Chordomas and Chondrosarcomas of the Skull Base and Spine

Chordomas and Chondrosarcomas of the Skull Base and Spine

Second Edition

Editors

Griffith R. Harsh, IV

Stanford University School of Medicine, Palo Alto Stanford, CA, United States

Francisco Vaz-Guimaraes

Michael E. DeBakey VA Medical Center, Houston, TX, United States

Contributing Advisors

Neurosurgery

Paul A. Gardner

Associate Professor of Neurosurgery, Department of Neurological Surgery, University of Pittsburgh School of Medicine, Co-Director, Center for Cranial Base Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States

Otolaryngology/Head and Neck Surgery

Peter Hwang

Professor of Otolaryngology, Chief, Division of Endoscopic Skull Base Surgery, Department of Otolaryngology and Head and Neck Surgery, Stanford University, Stanford, CA, United States

Robert K. Jackler

Edward C. and Amy H. Sewall Professor of Otorhinolaryngology and Chair, Department of Otolaryngology and Head and Neck Surgery, Stanford University, Stanford, CA, United States

Carl H. Snyderman

Professor of Otolaryngology and Neurological Surgery, Department of Otolaryngology, University of Pittsburgh School of Medicine, Co-Director, Center for Cranial Base Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States

Radiation Oncology

Jay S. Loeffler

Herman and Joan Suit Professor of Radiation Oncology and Chair, Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, Clark Center for Radiation Oncology, Boston, MA, United States

Medical Oncology/Orthopedics

Francis J. Hornicek

Associate Professor of Orthopaedics Chief, Orthopaedic Oncology Service, Co-director, Center for Sarcoma and Connective Tissue Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States

Table of Contents

Cover image

Title page

Copyright

Dedication

List of Contributors

Foreword

Preface

Section I. Embryology, Pathology, and Molecular Biology

Chapter 1. Embryology of the Skull Base and Vertebral Column

Introduction

The Skull Base

Embryological Development of the Notochord and Vertebral Column

Chapter 2. Pathology of Chordoma and Chondrosarcoma of the Axial Skeleton

Chordoma

Epidemiology

Classification and Pathology

Cytogenetics

Prognostically and Therapeutically Significant Pathological Features

Chondrosarcoma

Epidemiology

Classification and Pathology

Chapter 3. Molecular Drivers in Chordoma

Pathogenesis and Molecular Biology of Chordoma

Hypoxia and Angiogenesis in Chordoma

Apoptosis in Chordoma

Cancer Stem Cells

Animal Models of Chordoma

Molecular Drivers in Chordoma Invasion and Metastasis

Summary/Conclusions

Chapter 4. Molecular Drivers in Chondrosarcoma

Introduction

Clinicopathological Classification of Chondrosarcoma

Molecular Drivers in Chondrosarcoma

Summary/Conclusion

Section II. Demographics, Presentation, and Diagnosis

Chapter 5. Demographics, Presentation, and Diagnosis

Introduction

Demographics

Presentation

Diagnosis

Conclusions

Chapter 6. Differential Diagnosis of Clival and Spinal Tumors

Introduction

Congenital Tumors

Primary Cartilaginous Tumors

Primary Osseous Tumors

Central Nervous System Tumors

Secondary Neoplastic Tumors

Nonneoplastic Tumors

Other Tumors

Chapter 7. Imaging Cranial Base Chordoma and Chondrosarcoma

Imaging Technique

Part I: Chordoma

Part II: Chondrosarcoma

Part III: Potentially Confounding Lesions

Chapter 8. Imaging Chordoma and Chondrosarcoma of the Vertebrae and Sacrum

Part I: Chordoma

Part II: Chondrosarcoma

Part III: Potentially Confounding Lesions

Section III. Surgery of Skull Base Tumors

Chapter 9. Surgical Anatomy of the Skull Base

Introduction

General Skull Base Anatomy2

Essential Endoscopic Endonasal Anatomy: The Sphenoid Bone, Sphenoid Sinus, and Pituitary Gland (Fig. 9.4)

Anatomy of the Clivus and Environs

Chapter 10. Skull Base Tumors: Surgical Considerations

Introduction

Treatment Strategies

Skull Base Surgical Principles

Preoperative Assessment

Choice of Approach: Anatomic Considerations

Surgical Corridors to Anatomically Distinct Modules of the Skull Base

Anterior Approaches to Clival Tumors

Lateral Approaches to Clival and Petrous Tumors

Conclusions

Chapter 11. Midline Subfrontal Approaches: The Transbasal Approach and Extended Modifications to Access the Clivus

Introduction

Surgical Considerations: Selection of Approach

Preoperative Considerations

Surgical Positioning

Skin Incision

Standard Bifrontal Transbasal Approach

Extended Transbasal Approaches

Modified One-Piece Extended Transbasal Approach

Subcranial Approach

Combined Transbasal and Endoscopic Endonasal Approach

Reconstruction

Postoperative Management

Conclusion

Chapter 12. The Endoscopic Endonasal Approach to Chordomas and Chondrosarcomas

Introduction

Anatomy—Endonasal Perspective

Indications and Preoperative Planning

Approach

Sinus/Nasal Phase

Transmaxillary Approaches

Upper Clivus

Mid-clivus

Lower Clivus/Craniocervical Junction

Petrous Apex/Petroclival Junction/Cavernous Sinus/Occipital Condyle (Coronal Plane)

Limitations

Reconstruction

Postoperative Care

Results

Conclusion

Chapter 13. Transoral Approaches to Midline Skull Base Tumors

Summary

Chapter 14. Chordomas and Chondrosarcomas of the Skull Base: Anterolateral Approaches

Introduction

Indications and Preoperative Planning

Surgical Technique and Complication Avoidance

Postoperative Care

Results

Conclusions

Chapter 15. Lateral Approaches

Middle Cranial Fossa Approach

Extended Middle Cranial Fossa Approach

Preoperative Considerations

Patient Position and Monitoring

Extradural Exposure

Intradural Petrous Apicectomy

Extradural Petrous Apicectomy

Tumor Removal

Reconstruction

Potential Complications

Combination With Other Approaches

Benefits of the Intradural Option

Case Group (Intradural Option)

Benefits of the Extradural Option

Case Example (Extradural Option)

Chapter 16. Subtemporal–Preauricular Approach to the Infratemporal Fossa

Background

Application of the Approach

Preoperative Evaluation and Planning

Operative Approach

Closure and Reconstruction

Case 1

Case 2

Case 3

Chapter 17. Chordomas and Chondrosarcomas of the Skull Base: Transpetrosal Approaches

Indications and Preoperative Planning

Surgical Techniques Common to All Transpetrosal Approaches

Postoperative Care

Results

Illustrative Cases

Conclusions

Chapter 18. Chordomas and Chondrosarcomas of the Skull Base: Retrosigmoid Approaches

Introduction

Indications and Preoperative Planning

Surgical Techniques and Complication Avoidance

Postoperative Care

Results

Conclusions

Chapter 19. The Extreme Lateral Approach for Chordomas and Chondrosarcomas of the Craniovertebral Junction

Introduction

Pathophysiology

Surgical Anatomy

Indications

Preoperative Evaluation

Operative Procedure

Discussion

Conclusion

Chapter 20. Staged Approaches for Large Skull Base Chordomas and Chondrosarcomas

Introduction

Preoperative Planning

Conclusions

Chapter 21. Cerebral Revascularization for Skull Base Tumors

Preoperative Evaluation

Bypass Types and Selection

Operative Technique

Postoperative Care and Follow-Up

Results and Case Examples

Chapter 22. Skull Base Reconstruction Following Resection of Skull Base Chordomas and Chondrosarcomas

Introduction

Consideration and Goals of Skull Base Reconstruction

Reconstruction of the Skull Base

Postoperative Care

Outcomes

Complication

Recommendation

Conclusion

Case Presentation

Chapter 23. Stabilization of the Craniocervical Junction Following Resection of Chordomas and Chondrosarcomas of the Skull Base and Spine

Introduction

Surgical Technique

Important Considerations

Representative Case

Section IV. Surgery of Spinal and Sacral Tumors

Chapter 24. Chordomas and Chondrosarcomas of the Spine: Preoperative Planning, Surgical Strategies, and Complications Avoidance

