PEDIATRIC ONCOLOGY
Pediatric Bone and Soft Tissue Sarcomas
123
With 65 Figures and 26 Tables
Alberto Pappo (Ed.)
Alberto Pappo,MD Department of Pediatrics The Hospital for Sick Children 555 University Avenue
Toronto, ON M5G 1X8, Canada
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To my children Jonathan and Danielle, who define the essence of my daily life.
To Jack, my brother and trusted friend.
To my patients and their families,
from whom I learn the meaning of compassion, courage and caring.
Chapter 2 V
Dedication
The purpose of this book is to integrate the most re- cent advances in the diagnosis and treatment of pedi- atric bone and soft tissue sarcomas. The book is di- vided into two major sections, the first of which pres- ents salient concepts in epidemiology, the impact of novel tools in imaging and molecular biology, and the underlying principles for continued drug develop- ment. In the second section, the book embarks on an up-to-date survey of the diagnosis and treatment of each specific disease, with particular emphasis on the need for an integrative, multidisciplinary approach to diagnosis and treatment.
I am indebted to my colleagues and collaborators who have contributed their ideas, time, and knowl- edge to this project. I am also grateful for the contri-
butions and support of my colleagues and friends at The University of Texas Southwestern Medical School, St. Jude Children’s Research Hospital, and the Hospital for Sick Children in Toronto. In particular, I would like to thank Drs. George Buchanan, Charles Pratt, William Crist, David Parham, Jim Anderson, and Larry Kun for their friendship, mentorship, and wisdom. Their teachings will continue to be an end- less source of passion and inspiration. It is my wish that this book will provide answers, guidance and hope to medical professionals, children, and their families.
Alberto Pappo, MD
VII
Preface
1 Epidemiology of Bone and Soft Tissue Sarcomas Logan G. Spector, Julie A. Ross, Rajaram Nagarajan
1.1 Descriptive Epidemiology of Bone Tumors . . . . 1
1.2 Worldwide Statistics . . . 1
1.3 North American Statistics . . . 3
1.4 Mortality and Survivorship . . . 4
1.5 Etiology of Bone Sarcomas . . . 5
1.6 Bone Sarcomas: Future Directions . . . 7
1.7 Epidemiology of Soft Tissue Sarcomas . . . 7
References . . . 9
2 Pathologic and Molecular Techniques Used in the Diagnosis and Treatment Planning of Sarcomas Timothy Triche, Deborah Schofield 2.1 Introduction . . . 13
2.2 Standard Histopathology . . . 14
2.2.1 Light Microscopy . . . 14
2.2.2 Immunohistochemistry . . . 15
2.2.3 Electron Microscopy . . . 16
2.3 Cytogenetics . . . 16
2.3.1 Classical Cytogenetic Analysis . . . 16
2.3.2 In-Situ Hybridization . . . 18
2.3.3 Spectral Karyotyping . . . 19
2.3.4 Comparative Genomic Hybridization . . . . 20
2.4 Molecular Genetic Techniques . . . 20
2.4.1 Introduction . . . 20
2.4.2 PCR and Q-PCR . . . 20
2.4.3 Microarrays . . . 23
2.4.4 Proteomics . . . 27
2.4.5 Conclusion . . . 30
References . . . 31
