Molecular Surgical Pathology

✍ Scribed by Liang Cheng; George J. Netto; John N. Eble

• Publisher: Springer Nature
• Year: 2023
• Tongue: English
• Leaves: 725
• Category: Library

✦ Synopsis

Since the first edition of this book in 2012, the field of molecular pathology has expanded exponentially. The advent of complete cancer genome sequencing, new diagnostic molecular tests, and biomarkers for targeted therapy and immunotherapy have demonstrated the importance of molecular tools both in patient care and in the practice of pathology. Furthermore, the development of many new molecular technologies has revolutionized the practice of modern pathology. The rapid growth of this field has led to an expansion of knowledge of molecular processes and many more clinical applications in our daily practice of surgical pathology. Thus, this updated second edition of Molecular Surgical Pathology aims to serve as the best available “quick reference” for pathologists, oncologists, geneticists, primary care physicians, and other medical professionals with an interest in this specialty. Molecular Surgical Pathology 2nd Edition focuses on the practical utility of molecular techniques and on molecular biomarkers for the practicing surgical pathologist. The emphasis is on the impact of molecular pathology for tumor classification, diagnosis and differential diagnosis, as well as its implications for patient management and personalized care. This concise overview of molecular surgical pathology and molecular classification of tumors of different organ sites will help not only practicing physicians, but also those in training, including residents and fellows in various disciplines.

✦ Table of Contents

Preface
Contents
Contributors
1: Molecular Techniques/Molecular Diagnostics for Surgical Pathologists: An Overview
Introduction
Roles for Molecular Surgical Pathology
Background Information for Molecular Genomics
Background on Genome Organization
DNA Sequence Variation
Background for RNA Analysis
Overview of Molecular Methods
Sample Preparation
Sample Types
Sample Adequacy
Fixatives
DNA/RNA Extraction Basic Steps
Preparation of DNA from Formalin Fixed Paraffin Embedded Tissue
DNA Methylation
RNA Extraction
Quality Assessment of DNA and RNA
Cytogenetics
Background Information for Cytogenetics
Classes of Pathogenic Cytogenetic Variation
Cytogenetic Methods
Karyotyping
Fluorescent In Situ Hybridization
Microarrays
Molecular Diagnostics Basic Methods
DNA/RNA Electrophoresis
The Art of Detection
Target Amplification Versus Signal Amplification
Methods: PCR
Principles of PCR
Real-Time PCR
PCR Contamination
Real-Time PCR Formats
SNV Detection by PCR
Methods: Digital Droplet PCR (ddPCR)
Methods: Rolling Circle Amplification (RCA)
Methods: Hybridization Chain Reaction (HCR)
Methods: Branched DNA (bDNA)
Methods: Whole-Genome Amplification (WGA)
Sequencing
General Remarks
Methods: Sequencing/Sanger Sequencing
Second-Generation Sequencing
Second Generation Sequencing Platforms
Outline of a Representative Illumina Protocol
Outline of a Representative Thermo-Fisher (Ion Torrent) Protocol
Third-Generation Sequencing
PacBio
Oxford Nanoporetech
Other Applications of NGS
Bioinformatics
Single-Cell ‘Omics’
General Remarks
Single-Cell Protocols
Spatial ‘Omics: Not Quite the Final Frontier
General Remarks
In Situ Hybridization (ISH)
Single Molecule FISH (smFISH)
Representative Method: SeqFISH+
Representative Method: MERFISH
In Situ Sequencing
In Situ Capture–Ex Situ Sequencing (Generic)
Representative Implementation: GeoMx Digital Space Profiler
Representative Implementation: Seq-Scope Illumina
Representative Implementation: HDST
Representative Implementation: Visium (10× Genomics)
In Situ Genomic (DNA) Sequencing Extended by Ex Situ Sequencing
Analysis
Achievements of Spatial Genomics
Future Directions/Predictions
Further Reading
2: Bioinformatics, Digital Pathology, and Computational Pathology for Surgical Pathologists
Introduction
Bioinformatics, a Distinct Field in Pathology and Where Are We Now
Pathology Bioinformaticians and Their Role
Specialized Training in Bioinformatics
Definitions and Terminologies Related to Bioinformatics and Computational Pathology
Annotation
Artificial Intelligence (AI)
Black Box/Glass Box
Cloud Computing
Computational Pathology (CPATH)
Convolutional Neural Network (CNN)
Deep Learning
Data Augmentation
Digital Pathology (DP)
Gold Standard
Ground Truth
Image Analysis
Machine Learning (ML)
Metadata
Supervised Machine Learning
Unsupervised Machine Learning
Whole-Slide Image (WSI)
Differences Between Traditional Image Analysis and Computational Pathology
Digital Pathology, Machine Learning, and Computational Pathology
Training Algorithm
Case Selection
Whole-Slide Imaging
Traditional Image Analysis Enhanced by Machine Learning
Pathologist-Centered Medical System
Global Pathology Service Model
Examples of Bioinformatics and AI-Driven Pathology Workflow
Prostate Cancer
Colorectal Cancer
Breast Cancer
Cancer Cytopathology
Challenges and Limitations
Infrastructure Considerations
Processor Speed and Sources
Network Limitations
Acquiring Training Data
Data Variability
Public Sources
Crowdsourcing
Active Learning
Quality Control and Reliability of the Algorithm
Understanding Algorithms
Ethics
Cyber-Security
Future Directions
Conclusions
Further Reading
3: Molecular Cytopathology
Introduction
Cytology Sample Collection
Cytology Sample Preparation
Types of Molecular Alterations
Assays to Detect Different Molecular Alterations
Assay Validation and Molecular Testing Workflows
Clinical Settings for Molecular Cytopathology
