Neoplasms: Principles of Development and Diversity
Jules J. Berman, Ph.D., M.D.
© 2009 Jones and Bartlett Publishers, Sudbury, MA
Neoplasms: Principles of Development and Diversity is written for cancer researchers, oncologists, pathologists, and students of tumor biology. The book focuses on two existential mysteries.
1. Is cancer a single disease process that is manifested in many different types of tumors, or is cancer many different diseases, all related by excessive cell growth? If all cancer can be characterized by a single disease process, why haven't we isolated the process and cured cancer? If cancer is thousands of different diseases, how can we ever hope to cure all of the different kinds of cancer?
2. If cancer is characterized by the progressive accumulation of genetic abnormalities, and if every tumor specimen is genetically unique and distinct from every other tumor specimen, why do tumors fit into precisely named types? Worded another way, why does every unique tumor fall into one of the diagnostic entities (e.g., Warthin tumor, melanoma, lobular carcinoma of breast, and so on) that pathologists are taught to recognize?
The central thesis of the book is that by tackling these questions, it will be possible to develop a practical strategy to eradicate every type of human cancer.
The book is divided into three major parts. The first part, Speciation, covers the causes of cancer, and why we see the kinds of restricted cancer types that occur in man and animals. The concept of tumor speciation is key to building a classification of cancer, and it has been a constant wonder to me that authors who write cancer textbooks always accept the extant species of cancer as a "given" condition that does not require any deep thought or explanation. We cannot start thinking about how to classify cancers until we understand tumor speciation. The lack of any serious attention to the subject manifests itself in the popular piecemeal classifications of cancer, which are basically just lists of tumors that occur in an anatomic region (e.g. tumors of head and neck).
The second part of the book is Classification. This section describes the formal methods by which biological entities are classified. Though there are thousands of distinct named neoplasms, all neoplasms can be sensibly grouped into one of several dozen hierarchical biological classes, and these biological classes are characterized by shared developmental pathways (including precancer/cancer transitions), shared functional pathways (including genetic and epigenetic features), and shared restraints (determined by the cell lineage of the neoplasm).
None of this effort (i.e., understanding tumor speciation and constructing a neoplasm classification) has any value if it does not lead to the reduction of deaths from cancer. The last part of the book explains how a biological classification reduces the perceived complexity of cancer by assigning each tumor to one of several dozen classes of tumors that may be amenable to class-specific prevention, diagnosis, and treatment. This is the most important part of the book, because it suggests practical ways of eradicating cancer by applying pre-existing approaches (designed for individual cancers) to classes of cancer, using an available neoplasm classification.
The complete Table of Contents of Neoplasms: Principles of Development and Diversity follows:
Table of Contents
Preface xv
Introduction: What Will You Learn by Reading This Book? xix
Why Is Cancer Such a Difficult Disease to Understand? xix
Is Cancer One Disease or Many Diseases? xxii
Part I Speciation 1
1 What Properties Are Shared by All Cancers? . 3
1.1 Background 3
1.2 Are There Any Properties of Neoplasms that Are Not Found in Normal Cells? 4
1.3 Persistent Growth in Normal Cells 4
1.4 Invasion by Normal Cells 5
1.5 Metastasis by Normal Cells 5
1.6 Is There a Common Temporal Sequence Leading to the Development of Cancer? 7
