1 Introduction and Historical Back-
ground: Pediatric Hodgkin Lymphoma
S.S. Donaldson
1.1 The Way It Was . . . . . . . . . . . . . . . . . . . . 1
1.2 Lessons from the Children . . . . . . . . . . . . . 3
1.3 The Hidden Secrets –
The Discovery of Late Eff ects . . . . . . . . . . . 3
1.4 Current Optimal Management . . . . . . . . . . 4
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2 Biology and Pathology of Hodgkin’s
Disease
R.E. Hutchinson and A. Uner
2.1 History of Hodgkin’s Disease
Pathologic Classifi cation . . . . . . . . . . . . . . 7
2.2 Lineage of Hodgkin Reed-Sternberg
cells; B-cell phenotype . . . . . . . . . . . . . . . 9
2.3 Some Evidence of Antigen-Presenting
Function . . . . . . . . . . . . . . . . . . . . . . . . 10
2.4 Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . 10
2.5 NF-kappaB . . . . . . . . . . . . . . . . . . . . . . . 11
2.6 Jak/STAT Pathways . . . . . . . . . . . . . . . . . . 12
2.7 Tumor Necrosis Factor Receptor
(TNFR) Family . . . . . . . . . . . . . . . . . . . . . 12
2.8 Tumor Necrosis Factor Receptor-Associated
Factors (TRAFs) . . . . . . . . . . . . . . . . . . . . 12
2.9 Cytokines and Chemokines . . . . . . . . . . . . 13
2.10 Cytogenetics . . . . . . . . . . . . . . . . . . . . . . 14
2.11 Gene Profi le . . . . . . . . . . . . . . . . . . . . . . 14
2.12 Association with EBV . . . . . . . . . . . . . . . . 14
2.13 Pathology of Classical
Hodgkin Lymphoma . . . . . . . . . . . . . . . . 16
2.14 Immunophenotype of
Classical HRS cells . . . . . . . . . . . . . . . . . . 17
2.15 Flow Cytometry . . . . . . . . . . . . . . . . . . . . 18
Contents
2.16 Histologic Classifi cation of CHL . . . . . . . . . 19
2.16.1 Nodular Sclerosis HL . . . . . . . . . . . 19
2.16.2 Mixed Cellularity HL . . . . . . . . . . . . 20
2.16.3 Nodular Lymphocyte Rich CHL . . . . . 21
2.16.4 Lymphocyte Depleted HL . . . . . . . . 22
2.17 Nodular Lymphocyte Predominant
Hodgkin Lymphoma (NLPHL) . . . . . . . . . . . 22
2.18 Hodgkin Lymphoma in the Setting of HIV
Infection . . . . . . . . . . . . . . . . . . . . . . . . 23
2.19 Bone Marrow Involvement and
Histologic Staging . . . . . . . . . . . . . . . . . . 23
2.20 Pathology of Relapse and
Second Malignancy . . . . . . . . . . . . . . . . . 24
2.21 Diff erential Diagnosis of HL . . . . . . . . . . . . 25
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3 Treatment of Pediatric Hodgkin
Lymphoma
M.M. Hudson, C. Schwartz, and L.S. Constine
3.0 Introduction . . . . . . . . . . . . . . . . . . . . . . 35
3.1 Clinical Presentation . . . . . . . . . . . . . . . . . 36
3.1.1 Systemic Symptoms . . . . . . . . . . . . 37
3.1.2 Laboratory Evaluation . . . . . . . . . . . 37
3.1.3 Immunologic Status . . . . . . . . . . . . 38
3.2 Diff erential Diagnosis . . . . . . . . . . . . . . . . 39
3.3 Diagnostic Evaluation and Staging . . . . . . . 40
3.4 Prognostic Factors . . . . . . . . . . . . . . . . . . 43
3.5 Combination Chemotherapy . . . . . . . . . . . 45
3.6 Chemotherapy Alone Versus Combined
Modality Therapy . . . . . . . . . . . . . . . . . . . 49
