Dunphy Molecular Pathology of Hematolymphoid Diseases

1. Auflage 2010
ISBN: 978-1-4419-5698-9
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 4, 620 Seiten

Reihe: Molecular Pathology Library

The past two decades have seen an ever-accelerating growth in knowledge about molecular pathology of human diseases, which received a large boost with the sequencing of the human genome in 2003. Molecular diagnostics, molecular targeted therapy and genetic therapy, are now routine in many medical centers. The molecular field now impacts every field in medicine, whether clinical research or routine patient care. There is a great need for basic researchers to understand the potential clinical implications of their research whereas private practice clinicians of all types (general internal medicine and internal medicine specialists, me- cal oncologists, radiation oncologists, surgeons, pediatricians, family practitioners), clinical investigators, pathologists and medical laboratory directors and radiologists require a basic understanding of the fundam- tals of molecular pathogenesis, diagnosis, and treatment for their patients. Traditional textbooks in molecular biology deal with basic science and are not readily applicable to the medical setting. Most medical textbooks that include a mention of molecular pathology in the clinical s- ting are limited in scope and assume that the reader already has a working knowledge of the basic science of molecular biology. Other texts emphasize technology and testing procedures without integrating the clinical perspective. There is an urgent need for a text that fills the gap between basic science books and clinical practice. In the Molecular Pathology Library series, the basic science and the technology is integrated with the medical perspective and clinical application.

Autoren/Hrsg.

Dunphy, Cherie H.

Inhaltsverzeichnis

1;Molecular pathology Library seriesPhilip T. Cagle, MD, Series Editor;1
1.1;Series Preface;4
1.2;Contributors;8
2;1;14
2.1;Molecular Oncogenesis;14
2.1.1;Introduction;14
2.1.2;The Initiation and Maintenance of Oncogenic Programs: Genetic and Epigenetic Changes;14
2.1.3;Types of Genetic Changes in Hematolymphoid Neoplasms;14
2.1.4;Genetic Changes in Leukemia and Myeloid Disorders;15
2.1.4.1;Multistep Pathogenesis and the Cooperativity of Genetic Alterations;15
2.1.4.2;Proliferation and/or Survival Signals;15
2.1.4.3;Block of Differentiation;17
2.1.5;Epigenetic Changes and Their Impact on Leukemogenesis;18
2.1.6;The Involvement of Stem Cells and Stem Cell Characteristics in Leukemia;19
2.1.6.1;Therapies Targeting Leukemia-Specific Molecular Alterations;19
2.1.7;Oncogenesis of Malignant Lymphoma;20
2.1.7.1;Programmed Genetic Changes of Antigen Receptor Genes during Normal Lymphocyte Development;20
2.1.7.2;Generation of Antibody Diversity and B-Cell Lymphoma Development;20
2.1.7.2.1;Primary Immunoglobulin Gene Rearrangement;20
2.1.7.2.2;Oncogene Activation Caused by Illegitimate Recombination during Immunoglobulin Gene Rearrangement;21
2.1.7.2.3;IGH Translocations may Often be Detected in the Absence of Clinical Disease;21
2.1.7.2.4;The Germinal Center Reaction and Lymphomagenesis;22
2.1.7.2.5;Mutational Analysis of IGH Genes Captures the History of Malignant B-Cell Clones;22
2.1.7.3;Genetic Alterations in Peripheral T-Cell Lymphoma;23
2.1.7.4;Oncogenes and Oncogenic Pathways in Malignant Lymphoma;24
2.1.7.4.1;The Properties of the Activated Oncogene Determine the Biologic and Clinical Behavior of Lymphomas;24
2.1.7.4.1.1;BCL-2;24
2.1.7.4.1.2;CCND1 (Cyclin D1);24
2.1.7.4.1.3;C-MYC;25
2.1.7.4.1.4;BCL-6;25
2.1.7.4.2;Deregulation of the NF-kB Pathway;25
2.1.7.5;Tumor Suppressor Genes in Lymphoma;25
2.1.7.5.1;Inhibition of Death Receptor Signaling;25
2.1.7.6;MicroRNA Deregulation;26
2.1.7.7;Infectious Agents Contributing to Lymphomagenesis;26
2.1.8;Conclusion;26
2.2;References;26
3;2;31
3.1;Genetic Predispositions for Hematologic and Lymphoid Disorders;31
3.1.1;Introduction;31
3.1.2;Neurofibromatosis;31
3.1.2.1;Molecular Pathogenesis of NF1;33
3.1.2.2;Hematolymphoid Disorders Associated with NF1;33
3.1.2.3;Tests for NF1;34
3.1.3;Noonan Syndrome;34
3.1.3.1;Molecular Pathogenesis of NS;34
3.1.3.2;Hematolymphoid Disorders Associated with NS;35
3.1.3.3;Tests for NS;36
3.1.4;Fanconi Anemia;36
3.1.4.1;Molecular Pathogenesis of FA;37
3.1.4.2;Hematologic Disorders Associated with FA;37
3.1.4.3;Pathogenesis of Neoplasms Associated with FA;39
3.1.4.4;Tests for FA;39
3.1.5;Bloom’s Syndrome;39
3.1.5.1;Molecular Pathogenesis of BS;39
3.1.5.2;Hematolymphoid Disorders Associated with BS;40
3.1.5.3;Tests for BS;41
3.1.6;Nijmegen Breakage Syndrome;41
3.1.6.1;Molecular Pathogenesis of NBS;41
3.1.6.2;Hematolymphoid Disorders Associated with NBS;41
3.1.6.3;Tests for NBS;42
3.1.7;Ataxia-Telangiectasia;42
3.1.7.1;Molecular Pathogenesis of AT;43
3.1.7.2;Hematolymphoid Disorders Associated with AT;43
3.1.7.3;Tests for AT;43
3.1.8;Dyskeratosis Congenita;44
3.1.8.1;Molecular Pathogenesis of DC;44
3.1.8.2;Hematolymphoid Disorders Associated with DC;46
3.1.8.3;Tests for DC;46
3.1.9;Shwachman–Diamond Syndrome;46
3.1.9.1;Molecular Pathogenesis of SDS;46
3.1.9.2;Hematopoietic Disorders Associated with SDS;47
3.1.9.3;Tests for SDS;47
3.1.10;Diamond–Blackfan Anemia;48
3.1.10.1;Molecular Pathogenesis of DBA;48
3.1.10.2;Hematopoietic Disorders Associated with DBA;49
3.1.10.3;Tests for DBA;49
3.1.11;Primary Immune Deficiency Disorders;49
3.1.12;X-Linked Lymphoproliferative Disorder (Also See Chap. 38);50
3.1.12.1;Molecular Pathogenesis of XLP;50
3.1.12.2;Testing for XLP;51
3.1.13;Hyper-IgM Syndromes (Also See Chap. 38);51
3.1.13.1;Pathogenesis of HIGM;52
3.1.13.2;Hematolymphoid Disorders Associated with HIGM;53
3.1.13.3;Tests for HIGM;54
3.1.14;Hyper-IgE Syndromes;54
3.1.14.1;Pathogenesis of HIES;54
3.1.14.2;Hematolymphoid Disorders Associated with HIES;54
3.1.15;Common Variable Immune Deficiency (Also See Chap. 38);54
3.1.15.1;Molecular Pathogenesis of CVID;55
3.1.15.2;Hematolymphoid Disorders Associated with CVID;55
3.1.15.3;Tests for CVID;56
3.1.16;Wiskott–Aldrich Syndrome (Also See Chap. 39);56
3.1.16.1;Hematolymphoid Disorders Associated with WAS;56
3.1.16.2;Tests for WAS;57
3.1.17;Autoimmune Lymphoproliferative Syndrome (Also See Chap. 38);57
3.1.17.1;Molecular Pathogenesis of ALPS;57
3.1.17.2;Hematolymphoid Disorders Associated with ALPS;58
3.1.17.3;Tests for ALPS;58
3.1.18;Congenital Neutropenia Syndromes;58