Introduction

Rationale for Surgical Treatment

Surgical Technique for En Bloc Resection of Spine Tumors

Perioperative Complications

Conclusions

Chapter 25. Surgical Management of Chordomas and Chondrosarcomas of the Cervical Spine

Introduction

Surgical Management

Illustrative Cases

Conclusion

Chapter 26. Surgical Management of the Chordomas and Chondrosarcomas of the Thoracic Spine

Introduction

Preoperative Planning

Surgical Technique: Thoracic Spine En Bloc Spondylectomy

Complication Avoidance and Postoperative Care

Results

Summary

Chapter 27. Surgical Management of Chordomas and Chondrosarcomas of the Lumbar Spine

Introduction

Postoperative Care

Results

Conclusion

Chapter 28. Anatomical Considerations for Resection of Chordomas and Chondrosarcoma of the Sacrum

The Soft Tissues

The Sciatic Notch

Ligaments

The Sacrospinal Canal

Presacral Dissection

Osteotomy

Neurectomy

Closure

Chapter 29. Surgical Treatment of Sacral Chordoma

Introduction

Evidence for Surgical Resection

Lumbopelvic Reconstruction

Soft-Tissue Reconstruction

Conclusion

Section V. Radiation Therapy of Chordomas and Chondrosarcomas

Chapter 30. Fractionated Photon Radiation Therapy for Skull Base Chordomas and Chondrosarcomas

Introduction

Strategies for Delivering Fractionated Photon Radiation Therapy

Results of Modern Photon Therapy

Summary

Chapter 31. Stereotactic Radiosurgery for Skull Base Chordomas and Chondrosarcomas

Background

Radiobiological Principles

Indications for Radiotherapy

Radiation Techniques

Results

Complications

Conclusion

Chapter 32. Proton Therapy for Skull Base Chordomas and Chondrosarcomas

Introduction

Characteristics of Proton Radiation Therapy

History of Proton Radiation Therapy for Tumors of the Base of the Skull

Treatment Management

Modern Results

Chapter 33. Photon Irradiation for Spinal Chordomas and Chondrosarcomas

Introduction

External Beam Radiotherapy With Conventional Fractionation

Stereotactic Radiosurgery

Radiation Toxicity

Conclusions

Chapter 34. Proton Therapy for Spinal Chordomas and Chondrosarcomas

General Comments

General Considerations

Spine Chordomas and Chondrosarcomas

Sequencing of Radiation Therapy and Surgery

Conclusion

Chapter 35. Heavy Ion Radiation for Chordomas and Chondrosarcomas

Introduction

Radiobiological and Physical Principles

Biological Characteristics

Indications

Technical Characteristics

Results

Complications

Advantages of Carbon Ion

Limitations of Carbon Ions

Conclusions

Section VI. Special Considerations

Chapter 36. Chordomas and Chondrosarcomas in Children

Incidence

Presentation

Radiology

Pathology

Treatment

Outcomes and Prognosis

Conclusions

Chapter 37. Recurrent Skull Base Chordomas: Role of Surgery

Introduction

Diagnosis of Recurrent Tumor

Decision-Making

Morbidity and Mortality of Reoperation

Conclusions

Chapter 38. Systemic Therapies for Locally Recurrent or Metastatic Disease

Chordoma

Chondrosarcoma

Cytotoxic Therapy

Molecularly Targeted Therapy

Future Directions in Systemic Therapies for Chondrosarcomas

Chapter 39. Chordomas and Chondrosarcomas of the Axial Skeleton: Emerging Therapies and Future Directions

Introduction: Barriers to Traditional Therapies

Surgical Methods: Improvement in Techniques

Advances in Radiation Therapy: Radiation Therapy Emerging as a Useful Adjuvant

Systemic Therapy: Innovative Approaches to Metastatic and Locally Recurrent Disease

Chapter 40. Prognosis, Survival, and Surveillance

Chordoma

Chondrosarcoma

Section VII. Patient Advocacy

Chapter 41. The Chordoma Foundation

Introduction

Programs and Services

Conclusion

Chapter 42. Sarcoma Patient Advocacy: Hope and Help

Sarcoma Statistics

The Sarcoma Foundation of America

Sarcoma Research Grants

Patient Education

Disease Awareness

Legislative Advocacy

Summary

Index

Copyright

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Dedication

This work is dedicated to friends and mentors at the Stanford Healthcare, Massachusetts General Hospital, and University of Pittsburgh Medical Center whose collegiality and wisdom permitted the successful multidisciplinary treatment of these tumors; to the pioneers of skull base and spinal oncologic surgery whose vision and determination opened new possibilities; and to our patients whose courage and grace in dealing with their illness are truly inspiring.

List of Contributors

Siviero Agazzi,     University of South Florida College of Medicine, Tampa, FL, United States

B. Aika Shoo,     Stanford Medicine, Stanford, CA, United States

Ossama Al-Mefty

Barrow Neurological Institute, Phoenix, AZ, United States

Brigham and Women’s Hospital, Boston, MA, United States

Rami O. Al-Mefty

Harvard Medical School, Boston, MA, United States

Barrow Neurological Institute, Phoenix, AZ, United States

Christopher P. Ames,     University of California, San Francisco, CA, United States

Ramsey Ashour,     University of South Florida College of Medicine, Tampa, FL, United States

Samer Ayoubi,     Al-Mouwasat University Hospital, Damascus, Syria

Tej D. Azad,     Stanford University School of Medicine, Stanford, CA, United States

Andre Beer-Furlan,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Mark Bilsky,     Memorial Sloan Kettering Cancer Center, New York, NY, United States

Luis A.B. Borba,     Federal University of Parana, Curitiba, Brazil

Judith V.M.G. Bovée,     Leiden University Medical Center, Leiden, The Netherlands

Harley Brito da Silva

University of Washington, Seattle, WA, United States

Hospital Geral de Fortaleza, Fortaleza, Brazil

John F. Burke,     University of California, San Francisco, CA, United States

Mohamad Bydon,     Mayo Clinic, Rochester, MN, United States

Ricardo L. Carrau,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Rashmi Chugh,     University of Michigan, Ann Arbor, MI, United States

Michael A. Cohen,     Rutgers University-New Jersey Medical School, Newark, NJ, United States

Elizabeth J. Davis,     Vanderbilt University, Nashville, TN, United States

John D. Day,     University of Arkansas for Medical Sciences, Little Rock, AR, United States

Karen De Amorim Bernstein,     Harvard Medical School, Boston, MA, United States

Yvonne de Jong,     Leiden University Medical Center, Leiden, The Netherlands

Rafael De la Garza-Ramos,     Johns Hopkins University School of Medicine, Baltimore, MD, United States

Jürgen Debus

University of Heidelberg, Heidelberg, Germany

Heidelberg Ion Beam Therapy Center (HIT), Heidelberg, Germany

German Cancer Research Center (DKFZ), Heidelberg, Germany

Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany

Thomas F. DeLaney,     Harvard Medical School, Boston, MA, United States

Ahmad ElKhatib,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Jean A. Eloy,     Rutgers University-New Jersey Medical School, Newark, NJ, United States

Juan C. Fernandez-Miranda,     University of Pittsburgh School of Medicine and UPMC Center for Cranial Base Surgery, Pittsburgh, PA, United States

Nancy Fischbein,     Stanford University School of Medicine, Stanford, CA, United States

Dylann K. Fujimoto,     Stanford Medicine, Stanford, CA, United States

Paul A. Gardner,     University of Pittsburgh School of Medicine and UPMC Center for Cranial Base Surgery, Pittsburgh, PA, United States

Iris C. Gibbs,     Stanford Medicine, Stanford, CA, United States

Ziya L. Gokaslan,     Brown University School of Medicine, Providence, RI, United States

Louis Golden,     Stanford University School of Medicine, Stanford, CA, United States

Carlos R. Goulart,     SUNY Upstate Medical University, Syracuse, NY, United States

Ralph A. Hachem,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Griffith R. Harsh IV ,     Stanford University School of Medicine, Palo Alto, Stanford, CA, United States