3.7 Risk-Adapted Therapy . . . . . . . . . . . . . . . . 51
3.7.1 Treatment of Low-Risk Disease. . . . . . 51
3.7.2 Treatment of Intermediate- and
High-Risk Disease . . . . . . . . . . . . . . 53
3.8 Principles of Radiation Therapy . . . . . . . . . . 54
3.8.1 Volume Considerations . . . . . . . . . . 56
3.8.2 Dose Considerations . . . . . . . . . . . . 58
3.8.3 Energy . . . . . . . . . . . . . . . . . . . . . 59
VIII
3.9 Summary Recommendations for Primary
Disease/Selection of Therapy . . . . . . . . . . . 59
3.10 Acute Eff ects of Therapy . . . . . . . . . . . . . . 59
3.10.1 Chemotherapy Side-Eff ects . . . . . . . . 59
3.10.2 Radiation Side-Eff ects . . . . . . . . . . . 61
3.11 Future Directions . . . . . . . . . . . . . . . . . . . 61
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
4 Treatment of Relapsed/Refractory
Hodgkin Lymphoma
T.M. Trippett and A. Chen
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . 67
4.2 Strategies for Re-induction . . . . . . . . . . . . 67
4.2.1 Role of Re-induction Chemotherapy . . 68
4.2.2 Standard Re-induction with ICE . . . . . 68
4.2.3 Re-induction with Ifosfamide/
Vinorelbine (IV) . . . . . . . . . . . . . . . 69
4.3 High-Dose Therapy . . . . . . . . . . . . . . . . . . 70
4.3.1 Immunomodulation as a Therapeutic
Strategy to Augment High-Dose
Therapy . . . . . . . . . . . . . . . . . . . . 71
4.3.2 Reduced-Intensity/Non-myeloablative
Allogeneic Stem cell Transplantation . . 72
4.4 Salvage Strategies Following Transplantation 72
4.4.1 Combination Chemotherapy with
Gemcitabine/Vinorelbine (GEM/VRB) . 73
4.4.2 Molecular Targeting of the
NF-κB Pathway . . . . . . . . . . . . . . . . 74
4.4.2.1 Activation of NF-κΒ . . . . . . . . 74
4.4.2.2 Inhibition of NF-κB Through
Proteasome Inhibition . . . . . 75
4.4.2.3 Adult Clinical Trials . . . . . . . . 76
4.4.2.4 Pediatric Clinical Trials . . . . . . 77
4.4.2.5 Novel Retrieval Strategies
Incorporating Proteasome
Inhibition with Bortezomib . . 77
4.4.3 Targeted Immunotherapy Strategies . . 77
4.4.3.1 Epstein-Barr Virus
Directed Therapy . . . . . . . . . 77
4.4.3.2 Monoclonal Antibodies Targeting
Receptors Expressed in HL . . . 78
4.4.3.3 Radiolabeled Immunoglobulin
Therapy in HL . . . . . . . . . . . 79
4.5 Future Considerations . . . . . . . . . . . . . . . 79
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5 Non-Hodgkin’s Lymphoma:
Introduction and Historical Background
S.B. Murphy
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . 85
5.2 The Early Era, Pre-1970 . . . . . . . . . . . . . . . 86
5.3 The Latter Era, Post-1970s . . . . . . . . . . . . . 86
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
6 Biology and Pathology of Pediatric
Non-Hodgkin Lymphoma
S.L. Perkins and S.W. Morris
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . 91
6.2 Non-Hodgkin Lymphoma . . . . . . . . . . . . . 91
6.3 Pathologic Analysis. . . . . . . . . . . . . . . . . . 93
6.3.1 Morphology . . . . . . . . . . . . . . . . . 93
6.3.2 Immunophenotypic Analysis . . . . . . . 94
