metastasis

Bone marrow-derived cells in EMT and MET regulation

Therapeutic targets in bone metastasis and EMT

Perspective

Chapter 39: Histopathology of skeletal metastases

Abstract

Introduction

Several primary tumors with a predilection for skeletal metastasis

Metastatic carcinoma of unknown primary site

Conclusion

Chapter 40: Disseminated tumor cells in bone marrow of cancer patients

Abstract

Introduction

Biology of DTC

Clinical relevance of DTC in bone marrow

Conclusions

Acknowledgments

Chapter 41: MicroRNA-mediated regulation of bone metastasis formation: from primary tumors to skeleton

Abstract

Introduction

Development of skeletal metastases

Deregulation of microRNA expression modulates multiple steps of the metastatic cascade

Experimental evidence for the involvement of microRNAs in the metastatic cascade leading to bone metastasis formation

Concluding remarks

Chapter 42: Myeloma and osteoclast relationship

Abstract

Introduction

Osteoclastogenesis: molecular mechanisms

Pathophysiology of MM-induced osteoclastogenesis

OCs support MM cell survival: the vicious loop

Therapeutic implications

Conclusions

Section 2: Pre-clinical and clinical aspects

Animal models of bone metastases

Chapter 43: In vivo models used in studies of bone metastases

Abstract

Introduction

Models used in the studies of breast cancer bone metastases (Table 43.1)

In vivo models of prostate cancer bone metastases (Table 43.2)

Models used in the studies of multiple myeloma bone disease (Table 43.3)

Conclusions

Imaging of bone metastases

Chapter 44: Interventional radiologic techniques in management of bone tumors

Abstract

Introduction

Image-guided bone biopsy

Therapeutic embolization

Vertebroplasty

Bone tumor ablation

Chapter 45: Diagnosis of bone metastases in urological malignancies – an update

Abstract

Introduction

History and examination

Serum and bone markers for bone metastases

Imaging modalities

Bone biopsy

Urological malignancies – recommendations

Conclusion

Acknowledgment

Chapter 46: Pre-clinical molecular imaging of the seed and the soil in bone metastasis

Abstract

Clinical need for improved imaging modalities

Pre-clinical models to study tumor progression and metastasis

Small animal imaging modalities

Multimodality imaging

Functional imaging

Conclusions and future perspectives

Bone pain and cancer

Chapter 47: Mechanisms and management of bone cancer pain

Abstract

Epidemiology of bone cancer pain

Models of bone cancer pain

Nervous system reorganization in response to cancer-related bone pain

Pain management strategies

Chapter 48: Bone cancer: current opinion in palliative care

Abstract

Clinical problem

Development of murine model of bone cancer

Unique sensory innervation of bone

Tumor induced acidosis, bone pain, and fracture

Tumor associated stromal cells

Sensory and sympathetic nerve injury and sprouting in the tumor-bearing bone

Bone cancer-induced central sensitization

Conclusion

Chapter 49: Involvement of sympathetic nerves in bone metastasis

Abstract

Introduction

The vicious cycle of bone destruction

What primes the vicious cycle?

Chronic stress reduces survival rate in patients with breast cancer

Influence of sympathetic nerves on the bone microenvironment

Effect of chronic stress on bone metastasis

Beta-blockers for the prevention of breast cancer metastasis

Implications for other types of solid and blood cancers

Chapter 50: Pain control with palliative radiotherapy in patients with bone metastases

Abstract

Introduction

Principles of palliative radiation therapy

Mechanism of action in relief of painful bone metastases

Pain monitoring

Assessment of quality of life

Local field radiation therapy: clinical trials

Wide field radiation therapy: clinical trials

Side effects of local field radiotherapy

Side effects of wide field radiotherapy

Post-operative radiotherapy

Complications of bone metastases

Re-irradiation

Cost-effectiveness

Other treatment modalities and their integration with external beam radiotherapy

Perspectives and conclusions

New therapeutic approaches

Chapter 51: Cellular and molecular actions of bisphosphonates

Abstract

Introduction

BPs target the skeleton

Simple BPs are converted to toxic metabolites

Nitrogen-containing BPs inhibit FPP synthase

N-BPs prevent the prenylation of small GTPase proteins

Inhibition of FPP synthase causes accumulation of IPP and the formation of ApppI

Anti-tumor actions of bisphosphonates

Conclusions and perspectives

Chapter 52: The use of nitrogen-bisphosphonates to capture the potent anti-tumor arsenal of human peripheral blood γδ T cells for the treatment of bone cancer metastasis

Abstract

γδ T cells: lymphocytes intrinsically engineered for cancer immunotherapy

A fortuitous happenstance: when nitrogen-bisphosphonates and human peripheral blood γδ T cells met

Turning potential into practice: γδ T cells and nitrogen-bisphosphonates for cancer immunotherapy

In summary: moving bone cancer management forward with the support of γδ T cells

Chapter 53: Systemic treatment of bone metastases in castration-resistant prostate cancer (CRPC): pre-clinical to clinical point of view

Abstract

Introduction

Pathophysiology and pre-clinical advances

Clinical complications and treatments

Conclusions

Chapter 54: A multi-targeted approach to treating bone metastases

Abstract

Introduction

A model for successful cancer metastasis to bone

Targeting osteoclast function

Targeting osteoblast function

Targeting bone matrix

Targeting endothelial cell function

Enhancing immune response

Targeting tumor associated macrophages

Targeting hematopoietic progenitor cells

Bone and drug resistance

Conclusion

Chapter 55: Bone metastases in prostate cancer: pathophysiology, clinical complications, actual treatment, and future directions

Abstract

Mechanisms of bone metastasis

Clinical complications

Role of denosumab and zoledronic acid

Radium-223

Systemic treatment options

Chapter 56: Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases

Abstract

Introduction

Incidence, prevalence and survival

Diagnosis and types of bone metastases

Clinical consequences of bone metastases

Response to treatment in bone metastases

Predicting bone metastases

Bone physiology and turnover

Pathophysiology of bone metastases

Treatment of bone metastases

Clinical trials and use of bisphosphonates and bone active agents in breast cancer

