Toxicologic Pathology Nonclinical Safety Assessment 2nd Edition by Page R Bouchard, Chirukandath Gopinath, Jerry F Hardisty, Pritam S Sahota, James A Popp ISBN B07H35BHPB 9780429997464

Section IConcepts in Drug Development

Chapter 1 Overview of Drug Development

1.1 Scientific History

1.1.1 Origin of Modern Therapeutic Agents

1.2 Regulatory History

1.2.1 Regulatory Aspects of Drug Development

1.2.2 US Food and Drug Law

1.2.3 European Drug Law

1.2.4 Japanese Drug Law

1.2.5 International Harmonization

1.2.6 Current Regional Regulatory Differences

1.2.7 Regulatory Review Process

1.3 Sequence of Small-Molecule Drug Development

1.3.1 Selection of Areas for Drug Development

1.3.2 Scientific Expertise Required for Drug Development

1.3.3 Stages of Drug Development

1.3.4 Drug Discovery

1.3.5 Nonclinical Development

1.3.6 Clinical Development

1.3.7 Postmarketing

1.3.8 Decision Process for Advancement or Termination during Drug Development

1.3.9 Role and Responsibility of Toxicologic Pathologist in Drug Development

1.4 Approaches to Drug Development of Biotherapeutics

1.4.1 Approaches to Drug Development of Oligodeoxynucleotide Therapeutics

1.4.2 Approaches to Drug Development of Gene Therapy Products

1.5 Time and Resource Utilization in Drug Development

1.6 Future Changes in Drug Development

Chapter 2 Nonclinical Safety Evaluation of Drugs

2.1 Introduction

2.2 Lead Optimization Safety Assessment

2.3 Nonclinical Animal Toxicology Studies for Small Molecules

2.4 Nonclinical Animal Toxicology Studies for Biopharmaceuticals

2.5 Reversibility/Recovery of Drug-Induced Pathology in Nonclinical Safety Studies

2.6 Comparing Biopharmaceuticals to Traditional Small-Molecule Drugs

2.7 Immunotoxicology

2.8 Safety Pharmacology

2.9 Development and Reproductive Toxicology

2.10 Genetic Toxicology

2.11 Carcinogenicity Testing

2.12 Safety Assessment of Oncology Products

2.13 Challenges with Nonclinical Safety Assessment in the NHP

2.14 Reporting Pathology Data for the Regulatory Scientist and Clinician

Chapter 3 Nonclinical Safety Evaluation of Advanced Therapies

3.1 Introduction

3.2 Cell-based Therapies

3.2.1 Types

3.2.2 Safety Concerns

3.3 Gene Therapies

3.3.1 Ex Vivo Gene Therapies/Genetically Modified Cell Therapies

3.3.2 In Vivo Gene Therapies

3.3.3 T-Cell Based Immunotherapy

3.3.4 Genome Editing

3.3.5 Oncolytic Viruses

3.4 Expression Knockdown Therapies

3.4.1 Introduction to Expression Knockdown Therapies

3.4.2 Accumulation Effects: Basophilic Granules and Vacuolated Macrophages

3.4.3 Proinflammatory Effects

3.4.4 Renal Effects

3.4.5 Liver Toxicity

3.4.6 Thrombocytopenia

3.4.7 Newer Generation ASO Modalities

3.5 US FDA/CBER Regulatory Perspective on Cellular and Gene Therapies

Chapter 4 Nonclinical Safety Evaluation of Medical Devices

4.1 Introduction

4.2 Knowledge Base and Scientific Interactions

4.3 In Vivo Biological Evaluation of Biomaterials and Medical Devices

4.4 Terminology

4.4.1 Biomaterials

4.4.2 Biocompatibility

4.4.3 Biomaterial Extractables and Leachables

4.4.4 Medical Device Definition and Examples

4.4.5 Combination Products