1.7 Why Is It Important to Treat Cancers Early? 7
1.8 Cancer Morphology 8
1.9 General Rules for Naming Neoplasms 8
1.10 What Is a Cytologic Diagnosis? 9
1.11 Morphology of Malignant Cells 10
1.12 Cancerous Atypia and Reactive Atypia 12
1.13 How Can You Distinguish Reactive Atypia from Cancerous Atypia? 13
1.14 Dysplastic Cells and How They Differ from Cancer Cells 14
1.15 Nuclear Atypia in Cancer Cells 15
1.16 Why Are the Nuclei of Malignant Cells Different from Nuclei of Normal Cells? 15
1.17 Tumor Monoclonality 15
1.18 Monoclonal Proliferative Lesions 16
1.19 Clonal Expansion in Paroxysmal Nocturnal Hemoglobinuria 17
1.20 Clonal Expansions of Normal Cells that May Not Lead to Cancer 18
1.21 Polyclonal Expansions that May Lead to Monoclonal Cancer 18
1.22 Tumor Growth Regulation and Tumor Autonomy 18
1.23 Limits on Tumor Autonomy 19
Summary 19
Chapter 2 Carcinogenesis 21
2.1 Background 21
2.2 Oncogenes and Tumor Suppressor Genes 23
2.3 The Narrow Range of Tissue-Specificity of Oncogenes 24
2.4 Are There Tumors that Have Multiple Activated Oncogenes? 25
2.5 Do Tumor Suppressor Genes Cause Cancer? 25
2.6 Can Genetic Alterations in Cancer Cells Be Mediated (and Reversed) Through Epigenetic Modifications? 26
2.7 Tumor Initiation 27
2.8 Tumor Latency 28
2.9 Tumor Dormancy 29
2.10 Spontaneous Regression of Latent Tumors 30
2.11 Are Tumor Latency and Tumor Dormancy Related Phenomena? 31
2.12 Chemical Carcinogenesis 31
2.13 Why Do Chemical Carcinogens Need to Be Activated by Cells in Our Bodies Before They Can Cause Cancer? 32
2.14 Do We Know Which Chemicals Are Likely To Cause Cancer In Humans? 33
2.15 Naturally Occurring Carcinogens 33
2.16 Do Viruses Cause Cancer? 34
2.17 Are There Tumors that Arise Spontaneously,Without Initiation, and Without Any Contribution from an External Carcinogen? 35
2.18 Cancer Regression 36
2.19 The Inherited Syndromes that Cause Cancers 36
2.20 Minimal Number of Events Necessary for Tumor Development 37
2.21 Fast and Slow Carcinogenesis 38
2.22 Iatrogenic Insertional Carcinogenesis 38
2.23 Can Cancer Be Reversed By Modifying A Single Oncogene? 39
Summary 40
Chapter 3 The Mysteries of Tumor Diversity and of Type-Specific Tumor Uniformity 42
3.1 Background 42
3.2 Tumor Heterogeneity 43
3.3 How Are Clonality, Progression, and Heterogeneity Related? 44
3.4 The Complexity of Cancers 44
3.5 Tumor Diversity and the Disconnect Between Genotype and Phenotype 45
3.6 Animal Speciation and Tumor Speciation 46
3.7 Benign Tumors 47
3.8 Are There Benign Oncogenes? 48
Summary 49
Chapter 4 The Range of Neoplastic Phenotypes51
4.1 Background 51
4.2 Neoplastic Lesions 51
4.3 Do Benign Tumor Cells Develop into Malignant Tumor Cells over Time? 53
4.4 How Do We Know When a Lesion Is a Neoplasm? 54
4.5 Borderline Tumors 56
4.6 Precancers 57
4.7 Consensus Definition of Precancers 58
4.8 The Difference Between a Precancerous Condition and a Precancer 59
4.9 What Is the Difference Between a Benign Tumor and a Precancer? 59
4.10 Is There a Difference Between Precancer Genes and Cancer Genes? 60
4.11 Is There Value in Treating Precancers? 61
4.12 Hamartomas and Choristomas 62
4.13 Are Hamartomas Types of Neoplasms? 62
4.14 Hamartoma Syndromes 64
4.15 Is There a Pure Hamartoma Syndrome? 64
Summary 65
Chapter 5 What Can We Learn About Human Neoplasms by Studying Animals, Plants, Fish, and Insects? 67
5.1 Background 67
5.2 Neoplasia in Plants 68
5.3 Neoplasia in Insects 69
5.4 Neoplasia in the Amphibia 70
5.5 Carcinogenesis in Fish 71
5.6 Zebrafish 71
5.7 Neoplasia in Mammals 72
5.8 Oncogenes in the Animal Kingdom 75
5.9 Tumor Suppressor Genes in the Animal Kingdom 75
5.10 Why Do Whales Not Develop More Tumors Than Mice? 77
5.11 Evolutionary Mimicry and Evolutionary Convergence 78
5.12 Goodbye to the APUDoma 79
5.13 Are Animal Tumors Good Models for Human Tumors? 81
5.14 What Kinds of Questions Can Best Be Answered in Animal Systems? 81
5.15 Is Cancer Directly Transmissible from Organism to Organism? 82