Further Reading
4: Next-Generation Immunohistochemistry in the Workup of Neoplasm of Uncertain Lineage and CUP
Introduction: Immunohistochemistry Complements a Morphology and Epidemiology-Based Approach to Tumor Diagnosis
Immunohistochemistry Basics
IHC Protocol
IHC Optimization/Validation
IHC Readout
IHC Common Pitfalls
Next-Generation Immunohistochemistry
Cancer Epidemiology
Clinical Aspects of Cancer (Typically Carcinoma) of Unknown Primary
Broad Tumor Classes and Associated Screening Markers
Broad-Spectrum Epithelial Markers
S-100 Versus SOX10
Noncanonical Expression of Screening Markers
Immunohistochemical Approach to Small Round Blue Cell Tumor
Immunohistochemical Approach to Carcinoma Typing
Coordinate Expression of CK7/CK20
Immunohistochemical Approach to “Garden Variety Adenocarcinoma” Presenting in the Liver
Immunohistochemical Approach to Primary Versus Metastatic Ovarian Tumor with Mucinous Features
Immunohistochemical Approach to Tumors Presenting at Other Sites
Immunohistochemical Approach to Distinction of Squamous and Urothelial Carcinoma
Immunohistochemical Approach to Neuroendocrine Tumor Site of Origin Assignment
Immunohistochemical Approach to Neuroendocrine Carcinoma Site of Origin Assignment
Immunohistochemical Approach to the Distinction of NET G3 from NEC
Immunohistochemical Approach to Undifferentiated/Dedifferentiated Carcinoma
Immunohistochemical Approach to High-Grade Neoplasms Negative for Screening Markers
Immunohistochemistry for Hereditary Cancer Predisposition Syndromes
Further Reading
5: Molecular Pathology of Colorectal Tumors
Introduction
Epidemiology
Etiology
Prognosis and Treatment
Screening Guidelines
Pathogenesis and Molecular Classifications of Colorectal Cancer
Colorectal Carcinogenesis
Molecular Classifications of Colorectal Cancer
DNA-Based Genomic Classification by the Cancer Genome Atlas (TCGA)
RNA-Based Transcriptomic Profiling by Colorectal Cancer Subtyping Consortium
Practical Molecular Diagnostics of Colorectal Cancer
Universal Screening Algorithm
MMR Immunohistochemistry Interpretation and Pitfalls
Specimen Selection for CRC Molecular Testing
Established Predictive Biomarkers
RAS (KRAS and NRAS) for EGFR Antibody Immunotherapy Selection
BRAF Mutation
Microsatellite Instability for Therapy Selection
Emerging and Partially Established Biomarkers
Cancer Immunotherapy
Other Biomarkers with Targeted Therapy Implications
Hereditary Cancer Syndromes
Lynch Syndrome
Definition
Pathologic Features
Genetic Features
Lynch Syndrome Variants and Related Syndromes
Familial Adenomatous Polyposis and Variants
Definition
Clinical Features
Pathologic Features
Genetic Features
FAP Variants
Mut Y Homolog-Associated Polyposis Syndrome
Definition
Pathologic Features
Genetics Features
Serrated Polyposis Syndrome
Definition
Clinical Features
Pathologic Features
Genetic Features
Peutz–Jeghers Polyposis Syndrome
Definition
Clinical Features
Pathologic Features
Genetic Features
Juvenile Polyposis Syndrome
Definition
Clinical Features
Pathologic Features
Genetics
Cowden Syndrome
Definition
Clinical Features
Pathologic Features
Genetics Features
Other Polyposis Syndromes That Can Include Multiple Adenomas
Hereditary Mixed Polyposis Syndrome
Definition
Genetic Features
NTHL1-Associated Polyposis
Definition
Polymerase Proofreading-Associated Polyposis
Definition
Pathologic Features
AXIN2-Associated Polyposis Syndrome
Definition
Current Challenges and Emerging Trends
Further Reading
6: Molecular Pathology of Gastroesophageal Tumors
Introduction
Clinical and Molecular Features of Esophageal Neoplasms
Esophageal Squamous Cell Carcinoma
Esophageal Adenocarcinoma
Esophageal Undifferentiated Carcinoma
Other Esophageal Neoplasms
Clinical and Molecular Features of Gastric Neoplasms
Precursor Polyps
Gastric Adenocarcinoma
Gastric Neuroendocrine Carcinoma
Other Gastric Neoplasms
Genetic Predisposition Syndromes
Molecular Diagnostics for Gastroesophageal Cancers
Further Reading
7: Molecular Pathology of Pancreatic Tumors
Introduction to Normal Pancreas
Neoplasms with Ductal Differentiation
Pancreatic Ductal Adenocarcinoma
Clinical Features
Pathologic Features
Genetic Features
Variants of Ductal Adenocarcinoma
Adenosquamous Carcinoma
Colloid Carcinoma
Hepatoid Carcinoma
Medullary Carcinoma
Signet Ring Cell Carcinoma
Undifferentiated Carcinoma
Undifferentiated Carcinoma with Osteoclast-Like Giant Cells
Intraductal Papillary Neoplasms
Clinical Features
Pathologic Features
Genetic Features
Intraductal Oncocytic Papillary Neoplasm
Intraductal Tubulopapillary Neoplasm
Mucinous Cystic Neoplasm
Clinical Features
Pathologic Features
Genetic Features
Serous Cystadenoma
Clinical Features
Pathologic Features
Genetic Features
Neoplasms with Neuroendocrine Differentiation
Well-Differentiated Pancreatic Neuroendocrine Tumors
Clinical Features
Pathologic Features
Genetic Features
Neuroendocrine Carcinoma
Clinical Features
Pathologic Features
Genetic Features
Neoplasms with Ambiguous Direction of Differentiation
Solid Pseudopapillary Neoplasm
Clinical Features
Pathologic Features
Genetic Features
Neoplasms with Acinar Differentiation
Acinar Cell Carcinoma
Clinical Features
Pathologic Features
Genetic Features
Pancreatoblastoma
Clinical Features
Pathologic Features
Genetic Features
Hereditary/Genetic Syndromes
Mutations in the Fanconi Anemia/BRCA Pathway
Ataxia-Telangiectasia Mutated
Familial Atypical Multiple Mole Melanoma Syndrome
Peutz–Jeghers Syndrome
Hereditary Pancreatitis
Hereditary Nonpolyposis Colorectal Cancer
Familial Adenomatous Polyposis
von Hippel–Lindau Syndrome
Other Hereditary/Genetic Syndromes