Bone pain

Some general topics

Some problems

Chapter 57: Bone metastases – current status of bone-targeted treatments

Abstract

Multidisciplinary management of bone metastases

Bone-targeted agents in oncology

Prevention of skeletal morbidity in metastatic bone disease

Breast cancer

Prostate cancer

Other solid tumors

Multiple myeloma

Practical recommendations on use of bone-targeted agents in advanced cancer patients

Safety aspects

Future considerations

Chapter 58: Bone metastases, clinical trials II: zoledronic acid and denosumab in the prevention of bone metastases

Abstract

Introduction and background

Rationale

Z-FAST, ZO-FAST, and E-ZO-FAST

ABCSG-12

AZURE

The menopause issue

Adjuvant denosumab trials

Conclusion and perspectives

Index

Copyright Page

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List of Contributors

Catherine Alix-Panabieres, MD, PhD,     University Institute of Clinical Research UM1 - EA2415 - Epidemiology, Biostatistics & Public Health, Montpellier, France

Matthias J.E. Arlt, Phd,     Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zürich, Switzerland

Regis Bataille, MD, PhD,     Institut de Cancérologie de l’Ouest, Angers, France

Gillian Bedard, BSc(C),     Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

Dominik R. Berthold, MD,     Department of Medical Oncology, University Hospital Canton Vaud, Switzerland

Paolo Bianco, MD,     Stem Cell Lab, Anatomic Pathology, Sapienza University of Rome, Rome, Italy

Frédéric Blanchard, PhD,     INSERM UMR 957, Faculté de Médecine, F-44035 Nantes; Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France

Jean-Yves Blay, MD, PhD,     Medicine Department, Centre Léon Bérard; University Claude Bernard Lyon I; CRCL UMR5286/INSERM 1052, LYRIC (INCA-4664) Lyon, France

Damien Bolton, MD,     Department of Urology, Austin Hospital, University of Melbourne; Department of Surgery, Heidelberg, Melbourne, Australia

Marina Bolzoni, MS,     Hematology, University of Parma, Parma, Italy

Walter Born, PhD,     Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zürich, Switzerland

Sander M. Botter, PhD,     Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zürich, Switzerland

Corinne Bouvier, MD, PhD,     Service d’Anatomie pathologique et de Neuropathologie, Hôpital La Timone, CHU de Marseille, UMR 911, Faculté de Médecine de Timone, Marseille, France

Bénédicte Brounais-Le Royer, PhD,     INSERM UMR 957, Faculté de Médecine, F-44035 Nantes; Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France

Nicola J. Brown, PhD,     Microcirculation Research Group, Department of Oncology, CRUK/YCR Sheffield Cancer Research Centre, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, UK

Jeroen T. Buijs, PhD,     Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands

Daniel F. Camacho, BS,     Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

Preston Campbell, PhD,     Department of Medicine, Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, TN, USA

Daniel Chappard, MD, PhD,     GEROM Groupe Etudes Remodelage Osseux et bioMatériaux – LHEA, IRIS-IBS Institut de Biologie en Santé, CHU d’Angers, LUNAM Université, 49933 Angers Cedex, France

Stephane Chartier, BS,     Department of Pharmacology, University of Arizona, Tucson, AZ, USA

Hong Chou, MBBS, MMED,     Vancouver General Hospital, Vancouver, BC, Canada

Edward Chow, MBBS, MSc, PhD, FRCPC,     Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

Ronald Chow, BSc,     Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

Dimitrios Christoulas, MD, PhD,     Department of Hematology, 251 General Air Force Hospital, Athens, Greece

Anne-Marie Cleton-Jansen, PhD,     Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

Philippe Clézardin, PhD,     INSERM, UMR 1033, Lyon; University of Lyon, Villeurbanne, France

Denis R. Clohisy, MD,     Department of Orthopaedic Surgery and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

Robert Coleman, MD,     Yorkshire Cancer Research Professor of Medical Oncology, Sheffield Cancer Research Centre, Weston Park Hospital, Sheffield, UK

Nadège Corradini, MD,     INSERM, Equipe labellisée LIGUE 2012, UMR957; Université de Nantes, Nantes Atlantique Universités, laboratoire de Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Faculté de Médecine; University Hospital, Hôtel Dieu, CHU de Nantes; Service d’oncologie pédiatrique, Hôpital Mère-Enfant, Nantes, France

Martine Croset, PhD,     INSERM, UMR 1033, Lyon; University of Lyon, Villeurbanne, France

Gonzague de Pinieux, MD, PhD,     Service d’Anatomie et Cytologie Pathologiques, Hôpital Trousseau, CHRU de Tours, Faculté de Médecine, Université François Rabelais, Tours; INSERM, UMR957, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Equipe Labellisée Ligue Contre le Cancer 2012, Nantes, France

Olfa Derbel, MDF,     Medicine Department, Centre Léon Bérard, Lyon, France

Vincenzo Desiderio, PhD,     Department of Experimental Medicine, Section of Embryology and Histology, Second University of Naples, Naples, Italy

James R. Edwards, DPhil,     Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Headington, Oxford, UK

Florent Elefteriou, PhD,     Departments of Medicine, Pharmacology, and Cancer Biology, Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, TN, USA

Michelle Fealk, BA,     Department of Pharmacology, University of Arizona, Tucson, AZ, USA

Adrienne M. Flanagan, MD, PhD,     UCL Cancer Institute, London; Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex, UK

Pierrick G.J. Fournier, PhD,     Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA

Olivia Fromigué, PhD,     INSERM UMR-1132, and Université Paris Diderot, Sorbonne Paris Cité, Paris, France

Bruno Fuchs, MD, PhD,     Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, 8008 Zürich, Switzerland

Dingcheng Gao, PhD,     Department of Cardiothoracic Surgery; Neuberger Berman Lung Cancer Research Center; Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA

Panagiotis D. Gikas, MD,     Sarcoma Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, UK; Institute of Orthopaedics and Musculoskeletal Science, UCL, London, UK

Nicola Giuliani, MD, PhD,     Hematology, University of Parma, Parma, Italy

Michael Gnant, MD,     Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, Austria

Anne Gomez-Brouchet, MD, PhD,     Service d’Anatomie et Cytologie Pathologiques, CHU Rangueil, Toulouse; Faculté de Médecine Toulouse-Rangueil, France

Georg Gosheger, MD,     Department of Orthopaedics, University Hospital of Münster, Germany