6.3.3 Molecular and Cytogenetic Analysis . . 95
6.3.4 WHO Classifi cation of
Hematolymphoid Tumors . . . . . . . . 100
6.4 Molecular Pathogenesis of Pediatric NHL . . 101
6.5 Burkitt Lymphomas . . . . . . . . . . . . . . . . 101
6.5.1 Pathology . . . . . . . . . . . . . . . . . . 101
6.5.2 Biology and Molecular Mechanisms . 104
6.6 Diff use Large B-Cell Lymphomas . . . . . . . 107
6.6.1 Pathology . . . . . . . . . . . . . . . . . . 107
6.6.2 Biology and Molecular Mechanisms . 109
6.7 Anaplastic Large-Cell Lymphoma . . . . . . . 112
6.7.1 Pathology . . . . . . . . . . . . . . . . . . 112
6.7.2 Biology and Molecular Mechanisms . 117
6.8 Lymphoblastic Lymphoma . . . . . . . . . . . . 119
6.8.1 Pathology . . . . . . . . . . . . . . . . . . 119
6.8.2 Biology and Molecular Mechanisms . 121
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
7 B-Cell Lymphoma/Burkitt Lymphoma
I. Magrath
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . 142
7.2 Diagnosis and Imaging . . . . . . . . . . . . . . 142
7. 2.1 Burkitt Lymphoma . . . . . . . . . . . . 142
7.7.2 Diff use Large B-cell Lymphoma . . . . 143
7.2.3 Burkitt-like Lymphoma . . . . . . . . . 144
7.2.4 HIV-Associated B-cell Lymphomas . . 144
7.2.5 Imaging Studies . . . . . . . . . . . . . . 144
Contents
IX
7.3 Clinical Features . . . . . . . . . . . . . . . . . . . 146
7.4 Staging . . . . . . . . . . . . . . . . . . . . . . . . 148
7.4.1 Staging Procedures . . . . . . . . . . . . 150
7.5 Treatment . . . . . . . . . . . . . . . . . . . . . . 151
7.5.1 Early Studies in Africa . . . . . . . . . . 151
7.5.2 Non-Cross-Resistant Drugs and
Combination Therapy . . . . . . . . . . 152
7.5.3 Therapy Directed Towards
CNS Disease . . . . . . . . . . . . . . . . 154
7.5.4 Early Studies in the USA . . . . . . . . . 154
7.5.5 Comparison with Leukemia Treatment 155
7.5.6 Critical Components of Modern
Treatment Protocols . . . . . . . . . . . 155
7.5.6.1 Basic Drugs . . . . . . . . . . . . . . . 155
7.5.6.2 High-Dose MTX . . . . . . . . . . . . 156
7.5.6.3 The Role of Additional Drugs . . . 156
7.5.6.4 Dose Density . . . . . . . . . . . . . 157
7.5.6.5 Risk Adaptation . . . . . . . . . . . . 157
7.5.6.6 Prevention of CNS Disease . . . . . 159
7.5.6.7 Treatment of DLBCL with
Diff erent Regimens . . . . . . . . . . 160
7.5.6.8 Role of Surgery . . . . . . . . . . . . 160
7.5.6.9 Role of Radiation . . . . . . . . . . . 161
7.5.6.10 Tumor Lysis Syndrome . . . . . . . 162
7.6 Prognostic Factors . . . . . . . . . . . . . . . . . 163
7.6.1 Tumor Burden and Stage . . . . . . . . 163
7.6.2 Rapidity of Response . . . . . . . . . . . 164
7.6.3 Age and Sex . . . . . . . . . . . . . . . . 164
7.6.4 Histology . . . . . . . . . . . . . . . . . . 164
7.6.5 Molecular Characteristics . . . . . . . . 165
7.7 Outcome . . . . . . . . . . . . . . . . . . . . . . . 165
7.8 Management of Relapse . . . . . . . . . . . . . 166
7.9 Follicle Center Cell and Marginal Zone
Lymphomas . . . . . . . . . . . . . . . . . . . . . 167
7.10 Future Prospects . . . . . . . . . . . . . . . . . . 167