4.4.6 Maximum Implantable Dose (MID)

4.4.7 FDA Title 21 Code of Federal Regulations (21 CFR) Definitions

4.4.8 Premarket Approval (PMA)

4.4.9 Premarket Notification 510(k)

4.4.10 Humanitarian Use Device (HUD)

4.4.11 Investigational Device Exemption (IDE)

4.4.12 International Medical Device Regulators Forum (IMDRF)

4.4.13 Other Terms and Definitions

4.5 Device Materials and Forms

4.6 Regulatory Oversight

4.6.1 Global Medical Device Regulatory Agencies

4.6.2 Comparison of Global Device Classification Categories

4.6.3 Global Harmonization Task Force (GHTF) and International Medical Device Regulators Forum (IMDRF)

4.6.4 FDA Medical Device Risk Assessment Approach

4.6.5 Standards and Guidelines

4.6.5.1 Good Laboratory Practices (GLP)

4.6.5.2 International Organization for Standardization (ISO) Guidelines (

4.6.5.3 USP Convention (

4.6.5.4 American Society for Testing and Materials (ASTM;

4.6.5.5 Good Manufacturing Practices (GMPs) and Good Clinical Practices (GCPs)

4.6.5.6 Conformité Européenne Marking of Medical Device Products

4.7 Medical Device Testing Requirements

4.7.1 Study Design Considerations

4.7.1.1 Variable Pathways to Biocompatibility and Medical Device Testing

4.7.1.2 Safety, Efficacy, and Effectiveness of a Device

4.7.1.3 Engineering Design Failure Modes and Effects Analysis (DFMEA) for Risk Assessment

4.8 General Principles of Medical Device Testing Program

4.8.1 In Vitro and In Vivo Testing

4.8.1.1 Overview of Biocompatibility Evaluation Endpoints

4.8.2 Preliminary In Vitro and In Vivo Biomaterial and Medical Device Tests

4.8.2.1 Cytotoxicity

4.8.2.2 Genotoxicity

4.8.2.3 Sensitization

4.8.2.4 Pyrogenicity

4.8.2.5 Leachables and Extractables

4.8.2.6 Degradation

4.8.2.7 Hemocompatibility Studies

4.8.3 In Vivo Biomaterial and Medical Device Biocompatibility and Preclinical Animal Testing

4.8.3.1 Alternative Testing Procedures, 3Rs and Ethics of Medical Device Testing

4.8.3.2 Species Selection

4.8.3.3 Studies with Histopathology Endpoints

4.8.3.4 Special In Vivo Studies

4.9 In-Life Observations

4.9.1 Clinical Observations, Body Weight, and Food Consumption

4.9.2 Clinical Pathology

4.10 Local and Systemic Histopathology Assessment of Medical Devices

4.10.1 Organ Weights

4.10.2 Gross Pathology and Sample Collection

4.10.3 Tissue and Device Histological Preservation and Processing

4.10.4 Microscopic Pathology Assessment

4.10.5 Microscopic Tissue Responses to Materials and Medical Devices

4.10.6 Histochemical and Immunohistochemical Staining

4.10.7 Specialized and High-Resolution Microscopy Techniques

4.10.8 Quantitative and Semi-Quantitative Grading

4.10.9 Morphometry and Stereology

4.10.10 In Vivo Imaging and Computational Modeling

4.11 Medical Devices in Pediatric Patients and Juvenile Toxicology Testing

4.12 Special Biomaterials

4.12.1 Nanomaterials

4.12.2 Combination Devices and Drug Delivery Products

4.12.3 Bioengineering, Regenerative Medicine Products, and 3D Printing

4.13 Clinical Considerations

4.14 Conclusion

Chapter 5 Pathology and the Pathologist in Pharmaceutical Research and Development

