Diagnostic Pathology: Molecular Oncology, 3rd Edition

This expert volume in the Diagnostic Pathology series is an excellent point-of-care resource for practitioners at all levels of experience and training. Providing a clear understanding of molecular pathology as it relates to the transformation and pathogenesis of cancer in an era of personalized medicine, it incorporates the most recent scientific and technical knowledge in the field to provide a comprehensive overview of all key issues relevant to today’s practice. Richly illustrated and easy to use, the third edition of Diagnostic Pathology: Molecular Oncology is a visually stunning, one-stop resource for every practicing pathologist, hematopathologist, molecular pathologist, oncologist, or pathologist in training as an ideal day-to-day reference or as a reliable learning resource.

• Provides up-to-date, comprehensive coverage of relevant molecular tests and their clinical applications, along with organ-based chapters on the molecular genetic data relevant to individual disease entities
• Contains new chapters and substantial revisions to existing content that include updates from the 2022 International Consensus Classification and the WHO Classification of Haematolymphoid Tumours, fifth edition
• Provides expert guidance on selecting the right test(s) at the right time, as well as comparisons of molecular testing methods (e.g., FISH vs. cytogenetics)
• Includes current information for new actionable mutations and targeted therapies
• Covers ultrasensitive molecular techniques for minimal residual disease detection and disease monitoring
• Discusses circulating cell-free DNA analysis for detection of resistance-associated mutations and disease monitoring, and provides usage details
• Features an image-rich layout with more than 2,400 print and online-only images, including high-resolution H&E stains, immunostains, FISH images, gross pathology and clinical photographs, detailed full-color medical illustrations, and informative diagrams, charts, and schematics
• Employs consistently templated chapters, bulleted content, key facts, a variety of tables, annotated images, pertinent references, and an extensive index for quick, expert reference at the point of care
• Includes an eBook version that enables you to access all text, figures, and references with the ability to search, customize your content, make notes and highlights, and have content read aloud