3.1.18.1;Molecular Pathogenesis of Congenital Neutropenia Syndromes;58
3.1.18.2;Hematologic Neoplasias Associated with Congenital Neutropenia Syndromes;60
3.1.18.3;Tests for Congenital Neutropenia Syndromes;60
3.1.19;Summary;60
3.2;References;60
4;3;75
4.1;Prognostic Markers;75
4.1.1;Introduction;75
4.1.2;Chronic Lymphocytic Leukemia (Also See Chap..16);75
4.1.2.1;Immunoglobulin Variable Gene Mutation Analysis;75
4.1.2.2;Genomics;76
4.1.3;Multiple Myeloma (Also See Chap..19);77
4.1.4;Acute Myeloid Leukemia (Also See Chaps..34 and 35);77
4.1.4.1;FMS-Related Tyrosine Kinase 3 (Also See Chap..35);77
4.1.4.2;Nucleophosmin (Also See Chap..35);77
4.1.5;Non-Hodgkin Lymphoma;78
4.1.5.1;Diffuse Large B-Cell Lymphoma (Also See Chap..22);78
4.1.5.2;Marginal Zone Lymphoma (Also See Chap..17);79
4.2;References;79
5;4;83
5.1;Cancer Stem Cells: Potential Targets for Molecular Medicine;83
5.1.1;Introduction;83
5.1.1.1;The Cancer Stem Cell Hypothesis;83
5.1.1.1.1;Cancer Stem Cells, Defined;83
5.1.1.1.2;Historical Perspective;83
5.1.2;The Biology of Cancer Stem Cells;84
5.1.2.1;Cancer Stem Cell Identification;84
5.1.2.1.1;Functional Identification;84
5.1.2.1.1.1;In Vivo CSC Isolation Methods;84
5.1.2.1.1.2;In Vitro CSC Assays;84
5.1.2.1.1.3;Molecular Methods;84
5.1.2.1.2;Phenotypic Identification;85
5.1.2.1.2.1;Cell Surface Markers;85
5.1.2.1.3;In Vivo Monitoring of CSC;85
5.1.2.2;Molecular Pathogenesis of Cancer Stem Cells;85
5.1.2.2.1;Pathogenesis of CSC in Blast Crisis of CML (Also See Chap. 30);86
5.1.2.2.2;Molecular Changes Contributing to CSC Propagation in Blast Crisis of CML;86
5.1.3;Clinical Implications of Cancer Stem Cells;86
5.1.3.1;CSC in Cancer Diagnosis, Prognosis, and Monitoring;87
5.1.3.1.1;Cellular and Molecular Assays;87
5.1.3.1.2;Cellular and Molecular Imaging;87
5.1.3.2;CSC-Directed Cancer Treatment;88
5.2;References;88
6;5;91
6.1;Gene Therapy for Leukemia and Lymphoma;91
6.1.1;Introduction;91
6.1.2;Viral Vectors Used for Gene Therapy;91
6.1.3;Gene Targeting to Destroy Tumor Cells Directly;92
6.1.3.1;Tumor Suppressor Gene Therapy;92
6.1.3.2;Suicide Gene Therapy;92
6.1.3.3;RNA Interference;93
6.1.4;Gene Transfer to Enhance Immune Responses to Tumor Cells;94
6.1.4.1;Gene Transfer of Immunostimulating Cytokines;94
6.1.4.2;Gene Transfer of Costimulating Molecules;94
6.1.5;Modification of T-Cell Function by Gene Transfer;95
6.1.5.1;Chimeric T-Cell Receptors;95
6.1.5.2;Gene Transfer of TCR for Retargeting;96
6.1.5.3;Gene Transfer of Protective Genes;96
6.1.6;Conclusion and Future Directions;96
6.2;References;97
7;6;100
7.1;Chemical and Environmental Agents (Including Chemotherapeutic Agents and Immunosuppression);100
7.1.1;Introduction;100
7.1.2;Ionizing Radiation;100
7.1.2.1;Childhood Studies;100
7.1.2.1.1;Background Radiation (Natural and Man-Made);100
7.1.2.1.2;Parental Occupational Exposures;100
7.1.2.1.3;Parental Diagnostic Exposures;101
7.1.2.1.4;Childhood Diagnostic Exposures;101
7.1.2.2;Adult Studies (Table 6.1);101
7.1.2.2.1;Background Radiation (Natural and Man-Made);101
7.1.2.2.2;Occupational Exposures;101
7.1.2.2.3;Diagnostic/Treatment Exposures;101
7.1.3;Electromagnetic Fields;101
7.1.3.1;Childhood Studies;102
7.1.3.1.1;Direct Childhood Exposures;102
7.1.3.1.2;Parental Occupational Exposures;102
7.1.3.2;Adult Studies (Table 6.2);102
7.1.3.2.1;Residential Exposures;102
7.1.3.2.2;Occupational Exposures;102
7.1.4;Chemical Exposures;102
7.1.4.1;Childhood Studies;102
7.1.4.1.1;Pesticides and Fungicides;102
7.1.4.1.2;Solvents, Benzene and Other Hydrocarbons;103
7.1.4.2;Adult Studies (Table 6.3);103
7.1.4.2.1;Pesticides and Fungicides;103
7.1.4.2.2;Solvents, Benzene and Other Hydrocarbons;103
7.1.5;Smoking;105
7.1.5.1;Childhood Studies;105
7.1.5.1.1;Parental Smoking;105
7.1.5.2;Adult Studies (Table 6.4);105
7.1.6;Alcohol;106
7.1.6.1;Childhood Studies;106
7.1.6.1.1;Parental Alcohol Consumption;106
7.1.6.2;Adult Studies (Table 6.5);106
7.1.7;Diet, Vitamin, and Folate Supplementation;107
7.1.7.1;Childhood Studies;107
7.1.7.2;Adult Studies (Table 6.6);108
7.1.8;Drinking Water;108
7.1.8.1;Child Studies;108
7.1.8.2;Adult Studies;108
7.1.9;Immunosuppression and Viruses;108
7.1.10;Viruses (Also See Chap. 7);108
7.1.10.1;Child Studies;108
7.1.10.2;Adult Studies (Table 6.7);109
7.1.11;Transplantation;109
7.1.12;Arthritis;110
7.1.13;Chemotherapeutic Agents;110
7.1.14;Discussion;110
7.2;References;110
8;7;116
8.1;Viral Oncogenesis;116
8.1.1;Introduction;116
8.1.2;Do In Vitro Models Reflect In Vivo Effects?;116
8.1.3;Epstein–Barr Virus;117
8.1.3.1;Histochemical Assays for EBV;118
8.1.4;Human Herpes Virus 8/Kaposi’s Sarcoma-Associated Herpes Virus;118
8.1.5;Human T-Lymphotropic Virus;121
8.1.6;Hepatitis C Virus;122
8.1.7;Simian Vacuolating Virus 40;123
8.1.8;Measles Paramyxovirus;123
8.1.9;Conclusion;124
8.2;References;124
9;8;127
9.1;Techniques to Determine Clonality in Hematolymphoid Malignancies;127
9.1.1;Introduction;127
9.1.2;Cancer as Clonal Process;127
9.1.3;X Inactivation;127
9.1.4;Lymphomas;128
9.1.4.1;Lymphoid Development;128
9.1.4.2;B Cell Clonality;129
9.1.4.2.1;Light Chain Restriction;129
9.1.4.2.2;Molecular Methods for Determining B Cell Clonality;129
9.1.4.3;T Cell Clonality;131
9.1.4.3.1;T Cell Receptor Restriction;131
9.1.4.3.2;Molecular Methods for Determining T Cell Clonality;131
9.1.4.4;Natural Killer Cell Clonality;132
9.1.4.5;Other Clonal Markers in Lymphoid Malignancies;132
9.1.4.5.1;Translocations Resulting in Overexpression of Growth Regulatory Genes;132
9.1.4.5.2;Translocations Resulting in Production of a Novel Growth-Stimulating Protein;133
9.1.4.5.3;Clonal Viral Integration;133
9.1.5;Myeloid Stem Cell Neoplasms;133
9.1.5.1;Clonal Recurrent Chromosomal Translocations;133
9.1.5.2;Gene Mutations in Leukemia (Also see Chap. 35 on Acute Myeloid Leukemias with Normal Cytogenetics);133
9.1.5.3;JAK2 Mutation in Myeloproliferative Neoplasms (Also see Chap. 31 on Non-CML Myeloproliferative Neoplasms);134
9.1.6;Array-Based Techniques that may Determine Clonality;134
9.1.7;Summary;135
9.2;References;135
10;9;137
10.1;Techniques to Detect Defining Chromosomal Translocations/Abnormalities;137
10.1.1;Introduction;137
10.1.1.1;Conventional (Routine) Cytogenetics;137
10.1.1.2;Fluorescence In-Situ Hybridization (FISH);138
10.1.2;Cytogenetic Abnormalities in Hematolymphoid Malignancies;140
10.1.3;Acute Myeloid Leukemias (AML);140