3 Diagnostic Imaging of Pediatric Bone and Soft Tissue Sarcomas Thomas D. Henry, Mary E. McCarville, Fredric A. Hoffer 3.1 Introduction . . . 35
3.2 Initial Evaluation of Bone and Soft Tissue Sarcomas . . . 35
3.3 Imaging Techniques for Evaluating the Primary Tumor . . . 37
3.4 Staging . . . 38
3.4.1 Local Extent of the Tumor . . . 38
3.4.2 Detection of Metastatic Disease . . . 40
3.5 Criteria for Evaluating Treatment Response . . . 41
3.6 Outcome Criteria . . . 43
3.7 Biopsy of the Primary Lesion . . . 43
3.8 Imaging Characteristics of Specific Tumors . . . 44
3.8.1 Bone Sarcomas . . . 44
3.8.1.1 Osteosarcoma. . . 44
3.8.1.2 Chondrosarcoma . . . 48
3.8.1.3 Ewing Sarcoma of Bone . . . 48
3.8.2 Soft Tissue Sarcomas . . . 51
3.8.2.1 Differentiating Benign from Malignant Soft Tissue Lesions 51 3.8.2.2 Soft Tissue Ewing Sarcoma Family of Tumors . . . 52
3.8.2.3 Rhabdomyosarcoma . . . 54
3.8.2.4 Non-rhabdomyosarcoma Soft Tissue Sarcomas . . . 61
3.8.2.4.1 Synovial Sarcoma . . . 61
3.8.2.4.2 Congenital Fibrosarcoma . . . 62
3.8.2.4.3 Hemangiopericytoma . . . 63
3.8.2.4.4 Malignant Peripheral Nerve Sheath Tumors (MPNST) . . . 65
3.9 Post-treatment Imaging Concerns . . . 66
3.10 Radiofrequency Ablation . . . 66
References . . . 67 IX
Contents
X Contents
4 Local Control Issues in Pediatric Bone and Soft Tissue Sarcomas
John C. Breneman, David Rodeberg,
Ruth F. Lavigne, Ken Brown, Eugene S. Wiener
4.1 Significance of Local Control
in Pediatric Sarcomas . . . 71
4.2 Background to Local Control Modalities . . . 72
4.2.1 Patterns of Tumor Growth . . . 72
4.2.2 Surgery . . . 72
4.2.2.1 Biopsy Guidelines. . . 72
4.2.2.2 Surgical Margins . . . 72
4.2.3 Radiation Therapy . . . 73
4.2.3.1 Types of Radiation . . . 73
4.2.3.2 Techniques of Radiotherapy . . . . 73
4.2.3.3 Treatment Morbidity . . . 74
4.2.4 Combined Surgery and Radiotherapy for Local Control . . . 74
4.2.5 Chemotherapy for Local Control . . . 75
4.3 Ewing’s Sarcoma . . . 75
4.3.1 Surgery for Ewing’s Sarcoma . . . 75
4.3.2 Radiation Therapy for Ewing’s Sarcoma . . . 76
4.3.2.1 Radiotherapy Treatment Factors . . 76
4.4 Rhabdomyosarcoma . . . 77
4.4.1 Surgery for Rhabdomyosarcoma . . . 77
4.4.2 Radiotherapy for Rhabdomyosarcoma . . . 78
4.4.3 Site Specific Approaches to Local Control . 79 4.4.3.1 Orbit and Head & Neck . . . 79
4.4.3.2 Genitourinary: Bladder/Prostate . . 79
4.4.3.3 Vagina and Uterine Sites . . . 80
4.4.3.4 Paratestes. . . 80
4.4.3.5 Extremity . . . 80
4.4.3.6 Trunk . . . 81
4.5 Non-Rhabdomyosarcomatous Soft Tissue Sarcomas . . . 81
4.5.1 Surgery for Non-Rhabdo Soft Tissue Sarcomas . . . 81
4.5.2 Radiotherapy for Non-Rhabdo Soft Tissue Sarcomas . . . 82
4.6 Osteosarcoma . . . 83
4.6.1 Surgery for Osteosarcoma . . . 83
4.6.2 Radiotherapy for Osteosarcoma . . . 84
References . . . 84
5 Drug Discovery in Pediatric Bone and Soft Tissue Sarcomas Using In Vivo Models Jennifer K. Peterson, Peter J. Houghton 5.1 Introduction . . . 89
5.2 Pediatric Tumor Models . . . 90