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
8 Anaplastic Large-Cell Lymphoma
A. Reiter
8.1 Introduction . . . . . . . . . . . . . . . . . . . . . 175
8.2 Diagnosis and Imaging . . . . . . . . . . . . . . 177
8.3 Clinical Features . . . . . . . . . . . . . . . . . . . 178
8.4 Staging . . . . . . . . . . . . . . . . . . . . . . . . 181
8.5 Treatment and Outcome . . . . . . . . . . . . . 181
8.5.1 Stratifi cation of Treatment Intensity . 185
8.5.2 CNS Prophylaxis and CNS Therapy . . 185
8.5.3 Role of Local Therapy Modalities and
Pattern of Therapy Failure . . . . . . . 186
8.6 Prognostic Factors . . . . . . . . . . . . . . . . . . . 187
8.7 Management of Relapse . . . . . . . . . . . . . . . 189
8.8 Future Prospects . . . . . . . . . . . . . . . . . . . . . 190
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
9 Precursor B and Precursor T-Cell Lym-
phoblastic Lymphoma
J.T. Sandlund
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . 199
9.2 Diagnosis and Imaging . . . . . . . . . . . . . . 199
9.2.1 Diagnosis . . . . . . . . . . . . . . . . . . 199
9.2.2 Imaging/Staging . . . . . . . . . . . . . 201
9.3 Clinical Features . . . . . . . . . . . . . . . . . . . 202
9.4 Treatment . . . . . . . . . . . . . . . . . . . . . . . 202
9.4.1 Initial Management . . . . . . . . . . . 202
9.4.2 Treatment Overview . . . . . . . . . . . 203
9.4.2.1 Limited Stage Disease . . . . . . . . 203
9.4.2.2 Advanced Stage Disease . . . . . . 204
9.4.2.3 Central Nervous System
Prophylaxis and Treatment . . . . 205
9.5 Prognostic Factors . . . . . . . . . . . . . . . . . 208
9.6 Outcome . . . . . . . . . . . . . . . . . . . . . . . 208
9.7 Management of Relapse . . . . . . . . . . . . . 208
9.8 Future Prospects . . . . . . . . . . . . . . . . . . 208
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
10 Cutaneous T-Cell Lymphomas and Rare
T-Cell Non-Hodgkin Lymphomas
M.E. Kadin
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . 215
10.2 Mycosis Fungoides and Sezary Syndrome . . 216
10.2.1 Clinical Features . . . . . . . . . . . . . . 216
10.2.2 Pathology . . . . . . . . . . . . . . . . . . 217
10.2.3 Immunophenotype . . . . . . . . . . . 218
10.2.4 Genetic Features . . . . . . . . . . . . . 218
10.2.5 Prognosis . . . . . . . . . . . . . . . . . . 219
10.2.6 Therapy . . . . . . . . . . . . . . . . . . . 220
10.3 CD30+ Cutaneous T-Cell Lymphomas
Including Lymphomatoid Papulosis . . . . . 221
10.4 Lymphomatoid Papulosis . . . . . . . . . . . . 221
10.4.1 Clinical Features . . . . . . . . . . . . . . 221
10.4.2 Pathology . . . . . . . . . . . . . . . . . . 222
10.4.3 Immunophenotype . . . . . . . . . . . . 223
10.4.4 Genetic Features . . . . . . . . . . . . . 223
10.4.5 Prognosis . . . . . . . . . . . . . . . . . . 223
10.5 Primary Cutaneous Anaplastic
Large-cell Lymphoma . . . . . . . . . . . . . . . 224
10.5.1 Clinical Features . . . . . . . . . . . . . . 224
10.5.2 Pathology . . . . . . . . . . . . . . . . . . 224
10.5.3 Diff erential Diagnosis . . . . . . . . . . 224