SECTION 1: INTRODUCTION

4 Structure of Chromosomes and Nucleic Acids

Jeremy C. Wallentine, MD

8 DNA Replication, Transcription, and Translation

Jeremy C. Wallentine, MD

12 Gene Mutations

Jeremy C. Wallentine, MD

SECTION 2: COMMON TECHNIQUES FOR ANALYSIS OF ALTERATIONS IN CHROMOSOMES AND DNA

18 Cytogenetics and FISH

Mohammad A. Vasef, MD and David R. Czuchlewski, MD

22 Chromosomal Microarray

Sibel Kantarci, PhD, Durga Cherukuri, PhD, and

Mohammad A. Vasef, MD

26 Amplification Methods

Devon Chabot-Richards, MD

30 DNA High-Resolution Melting Curve Analysis

Amer Mahmoud, MD, FCAP

32 Sequencing Technologies

Eric Y. Loo, MD and Mohammad A. Vasef, MD

36 High-Throughput Methods in Molecular Pathology

Rama Gullapalli, MD, PhD

38 DNA Methylation Analysis

Devon Chabot-Richards, MD

SECTION 3: MOLECULAR GENETIC TESTS IN HEMATOPOIETIC TUMORS

42 BCR::ABL1 Fusion Gene

Eric Y. Loo, MD and Mohammad A. Vasef, MD

46 PML::RARA Fusion Gene

Devon Chabot-Richards, MD

48 Reverse Transcription PCR for Other Myeloid

Leukemia Transcripts

Kristin Hunt Karner, MD

50 FLT3, NPM1, and CEBPA Mutations

Devon Chabot-Richards, MD

54 JAK2 Mutations and Rearrangements

Mohammad A. Vasef, MD

56 MPL Mutations

Eric Y. Loo, MD and David R. Czuchlewski, MD

58 Calreticulin (CALR) Mutations

Eric Y. Loo, MD and Mohammad A. Vasef, MD

60 CSF3R Mutations

Amer Mahmoud, MD, FCAP

62 SETBP1 Mutations

Amer Mahmoud, MD, FCAP

64 KIT Mutations

Eric Y. Loo, MD and Mohammad A. Vasef, MD

68 IDH1 and IDH2 Mutations

Eric Y. Loo, MD and David R. Czuchlewski, MD

70 Other Mutations and Gene Panel Testing in Myeloid Neoplasms

Mohammad A. Vasef, MD and David R. Czuchlewski, MD

72 Immunoglobulin Heavy (IGH) Chain Gene

Rearrangements

Mohammad A. Vasef, MD and Anna P. Matynia, MD

76 T-Cell Receptor Gamma (TRG) and Delta (TRD) Chain

Rearrangements

Mohammad A. Vasef, MD and Anna P. Matynia, MD

80 T-Cell Receptor Beta (TRB) Chain Gene

Rearrangements

Mohammad A. Vasef, MD and Anna P. Matynia, MD

84 Southern Blot Analysis of Antigen Receptor Genes

Mohammad A. Vasef, MD

86 EBV-Associated Human Neoplasms

Mohammad A. Vasef, MD

94 MYD88 Mutation

Giovanni Insuasti-Beltran, MD

96 NOTCH1 Mutation

Giovanni Insuasti-Beltran, MD

98 EZH2 Mutation

Amer Mahmoud, MD, FCAP

SECTION 4: MOLECULAR GENETIC TESTS IN SOLID TUMORS, BONE AND SOFT TISSUE TUMORS, AND CNS TUMORS

104 ALK Gene Rearrangements and Mutations

Guanghua Wang, MD

106 ROS1 Rearrangements

Mohammad A. Vasef, MD and David R. Czuchlewski, MD

108 RET Rearrangements

Eric Y. Loo, MD and David R. Czuchlewski, MD

110 FISH for MET Amplifications

Devon Chabot-Richards, MD

114 FISH for ERBB2 (HER2) Gene Amplifications

Kristin Hunt Karner, MD

116 KRAS Mutations

Guanghua Wang, MD

118 BRAF Mutations

Yongjie Zhou, MD, PhD and Guanghua Wang, MD

120 EGFR Mutations

Guanghua Wang, MD

122 Targeted Hotspot Gene Panel Using Massively Parallel Sequencing (Next-Generation Sequencing)

Mohammad A. Vasef, MD and David R. Czuchlewski, MD

124 Targeted Hotspot Gene Panel Table

Mohammad A. Vasef, MD and David R. Czuchlewski, MD

130 MGMT Promoter Gene Methylation Assay

Devon Chabot-Richards, MD

SECTION 5: MOLECULAR PATHOLOGY OF MYELOID NEOPLASMS

134 Molecular Work-Up of Myeloid Neoplasms

Mohammad A. Vasef, MD and David R. Czuchlewski, MD

MYELOPROLIFERATIVE NEOPLASMS

136 Clonal Hematopoiesis and Pre-Malignant Clonal Cytopenia

Mohammad A. Vasef, MD

140 Chronic Myeloid Leukemia, BCR-ABL1 Positive

Mohammad A. Vasef, MD, Kaaren K. Reichard, MD, and David R. Czuchlewski, MD

148 Chronic Neutrophilic Leukemia

Devon Chabot-Richards, MD and David R. Czuchlewski, MD

152 Polycythemia Vera

Mohammad A. Vasef, MD and M. Carmen Frias Kletecka, MD

156 Primary Myelofibrosis

Devon Chabot-Richards, MD and Kaaren K. Reichard, MD

160 Essential Thrombocythemia

Giovanni Insuasti-Beltran, MD

164 Chronic Eosinophilic Leukemia, NOS

Devon Chabot-Richards, MD and Kaaren K. Reichard, MD

166 Myeloproliferative Neoplasms, Unclassifiable

Devon Chabot-Richards, MD and Kaaren K. Reichard, MD

MASTOCYTOSIS

170 Mastocytosis

Mohammad A. Vasef, MD

MYELOID/LYMPHOID NEOPLASMS WITH EOSINOPHILIA AND GENE REARRANGEMENT

178 Myeloid/Lymphoid Neoplasms With Eosinophilia and Gene Rearrangement

Devon Chabot-Richards, MD and David R. Czuchlewski, MD

MYELODYSPLASTIC SYNDROME (MDS)

182 Overview and Classification of Myelodysplastic Syndrome

Devon Chabot-Richards, MD, David R. Czuchlewski, MD, and Carla S. Wilson, MD, PhD