5.16 Transmission of Virally-Induced Cancers 82
5.17 What Can We Learn from the Differences Between Animal and Human Tumors? 83
5.18 The Hepatopancreas of Arthropods, Gastropods, and Fish 83
Summary 84
Part II Classification 85
Chapter 6 What Does Classification of All Animals Tell Us About the Classification of All Neoplasms? . 87
6.1 Background 87
6.2 What Is Speciation and How Does It Relate to Evolution, Taxonomy, and Classification? 88
6.3 How Does Animal Classification Relate to the Classification of Neoplasms? 89
6.4 What Is the Most Common Impediment to Classifying a Species? 89
6.5 The Sui Generis Taxon 90
6.6 The Classification of Organisms Is Not Strictly Cladistic 91
Summary 92
Chapter 7 Classification of Neoplasms 93
7.1 Background 93
7.2 The Challenge of Classifying Neoplasms 93
7.3 Molecular Analyses of Neoplasms 94
7.4 Formal Principles of Biological Classification 95
7.5 Current status of Tumor Classification 96
Summary 99
Chapter 8 Classification by Morphology (What the Tumor Looks Like) 100
8.1 Background 100
8.2 Epithelial and Nonepithelial Tumors 102
8.3 Tumor Variants 106
8.4 Determining Histogenesis 108
8.5 Morphology and the Invention of Rare Tumors 109
8.6 What Is a Rare Tumor? 109
8.7 Why Are Rare Tumors Important? 110
8.8 The Importance of Uncommon Variants of Common Tumors 111
8.9 Example Case: Gastrointestinal Stromal Tumor 111
8.10 What Do Rare Tumors Have in Common with Uncommon Variants of Common Tumors? 114
8.11 What Can We Learn from Uncommon Variants of Common Tumors? 114
8.12 Can We Understand Common, Sporadic Tumors by Studying Rare, Inherited Tumors? 115
8.13 Will We Learn How to Prevent Common Tumors by Studying Rare Tumors? 124
8.14 Why Are We Likely to Prevent and Cure Rare Tumors Before We Cure Common Tumors? 125
8.15 Are Sporadic Tumors Always Characterized by the Same Mutation that Is Present in the Germline of Patients Who Develop These Tumors as Part of an Inherited Condition? 126
Summary 127
Chapter 9 Classification by Cause 128
9.1 Background 128
9.2 Determining the Cause of a Cancer 129
9.3 Carcinogen Exposure and Type of Cancer 130
9.4 How Does Sunlight Produce Melanomas in Locations that Are Not Exposed to Sunlight? 131
9.5 Are the Steps in Chemical Carcinogenesis Cell Type Dependent? 131
9.6 Why Do Liver Tumors Occur Less Frequently than Tumors of the Lung and Colon? 131
9.7 Variations in Tumor Progression 133
9.8 Clastogens and Leukemias 134
9.9 Why Do Chromosome Breakage Syndromes Often Cause Leukemias and Seldom Cause Carcinomas? 134
9.10 Myeloproliferative Disorders, Myelodysplasias, and Preleukemic Conditions 136
9.11 What Are the Chief Differences Between Myelodysplasias and Myeloproliferative Disorders? 137
9.12 What Are the Features Shared Among Tumors Produced by a Particular Carcinogen? 138
9.13 Do Some Carcinogens Cause Only Benign Tumors and Others Cause Only Malignant Tumors? 138
9.14 Tumors Caused by Viruses 139
9.15 Immune Surveillance and the Role of Immunosuppression in Carcinogenesis 140
9.16 Why Do the Tumors that Occur in Some Tumor Inheritance Syndromes Cross Multiple Cell Lineages? 141
Summary 142
Chapter 10 Classification by Topography (Where the Tumor Is Located) 144
10.1 Background 144
10.2 The Range of Tumors Occurring in a Single Organ 145
10.3 Subsets of Anatomic Classifications 146
Summary 146
Chapter 11 Classification by the Age at Which the Cancer Occurs 148
11.1 Background 148
11.2 What Tumors Occur in Infants and Children? 148
11.3 The PNET Tumors 150
11.4 What Is the EWS Family of Tumors? 151
11.5 Leukemias 152
11.6 Transplacental Carcinogenesis 153
11.7 There Are Only a Few Known Human Transplacental Carcinogens 154
11.8 Why Are Congenital and Childhood Tumors Extremely Rare? 154
11.9 Why Does Transplacental Carcinogenesis Seldom Produce Tumors of Primitive Cells? 155
11.10 Why Are the Early-Stage Embryos Resistant to Carcinogenesis? 156
11.11 Congenital Tumors in Humans 156
