The Pathobiology of Neoplasia

This book is directed primarily to advanced graduate and medical students, postdoctoral trainees, and established investigators having basic research interests in neoplasia. Its content is based in part on the lecture outlines and selected histopathology laboratory components of an advanced course entitled The Pathobiology of Experimental Animal and Human Neoplasia, developed by me for the Experimental Pathology Curriculum of the Department of Pathology at the Medical College of Virginia. In this regard, an effort has been made to integrate pathology with carcinogenesis, genetics, biochemistry, and cellular and molecular biology in order to present a comprehensive and current view of the neoplastic process. For focus, emphasis is mainly being placed on the neoplastic cells themselves, and not on associated host-mediated responses. It ishoped that this book will accomplish its purpose of providing students and researchers who already possess strong but diverse basic science backgrounds with unifying concepts in tumor pathobiology, so as to stimulate new research aimed at furthering our understanding of neoplastic disease. I wish to express my appreciation and heartfelt thanks to the authors, whose individual ranges of expertise and research experience clearly bring to their respective chapters unique perspectives that easily transcend any redundancy that may be present. In addition, I am grateful to Drs. George Vennart, Saul Kay, and Fred Meier, and to Ms. Connie Wilkerson of the Department of Pathology at MCV, for their helpful comments and their review of some of the material.