10.1.3.1;World Health Organization (WHO): AML with Recurrent Cytogenetic Translocationst(8;21);14110.1.3.2;FISH for t(821);14110.1.3.3;t(1517)(q22q21)142
10.1.3.4;FISH for t(15;17);14210.1.3.5;inv(16)(p13q22)/del(16)(q22)/t(1616)(p13q22)142
10.1.3.6;FISH for Chromosome 16 Rearrangements;142
10.1.3.7;11q23 Rearrangements;143
10.1.3.8;FISH for 11q23 (MLL);143
10.1.3.9;Abnormalities Seen in AML with Multi-Lineage Dysplasia;143
10.1.3.10;Secondary or Therapy-Related AML;143
10.1.4;Chronic Myeloid Leukemia (CML): t(9;22)(q34q11.2)143
10.1.5;Myelodysplastic Syndromes (MDS);144
10.1.5.1;5q Syndrome;144
10.1.5.2;Monosomy 7/7q—;144
10.1.5.3;Other Abnormalities in MDS;144
10.1.6;Acute Lymphoblastic Leukemia (ALL);144
10.1.6.1;Cytogenetic Abnormalities Seen in T-ALL;144
10.1.6.2;Cytogenetic Abnormalities Seen in Pre B-ALL;145
10.1.6.3;Numerical Abnormalities in Pre-B-ALL;145
10.1.6.4;Structural Rearrangements;145
10.1.6.4.1;Translocations Associated with Pre B ALL;145
10.1.6.4.1.1;t(12;21)(p13q22)145
10.1.6.4.2;Myeloid Lymphoid Leukemia (MLL) Rearrangements;145
10.1.6.4.2.1;t(4;11)(q21q23)146
10.1.6.4.2.2;t(1;19)(q23p13.3)146
10.1.6.4.2.3;t(9;22)(q34q11.2)146
10.1.6.5;Pediatric ALL;146
10.1.6.6;Adult ALL;146
10.1.7;Non-Hodgkin Lymphomas (NHL);146
10.1.7.1;Follicular Lymphoma and Diffuse Large B-Cell Lymphomas with t(14;18);14610.1.7.1.1;t(14,18)(q32:q21) Follicular and Diffuse Large B-Cell Lymphomas146
10.1.7.1.2;Mantle Cell Lymphoma with t(11;14);14610.1.7.1.3;FISH for t(1114)(q13q32) Mantle Cell Lymphoma147
10.1.7.1.4;Burkitt Lymphoma with t(8;14) and Other Burkitt Translocations147
10.1.7.1.5;FISH for t(8;14) and Other Burkitt Translocations147
10.1.7.1.6;Anaplastic Large Cell Lymphoma;147
10.1.7.1.7;FISH for ALK Rearrangements;147
10.1.7.1.8;Splenic Marginal Zone Lymphoma;147
10.1.7.1.9;Mucosa-Associated Lymphoid Tissue Lymphoma (MALT);147
10.1.8;Multiple Myeloma (Plasma cell myeloma);147
10.1.8.1;FISH Studies for Multiple Myeloma;148
10.1.9;Spectral Karyotyping;148
10.1.10;DNA Microarray;148
10.1.11;Polymerase Chain Reaction;149
10.1.11.1;Reverse Transcriptase PCR (RT-PCR);150
10.1.11.2;Real-Time Quantitative PCR;150
10.1.11.3;BCR-ABL1 [t(9;22)];15010.1.11.4;PML-RARA [t(1517)];15210.1.11.5;BCL2-IGH [t(1418)];15310.1.11.6;MLL (11q23)153
10.1.11.7;Other Translocations;153
10.1.12;Immunohistochemistry;154
10.1.12.1;Acute Myeloid Leukemias;154
10.1.12.1.1;PAX 5 [t(8;21)];15410.1.12.1.2;CBFb(beta)-SMMHC Protein [inv(16)(p13q22)]154
10.1.12.2;Non-Hodgkin Lymphomas;154
10.1.12.2.1;BCL-2 [t(14;18)];15410.1.12.2.2;Cyclin D1 [t(1114)];15510.1.12.2.3;C-myc (Burkitt translocations)155
10.1.12.2.4;ALK-1 [t(2;5)];15610.1.12.3;Multiple Myeloma156
10.1.12.3.1;Cyclin D1;156
10.2;References;156
11;10;161
11.1;Molecular Techniques to Detect Disease and Response to Therapy: Minimal Residual Disease;161
11.1.1;Overview;161
11.1.2;Molecular Approaches to MRD Monitoring;161
11.1.2.1;Patient Samples;161
11.1.2.2;Targets;161
11.1.2.2.1;Antigen Receptor Rearrangements in the Immunoglobulin Super Family;161
11.1.2.2.2;Chromosomal Translocations Resulting in Fusion-Gene Transcripts Followed by RNA Analysis;162
11.1.2.2.3;Chromosomal Aberrations Resulting in a Fusion Gene Followed with DNA;162
11.1.2.2.4;Additional Considerations in the Use of RNA or DNA;162
11.1.2.2.5;“Point” Mutations;163
11.1.2.2.6;Aberrant Gene Expression;163
11.1.2.3;Other Techniques to Monitor MRD;163
11.1.2.3.1;Karyotype and FISH;163
11.1.2.3.2;Flow Cytometry;163
11.1.2.3.3;Microarrays;163
11.1.2.3.4;Transcription-Mediated Amplification (TMA)-Hybridization Protection Assay (HPA);163
11.1.2.4;Quantitative PCR and RT-PCR;164
11.1.2.4.1;Quantitative PCR Techniques (Nested, Competitive, Real-Time);164
11.1.2.4.2;RQ-PCR Assay Design;164
11.1.2.4.3;Samples;164
11.1.2.4.4;RNA Extraction;164
11.1.2.4.5;Reverse Transcription (RT);164
11.1.2.4.6;RQ-PCR Amplification;165
11.1.2.4.7;Quantitation, Standard Curve Method;165
11.1.2.4.8;Quantitation, DDCT Method;165
11.1.2.4.9;Data Analysis and Reporting of Results;166
11.1.2.4.10;Units of Measurement and Assay Standardization;167
11.1.2.4.11;Sensitivity, Specificity, and Precision;168
11.1.2.4.12;Controls/Normalizing Genes;168
11.1.2.4.13;Assay Validation;168
11.1.2.4.14;Working with Clinicians;169
11.1.2.4.15;Ensuring Quality;169
11.1.3;Future Directions;169
11.2;References;169
12;11;173
12.1;Detection of Resistance to Therapy in Hematolymphoid Neoplasms;173
12.1.1;Introduction;173
12.1.2;Resistance to Targeted Tyrosine Kinase Inhibitors;173
12.1.2.1;Resistance to Inhibitors of BCR-ABL;173
12.1.2.1.1;Mutations in the ABL Tyrosine Kinase Domain;173
12.1.2.1.2;Amplification of the BCR-ABL Fusion Gene;174
12.1.2.1.3;BCR-ABL Independent Resistance: Downstream Targets;174
12.1.2.2;KIT Mutation and Imatinib Response;175
12.1.2.3;FLT3 IN AML;175
12.1.3;Multidrug Resistance;175
12.1.3.1;P-glycoprotein (MDR-1);175
12.1.3.2;Detection of MDR in Hematologic Malignancies;176
12.1.3.3;Other Multidrug Resistance Proteins;176
12.1.4;Other Molecular Mechanisms of Resistance;176
12.1.4.1;Microarray Analysis;176
12.2;References;176
13;12;180
13.1;Monitoring Engraftment of Bone Marrow Transplant by DNA Fingerprinting;180
13.1.1;Introduction;180
13.1.2;A Brief History of DNA Fingerprinting Methods;180
13.1.2.1;Past;180
13.1.2.2;Present;180
13.1.2.3;Future;181
13.1.3;Monitoring Engraftment of Bone Marrow Transplant;181
13.1.3.1;Microsatellite Markers;181
13.1.3.2;Technical Considerations;181
13.1.3.2.1;Identification of Informative Markers;181
13.1.3.2.2;Quantitative Calculations;182
13.1.3.2.3;Sensitivity;182
13.1.4;Clinical Considerations;182
13.1.4.1;Enriched Populations;182
13.1.4.2;Chromosomal Abnormalities;182
13.1.4.3;Impact on Future Genetic Testing;182
13.2;References;182
14;13;184
14.1;Gene Expression Profiling;184
14.1.1;Introduction;184
14.1.2;Techniques of Gene Expression Profiling;184
14.1.3;Supervised Gene Expression Profiling;184
14.1.4;Unsupervised Gene Expression Profiling;184
14.1.5;Usefulness of Ready-Made Macroarrays;185
14.1.6;Practical Applications in Diagnostic Hematopathology;185
14.1.6.1;Prognostic Factors in Chronic Lymphocytic Leukemia and Correlation with Practical Clinical Applicability (See Table 13.1);185
14.1.6.1.1;IgVH Mutational Status;185
14.1.6.2;ZAP70;186
14.1.6.2.1;Methods of Detection of ZAP70 Expression;186
14.1.6.2.2;Discordance Between IgVH Mutational Status and ZAP70 Expression;186
14.1.7;Diagnosis of Mantle Cell Lymphoma;187
14.1.8;Diagnosis of Hairy Cell Leukemia;187
