Pediatric Liver Tumors (eBook)

Prof.Dr.med.em Arthur Zimmermann graduated in Medicine at the University of Berne, Switzerland. He attended the local Pathology Residency Program, followed by several years of experipmental basic research in the fields of cancer cell cycle mutants and mechanisms of leukocyte and cancer cell motility. As chief of staff and then head of the division of surgical pathology at the University of Berne he specialized in hepatobiliary and pancreatic tumor pathology, where he became the author and coauthor of more than 500 publications. Until July 2009, Prof. Zimmermann was Acting Director of the Institute of Pathology of the University of Berne. As an expert in pediatric liver tumors he is an international consultant and holds the Pathology Review Center for the International Childhood Liver Tumor Study Group ( SIOPEL ). Prof. Giorgio Perilongo graduated in Medicine in 1980 at the University of Padua, Italy; he then attended the local Pediatric Residency program for then completing his post-graduate education with a fellowship in Hematology-Oncology first and in Neuro-Oncology thereafter at the Children’s Hospital of Philadelphia. Presently he is the Chairman of the Department of Pediatrics of the University Hospital in Padua. He was among the founders of the International Childhood Liver Tumor Study Groups (otherwise known as SIOPEL group), the international cooperative research group on childhood liver tumors based in Europe conceived within the umbrella of the International Society of Pediatric Oncology. Within this group is has and he is still playing a very active role. He chaired a series of clinical trials already published in the main international scientific journals.

Pediatric Oncology 1
Copyright Page 3
Foreword 4
Contents 7
Contributors 9
1: Introduction 11
2: Historical Background 12
2.1 Introduction 12
2.2 The Dark Ages 13
2.3 Advent of Printing 13
2.4 Early Children’s Hospital 13
2.5 Pioneer Pathologists and/or Their Textbooks 14
2.6 Pioneers in Surgical Anatomy and Liver Surgery 14
2.7 Liver Transplantation 14
2.8 International Oncology Groups 15
2.8.1 COG 15
2.8.2 SIOP 15
2.8.3 SIOPEL (SIOP Epithelial Liver tumors) 15
2.8.4 IPSO 16
2.8.5 SIOP ASIA 16
2.8.6 PODC (Pediatric Oncology in Developing Countries) 16
2.8.7 EONS (European Oncology Nursing Specialists) 16
2.9 National Pediatric Oncology Societies 16
2.10 Clinical Liver Trials 17
2.11 Conclusions and Future Outlook 17
References 21
3: Epidemiology of Pediatric Liver Tumors 24
3.1 Introduction 24
3.2 Descriptive Epidemiology of Pediatric Liver Tumors 25
3.2.1 Spectrum and Frequency of Liver Tumors in Children 25
3.2.2 International Variations in Incidence 25
3.2.3 Time Trends in Incidence 27
3.3 Analytical Epidemiology of Hepatoblastoma and Hepatocellular Carcinoma in Children 27
3.3.1 Overview of Environmental Risk Factors 27
3.3.2 Very Low Birth Weight and Hepatoblastoma 28
3.3.3 Parental Tobacco Smoking and Hepatoblastoma 29
3.3.4 Associations with Heritable Cancer Predisposition, Congenital Malformation Syndromes, and Anomalies 29
3.3.5 Etiology of Hepatocellular Carcinoma in Children 30
3.4 Implications of Findings from Analytical Studies of Pediatric Liver Tumors 31
3.5 Conclusions 32
References 33
4: Molecular Aspects of Hepatoblastoma 36
4.1 Introduction 36