5.3 General Criteria for Selecting Appropriate Models . . . 91
5.4 Expression Profiles . . . 91
5.5 Criteria for Selecting RMS Xenografts for Drug Evaluation . . . 92
5.5.1 In Vivo Models in Drug Discovery . . . 93
5.5.2 Models for Optimizing Therapy . . . 94
5.6 Combination Therapy . . . 95
5.7 Molecular Targeted Agents . . . 97
5.8 Combining Signal Transduction Inhibitors . . . . 97
5.9 Future Directions . . . 99
References . . . 100
6 Pediatric Rhabdomyosarcoma: Biology and Results of the North American Intergroup Rhabdomyosarcoma Trials Alberto Pappo, Fred G. Barr, Suzanne L. Wolden 6.1 Epidemiology . . . 104
6.2 Pathology and Biology of Rhabdomyosarcoma . 105 6.2.1 Pathologic Classification of Rhabdomyosarcoma . . . 105
6.2.2 Chromosomal Translocations in Alveolar Rhabdomyosarcoma . . . 106
6.2.3 Allelic Loss of 11p15.5 in Embryonal Rhabdomyosarcoma . . . 108
6.2.4 Other Genetic Changes in Rhabdomyosarcoma . . . 108
6.3 Clinical Presentation and Evaluation of Extent of Disease . . . 110
6.3.1 Head and Neck Region . . . 110
6.3.2 Genitourinary Tumors . . . 110
6.3.3 Extremity Tumors . . . 110
6.3.4 Trunk . . . 110
6.3.5 Other Sites . . . 111
6.4 Staging . . . 111
6.5 Prognostic Factors . . . 114
6.6 Treatment . . . 114
6.7 Role of Local Therapies . . . 115
6.8 Multi-institutional Trials . . . 117
6.8.1 Clinical Group I . . . 117
6.8.2 Clinical Group II . . . 120
6.8.3 Clinical Group III . . . 120
6.8.4 Clinical Group IV . . . 121
6.9 Management of Specific Tumor Sites . . . 121
6.9.1 Parameningeal Tumors . . . 121
6.9.2 Orbital Tumors . . . 121
6.9.3 Head and Neck Non-Orbital, Non-Parameningeal Tumors . . . 122
6.9.4 Parotid Tumors . . . 122
6.9.5 Extremity Tumors . . . 123
6.9.6 Paratesticular Rhabdomyosarcoma . . . 123
XI Contents
6.9.7 Female Genital Tract Tumors . . . 123
6.9.8 Bladder and Prostate Rhabdomyosarcoma . 124 6.10 Other Sites . . . 125
6.10.1 Biliary Tract Tumors . . . 125
6.10.2 Perineal and Perianal Rhabdomyosarcoma . 125 6.10.3 Pelvic and Retroperitoneal Rhabdomyosarcoma . . . 125
6.11 Acute and Long Term Effects of Therapy . . . 125
6.12 Future Directions . . . 127
6.13 Outcome and Therapy of Relapse . . . 127
References . . . 128
7 Non-Rhabdomyosarcoma Soft Tissue Sarcomas Sheri L. Spunt, Suzanne L. Wolden, Deborah E. Schofield, Stephen X. Skapek 7.1 Epidemiology/Pathogenesis . . . 134
7.1.1 Incidence . . . 134
7.1.2 Risk Factors . . . 134
7.2 Pathology/Molecular Pathology . . . 135
7.2.1 Molecular Pathogenesis . . . 137
7.2.2 Synovial Sarcoma and the SYT/SSX Translocation . . . 139
7.2.3 Infantile Fibrosarcoma and ETV6-NTRK3 . . 139
7.2.4 Rhabdoid Tumor and INI1 . . . 139
7.2.5 Inflammatory Myofibroblastic Tumor and ALK . . . 140
7.2.6 Gastrointestinal Stromal Tumors and the KIT Transferase . . . 140
7.2.7 Dermatofibrosarcoma Protuberans and PDGF . . . 140
7.3 Histologic Classification . . . 140
7.3.1 Synovial Sarcoma . . . 141
7.3.2 Malignant Peripheral Nerve Sheath Tumor . 142 7.3.3 Infantile Fibrosarcoma . . . 142
7.3.4 Adult Type Fibrosarcoma . . . 143