5.1 Introduction

5.2 Toxicologic Pathology

5.2.1 Introduction: The Role of the Toxicologic Pathologist in Industry

5.2.2 The Toxicologic Pathologist and the Toxicity Study

5.2.3 The Study Pathologist Role

5.2.4 Study Nomenclature

5.2.5 Study Results and Interpretation

5.2.6 Approaches and Challenges of Toxicologic Histopathology

5.2.7 Toxicologic Pathology Training, Career Directions, Specialization, and Organizations

5.3 Investigative Pathology in Pharmaceutical R&D

5.3.1 Introduction

5.3.2 Selection and Evaluation of Drug Targets

5.3.3 The Use and Evaluation of Genetically Modified Animals

5.3.4 Early Evaluation of Drug Effects

5.3.5 Pathophysiology of the Findings

5.3.6 Biomarkers

5.4 The Future of Pathology in R&D

5.4.1 Introduction

5.4.2 Advances in Technology

5.4.3 Data Generation, Handling, and Integration

5.4.4 Human Systems and Data

5.4.5 Regulatory (Societal) Environment and Expectations

5.4.6 The Individual Pathologist in the Future

Chapter 6 Routine and Special Techniques in Toxicologic Pathology

6.1 Introduction

6.2 Routine Techniques

6.2.1 Necropsy Procedures

6.2.1.1 Terminal Procedures

6.2.1.2 Dissection and Gross Examination

6.2.1.3 Description of Gross Lesions

6.2.1.4 Organ Weights

6.2.1.5 Tissue Fixation

6.2.2 Histology Procedures

6.2.2.1 Trimming

6.2.2.2 Processing

6.2.2.3 Embedding

6.2.2.4 Sectioning (Microtomy)

6.2.2.5 Staining

6.2.2.6 Coverslipping

6.2.2.7 Histotechnique Quality Assessment

6.3 Special Techniques

6.3.1 Introduction

6.3.2 Imaging Methods

6.3.2.1 Electron Microscopy

6.3.2.2 Fluorescence Microscopy

6.3.2.3 Digital Microscopy

6.3.2.4 Noninvasive (In Vivo) Imaging

6.3.2.5 Digital Image Data and Compliance with GLP Regulations

6.3.3 In Situ Protein, DNA, and RNA Assays

6.3.3.1 Immunolabeling (IHC and Immunofluorescence)

6.3.3.2 Probe Hybridization Labeling (Chromogenic In Situ Hybridization and FISH)

6.3.4 Laser Microdissection

6.3.5 Flow Cytometry and Fluorescence-Activated Cell Sorting

6.3.6 Laser Scanning Cytometry

Chapter 7 Principles of Clinical Pathology

7.1 Introduction

7.2 Study Design Factors

7.2.1 Test Selection

7.2.2 Test Frequency and Timing

7.2.3 Sources of Variability

7.3 Data Interpretation

7.3.1 Reversibility

7.4 Interpretation of Hematology Data

7.4.1 Erythrocytes, Leukocytes, and Platelets

7.4.2 Increased Red Cell Mass

7.4.3 Decreased Red Cell Mass

7.4.3.1 Blood Loss

7.4.3.2 Hemolysis

7.4.3.3 Bone Marrow Toxicity

7.4.3.4 Indirect Causes of Nonregenerative Conditions

7.4.4 Physiological Leukocytosis

7.4.5 Stress-Induced Leukocyte Response

7.4.6 Inflammation

7.4.7 Miscellaneous Effects on Leukocytes

7.4.8 Platelets

7.4.9 Bone Marrow Smear Evaluation

7.4.10 Coagulation

7.5 Clinical Chemistry Tests and Interpretation

7.5.1 Tests of Liver Integrity and Function

7.5.1.1 Enzymes

7.5.1.2 Bilirubin

7.5.1.3 Markers of Liver Function

7.5.2 Tests of Kidney Function

7.5.3 Proteins, Carbohydrates, and Lipids

7.5.3.1 Serum Proteins

7.5.3.2 Serum Glucose

7.5.3.3 Serum Lipids

7.5.4 Minerals and Electrolytes

7.5.4.1 Serum Calcium and Inorganic Phosphorus

7.5.4.2 Serum Sodium, Potassium, and Chloride

7.5.4.3 Miscellaneous Serum Chemistry Tests

7.6 Urinalysis, Urine Chemistry, and Biomarker Tests, and Interpretation

7.6.1 Urinalysis

7.6.1.1 Physicochemical Properties of Urine

7.6.1.2 Reagent Strip Tests

7.6.1.3 Microscopic Evaluation of Urine Sediment

7.6.2 Urine Chemistry Tests

7.6.3 Urine Biomarkers

7.7 Safety Biomarkers as Adjunct Tests

7.7.1 Cardiac Injury Biomarkers

7.7.2 Protein Biomarkers of Inflammation and Immune Response

7.7.3 Exploratory Biomarkers for Liver Injury

7.7.4 Exploratory Biomarkers for Skeletal Muscle Injury

Chapter 8 Toxicokinetics and Drug Disposition

8.1 Introduction and Objective

8.2 Importance of Exposure-Based Interpretation

8.3 TK or PK Parameters: What They Are, How They Are Derived, and What They Mean

8.3.1 Plasma Concentration–Time Curves: Where the Numbers Come from

8.3.2 TK Parameters Derived from Raw Data

8.3.3 TK Parameters Derived from Transformed Data

8.3.4 Multiple Dose TK Parameters: Accumulation

8.4 Importance of Experimental Design and Data Presentation

8.5 Important Chemical and Biological Factors Governing TK: Absorption, Distribution, Metabolism, Excretion, and Transport

