Precision Cancer Medicine: Role of the Pathologist

Foreword
Preface
Contents
Part I: The Evolution of Pathology and Precision Medicine
1: Introduction: From ‘Tissue Diagnosis’ to Biomarkers
1.1 A Brief History of Pathology: The Progression to Precision Cancer Medicine
1.1.1 Cure as a Generic Rationale for Cancer Treatment
1.2 The Microscope Invents Pathology and Pathologists
1.3 Seeking a Cure for Non-Symptomatic Early Stage Cancer; Cancer Screening
1.4 Development of Targeted Therapies
References
2: The Advent of Biomarker Testing
2.1 Biomarkers in Medicine and Cancer
2.1.1 Biomarkers in Cancer
2.2 Basis of Prediction of Response to Therapy
2.3 Role of Pathology and the Pathologist in the Advent of Precision Cancer Medicine
2.3.1 New Types of Tests: Companion and Complementary Diagnostics
2.3.2 Evolution to Revolution: The Changing Role for Pathology
2.4 The Development Pathway for Targeted Therapeutics and Precision Diagnostics
References
3: The Practical Challenges for Pathology: Multiple Rapidly Evolving Methods
3.1 Role in the Development Pathway for Targeted Therapeutics and Precision Diagnostics
3.1.1 Pre-Clinical Research
3.2 Conversion of IHC from a ‘Qualitative’ Stain; to a Quantitative Assay
3.3 ISH and Multiplex Immunofluorescence Methods for Multiple Biomarkers
3.4 FFPE Extraction Based Molecular Methods, PCR, NGS and Proteomics
3.5 Going Digital
3.6 Virtual Biomarkers—Molecular Morphology in the Digital Dimension
3.7 Total Integrative Pathology; the Big Data Problem
3.8 Part I as an entry to Parts II, III & IV
References
Part II: Precision Medicine Demands Precision Pathology
4: Evolution of the Total Test Approach to Tissue Based Pathological Analysis
4.1 Introduction: The Microscope ‘Invented’ the Pathologist
4.1.1 Re-Invention
4.1.2 Morphology Plus
4.2 IHC: A Stain ‘Repurposed’ as an Assay
4.3 In-Situ Hybridization
4.4 Molecular Extraction Based Methods; Abandoning Morphology?
4.5 Emerging Methods in Microscopy and Microimaging
4.6 The Total Test: Pre-Analytical, Analytical and Post-Analytical Phases (Table 4.3)
References
5: Pre-Analytic Phase: Test Selection; Specimen Acquisition and Handling
5.1 The Pre-Analytical Phase Defined
5.2 Test Selection—‘Fit for Purpose’
5.3 Digital Pre-Analytic Quality
5.4 Turn-Around Time (TAT); Cost; Reimbursement Issues
References
6: Pre-Analytic Phase: Specimen Type and Acquisition
6.1 The Specimen
6.2 Excision Biopsy and Surgical Resection
6.3 FNA, Core Needle Biopsy
6.4 Cytologic Preparations
6.5 Liquid Biopsy
References
7: Pre-Analytical Phase: Biopsy/Tissue Handling and Processing
7.1 Pre-Analytical Variables (Table 7.1)
7.2 Transport, Warm and Cold Ischemia
7.3 Fixation and Paraffin Embedding (FFPE)
7.3.1 Total Fixation Time
7.3.2 Nature of the Antigen
7.3.3 Fixation Time in Relation to Effectiveness of Different Antibodies
7.3.4 Antigen Retrieval (in Analytic Phase)
7.3.5 Fixation of Tissues Employed for Validation and Controls
7.4 Processing
7.5 Tissue Sectioning and Storage
7.5.1 Sectioning: Thickness
7.5.2 Glass Slides
7.5.3 Section Storage Time: Cut Slide Stability
References
8: Analytical Phase: Protocol and Antigen Retrieval
8.1 The Analytical Phase Defined
8.2 Deparaffinization and Optional Blocking Procedures
8.2.1 Blocking Steps
8.3 Antigen Retrieval (AR) or Heat Induced Epitope Retrieval (HIER)
References
9: Analytical Phase: Principles for Immunohistochemistry (IHC)