Summary of Molecular Pathology of Pancreatic Cancer
Further Reading
8: Molecular Pathology of Liver Tumors
Introduction
Hepatocellular Adenoma
Definition
Clinical Features
Pathologic Features
Differential Diagnosis
Genetic Features
Prognosis and Predictive Factors
Hepatocellular Carcinoma
Definition
Clinical Features
Pathologic Features
Diagnosis and Differential Diagnosis
Genetic Features
Prognosis and Predictive Factors
Intrahepatic Cholangiocarcinoma
Definition
Clinical Features
Pathologic Features
Differential Diagnosis
Genetic Features
Prognosis and Predictive Factors
Combined Hepatocellular-Cholangiocarcinoma
Definition
Clinical Features
Pathologic Features
Differential Diagnosis
Genetic Features
Prognosis and Predictive Factors
Hepatoblastoma
Definition
Clinical Features
Pathologic Features
Differential Diagnosis
Genetic Features
Prognosis and Predictive Factors
Hepatic Neuroendocrine Neoplasms
Definition
Clinical Features
Pathologic Features
Differential Diagnosis
Genetic Features
Prognosis and Predictive Factors
Malignant Vascular Neoplasms
Definitions
Clinical Features
Pathologic Features
Differential Diagnosis
Genetic Features
Prognosis and Predictive Factors
Hepatic Angiomyolipoma
Definitions
Clinical Features
Pathologic Features
Differential Diagnosis
Genetic Features
Prognosis and Predictive Factors
Summary of Molecular Pathology of Liver Tumors
Further Reading
9: Molecular Pathology of Lung Tumors
Introduction
Clinical Features
Molecular Genetic Pathology
Epidermal Growth Factor Receptor (EGFR)
Molecular Diagnostics
KRAS Proto-Oncogene, GTPase (KRAS)
Molecular Diagnostics
B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF)
Molecular Diagnostics
ALK Receptor Tyrosine Kinase (ALK)
Molecular Diagnostics
ROS Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1)
Molecular Diagnostics
Ret Proto-Oncogene (RET)
Molecular Diagnostics
MET Proto-Oncogene, Receptor Tyrosine Kinase (MET)
Molecular Diagnostics
Neurotrophic Receptor Tyrosine Kinases 1/2/3 (NTRK1/2/3)
Molecular Diagnostics
Other Alterations in Lung Adenocarcinoma
Less Common Oncogenic Mutations with Emerging Clinical Significance
Less Common Gene Fusions and Amplifications
Other Tumor Suppressor Gene Mutations
Molecular Pathology Related to NSCLC Immunotherapy
Considerations of Molecular Tests for NSCLC Management
Important Molecular Alterations in Other Lung Carcinomas
Squamous Cell Carcinoma (SCC)
Small Cell Lung Carcinoma (SCLC)
Genetically Defined Thoracic Tumor Entities
NUT Carcinoma
Molecular Diagnostics
Thoracic SMARCA4-Deficient Undifferentiated Tumor (SMARCA4-UT)
Molecular Diagnostics
Important Molecular Alterations in Mesothelioma
Further Reading
10: Molecular Pathology of Breast Tumors
Introduction
Normal Characteristics of the Female Human Breast
Gross, Microscopic, and Molecular Anatomy
Breast Development
Traditional Pathological Classification and Biomarkers in Routine Clinical Practice
Estrogen Receptor and Progesterone Receptor
Progesterone Receptor
Ki67 and ER+ Breast Cancer
Human Epidermal Growth Factor Receptor 2 Gene
HER2-low
TNBC
Immunohistochemistry
Guidelines for Hormone Receptor and HER2 Testing in Breast Cancer
ASCO-CAP Guidelines for HER2 Assessment
ASCO-CAP Guidelines for Hormone Receptor Assessment
Molecular Subtypes (Intrinsic Subtypes)
Multigene Prognostic Indices in ER+/HER– Tumors
Oncotype DX
The Mammaprint
Prosigna (PAM50) Assay
Breast Cancer Index (BCI)
Endopredict
Concordance between Assays
Familial and Hereditary Breast Cancer
BRCA1 and BRCA2
Non-BRCA Hereditary Breast Cancer
Familial Breast Cancer
Next-Generation Sequencing Assays Molecular Breast Pathology to Advance Personalized Treatment of Cancer
p53 Mutations
PI3KCA Mutations
ESR1 Mutations
Hormonally Directed Therapeutics
Recent Developments in the Breast Cancer Landscape that Revolutionize the Treatment Strategies
CDK4/6 Inhibitors in Breast Cancer- Co-Targeting CDk4/6 with Endocrine Therapy
Landscape of HER2-low Metastatic Breast Cancer and Antibody Drug Conjugates (ADCs) for HER2+ Disease
The Immune Landscape of Breast Cancer and Immune Checkpoint Inhibitors
Clinical Utility of Trop-2 in Breast Cancer
Summary and Conclusions
Further Reading
11: Molecular Pathology of Ovarian Tumors
Introduction
Classification of Ovarian Epithelial Neoplasms
Type I Tumors
Type II Tumors
Molecular Pathways and Alterations by Tumor Type
Type I Ovarian Tumors
Low-Grade Serous Tumors
Introduction
Genetic Pathways: Functions, Role in Pathogenesis, and Frequency of Abnormalities
Clinical Implications
Summary
Endometrioid and Clear Cell Carcinomas
Introduction
Genetic Pathways: Functions, Role in Pathogenesis, and Frequency of Abnormalities
Clinical Implications
Summary
Mucinous Tumors
Introduction
Genetic Pathways: Functions, Role in Pathogenesis, and Frequency of Abnormalities
Clinical Implications
Summary
Brenner Tumors
Type II Ovarian Tumors
High-Grade Serous Carcinoma and Carcinosarcoma
Introduction
Genetic Pathways: Functions, Role in Pathogenesis, and Frequency of Abnormalities
Clinical Implications
Summary
Undifferentiated/Dedifferentiated Carcinoma
Molecular Abnormalities Not Associated with Specific Histology
Molecular Abnormalities Associated with Rarer/Nonepithelial Ovarian Cancers
Hereditary/Familial Ovarian Cancers
Conclusions
Further Reading
12: Molecular Pathology of Endometrial Tumors
Introduction
WHO Classification of Endometrial Carcinoma (WHO 2020)
Histological Grade
Reproducibility of Histological Typing
Molecular Features of Endometrioid–Endometrial Carcinoma
Microsatellite Instability/Mismatch Repair Deficiency