7.3.5 Rhabdoid Tumor . . . 143
7.3.6 Inflammatory Myofibroblastic Tumor . . . . 144
7.3.7 Gastrointestinal Stromal Tumor . . . 144
7.3.8 Infantile Hemangiopericytoma . . . 145
7.3.9 Desmoplastic Small Round Cell Tumor . . . 145
7.3.10 Grading Systems . . . 146
7.4 Clinical Presentation and Diagnosis . . . 146
7.4.1 Presenting Features . . . 146
7.4.2 Differential Diagnosis . . . 146
7.4.3 The Diagnostic Biopsy . . . 147
7.4.4 Evaluation of Disease Extent . . . 147
7.5 Prognostic Factors and Clinical Staging . . . 148
7.5.1 Prognostic Factors . . . 148
7.5.2 Clinical Staging . . . 149
7.6 Treatment . . . 150
7.6.1 Surgery . . . 150
7.6.1.1 Surgical Management of the Primary Tumor. . . 150
7.6.1.2 Surgical Management of Metastases . . . 151
7.6.2 Radiation Therapy . . . 151
7.6.2.1 Radiation Planning . . . 152
7.6.2.2 Timing of Radiotherapy . . . 153
7.6.2.3 Brachytherapy . . . 153
7.6.2.4 New Technologies . . . 154
7.6.2.5 Acute Side Effects of Radiotherapy. . 154
7.6.2.6 Long-Term Side Effects of Radiotherapy. . . 154
7.6.3 Chemotherapy . . . 155
7.6.3.1 Adjuvant Chemotherapy . . . 155
7.6.3.2 Neoadjuvant Chemotherapy. . . 156
7.6.3.3 Other Approaches to the Use of Standard Chemotherapy157 7.6.3.4 High-Dose Chemotherapy . . . 157
7.6.3.5 Novel Agents . . . 157
7.6.3.6 Late Effects of Chemotherapy . . . . 158
7.7 Current Problems and Future Challenges . . . . 158
References . . . 158
8 Fibrous and Fibrohistiocytic Tumors Diane Nam, Benjamin A. Alman 8.1 Fibrous and Fibrohistiocytic Tumors . . . 164
8.2 Soft Tissue Fibrous Tumors . . . 164
8.2.1 Epidemiology/Pathogenesis . . . 165
8.2.2 Pathology/Molecular Biology . . . 166
8.2.3 Clinical Presentation and Diagnosis . . . 166
8.2.4 Prognostic Factors and Clinical Staging . . . 167
8.2.4.1 Treatment of Fibrous Tumors. . . 168
8.2.4.2 Current Problems and Future Challenges . . . 168
8.3 Fibrohistiocytic Tumors . . . 169
8.4 So-Called Fibrohistiocytic Tumors . . . 169
8.4.1 Histologic Classification . . . 169
8.4.2 Benign . . . 170
8.4.2.1 Benign Fibrous Histiocytoma. . . . 170
8.4.2.1.1 Epidemiology/Pathogenesis . . . 170
8.4.2.1.2 Pathology/Molecular Pathology. . . 171
8.4.2.1.3 Clinical Presentation and Diagnosis . 171 8.4.2.1.4 Prognostic Factors and Clinical Staging . . . 171
8.4.2.2 Giant Cell Tumor of Tendon Sheath and Diffuse-Type Giant Cell Tumor . 172 8.4.2.2.1 Epidemiology/Pathogenesis . . . 172
8.4.2.2.2 Pathology/Molecular Pathology. . . 172
8.4.2.2.3 Clinical Presentation and Diagnosis . 172 8.4.2.2.4 Prognostic Factors and Clinical Staging . . . 173
XII Contents
8.4.3 Intermediate . . . 173
8.4.3.1 Giant Cell Fibroblastoma and Dermatofibrosarcoma Protuberans. . . 173
8.4.3.1.1 Epidemiology/Pathogenesis . . . 173
8.4.3.1.2 Pathology/Molecular Pathology. . . 173
8.4.3.1.3 Clinical Presentation and Diagnosis . 174 8.4.3.1.4 Prognostic Factors and Clinical Staging . . . 174
8.4.3.2 Plexiform Fibrohistiocytic Tumor. . 174
8.4.3.2.1 Epidemiology/Pathogenesis . . . 174
8.4.3.2.2 Pathology/Molecular Pathology. . . 174