Francis J. Hornicek,     David Geffen School of Medicine at UCLA, Los Angeles, CA, United States

Robert K. Jackler,     Stanford University School of Medicine, Palo Alto, Stanford, CA, United States

Ali Jamshidi,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Paulo A.S. Kadri,     Federal University of Mato Grosso do Sul, Campo Grande, Brazil

Darcy A. Kerr,     University of Miami Miller School of Medicine, Miami, FL, United States

Ilya Laufer,     Memorial Sloan Kettering Cancer Center, New York, NY, United States

Stefan Lieber,     University of Pittsburgh Medical Center, Pittsburgh, PA, United States

James K. Liu,     Rutgers University-New Jersey Medical School, Newark, NJ, United States

Dennis T. Lockney,     University of Florida, Gainesville, FL, United States

Natalie A. Lockney,     Memorial Sloan Kettering Cancer Center, New York, NY, United States

Tobias A. Mattei,     Eastern Maine Medical Center, Bangor, ME, United States

Ehud Mendel,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Ahmed Mohyeldin,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

Thomas W. Morris III ,     University of Arkansas for Medical Sciences, Little Rock, AR, United States

Donato Pacione,     NYU Langone Medical Center, New York, NY, United States

Hafiz Patwa,     Wake-Forest University, NC, United States

Arjun Pendharkar,     Stanford University School of Medicine, Stanford, CA, United States

Daniel M. Prevedello,     The Ohio State University Wexner Medical Center, Columbus, OH, United States

John K. Ratliff,     Stanford University School of Medicine, Stanford, CA, United States

Vinod Ravikumar,     Stanford University School of Medicine, Stanford, CA, United States

Krishna I.A. Reddy,     Vanderbilt University Medical Center, Nashville, TN, United States

Laurence D. Rhines,     The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Andrew E. Rosenberg,     University of Miami Miller School of Medicine, Miami, FL, United States

Michael M. Safaee,     University of California, San Francisco, CA, United States

Adam Schmitt,     Memorial Sloan Kettering Cancer Center, New York, NY, United States

Scott M. Schuetze,     University of Michigan, Ann Arbor, MI, United States

Joseph H. Schwab,     Harvard Medical School, Boston, MA, United States

Herbert S. Schwartz,     Vanderbilt University Medical Center, Nashville, TN, United States

Laligam N. Sekhar,     University of Washington, Seattle, WA, United States

Chandranath Sen,     NYU Langone Medical Center, New York, NY, United States

Alexander B.G. Sevy

Stanford University School of Medicine, Palo Alto, Stanford, CA, United States

Louisiana State University School of Medicine, New Orleans, LA, United States

Ritu Shah,     University of South Florida College of Medicine, Tampa, FL, United States

Jerry D. Slater,     Loma Linda University Medical Center, Loma Linda, CA, United States

Carl H. Snyderman,     University of Pittsburgh School of Medicine and UPMC Center for Cranial Base Surgery, Pittsburgh, PA, United States

Scott G. Soltys,     Stanford Medicine, Stanford, CA, United States

Josh Sommer,     Chordoma Foundation, Durham, NC, United States

David C. Straus

University of South Carolina School of Medicine, Columbia, SC, United States

Palmetto Health-USC Medical Group, Columbia, SC, United States

Ian Suk,     Johns Hopkins University School of Medicine, Baltimore, MD, United States

Claudio E. Tatsui,     The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Alisson R. Teles,     McGill University, Montreal, QC, Canada

Bert E. Thomas IV ,     Sarcoma Foundation of America, Damascus, MD, United States

Jonathan G. Thomas,     Drexel Neurosciences Institute, Philadelphia, PA, United States

Elizabeth C. Tyler-Kabara

University of Pittsburgh School of Medicine, Pittsburgh, PA, United States

UPMC Center for Cranial Base Surgery, Pittsburgh, PA, United States

Matthias Uhl

University of Heidelberg, Heidelberg, Germany

Heidelberg Ion Beam Therapy Center (HIT), Heidelberg, Germany

German Cancer Research Center (DKFZ), Heidelberg, Germany

Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany

Harry van Loveren,     University of South Florida College of Medicine, Tampa, FL, United States

Francisco Vaz-Guimaraes,     Baylor College of Medicine, Houston, TX, United States

Anand Veeravagu,     Stanford University School of Medicine, Stanford, CA, United States

Eric W. Wang,     University of Pittsburgh School of Medicine and UPMC Center for Cranial Base Surgery, Pittsburgh, PA, United States

Evan White,     University of California San Diego School of Medicine, La Jolla, CA, United States

Brian J. Williams

The University of Texas MD Anderson Cancer Center, Houston, TX, United States

University of Louisville, Louisville, KY, United States

Jean-Paul Wolinsky,     Johns Hopkins University School of Medicine, Baltimore, MD, United States

Andrew J. Wroe,     Loma Linda University Medical Center, Loma Linda, CA, United States

Josh Yamada,     Memorial Sloan Kettering Cancer Center, New York, NY, United States

Ashraf S. Youssef,     University of Colorado School of Medicine, Aurora, CO, United States

Georgios Zenonos,     University of Pittsburgh Medical Center, Pittsburgh, PA, United States

Foreword

A dramatic change in the outlook for patients with chordoma and chondrosarcoma has occurred in the last 25  years. With the availability of computed tomography and magnetic resonance imaging, the development of new cranial base and spinal surgical techniques, and the emergence of new radiation therapy and radiosurgical modalities with more precise planning and localization, the outlook for these patients has markedly improved.

Much of this progress is attributable to the increased use of a team approach in planning and delivering treatment. Competitiveness among specialists has been replaced by collaboration and cooperation. The neurosurgeon, orthopedic surgeon, otolaryngologist–head and neck surgeon, and radiation oncologist now work together as a team to plan the best strategy for each patient. This team depends on a strong infrastructure of experts in diagnostic radiology, pathology, anesthesia, and electrophysiological monitoring.

This book brings together a distinguished group of experts from these diverse disciplines underscoring the importance of the team approach in the care of these patients. The authors are leaders in their fields, and the presentation of their knowledge in these 42 chapters will help improve the care of patients with chordoma and chondrosarcoma.

Robert K. Jackler, MD

Preface

Chordomas and chondrosarcomas of the skull base and spine present formidable challenges to effective treatment by virtue of the perilous anatomy of their location and their tendency to recur locally. These challenges have prompted numerous advances in surgery and radiation therapy of the skull base, mobile spine, and sacrum over the last two decades. Many such advances have resulted from the cooperation of physicians of different disciplines, including otolaryngologists–head and neck surgeons, ophthalmologic surgeons, spinal orthopedic surgeons, radiation therapists, and medical oncologists, in terms of both progress in the field and the outcome of an individual patient. The intent of this publication is to provide multiple perspectives on these tumors from specialists in a wide variety of disciplines.

To achieve a truly multidisciplinary product, we consulted with senior experts in each discipline: Robert K. Jackler, MD, Peter Hwang, MD, and Carl H. Snyderman, MD, in Otolaryngology-Head and Neck Surgery; Francis J. Hornicek, MD, in Orthopedic Spine Surgery; Paul A. Gardner, MD, in Neurological Surgery; and Jay S. Loeffler, MD, in Radiation Oncology. Each contributed a major chapter and provided recommendations for the inclusion of specific topics and particular authors in the book. We are very grateful to all of them for their contributions.

The book is organized into seven separate sections: Embryology, Pathology, and Molecular Biology; Demographics, Presentation and Diagnosis; Surgery of Skull Base Tumors; Surgery of Spinal and Sacral Tumors; Radiation Therapy of Chordomas and Chondrosarcomas; Special Considerations; and Patient Advocacy. The chapters in the third to fifth sections focus on alternative surgical and complementary therapeutic approaches to the respective region. Each surgical section includes a review of the critical surgical anatomy, the rationale for choice of particular approaches, the details of surgical technique, and patient outcome. The section on radiation therapy both incorporates the landmark contributions of the Proton Radiation Therapy Group at the Massachusetts General Hospital and explores the potential of other emerging modalities such as stereotactic radiosurgery and heavy ion therapy. The final section includes statements from leaders of the Chordoma Foundation and the Sarcoma Foundation of America, two advocacy organizations of great value to patients, clinicians, and scientists.