Phosphatase and Tensin Homolog (PTEN)
PIK3CA and PIK3R1
RAS–MAPK Pathway
Beta-Catenin
ARID1A
Molecular Features of Serous Carcinoma
TP53
Other Alterations
Molecular Features of Clear Cell Carcinoma
Molecular Features of Mixed Endometrioid–Nonendometrioid Adenocarcinomas
Molecular Features of Endometrioid Carcinomas with Ambiguous Features
Molecular Features of Undifferentiated Carcinoma and Dedifferentiated Carcinoma
Molecular Features of Carcinosarcoma (Malignant Mixed Müllerian Tumors)
Molecular Features of Mesonephric-Like Carcinomas
Molecular Aspects of Staging
Intratumor Heterogeneity
cDNA Array Results
TCGA-Based Molecular Classification
Current Targeted Therapies
Potential-Targeted Therapies Approaches
Summary
Further Reading
13: Molecular Pathology of Kidney Tumors
Introduction
Genetic Renal Neoplasia Syndromes
von Hippel–Lindau Disease
Molecular Pathogenesis
Clinical and Pathologic Manifestations
Hereditary Papillary Renal Carcinoma
Molecular Pathogenesis
Hereditary Leiomyomatosis and Renal Cell Carcinoma
Molecular Pathogenesis
Clinical and Pathologic Manifestations
Tuberous Sclerosis
Molecular Pathogenesis
Clinical and Pathologic Manifestations
Birt–Hogg–Dubé Syndrome
Molecular Pathogenesis
Clinical and Pathological Manifestations
Succinate Dehydrogenase Germline Mutations
Molecular Pathogenesis
Clinical and Pathologic Manifestations
Constitutional Chromosome 3 Translocation
BAP1 Mutations and Familial Kidney Cancer
Clinical and Pathologic Manifestations
Cowden Syndrome (PTEN Hamartoma Tumor Syndrome)
Malignant Neoplasms
Clear Cell Renal Cell Carcinoma
Light Microscopy
Molecular Characteristics
Multifocality
Molecular Differential Diagnosis
Papillary Renal Cell Carcinoma
Light Microscopy
Molecular Characteristics
Multifocality
Molecular Differential Diagnosis
Hereditary Leiomyomatosis RCC Syndrome–Associated RCC
Chromophobe Renal Cell Carcinoma
Light Microscopy
Molecular Characteristics
Molecular Differential Diagnosis
Collecting Duct Carcinoma
Light Microscopy
Molecular Characteristics
Molecular Differential Diagnosis
Renal Medullary Carcinoma
Light Microscopy
Molecular Characteristics
MiT Family Translocation Carcinoma
TFE3-Rearranged/Xp11.2 Translocation Renal Cell Carcinoma
Light Microscopy
Molecular Characteristics
Molecular Differential Diagnosis
TFEB-Rearranged/T(6;11) Renal Cell Carcinoma
Light Microscopy
Molecular Characteristics
TFEB-Amplified Renal Cell Carcinoma
Molecular Differential Diagnosis
SDH-Deficient Renal Carcinoma
Mucinous Tubular and Spindle Cell Carcinoma
Molecular Characteristics
Tubulocystic Renal Cell Carcinoma
Molecular Characteristics
Acquired Cystic Disease-Associated Renal Cell Carcinoma
Light Microscopy
Molecular Characteristics
Thyroid-Like Follicular Renal Cell Carcinoma
Light Microscopy
Molecular Characteristics
Molecular Differential Diagnoses
ALK Rearrangement-Associated Renal Cell Carcinoma
Light Microscopy
Molecular Characteristics
Renal Cell Carcinoma with Fibromyomatous Stroma
Light Microscopy
Molecular Characteristics
Eosinophilic Solid and Cystic Renal Cell Carcinoma
Light Microscopy
Molecular Characteristics
Unclassified Renal Cell Carcinoma
Sarcomatoid Renal Cell Carcinoma
Molecular Characteristics
Other Tumors
Eosinophilic Vacuolated Tumor
Light Microscopy
Molecular Characteristics
Epithelioid Angiomyolipoma and Other Renal PEComas
Molecular Characteristics
Adult Nephroblastoma (Wilms Tumor)
Neuroendocrine Tumors/Carcinomas
Molecular Characteristics
Primitive Neuroectodermal Tumor/Ewing Family of Tumors
Urothelial Carcinoma
Molecular Characteristics
Molecular Differential Diagnosis
Unknown/Low Malignant Potential Neoplasms
Multilocular Cystic Renal Neoplasm, Low Malignant Potential
Clear Cell Papillary Renal Cell Tumor
Molecular Characteristics
Molecular Differential Diagnosis
Papillary Renal Neoplasm with Reverse Polarity
Light Microscopy
Molecular Characteristics
Low-Grade Oncocytic Tumor
Light Microscopy
Molecular Characteristics
Atrophic Kidney-Like Lesion
Light Microscopy
Benign Neoplasms
Angiomyolipoma
Oncocytoma
Molecular Differential Diagnosis
Papillary Adenoma
Cystic Nephroma
Adult Cystic Nephroma
Pediatric Cystic Nephroma
Mixed Epithelial and Stromal Tumor
Juxtaglomerular Cell Tumor
Metanephric Adenoma
Molecular Characteristics
Molecular Differential Diagnosis
Renomedullary Interstitial Cell Tumor (Medullary Fibroma)
Pediatric Neoplasms
General Molecular Characteristics
Nephroblastoma (Wilms Tumor)
Molecular Characteristics
Clear Cell Sarcoma
Molecular Characteristics
Rhabdoid Tumor
Molecular Characteristics
Congenital Mesoblastic Nephroma
Molecular Characteristics
Metanephric Tumors
Molecular Characteristics
Neuroblastoma
Molecular Characteristics
Renal Cell Carcinoma Associated with Neuroblastoma
Light Microscopy
Molecular Characteristics
Pediatric Cystic Nephroma
Molecular Characteristics
Further Reading
14: Molecular Pathology of Prostate Cancer
Introduction
Biology of Prostatic Epithelium
Epidemiology and Etiology of Prostate Cancer
Clinical Features
Histopathology of Prostate Cancer
Precursor Lesions
Intraductal Carcinoma (IDC-P)
Acinar Adenocarcinoma
Ductal Adenocarcinomas
Rare Subtypes
Neuroendocrine Carcinoma (NEPC)
Other Histological Variants/Patterns of Differentiation
Grading of Adenocarcinoma
Artificial Intelligence in Prostate Cancer Histopathology
Molecular Features of Prostate Cancer
Germline Alterations
Somatic Genomic Alterations in Prostate Cancer
ETS Gene Fusions
Other Apparently Mutually Exclusive (with ETS Alterations) and Truncal Somatic Mutations
Other Genetic Alterations in Prostate Cancer