8.5.1 Factors Governing Oral Absorption

8.5.2 Species Differences in GI Physiology

8.5.3 Drug Distribution, Protein Binding, and the Importance of Free (Unbound) Drug and Regulation of Concentrations in Privileged Sites

8.5.4 Determining Tissue Distribution: Quantitative Whole-Body Autoradiography (QWBA), Microautoradiography (MARG), and Mass Spectrometric Imaging (MSI)

8.5.5 Examples of Sex and Species Differences in Drug Metabolism

8.5.5.1 Sex Differences in CYP Metabolism in Rodents

8.5.5.2 Species Differences in Metabolic Enzymes and Induction

8.5.5.3 Species Differences in Transporters

8.6 Summary

Chapter 9 Toxicogenomics in Toxicologic Pathology

9.1 Introduction

9.1.1 –Omics: The Basics

9.1.2 The –Omics Revolution

9.1.3 Basic Array Technologies

9.1.4 The Toxicologic Pathologist’s Role in Toxicogenomics

9.1.5 Pathway and Network Analyses

9.1.6 Applications of Toxicogenomics

9.1.6.1 Phenotypic Anchoring

9.1.7 Predictive vs Mechanistic Toxicogenomics

9.1.8 Prediction of Carcinogens Using Toxicogenomics

9.1.8.1 Genotoxic vs Nongenotoxic

9.1.9 Toxicogenomics and Risk Assessment

9.1.10 Toxicogenomic Profiling of Hepatotoxicity

9.1.11 Toxicogenomic Profiling of Nephrotoxicity

9.1.12 Toxicogenomic Profiling of Cardiotoxicity

9.1.13 Toxicogenomic Databases

9.2 Summary and Conclusions

Glossary

Chapter 10 Spontaneous Lesions in Control Animals Used in Toxicity Studies

10.1 Introduction

10.2 Rat

10.3 Mouse

10.4 Dog

10.5 Monkey

10.6 Minipig

10.7 Summary

Section IIOrgan Systems

Chapter 11 Gastrointestinal Tract

11.1 Introduction

11.2 Embryology

11.3 Functional Anatomy

11.3.1 Oral Cavity

11.3.2 Tongue

11.3.3 Salivary Glands

11.3.4 Esophagus

11.3.5 Stomach

11.3.6 Small and Large Intestines

11.3.7 Intestinal Absorption and Secretion

11.3.8 Biotransformation

11.3.9 Enterohepatic Circulation

11.3.10 Bacteria

11.3.11 Lymphoid Tissue

11.3.12 Enteric Nervous System

11.4 Nonproliferative and Proliferative Morphologic Responses

11.4.1 Oral Cavity and Tongue

11.4.1.1 Proliferative Changes of Oral Cavity and Tongue

11.4.2 Salivary Glands

11.4.2.1 Proliferative Changes of Salivary Glands

11.4.3 Esophagus

11.4.3.1 Proliferative Changes of Esophagus

11.4.4 Stomach

11.4.4.1 Nonglandular Stomach

11.4.4.2 Glandular Stomach

11.4.5 Small and Large Intestines

11.4.5.1 Proliferative Changes of Small and Large Intestines

11.5 Methods of Evaluation

11.5.1 Assessment of Structural Integrity and Biomarkers

11.5.2 Assessment of Proliferation of Mucosal Cells

11.5.3 Toxicogenomics and Metabonomics

11.6 Animal Models

11.6.1 Sjögren’s Syndrome

11.6.2 Gastritis

11.6.3 Mucositis

11.6.4 Inflammatory Bowel Disease

11.6.5 Models of Colorectal Neoplasia

11.6.6 Porcine Models in Biomedical Research

Chapter 12 Liver, Gallbladder, and Exocrine Pancreas

12.1 Liver

12.1.1 Introduction