François Gouin, MD, PhD,     INSERM, UMR 957, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, Equipe Ligue Contre le Cancer 2012, Université de Nantes, Faculty of Medicine; Department of Orthopaedic and Traumatology, Nantes University Hospital, France

Theresa A. Guise, MD,     Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA

Shuko Harada, MD,     Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

Jendrik Hardes, MD,     Department of Orthopaedics, University Hospital of Münster, Germany

Esther I. Hauben, MD, PhD,     Department of Pathology, University of Leuven, Leuven, Belgium

Wei He, MD,     Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China

Fernanda G. Herrera, MD, PhD,     Department of Radiation-Oncology, University Hospital Canton Vaud, Switzerland

Marie-Françoise Heymann, MD, PhD,     INSERM, UMR 957, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, Equipe Ligue Contre le Cancer 2012, Université de Nantes, Faculty of Medicine; Department of Human Pathology, Nantes University Hospital, France

David G. Hicks, MD,     Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA

Pancras C.W. Hogendoorn, MD, PhD,     Leiden University Medical Center, Leiden, The Netherlands

Ingunn Holen, PhD,     Department of Oncology, Medical School, University of Sheffield, Sheffield, UK

Hakan Ilaslan, MD,     Imaging Institute Musculoskeletal Division, Cleveland Clinic Foundation, Cleveland, OH, USA

Bertrand Isidor, MD,     INSERM, UMR 957, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, Equipe Ligue Contre le Cancer 2012, Université de Nantes, Faculty of Medicine; Department of Medical Genetic, Nantes University Hospital, France

Camille Jacques, BSc,     INSERM, UMR-S 957, F-44035 Nantes; Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, F-44035 Nantes, France

Patricia Juàrez, PhD,     Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA

Simon Junankar, PhD,     Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia

Dieter Kabelitz, MD,     Institute of Immunology, Christian-Albrechts University Kiel, Kiel, Germany

Shirin Kalyan, PhD,     Institute of Immunology, Christian-Albrechts University Kiel, Kiel, Germany

Udo Kontny, MD,     Division of Pediatric Oncology and Stem Cell Transplantation, Department of Pediatrics and Adolescent Medicine, University Medical Center Aachen, Aachen, Germany

Sakari Knuutila, PhD,     Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

Marcella La Noce, PhD,     Department of Experimental Medicine, Section of Embryology and Histology, Second University of Naples, Naples, Italy

Audrey Lamora, BSc,     INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012 Nantes; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France

Francois Lamoureux, PhD,     INSERM, UMR 957, Nantes F-44035; Université de Nantes, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes F-44035, France

Nicholas Lao, BMSc(C),     Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

Nathan Lawrentschuk, MD,     University of Melbourne, Department of Surgery and Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Melbourne, Australia

Michelle A. Lawson, PhD,     Department of Oncology, Medical School, University of Sheffield, Sheffield, UK

Fernando Lecanda, PhD,     Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

Jiyun Lee, MD,     Genetics Laboratory, Department of Pediatrics at University of Oklahoma, Health Sciences Center, Oklahoma City, OK, USA; Department of Pathology, Korea University, Seoul, South Korea

Frédéric Lézot, DDS-PhD,     INSERM UMR 957, Nantes University, Faculty of Medicine, Nantes F-44035, France

Shibo Li, MD,     Genetics Laboratory, Department of Pediatrics at University of Oklahoma, Health Sciences Center, Oklahoma City, OK, USA

Andrej Lissat, MD,     Division of Pediatric Hematology and Oncology, Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany

Joseph Ludwig, MD,     Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Jorma A. Määttä, PhD,     School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio; Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, Turku, Finland

Paul I. Mallinson, MBChB, FRCR, FRCPC,     Vancouver General Hospital, Vancouver, BC, Canada

Patrick W. Mantyh, PhD,     Department of Pharmacology, University of Arizona; Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

Pierre J. Marie, PhD,     INSERM UMR-1132, and Université Paris Diderot, Sorbonne Paris Cité, Paris, France

Andreas F. Mavrogenis, MD,     University of Bologna, Department of Orthopaedics, Orthopaedic Oncology Service, Istituto Ortopedico Rizzoli, Bologna, Italy

Himabindu Mikkilineni, MD,     Imaging Institute Musculoskeletal Division, Cleveland Clinic Foundation, Cleveland, OH, USA

Vivek Mittal, PhD,     Department of Cardiothoracic Surgery; Neuberger Berman Lung Cancer Research Center; Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA

Dominique Modrowski, PhD,     INSERM UMR-1132, and Université Paris Diderot, Sorbonne Paris Cité, Paris, France

Peter L. Munk, MDCM,     Vancouver General Hospital, Vancouver, BC, Canada

Benjamin Navet, PhD,     INSERM UMR 957, Nantes University, Faculty of Medicine, Nantes F-44035, France

Tarja Niini, PhD,     Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

Patrick W. O’Donnell, MD, PhD,     Department of Orthopaedic Surgery, Markey Cancer Center, University of Kentucky, Lexington, KY, USA

Guillaume Odri, MD,     INSERM, UMR 957, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, Equipe Ligue Contre le Cancer 2012, Université de Nantes, Faculty of Medicine; Department of Orthopaedic and Traumatology, Nantes University Hospital, France

Benjamin Ory, PhD,     INSERM, UMR-S 957, F-44035 Nantes; Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, F-44035 Nantes, France

Hugue A. Ouellette, MD,     Vancouver General Hospital, Vancouver, BC, Canada

Francesca Paino, PhD,     Department of Experimental Medicine, Section of Embryology and Histology, Second University of Naples, Naples, Italy

K. Pantel, MD, Dr. med.,     Department of Tumor Biology, Center of Experimental Medicine, University Cancer Center, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Federica Papaccio, MD, PhD,     Department of Experimental Medicine, Section of Embryology and Histology, Second University of Naples, Naples, Italy

Gianpaolo Papaccio, MD, PhD,     Department of Experimental Medicine, Section of Embryology and Histology, Second University of Naples, Naples, Italy

Paul C. Park, MD, PhD,     Transformative Pathology, The Ontario Institute for Cancer Research, Department of Pathology and Molecular Medicine, Queens University, Kingston, ON, Canada