Epigenetic Alterations in Prostate Cancer
Tumor Microenvironment in Prostate Cancer
Prognostic Utility of Somatic Tissue-based Genetic Testing
Suggested Readings
15: Molecular Pathology of Urinary Bladder Tumors
Introduction
Oncogenic Pathways in Urothelial Carcinoma of the Urinary Bladder
Prognostic Biomarkers in Bladder Cancer
General Background
Chromosomal Numerical Alterations–Early Culprit of Genetic Instability in Bladder Cancer
Receptor Tyrosine Kinase Alterations
p53, Cell Cycle Regulators, and Proliferation Activity Index
Epigenetic Alterations
Intrinsic Molecular Genomic Subtypes of Urothelial Carcinoma
Bladder Cancer TCGA 2014
Bladder Cancer TCGA 2017
Molecular Markers for Early Detection of Urothelial Carcinoma
UroVysion
BTA-Stat
NMP22
ImmunoCyt
UroSEEK
Circulating Tumor Cells
Other Markers
Molecular Grading and Staging of Bladder Cancer
Molecular Grading
Molecular Staging
Molecular Detection of Lymph Node Metastasis
Targeted Therapy and Predictive Markers in Bladder Cancer
Immunotherapy in Bladder Cancer
Summary
Suggested Reading
16: Molecular Pathology of Testicular Cancer
Introduction
Germ Cell Tumors
General Classification
Type I (Pediatric) Germ Cell Tumor
Type II (Adult) Germ Cell Tumors
Type III Germ Cell Tumors (Spermatocytic Tumor)
Selected Sex Cord-Stromal Tumors
Leydig Cell Tumors
Sertoli Cell Tumors
Granulosa Cell Tumors
Summary
Suggested Reading
17: Molecular Pathology of Melanoma and Nonmelanoma Skin Tumors
Introduction
Ultraviolet Radiation and Skin Cancer
Melanoma
Overview
Pathogenesis
Diagnosis
Classification
Melanomas Arising in Sun-Exposed Skin
Pathway I: Low-Cumulative Solar Damage (Low-CSD)/SSM
Epidemiology
Clinical Features
Histopathology
Precursor Lesions
Molecular Features
Pathway II: High-CSD Melanoma/LMM
Epidemiology
Clinical Features
Histopathology
Precursor Lesions
Molecular Features
Pathway III: Desmoplastic Melanoma (DM)
Epidemiology
Clinical Features
Histopathology
Precursor Lesions
Molecular Features
Melanomas Arising at Sun-Shielded Sites or Without Known Etiological Associations with UVR Exposure
Pathway IV: Malignant Spitz Tumor (Spitz Melanoma; SM)
Epidemiology
Clinical Features
Histopathology
Precursor Lesions
Molecular Features
Pathway V: Acral Melanoma
Epidemiology
Clinical Features
Histopathology
Precursor Lesions
Molecular Features
Pathway VI: Mucosal Melanoma (MM)
Epidemiology
Clinical Features
Histopathology
Precursor Lesions
Molecular Features
Pathway VII: Melanoma Arising in a Congenital Nevus
Epidemiology
Clinical Features
Histopathology
Precursor Lesions
Molecular Features
Pathway VIII: Melanoma Arising in a Blue Nevus
Epidemiology
Clinical Features
Histopathology
Precursor Lesions
Molecular Features
Pathway IX: Uveal Melanoma
Epidemiology
Clinical Features
Histopathology
Precursor Lesions
Molecular Features
Nodular Melanoma
Pediatric Melanoma
Immunotherapy and Targeted Therapy
Nonmelanoma Skin Cancer
Basal Cell Carcinoma
Clinical Features
Genetics and Pathogenesis
Histopathology
Molecular Therapies and Drug Resistance Mechanisms
Squamous Cell Carcinoma
Overview
Pathogenesis
Squamous Cell Carcinoma Precursors
Squamous Cell Carcinoma In Situ (Bowen disease)
Invasive Squamous Cell Carcinoma
Molecular Features
Immunotherapy for SCC
Merkel Cell Carcinoma
Overview
Pathogenesis
Clinical Features
Histopathology
Molecular Features
Immunotherapy
Dermatofibrosarcoma Protuberans
Overview
Pathogenesis
Clinical Features
Histopathology
Molecular Features
Therapy
Cutaneous Adnexal Neoplasms
Trichoblastoma
Overview
Clinical features
Histopathology
Molecular Features
Cylindroma and Spiradenoma
Overview
Clinical Features
Histopathology
Molecular Features
Pilomatricoma
Overview
Clinical Features
Histopathology
Molecular Features
Pilomatrical Carcinoma
Sebaceous Neoplasms
Overview
Clinical Features
Histopathology
Molecular Features
Genetic/Hereditary Syndromes
Familial Melanoma
Xeroderma Pigmentosum
Carney Complex
BAP-1 Tumor Predisposition Syndrome (BAP1-TPDS)
Muir Torre Syndrome
Brooke–Spiegler Syndrome
Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)
Suggested Reading
Ultraviolet Light and Skin Cancer
Melanoma
Nonmelanoma Skin Cancer
Merkel Cell Carcinoma
Dermatofibrosarcoma Protuberans
Cutaneous Adnexal Neoplasms
Genetic/Hereditary Syndromes
18: Molecular Pathology of Head and Neck Tumors
Introduction
Conventional Squamous Cell Carcinoma
Squamous Cell Carcinoma of the Oral Cavity
Squamous Cell Carcinoma of the Hypopharynx, Larynx, Trachea, and Parapharyngeal Space
Precursors to Conventional Squamous Cell Carcinoma
Oral Cavity Dysplasia
Laryngeal Dysplasia
Laryngeal Squamous Papilloma
Human Papillomavirus-Associated Squamous Cell Carcinoma of the Oropharynx
Immunotherapy for Head and Neck Cancer
Additional Oral Cavity Tumors
Ectomesenchymal Chondromyxoid Tumor
GLI1-Altered Mesenchymal Neoplasms
Nasal Cavity, Paranasal Sinus, and Skull Base Tumors
Sinonasal Papilloma
Inverted Type
Oncocytic Type
Exophytic Type
Types of Carcinoma
Squamous Cell Carcinoma
Keratinizing Squamous Cell Carcinoma
Nonkeratinizing Squamous Cell Carcinoma
Intestinal-Type Adenocarcinoma
Nonintestinal-Type Adenocarcinoma
Neuroendocrine Carcinoma
Lymphoepithelial Carcinoma
NUT Carcinoma
SWI/SNF-Deficient Malignancies
SMARCB1 (INI-1)-Deficient Sinonasal Carcinoma
SMARCA4 (BRG1)-Deficient Sinonasal Carcinoma
IDH-Mutant Sinonasal Carcinoma
Human Papillomavirus-Associated Multiphenotypic Sinonasal Carcinoma
Mesenchymal Tumors
Nasal Chondromesenchymal Hamartoma
Sinonasal Glomangiopericytoma
Biphenotypic Sinonasal Sarcoma
Spindle Cell/Sclerosing Rhabdomyosarcoma
Emerging Molecularly-Defined Entities