186 Myelodysplastic Syndromes With Single-Lineage Dysplasia

Kristin Hunt Karner, MD

190 Myelodysplastic Syndrome With Ring Sideroblasts

Mohammad A. Vasef, MD and Carla S. Wilson, MD, PhD

194 Myelodysplastic Syndrome With Multilineage Dysplasia

Kristin Hunt Karner, MD

198 Myelodysplastic Syndrome With Isolated del(5q)

Giovanni Insuasti-Beltran, MD

202 Myelodysplastic Syndrome, Unclassifiable

Kristin Hunt Karner, MD

206 Childhood Myelodysplastic Syndrome and Refractory Cytopenia of Childhood

Devon Chabot-Richards, MD and Carla S. Wilson, MD, PhD

MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS

212 Overview of Myelodysplastic/Myeloproliferative Neoplasms

Devon Chabot-Richards, MD

214 Chronic Myelomonocytic Leukemia

Kristin Hunt Karner, MD

218 Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative

Devon Chabot-Richards, MD

222 Juvenile Myelomonocytic Leukemia

Devon Chabot-Richards, MD and Qian-Yun Zhang, MD, PhD

224 Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

Devon Chabot-Richards, MD and Kathryn Foucar, MD

ACUTE MYELOID LEUKEMIA

228 Overview of Acute Myeloid Leukemia

Mohammad A. Vasef, MD and Kaaren K. Reichard, MD

236 Acute Myeloid Leukemia With t(8;21); RUNX1-RUNX1T1

Devon Chabot-Richards, MD, Kaaren K. Reichard, MD, and David R. Czuchlewski, MD

240 Acute Myeloid Leukemia With inv(16) or t(16;16); CBFB-MYH11

Devon Chabot-Richards, MD, Kaaren K. Reichard, MD, and David R. Czuchlewski, MD

244 Acute Promyelocytic Leukemia With t(15;17); PMLRARA

Mohammad A. Vasef, MD

250 Acute Myeloid Leukemia With t(9;11); MLLT3-KMT2A

Devon Chabot-Richards, MD, Kaaren K. Reichard, MD, and David R. Czuchlewski, MD

254 Acute Myeloid Leukemia With t(6:9); DEK-NUP214

Eric Y. Loo, MD and David R. Czuchlewski, MD

256 Acute Myeloid Leukemia With inv(3) or t(3;3); GATA2, MECOM

Eric Y. Loo, MD and David R. Czuchlewski, MD

258 Acute Myeloid Leukemia (Megakaryoblastic) With t(1;22); RBM15-MRTFA

Eric Y. Loo, MD and David R. Czuchlewski, MD

260 Acute Myeloid Leukemia With Myelodysplasia-

Related Changes

Mohammad A. Vasef, MD, David R. Czuchlewski, MD, and Kathryn Foucar, MD

262 Acute Myeloid Leukemia, NOS

Kristin Hunt Karner, MD

268 Therapy-Related Myeloid Neoplasms

Mohammad A. Vasef, MD and Kathryn Foucar, MD

274 Myeloid Sarcoma

Devon Chabot-Richards, MD

278 Myeloid Proliferations Associated With Down Syndrome

Eric Y. Loo, MD and David R. Czuchlewski, MD

BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM

282 Blastic Plasmacytoid Dendritic Cell Neoplasm

Mohammad A. Vasef, MD

SECTION 6: MOLECULAR PATHOLOGY OF LYMPHOID NEOPLASMS

290 Overview of Lymphoid Neoplasms

Nadine Aguilera, MD

294 Molecular Work-Up of Lymphoid Neoplasms

Mohammad A. Vasef, MD and David R. Czuchlewski, MD

DETERMINATION OF CLONALITY IN B-, T-, AND NK-CELL NEOPLASMS

296 Lymphoma-Associated Chromosomal Translocations

Kristin Hunt Karner, MD