12.1.2 Hepatocellular Degeneration, Necrosis, and Regeneration

12.1.2.1 Morphological Patterns of Hepatocellular Necrosis

12.1.2.2 Clinical Chemistry Biomarkers of Hepatocellular Injury

12.1.2.3 Differential Diagnosis

12.1.2.4 Significance in Safety Assessment

12.1.3 Cellular Adaptations and Accumulations

12.1.3.1 Alterations in Hepatocyte Size and Number

12.1.3.2 Cytoplasmic Accumulations and Inclusions (Nonpigment)

12.1.3.3 Glycogen

12.1.3.4 Cytokeratin

12.1.3.5 Drug or Drug Metabolite

12.1.3.6 Cytoplasmic Pigments

12.1.4 Nuclear Alterations

12.1.4.1 Multinucleated Hepatocytes

12.1.5 Biliary Changes, Nonneoplastic

12.1.6 Interstitial and Vascular Changes, Nonneoplastic

12.1.6.1 Hepatic Inflammatory Cells, Kupffer Cells, and Hematopoietic Cells

12.1.7 Endothelial Cell Response

12.1.8 Stellate Cell Response

12.1.9 Hepatic Proliferative Lesions

12.1.9.1 Hepatocytes

12.1.9.2 Hepatoblastoma

12.1.9.3 Bile Duct Epithelium

12.1.9.4 Endothelial Tumors

12.1.9.5 Stellate Cell Tumors (Ito Cell Tumors)

12.1.9.6 Kupffer Cell Tumors

12.1.9.7 Histiocytic Sarcoma

12.2 Gallbladder

12.3 Exocrine Pancreas

12.3.1 Introduction

12.3.2 Embryology

12.3.3 Gross Anatomy

12.3.4 Microscopic Anatomy

12.3.5 Immunohistochemical Markers

12.3.6 Physiology of Secretion

12.3.7 Pathology of Exocrine Pancreas

12.3.7.1 Secretory Depletion, Acinar Cells

12.3.7.2 Increased Zymogen Granules

12.3.7.3 Vacuolation

12.3.7.4 Apoptosis, Necrosis, and Regeneration of Acinar Epithelium

12.3.7.5 Inflammation (Pancreatitis)

12.3.7.6 Ductular Metaplasia (Tubular Complexes)

12.3.7.7 Acinar Cell Injury at the Endocrine–Exocrine Interface

12.3.7.8 Incretin-Based Therapeutics

12.3.7.9 Metaplasia, Hepatocytic (Pancreatic Hepatocytes)

12.3.7.10 Pancreatic Proliferative Lesions

12.3.8 Biomarkers

Chapter 13 Respiratory System

13.1 General Introduction

13.2 Embryology of the Respiratory System

13.3 Functional Anatomy of the Respiratory System

13.3.1 Nasal Cavity

13.3.2 Pharynx

13.3.3 Larynx

13.3.4 Trachea and Airways

13.3.5 Lung

13.3.6 Alveolar Macrophage

13.3.7 Mucins and Surfactant in Lungs and Airways

13.3.7.1 Mucins

13.3.7.2 Surfactant

13.4 Ancillary Tests of Respiratory System Function or Damage

13.5 Nonneoplastic Nasal Cavity Findings

13.5.1 Atrophy

13.5.2 Degeneration

13.5.3 Necrosis

13.5.4 Eosinophilic Globules (Inclusions, Droplets)

13.5.5 Erosion/Ulceration

13.5.6 Regeneration

13.5.7 Inflammation

13.5.7.1 Acute Inflammation (Inflammation, Neutrophilic)

13.5.7.2 Chronic Inflammation (Inflammation, Mononuclear/Lymphohistiocytic)

13.5.7.3 Chronic Active Inflammation

13.5.7.4 Granulomatous Inflammation

13.5.8 Nasal-Associated Lymphoid Tissue

13.5.9 Vascular Changes

13.5.10 Hyperplasia

13.5.10.1 Epithelial (Squamous, Respiratory, Olfactory, Transitional)

13.5.10.2 Goblet (Mucous) Cell Hyperplasia

13.5.10.3 Basal Cell Hyperplasia

13.5.11 Metaplasia