14.1.9;Grade and Disease Aggressiveness in Follicular Lymphoma;188
14.1.10;Subgrouping Diffuse Large B-Cell Lymphoma and Correlation with Immunohistochemical Markers;188
14.1.11;Differentiation of Classical Hodgkin Lymphoma from Lymphocyte-Predominant Hodgkin Lymphoma and From Diffuse Large B-Cell Lymph;189
14.1.12;Class Assignment of Pediatric Precursor B Lymphoblastic Leukemia;189
14.1.13;Distinctive Gene Expression Signatures of Precursor T-Cell Lymphoblastic Leukemia and Correlation with Stage of Differentiat;190
14.1.14;Association of Distinct Gene Expression Profiles with Acute Myeloid Leukemias with Recurring and Complex Abnormalities and Cor;190
14.1.15;AMLS with FLT3 Length Mutation;194
14.1.16;Summary;195
14.2;References;195
15;14;197
15.1;Proteomics of Human Malignant Lymphoma;197
15.1.1;Introduction;197
15.1.2;Biological Samples for Proteomics;197
15.1.3;General Strategy for Proteomics;197
15.1.3.1;Protein Microarrays;197
15.1.3.2;Mass Spectrometry-Based Proteomics;198
15.1.3.3;Peptide Sequencing by MS/MS;198
15.1.3.4;Quantitative Proteomics;198
15.1.4;Proteomic Studies of Human Malignant Lymphoma;199
15.1.4.1;Proteomic Studies of B-Cell Lymphomas;199
15.1.4.1.1;Analysis of Interacting Partners of B-Cell Lymphoma Oncogenes;200
15.1.4.1.2;Proteomic Analysis of Follicular Lymphoma Transformation;201
15.1.4.1.3;Proteomic Consequences of Signaling Pathway Inhibition;201
15.1.4.1.4;Global Protein Profiling Studies;201
15.1.4.1.4.1;Burkitt Lymphoma;201
15.1.4.1.4.2;Hodgkin Lymphoma;202
15.1.4.2;Proteomic Studies for Identification of Potential Lymphoma Biomarkers;203
15.1.4.2.1;Protein Identification From FFPE Cells;204
15.1.4.3;Proteomic Studies of Anaplastic Large Cell Lymphoma;204
15.1.4.3.1;Global Profiling of ALCL Proteome;205
15.1.4.3.2;Identification of ALK Interactome;205
15.1.4.3.3;Proteomic Changes Induced by HSP90;205
15.1.5;Conclusions and Future Directions;206
15.2;References;206
16;15;209
16.1;Mouse Models of Hematolymphoid Malignancies;209
16.1.1;Introduction;209
16.1.2;Hematopoiesis;209
16.1.3;Characterization of Mouse Models;210
16.1.3.1;Clinical Pathology;210
16.1.3.1.1;Complete Blood Count;210
16.1.3.1.2;Biochemical Parameters;211
16.1.3.2;Anatomic Pathology;211
16.1.3.2.1;Macroscopic Evaluation;211
16.1.3.2.2;Microscopic Evaluation;211
16.1.3.3;Ancillary Testing;211
16.1.4;Lymphoid Neoplasms;211
16.1.5;Nonlymphoid Neoplasms;212
16.1.5.1;Myeloid Leukemia;212
16.1.5.2;Erythroid Leukemia;212
16.1.6;Conclusion;213
16.2;References;213
17;16;216
17.1;Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma;216
17.1.1;Introduction;216
17.1.2;Familial Predisposition;216
17.1.3;Cytogenetic Features;216
17.1.4;Immunoglobulin Genes;218
17.1.5;Epigenetic Factors;219
17.1.6;Clinical Implications;220
17.2;References;220
18;17;226
18.1;Marginal Zone B-Cell Lymphoma;226
18.1.1;Introduction;226
18.1.2;Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma);226
18.1.2.1;Definition;226
18.1.2.2;Clinical Features;226
18.1.2.3;Morphology and Immunophenotype;227
18.1.2.4;Prognosis and Predictive Factors;227
18.1.2.5;Cytogenetic and Molecular Genetic Features;227
18.1.2.5.1;t(11;18)(q21q21)/API2-MALT1227
18.1.2.5.2;t(14;18)(q32q21)/IGH-MALT1228
18.1.2.5.3;t(1;14)(p22q32)/BCL10-IgH228
18.1.2.5.4;The t(11;18), t(1418), and t(114) Activate the NF-kB Pathway228
18.1.2.5.5;t(3;14)(p14q32)/Forkhead Box P1-IGH229
18.1.2.5.6;Translocation-Negative Cases;229
18.1.2.6;Differential Diagnosis;230
18.1.3;Immunoproliferative Small Intestinal Disease;230
18.1.3.1;Definition;230
18.1.3.2;Clinical Features;230
18.1.3.3;Morphology and Immunophenotype;230
18.1.3.4;Cytogenetic and Molecular Genetic Features;230
18.1.4;Nodal Marginal Zone Lymphoma;230
18.1.4.1;Definition;230
18.1.4.2;Clinical Features;230
18.1.4.3;Morphology and Immunophenotype;231
18.1.4.4;Differential Diagnosis;231
18.1.4.5;Cytogenetic and Molecular Genetic Features;231
18.1.4.5.1;Pediatric Nodal Marginal Zone Lymphoma;231
18.1.5;Splenic B-Cell Marginal Zone Lymphoma;231
18.1.5.1;Definition;231
18.1.5.2;Clinical Features;231
18.1.5.3;Prognosis and Predictive Factors;232
18.1.5.4;Morphology and Immunophenotype;232
18.1.5.5;Differential Diagnosis;232
18.1.5.6;Cytogenetic and Molecular Genetic Features;232
18.2;References;233
19;18;237
19.1;Lymphoplasmacytic Lymphoma;237
19.1.1;Introduction;237
19.1.2;Epidemiology;238
19.1.3;Cell of Origin;238
19.1.4;Cytogenetics;238
19.1.5;Molecular Genetics;239
19.1.6;Proteinomics;239
19.1.7;Activated Signaling Pathways;239
19.1.8;Differential Diagnosis;239
19.1.9;Conclusions;241
19.2;References;241
20;19;244
20.1;Molecular Pathology of Plasma Cell Neoplasms;244
20.1.1;Introduction;244
20.1.2;Techniques for the Assessment of Molecular Abnormalities in Plasma Cell Neoplasms;244
20.1.2.1;Metaphase Cytogenetic Studies;244
20.1.2.2;Fluorescence In Situ Hybridization Analysis;244
20.1.2.3;Immunohistochemistry;246
20.1.2.4;Array-Based Genotyping;246
20.1.3;Clinically Significant Molecular Abnormalities in Plasma Cell Myeloma;246
20.1.3.1;Chromosome 13 Abnormalities;246
20.1.3.2;Del(17p) and p53 Abnormalities;246
20.1.3.3;Immunoglobulin Heavy Chain (14q32) Translocations;247
20.1.3.4;t(11;14)(q13q32) IGH/CCND1247
20.1.3.5;t(4;14)(p16q32) MMSET/IGH247
20.1.3.6;t(14;16)(q32q23) IGH/CMAF247
20.1.3.6.1;Other IGH Translocations;248
20.1.3.7;Other Chromosomal Abnormalities;248
20.1.4;A Practical Approach to Molecular Evaluation of Plasma Cell Myeloma;248
20.2;References;248
21;20;251
21.1;The Roles of Molecular Techniques in the Diagnosis and Management of Follicular Lymphoma;251
21.1.1;Introduction;251
21.1.2;Practical Aspects of Molecular Genetic Testing in the Diagnosis and Management of Follicular Lymphoma;251
21.1.2.1;Molecular Genetic Tests Available for FL;252
21.1.3;The Molecular Pathogenesis of FL and Its Impact on Molecular Diagnostics;252
21.1.3.1;What Goes Wrong to Make Follicular Lymphoma? The “First” Hit;253
21.1.3.2;The “Second” Hit;253
21.1.3.2.1;Immunoglobulin Genes in FL;254
21.1.3.2.2;Molecular Genetic Analysis by Gene Expression Profiling Largely Reflects the Microenvironment (Also See Chap. 13);255
21.1.3.3;The “Third Hit”: Mechanisms of Large Cell Transformation;255
21.1.3.4;Molecular Variants of FL;255
21.1.3.5;Implications of Pathogenesis for Molecular Assays;255
21.1.3.5.1;Clonality Detection by IG PCR;255
21.1.3.5.2;Detection of BCL2 Translocations;256
21.2;References;256
22;21;258
22.1;Mantle Cell Lymphoma;258
22.1.1;Introduction;258