8.4.3.2.3 Clinical Presentation and Diagnosis . 175 8.4.3.2.4 Prognostic Factors and Clinical Staging . . . 175
8.4.3.3 Giant Cell Tumor of Soft Tissue . . . 175
8.4.3.3.1 Epidemiology/Pathogenesis . . . 175
8.4.3.3.2 Pathology/Molecular Pathology. . . 175
8.4.3.3.3 Clinical Presentation and Diagnosis. . . 175
8.4.3.3.4 Prognostic Factors and Clinical Staging . . . 176
8.4.3.3.5 Treatment of Fibrohistiocytic Tumors 176 8.5 Current Problems and Future Challenges . . . . 176
References . . . 177
9 Ewing Sarcoma Family of Tumors Carlos Rodriguez-Galindo, Fariba Navid, Joseph Khoury, Matthew Krasin 9.1 Introduction . . . 181
9.2 Epidemiology . . . 182
9.3 Pathogenesis . . . 182
9.4 Pathology . . . 185
9.4.1 Microscopic Features . . . 185
9.4.2 Molecular Pathology . . . 186
9.5 Clinical Features . . . 188
9.5.1 Extraosseous ESFT . . . 189
9.5.2 Laboratory and Radiologic Evaluation . . 189
9.5.3 Prognostic Factors . . . 190
9.6 Treatment . . . 192
9.6.1 Treatment of Patients with Localized Disease . . . 192
9.6.1.1 Four-Drug Regimens . . . 192
9.6.1.2 Role of Ifosfamide and Etoposide . 192 9.6.1.3 Increasing Dose Intensity. . . 195
9.6.1.4 Current Studies . . . 199
9.6.2 Local Control in ESFT . . . 199
9.6.2.1 Surgical Therapy . . . 200
9.6.2.2 Surgery and Adjuvant Radiation Therapy . . . 201
9.6.2.3 Definitive Radiation Therapy . . . . 202
9.6.2.4 Role of Systemic Chemotherapy in Local Control . . . 202
9.6.3 Treatment of Metastatic ESFT . . . 203
9.6.4 Myeloablative Therapy with Hematopoietic Stem Cell Rescue for Metastatic ESFT . . . 205
9.6.5 Second Malignancies . . . 207
9.6.6 Recurrent ESFT . . . 208
9.7 Future Developments . . . 208
References . . . 211
10 Osteosarcoma Paul A. Meyers 10.1 Incidence . . . 219
10.2 Etiology/Pathogenesis . . . 219
10.3 Molecular Biology . . . 220
10.4 Pathology . . . 221
10.5 Clinical Presentation and Natural History . . . 222
10.6 Diagnostic Evaluation . . . 222
10.7 Biopsy . . . 223
10.8 Staging . . . 223
10.9 Prognostic Factors . . . 223
10.10 Treatment . . . 225
10.11 Surgery . . . 227
10.12 Radiation Therapy . . . 227
10.13 Recurrent Disease . . . 228
10.14 Future Directions . . . 228
References . . . 228
Subject Index . . . 235
Benjamin A. Alman,MD
Division of Orthopaedic Surgery and Program in Developmental Biology
Hospital for Sick Children, University of Toronto 555 University Avenue
Toronto, ON M5G 1X8, Canada
Fred G. Barr,MD
Department of Pathology and Medicine The Children’s Hospital of Philadelphia 34th Street and Civic Center Boulevard Philadelphia, PA 19104-4399, USA
John C. Breneman,MD
Department of Radiation Oncology
University of Cincinnati, Barrett Cancer Center 234 Goodman Street, Cincinnati, OH 45219, USA
Ken Brown,MD
Department of Orthopedics Vancouver Children’s Hospital 4480 Oak Street, Room A207
Vancouver, British Columbia V6H 3V4, Canada
Thomas D. Henry,MD
Department of Radiological Sciences Division of Diagnostic Imaging St. Jude Children’s Research Hospital 332 N. Lauderdale St.