Inhalt
Introduction: Chronology of Significant Events in the Study of Neoplasia.- 1. Classification of Neoplasms.- 1. Introduction.- 2. Non-Neoplastic Adaptive Growth Changes.- 2.1. Atrophy.- 2.2. Hypertrophy.- 2.3. Hyperplasia.- 2.4. Metaplasia.- 2.5. Dysplasia.- 3. Preneoplastic Lesions and Malformations.- 4. Anaplasia and Differentiation in Neoplasms.- 5. Pathobiologic Characteristics of Benign and Malignant Neoplasms.- 6. Nomenclature of Neoplasms.- 7. Grading and Staging of Malignant Neoplasms.- References.- 2. Chemical Carcinogenesis in Experimental Animals and Humans.- 1. Background.- 2. Metabolism of Chemical Carcinogens.- 2.1. Aromatic Compounds.- 2.2. Aliphatic Compounds.- 2.3. Miscellaneous.- 3. Classification of Chemical Carcinogens.- 3.1. Direct-Acting versus Indirect-Acting Carcinogens.- 3.2. Genotoxic versus Epigenetic Carcinogens.- 3.3. Initiators and Promoters.- 4. Structure-Activity Relationships.- 5. Relevance to Humans.- References.- 3. DNA Adducts and Carcinogenesis.- 1. General Considerations.- 2. DNA Adduct Determination and Quantitation.- 3. DNA Adducts from Specific Classes of Carcinogens.- 3.1. N-Nitrosamines.- 3.2. Aflatoxins.- 3.3. Aromatic Amines.- 3.4. Polycyclic Aromatic Hydrocarbons.- 4. Conclusions.- References.- 4. Oncogenic Viruses.- 1. Introduction.- 1.1. Purpose.- 1.2. Overview and Historic Events.- 1.3. Classification.- 2. Host Cells, Tumor Viruses, and Their Interactions.- 2.1. Host Cells.- 2.2. Tumor Viruses.- 2.3. Interactions: Proto-Oncogenes and Retro-Oncogenes.- 3. Common Pathways of Cell Transformation and Neoplasia: Unifying Features of Viral Oncogenesis.- 3.1. Virus-Induced Transformation.- 3.2. Unifying Features of Viral Carcinogenesis.- 4. Pathobiology of Oncogenic Viruses and Experimental Animal Models of Virus-Induced Human Neoplasia.- 4.1. DNA Tumor Viruses.- 4.2. RNA Tumor Viruses.- 5. Immunologic Aspects of Virus-Induced Neoplasia.- 5.1. Virus-Associated Antigens.- 5.2. Effector Mechanisms of Virus-Induced Tumor Immunity.- 6. Concluding Remarks.- References.- 5. Radiation Carcinogenesis.- 1. Introduction.- 1.1. Historic Perspective.- 1.2. Ionizing Radiation and Its Interaction with Matter.- 2. Radiation Carcinogenesis in Vivo.- 2.1. The Human Experience.- 2.2. Radiation Carcinogenesis in Animal Models.- 3. Pathology of Radiation Carcinogenesis in Vivo.- 3.1. Incidence and Morphology.- 3.2. Relative Tissue Sensitivity.- 3.3. Latency.- 4. Radiation Transformation in Vitro.- 4.1. Experimental Techniques.- 4.2. Properties of Transformed Cells.- 5. Factors Influencing Radiation Carcinogenesis or Transformation.- 5.1. Physical Factors.- 5.2. Host/Environmental Factors.- 6. Pathogenesis of Radiation Carcinogenesis.- 6.1. Multistep Process: Initiation and Promotion.- 6.2. DNA as a Critical Target.- 6.3. Oncogenes in Radiation Carcinogenesis.- 7. Conclusion.- References.- 6. The Multistage Concept of Carcinogenesis.- 1. Types of Tumorigenic Enhancement.- 2. Multistage Skin Tumorigenesis.- 3. Multistage Tumorigenesis in Nonepidermal Systems.- 3.1. Bladder.- 3.2. Liver.- 3.3. Respiratory Tract.- 3.4. Intestine.- 3.5. Mammary Gland.- 3.6. Other Nonepidermal Systems.- 4. Multistage Models of Neoplasia in Cell-Culture Systems.- 4.1. Measurement of Multistage Development of Cell Transformation.- 4.2. Measurement of Promoter-Induced Changes in Intercellular Relationships.- 4.3. Measurement of Promoter-Induced Changes in Membrane Function.- 4.4. Measurement of Changes in Cellular Differentiation.- 5. Conclusions.- References.- 7. Organ and Species Specificity in Chemical Carcinogenesis and Tumor Promotion.- 1. Introduction.- 2. Organ and Species Specificity Attributable to Metabolism.- 3. Biologic Effects of Alkylating Agents.- 3.1. Direct-Acting Compounds.- 3.2. Metabolism-Dependent Compounds.- 3.3. Molecular Targets of Alkylating Agents.- 4. Organ and Species Specificity in Tumor Promotion.- 4.1. Promotion in Squamous Epithelia.- 4.2. Promotion in Nonsquamous Epithelia.- 4.3. Dietary Factors That Promote Carcinogenesis.- References.- 8. DNA Repair Mechanisms and Carcinogenesis.- 1. Introduction.- 2. Damage to DNA.- 3. DNA Repair Systems.- 3.1. Direct Repair of Damage.- 3.2. Excision Repair.- 4. Relationship of DNA Repair to Carcinogenesis.- 4.1. Causes of Incomplete DNA Repair.- 4.2. Mechanisms for Tolerating Unrepaired DNA Damage.- 5. Summary.- References.- 9. Preneoplasia and Precancerous Lesions.- 1. Introduction.- 2. Preneoplastic and Precancerous Lesions in Experimental Animals.- 2.1. Squamous Cell Papilloma as a Precancerous Lesion in Mouse Skin Carcinogenesis.- 2.2. Precursor Lesions Associated with Hepatocarcinogenesis in the Rat.- 3. Preneoplastic and Precancerous Lesions in Humans.- 3.1. Cervical Dysplasia and Carcinoma in Situ of the Uterine Cervix.- 3.2. Adenomatous Polyps of the Colon and Rectum.- 3.3. Dysplastic Nevi.- 3.4. Liver Cell Dysplasia and Adenomatous Hyperplastic Liver Nodules.- 3.5. Other Examples of Putative Epithelial Cell Preneoplasia.- 4. Conclusions.- References.- 10. Tumor Progression and the Clonal Evolution of Neoplasia.- 1 Introduction.- 2. Structural Variation in Tumors.- 3. Foulds' General Principles of Tumor Progression.- 4. Clonal Origins of Neoplasms in Humans and Experimental Animals.- 5. Mechanisms of Tumor Progression.- 5.1. Aneuploidy and Tumor Progression.- 5.2. Oncogenes and Tumor Progression.- 6. Conclusions.- References.- 11. Cytogenetics and Human Neoplasia.- 1. Introduction.- 2. Chromosomal Symbols, Abbreviations, and Nomenclature.- 3. Computer Data Management.- 4. Constitutional versus Acquired Chromosomal Abnormalities in Cancer.- 4.1. Constitutional Chromosomal Abnormalities.- 4.2. Acquired Chromosomal Abnormalities.- 5. Cytogenetic Dissection of a Translocation between Chromosomes 9 and 22: The Philadelphia Translocation.- 5.1. The Philadelphia Translocation Occurs in Multiple Types of Leukemia and Related Disorders.- 5.2. Biology of Cell Lineages.- 5.3. Molecular Dissection of the Ph Translocation.- 6. Cytogenetic Dissection of the Acute Nonlymphocytic Leukemias.- 6.1. The French-American-British Classification of ANLL.- 6.2. Primary Chromosomal Rearrangements and Numerical Changes.- 6.3. Cytogenetic Dissection: A New Perspective on ANLL.- 7. Cytogenetic Dissection of ALL.- 8. Other Hematologic Conditions.- 9. Comments on Chromosomal Changes in Hematol…

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