22.1.2;Epidemiology;258
22.1.3;Clinical Presentation;258
22.1.4;Histopathology;258
22.1.5;Immunophenotype;258
22.1.6;Pathogenesis;259
22.1.6.1;Initial Oncogenic Event;259
22.1.6.2;Secondary Genetic Alterations;259
22.1.6.3;Pathway Dysregulations in MCL;260
22.1.6.3.1;Dysregulations in Cell Cycle Control;260
22.1.6.3.2;Dysregulations in DNA Damage Response Pathway;260
22.1.6.3.3;Dysregulations in Cell Survival Pathway;261
22.1.6.3.4;Dysregulations in MicroRNA-17–92 Expression;261
22.1.7;Molecular Diagnosis;262
22.1.8;Proteomics and Antibody-Based Protein Array;262
22.1.9;Prognosis;263
22.1.10;Therapy;263
22.1.11;Summary;263
22.2;References;263
23;22;267
23.1;Diffuse Large B-Cell Lymphomas;267
23.1.1;Introduction;267
23.1.2;Distinction of De Novo DLBCL from DLBCL of Follicular Origin;267
23.1.3;Subgrouping of DLBCL and Prediction of Prognosis;267
23.1.4;Correlation of Immunohistochemical Analyses with GEP Data in DLBCL;270
23.1.5;Correlation of GEP Data and Immunohistochemical Patterns with Cytogenetic Abnormalities in DLBCL;270
23.1.6;Future Directions;271
23.1.7;Differentiation from Burkitt Lymphoma;271
23.1.8;Differentiation of De Novo DLBCL, De Novo CD5+ DLBCL, and Mantle Cell Lymphoma;272
23.1.9;AIDS-Related DLBCL;273
23.1.10;Cutaneous Large B-Cell Lymphoma;274
23.1.11;Primary Mediastinal Large B-cell Lymphoma;274
23.1.12;Summary;275
23.2;References;275
24;23;277
24.1;The Molecular Pathology of Burkitt Lymphoma;277
24.1.1;History and Clinical Features of Burkitt Lymphoma;277
24.1.2;EBV and Burkitt Lymphoma (Also See Chap..7);278
24.1.3;Myc and Burkitt Lymphoma;279
24.1.4;Diagnosis of Burkitt Lymphoma;280
24.1.4.1;Microarray Profiling;282
24.1.5;Therapy of Burkitt Lymphoma/Leukemia;282
24.1.5.1;New Therapeutic Agents;283
24.2;References;283
25;24;286
25.1;Precursor B-Cell Acute Lymphoblastic Leukemia;286
25.1.1;Introduction;286
25.1.2;Abnormalities of Chromosome Number;287
25.1.2.1;High Hyperdiploidy;287
25.1.2.2;Hypodiploidy;287
25.1.3;Frequent Structural Chromosome Abnoramlities;288
25.1.3.1;t(12;21)(p13q22) ETV6-RUNX1288
25.1.3.1.1;Molecular Characterization of the ETV6-RUNX1 Fusion (Figure 24.1a)74;288
25.1.3.1.2;Prognostic Significance of ETV6-RUNX1;288
25.1.3.1.3;ETV6-RUNX1 in Relapsed Pediatric ALL;290
25.1.3.2;Philadelphia Chromosome: t(9;22)(q34q11.2)BCR-ABL1290
25.1.3.2.1;Molecular Characterization of the BCR-ABL1 Fusion (Figure 24.1b)74;290
25.1.3.2.2;Prognostic Significance of BCR-ABL1;290
25.1.3.2.3;New Therapies for BCR-ABL1+ ALL;290
25.1.3.3;Rearrangements of the MLL Gene at 11q23;291
25.1.3.3.1;Molecular Description of MLL, Fusion Partners, and the MLL Fusion Genes (Figure 24.1c)74;291
25.1.3.3.2;Prognostic Significance of MLL Rearrangements;292
25.1.3.3.3;Transplantation Therapy for ALL with MLL Rearrangements;292
25.1.3.4;t(1;19)(q23p13.3)TCF3-PBX1292
25.1.3.4.1;Molecular Description of the TCF3-PBX1 Fusion (Figure 24.1d)74;293
25.1.3.4.2;Prognostic Significance of TCF3-PBX1;293
25.1.3.5;Abnormalities of Chromosome Arm 9p;293
25.1.3.5.1;Molecular Characterization of Gene Mutations and Deletions Mapping to 9p;293
25.1.3.5.2;Prognostic Significance of 9p Abnormalities;294
25.1.3.6;Intrachromosomal Amplification of Chromosome 21 and RUNX1 Gene Amplification;294
25.1.3.7;Detection of Minimal Residual Disease by Molecular Methods in Patients with Chromosomal Abnormalities;294
25.1.4;B-Precursor Lymphoblastic Lymphoma;295
25.1.5;Conclusions and Future Directions;295
25.2;References;295
26;25;307
26.1;Molecular Genetics of Mature T/NK Neoplasms;307
26.1.1;Introduction;307
26.1.2;Diagnosis of T/NK Neoplasms;307
26.1.3;Mycosis Fungoides;309
26.1.4;Anaplastic Large Cell Lymphoma, ALK-Positive;309
26.1.5;Angioimmunoblastic T Cell Lymphoma;311
26.1.6;Natural Killer/T Cell Neoplasms;313
26.1.7;Extranodal Peripheral T Cell Lymphomas;315
26.1.8;T-Prolymphocytic Leukemia;317
26.1.9;Adult T Cell Leukemia/Lymphoma;318
26.1.10;T-Large Granular Lymphocyte Leukemia;319
26.1.11;Therapeutic Implications of T-Cell Receptors and Molecular Pathways;320
26.2;References;320
27;26;326
27.1;Precursor T-Cell Neoplasms;326
27.1.1;Introduction;326
27.1.2;Activating Mutations in the NOTCH1 Signaling Pathway;327
27.1.3;Aberrant Expression of Transcription Factor Oncogenes;328
27.1.4;Basic Helix-Loop-Helix Transcription Factor Oncogenes TAL1, TAL2, LYL1, and BHLHB1;328
27.1.5;LIM Only Domain Factors LM01 and LM02;329
27.1.6;Homeobox Transcription Factors TLX1, TLX3 and HOXA9;329
27.1.6.1;MYB;330
27.1.6.2;MYC;330
27.1.6.3;Transcription Factor Fusion Oncogenes;330
27.1.6.4;MLL-MLLT1;331
27.1.6.5;PICALM-MLLT10 (CALM-AF10);331
27.1.6.6;SET-NUP214;331
27.1.6.7;NUP98 Fusion Oncogenes;331
27.1.6.8;Aberrant Activation of Tyrosine Kinase Oncoproteins;332
27.1.6.8.1;NUP214-ABL and EML1-ABL;332
27.1.6.8.2;JAK1 Mutations;332
27.1.6.8.3;FLT3 Mutations;333
27.1.6.8.4;LCK Translocation and Overexpression;333
27.1.6.8.5;RAS Gene Mutations and Loss of NF1;333
27.1.6.8.6;Mutational Loss of PTEN;333
27.1.6.8.7;Alterations in Cyclin-Dependent Kinase Inhibitors and Cyclin D2 Overexpression;334
27.1.6.8.8;Clinical Implications for Therapy Stratification and Molecularly Targeted Drugs;334
27.2;References;335
28;27;344
28.1;Classical Hodgkin Lymphoma and Nodular Lymphocyte Predominant Hodgkin Lymphoma;344
28.1.1;Background;344
28.1.2;Hodgkin “Disease” Is a B-Cell “Lymphoma”;344
28.1.3;Oncogenic Events in Classical Hodgkin Lymphoma;346
28.1.3.1;Mutations;346
28.1.3.2;Chromosomal Gains/Genomic Amplifications;346
28.1.3.3;Chromosomal Losses;346
28.1.3.4;Epigenetic Events;347
28.1.3.5;Translocations;347
28.1.3.5.1;microRNAs (miRNAs);347
28.1.3.6;Gene Expression Profiling;347
28.1.3.7;Proteomics (Also See Chap. 14);347
28.1.3.8;Genetic Predisposition;347
28.1.4;Role of EBV (Also See Chap. 7);348
28.1.5;The Peculiar Phenotype of HRS Cells;348
28.1.6;Disrupted Cellular Pathways;350
28.1.7;Nodular Lymphocyte Predominant Hodgkin Lymphoma;351
28.1.8;Summary;351
28.2;References;351
29;28;356
29.1;Posttransplant Lymphoproliferative Disorder;356
29.1.1;Introduction;356
29.1.2;Clinical Setting;356
29.1.3;Histopathology;356
29.1.4;Clonality and Clonal Evolution;357
29.1.5;Mechanisms of Viral Lymphomagenesis;358
29.1.6;Host Chromosomal Genetic Alteration;359
29.1.7;EBV-Negative PTLD;359
29.1.8;Blood Tests to Diagnose, Predict and Monitor PTLD;359
29.1.9;Therapy;360
29.1.10;Conclusion;360
29.2;References;360
30;29;363
30.1;AIDS-Related Lymphomas;363
30.1.1;Introduction;363