11.12 Why Do Pediatric Tumors Respond So Well to Chemotherapeutic Agents and Adult Tumors Respond So Poorly? 157
11.13 Why Can We Infer that Most Tumors Occurring in Adults Have a Long Latency? 157
11.14 What Do We Learn from Age at Diagnosis and Synchronous Appearance of Tumors in Germline Mutation Syndromes? 158
Summary 159
Chapter 12 Classification by Function and Common Pathways 160
12.1 Background 160
12.2 Endocrine Neoplasia 162
12.3 Pathways 164
Summary 167
Chapter 13 Molecular Classification of Neoplasms 168
13.1 Background 168
13.2 Fundamental Properties Are Not Always Good Classifiers 169
13.3 Limitations of a Molecular Classification of Neoplasms 169
13.4 A Genetic Classification for the Major Categories of Human Tumors 172
13.5 Complexities in the Genetic Approach to Cancer Classification 172
13.6 Proteomic Classification of Cancer 175
13.7 Epigenomic Classification of Cancer 176
13.8 Is a Human Tumor Genome Project Feasible? 179
Summary 179
Chapter 14 Classification by Developmental Lineage Is Best 180
14.1 Background 180
14.2 Lineage Can Be Determined with Certainty 182
14.3 Developmental Lineage Pathways Are Often Preserved in Tumors 183
14.4 Are There Examples of Tumors of Unknown Lineage? 184
14.5 Are There Tumors That Arise Through Transdifferentiation? 184
Summary 186
Chapter 15 The Six Major Classes of Neoplasms 187
15.1 Background 187
15.2 Class Endoderm/Ectoderm Neoplasms 188
15.3 Class Mesoderm Neoplasms 190
15.4 Class Neuroectoderm Neoplasms 190
15.5 Class Neural Crest Neoplasms 190
15.6 Class Germ Cell (Includes Teratomatous) Neoplasms 191
15.7 Class Trophectoderm (Cells of Extraembryonic Origin) Neoplasms 192
15.8 Primitive Tumors Are Somatic Neoplasms that Occur in Different Classes and that Are Unrelated to Germ Cell Tumors 193
15.9 Organs with Multiple Anlagen 193
15.10 Rhabdoid Tumor: The Neoplasm that Breaks All the Rules 194
Summary 197
Chapter 16 Ectodermal and Endodermal Neoplasms 198
16.1 Background 198
16.2 Properties of Class Endoderm/Ectoderm 199
16.3 Neoplasms that Are Too Numerous to Count 199
16.4 Tumors of Class Endoderm/Ectoderm in Childhood 200
16.5 Why Are the Major Embryonic Layers of Ectoderm and Endoderm Combined in the Developmental Classification? 201
16.6 The Differences Between Endoderm and Ectoderm 201
16.7 Polyphyly and the Strange Origin of Transitional Cells 202
16.8 Squamous Cell Carcinomas 203
16.9 Adenocarcinoma 204
16.10 Endodermal and Ectodermal Tumors that Do Not Seem to Follow the Rules 207
16.11 The Genetic Causes of Class Endoderm/Ectoderm Tumors 208
16.12 Can a Single Gene Alteration Characterize a Tumor of Class Endoderm/Ectoderm? 208
Summary 209
Chapter 17 Mesodermal Neoplasms 211
17.1 Background 211
17.2 The Mesenchyme 211
17.3 Coelomic Tissues 211
17.4 The Subcoelomic Mesodermal Tissues 213
17.5 Generalizations about Mesodermal Tumors 213
17.6 Why Do Soft Tissue Tumors Have Simple Genetic Markers? 213
17.7 Why Do Tumors of Mesodermal Origin Occur Infrequently? 214
17.8 Renal Cancer and Uterine Cancer, So Misunderstood 215
17.9 Leukemias and Lymphomas 217
17.10 Helicobacter-Induced Prelymphoma 218
Summary 218
Chapter 18 Tumors of Neuroectoderm (Brain and Central Nervous System) 220
18.1 Background 220
18.2 The Types of Neuroectodermal Tumors 222
18.3 PNET Tumors Do Not Belong in Class Neuroectoderm 222
18.4 The So-Called Blastomas of Neuroectodermal Origin (Glioblastoma, Ependymoblastoma, Medulloblastoma, Retinoblastoma, and Pineoblastoma) 223
18.5 Phakomatoses 224
Summary 225
Chapter 19 Neural Crest Tumors 226
19.1 Background 226
19.2 The Neural Crest in Human Development 229
19.3 Tumors of the Peripheral Nervous System 230
19.4 Melanocytic Lesions 231
19.5 Odontogenic Tumors 232
19.6 Ameloblastomas 232
19.7 Endocrine Tumors of Neural Crest Origin 233
19.8 Cladistics and the Neural Crest-Derived Mesenchymal Tumors 233
19.9 Meningiomas 235
19.10 Triton Tumors 235
Summary 235
Chapter 20 Tumors of Class Germ Cell and Class Trophectoderm 237