DEK::AFF2 Fusion-Associated Carcinoma
Adamantinoma-Like Ewing Sarcoma
Hematolymphoid Tumors
Extranodal NK/T-Cell Lymphoma, Nasal Type
Neuroectodermal Tumors
Olfactory Neuroblastoma
Nasopharyngeal Tumors
Nasopharyngeal Angiofibroma
Nasopharyngeal Carcinoma
Nonkeratinizing Squamous Cell Carcinoma
Keratinizing Squamous Cell Carcinoma
Odontogenic Tumors
Ameloblastoma
Ameloblastic Carcinoma
Odontogenic and Non-Odontogenic Developmental Cysts
Odontogenic Keratocyst
Calcifying Odontogenic Cyst
Giant Cell Lesions
Central Giant Cell Lesion
Peripheral Giant Cell Lesions
Ear
External Auditory Canal Squamous Cell Carcinoma
Middle and Inner Ear Tumors
Endolymphatic Sac Tumor
Paraganglioma
Suggested Reading
19: Molecular Pathology of Salivary Gland Tumors
Introduction
Practical Tips for Utilizing Molecular Techniques in Salivary Gland Tumors
Fine-Needle Aspiration
Tissue Preparation of Biopsies and Resection Specimens
Tissue Selection for Testing
Malignant Neoplasms
Acinic Cell Carcinoma
Light Microscopy
NR4A3 Rearrangement
Utility of NR4A3 Rearrangement in the Diagnosis of AciCC
Other Genetic Changes in AciCC
Adenoid Cystic Carcinoma
Light Microscopy
MYB Alterations
Utility of MYB Alteration in the Diagnosis of AdCC
Other Genetic Alterations Described in AdCC
Epithelial Myoepithelial Carcinoma
Light Microscopy
HRAS Mutations
Utility of Detecting HRAS Mutations in the Diagnosis of EMC
Other Genetic Changes Observed in EMC
Hyalinizing Clear Cell Carcinoma
Light Microscopy
EWSR1 Rearrangement
Utility of Detecting EWSR1 Gene Rearrangement
Other Genetic Changes in HCCC
Intraductal Carcinoma
Light Microscopy
RET Rearrangement
Utility of RET Rearrangement in the Diagnosis of Intraductal Carcinoma
Mucoepidermoid carcinoma
Light Microscopy
MAML2 Rearrangement
Utility of MAML2 Rearrangement in Diagnosis of MEC
Microsecretory Adenocarcinoma
Light Microscopy
SS18 Rearrangement
Utility of SS18 in the Diagnosis of MSA
Other Genetic Changes in MSA
Myoepithelial Carcinoma
Light Microscopy
PLAG1 and HMGA2 Genetic Changes
EWSR1 Rearrangement
Utility of Detecting PLAG1 or EWSR1 Rearrangement
Polymorphous Adenocarcinoma
Light Microscopy
PRKD Gene Alterations
Utility of Detecting PRKD Gene Alterations in PAC
Salivary Duct Carcinoma
Light Microscopy
Androgen Receptor
Human Epidermal Growth Factor Receptor 2 (HER2)
Utility of Detecting AR and HER2 in SDC
Other Genetic Alterations in SDC
Sclerosing Microcystic Adenocarcinoma
Light Microscopy
CDK11B Mutations
Utility of Detecting CDK11B Mutations
Secretory Carcinoma
Light Microscopy
ETV6 Rearrangement
Utility of Detecting ETV6 or NTRK Rearrangement in SC
Other Genetic Changes in SC
Pleomorphic Adenoma
Light Microscopy
PLAG1 or HMGA2 Rearrangement
Utility of Detecting PLAG1 or HMGA2 Rearrangement in PA
Carcinoma Ex-Pleomorphic Adenoma
Light Microscopy
PLAG1 or HMGA2 Rearrangement
Utility of Detecting PLAG1 or HMGA2 Rearrangement in CXPA
Other Genetic Changes in CXPA
Basal Cell Adenoma
Light Microscopy
CTNNB1 and CYLD1 Mutations
Detection of CTNNB1 and CYLD1 Mutations
Basal Cell Adenocarcinoma
Suggested Reading
Introduction
Acinic Cell Carcinoma
Adenoid Cystic Carcinoma
Epithelial Myoepithelial
Hyalinizing Clear Cell Carcinoma
Intraductal Carcinoma
Mucoepidermoid Carcinoma
Microsecretory Adenocarcinoma
Myoepithelial Carcinoma
Polymorphous Adenocarcinoma
Salivary Duct Carcinoma
Sclerosing Microcystic Adenocarcinoma
Secretory Carcinoma
Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma
Basal Cell Adenoma and Adenocarcinoma
20: Molecular Pathology of the Heart and Cardiovascular System
Selected Primary Tumors of the Heart and Cardiovascular System
Introduction
Benign Tumors
Myxoma
Papillary Fibroelastoma
Rhabdomyoma
Fibroma
Lipomatous Hypertrophy of the Atrial Septum
Paraganglioma
Hemangioma
Cystic Tumor of the Atrioventricular Node
Malignant Tumors
Angiosarcoma
Undifferentiated Pleomorphic Sarcoma
Intimal Sarcoma
Selected Hereditary/Genetic Syndromes
Introduction
Cardiomyopathies
Hypertrophic Cardiomyopathy
Arrhythmogenic Cardiomyopathy
Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD)
Desmin-Related Cardiomyopathy
Nemaline Myopathy
Phospholamban Cardiomyopathy
Deposition and Storage Disorders
Pompe Disease (Glycogen Storage Disease Type IIa)
Danon Disease (Glycogen Storage Disease Type IIb)
Anderson-Fabry Disease
Hereditary Transthyretin Amyloidosis
Hereditary Aortic Diseases
Marfan Syndrome
Vascular Ehlers-Danlos Syndrome
Loeys–Dietz Syndrome
Suggested Reading
21: Molecular Pathology of Endocrine Tumors
Thyroid Tumors
Papillary Thyroid Carcinoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Invasive Encapsulated Follicular Variant Papillary Carcinoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Follicular Thyroid Carcinoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Oncocytic Thyroid Carcinoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Follicular-Derived Carcinomas, High-Grade
Definition
Clinical Features
Pathology Features
Genetic Features
Anaplastic Thyroid Carcinoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Hyalinizing Trabecular Tumor
Definition
Clinical Features
Pathologic Features
Genetic Features
Cribriform Morular Thyroid Carcinoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Medullary Thyroid Carcinoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Parathyroid Tumors
Parathyroid Adenoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Atypical Parathyroid Tumor
Definition
Clinical Features
Pathologic Features
Genetic Features
Parathyroid Carcinoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Adrenal Cortical Tumors