We hope that this text will both serve as a reference for anyone caring for patients with these challenging tumors and document the importance of multidisciplinary collaboration to progress in oncology.

Griffith R. Harsh IV 

Francisco Vaz-Guimaraes

Section I

Embryology, Pathology, and Molecular Biology

Outline

Chapter 1. Embryology of the Skull Base and Vertebral Column

Chapter 2. Pathology of Chordoma and Chondrosarcoma of the Axial Skeleton

Chapter 3. Molecular Drivers in Chordoma

Chapter 4. Molecular Drivers in Chondrosarcoma

Chapter 1

Embryology of the Skull Base and Vertebral Column

Darcy A. Kerr, and Andrew E. Rosenberg     University of Miami Miller School of Medicine, Miami, FL, United States

Abstract

The development of the human skeleton begins soon after conception; the skeleton continues to grow until a peak bone mass is achieved during young adulthood and then remodels throughout adult life. The formation of the skeleton depends on the basic biological processes of cell proliferation, migration, differentiation, and maturation. The genetic control of these fundamental processes, especially with regard to the development of the skeletal system, is not yet fully understood; however, homeobox genes, which regulate anatomic site-specific morphogenesis, have been shown to contain the codes for the architectural blueprint of the bones of the body. The specific genes, including those that encode a variety of transcription factors, growth factors, and receptors, involved in these processes are being defined; however, our current understanding of the embryology of the human skull base and vertebral column is still largely based on morphological studies of embryos. The human skull base and vertebral column are highly intricate structures, and this is reflected in the complexity of their embryological development. Although many of the basic processes of their formation are similar to those of the remainder of the skeleton, the presence of the brain and notochord and their inductive effects makes the development of these anatomic regions unique.

Keywords

Embryology; Homeobox genes; Notochord; Skull base; Spine; Vertebra

Outline

Introduction

The Skull Base

Genetic Control of Skull Base Development

Embryology of the Skull Base

Embryological Development of the Notochord and Vertebral Column

References

© 2018 Elsevier Inc. All rights reserved. Please note that the copyright for the original figures submitted by the contributors is owned by Contributors.

Introduction

The development of the human skeleton begins soon after conception; the skeleton continues to grow until a peak bone mass is achieved during young adulthood and then remodels throughout adult life. The formation of the skeleton depends on the basic biological processes of cell proliferation, migration, differentiation, and maturation. The genetic control of these fundamental processes, especially with regard to the development of the skeletal system, is not yet fully understood; however, homeobox genes, which regulate anatomic site-specific morphogenesis, have been shown to contain the codes for the architectural blueprint of the bones of the body.¹,² The specific genes, including those that encode a variety of transcription factors, growth factors, and receptors, involved in these processes are being defined³; however, our current understanding of the embryology of the human skull base and vertebral column is still largely based on morphological studies of embryos.

The human skull base and vertebral column are highly intricate structures; this is reflected in the complexity of their embryological development. Although many of the basic processes of their formation are similar to those of the remainder of the skeleton, the presence of the brain and notochord and their inductive effects makes the development of these anatomic regions unique.

The Skull Base

The human skull is the most intricate portion of the axial skeleton and has evolved to house the brain and sense organs and to facilitate the ingestion of food. The skull base is an anatomically complex and integrative region, and its shape has been influenced by phylogenetic, functional, and developmental forces.⁴ The skull base is defined as the portion that is in contact with, and supports, the inferior aspect of the brain and brainstem. It is composed of portions of a variety of different bones, including the occipital bone, temporal bone, sphenoid bone, orbital plates of the frontal bone, and the ethmoid’s cribriform plate.⁵

Genetic Control of Skull Base Development

Genes regulating the development of the skull base include those from the Dickkopf family (Dkk), matrix metallopeptidase 9 (MMP-9), Indian hedgehog, and Sonic hedgehog (Shh). Skull base chondrogenesis is thought to be delayed during embryogenesis compared with chondrogenesis of the axial skeleton due to its unresponsiveness to Shh signaling.⁴

Studies utilizing loss-of-function mutations generated in mice suggest that the Dlx homeobox gene may also play an important role in the formation of craniofacial structures.⁶,⁷ Dlx5 and Dlx6 are expressed in the perichondrium where they direct the normal progression of enchondral ossification; mice with loss of function of Dlx5 and Dlx6 genes show delayed cartilage maturation and downstream osteogenesis.⁷ Similarly, Msx homeobox gene family members have been isolated from a range of organisms including humans, and Msx1 and Msx2 are widely expressed in vertebrate embryonic development. They are characteristically expressed at sites where epithelial–mesenchymal interactions take place and are strongly expressed in developing craniofacial regions.³ Heterodimers form between Msx and other homeodomain proteins such as Dlx; in vitro, the formation of heterodimers results in mutual functional antagonism, and these interactions may play a role in controlling craniofacial patterning in vivo.³ Msx regulatory proteins function as transcriptional repressors, and the Msx homeodomain interacts directly with the TATA-binding protein of the general transcription complex.³ The transforming growth factor-β/Msx2 signaling cascade has been shown via knockout mice experiments to be critical for the development of the caudal region of the skull where it regulates the proliferation of chondrocytes and prevents premature enchondral ossification. The Wolf-Hirschhorn syndrome candidate 1 (Whsc1) gene has also been shown to be important for the ossification of cranial bone elements. In knockout mice, Whsc 1 deficiency leads to disrupted ossification of the occipital bone and associated decreased levels of alkaline phosphatase activity. This deficiency leads to decreased expression of the bone-related proteins osteopontin and collagen type 1a.⁸

Most of the craniofacial skeletal elements originate from ectoderm-derived, multipotent neural crest cells that migrate ventrally from the closing dorsal neural folds. Bone morphogenetic protein (BMP) signaling has emerged as a key regulator of the development of neural crest cells and their derivates. Studies in mice have shown that precise regulation of BMP signaling is necessary for proper craniofacial development and coordination of self-renewal and differentiation pathways.⁹,¹⁰ BMP signaling is believed to regulate evolutionary change in craniofacial morphology. Downstream effector pathways for BMP signaling are complex and are not yet fully understood, but Smad, MapK, and microRNA processing and transcription elements are involved.¹⁰ Experimental evidence in mice has demonstrated that conditional overexpression of BMP-4 leads to dramatic facial skeletal changes and that the inactivation of BMP-2, BMP-4, and BMP-7 leads to complete or partial loss of multiple cranial neural crest–derived skeletal elements, emphasizing a critical role for BMP signaling in the development of membranous bone and cartilage.¹⁰ Noggin is a major BMP antagonist expressed during embryological development. In mice, lack of Noggin leads to abnormal skull base structure, with decreased anteroposterior and increased mediolateral lengths.⁹

Embryology of the Skull Base

The occipital bone is one of the first bones of the skull to develop and consists of four parts, namely, one basilar, one squamous, and two condylar parts, that encircle the foramen magnum.⁸ Although some of the skull base bones form from intramembranous ossification, namely, the orbital plates of the frontal bone and the lateral aspects of the greater sphenoidal wings, most of the bones of the skull base are initially preformed in cartilage (enchondral ossification) and together they represent the chondrocranium.