30.1.2;Oncogenic Viruses (Also See Chap. 7);363
30.1.2.1;Epstein–Barr Virus (EBV; HHV4)363
30.1.2.1.1;Latency Membrane Protein-1 (LMP1);363
30.1.2.1.2;Latency Membrane Protein-2 (LMP2A);364
30.1.2.1.3;EBV Nuclear Antigen 2 (EBNA2);364
30.1.2.2;Kaposi Sarcoma Herpesvirus (KSHV; HHV8)364
30.1.2.2.1;Latent Nuclear Antigen-1 (LANA; LNA-1 Open Reading Frame [ORF] 73)364
30.1.2.2.2;Viral Cyclin (v-Cyclin; ORF 72)364
30.1.2.2.3;Viral Fas-Associated Death Domain Interleukin-1b-Converting Enzyme Inhibitory Protein (v-FLIP; ORF71/K13)364
30.1.2.2.4;Viral Interleukin 6 (v-IL-6; K2)364
30.1.2.2.5;Viral Interferon Regulatory Factor (v-IRF3; LANA2 ORFK10.5)364
30.1.3;Classification of AIDS-Related Lymphomas;364
30.1.3.1;Lymphomas Also Occurring in Immunocompetent Individuals;365
30.1.3.1.1;Burkitt Lymphoma (BL);365
30.1.3.1.2;Diffuse Large B-Cell Lymphoma (DLBCL);368
30.1.3.2;Lymphomas Occurring More Specifically in HIV-Positive Patients;371
30.1.3.2.1;Primary Effusion Lymphoma (PEL) and Extra-Cavitary PEL (EC-PEL);372
30.1.3.2.2;Large B-Cell Lymphoma Arising in HHV8 (KSHV)-Associated Multicentric Castleman Disease (MCD);374
30.1.3.2.3;Plasmablastic Lymphoma;374
30.1.3.2.4;Lymphomas Occurring in Other Immunodeficient States;374
30.1.3.2.5;Polymorphic Lymphoid Proliferations;374
30.2;References;375
31;30;382
31.1;Chronic Myelogenous Leukemia;382
31.1.1;Introduction;382
31.1.2;Diagnostic Criteria;382
31.1.3;Clinicopathologic Features;382
31.1.4;Standard Therapy;384
31.1.5;Molecular Monitoring of CML;384
31.1.6;Routine Monitoring Algorithms;384
31.1.7;Assay Design and Quality Control Considerations for BCR-ABL RQ-PCR;385
31.1.8;Molecular Mechanisms of Therapy Resistance in CML (Also See Chap. 11);385
31.1.8.1;Primary Imatinib Resistance;385
31.1.8.2;Secondary Imatinib Resistance and Blast Transformation;386
31.1.8.3;ABL KD Mutation;386
31.1.9;Clonal Evolution;387
31.2;References;387
32;31;390
32.1;Molecular Pathogenesis of Nonchronic Myeloid Leukemia Myeloproliferative Neoplasms;390
32.1.1;Introduction;390
32.1.2;Cytogenetics of Nonchronic Myeloid Leukemia Myeloproliferative Neoplasms;391
32.1.3;Molecular Pathways Involving MPN;392
32.1.4;JAK2V617F Mutations;392
32.1.4.1;Other JAK Mutations;393
32.1.4.2;MPLW515 Mutations;393
32.1.5;Expression Profiling Findings in MPNS;394
32.1.6;Molecular-Targeted Therapy;395
32.2;References;395
33;32;399
33.1;Molecular Pathology of Myelodysplastic/Myeloproliferative Neoplasms, Myeloid and Lymphoid Neoplasms with Eosinophilia and Abn;399
33.1.1;Myelodysplastic/Myeloproliferative Neoplasms: General Aspects;399
33.1.2;Chronic Myelomonocytic Leukemia;399
33.1.3;Atypical Chronic Myeloid Leukemia, BCR–ABL1 Negative;400
33.1.4;Juvenile Myelomonocytic Leukemia;401
33.1.5;Refractory Anemia with Ring Sideroblasts and Marked Thrombocytosis;402
33.1.6;Other Unclassifiable Myelodysplastic/Myeloproliferative Neoplasms;403
33.1.7;Myeloid and Lymphoid Neoplasms Associated with Eosinophilia and Abnormalities of PDGFRA, PDGFRB, and FGFR1 Rearrangement: Ge;403
33.1.8;Myeloid and Lymphoid Neoplasms Associated with PDGFRA Rearrangement;403
33.1.8.1;Myeloid Neoplasms Associated with PDGFRB Rearrangement;404
33.1.9;Myeloid and Lymphoid Neoplasms Associated with FGFR1 Rearrangement;404
33.1.10;Mastocytosis;405
33.1.11;Summary;405
33.2;References;407
34;33;411
34.1;Molecular Pathogenesis of Myelodysplastic Syndromes;411
34.1.1;Introduction;411
34.1.2;MDS Associated with Recurrent Cytogenetic Abnormalities and Molecular Genetic Lesions;413
34.1.3;Gene Expression Profiling Findings in MDS;414
34.1.4;Single Nucleotide Polymorphisms Profiling Findings in MDS;414
34.1.5;Cytokine Profiling Findings in MDS;415
34.1.6;Molecular Pathways Involved in MDS;415
34.1.6.1;Oncogenes;415
34.1.6.2;Cell Cycle Regulatory Genes;416
34.1.6.3;Apoptotic Genes;416
34.1.6.4;Growth Factor and Angiogenesis Genes;416
34.1.6.5;Receptor Tyrosine Kinase Genes;416
34.1.7;Epigenomic Changes in MDS;416
34.1.7.1;Methylation;416
34.1.7.2;Histone Deacetylation;416
34.1.7.3;Targeted Therapies;417
34.2;References;417
35;34;422
35.1;Acute Myeloid Leukemias with Recurrent Cytogenetic Abnormalities;422
35.1.1;Introduction;422
35.1.2;Epidemiology;422
35.1.3;Clinical Features;422
35.1.4;Examination of the Peripheral Blood and Bone Marrow;423
35.1.4.1;Morphologic Features;423
35.1.4.2;Cytochemical Features;424
35.1.4.3;Immunophenotyping Using Flow Cytometry;424
35.1.4.4;Immunohistochemical Analyses;425
35.1.4.5;Electron Microscopy;425
35.1.4.6;Cytogenetic and Molecular Markers;425
35.1.4.7;Gene Expression Profiling;425
35.1.4.8;Prognostic Indicators;425
35.1.5;Molecular Abnormalities in AML;426
35.1.6;Molecular Mechanisms of AML;426
35.1.7;AML with Recurrent Genetic Abnormalities;427
35.1.7.1;AML with t(8;21)(q22q22.3) RUNX1–RUNX1T1 (AML1/ETO or RUNX1/MTG8)427
35.1.7.2;AML inv(16)(p13.1q22) or t(16;16)(p13.1q22) CBFb-MYH11428
35.1.7.3;Acute Promyelocytic Leukemia with t(15;17)(q22q21) PML/RARA, and Variants428
35.1.7.4;AML with t(9;11)(p22q23), MLLT3–MLL430
35.1.7.5;AML with t(6;9)(p23q34) DEK–NUP214430
35.1.7.6;AML with inv(3)(q21q26.2) or t(3;3)(q21q26.2) RPN1-EVI1431
35.1.7.7;AML (Megakaryoblastic) with t(1;22)(p13q13) RBM15-MKL1431
35.1.7.8;AML with Gene Mutations;432
35.1.7.9;Translocations in AML Not Included in AML with Recurrent Genetic Abnormality Category of WHO 2008 Classification;432
35.1.7.9.1;AML with 11q23 (MLL) Abnormalities Other than t(9;11);43235.1.7.10;AML with the Translocation t(1116)(q23p13.3)433
35.1.7.11;AML with Other Translocations Involving 11q23;433
35.1.7.12;AML with 11q23 Rearrangements and Normal Conventional Cytogenetics or Trisomy 11;433
35.1.7.12.1;AML with inv(11)(p15q22);433
35.1.7.12.2;AML with t(16;21)(p11q22)433
35.1.7.12.3;AML with t(12;22)(p13q11)434
35.1.7.12.4;AML with t(8;16)(p11p13)434
35.1.7.12.5;AML with t(3;21)(q26q22)434
35.1.7.12.6;AML with t(9;22)(q34q11)434
35.1.7.12.7;AML with t(7;11)(p15p15)435
35.2;References;435
36;35;442
36.1;Acute Myeloid Leukemias with Normal Cytogenetics;442
36.1.1;Introduction;442
36.1.2;Abnormalities Affecting Proliferation/Apoptosis of Leukemia Cells Directly;442
36.1.2.1;FLT3 Gene Mutations (Also See Chapter 11);442
36.1.2.2;RAS Gene Mutations;443
36.1.2.3;Kit Gene Mutations;444
36.1.2.4;G-CSF Receptor Gene Mutations;444
36.1.2.5;NPM1 Gene Mutations;444
36.1.2.6;RB1 Gene Mutations;445
36.1.2.7;P53 Gene Mutations;445
36.1.2.8;STAT Activation;445
36.1.2.9;CXCR4 Overexpression;445