Alexander H.G. Paterson, MB, ChB, MD,     University of Calgary, Calgary; Department of Medicine, Tom Baker Cancer Centre, Calgary, Alberta, Canada

Ana Patiño-García, PhD,     Laboratory of Pediatrics, Clínica Universidad de Navarra, University of Navarra, Pamplona, Navarra, Spain

Kenneth J. Pienta, PhD,     Brady Urological Institute, Baltimore, MD, USA

Marko Popovic, BHSc(C),     Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

Nieroshan Rajarubendra, MD,     Department of Urology, Austin Hospital, University of Melbourne; Department of Surgery, Heidelberg, Melbourne, Australia

Françoise Redini, MD, PhD,     INSERM, Equipe labellisée LIGUE 2012, UMR957, Nantes; Université de Nantes, Nantes Atlantique Universités, laboratoire de Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Faculté de Médecine, Nantes; University Hospital, Hôtel Dieu, CHU de Nantes, France

Kimberley J. Reeves, PhD,     Breakthrough Breast Cancer Unit, Institute of Cancer Sciences, University of Manchester, Cancer Research UK Manchester Institute, Manchester, UK

Clemens Reisinger, MD, Dr. med.,     Vancouver General Hospital, Vancouver, BC, Canada

Mara Riminucci, MD, PhD,     Stem Cell Lab, Anatomic Pathology, Sapienza University of Rome, Rome, Italy

Lidia Rodriguez, BSc,     INSERM, UMR-S 957, F-44035 Nantes; Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, F-44035 Nantes, France

Michael J. Rogers, PhD,     Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia

Pietro Ruggieri, MD, PhD,     University of Bologna, Department of Orthopaedics, Orthopaedic Oncology Service, Istituto Ortopedico Rizzoli, Bologna, Italy

Benedetto Sacchetti, PhD,     Stem Cell Lab, Anatomic Pathology, Sapienza University of Rome, Rome, Italy

Markus J. Seibel, MD, PhD,     Bone Research Program, ANZAC Research Institute, University of Sydney; Department of Endocrinology and Metabolism, Concord Hospital, Concord, Sydney, NSW, Australia

Shamini Selvarajah, PhD,     Advanced Molecular Diagnostics, Division of Molecular Diagnostics, Department of Pathology, Mount Sinai Hospital, Toronto, ON, Canada

Gene P. Siegal, MD, PhD,     Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

Sofia Sousa, MSc,     School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

Jeremy A. Squire, PhD,     Departments of Genetics and Pathology, Faculdade de Medicina de Ribeirão Preto, University of Sao Paulo, 3900 Ribeirão Preto, SP Brazil

Andrea R. Sternenberger, MS,     Genetics Laboratory, Department of Pediatrics at University of Oklahoma, Health Sciences Center, Oklahoma City, OK, USA

Arne Streitbuerger, MD,     Department of Orthopaedics, University Hospital of Münster, Germany

Verena Stresing, PhD,     INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France

Murali Sundaram, MD, FRCR,     Imaging Institute Musculoskeletal Division, Cleveland Clinic Foundation, Cleveland, OH, USA

Julie Talbot, PhD,     INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France

Ping Tang, MD, PhD,     Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA

Thomas Tawadros, MD, PhD,     Department of Urology and Medical Oncology, University Hospital Canton Vaud, Switzerland

Evangelos Terpos, MD, PhD,     Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece

Christian Thomas, MD, PhD,     Department of Urology, University of Mainz, Mainz, Germany

Erik W. Thompson, MD,     St. Vincent’s Institute and University of Melbourne Department of Surgery, St Vincent’s Hospital, Melbourne; Institute of Health and Biomedical Innovation, Queensland Institute of Technology, Brisbane, Australia

Michelle L. Thompson, PhD,     Department of Pharmacology, University of Arizona, Tucson, AZ, USA

Roberto Tirabosco, MD,     Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex, UK

Virginia Tirino, PhD,     Department of Experimental Medicine, Section of Embryology and Histology, Second University of Naples, Naples, Italy

Franck Tirode, PhD,     INSERM U830 – Institut Curie, Paris, France

Valèrie Trichet, PhD,     INSERM, Equipe labellisée LIGUE 2012, UMR957, Nantes; Université de Nantes, Nantes Atlantique Universités, laboratoire de Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Faculté de Médecine, Nantes, France

Geertje van der Horst, PhD,     Department of Urology, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands

Gabri van der Pluijm, PhD,     Department of Urology, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands

Franck Verrecchia, PhD,     INSERM, UMR 957, Equipe labellisée Ligue contre le Cancer 2012, Nantes; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France

Carl R. Walkley, PhD,     St. Vincent’s Institute, Fitzroy, Victoria; Department of Medicine at St. Vincent’s Hospital, University of Melbourne, Fitzroy, Victoria, Australia

Shi Wei, MD, PhD,     Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

Maria Zielenska, PhD,     Molecular Pathology Laboratory, Senior Associate Scientist, Genetics & Genome Biology, Hospital for Sick Children, Toronto; Department of Laboratory Medicine & Pathobiology, Toronto, ON, Canada

Foreword

The skeleton is the most common site of metastatic disease and bone metastases have a devastating impact on quality of life. The field of tumor bone disease has seen considerable progress over the last 2 or 3 decades. The multiple interactions between tumor cells and the bone microenvironment contribute to the development of metastases both within and probably outside bone. These multidirectional interactions between cancer cells, bone cells and the bone microenvironment lead to a self-sustaining vicious cycle of bone destruction. The understanding of the key role of osteoclasts in the genesis of cancer-associated bone disease has led to the extensive use of bone resorption inhibitory drugs. The introduction of bisphosphonates and more recently denosumab in our therapeutic armamentarium has significantly improved the prognosis of patients with tumor bone disease. These compounds are now an integral part of our therapeutic means for the treatment and the prevention of skeletal complications related to tumor bone disease. However, much progress remains to be done and further clinical improvements will only come from a better understanding of osteotropism, osteomimetism and the interactions between cancer cells and the various components of the bone tissue.