The specific elements of the cranial base are derived from cells that originate in, and subsequently migrate from, the neural crest and paraxial mesoderm.⁵ The first two pharyngeal arches contribute to the cranial skeletal elements. Local factors, including cell–cell and cell–substrate interactions, control the migration so that the cells condense between the developing brain and foregut to produce the ectomeningeal capsule. The ectomeningeal capsule is the earliest morphological stage in the development of the skull and forms during the fourth week of intrauterine life, a time at which the development of the other major organ systems is already well underway.¹¹ The cells that compose the ectomeningeal capsule differentiate into chondroblasts on the 40th day (week 7) of gestation. They form multiple centers of chondrification, (presphenoid cartilage, basisphenoid cartilage, nasal capsule, orbitosphenoid, alisphenoid, otic capsule, parachordal cartilage, and fused sclerotomes of the occipital somites), many of which are bilateral and symmetrical (Fig. 1.1). The production of cartilage heralds the formation of the chondrocranium, and this process requires the presence of the brain and other neural structures because they exert important inductive forces.⁵ The development of the occipital bone depends on signaling from the rhombencephalon.⁸ By the eighth week of embryogenesis the separate centers of chondrification grow and fuse with one another, creating a solid cartilaginous structure known as the chondrobasicranium or the basal plate (Figs. 1.1 and 1.2). The basal plate is perforated by preexisting structures, including cranial nerves and blood vessels, and these passageways eventually become the foramina of the mature skull base.

Figure 1.1  Embryonic basal cartilages in relation to the developing skull base and those portions that form from endochondral and intramembranous ossification.

Figure 1.2  Median sagittal section through the chondrocranium of a 7-week-old human embryo. The oral cavity is to its left and the developing brain is to its right. The developing pituitary is the dark round structure located just right of midline near the top of the illustration.

Ossification of the chondrocranium (endochondral ossification) begins during the eighth week of gestation, and initially, 110 centers of bone formation can be identified throughout the skull.⁵,¹¹ The ossification centers enlarge and fuse so that in the young adult the cranium contains 32 separate bones.¹¹ Skeletogenesis and apoptosis, regulated primarily by MMP-9 and Dkk family genes, are important in this process.⁴ The sequence of ossification tends to progress from the foramen magnum toward the frontal bone and from the lateral aspects of the cartilage plate toward the midline. The centrally localized notochord is thought to be key to cranial base ossification and the maintenance of bilateral symmetry through its anatomical location and the production of chordin, a regulator of BMP-7.¹²

Intramembranous ossification also begins during the eighth week of gestation, and the two processes of bone formation (intramembranous and endochondral) accelerate, whereas the cartilage of the chondrocranium is concurrently resorbed (Fig. 1.1). Eventually, by birth, most of the cranium has become a bony structure with the remnants of the chondrocranium persisting in the form of growth plates in the sphenooccipital and sphenopetrous sutures, and at the apices of the petrous and occipital bones.⁵ The cartilage in the growth plates continues to proliferate, and in conjunction with sustained bone formation, and remodeling in response to the expansile forces exerted by the neighboring brain and neural structures, the skull base gradually acquires its adult form. The cartilage of the sphenooccipital synchondrosis is responsible for the majority of growth of the skull base in postnatal life, and during the middle of the second  decade of life, it finally undergoes resorption, which permits bony fusion of the sphenoid and occipital bones.⁵

Embryological Development of the Notochord and Vertebral Column

The notochord is the anatomic structure that defines phylum Chordata of the animal kingdom to which subphylum Vertebrata belongs. The notochord has played a fundamental and dynamic role in the evolution of the skeleton, with important patterning and structural functions. In the most primitive vertebrate, amphioxus, it comprises the entire skeleton in the adult organism. However, in higher animals, including humans, it exists as a functioning structure for only a short period. During its temporary existence in this setting, it serves as a transient axis of support, provides for the initial axis of orientation of the developing embryo, and most importantly, plays a vital role in the induction of the tissues, which eventually form the vertebral column.¹³

The notochord arises from the dorsal organizer, a region of the vertebrate gastrula that when transplanted into a host embryo induces a second embryonic axis. The dorsal organizer gives rise to a morphologically and molecularly distinct type of mesoderm called the chordamesoderm, which subsequently becomes the notochord. The genetic loci responsible for these transitions have been identified in zebrafish genetic screens.¹⁴

In humans, the notochord begins to form on day 17. Its development is heralded by the migration of cells originating from the primitive pit that move cranially between the ectoderm and endoderm, where they align in the midline to form the notochordal, or head, process (Fig. 1.3). The notochordal process continues to grow until it contacts the prochordal plate, which is a component of the oropharyngeal membrane. Laterally, migrating mesodermal cells that originate from the primitive streak surround the notochord and some condense to form two longitudinal pillar-like structures, known as the paraxial mesoderm. The ectoderm and the mesoderm overlying the notochord form the neural plate, and the ectodermal component, known as the neuroectoderm, gives rise to the central nervous system (Fig. 1.4).

In the human embryo the notochord is a solid rod-like structure composed of cords and small cohesive nests of epithelial cells. The notochordal cells may be polyhedral, stellate, or elongate and have moderate amounts of cytoplasm. In some cells the cytoplasm contains multiple vacuoles that scallop the nuclei, thereby forming the so-called physaliphorous or bubbly cells.¹³ In a Notch-dependent manner, the notochord becomes organized with a distinct outer sheath and an inner cellular region. The inner vacuolated cells exert osmotic pressure, whereas the outer cells secrete a thick perinotochordal extracellular basement membrane. This arrangement affords the combination of strength and flexibility necessary for the notochord to perform its structural functions.¹⁴,¹⁵ The stroma of the notochord is mucinous and contains abundant mucopolysaccharides. The notochordal tract begins within the sphenoid, just posterior to the hypophyseal fossa. At that point, it exits the bone and proceeds distally adjacent to the ventral surface of the basisphenoid in close proximity to the pharynx. It then reenters the bone in the basiocciput and continues through the middle of the apical odontoid ligament, odontoid process, and the centers of the vertebra to the end of the coccyx (Fig. 1.5).¹³ The life span of the intact notochord is short. Those segments of notochord that become surrounded by mesenchymal precartilaginous cells of the paraxial mesoderm begin to disappear by the seventh week of gestation, as the formation of the cartilage anlage of the vertebral body is initiated. This process is rapid so that by the 10th week of gestation all that remains of the notochord in these areas is a mucoid sheath that is subsequently obliterated by the ossification centers that have developed in the vertebral bodies. In regions occupied by developing intervertebral disks, the notochord persists as the nucleus pulposus of the definitive intervertebral disk, where it becomes surrounded by the annulus fibrosus (Fig. 1.6).¹³ During the 18th week of gestation, the expanding annulus fibrosus starts to encroach upon the notochordal remnants so that by birth the notochordal cells in these areas begin to disappear.¹³ It is unclear exactly when the notochordal cells completely disappear from this site, but most investigators feel that it occurs during childhood or by the time growth ceases.¹⁶

Figure 1.3  Embryologic development of the notochord from the primitive pit.

Figure 1.4  Cross-section through an embryo showing the relationship of the notochord to the developing central nervous system, paraxial mesoderm, and somites and gut.

The human spine is complex, and functionally, it integrates 33 vertebrae, more than 97 diarthroses, and numerous collagenous and elastic ligaments. A large array of nerves and blood vessels course throughout its compartments and tendons and insert into its surface. Accordingly, it is not surprising that the embryological development of the spine is complicated. The elaboration of the notochord is intimately associated with the induction of the formation of the spinal column. This process is mediated through signaling molecules such as Shh, which in animal studies initiate the expression of other genes important in the genesis of the spine.¹⁷ The earliest morphological evidence of the formation of the vertebral column occurs by day 17 of gestation. By day 19, each side of the paraxial mesoderm segregates into three distinct zones, including the medial paraxial column, the intermediate column, and the lateral mesodermal plate.¹⁸,¹⁹ The somites develop from the medial paraxial columns, the intermediate columns produce the urogenital system, and the body wall of the celomic cavities form from the lateral mesodermal plates.¹⁸,¹⁹ The somites form on about day 20 of gestation, as the cells in the anterior portions of the paraxial columns condense into bilaterally symmetrical block-like segments. The site of formation of the first paired segments is just distal to the most cephalad portion of the notochord. During the following 10  days, 38 additional pairs appear distally, and eventually a total of 42–44 pairs develop. The somite is composed of the dorsal dermomyotome and a ventral sclerotome. The dermomyotome is the source of the dermis and myocytes of the dorsal aspect of the trunk. The cells of the sclerotome migrate and encase the notochord and form the primordial or membranous vertebral column and ribs (Fig. 1.7). Homeobox genes shown to be important in controlling this phase of spine development include the mouse bagpipe gene and Hox genes.²⁰,²¹ In vertebrates, the Hox genes are crucial for directing different vertebral morphologies and play a role in elongation of the trunk-to-tail axis. The 39 mammalian Hox genes are clustered at four distinct genomic loci (HoxA, HoxB, HoxC, and HoxD), and they are expressed in ordered, partially overlapping spatial and temporal domains during embryogenesis.²² Hox transcription produces noncoding regulatory RNAs, including microRNAs (miRNAs). In mice, this includes the miR-196 family of miRNAs, which has been shown to be essential for determining the number of vertebrae and patterning vertebral identity. The miR-196 family also provides negative regulation of the Hox genes.²² The cells within the membranous vertebral column undergo proliferation at equidistant intervals, thereby forming alternating hyper and hypocellular segments. Hyaline cartilage formation commences during the sixth week of gestation and begins in the hypocellular segment, where three paired centers of chondrification appear. The first pair encases the notochord, and they join one another ventrally to produce the centrum of the vertebral body. The second pair forms posteriolateral to the developing spinal cord and coalesces to become the neural arch and spinous process. The last pair originates midway between the other two pairs, and eventually creates the transverse processes (Fig. 1.8). The annulus fibrosus of the disk is derived from the hypercellular zones of the membranous vertebral column, and as previously mentioned, the nucleus pulposus forms from expansion and proliferation of the notochordal remnants. As chondrification of the centrum progresses, the notochord becomes entrapped and constricted and ultimately undergoes complete degeneration. The process of breaking down the notochord, as well the formation of the intervertebral disks, has been shown to depend on the presence of type 2 collagen.²³