4.2 Basics of Hepatoblastoma 36
4.3 Familial Forms of Hepatoblastoma 37
4.5 Altered Developmental Signaling Pathways in Hepatoblastoma 40
4.5.1 The Wnt Signaling Pathway 40
4.5.2 The Hedgehog Signaling Pathway 42
4.5.3 The Insulin-Like Growth Factor Axis 43
4.5.4 The Hepatocyte Growth Factor/c-Met Pathway 44
4.6 Epigenetically Altered Tumor Suppressor Genes in Hepatoblastoma 45
4.7 Gene Signatures as Predictors of Outcome 46
References 47
5: Ontogenetic Aspects of Liver Tumors 52
5.1 Introduction 52
5.2 Liver Ontogenesis: Pathways from Endoderm to Liver 52
5.2.1 Generation of the Hepatoblast and Hepatocyte Lineages 52
5.2.2 Development of the Cholangiocyte Lineage and the Bile Duct System 53
5.3 Stem Cells in the Pathogenesis of Hepatoblastomas 54
5.4 Undifferentiated Epithelial Hepatoblastomas and the Rhabdoid Cell/INI1 Connection 55
5.5 Beyond Hepatoblasts: Tumors with More Differentiated Liver Cell Lineages 56
5.6 Bimodal Differentiation: Cholangioblastic Hepatoblastomas and Ductal Plate Tumors May Recapitulate Early Steps of Hepato 56
5.7 Epithelial-Mesenchymal Transition as a Pathogenic Mechanism in Mixed Hepatoblastomas and Related Tumors 57
5.8 Conclusion 58
References 58
6: Translational Investigations of Liver Tumors: Sampling Strategies and Banking 61
6.1 Introduction 61
6.2 SIOPEL Liver Tumour Storage Programme 62
6.2.1 Tumor Tissue Collection 62
6.2.2 Tumor Tissue Storing 63
6.2.3 Tumor Tissue Distribution 64
6.3 Discussion 65
References 65
7: Clinical Presentation and Diagnosis 67
7.1 Malignant Liver Tumors 67
7.1.1 Age at Diagnosis 67
7.1.2 Clinical Symptoms 68
7.1.3 Laboratory Investigations 68
7.1.4 Imaging 70
7.1.5 Biopsy 70
7.2 Benign Tumors 70
7.2.1 Vascular Tumors 70
7.2.2 Mesenchymal Hamartomas 71
7.2.3 Focal Nodular Hyperplasia 71
7.2.4 Adenoma 71
7.3 Conclusion 71
References 71
8: Imaging and Staging of Pediatric Liver Tumors 73
8.1 Imaging Techniques 73
8.1.1 Ultrasound (US) 73
8.1.2 Computed tomography (CT) 75
8.1.3 Magnetic Resonance Imaging (MRI) 77
8.1.4 Nuclear Medicine 77
8.1.5 Obsolete Imaging Techniques 77
8.2 Approach to Differential Diagnosis 78
8.2.1 Benign Tumors 78
8.2.2 Malignant Tumors 78
8.3 Staging Systems 80
8.4 Local Staging 80
8.4.1 PRETEXT 80
8.4.1.1 PRETEXT I (Fig. 8.6) 81
8.4.1.2 PRETEXT II (Fig. 8.7) 81
8.4.1.3 PRETEXT III (Fig. 8.8) 82
8.4.1.4 PRETEXT IV (Fig. 8.9) 82
8.4.2 Imaging of Segmental and Vascular Anatomy 82
8.4.3 Multifocal Tumor (F) 83
8.5 Vascular Involvement (P, V) 83
8.6 Extrahepatic Spread in the Abdomen (E, H) 86
8.7 Metastatic Disease (M, N) 87
References 89
9: Pathology of Pediatric Liver Tumors 91
9.1 Hepatoblastoma and Related Tumors 91
9.1.1 Introduction 91
9.1.2 Classification of Hepatoblastoma 91
9.1.3 Macroscopy 92
9.1.4 Histopathology of Hepatoblastomas 92
9.1.4.1 Fetal Hepatoblastoma: The Differentiated Phenotype with a Favorable Histology 93
9.1.4.2 Embryonal Histology: A Common Partner of Fetal Tissue Components 94
9.1.4.3 Macrotrabecular Hepatoblastoma: A Distinct Growth Pattern 95
9.1.4.4 Undifferentiated Epithelial Hepatoblastomas 96
Small Cell Undifferentiated Hepatoblastoma (HB-SCUD) 96
Other Phenotypes of Undifferentiated Hepatoblastoma 99
Undifferentiated Hepatoblastoma with Rhabdoid Features and Malignant Rhabdoid Tumor 99
9.1.4.5 Grading of Epithelial Types of Hepatoblastoma 100