Definition
Adrenal Cortical Nodular Disease
Definition
Clinical Features
Pathologic Features
Genetic Features
Adrenal Cortical Adenoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Adrenal Cortical Carcinoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Pheochromocytomas and Paragangliomas
Definition
Pheochromocytoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Paragangliomas
Definition
Clinical Features
Pathologic Features
Genetic Features
Hereditary Pheochromocytomas and Paragangliomas
Suggested Readings
Thyroid Tumors
Parathyroid Tumors
Adrenal Cortical Tumors
Adrenal Medullary Tumors and Paragangliomas
22: Molecular Pathology of Soft Tissue and Bone Tumors
General Concepts
Definition
Clinical Features
Basic Principles
Gene Fusions and Gene Promiscuity
General Technical Considerations
Karyotype Analysis
Fluorescence in situ Hybridization (FISH)
Single Gene Sequencing Assays
Next-Generation Sequencing
Chromosomal Microarray
Methylation Studies
Multimodal Diagnostic Approach
Diagnostic Molecular Alterations in Soft Tissue and Bone Tumors
Round Cell Sarcomas
BCOR::CCNB3 sarcoma
Spindle Cell Sarcomas
Infantile Fibrosarcoma
Epithelioid Sarcomas
Epithelioid Hemangioendothelioma
Pleomorphic Sarcomas
Osteosarcoma
Myxoid Sarcomas
Extraskeletal Myxoid Chondrosarcoma
Predictive Molecular Alterations in Soft Tissue and Bone Tumors
Suggested Reading
23: Molecular Pathology of the Central Nervous System
Central Nervous System Tumors
Introduction
Glial Tumors
Introduction
Adult-Type Diffuse Gliomas
Adult-Type Diffuse Gliomas, IDH Mutant
Astrocytoma, IDH Mutant
Definition
Clinical Features
Pathologic Features
Genetic and Biomarker Findings
Oligodendroglioma, IDH Mutant and 1p/19q Codeleted
Definition
Clinical Features
Pathologic Features
Genetic Features
Adult-Type Diffuse Gliomas, IDH Wildtype
Glioblastoma, IDH Wildtype
Definition
Clinical Features
Pathologic Features
Genetic Features
Pediatric-Type Diffuse Gliomas
Diffuse Gliomas, H3 Defined
Diffuse Midline Glioma, H3K27-Altered
Definition
Clinical Features
Pathologic Features
Genetic Features
Diffuse Hemispheric Glioma, H3 G34 Mutant
Definition
Clinical Features
Pathologic Features
Genetic Features
Diffuse Pediatric-Type High-Grade Glioma, H3 Wildtype, and IDH Wildtype
Definition
Clinical Features
Pathologic Features
Genetic Features
Infant-Type Hemispheric Glioma
Definition
Clinical Features
Pathologic Features
Genetic Features
Pediatric-Type Diffuse Low-Grade Gliomas
Diffuse Low-Grade Glioma, MAPK Pathway-Altered
Definition
Clinical Features
Pathologic Features
Genetic Features
Diffuse Astrocytoma, MYB- or MYBL1-Altered
Definition
Clinical Features
Pathologic Features
Genetic Features
Polymorphous Low-Grade Neuroepithelial Tumor of the Young
Definition
Clinical Features
Pathologic Features
Genetic Features
Angiocentric Glioma
Definition
Clinical Features
Pathologic Features
Genetic Features
Circumscribed Astrocytic Gliomas
Pilocytic Astrocytoma
Definition
Clinical Features
Pathologic Features
Genetic Features
High-Grade Astrocytoma with Piloid Features
Pleomorphic Xanthoastrocytoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Astroblastoma, MN1-Altered
Chordoid Glioma
Subependymal Giant Cell Astrocytoma
Ependymal Tumors
Introduction
Posterior Fossa Ependymoma
Supratentorial Ependymoma
Spinal Ependymoma
Myxopapillary Ependymoma
Subependymoma
Glioneuronal and Neuronal Tumors
Introduction
Ganglioglioma
Definition
Clinical Features
Pathologic Features
Genetic Features
Dysembryoplastic Neuroepithelial Tumor
Desmoplastic Infantile Astrocytoma/Ganglioglioma
Diffuse Glioneuronal Tumor with Oligodendroglioma-Like Features and Nuclear Clusters
Papillary Glioneuronal Tumor
Rosette-Forming Glioneuronal Tumor
Myxoid Glioneuronal Tumor
Diffuse Leptomeningeal Glioneuronal Tumor
Multinodular and Vacuolated Neuronal Tumor
Central Neurocytoma
Extraventricular Neurocytoma
Embryonal Tumors
Introduction
Medulloblastoma
Definition
Clinical Features
Histopathologic Patterns
Molecular Groups
Cancer Predisposition Syndromes and Genes Associated with Medulloblastoma
Prognosis and Risk Stratification
Atypical Teratoid/Rhabdoid Tumor
Definition
Clinical Features
Pathologic Features
Genetic Features
Cribriform Neuroepithelial Tumor
Embryonal Tumor with Multilayered Rosettes
CNS Neuroblastoma, FOXR2-Activated
CNS Tumor with BCOR Internal Tandem Duplication
Choroid Plexus Tumors
Definition
Clinical Features
Pathologic Features
Genetic Features
Pineal Parenchymal Tumors
Meningioma
Definition
Clinical Features
Pathologic Features (Fig. 23.22)
Genetic Features
Craniopharyngioma
Hemangioblastoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Solitary Fibrous Tumor
Germ Cell Tumors
Definition
Clinical Features
Pathologic Features
Genetic Features
Peripheral Nerve Sheath Tumors
Schwannoma
Definition
Clinical Features
Pathologic Features
Genetic Features
Neurofibroma
Malignant Melanotic Nerve Sheath Tumor
Malignant Peripheral Nerve Sheath Tumor
Paraganglioma of the Cauda Equina (Cauda Equina Neuroendocrine Tumor)
Nonneoplastic Brain Disorders
Introduction
General Molecular/Cellular Mechanisms of Neurodegeneration
Protein Aggregation and Transport Dysfunction
Mitochondria Dysfunction
Neuroinflammation
Survival vs. Apoptosis Factors
Alzheimer Disease
Clinical/Epidemiology
Gross and Histological Neuropathology
Genes Associated with Sporadic and Familial AD (Table 23.3)
Possible Molecular Mechanisms of Pathogenesis of AD
Diagnosis
Parkinson Disease
Clinical/Epidemiology
Gross and Histologic Neuropathology
Associated Genes
Possible Molecular Mechanisms of Pathogenesis