Figure 1.5  Notochord-traversing cartilaginous embryonic vertebral bodies and intervertebral disks (human embryo at approximately seventh week of gestation).

Figure 1.6  Notochordal remnant in a 38-week-old human fetus, surrounded by fibrocartilage of the annulus fibrosus.

Figure 1.7  Membranous stage of the vertebral column (human embryo at approximately fifth week of gestation) with block-like condensations of mesenchymal cells representing the future vertebral bodies. The developing spinal cord fills the right portion of the illustration.

Figure 1.8  Cross-section through a cartilaginous vertebral body and portion of the posterior arch. Note the spinal cord and dorsal root ganglia.

Ossification of the vertebrae begins by week 9 of gestation and is initiated simultaneously in three centers: one in the centrum and two in the vertebral arch. Ossification of the centra begins in the lower thoracic and upper lumbar vertebrae and progresses caudally, leaving the cervical and upper thoracic cervical levels to be the last to undergo ossification. The entire cartilage model of the centrum is replaced by bone, except for plates that persist at the most distal and proximal ends of the vertebral bodies. These cartilaginous structures function as epiphyseal plates and are responsible for the longitudinal growth of the spine. Ossification of the posterior elements begins in the cervical spine and proceeds caudally. However, the laminae of the arches in the lumbar region are the first to fuse, and the more cephalic levels follow this in relative sequential order. Secondary centers of ossification develop in the tips of the spinous and transverse processes during childhood, and fusion of all the ossification centers is not completed until the third decade of life.

References

1. Capecchi M.R. Function of homeobox genes in skeletal development. Ann NY Acad Sci. 1996;785:34–37.

2. Boncinelli E. Homeobox genes and disease. Curr Opin Genet Dev. 1997;7(3):331–337.

3. Alappat S, Zhang Z.Y, Chen Y.P. Msx homeobox gene family and craniofacial development. Cell Res. 2003;13(6):429–442.

4. Di Ieva A, Bruner E, Haider T, et al. Skull base embryology: a multidisciplinary review. Childs Nerv Syst. 2014;30(6):991–1000.

5. Ricciardelli E.J. Embryology and anatomy of the cranial base. Clin Plast Surg. 1995;22(3):361–372.

6. Kraus P, Lufkin T. Mammalian dlx homeobox gene control of craniofacial and inner ear morphogenesis. J Cell Biochem. 1999(Suppl. 32–33):133–140.

7. Kraus P, Lufkin T. Dlx homeobox gene control of mammalian limb and craniofacial development. Am J Med Genet A. 2006;140(13):1366–1374.

8. Bernard S, Loukas M, Rizk E, Oskouian R.J, Delashaw J, Tubbs R.S. The human occipital bone: review and update on its embryology and molecular development. Childs Nerv Syst. 2015;31(12):2217–2223.

9. Matsui M, Klingensmith J. Multiple tissue-specific requirements for the BMP antagonist noggin in development of the mammalian craniofacial skeleton. Dev Biol. 2014;392(2):168–181.

10. Bonilla-Claudio M, Wang J, Bai Y, Klysik E, Selever J, Martin J.F. Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development. Development. 2012;139(4):709–719.

11. Sperber H. The cranial base. In: Craniofacial embryology. 1989:101 London.

12. Santaolalla-Montoya F, Martinez-Ibarguen A, Sanchez-Fernandez J.M, Sanchez-del-Rey A. Principles of cranial base ossification in humans and rats. Acta Otolaryngol. 2012;132(4):349–354.

13. Horwitz T. Developmental anatomy. In: The human notochord. A study of its development and regression, variations, and pathologic derivative chordoma. Private Printing; 1977:7–104. .

14. Stemple D.L. Structure and function of the notochord: an essential organ for chordate development. Development. 2005;132(11):2503–2512.

15. Corallo D, Trapani V, Bonaldo P. The notochord: structure and functions. Cell Mol Life Sci. 2015;72(16):2989–3008.

16. Schmorl G, Junghanns H. Development, growth, anatomy and function of the spine. In: The human spine and health and disease. New York: Grune and Stratton; 1975:14–21.

17. Furumoto T.A, Miura N, Akasaka T, et al. Notochord-dependent expression of MFH1 and PAX1 cooperates to maintain the proliferation of sclerotome cells during the vertebral column development. Dev Biol. 1999;210(1):15–29.

18. Parke W. Development of the spine. In: Menzes A, Sonntag V, eds. Principles of spinal surgery. New York: McGraw-Hill; 1996:3–33.

19. McLone D, Dias M. Developmental anatomy of the spine. In: Rothman R, Simeone F, eds. The spine. Philadelphia: W.B. Saunders, Co.; 1992:59–68.

20. Lettice L.A, Purdie L.A, Carlson G.J, Kilanowski F, Dorin J, Hill R.E. The mouse bagpipe gene controls development of axial skeleton, skull, and spleen. Proc Natl Acad Sci USA. 1999;96(17):9695–9700.

21. Galis F. On the homology of structures and hox genes: the vertebral column. Novartis Found Symp. 1999;222:80–91 discussion 91–94.

22. Wong S.F, Agarwal V, Mansfield J.H, et al. Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs. Proc Natl Acad Sci USA. 2015;112(35):E4884–E4893.

23. Aszodi A, Chan D, Hunziker E, Bateman J.F, Fassler R. Collagen II is essential for the removal of the notochord and the formation of intervertebral discs. J Cell Biol. 1998;143(5):1399–1412.

Chapter 2

Pathology of Chordoma and Chondrosarcoma of the Axial Skeleton

Darcy A. Kerr, and Andrew E. Rosenberg     University of Miami Miller School of Medicine, Miami, FL, United States

Abstract

The skull is an uncommon location for primary bone tumors. Those that arise in this location are often malignant, and the most common are chordoma and chondrosarcoma. These tumors have some overlapping clinicopathological features but can be distinguished by their morphology and immunohistochemical profile. Histologically chordoma demonstrates lobules of cohesive polyhedral cells with vacuolated cytoplasm in a mucinous or myxoid matrix; immunohistochemistry for brachyury is positive. Chondrosarcoma shows chondrocytes with increased cellularity and atypia in a hyaline or myxoid cartilaginous matrix; immunohistochemistry for brachyury is negative. Chordoma is the most common primary sarcoma of the axial skeleton and arises with approximately equal frequently in the skull base, mobile spine, and sacrococcygeal region. The spine is a more common site than the skull base for chondrosarcoma. Chordoma and chondrosarcoma are usually treated by a combining surgical resection and radiation therapy. Overall, chondrosarcoma has a better prognosis than chordoma.