PRECURSOR LYMPHOID NEOPLASMS

300 B-Lymphoblastic Leukemia/Lymphoma With Recurrent Genetic Abnormalities

Kristin Hunt Karner, MD

304 B-Lymphoblastic Leukemia/Lymphoma, BCR-ABL1- Like (Ph-Like ALL)

Joanna L. Conant, MD and Mohammad A. Vasef, MD

308 T-Lymphoblastic Leukemia/Lymphoma

Mohammad A. Vasef, MD

MATURE B-CELL NEOPLASMS

314 Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia

Devon Chabot-Richards, MD

320 B-Cell Prolymphocytic Leukemia

Aaron Auerbach, MD, MPH

324 Splenic Marginal Zone Lymphoma

Aaron Auerbach, MD, MPH and Roberto N. Miranda, MD

330 Hairy Cell Leukemia

Mohammad A. Vasef, MD

334 Splenic B-Cell Lymphoma/Leukemia, Unclassifiable

Nadine Aguilera, MD

340 Lymphoplasmacytic Lymphoma

Aaron Auerbach, MD, MPH

346 Monoclonal Gammopathy of Undetermined Significance

Nadine Aguilera, MD

350 Plasma Cell Myeloma

Nadine Aguilera, MD and Carla S. Wilson, MD, PhD

358 Follicular Lymphoma

Aaron Auerbach, MD, MPH and C. Cameron Yin, MD, PhD

364 Mantle Cell Lymphoma

Aaron Auerbach, MD, MPH

370 Diffuse Large B-Cell Lymphoma

Nadine Aguilera, MD

380 Burkitt Lymphoma

Aaron Auerbach, MD, MPH and Carlos Bueso-Ramos, MD, PhD

MATURE T- AND NK-CELL NEOPLASMS

388 T-Cell Prolymphocytic Leukemia

Nadine Aguilera, MD

392 NK-Cell Large Granular Lymphocytic Leukemia

Nadine Aguilera, MD

396 Aggressive NK-Cell Leukemia

Nadine Aguilera, MD

400 Extranodal NK-/T-Cell Lymphoma, Nasal Type

Aaron Auerbach, MD, MPH and L. Jeffrey Medeiros, MD

404 Adult T-Cell Leukemia/Lymphoma

Nadine Aguilera, MD

410 Intestinal T-Cell Lymphoma

Aaron Auerbach, MD, MPH and Sa A. Wang, MD

416 Hepatosplenic T-Cell Lymphoma

Aaron Auerbach, MD, MPH and Roberto N. Miranda, MD

420 Subcutaneous Panniculitis-Like T-Cell Lymphoma

Aaron Auerbach, MD, MPH

424 Mycosis Fungoides/Sézary Syndrome

Aaron Auerbach, MD, MPH and Sa A. Wang, MD

428 Primary Cutaneous CD30-Positive T-Cell

Lymphoproliferative Disorders

Aaron Auerbach, MD, MPH

432 Peripheral T-Cell Lymphoma, NOS

Aaron Auerbach, MD, MPH

438 Angioimmunoblastic T-Cell Lymphoma

Aaron Auerbach, MD, MPH

444 Anaplastic Large Cell Lymphoma, ALK Negative

Mohammad A. Vasef, MD

450 Anaplastic Large Cell Lymphoma, ALK Positive

Mohammad A. Vasef, MD

SECTION 7: MOLECULAR PATHOLOGY OF DENDRITIC CELL AND HISTIOCYTIC NEOPLASMS

458 Histiocytic Sarcoma

Nadine Aguilera, MD

466 Tumors Derived From Langerhans Cells

Guanghua Wang, MD

472 Interdigitating Dendritic Cell Tumor

Aaron Auerbach, MD, MPH and Sa A. Wang, MD

476 Follicular Dendritic Cell Neoplasm

Aaron Auerbach, MD, MPH

SECTION 8: MOLECULAR PATHOLOGY OF SOLID TUMORS HEAD AND NECK, INCLUDING SINONASAL TUMORS AND SALIVARY GLANDS

482 HPV-Associated Head and Neck Carcinomas

Thèrése Bocklage, MD

488 Head and Neck Mucosal Squamous Cell Carcinoma, Non-HPV Related

Thèrése Bocklage, MD

494 Important Alterations in Non-HPV-Related Head and

Neck Squamous Cell Carcinoma