13.6 Neoplastic Nasal Cavity Changes

13.6.1 Squamous Cell Papilloma

13.6.2 Adenoma

13.6.3 Squamous Cell Carcinoma

13.6.4 Adenocarcinoma

13.6.5 Adenosquamous Carcinoma

13.6.6 Neuroepithelial Carcinoma (Olfactory Neuroblastoma)

13.7 Larynx, Trachea, and Bronchi

13.7.1 Epithelial Degeneration and Regeneration of Larynx and Airways

13.7.2 Necrosis

13.7.3 Erosion/Ulceration

13.7.4 Ectasia of Submucosal Glands

13.7.5 Inflammation

13.7.6 Hyperplasia

13.7.7 Squamous Metaplasia

13.8 Bronchioles

13.8.1 Club Cell Changes

13.8.1.1 Club Cell Hypertrophy

13.8.1.2 Club Cell Inclusions

13.8.1.3 Club Cell Degeneration/Necrosis

13.8.1.4 Mucous Cell Metaplasia

13.8.1.5 Club Cell Proliferation

13.8.1.6 Club Cell Phospholipidosis

13.8.1.7 Club Cell Lipid Vacuolation

13.8.2 Bronchiolar Microlithiasis

13.8.3 Airway Wall Remodeling

13.8.4 Bronchiolitis Obliterans

13.8.5 Bronchiolization

13.8.6 Neoplastic Changes in Larynx and Trachea and Airways

13.8.6.1 Papilloma

13.8.6.2 Squamous Cell Carcinoma

13.8.6.3 Adenocarcinoma

13.9 Lung Parenchyma

13.9.1 Macrophage Reactions

13.9.2 Foamy Macrophage Reactions

13.9.2.1 Phospholipidosis

13.9.2.2 Pulmonary Alveolar Proteinosis

13.9.3 Pigmented AM Reactions

13.9.4 Interstitial Macrophage Reactions

13.9.5 Subpleural/Pleural Macrophage Reactions

13.9.6 Intravascular Macrophage Reactions

13.9.7 Reversibility/Adversity of Macrophage Reactions

13.9.8 Type II Pneumocyte Hypertrophy

13.9.9 Type II Pneumocyte Hyperplasia

13.9.10 Surfactant Dysfunction

13.9.11 Diffuse Alveolar Damage

13.10 Inflammatory Reactions in the Lung

13.10.1 Acute Inflammatory Reactions

13.10.2 Chronic Inflammatory Reactions

13.10.3 Granulomatous Inflammatory Reactions

13.10.4 Regional Lymph Node/BALT Reactions

13.10.5 Pneumonia

13.10.6 Eosinophilic Crystalline Pneumonia

13.11 Pulmonary/Pleural Fibrosis

13.12 Emphysema

13.13 Alveolar Interstitial Mineralization

13.14 Alveolar Microlithiasis

13.15 Vascular Lesions

13.15.1 Perivascular Eosinophil Accumulation

13.15.2 Edema

13.15.3 Embolism

13.15.4 Alveolar Hemorrhage

13.15.5 Pulmonary Arteriopathy

13.15.6 Vascular Mineralization

13.15.7 Bronchial Arteriopathy

13.15.8 Congestion

13.16 Neoplastic Changes in Lungs

13.16.1 Bronchioloalveolar Adenoma

13.16.2 Cystic Keratinizing Epithelioma

13.16.3 Bronchioloalveolar Carcinoma

Acknowledgments

Chapter 14 Urinary System

14.1 Kidney

14.1.1 Introduction

14.1.1.1 Functional Anatomy

14.1.1.2 Embryology

14.1.1.3 Ancillary Tests of Renal Function or Damage

14.1.2 Glomerular Changes

14.1.2.1 Glomerulonephritis

14.1.2.2 Mesangioproliferative Glomerulopathy

14.1.2.3 Hyperplasia, Mesangial

14.1.2.4 Glomerulosclerosis

14.1.2.5 Hyaline Glomerulopathy

14.1.2.6 Mesangiolysis

14.1.2.7 Amyloidosis

14.1.3 Glomerular Atrophy

14.1.3.1 Bowman’s Space Enlargement

14.1.3.2 Metaplasia and Hyperplasia of Bowman’s Capsule