Keywords

Chondrosarcoma; Chordoma; Neoplasm; Sarcoma; Skull base; Spine

Outline

Chordoma

Introduction

Epidemiology

Classification and Pathology

Conventional Chordoma

Chondroid Chordoma

Dedifferentiated Chordoma

Cytogenetics

Prognostically and Therapeutically Significant Pathological Features

Chondrosarcoma

Introduction

Epidemiology

Classification and Pathology

References

Further Reading

© 2018 Elsevier Inc. All rights reserved. Please note that the copyright for the original figures submitted by the contributors is owned by Contributors.

The axial skeleton is composed of a variety of tissues, including bone, hyaline cartilage, fibrocartilage, notochord, elastic tissue, tendon, ligament, peripheral and central nervous tissue, fat, hematopoietic elements, smooth muscle, skeletal muscle, blood vessels, and synovium. Neoplasms of the axial skeleton may recapitulate any of these components; however, the types of primary tumors that arise in this structure tend to be restricted in their phenotype. The most common primary benign bone tumor of the skull and spine is hemangioma, and the most common primary bone malignancies, aside from myeloma, are chordoma and chondrosarcoma.

Chordoma

Introduction

Chordoma is an unusual and uncommon primary malignant tumor of the bone that is defined by its phenotype, which recapitulates the embryonic notochord. The history of chordoma dates back to 160  years when Lushka and Virchow in 1856 and 1857, respectively, first described pathological lesions involving the clivus whose morphology resembled that of the notochord.¹ Virchow presented the initial detailed description of these lesions. Soon thereafter in 1858, Muller proposed that these tumors were related to the notochord, and in 1894, Ribbert coined the term chordoma.²

Epidemiology

The true incidence of chordoma is unknown. In several large studies, it accounted for 1%–4% of all primary malignant bone tumors.³,⁴ In more recent data, collected by the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program, which included 12,931 primary malignant tumors of the bone diagnosed between the years 1973 and 2012, 8.3% or 1080 cases were chordoma, and chordoma followed osteosarcoma, chondrosarcoma, and Ewing sarcoma in frequency.⁵ Updated SEER data report an overall incidence rate of chordoma of 0.84 per 1,000,000.⁶ SEER data from the years 1973 to 2003 show that chordoma follows chondrosarcoma and accounts for 26% of primary bone malignancies of the spine in patients who present with a nonmetastatic primary bone malignancy.⁷ In a report from the Leeds Regional Bone Tumor Registry, chordoma was the most common primary malignant tumor of the axial skeleton.⁸ Information from the Swedish Registry documented the annual incidence of chordoma in that country to be 0.5% per million individuals and indicated that chordoma was responsible for 17.5% of all primary malignant bone tumors and 20% of those arising in the spine.⁹ Similar epidemiologic characteristics were found in Finland.¹⁰

Chordoma occurs in all age groups, but the majority arises during adulthood, with the median age of affected individuals being 58  years and 65% of patients being younger than 65  years at the time of diagnosis.³,⁴,⁶,¹¹ Specifically, children, young adults, adults, and the elderly have incidence rates of 0.14, 0.43, 1.08, and 2.62 per million population, respectively.⁶ Chordomas originating in the base of the skull present a decade earlier than those that develop in the spine, especially the sacrum.¹² The occurrence of chordoma in children is unusual, representing <5% of all chordomas, but in our experience and from data in the literature, it usually originates in the skull base and cervical spine and rarely in the sacrum.¹³–²⁰ Most studies of chordomas have shown that there is a male predominance of approximately 2:1 for tumors arising in the sacrum and mobile spine,²¹–²⁷ whereas in the skull base, the gender distribution is nearly equal.²⁸–³⁰ In the SEER data, the vast majority of tumors arose in whites, whereas only 2.2% affected African Americans.³¹

The pathogenesis of chordoma is not fully elucidated, but numerous lines of evidence suggest that T (brachyury), a gene that encodes brachyury, a transcription factor that regulates notochord development, is crucial for the initiation and progression of chordoma.³²,³³ Although it is generally accepted that these tumors arise from persistent rests of notochord within rigid bony structures, and not intervertebral disks, this hypothesis has never been proven. Evidence supporting this hypothesis linking notochordal cell rests to chordoma include similar topographical distribution, morphological overlap at the light and electron microscopic levels, shared immunophenotype, and molecular phenotyping studies.³⁴,³⁵ Chordoma has no known association with irradiation or other environmental factors. A very small percentage of cases have a familial pattern of inheritance, and in at least one case, the mode of inheritance was probably autosomal dominant.³⁶,³⁷ A subset of both sporadic and hereditary chordomas has somatic chromosomal gain at the T locus.³²,³⁸ In four families with familial chordoma, high-resolution array comparative genomic hybridization showed unique duplications in 6q27, leading to T gene duplication.³⁹ A study sequencing the T gene and measuring copy number variants in 24 familial cases, 103 sporadic cases, and 160 unrelated controls highlighted the importance of genetic variations in the T gene for both familial and sporadic chordoma. It demonstrated that germline T duplication is relatively common in families with chordoma (44%) but extremely rare in sporadic cases and suggested a complex susceptibility related to T.⁴⁰ Broad genotyping of individuals with sporadic chordoma has highlighted recurrent single nucleotide polymorphisms (SNPs) in the T DNA–binding domain, suggesting that misregulation of genes controlled by T may be important in the pathogenesis of chordoma.⁴¹ Pathways shown to be important in chordoma tumorigenesis include cell cycle regulatory pathways and activated receptor kinase pathways; additionally, DNA methylation of tumor suppressor genes and microRNA’s has been demonstrated to modulate relevant pathways (see Chapter 4).³³,⁴²

The anatomic distribution of chordoma is largely restricted to the axial skeleton, and this is in keeping with the purported tumor origin from persistent notochord. The overwhelming majority of chordomas arise within bone; they have never been reported to originate in the intervertebral disk. Historical studies reported that approximately 50% of chordomas develop in the sacrococcygeal region, whereas more modern data with larger numbers of patients suggest an approximately even distribution of tumors between the sacral region, mobile spine, and sphenooccipital region.³¹ Within the mobile spine, one series of 40 cases showed that 48% of tumors arose in the cervical spine, 33% in the lumbar spine, and 17% in the thoracic spine.²⁷

Classification and Pathology

Pathologically, chordoma is classified into the conventional, chondroid, and dedifferentiated variants. A component of the conventional type is virtually always found in the chondroid and dedifferentiated variants.

Conventional Chordoma

Conventional chordoma grows with a lobular architectural pattern and grossly is soft, slimy, gray-tan, and well delineated from the surrounding soft tissues (Fig. 2.1). The size of the tumors is variable, but the largest are usually found in the sacrum, where they frequently span greater than 10  cm in greatest dimension; the smallest typically arise in the skull base and may be only several centimeters in size. In bone, the tumor infiltrates the marrow space, encasing preexisting bony trabeculae, and permeates the Haversian systems of the cortex. Once the cortex is transgressed, the neoplasm usually extends into the soft tissues where it forms a well-demarcated soft tissue mass.

Figure 2.1  Chordoma arising in the sacrum, destroying the vertebral bodies, forming a large anterior soft tissue mass and extending into the spinal canal. The tumor is solid, glistening, and focally hemorrhagic.

Figure 2.2  Chordoma composed of nests and chords of tumor cells that grow in a mucinous matrix.

Histologically, conventional chordoma is composed of lobules of cells arranged in cords and cohesive nests (Fig. 2.2). It is common for one tumor cell to wrap around its neighbor as if one cell is hugging the other. Generally, the tumor cells are large, polyhedral, and epithelial in appearance and vary little in size and shape. The nuclei are of moderate size, darkly staining, and may contain small nucleoli or pseudoinclusions (Fig. 2.3). The tumor cells have abundant pink cytoplasm, and some contain single, large or multiple, small, round, clear cytoplasmic vacuoles that impart a bubbly appearance to the cytoplasm (Figs. 2.3 and 2.4). These vacuolated cells are known as physaliphorous cells, a term coined by Virchow in 1857 (derivation in Greek for bubble-bearing), and have since that time become recognized as characteristic of chordoma.¹ Physaliphorous cells may also contain a single large, clear vacuole that displaces the nucleus peripherally, causing the cell to mimic an adipocyte—tumors with many of these cells have been called lipoid chordomas.⁴³

Figure 2.3  Chordoma cell nuclei have identifiable nucleoli and the cytoplasm is abundant.