10.5.4 Immunophenotype . . . . . . . . . . . . 225
10.5.5 Genetic Features . . . . . . . . . . . . . 225
10.5.6 Therapy . . . . . . . . . . . . . . . . . . . 225
Contents
X
10.6 Subcutaneous Panniculitis-like
T-Cell Lymphoma . . . . . . . . . . . . . . . . . . 225
10.6.1 Clinical Features . . . . . . . . . . . . . . 226
10.6.2 Pathology . . . . . . . . . . . . . . . . . . 226
10.6.3 Immunophenotype . . . . . . . . . . . 226
10.6.4 Genetic Features . . . . . . . . . . . . . 227
10.6.5 Therapy . . . . . . . . . . . . . . . . . . . 227
10.7 Hepatosplenic T-Cell Lymphoma . . . . . . . 227
10.7.1 Clinical Features . . . . . . . . . . . . . . 227
10.7.2 Pathology . . . . . . . . . . . . . . . . . . 227
10.7.3 Immunophenotype . . . . . . . . . . . 227
10.7.4 Genetic Features . . . . . . . . . . . . . 227
10.7.5 Therapy . . . . . . . . . . . . . . . . . . . 228
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
11 Lymphoproliferative Disorders
Related to Immunodefi ciencies
T.G. Gross and B. Shiramizu
11.1 Introduction . . . . . . . . . . . . . . . . . . . . . 233
11.2 Epstein-Barr Virus . . . . . . . . . . . . . . . . . . 234
11.3 Post-transplant Lymphoproliferative
Disease . . . . . . . . . . . . . . . . . . . . . . . . 236
11.3.1 PTLD Following Blood or Marrow
Transplantation . . . . . . . . . . . . . . 239
11.3.2 PTLD Following Solid Organ
Transplantation . . . . . . . . . . . . . . 240
11.4 HIV-Related Malignancies . . . . . . . . . . . . 242
11.5 Lymphoproliferative Disease in Primary
Immunodefi ciencies . . . . . . . . . . . . . . . . 246
11.6 Summary . . . . . . . . . . . . . . . . . . . . . . . 250
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
12 Late Eff ects Following Lymphoma
Treatment
D.L. Friedman and A.T. Meadows
12.1 Introduction . . . . . . . . . . . . . . . . . . . . . 259
12.2 Second Malignant Neoplasms . . . . . . . . . 260
12.3 Neurocognitive . . . . . . . . . . . . . . . . . . . 261
12.4 Cardiovascular . . . . . . . . . . . . . . . . . . . . 261
12.5 Pulmonary . . . . . . . . . . . . . . . . . . . . . . 263
12.6 Bone and Body Composition . . . . . . . . . . 264
12.7 Endocrine . . . . . . . . . . . . . . . . . . . . . . . 264
12.7.1 Thyroid Gland . . . . . . . . . . . . . . . 264
12.8 Reproductive Endocrine . . . . . . . . . . . . . 265
12.8.1 Male Gonadal Function . . . . . . . . . 265
12.8.2 Female Gonadal Function . . . . . . . . 265
12.8.3 Reproduction . . . . . . . . . . . . . . . 266
12.9 Dental . . . . . . . . . . . . . . . . . . . . . . . . . 267
12.10 Spleen . . . . . . . . . . . . . . . . . . . . . . . . . 267
12.11 Psychosocial . . . . . . . . . . . . . . . . . . . . . 268
12.12 Mortality . . . . . . . . . . . . . . . . . . . . . . . 268
12.13 Monitoring for Late Eff ects . . . . . . . . . . . 269
12.14 Research Challenges for Lymphoma
Survivors . . . . . . . . . . . . . . . . . . . . . . . 269
12.15 Future Directions . . . . . . . . . . . . . . . . . . 273
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Subject Index . . . . . . . . . . . . . . . . . . . . . . . 281