I have the privilege to preface this comprehensive state-of-the-art book. Several books covering various aspects of tumor bone disease are now available. However, this Second Edition of Bone Cancer has several outstanding features. The chapters are written by recognized experts in the field and they cover all essential basic and clinical aspects of cancer-induced bone disease. The title Bone Cancer is justified by the fact that, besides metastatic bone disease, a large part of the book is devoted to various primary malignant bone tumors, covering their biology, the usefulness of markers and of animal models, and current or promising therapeutic approaches. Covering both primary and secondary bone tumors in the same book is even more important that interactions between researchers and clinicians from both fields should be particularly fruitful. Compared to the first edition, many more chapters have been added. Recent developments in the field are amply covered, including the importance of cancer stem cells and the bone tumor niche, the key role of all types of cells within bone -including osteocytes and macrophages-, miRNA, molecular imaging, and new therapeutic targets. Such developments have opened the way to a promising new therapeutic avenue, namely the prevention of bone metastases, which is indeed covered in the last chapter.

I recommend this book to all researchers in the bone field but also to clinicians who have to take care of cancer patients with primary or secondary bone tumors.

Professor Jean-Jacques Body

CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium

The task of putting this book together was an ambitious one that has succeeded admirably in bringing together the genetics, pathogenesis, imaging and treatment of primary and of metastatic bone cancers. Although primary tumors of bone differ from secondary tumors in many ways, they have much in common. They each need to establish and progress in a tissue that provides a harsh environment, so must share certain properties that help them to make their way. In developing this from the First Edition (published 2010), the editor, Dominique Heymann, has extended its scope and depth of coverage in a number of important areas, including basic bone biology, animal models, and genetics and imaging of sarcoma. Most importantly also, metastatic bone disease is given appropriate attention. There are many lessons to be learned from the differences and similarities between the growth in bone of primary and secondary tumors.

At the risk of betraying prejudice in coming to this as a bone biologist, it is tempting to wonder at the biological importance of the skeleton, revealed in the last few decades as much more than a protective framework for the really interesting organs. We need only reflect on the wide range of skeletal phenotypes that result from genetic changes in mouse and man, in transcription factors, cytokines, growth factors and hormones. The stem cells of bone, both hemopoietic and mesenchymal, have become amenable to study in ways that reveal the close harmony between bone as an organ and the blood cells that it hosts. Regulatory factors previously considered to be the realm of hematology, immunology, and neuroscience have emerged as being necessary for normal bone development. Bone is even now considered to be an endocrine organ, and to engage in two-way communication with the central nervous system. These remarkable properties of bone are taken into consideration within the context of the chapters in this book, and due consideration is given to basic bone cell biology in the selection of chapters and authors.

A comprehensive coverage of osteosarcoma and Ewing’s sarcoma is provided in the volume. Among the challenges of osteosarcoma are that it is the most common primary tumour of bone, the most prevalent in children, and although long-term survival now approaches 70%, patients with metastatic disease face less than 20% survival. At presentation approximately 20% of patients have metastases and almost all patients with recurrent OS have metastatic disease. The advent of cytotoxic chemotherapy in the 1960’s and improved surgical approaches have improved prognosis, but this has plateaued in the last 30 years. Advances in pathological grading of osteosarcoma have made major contributions to clinical decision-making, as has the application of new methods of imaging. All of these are featured in the book, to illustrate the multi-disciplinary approaches that are required in the management of osteosarcoma and Ewing’s sarcoma.

Improved preclinical platforms are needed, and especially in these low frequency cancers, the development of tractable model systems that reflect the human disease in both clinical spectrum and response to therapy. These subjects are dealt with in many chapters that reveal prospects of improved preclinical testing. The recent advent of more sophisticated genetically engineered murine models and the increasing push to move to primary xenografts have signified a shift in focus for osteosarcoma. Advances in mouse genetic manipulation approaches have yielded numerous recent examples of OS models that show high fidelity to the human disease. These mouse models, coupled with models in zebrafish and spontaneous disease in pet dogs, form the basis for new preclinical testing approaches. It is to be hoped that these models can also lead the way to developing treatments for metastatic disease.

One property common to osteosarcoma and to secondary cancer in bone is the ability to promote the formation of osteoclasts that can excavate a space for the tumor. This property of osteosarcoma is highlighted by several authors, but it is a special feature of metastatic bone disease. The great propensity of breast cancers to establish and grow as metastases in bone was recognised by Stephen Paget in the late nineteenth century, leading to his concept of the bone soil being favorable for the breast cancer seed. His idea that cancers, in order to grow in distant organs, need special properties to suit them to those organs, summarizes modern views of the metastatic process. Even with increasing knowledge of the complexity of metastasis generation, that does not change.

Many special properties of bone as an organ make it harsh and unwelcoming to tumor cells that arrive there, including the hardness of bone as a tissue, its constantly changing environment that requires communication processes encompassing cells of mesenchymal, hemopoietic and immunological lineages and their cytokine products, and its susceptibility to circulating hormones.

All of these aspects are covered in the several chapters, those concerned with both basic and clinical aspects of cancer interaction with the skeleton. The recurring theme throughout these discussions is that there are indeed special properties of the bone microenvironment that influence cancer cell behavior. This has been a great driver of treatment, and reviews are provided of the efficacy of bone resorption inhibitors such as bisphosphonates and RANKL blockade. The more we can understand this, the greater the chance of intervening therapeutically in this destructive symbiosis that so often establishes itself between certain malignancies and the skeleton.

As a compilation of current information on bone cancer at its broadest, this book provides a valuable resource, and Dominique Heymann is to be congratulated on his achievement in bringing together these authors from many countries, selected for the authoritative contributions that they make to understanding of the biology of bone cancer.

T. John Martin, FRS

University of Melbourne

St. Vincent’s Institute of Medical Research

9 Princes Street

Fitzroy 3065

Victoria

Australia

November 6, 2013

Preface

Genetic or environmental deregulation of bone cells and/or of their microenvironment leads to development of bone cancers, including primary bone tumors (osteosarcoma, Ewing’s sarcoma, chondrosarcomas, giant cell tumors) that originate from bone cells or mesenchymal stem cells. Bone tissue is also a privileged site for development of metastases, attracting tumor cells derived from non-bone cells such as breast cancer cells or prostate carcinomas cells. Some tumor cells, including myeloma cells, initially proliferate in bone sites and then deregulate the balance between bone absorption and resorption in favor of an osteolytic process.