Thèrése Bocklage, MD

496 Translocation-Specific Salivary Gland Tumors 1

Thèrése Bocklage, MD

504 Translocation-Specific Salivary Gland Tumors 2

Thèrése Bocklage, MD

512 Nasopharyngeal EBV-Related Squamous Cell Carcinoma

Thèrése Bocklage, MD

516 Other Head and Neck Tumors

Thèrése Bocklage, MD

THYROID

524 Papillary Thyroid Carcinoma

Giovanni Insuasti-Beltran, MD

528 Follicular Thyroid Carcinoma

Giovanni Insuasti-Beltran, MD

532 Poorly Differentiated Thyroid Carcinoma

Von Samedi, MD, PhD

536 Undifferentiated Thyroid Carcinoma

Von Samedi, MD, PhD

540 Medullary Thyroid Carcinoma

Giovanni Insuasti-Beltran, MD

LUNG546 Adenocarcinoma, Lung

Jeremy C. Wallentine, MD

554 Squamous Cell Carcinoma, Lung

Jeremy C. Wallentine, MD

558 Small Cell Neuroendocrine Carcinoma

Samuel Reynolds, MD

562 Mesothelioma

Mohammad A. Vasef, MD

LUMINAL GASTROINTESTINAL TRACT

564 Gastric Adenocarcinoma

Joshua Anspach Hanson, MD

568 Colorectal Adenocarcinoma and Precancerous Lesions

Joshua Anspach Hanson, MD

574 Gastrointestinal Stromal Tumor

Joshua Anspach Hanson, MD

LIVER582 HNF1a-Inactivated Hepatocellular Adenoma

Joshua Anspach Hanson, MD

586 ß-Catenin-Activated Hepatocellular Adenoma

Joshua Anspach Hanson, MD

590 Inflammatory Hepatocellular Adenoma

Joshua Anspach Hanson, MD

594 Hepatocellular Carcinoma

Rama Gullapalli, MD, PhD

PANCREATICOBILIARY

598 Pancreatic Ductal Adenocarcinoma

Von Samedi, MD, PhD

602 Pancreatic Mucinous Cystic Neoplasm

Von Samedi, MD, PhD

604 Pancreatic Intraductal Papillary Mucinous Neoplasm

Von Samedi, MD, PhD

606 Cholangiocarcinoma

Rama Gullapalli, MD, PhD

TESTIS

608 Testicular Germ Cell Tumors

Edgar Fischer, MD, PhD

KIDNEY

614 Clear Cell Renal Cell Carcinoma

Edgar Fischer, MD, PhD

618 Chromophobe Renal Cell Carcinoma

Edgar Fischer, MD, PhD

620 Papillary Renal Cell Carcinoma

Edgar Fischer, MD, PhD

622 TFE3-Rearranged and TFEB-Altered Renal Cell Carcinomas

Edgar Fischer, MD, PhD

626 Wilms Tumor

Marc Barry, MD

632 Clear Cell Sarcoma of Kidney

Marc Barry, MD

634 Oncocytoma

Marc Barry, MD

636 Rhabdoid Tumor of Kidney

Marc Barry, MD

BLADDER638 Urothelial Carcinoma

Marc Barry, MD

ADRENAL644 Pheochromocytoma/Paraganglioma

Samuel Reynolds, MD

650 Adrenal Cortical Carcinoma

Samuel Reynolds, MD

656 Neuroblastoma

Samuel Reynolds, MD, Thèrése Bocklage, MD, and Giovanni Insuasti-Beltran, MD

664 Adrenal Cortical Adenoma

Samuel Reynolds, MD

PROSTATE

668 Prostatic Adenocarcinoma, Acinar Type and High-Grade Prostatic Intraepithelial Neoplasia

Edgar Fischer, MD, PhD

BREAST

672 ADH and DCIS (Dysplastic, Premalignant)

David G. Hicks, MD

678 Ductal Carcinomas

David G. Hicks, MD

684 Lobular Carcinoma

David G. Hicks, MD

690 Carcinoma With Medullary Features, Breast

Rania Bakkar, MD

696 Metaplastic Breast Carcinoma

Rania Bakkar, MD

702 Phyllodes Tumors

Rania Bakkar, MD

708 Basal-Like and Triple-Negative Carcinomas