14.1.4 Tubule Changes

14.1.4.1 Tubule Degeneration and Tubule Basophilia

14.1.4.2 Vacuolation

14.1.4.3 Renal Phospholipidosis

14.1.4.4 Pigmentation and Inclusion Bodies

14.1.4.5 Diabetic Nephropathy and Tubule Glycogenosis

14.1.4.6 Tubule Dilation and Cystic Tubules

14.1.4.7 Casts

14.1.4.8 Necrosis

14.1.4.9 Infarction

14.1.4.10 Tubule Atrophy

14.1.4.11 Tubule Regeneration

14.1.4.12 Karyomegaly

14.1.4.13 Tubule Hypertrophy

14.1.4.14 Chronic Progressive Nephropathy

14.1.4.15 Hyaline Droplets and α-2U-Globulin Nephropathy

14.1.4.16 Crystalluria, Obstructive Nephropathy, and Retrograde Nephropathy

14.1.4.17 Papillary Changes

14.1.4.18 Papillary Necrosis

14.1.4.19 Pyelonephritis

14.1.5 Interstitial and Vascular Changes

14.1.5.1 Interstitial Inflammation and Interstitial Nephritis

14.1.5.2 Interstitial Fibrosis

14.1.5.3 Periarteritis and Vasculitis

14.1.5.4 Lesions of the Renal Pelvis

14.1.5.5 Hydronephrosis

14.1.5.6 Miscellaneous Lesions of the Kidney

14.1.5.7 Inclusion Bodies

14.1.6 Hyperplastic and Neoplastic Changes

14.1.6.1 Hyperplastic Lesions

14.1.6.2 Renal Tubule Hyperplasia

14.1.6.3 Renal Pelvis

14.1.6.4 Neoplastic Lesions of the Kidney

14.1.6.5 Renal Tubule Neoplasms

14.1.6.6 Connective Tissue Neoplasms

14.1.6.7 Embryonic Primordium Neoplasia

14.1.6.8 Fibrosarcoma/Sarcoma

14.1.6.9 Hematogenous/Metastatic Neoplasms

14.1.6.10 Neoplasms of the Renal Pelvis

14.2 Urinary Bladder, Ureters, and Urethra

14.2.1 Nonneoplastic Lesions of the Lower Urinary Tract

14.2.2 Hyperplastic Lesions of the Lower Urinary Tract

14.2.3 Neoplastic Lesions of the Lower Urinary Tract

14.2.3.1 Papilloma

14.2.3.2 Carcinoma

14.2.3.3 Squamous Cell Carcinoma

14.2.3.4 Adenocarcinoma

14.2.3.5 Connective Tissue and Smooth Muscle Neoplasms

14.2.3.6 Mesenchymal Proliferation Lesion

14.2.3.7 Hematogenous/Metastatic Neoplasms

Chapter 15 Hematopoietic System

15.1 Introduction

15.2 Ontogeny

15.3 Anatomy and Physiology

15.3.1 Sites and Macroscopic Appearance

15.3.2 Microscopic Structure and Cellular Composition

15.3.3 Cytologic Appearance of Hematopoietic Cells

15.3.4 Hematopoiesis

15.4 Bone Marrow Evaluation

15.4.1 Histopathologic Collection, Processing, and Evaluation

15.4.2 Cytologic Sample Collection, Processing, and Evaluation

15.4.3 Additional Bone Marrow Evaluations

15.5 Alterations in Hematopoiesis

15.5.1 Generalized Hematopoietic Cell Increases or Decreases

15.5.2 Increases in Erythroid, Myeloid, and Megakaryocytic Numbers

15.5.3 Decreases in Erythroid, Myeloid, and Megakaryocytic Numbers

15.5.4 Hematopoietic Cell Dysplasia

15.5.5 Reactivity and Inflammation

15.5.6 Necrosis

15.5.7 Stromal Alterations and Proliferations

15.5.8 Fibrosis/Myelofibrosis

15.5.9 Fibro-Osseous Proliferations

15.5.10 Focal Lipomatosis

15.5.11 Serous Atrophy of Fat/Gelatinous Transformation

15.5.12 Neoplasia