9.1 Reagents and Protocol for Biomarker Labelling; Selection and Validation
9.2 Lab Developed Tests (LDTs)—Manual and Automated
9.2.1 Manual IHC Stains
9.2.2 Automated IHC Stains
9.3 Ready to Use IHC Tests (RTUs)
9.4 Approved IHC Biomarker Assays (FDA, CE Marked)
9.5 Detection Systems and Amplification
9.6 Introduction to Fit for Purpose Controls: Required Characteristics
9.6.1 The Six Required Characteristics of Controls—Reference Standards
9.7 FDA Classification of IHC Tests: Classes I, II and III
References
10: Analytical Phase: Current Controls; Fit for Purpose Selection and Validation
10.1 Guides for Selection of Control Materials
10.2 Negative Controls
10.2.1 Negative Reagent Controls (See Table 10.2)
10.2.2 Negative Tissue Controls: External and Internal
10.3 Positive Controls: External and Internal
10.3.1 Positive External Tissue Controls
10.3.2 Positive Internal Tissue Controls
10.4 Tissue Micro-Arrays (TMAs): ‘Sausages’ and Tumor Tissue Banks
References
11: Analytical Phase: Alternative and New Control Systems
11.1 Alternative and New Control Systems
11.2 Cell Lines
11.3 Faux or Pseudo-Tissues
11.4 Protein Spots
11.5 Internal Controls and Internal Reference Standards
11.6 Quantifiable Internal Reference Standards (QIRS)
11.7 Quantitative In Situ Proteomics (QISP)
References
12: Post-Analytic Phase: Interpretation, Scoring and Reporting of Biopsy Results
12.1 Assessment of Controls
12.2 Sensitivity and Specificity
12.2.1 Positive and Negative Results in Relation to Controls
12.2.2 Sensitivity
12.2.3 Specificity
12.3 Verification and Validation IHC Biomarker Assays
12.3.1 Verification
12.3.2 Validation
12.4 Practical Issues in Validation
12.5 Validation of Pre-Analytical and Analytical Phases: LDTs, RTUs and Approved Biomarker Tests
12.6 Quality Management Systems (QMS): Quality Assurance (QA), Quality Control (QC)
12.6.1 External Quality Assessment and Proficiency Testing
References
13: Description and Interpretation of Results; The Pathology Report
13.1 Content and Organization of Report
13.1.1 Descriptive
13.1.2 Integrated and Standardized Reporting
13.2 Scoring; Including Validation of Scoring Method
13.3 Scoring Systems
13.4 Percentage Based Scores
13.4.1 Conversion to Positive and Negative Results
13.4.2 Percentage Combined with Intensity and/or Pattern
13.4.3 Concordance Training
13.4.4 Consensus or Ring Studies
13.5 Addition of Immune Cell Assessment
13.5.1 Immune Scoring; Immunoscore
13.5.2 Composite or Proportion Scores
13.5.3 Field of View (FOV) Selection Errors
13.6 Phenotypic Cell Identification and Scoring: Multiplex Methods
13.7 Digital Computerized Scoring Algorithms
References
14: Immunofluorescence, In Situ Hybridization and Alternative Forms of ‘Labeled’ Microscopy
14.1 Labeled Microscopy Methods
14.2 Immunofluorescence—IF
14.3 In Situ Hybridization—ISH
14.4 RNA Scope
14.5 Advanced Multiplex Microscopy and Other Emerging Methods
14.5.1 Brightfield (IHC) Versus Immunofluorescence (IF) Methods
14.5.2 Multiplex Digital IF
14.5.2.1 The Sequential Method
14.5.2.2 The Simultaneous Method
14.6 MIBI Microscopy (Multiplex Ion Beam Imaging)
14.7 Raman Microscopy (Vibrational) Spectroscopy (RMS)
14.8 Part II—Summary
References
Part III: Role of the Pathologist in Predictive Biomarker Analysis
15: Implementation of Precision Cancer Diagnostic Test
15.1 Introduction to Role of the Pathologist in Predictive Biomarker Analysis
15.2 Implementation of Predictive Biomarker Tests
15.3 Analytical Validation