The last 2 decades have witnessed an explosion in the field of bone biology, marked by significant advances that have opened up entirely new areas for investigation. Indeed, molecular mechanisms that control bone remodeling have been extensively investigated, and some novel scientific fields have emerged. This was the case for osteoimmunology, after identification of a set of molecules (RANKL, OPG, OSCAR) allowing communication between bone cells (ostoclasts, osteoblasts) and immune cells (monocytes, lymphocytes, dendritic cells). Similarly, concepts based on the neuronal regulation of bone mass have emerged recently with the rehabilitation of already know bone factors with new hormonal functions, for example osteocalcin. Circulating tumor cells appear to be a prognostic biological marker related to recurrent oncologic diseases, and may be identified following their isolation from blood, which in itself raises new technological challenges. Tumor cell dormancy may be the future end point of new therapies in oncology. This book provides an overview of recent epidemiological data of bone tumors, including primary bone tumors (bone sarcomas) and bone metastases. Their biological and molecular aspects (protein and gene) clearly identify new therapeutic targets and approaches. In addition to a full description of the innovative biological aspects of bone tissue, bone sarcomas, and bone metastases, this book also addresses more recent clinical aspects, including histopathology, imaging of bone tumors, management of bone pain, and conventional therapeutic care. Finally, better knowledge of biological mechanisms associated with the development of many pre-clinical models allows the emergence of new therapeutic approaches towards bone tumors.

This book, a description of bone tumors from basic to clinical aspects supported by the most recent data available, is specifically dedicated to medical students and scientists, health professionals, researchers, and teachers working in the osteo-articular field. This second edition has been enriched by additional reviews written by international specialists in bone biology and disease. This second edition includes 58 chapters written by 50 professional teams from 14 countries. I would like to thank all the authors for their work and their kindness in sharing their expertise with students, colleagues, and all readers.

Dominique Heymann, PhD

Professor, Faculty of Medicine, University of Nantes

Head of Pathophysiology of Bone Resorption and

Therapy of Primitive Bone Tumors,

INSERM, Nantes, France

I

Basic aspects of bone cancers

Section 1: Epidemiology of bone cancer

Section 2: Bone microenvironment and bone cancer

Section 3: Markers of bone cancer (cells, genes and proteins)

Section 1

Epidemiology of bone cancer

Epidemiology of primary bone tumors and economical aspects of bone metastases

Chapter 1

Epidemiology of primary bone tumors and economical aspects of bone metastases

Esther I. Hauben¹

Pancras C.W. Hogendoorn²

¹  Department of Pathology, University of Leuven, Leuven, Belgium

²  Leiden University Medical Center, Leiden, The Netherlands

Abstract

Malignant primary bone tumors are rare and are outnumbered by metastasis to the bone and hematological disorders. The most common primary malignant bone tumors are: osteosarcoma, chondrosarcoma, Ewing sarcoma and undifferentiated pleomorphic sarcoma. Osteosarcoma and Ewing sarcoma, accounting for approximately 50% of the malignant bone tumors, affect mostly children and young adults and have a major impact of the life of the patient and his family. Besides the burden of illness there is also an important financial burden. The direct costs for the health care system, related to diagnosis and treatment, can be estimated rather easily. However, the direct costs for the family, and more so the indirect costs of diminished or loss of productivity, and of pain and suffering are more difficult to calculate and are underestimated. This is more relevant in the younger age group, due to the prolonged survival of these patients after initial treatment.

Keywords

malignant bone tumors

bone metastases

costs of illness

epidemiology

Introduction

Primary bone tumors are rare and as such they form a difficult category of tumors for appropriate recognition and classification, both for treating clinicians as well as radiologists and pathologists. They account for less than 0.2% of the malignancies registered in the SEER database¹. The occurrence of bone sarcomas ranges between 0.8 and 2 cases per person per year¹. As compared with soft tissue sarcomas, bone sarcomas occur with only 1/10th the frequency of the former¹. The most common primary bone sarcomas are osteosarcoma, chondrosarcoma, Ewing sarcoma, and undifferentiated pleomorphic sarcoma, previously known as MFH of bone. However, particularly children and adolescents are affected, which means that bone tumors have a major impact on the life of the patient and their immediate family. The incidence of benign bone tumors is considerably higher. A number, however, are asymptomatic and therefore do not come to the patient’s or doctor’s attention. Therefore, benign bone tumors most likely are underreported, but nevertheless they are a rare event, compared with other benign tumors occurring in the body. Another confounding factor is the high discrepancy rate at histological review of bone tumors, which make most population-based series somewhat unreliable². On the other hand, consultation series or expert center series are likely to over-report difficult/unusual cases.

Bone tumors can occur spontaneously; however, a substantial number occur in the context of a hereditary disorder, thus implicating a detailed family history in every new case. If suspected for a hereditary context, a proper work-up, often in close collaboration with clinical geneticists, is mandatory³,⁴. This hereditary aspect might explain the higher incidence in some regional populations.

A subgroup of primary bone malignancies occur secondary to benign precursor lesions in the bone, such as bone infarction, chronic osteomyelitis, Ollier disease, fibrous dysplasia, or Paget’s disease of bone⁵–⁹, so the incidence comprises the occurrence of the primary condition in the population. For instance, there is a well-known regional incidence difference for Paget’s disease of bone. Recent attention has been drawn to small numbers of cases of bone sarcomas in association with metallic prostheses and implants, but a causal relation has not been proven.

Both benign and malignant primary tumors of bone are outnumbered by far by metastases to bone from epithelial cancers or melanoma and hematological disorders such as multiple myeloma/plasmacytoma.

Incidence of primary bone tumors

The incidence of bone tumors, especially primary bone sarcomas, compared with malignant tumors in general, is very low. Review of large series revealed that approximately 0.2% of all neoplasms are bone sarcomas¹⁰–¹². In Europe about two new primary bone sarcomas arise per 100,000 persons a year. Interestingly, at childhood there is a steep shift in frequency of occurrence over the age span¹³. From the first year of life, the incidence increases from 3.9 per 100,000 to a peak of 142.9 per 100,000 at the age of 15¹³. In the archives of the Netherlands Committee of Bone Tumours, comprising over 14,000 cases of bone tumors and tumor-like lesions, the percentages of sarcomas in decreasing order of frequency for malignant bone tumors are: osteosarcoma (37%), chondrosarcoma (23.6%), Ewing sarcoma (12.2%), undifferentiated pleomorphic sarcoma of bone (10.9%), non-Hodgkin’s lymphoma of bone (3.3%), malignancy in giant cell tumor (2.3%), Paget sarcoma 1%, and adamantinoma (0.8%)¹⁰.