Memphis, TN 38105-2794, USA
Fredric A. Hoffer,MD
Department of Radiological Sciences Division of Diagnostic Imaging St. Jude Children’s Research Hospital 332 N. Lauderdale St.
Memphis, TN 38105-2794, USA
Peter J. Houghton,PhD
Department of Molecular Pharmacology St. Jude Children’s Research Hospital 332 N. Lauderdale Street
Memphis, TN 38105-2794, USA
Joseph Khoury,MD Department of Pathology
St. Jude Children’s Research Hospital 332 N. Lauderdale Street
Memphis, TN 38105-2794, USA
Matthew Krasin,MD Radiological Sciences
St. Jude Children’s Research Hospital 332 N. Lauderdale Street
Memphis, TN 38105-2794, USA
Ruth F. Lavigne,MD
Radiation Oncology, Barrett Cancer Center 234 Goodman Street, Cincinnati, OH 45219, USA
XIII
Contributors
Chapter 2
XIV Pediatric Cerebellar AstrocytomasContributors
Mary E. McCarville,MD
Department of Radiological Sciences Division of Diagnostic Imaging St. Jude Children’s Research Hospital 332 N. Lauderdale St.
Memphis, TN 38105-2794, USA
Paul A. Meyers,MD Department of Pediatrics
Memorial Sloan Kettering Cancer Center 1275 York Ave., New York, NY 10021, USA
Rajaram Nagarajan,MD
Department of Pediatrics, Division of Epidemiology University of Minnesota, 420 Delaware Street SE, MMC 715, Minneapolis, MN 55455, USA
Diane Nam,MD
Resident in Orthopaedic Surgery
Hospital for Sick Children, University of Toronto 555 University Avenue
Toronto, ON M5G 1X8, Canada
Fariba Navid,MD
Department of Hematology/Oncology St. Jude Children’s Research Hospital 332 N. Lauderdale Street
Memphis, TN 38105-2794, USA
Alberto Pappo,MD Department of Pediatrics The Hospital for Sick Children 555 University Avenue
Toronto, ON M5G 1X8, Canada
Jennifer K. Peterson,PharmD
Department of Molecular Pharmacology St. Jude Children’s Research Hospital 332 N. Lauderdale Street
Memphis, TN 38105-2794, USA
David Rodeberg,MD
Pediatric Surgery, Mayo Clinic
200 1st Street, SW, Rochester, MN 55905, USA
Carlos Rodriguez-Galindo,MD
Department of Hematology/Oncology St. Jude Children’s Research Hospital 332 N. Lauderdale Street
Memphis, TN 38105-2794, USA
Julie A. Ross,PhD
Department of Pediatrics, Division of Epidemiology University of Minnesota, 420 Delaware Street SE, MMC 715, Minneapolis, MN 55455, USA
Deborah Schofield,MD Department of Pathology
Children’s Hospital of Los Angeles
4650 Sunset Boulevard, Los Angeles, CA 90027, USA
Stephen X. Skapek,MD
Department of Hematology/Oncology St. Jude Children’s Research Hospital 332 N. Lauderdale Street
Memphis, TN 38105-2794, USA
Logan Spector,PhD
Department of Pediatrics, Division of Epidemiology University of Minnesota, 420 Delaware Street SE, MMC 715, Minneapolis, MN 55455, USA
Sheri L. Spunt,MD
Department of Hematology/Oncology St. Jude Children’s Research Hospital 332 N. Lauderdale Street
Memphis, TN 38105-2794, USA
Timothy Triche,MD Department of Pathology
Children’s Hospital of Los Angeles
4650 Sunset Boulevard, Los Angeles, CA 90027, USA
Eugene S. Wiener,MD
Children’s Hospital of Pittsburgh
3705 Fifth Avenue, Pittsburgh, PA 15213, USA
Suzanne L. Wolden,MD
Department of Radiation Oncology Memorial Sloan Kettering Cancer Center
1275 York Avenue, New York, NY 10021-6094, USA