15.3.1 Repeatability
15.3.2 Intermediate Precision
15.3.3 Role of the Pathologist in Repeatability and Intermediate Studies
15.3.4 Reproducibility
15.3.5 Total Test Reproducibility
15.3.6 Role of the Pathologist in Assay Reproducibility Studies
15.4 Clinical Validation
15.4.1 The Role of the Pathologist
15.5 Clinical Utility
15.5.1 The Role of the Pathologist
15.6 Summary & Future Needs & Trends
References
16: Role of Pathologist in Precision Cancer Diagnosis
16.1 Introduction
16.2 Regulatory Body and Expert Opinion Based Recommendations
16.3 Role of Pathologist in Assurance of Good Diagnostic Practice
16.4 Internal Quality Assurance of Pre-Analysis Phase
16.4.1 Potential Errors Due to Inadequate Tissue Preservation
16.4.1.1 Potential Causes of False Negative or Weak Results
16.4.2 Adequacy and Representativeness of Biopsy Material
16.5 Internal Quality Assurance of Analysis Phase
16.5.1 Pre-Analytic Phase Exclusion Factors
16.5.2 Analytic Phase Exclusion Factors
16.5.3 Evaluation of the Quality of Biopsy Material
16.5.4 Evaluation of Distribution and Quantity of Tumour Tissue
16.5.5 Assessment of Quality of Assay Performance
16.5.6 Selection and Use of Control
16.6 Quality Assurance of Post-Analytic Phase
16.6.1 Post Analysis Factors Influencing Quality of Biomarker Assessment
16.6.2 Indication Specific Interpretation, Scoring and Reporting
16.6.3 Assessment of Appropriateness and Completeness of Biomarker Analysis
16.6.4 Evaluation of Accuracy of the Results
16.7 Summary and Future Needs & Trends
References
17: Role of Pathologist in Precision Molecular and Digital Image Analyses
17.1 Introduction
17.2 Role of Pathologist in Morpho-Molecular Diagnosis of Cancer
17.3 Role of Pathologist in Molecular Analysis of Cancer
17.4 Role of Pathologist in Guidance of Cancer Molecular Profiling
17.5 Role of Pathologist in Analysis of Tumour Heterogeneity
17.6 Role of Pathologist in Analysis of Tumour Micro-Environment (TME)
17.7 Future Role of Pathologist in Emerging Morpho-Molecular Cancer Diagnostics
References
Part IV: Digital and Computational Pathology and Their Role in Precision Oncology
18: Introduction to Digital and Computational Pathology
References
19: AI in the Pre-Analytical Phase
19.1 The Workflow Design
19.2 Sample and Quality Management
19.3 Quality Control and Validation
19.4 CIS, LIS, DIS and PACS
19.5 Workflow Integration, Connectivity and Interoperability
References
20: AI in the Analytical Phase
20.1 Overcoming Variabilities
20.2 Telepathology
20.3 Standardization, Harmonization and Concordance
20.4 Scanning and Whole Slide Imaging
20.5 Image Analysis
20.6 Advanced Microscopy
References
21: AI in the Post-Analytical Phase
21.1 Dealing with Complexity
21.2 Artificial Intelligence, Machine Learning and Topology
21.3 Computational Pathology
21.4 The Science of Data or Data Science
21.5 Algebraic Pathology
21.6 Encoded Pathology
21.7 Disease Modelling and Simulation
References
22: AI in the Decision Phase
22.1 Examples of Clinical Utility
22.2 Prognosis of Cancer
22.3 Predicting Treatment Outcomes
22.4 Clinical Decision Support Through Applications
22.4.1 Colorectal Cancer
22.4.2 Lung Cancer
22.4.3 Melanocytic Lesions
22.4.4 Lymphoid Aggregates
22.4.5 Bladder Cancer
22.4.6 Renal Biopsies
22.4.7 Breast Cancer
22.4.8 Prostate Cancer
22.4.9 Thyroid Cancer
22.4.10 Cytology
22.4.11 Biobanking
22.5 Opportunity for Discovery of Novel Biomarker
References
Index