Fibrosarcoma and malignant fibrous histiocytoma are diagnoses of exclusion and not frequently encountered nowadays. This is reflected by a change in insights with regard to classification of these tumors, which in practice commonly appear to be poorly differentiated osteosarcoma, or dedifferentiated chondrosarcoma. A terminology of undifferentiated pleomorphic sarcoma of bone is nowadays preferred, acknowledging the fact that true histiocytic differentiation is lacking in these tumors. For benign tumors, enchondroma are the most frequent (27.7%) followed by giant cell tumors (21.5%), osteochondroma (14%), osteoid osteoma (10.5%), chondroblastoma (9%), and osteoblastoma (5.7%)¹⁰. An age-dependent frequency difference is present, however¹³, as discussed below.

Age

Bone tumors have an age-related presentation. There are two age-specific peaks in frequency in bone sarcomas. The first peak occurs in the second decade of life, and consists of osteosarcoma and Ewing sarcoma in case of malignant tumors, and osteochondroma in the benign group¹³. The second peak, slightly increasing from the fourth decade, has its top after the sixth decade and includes chondrosarcoma, undifferentiated pleomorphic sarcoma, chordoma, and osteosarcoma, including Paget and radiation-induced sarcomas. Chondrosarcomas are somewhat equally distributed over all the decades, rarely found in the first 20 years of life and slightly increasing thereafter. Malignant progression of osteochondroma, as in multiple osteochondroma, is only seen a number of years after closure of the growth plate and can be recognized by restart of growth of the cartilaginous cap of a pre-existent osteochondroma¹⁴.

The majority of benign bone tumors and tumor-like lesions in young patients are seen in the first and second decades of life. In about half, the median age is in the second decade (solitary bone cysts, aneurysmal bone cysts, non-ossifying fibroma, fibrous cortical defect, enchondroma, Langerhans cell histiocytosis, osteochondroma, chondroblastoma, osteoblastoma, and osteoid osteoma). The median age incidence of the others is not specifically age-related, and may be seen in the first decade extending even into the sixth or seventh decade (i.e. juxtacortical chondroma, parosteal osteosarcoma, desmoplastic fibroma). Giant cell tumors occur almost exclusively after closure of the epiphyseal plate.

Gender

The male–female ratio has little diagnostic contribution for most bone tumors, as in general there is no striking difference and both sexes are roughly equally affected. In osteosarcoma the male–female ratio is 1:1. In Ewing sarcoma, Paget’s sarcoma, chordoma and primary osseous non-Hodgkin lymphoma there is a higher prevalence in males (2:1). Some male predominance is seen in some benign lesions such as osteochondroma, chondroblastoma, osteoid osteoma, solitary bone cyst, or osteoblastoma. Whether this correlates with a higher incidence of trauma in males, which attracts attention to an underlying, previously asymptomatic tumor is unknown.

Site distribution

Bone tumors have preference for the long bones of the extremities. The metaphysis is the preferred site for malignant bone tumors, especially that of the distal and proximal femur, the proximal tibia and proximal humerus, which are the affected sites in more than 80% of osteosarcoma. Depending on the extent of the tumor, the epiphysis, and even diaphysis, might also be affected.

Most central chondrosarcomas are restriction to the long bone marrow space, mostly in metaphysial and diaphysial locations. Undifferentiated pleomorphic sarcoma of bone arises and extends mostly in the metaphysis, like osteosarcoma, again adding to the question if this should not be regarded as a poorly differentiated form of osteosarcoma. Ewing sarcoma tends to arise more frequent in the diaphysis, but may extend also in the metaphysis. Chordomas are sited exclusively in the sacrum, vertebra and skull, except for very rare casuistic presentations in the long bones. Other sites than the long bones for sarcomas are the flat bones such as pelvis, scapula and ribs (chondrosarcoma and Ewing sarcoma) and craniofacial bones (osteosarcoma). Adamantinoma is almost pre-eminently sited in the tibia and sometimes the fibula.

In benign tumors the epiphyseal location is restricted for chondroblastoma, osteoblastoma and dysplasia epiphysialis hemimelica. Solitary and aneurysmal bone cysts occur metaphysically, usually close to the epiphysis. All osteochondroma originate in the metaphysis of long bones and increase the distance to the epiphysis during growth. Fibrous dysplasia can occur at all sites in all bones. Lesions in the phalangeal bones are statistically almost always enchondroma, with rare exceptions¹⁵,¹⁶.

Incidence of bone tumors as a secondary event

Both benign as well as malignant bone tumors can occur as a result of a pre-existing non-tumorous condition of bone or as a result of an unrelated condition such as Paget’s disease¹⁷,¹⁸, chronic inflammation¹⁹, irradiation²⁰–²², bone infarction²³, or prostheses²⁴.

Racial differences in incidence of primary bone tumors

While there are some differences reported in incidence between different national registries in the frequency of occurrence, most striking racial differences are reported with regard to Ewing sarcoma²⁵ and giant cell tumor of bone²⁶. GWAS studies point to the absence of certain polymorphisms in the germ line, explaining the extremely low incidence of Ewing sarcoma in populations of African descent. Giant cell tumors of bone tend to occur more frequent in the Asian population for as yet unknown reasons.

Incidence of bone metastases

The incidence of malignant tumors metastasizing to the skeleton is dependent of the incidence of a given cancer and can vary demographically. After lung and liver, the skeletal system is the most common site to be involved by metastatic tumor²⁷ and metastatic carcinoma is the most frequent malignancy of bone¹². Preferred sites are spine, pelvis, femur, and rib in descending order²⁸.

The most common cancers metastasizing to bone are breast, lung, prostate, kidney, and thyroid cancer²⁹. Skeletal metastases develop in 70–80% of patients with breast or prostate cancer and in 40% of patients with advanced lung cancer³⁰.