Diagnosis
Amyotrophic Lateral Sclerosis/Motor Neuron Disease
Clinical
Gross and Histological Neuropathology
Associated Genes and Possible Molecular Mechanisms of Pathogenesis
Diagnosis
Tauopathies
General Comments
FTDP-17T
Progressive Supranuclear Palsy
Corticobasal Degeneration
Pick Disease
Trinucleotide Repeat Diseases
General Comments
Huntington Disease
Clinical
Gross and Histologic Neuropathology
Associated Genes
Possible Molecular Mechanisms of Pathogenesis
Diagnosis
Friedrich Ataxia
Clinical
Gross and Histological Neuropathology
Associated Genes
Possible Molecular Mechanisms of Pathogenesis
Diagnosis
Suggested Reading
Central Nervous System Tumors
Nonneoplastic Brain Disorders
24: Molecular Pathology of Lymphoma
Introduction
Types of Lymphoma
Clinical Features
Testing Employed
B-Cell Lymphomas
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Hairy Cell Leukemia
Nodal Marginal Zone Lymphoma
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma)
Splenic Marginal Zone Lymphoma
Lymphoplasmacytic Lymphoma
Plasma Cell Myeloma
Mantle Cell Lymphoma
Follicular Lymphoma
Diffuse Large B-Cell Lymphoma, NOS
Burkitt Lymphoma
High-Grade B-Cell Lymphoma
T/NK-Cell Lymphomas
T-Cell Prolymphocytic Leukemia
T-Cell Large Granular Lymphocytic Leukemia
Adult T-Cell Leukemia/Lymphoma
Extranodal NK/T-Cell Lymphoma, Nasal Type
Angioimmunoblastic T-Cell Lymphoma and Other T-Cell Lymphomas of T Follicular Helper Cell Origin
Peripheral T-Cell Lymphoma, NOS
Anaplastic Large Cell Lymphoma
Mycosis Fungoides
Sezary Syndrome
Intestinal T-Cell Lymphoma
Hepatosplenic T-Cell Lymphoma
Suggested Reading
25: Molecular Pathology of Leukemia
Introduction
Hereditary Leukemia Syndromes
Myeloid Neoplasms with Germline Predisposition
Myeloid Neoplasms with Germline Predisposition Without a Preexisting Disorder or Organ Dysfunction
Acute Myeloid Leukemia with Germline CEBPA Mutation
Myeloid Neoplasms with Germline DDX41 Mutation
Myeloid Neoplasms with Germline Predisposition and Preexisting Platelet Disorders
Myeloid Neoplasms with Germline RUNX1 Mutation
Myeloid Neoplasms with Germline ANKRD26 Mutation, also Known as Thrombocytopenia 2
Myeloid Neoplasms with Germline ETV6 Mutation, also Known as Thrombocytopenia 5
Myeloid Neoplasms with Germline Predisposition and Other Organ Dysfunction
Myeloid Neoplasms with Germline GATA2 Mutation
Myeloid Neoplasms Associated with Bone Marrow Failure Syndromes
Myeloid Neoplasms Associated with Telomere Biology Disorders
Juvenile Myelomonocytic Leukemia (JMML) Associated with Neurofibromatosis, Noonan Syndrome, Or Noonan Syndrome-Like Disorders
Myeloid Neoplasms Associated with Down Syndrome
Transient Abnormal Myelopoiesis Associated with Down Syndrome (DS-TAM)
Myeloid leukemia Associated with Down Syndrome (ML-DS)
Myeloid Leukemias
Introduction
Acute Myeloid Leukemia with Recurrent Genetic Abnormalities
Acute Myeloid Leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1
Acute Myeloid Leukemia with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB::MYH11
Acute Promyelocytic Leukemia with t(15;17)(q24;q21); PML::RARA
Acute Myeloid Leukemia with t(9;11)(p21.3;q23.3); MLLT3::KMT2A or other KMT2A rearrangement
Acute Myeloid Leukemia with t(6;9)(p23;q34.1); DEK:NUP214
Acute Myeloid Leukemia with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
Acute Myeloid Leukemia (Megakaryoblastic) with t(1;22)(p13.3;q13.1); RBM15::MRTFA
Acute Myeloid Leukemia with BCR::ABL1
Acute Myeloid Leukemia with Mutated NPM1
Acute Myeloid Leukemia with In-Frame bZIP CEBPA mutation
Acute Myeloid Leukemia with Mutated RUNX1
Acute Myeloid Leukemia with Myelodysplasia-related Changes (AML-MRC)
Therapy-Related Myeloid Neoplasms (t-MN)
Myeloid Sarcoma
Lymphocytic Leukemias
B-Lymphoblastic Leukemia (B-ALL)/Lymphoma (B-LBL)
B-Lymphoblastic Leukemia/Lymphoma with Recurrent Genetic Abnormalities
B-Lymphoblastic Leukemia/Lymphoma with t(9;22)(q34.1;q11.2); BCR::ABL1
B-Lymphoblastic Leukemia/Lymphoma with t(v;11q23.3); KMT2A-Rearranged
B-Lymphoblastic Leukemia/Lymphoma with t(12;21)(p13.2;q22.1); ETV6:RUNX1
B-Lymphoblastic Leukemia/Lymphoma with Hyperdiploidy
B-Lymphoblastic Leukemia/Lymphoma with Hypodiploidy
B-Lymphoblastic Leukemia/Lymphoma with t(5;14)(q31.1;q32.1); IGH/IL3
B-Lymphoblastic Leukemia/Lymphoma with t(1;19)(q23;p13.3); TCF3::PBX1
B-Lymphoblastic Leukemia/Lymphoma, BCR::ABL1–Like (Ph-Like ALL)
B-Lymphoblastic Leukemia/Lymphoma with iAMP21
Emerging Subtypes
Hairy Cell Leukemia (HCL)
Other Mature B-Cell Leukemias
T lymphoblastic Leukemia (T-ALL)/Lymphoma (T-LBL)
Early T-Cell Precursor Lymphoblastic Leukemia (ETP-ALL)
Mature T- and NK-Cell Leukemias
T-Cell Prolymphocytic Leukemia
T-Cell Large Granular Lymphocytic Leukemia
Chronic Lymphoproliferative Disorder of NK Cells (CLPD-NK)
Aggressive NK-Cell Leukemia
Adult T-Cell Leukemia/Lymphoma
Mycosis Fungoides (MF)/Sézary Syndrome (SS)
Acute Leukemias of Ambiguous Lineage
Acute Undifferentiated Leukemia
Mixed Phenotype Acute Leukemia (MPAL)
MixedPhenotype Acute Leukemia with t(9;22)(q34.1;q11.2); BCR::ABL1
MixedPhenotype Acute Leukemia with t(v;11q23.3); KMT2A-Rearranged
MixedPhenotype Acute Leukemia, B/Myeloid
Mixed Phenotype Acute Leukemia, T/Myeloid
Mixed Phenotype Acute Leukemia, NOS
Acute Leukemias of Ambiguous Lineage, NOS
Suggested Triage and Workup of Leukemia Specimens
Flow Cytometry
Fluorescence In Situ Hybridization (FISH)
Conventional Cytogenetics
Molecular DNA/RNA Assays
Common Assays
BCR::ABL1
PML-RARA
Ph-Like
FLT3/NPM1
IDH1/2 Mutations
Clonality Studies: T- and B-Cell
Massively Parallel (Next-Generation) Sequencing Gene Panels
Suggested Reading
Index