Figure 2.4  Physaliphorous cells containing multiple clear cytoplasmic vacuoles.

Because physaliphorous cells are not always present in chordomas and other types of tumors, including chondrosarcoma, may have similar appearing cells, their diagnostic significance is limited. Additional morphological heterogeneity in otherwise conventional chordomas includes cells that demonstrate nuclear pleomorphism, and sometimes the cells are elongate and spindle shaped.³⁰ Special histochemistry demonstrates that the neoplastic cells contain periodic acid–Schiff-positive diastase-sensitive glycogen. Ultrastructurally, the neoplastic cells have cytoplasmic processes that wrap around an adjacent cell, villous-like surface projections, abundant cytoplasmic glycogen, mitochondria-rough endoplasmic reticulum complexes, and epithelial features, including well-developed desmosomes, intracytoplasmic lumina, and tonofilament-like bundles of intermediate filaments.⁴⁴–⁴⁶ The vacuoles of the physaliphorous cells do not stain with any of the special stains, and according to ultrastructural analysis, they may be formed from dilated rough endoplasmic reticulum, cytoplasmic inclusions of the extracellular space, or intracellular lumina.⁴⁴–⁴⁶

Immunohistochemically, conventional chordoma typically expresses the epithelial markers keratin and epithelial membrane antigen, and the vast majority also stain with antibodies to the calcium-binding protein S-100.⁴⁷ Immunohistochemistry for brachyury has emerged as a highly sensitive and specific marker for chordoma.³⁵

In most conventional chordomas, mitoses are usually limited in number and foci of necrosis are common, especially in large tumors.

The stroma in conventional chordoma is usually mucinous and myxoid and typically appears frothy and basophilic. It is usually abundant and surrounds the cords and nests of cells (Fig. 2.2). The myxoid stroma is rich in acid and sulfated mucopolysaccharides and stains faintly with mucicarmine, strongly with alcian blue, and not at all with phosphotungstic acid hematoxylin.⁴,⁴⁸,⁴⁹ Staining of the matrix is not significantly reduced by prior digestion with hyaluronidase.⁴⁸,⁴⁹

Chondroid Chordoma

Chondroid chordoma was identified as a clinicopathological entity in 1973. It was defined as a tumor that contained areas of conventional chordoma as well as regions that resembled low-grade hyalinetype chondrosarcoma.⁴⁷ In the initial description, the clinical significance of chondroid chordoma was that affected patients had a better prognosis than those with conventional chordoma.⁴⁷ Following its description there was controversy regarding the existence of the tumor because some investigators argued that it merely represented a form of chondrosarcoma.⁵⁰ Subsequently, several studies have convincingly shown that chondroid chordoma is a distinct morphological variant of chordoma, does not behave biologically differently from conventional chordoma, and is not a chondrosarcoma.²⁹,⁵⁰–⁵² The initial studies suggesting that chondroid chordoma had a better prognosis than conventional chordoma may have been impacted by the inclusion of some chondrosarcoma cases in the chondroid chordoma cohort.⁵¹,⁵³

Figure 2.5  Chondroid chordoma containing foci of conventional chordoma with adjacent chondroid regions in which the tumor cells are individually arranged in lacunar spaces in a more solid hyaline appearing matrix.

Figure 2.6  Immunohistochemistry of chondroid chordoma showing that the cells in the conventional and chondroid areas strongly express keratin.

Chondroid chordoma most commonly arises in the skull base, less frequently in the mobile spine, and seldom in the sacrococcygeal area. Morphologically, the chondroid regions may merge with or be sharply demarcated from the classic component (Fig. 2.5). The chondroid component is characterized by neoplastic cells arranged individually in lacunar spaces that are surrounded by a solid, hyalinized matrix similar in appearance to the matrix in hyaline cartilage (Fig. 2.5). The amount of the chondroid component can vary, and in some cases, it may be abundant, causing diagnostic confusion with chondrosarcoma. The chondroid element has the same ultrastructural features⁴⁵ and immunohistochemical profile⁴⁶,⁵² as the conventional component (Fig. 2.6). Accordingly, the chondroid tissue represents a change in the matrix and distribution of cells in a chordoma that causes it to mimic hyaline cartilage and, importantly, does not represent true hyaline cartilage.

Dedifferentiated Chordoma

Dedifferentiated chordoma is the rarest subtype of chordoma. It is composed of areas of conventional chordoma and regions that have the morphology of a high-grade or poorly differentiated spindle cell sarcoma.⁵⁴–⁵⁸ This phenomenon affects fewer than 5% of conventional chordomas and most frequently complicates sacrococcygeal tumors.⁵⁵,⁵⁷ The dedifferentiated component may arise de novo within the primary tumor, in a recurrence, or within a chordoma after it has been irradiated.⁵⁴–⁵⁸ Morphologically, the dedifferentiated component is usually distinct from the areas of conventional chordoma and has the light microscopic features, immunohistochemical phenotype, and ultrastructural characteristics of a poorly differentiated pleomorphic sarcoma, although in some tumors it has the histology of osteosarcoma.⁵⁴–⁵⁸ The pathophysiology underlying the development of dedifferentiation in chordoma is not known with certainty. The entity probably arises from sarcomatous transformation of chordoma cells rather than as a manifestation of a collision tumor.⁵⁵,⁵⁷,⁵⁸ Immunohistochemically, dedifferentiated chordoma loses expression of brachyury and keratin.³⁵ The significance of identifying dedifferentiated chordoma is its aggressive biologic behavior because these tumors are usually rapidly fatal and systemic spread occurs in about 90% of cases.⁵⁸

Cytogenetics

Cytogenetic analysis of chordoma has shown numerous cytogenetic abnormalities. To date, no tumor-specific rearrangements have been documented. Most cytogenetically interrogated chordomas show several numerical and structural rearrangements in the setting of near-diploid or moderately hypodiploid karyotypes.⁵⁹ Frequent aberrations include partial or complete loss of chromosome arms 1p, 3p, 4q, 10q, and 13q, and partial or complete gain of material from chromosome arms 7p, 7q, 12q, 17q, 20q, and 22q.³³,³⁷,³⁸,⁵⁹,⁶⁰ Loci that are frequently deleted or amplified include 1p36 (containing the RIZ locus that encodes a zinc finger protein and the RUNX3 locus that encodes a transcription factor), 1p25 (HPC1, hereditary human prostate cancer susceptibility locus), 2p13 (the TGF-alpha, transforming growth factor-alpha locus), and 7q33 (the AKR1B10 locus, encoding an aldo-keto reductase). Additionally, the CDKN2A and CDKN2B loci on chromosome 9p21, encoding cyclin-dependent kinase inhibitors p16 and p15, respectively, are deleted in up to 70%–85% of tumors, PTEN on chromosome 10q in 80% of tumors, and SMARCB1 on chromosome 22q in 75% of tumors.³³,³⁸,⁵⁹ Genome-wide high-resolution SNP array and next-generation sequencing studies on 16 cases of sporadic chordomas found that chordomas frequently exhibit nonrandom gene copy number losses across the genome (chromosomes 3, 9p, 1p, 14, 10, and 13) and that the mutation rate is low, with the mutated genes often targeting chromatin regulatory genes.⁶¹ The gene most frequently affected by either deletion or mutations is SETD2.⁶¹ The recently described mechanism of chromothripsis, the shattering of chromosomes in a single catastrophic event followed by recombination leading to tens to hundreds of genetic rearrangements involving localized genomic regions, has been implicated as a causal mechanism for genetic rearrangements in chordoma.³⁸,⁶²

Prognostically and Therapeutically Significant Pathological Features

The prognosis of chordoma is affected by a variety of pathological characteristics. Several reports have suggested