Pathology of bone metastases

Neoplastic involvement of the bone causes increased bone turnover and uncoupling of bone formation and resorption. Clinically this results in pain, risk of fracture, hypercalcemia and sometimes spinal cord compression²⁸,³⁰. Treatment consists of pain relieving medication, radiation therapy, and if necessary surgery. The denominator skeletal related event (SRE) encompasses pain, radiotherapy, reduced mobility, symptoms of hypercalcemia, pathologic, fracture, spinal cord compression, and bone marrow infiltration. Approximately half of patients with bony metastasis develop at least one SRE (Table 1.1). Consequences for the patients are severe and consist of impairment or loss of functionality, loss of quality of life, and decreased survival. SREs have also financial implications for the health care system and thus the community, and for the patient. The financial impact of SREs is greater for cancers with prolonged survival. The median survival after presentation with a bony metastasis is 2–3 years for patients with breast cancer or prostate cancer and a median of 4 months for patients with lung cancer³¹.

Table 1.1

Pathology of bone metastases

# pt: number of patients with bone metastasis.

SRE+: number of patients with bone metastasis and 1 or more SREs.

RT: number of patients with radiation therapy.

FR: number of patients with fracture.

Surg: number of patients with surgery.

Cost: cost of treatment of SREs:aover 24 months, bover 36 months, cover 60 months, dover 12 months, efirst year of treatment.

Cost of illness

Cost of illness (COI) is defined as the value of the resources that are expended or forgone as a result of a health problem. It includes health sector costs (direct costs), the value of decreased or lost productivity by the patient (indirect costs), and the cost of pain and suffering (intangible costs)³². Direct costs for the health sector are: hospitalization, medication, emergency transport, and medical care. In addition, the patients and family have costs directly related to treatment of illness, as there are non-refunded payments for hospitalization, medical visits and drugs; transportation of patient and family for health visits; transportation of family to visit the hospitalized patient; modifications at home as a result of illness; and costs for taking care of the patient at home.

Decreased or lost productivity can be the result of illness, premature death, side effects of illness or treatment, or time spending receiving treatment. This not only affects the patient but also the family members, who reduce or stop their employment to take care of the patient. With premature death, the indirect cost is the loss in potential wage and benefits.

From the foregoing, it is clear that it is difficult to estimate the COI. The easiest cost to calculate is the direct cost for the health care system. The direct costs for the patient are more difficult to estimate, because data on the costs are usually insufficient or inexact. The most difficult to estimate are the intangible costs, and the cost of loss of productivity. Most studies on the economic burden of illness focus only on the direct medical costs for the health care sector, thus underestimating the total cost of illness.

Cost analysis gives an indication of the financial impact of disease, and provides information to policy makers, researchers, and medical specialists that can be considered in making more efficient use of resources. Additionally, on the basis of distinction between different cost components, it may be possible to estimate the financial aspect of various treatment strategies, which can influence the choice of treatment.

Economical burden of bone metastasis

Studies on the economical impact of bone metastasis are rare and only report on the costs for the health care sector. The first study on the subject was done in the Netherlands in 2003. Groot and colleagues³³ investigated the cost of treatment for SREs in patients with prostate cancer metastatic to the bone. They followed 28 patients with SRE because of prostate cancer metastatic to the bone for a period of 24 months. The overall cost of treatment per patient for this period was €13,051 of which €6973 (50%) was spent in the treatment of SREs. The overall cost was calculated on the whole of the medical care, including manpower, material, and overhead cost (e.g. housing). For the cost directly related to the treatment of SREs, the costs of radiation therapy, hospitalization, and surgical intervention were taken in account. Thus, this is the direct cost for the health care sector. They did not look at the eventual cost of patient care in a nursing facility, and direct or indirect costs for the patient. Indirect costs are estimated to be limited in patients with prostate cancer. In their study on 28 patients, bone metastases developed after the age of 60, with a mean age of 73 years. This is a non-active population from the viewpoint of employment.

In 2004 a second study was published, this time from the US on the cost of treating SREs in patients with lung cancer³⁴. In a US health insurance claim database 534 patients were identified with lung cancer and skeletal involvement. Costs were estimated on the basis of the claims made, and did not include overhead costs. Of these 534 patients, 55% developed at least one SRE. In the SRE patient group, 68% received radiation therapy, 35% suffered a pathologic fracture, and 14% had bone surgery. The mean age at first SRE was 66.4 years, which also indicates that indirect costs due to loss of productivity tend to be limited. The mean survival after first SRE was 4.1 months. The estimated life-time SRE related cost after 36 months is $11,979 of which 61% goes on radiation therapy. These and other studies are summarized in Table 1.1. Data are difficult to compare due to the difference in costs included, the method of treatment, e.g. single fraction or multiple fraction radiation therapy, the period over which the costs are calculated, the method of calculation, and index changes over the years.

These studies give an idea on the cost of treatment of SREs but not on the impact of SREs on the total direct medical care of cancer patients. Delea and colleagues³⁵ repeated their study on lung cancer patients with bone metastases, but now compared the costs of treatment for patients with SREs with patients without SREs. The additional cost for SRE patients on the total cost for cancer treatment was $27,982 per patient. The same exercise was done for patients with breast cancer with bone metastases³⁶. Total medical care costs over 60 months in patients with SREs were $48,173 greater than in non-SRE patients. For women younger than 65 years of age the additional cost for treatment of SREs is $62,286, and for women above 65, $36,452. This is a reflection of the better survival rates among younger woman. The lower additional cost for SRE treatment in lung cancer patients is explained by the fact that patients with lung cancer metastatic to bone have a median survival of 4.1 months, whereas women with breast cancer and metastatic bone disease experience a mean life expectancy of 2–3 years.

Nevertheless, these studies do not give an idea of the economical impact of metastatic bone disease (MBD). Patients with MBD are expected to cost more to the health care sector than patients without, because of, e.g. intensified follow-up or SRE preventive treatment with bisphosphonates. The costs of treatment attributable to the treatment of SREs have been reduced in recent years due to the use of bisphosphonates and especially zoledronic acid³⁷,³⁸, but they also come with a price tag and MBD