20.1 Background 237
20.2 Definitions 237
20.3 Diverse Nature of Germ Cell Tumors 239
20.4 Embryonic Stem Cell Tumors 240
20.5 Germ Cell Tumors Are Not Equivalent to Stem Cell Tumors 241
20.6 What Is the Stem Cell Theory of Cancer? 241
20.7 Tumors of Class Trophectoderm (Gestational Trophoblastic Tumors) 245
20.8 Complete and Partial Hydatidiform Moles 246
20.9 Why Does Paternal Disomy Lead to Hydatidiform Moles? 247
20.10 The Totipotent Fascination of the 129 Mouse 247
Summary 249
Chapter 21 Specialized Cancer Nomenclatures and the Developmental Lineage Classification and Taxonomy of Neoplasms 251
21.1 Background 251
21.2 Nomenclatures, Taxonomies, Classifications 252
21.3 Inconsistent Meanings Within Standard Medical Nomenclatures 252
21.4 Incompleteness in Standard Nomenclatures 255
21.5 Striving for Completeness 256
21.6 Informatics Support Within the Developmental Classification 258
21.7 Coding Medical Information 258
21.8 Re-Coding Data 260
Summary 262
Chapter 22 Cancer Ontologies . 263
22.1 Background 263
22.2 Introduction to Ontologies 264
22.3 Ontologies and Complexity 264
22.4 The National Cancer Institute’s Thesaurus 266
22.5 GO, the Gene Ontology that Is Not an Ontology 268
22.6 Converting Classifications into Ontologies 269
Summary 270
Part III Cancer Research and the End of Neoplasms 273
Chapter 23 Class-Dependent Cancer Prevention, Diagnosis, and Treatment 275
23.1 Background 275
23.2 The Malignancy Detector 275
23.3 Why Are There So Few Tumors that We Can Now Cure? 278
23.4 First Priority: Drugs that Induce Precancer Regression 279
23.5 Second Priority: Cancer Prevention 281
23.6 Third Priority: Treatments for Tumors of Primitive Cells (Almost All of Which Are Tumors of Childhood) 284
23.7 Fourth Priority: Vaccines Against Oncogenic Viruses 284
23.8 Fifth Priority: Epigenomic Drugs for Germ Cell Tumors 285
23.9 Sixth Priority: Treatments for Tumors of Mesoderm, Neuroectoderm, and Neural Crest 285
23.10 Seventh Priority: Nonsurgical Treatment for Benign Neoplasms 286
23.11 Eighth Priority: New Diagnostic and Predictive Markers for Cancers 287
23.12 Ninth Priority: Use Experience Obtained From Items 1, 3, 6, and 7 to Develop Targeted Drug Treatments for Endoderm/Ectoderm Tumors 289
Summary 290
Chapter 24 Finding Neoplasms: Suggestions for Cancer Researchers 292
24.1 Background 292
24.2 What Do Pathologists Do? 293
24.3 Times Are Changing 294
24.4 Who Owns the Tissues and Reports that Are Archived Within Pathology Departments? 296
24.5 What Role Will Computers Play in Cancer Treatment? 298
24.6 Pathologists and Nonpathologists 299
Summary 300
Chapter 25 Principles 302
25.1 Background 302
25.2 Principles of Neoplasms 303
Summary 305
Glossary 307
References 369
Index 395
Figure Credits 425
Author Biography 429
Jules Berman, Ph.D., M.D., received his bachelor's degrees in Mathematics and in Earth and Planetary Sciences from MIT, his Ph.D. from Temple University, and his M.D. from the University of Miami. He received post-doctoral training in the NCI's Laboratory of Experimental Pathology. He received residency training at the George Washington University Medical Center. He served as the chief of Anatomic Pathology at the VA Hospital in Baltimore where he held adjunct appointments at Johns Hopkins Medical Center and the University of Maryland Medical Center. From 1998 to 2005 he was Program Director for Pathology Informatics in NCI's Cancer Diagnosis Program. He is a past President of the Association for Pathology Informatics. Jules Berman has first-authored more than 100 publications. Today, he is a free-lance science writer.
Key words: tumors, tumour, neoplasms, neoplasia, carcinogenesis,
tumor development, cancer research, neoplastic development, precancer
preneoplasia, preneoplastic, perinatal carcinogenesis, tumor
progression, tumor latency, tumor dormancy, tumors of childhood,
pediatric tumors
Last modified: September 26, 2008
Books by Jules Berman