9.1.4.6 Mixed Epithelial and Mesenchymal Hepatoblastomas 100
Mixed Epithelial and Mesenchymal Hepatoblastoma Without Teratoid Features 100
Mixed Epithelial and Mesenchymal Hepatoblastoma with Teratoid Features 100
9.1.5 Immunohistochemistry of Hepatoblastomas 102
9.1.6 Growth Patterns, Proliferation, and Differentiation Characteristics in Hepatoblastomas 103
9.1.7 Chemotherapy Effects in Hepatoblastomas 105
9.1.8 Cholangioblastic Hepatoblastoma (Hepatoblastomas with Cholangioblastic Features) and “Ductal Plate Tumors” 107
9.1.9 Transitional Liver Cell Tumor (TLCT) 107
9.1.10 Tumors Possibly Related to the Hepatoblastoma Tumor Family 109
9.2 Pediatric Hepatocellular Carcinoma 110
9.2.1 Definition and Epidemiology 110
9.2.2 Etiology 110
9.2.3 Pathology of Adult-Type Hepatocellular Carcinoma 111
9.2.3.1 Gross Presentation 111
9.2.3.2 Histology of Adult-Type Hepatocellular Carcinoma 112
9.2.4 Fibrolamellar Hepatocellular Carcinoma 113
9.2.5 Differential Diagnoses 114
9.2.6 New Knowledge on Pathogenic/Molecular Pathways 115
9.2.7 Conclusion 115
References 116
10: Surgical Treatment 121
10.1 Introduction 121
10.2 Biopsy 121
10.3 Liver Resections 123
10.3.1 Liver Anatomy and Resectability Assessment 124
10.3.1.1 Hepatic Anatomy 124
10.3.1.2 Resectability 125
10.3.2 Technical Aspects 129
10.3.2.1 Typical Liver Resections 131
10.3.2.2 Atypical Liver Resections 132
10.3.2.3 Special Surgical Techniques 132
10.3.3 Tumor Residuum 133
10.3.4 Complications and Their Management 134
10.3.4.1 Bleeding 134
10.3.4.2 Bile Leak and Stricture 134
10.3.4.3 Others 134
10.4 Surgery for Metastases 135
10.4.1 Pulmonary Metastases 135
10.5 Surgery for Recurrent Disease 136
References 137
11: Liver Transplantation for Unresectable Liver Tumors in Children 140
11.1 Introduction 140
11.2 Hepatoblastoma 141
11.2.1 PRETEXT and Liver Transplantation for HB in SIOPEL 141
11.2.2 Outcomes of Transplantation for HB Reported in Literature 143
11.2.3 Guiding Principles to Consider for Transplant in HB 145
11.2.4 Recommendations for Liver Transplantation in Current Multicenter HB Studies 148
11.2.5 Post-Transplant Immunosuppression 149
11.3 Hepatocellular Carcinoma 149
11.3.1 Outcomes of Transplantation for HCC Reported in Literature 150
11.3.2 Guiding Principles to Consider for Liver Transplant in HCC 151
11.3.3 Contemporary Recommendations for Liver Transplantation in HCC in Children 152
11.4 Transplant for Other Pediatric Liver Tumors 153
11.4.1 Infantile Hepatic Hemangioma, Infantile Hemangioendothelioma of the Liver (IHHE), and Angiosarcoma 153
11.4.2 Malignant Epithelioid Hemangioendothelioma 154
11.4.3 Mesenchymal Hamartoma 154
11.4.4 Inflammatory Myofibroblastic Tumor 154
11.4.5 Undifferentiated (Embryonal) Sarcoma 155
11.5 Pediatric Liver Unresectable Tumor Observatory (Pluto) 155
11.6 Conclusion 155
References 156
12: Chemotherapy for Childhood Hepatoblastoma and Hepatocellular Carcinoma 160
12.1 Hepatoblastoma 160
12.1.1 Why Chemotherapy? 160
12.1.2 When Chemotherapy? 161
12.1.3 Which Chemotherapy? 162
12.2 The North American Experience (Table 12.1) 163
12.3 The SIOPEL Experience (Table 12.2) 165
12.4 Other Regimens 166
12.5 Hepatocellular Carcinoma 167
12.5.1 The North American Experience 167
12.5.2 The SIOPEL Experience 167
12.6 The German Experience 168
12.6.1 Other Experiencees 168
12.6.2 Overall Conclusive Remarks 168