36.1.3;Antigen Receptor Gene Rearrangement;446
36.1.3.1;BAALC Gene;446
36.1.3.2;CEBPA Gene;446
36.1.3.3;ERG Gene;447
36.1.3.4;MN1 Gene;447
36.1.4;Other Prognostic Factors in Karyotypically Normal AML;447
36.1.5;Abnormalities Affecting Proliferation/Apoptosis of Leukemia Cells Directly;447
36.1.5.1;Osteoblasts;448
36.1.5.2;Leptin;448
36.1.5.3;Microvasculature;448
36.1.6;Conclusions;449
36.2;References;449
37;36;456
37.1;Acute Myeloid Leukemia with Myelodysplasia-Related Changes and Therapy-Related Acute Myeloid Leukemia;456
37.1.1;Introduction;456
37.1.2;Classification of AML;456
37.1.3;Dysplasia in Myeloid Cells;458
37.1.4;Detection of Dysplasia Using Flow Cytometric Immunophenotyping;458
37.1.5;Cytochemical Features of AML;458
37.1.6;Immunophenotype;458
37.1.7;Genetics and Molecular Markers;458
37.1.8;Gene Expression Profiling;460
37.1.9;DNA Methylation;461
37.1.10;Summary;461
37.2;References;462
38;37;465
38.1;Molecular Pathology of Hemoglobin and Erythrocyte Membrane Disorders;465
38.1.1;Introduction;465
38.1.2;Molecular Pathology of Hemoglobin Disorders;465
38.1.2.1;The Thalassemia Syndromes;466
38.1.2.1.1;Introduction;466
38.1.2.1.2;b Thalassemia Syndromes;467
38.1.2.1.2.1;Introduction;467
38.1.2.1.2.2;Molecular Pathology and Pathophysiology;467
38.1.2.1.2.3;Clinical Features and Therapy;467
38.1.2.1.2.3.1;b Thalassemia Major;467
38.1.2.1.2.3.2;b Thalassemia Intermedia;469
38.1.2.1.2.3.3;b Thalassemia Trait;469
38.1.2.1.2.3.4;db Thalassemia;469
38.1.2.1.2.3.5;HB E-b Thalassemia;469
38.1.2.1.2.3.6;Hemoglobin Lepore;469
38.1.2.1.3;Thalassemia Syndrome not Associated with a Globin Gene Mutation;470
38.1.2.1.4;a Thalassemia Syndromes;470
38.1.2.1.4.1;Molecular Pathology and Pathophysiology;470
38.1.2.1.4.2;Clinical Features and Therapy;471
38.1.2.1.4.2.1;a+ Thalassemia;471
38.1.2.1.4.2.2;a0 Thalassemia;471
38.1.2.1.4.2.3;Hb H Disease;471
38.1.2.1.4.2.4;HB Bart’s and Hydrops Fetalis;471
38.1.2.1.4.2.5;a Thalassemia Associated with Mental Retardation;471
38.1.2.1.4.2.6;Acquired Hb H Disease;472
38.1.2.1.4.2.7;Hb Constant Spring;472
38.1.2.2;Sickle Cell Disease;472
38.1.2.2.1;Introduction;472
38.1.2.2.2;Molecular Pathology and Pathophysiology;472
38.1.2.2.3;Clinical Features and Therapy;472
38.1.2.3;Sickle Cell Variants;473
38.1.2.3.1;Hb SC Disease;473
38.1.2.3.2;Sickle-b Thalassemia;473
38.1.2.3.3;Sickle Cell Trait;473
38.1.2.3.4;Other Sickle Cell Variants;474
38.1.2.4;Hereditary Persistence of Fetal Hemoglobin Syndromes;474
38.1.2.5;Unstable Hemoglobin Variants;474
38.1.2.6;Hemoglobin Variants with Altered Oxygen Affinity;475
38.1.2.7;Methemoglobinemias;475
38.1.2.8;Laboratory Evaluation and Diagnosis of Hemoglobinopathies;476
38.1.2.8.1;Complete Blood Count and Examination of a Blood Film;476
38.1.2.8.2;Sickle Solubility Test;476
38.1.2.8.3;Hemoglobin Electrophoresis at Alkaline pH;476
38.1.2.8.4;Hemoglobin Electrophoresis at Acid pH;476
38.1.2.8.5;Isoelectric Focusing;476
38.1.2.8.6;Capillary Electrophoresis;476
38.1.2.8.7;High-Performance Liquid Chromatography;477
38.1.2.8.8;Hb A2 Quantitation by Column Chromatography;477
38.1.2.8.9;Hb F Quantitation;477
38.1.2.8.10;z Globin Detection in a0 Thalassemia Carriers;477
38.1.2.8.11;DNA-Based Tests;477
38.1.3;Molecular Pathology of Erythrocyte Membrane Disorders;477
38.1.3.1;Hereditary Spherocytosis;477
38.1.3.2;Pathophysiology;477
38.1.3.3;History and Physical;478
38.1.3.4;Laboratory Testing;479
38.1.3.4.1;Peripheral Blood Smear;479
38.1.3.4.2;Blood Count and RBC Indices;479
38.1.3.4.3;Osmotic Fragility;480
38.1.3.4.4;Other Tests;480
38.1.3.5;Molecular Studies;480
38.1.3.5.1;Markers of Hemolysis;480
38.1.3.5.2;Pathologic Findings;480
38.1.3.6;Differential Diagnosis;480
38.1.3.7;Complications;481
38.1.3.8;Treatment;481
38.1.3.8.1;Specific Therapy;481
38.1.3.8.2;Supportive Care;481
38.1.3.9;Hereditary Elliptocytosis, Hereditary Pyropoikilocytosis, and Related Disorders;482
38.1.3.9.1;Clinical Syndromes;482
38.1.3.9.2;Pathophysiology;482
38.1.3.9.3;History and Physical;482
38.1.3.9.4;Laboratory Testing;483
38.1.3.9.4.1;Peripheral Blood Smear;483
38.1.3.9.4.2;Blood Count and Erythrocyte Indices;483
38.1.3.9.4.3;Osmotic Fragility;483
38.1.3.10;Molecular Studies;483
38.1.3.10.1;Markers of Hemolysis;483
38.1.3.11;Differential Diagnosis;483
38.1.3.12;Treatment and Outcome;483
38.1.3.12.1;Specific Therapy;483
38.1.3.12.2;Supportive Care;483
38.1.3.12.3;Complications and Outcome;483
38.1.3.13;Hereditary Stomatocytosis Syndromes;483
38.1.3.13.1;Xerocytosis;484
38.1.3.13.2;Hydrocytosis (Stomatocytosis);484
38.1.3.13.3;Intermediate Syndromes;484
38.1.3.13.4;Acanthocytosis;484
38.1.3.13.5;Abetalipoproteinemia;484
38.1.3.13.6;McLeod Phenotype;484
38.1.3.13.7;Neuroacanthocytosis Syndromes;485
38.2;References;485
39;38;490
39.1;White Blood Cell and Immunodeficiency Disorders;490
39.1.1;Introduction;490
39.1.2;Severe Combined Immunodeficiency (Also See Chap. 2);490
39.1.3;Antibody Deficiency;491
39.1.3.1;The Agammaglobulinemias;491
39.1.3.2;Hyper-IGM Syndrome (Elevated IGM, Decreased IGG, A, and E) (Also See Chap. 2);493
39.1.3.3;Common Variable Immunodeficiency (Also See Chap. 2);493
39.1.4;Cellular Deficiencies;494
39.1.4.1;Undue Susceptibility to Mycobacteria: IFNGAMMA/IL-12 AXIS;494
39.1.4.2;Autoimmunity;494
39.1.4.3;Lymphoproliferative Disorders;496
39.1.5;Phagocyte and Innate Defects;496
39.1.5.1;Chronic Granulomatous Disease;496
39.1.5.2;Leukocyte Adhesion Deficiency;496
39.1.5.3;Herpes Virus Encephalitis;497
39.2;References;497
40;39;501
40.1;Molecular Basis of Disorders of Hemostasis and Thrombosis;501
40.1.1;Introduction and Overview of Coagulation;501
40.1.2;Disorders of Soluble Clotting Factors;502
40.1.2.1;Fibrinogen (Factor I) Abnormalities;502
40.1.2.2;Prothrombin (Factor II) Deficiency;504
40.1.2.3;Factor V Deficiency;504
40.1.2.4;Factor VII Deficiency;504
40.1.2.5;Hemophilia A and Hemophilia B (Classic Hemophilia and Christmas Disease);504
40.1.2.6;Factor X Deficiency;505
40.1.2.7;Factor XI Deficiency;505
40.1.2.8;Deficiencies of Factor XII, Prekallikrein, and High Molecular Weight Kininogen;505
40.1.2.9;Factor XIII Deficiency;505
40.1.2.10;Multiple Clotting Factor Deficiencies;506
40.1.2.11;Von Willebrand Disease;506
40.1.2.12;Acquired Clotting Factor Deficiencies;507
40.1.3;Disorders of Fibrinolysis;508
40.1.4;Disorders of Platelet Number or Function;508
40.1.4.1;Disorders of Platelet Production;508
40.1.4.1.1;The MYH9-Associated Disorders;508
40.1.4.1.2;Defects in Transcription Factors;509