David G. Hicks, MD and Susan C. Lester, MD, PhD

CERVIX/VULVA/VAGINA

718 Preneoplastic Conditions, Cervix/Vulva/Vagina

Nancy Joste, MD

722 Squamous Cell Carcinoma, Cervix/Vulva/Vagina

Nancy Joste, MD

726 Adenocarcinoma, Cervix/Vulva/Vagina

Nancy Joste, MD

UTERUS730 Endometrial Intraepithelial Neoplasia

Lesley Lomo, MD

732 Uterine Endometrioid Carcinoma

Lesley Lomo, MD

736 Uterine Serous Carcinoma

Lesley Lomo, MD

738 Clear Cell Carcinoma, Uterus

Lesley Lomo, MD

742 Uterine Sarcomas

Thèrése Bocklage, MD

OVARIES/FALLOPIAN TUBE

750 Serous Tumors of Ovary and Fallopian Tube

Rania Bakkar, MD

756 Other Surface Epithelial Tumors of Ovary

Rania Bakkar, MD

762 Sex Cord-Stromal Tumors of Ovary

Rania Bakkar, MD

768 Germ Cell Tumor, Ovary

Aaron Auerbach, MD, MPH

SKIN

772 Preneoplastic Conditions, Skin

David Cassarino, MD, PhD

776 Melanoma

David Cassarino, MD, PhD

780 Squamous Cell Carcinoma, Skin

David Cassarino, MD, PhD

784 Basal Cell Carcinoma, Skin

David Cassarino, MD, PhD

788 Other Skin Conditions

David Cassarino, MD, PhD

BONE

792 Overview of Molecular Pathology of Bone and Soft Tissue Tumors

Thèrése Bocklage, MD

798 Osteosarcomas

Thèrése Bocklage, MD

806 Ewing Sarcoma

Thèrése Bocklage, MD

812 Other Small Round Blue Cell Sarcomas

Thèrése Bocklage, MD

818 Giant Cell Tumor of Bone

Thèrése Bocklage, MD

824 Intermediate and Malignant Cartilaginous Tumors of Bone

Thèrése Bocklage, MD

SOFT TISSUE834 Intermediate and Malignant Myofibroblastic/Fibroblastic Tumors

Thèrése Bocklage, MD

844 Liposarcomas

Thèrése Bocklage, MD

854 Muscle Sarcomas

Thèrése Bocklage, MD

864 Intermediate and Malignant Vascular Tumors

Thèrése Bocklage, MD

872 Malignant Peripheral Nerve Sheath Tumor

Thèrése Bocklage, MD and David R. Lucas, MD

878 Representative Genetic Findings in Bone and Soft Tissue Tumors

Thèrése Bocklage, MD

SARCOMAS OF UNCERTAIN DIFFERENTIATION

884 Rare Sarcomas of Uncertain Differentiation With Specific Molecular Alterations

Thèrése Bocklage, MD

CNS

894 Glioblastoma, IDH Wild Type

Mohammad A. Vasef, MD, Karen SantaCruz, MD, and Elisabeth Rushing, MD

898 Astrocytoma, IDH Mutant

Elisabeth Rushing, MD and Karen SantaCruz, MD

902 Pilocytic Astrocytoma

Aaron Auerbach, MD, MPH, Karen SantaCruz, MD, and Elisabeth Rushing, MD

906 Oligodendroglioma, IDH Mutant, and 1p/19q Codeleted

Aaron Auerbach, MD, MPH, Karen SantaCruz, MD, and Elisabeth Rushing, MD

910 Ependymoma

Fausto J. Rodríguez, MD

916 Medulloblastoma

Fausto J. Rodríguez, MD

922 Choroid Plexus Tumors

Fausto J. Rodríguez, MD

926 Meningioma

Karen SantaCruz, MD

930 Retinoblastoma

Fausto J. Rodríguez, MD

SECTION 9: QUALITY ASSURANCE AND REGULATORY ISSUES

936 Federal Agencies and Regulation of Laboratories

Amer Mahmoud, MD, FCAP

938 FDA Regulations

Yongjie Zhou, MD, PhD

944 Proficiency Testing and Accreditation

Amer Mahmoud, MD, FCAP