References 168
13: Salvage Strategies 171
13.1 Failures in Hepatoblastoma 171
13.2 Salvage Modalities 173
13.3 Chemotherapeutic Agents in Salvage Treatment 173
13.4 High-Dose Chemotherapy 176
13.5 Conclusions 179
References 180
14: Alternative Approaches for Treatment 183
14.1 Introduction 183
14.2 Theoretical Aspects of Intraarterial Chemotherapy 183
14.3 Technical Aspects of Hepatic Artery Chemoembolization 185
14.3.1 Complications 187
14.4 Results of Hepatic Artery Chemoembolization 187
14.5 Other Transarterial Techniques 189
14.6 Percutaneous Tumor Ablation 191
14.7 Portal Vein Embolization 191
References 193
15: Supportive Therapy and Toxicity 195
15.1 Introduction 195
15.2 Supportive Care 195
15.2.1 Safer Blood Products 195
15.2.2 Central Intravenous Catheters 196
15.2.3 Improved Nutritional Support and Antiemetic Therapy 196
15.2.4 Management of Infection and Prophylaxis 197
15.3 Toxicity 197
15.3.1 Platinum-Containing Agents 197
15.3.1.1 Administration 197
15.3.1.2 Acute Toxicity 197
Nausea and Vomiting 197
Allergic Reactions 198
Bone Marrow Toxicity 198
15.3.1.3 Late Toxicity 198
Renal Toxicity 198
Hearing Loss 198
Neurological Toxicity 201
15.3.2 Doxorubicin 201
15.3.2.1 Administration 201
15.3.2.2 Acute Toxicity 201
Nausea and Vomiting 201
Bone Marrow Toxicity 201
Mucositis 201
15.3.2.3 Late Toxicity 201
Cardiotoxicity 201
15.3.3 Vincristine 203
15.3.3.1 Administration 203
15.3.3.2 Side Effects 203
15.4 Conclusion 203
References 203
16: Challenges and Opportunities of International Therapeutic Trials 206
16.1 Introduction 206
16.2 Challenges 207
16.2.1 Clinical Trials in Very Rare Diseases 207
16.2.2 Staging Systems 207
16.3 Trial Designs 208
16.3.1 The Hypothesis Dictates the Trial Design 208
16.3.2 Biomolecular Investigations 209
16.3.3 Case Report Forms 209
16.4 Trial Conduct 209
16.4.1 Why Bother to Treat Patients in Clinical Trials? 209
16.4.2 Complete Documentation of All Included Patients 210
16.4.3 Interim Monitoring 210
16.5 Presentation and Interpretation of Results 211
16.5.1 Intention to Treat Analysis 211
16.6 Opportunities 212
References 212
17: Tumors Other than Hepatoblastoma and Hepatocellular Carcinoma 213
17.1 Introduction 213
17.2 Undifferentiated (Embryonal) Sarcoma of the Liver 213
17.2.1 Introduction 213
17.2.2 Epidemiology and Etiology 214
17.2.3 Clinical Presentation and Diagnosis 214
17.2.4 Pathology 215
17.2.5 Treatment 215
17.2.5.1 Therapy of Non-ruptured Solitary Hepatic Lesions with or Without Metastases 215
17.2.5.2 Therapy in Case of Tumor Rupture 218
17.2.5.3 Therapy of Multifocal Tumors 218
17.2.5.4 Relapsing Tumor 218
17.3 Hepatobiliary Rhabdomyosarcoma 218
17.3.1 Introduction 218
17.3.2 Clinical Presentation and Diagnosis 218
17.3.3 Pathology 219
17.3.4 Treatment 219
17.4 Malignant Rhabdoid Tumor of the Liver 220
17.5 Angiosarcoma of the Liver 220
17.5.1 Introduction 220
17.5.2 Clinical Presentation and Diagnosis 220
17.5.3 Pathology 220
17.5.4 Treatment 221
17.6 Other Hepatic Vascular Tumors 221
17.6.1 Infantile Hepatic Hemangioendothelioma 221
17.6.2 Epithelioid Hemangioendothelioma of the Liver 222
17.7 Mesenchymal Hamartoma 222
17.7.1 Introduction 222
17.7.2 Clinical Presentation and Diagnosis 223
17.7.3 Treatment 223
17.8 Conclusion 223
References 223
18: Future Prospective 226
References 228
Index 229