40.1.4.1.3;Defects in Platelet Production;509
40.1.4.2;Disorders of Platelet Function;509
40.1.4.2.1;Defects in Platelet Adhesion;509
40.1.4.2.2;Defects in Platelet Aggregation;510
40.1.4.2.3;Disorders of Platelet Secretion: The Storage Pool Diseases;510
40.1.4.2.3.1;Defects in Alpha Granules;510
40.1.4.2.3.2;Defects in Dense Granules;510
40.1.4.2.3.3;The Scott Syndrome;511
40.1.4.3;Disorders of Platelet Destruction;511
40.1.4.3.1;Antibody-Mediated Platelet Destruction;511
40.1.4.3.2;Thrombotic Microangiopathies;512
40.1.4.3.3;Heparin-Induced Thrombocytopenia;512
40.1.5;Thrombophilia;512
40.1.5.1;The Protein C Pathway and Thrombosis;513
40.1.5.2;Antithrombin Deficiency;514
40.2;References;514
41;40;519
41.1;Sarcoidosis: Are There Sarcoidosis Genes?;519
41.1.1;Introduction;519
41.1.2;Morphology and Its Implications;519
41.1.3;Variants of Sarcoidosis;519
41.1.3.1;Löfgren’s Disease/Acute Sarcoidosis;519
41.1.3.2;Nodular Sarcoidosis;519
41.1.4;Necrotizing Sarcoid Granulomatosis;520
41.1.5;What Is the Meaning of Indistinguishable Differentials?;520
41.1.6;The Cells in Sarcoidosis;521
41.1.6.1;T Lymphocytes;521
41.1.6.2;Epithelioid Cells;521
41.1.6.3;Giant Cells (Foreign Body and Langerhans Type);521
41.1.7;Mycobacteria and Other Trigger Mechanisms: Is Sarcoidosis an Infectious Disease?;522
41.1.8;Risk Factors;522
41.1.8.1;The Steps of an Immune Reaction and What Might Happen in Sarcoidosis;522
41.1.8.2;Antigen Uptake and Processing;523
41.1.8.3;Antigen Presentation, Costimulatory Molecules, and Gene Polymorphisms and Where They Come into Play;523
41.1.8.4;Human Leukocyte Antigen Class I Genes;524
41.1.8.5;Human Leukocyte Antigen Class II Genes;524
41.1.9;Effector Mechanisms, the Lymphocyte-Macrophage Network, and Gene Expression in Sarcoidosis;524
41.1.10;Disease Modifier Genes and Aspects of Organ Involvement in Sarcoidosis;526
41.2;References;527
42;41;530
42.1;Castleman’s Disease;530
42.1.1;Introduction;530
42.1.2;Clinical Classification;530
42.1.2.1;Unicentric Castleman’s Disease;530
42.1.2.2;Multicentric Castleman’s Disease;530
42.1.2.3;HIV Status and Castleman’s Disease;530
42.1.3;Epidemiology;531
42.1.4;Histopathological Classification of Castleman’s Disease;531
42.1.4.1;Relationship Between Histological Type and Clinical Classification;531
42.1.5;Pathogenesis of Castleman’s Disease;531
42.1.6;Diagnosis;532
42.1.7;Therapy;532
42.2;References;532
43;42;534
43.1;Molecular Pathology of Histiocytic Disorders;534
43.1.1;Introduction;534
43.1.2;Langerhans Cell Histiocytosis;534
43.1.2.1;Clinicopathologic Features;534
43.1.2.2;Immunohistochemistry of LCS in Normal Tissues and LCH;535
43.1.2.3;Host Genetic Factors in Langerhans Cell Histiocytosis;536
43.1.2.3.1;Epidemiologic Data;536
43.1.2.3.2;Increased Chromosomal Breakage in LCH Patients;536
43.1.2.3.3;The Role of Cytokines and Cytokine Gene Polymorphisms in LCH;536
43.1.2.3.4;HLA Haplotypes in LCH Patients;537
43.1.2.3.5;CD45 Splicing Defects;537
43.1.2.4;Clonality Studies in LCH;537
43.1.2.4.1;Conventional Cytogenetics and Ploidy Studies;537
43.1.2.4.2;HUMARA Studies;537
43.1.2.4.3;Comparative Genomic Hybridization (CGH) and Loss of Heterozigosity (LOH) Studies in LCH;537
43.1.2.5;Gene Expression Profiling in LCH;538
43.1.2.6;Alterations of Cell Cycle Proteins in LCH;538
43.1.3;Erdheim-Chester Disease;538
43.1.3.1;Clinicopathologic Features;538
43.1.3.2;Immunohistochemistry;539
43.1.3.3;Chemokine Network in ECD;539
43.1.3.4;Clonality Studies;539
43.1.4;Hemophagocytic Lymphohistiocytosis;539
43.1.4.1;Clinicopathology Features;539
43.1.4.2;Immunophenotypic and Immunologic Abnormalities;540
43.1.4.3;Host Genetic Factors in HLH;540
43.1.4.4;CD45 Splicing Abnormalities;541
43.1.4.5;Host Genetic Factors in SHLH;541
43.1.4.6;Cytokines in HLH;541
43.1.5;Juvenile Xanthogranuloma;541
43.1.5.1;Clinicopathologic Features;541
43.1.5.2;Immunohistochemistry;542
43.1.5.3;Proliferation and Apoptosis in JXG;542
43.1.5.4;Other Molecular Findings;542
43.1.6;Kikuchi-Fujimoto Disease (See Also Chaps. 43 and 44);542
43.1.6.1;Clinicopathologic Features;542
43.1.6.2;Immunohistochemistry;542
43.1.6.3;HLA Subtypes in KFD;543
43.1.6.4;Infectious Agents in KFD;543
43.1.7;Lysosomal Storage Disorders;543
43.1.7.1;Clinicopathologic Features;543
43.2;References;546
44;43;550
44.1;Reactive Lymphadenopathies: Molecular Analysis;550
44.1.1;Overview;550
44.1.1.1;B Cell Processes;550
44.1.1.2;T Cell Processes;552
44.1.1.3;Specific Entities;553
44.1.1.4;Medication-Related Lymphoid Proliferations;554
44.2;References;554
45;44;557
45.1;Molecular Pathology of Infectious Lymphadenitides;557
45.1.1;Introduction;557
45.1.2;Bacterial Lymphadenitis;558
45.1.2.1;Bartonella spp.;558
45.1.2.1.1;Summary;561
45.1.2.2;T. whipplei (Whipple’s Disease);561
45.1.2.2.1;Summary;562
45.1.2.3;C. trachomatis, Serovars L1–L3 (Lymphogranuloma Venereum, LGV);562
45.1.2.3.1;Summary;563
45.1.2.4;T. pallidum (Syphilis);563
45.1.2.4.1;Summary;564
45.1.2.5;Broad Range Detection of Bacteria;564
45.1.3;Mycobacterial Lymphadenitis;564
45.1.3.1;M. tuberculosis Complex;565
45.1.3.2;Mycobacteria Other Than Tuberculosis (MOTT);566
45.1.3.3;General Mycobacterial Detection;567
45.1.4;Fungal Lymphadenitis;567
45.1.4.1;Introduction;567
45.1.4.2;Histoplasma capsulatum;567
45.1.4.3;Coccidioides;570
45.1.4.4;Cryptococcus neoformans;571
45.1.4.5;Panfungal Approaches to Molecular Mycology;571
45.1.4.5.1;Summary;572
45.1.5;Parasitic Lymphadenitis;572
45.1.5.1;Toxoplasma gondii;572
45.1.5.2;Leishmania spp.;573
45.1.6;Viral Lymphadenitis;574
45.1.6.1;Introduction;574
45.1.6.2;Herpesviruses;574
45.1.6.3;Other Viruses;575
45.1.6.4;Lymphadenitides of Suspected Infectious Origin;575
45.1.6.5;Kikuchi–Fujimoto Disease;575
45.1.6.6;Kimura Disease;575
45.1.7;Summary;576
45.2;References;576
46;45;584
46.1;Gene Therapy for Nonneoplastic Hematologic and Histiocytic Disorders;584
46.1.1;Introduction;584
46.1.2;Vectors for HSC Applications;584
46.1.2.1;Gammaretrovirus;584
46.1.2.2;Lentivirus;585
46.1.2.3;Alternate Retroviruses;585
46.1.2.4;Adenoviral Vectors;587
46.1.2.5;Adeno-Associated Virus Vectors;587
46.1.2.6;Nonviral Vectors;587
46.1.3;Early Studies;588
46.1.4;Clinical Trials;588
46.1.4.1;Recent Success;589
46.1.4.2;Hemophilias;589
46.1.4.3;Risks of Gene Therapy;590
46.1.5;Retrovirus Integration and Insertional Mutagenesis;590
46.1.6;Future Directions;591
46.1.6.1;Nonintegrating Vectors;591
46.1.6.2;Targeted Integration;591
46.2;References;592