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Non-NeoplasticHematopathologyand Infections

NON-NEOPLASTICHEMATOPATHOLOGYAND INFECTIONSHernani D. CualingDepartment of Pathology and Cell BiologyUniversity of South Florida, College of Medicine

Parul BhargavaIsrael Deaconess Medical Center

Ramon L. SandinDepartment of Hematopathology and Laboratory Medicine:Clinical Microbiology & Virology, Moffitt Cancer Center

A John Wiley & Sons, Inc., Publication

Copyright © 2012 Wiley-Blackwell, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

ISBN: 9780470646007

Printed in Singapore

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I dedicate this book to my beloved family: Rawia, Kareem, Phillip, and Andrew; to my teachersand students; and to my native and adopted country, the Philippines and USA.

Hernani D. Cualing, MD

To my hematology gurus Dr A Bagg, Dr M Kadin, Dr T Singh and my students for the inspirationand to my husband Pankaj, my daughters Kaveri & Kimya for their unyielding

support through the perspiration.

Parul Bhargava, MD

To Mayra, my wife, and Beatriz, my daughter, who constitute the pillarsof inspiration and strength in my life!

Ramon L. Sandin, MD

CONTENTS

Contributors, xixForeword, xxiiiPreface, xxvAcknowledgments, xxviiIntroduction, xxix

PART I Non-neoplastic Hematology 1

CHAPTER ONENon-neoplastic Disorders of White BloodCells 3

Rebecca A. Levy, Vandita P. Johari,and Liron Pantanowitz

Overview of WBC Production and Function, 3Leukocytes, 3

Leukemoid Reaction, 4

Left Shift, 5

Quantitative Disorders of WBCS, 6Disorders of Neutrophils, 6

Disorders of Lymphocytes, 12

Disorders of Plasma Cells, 16

Disorders of Monocytes, 16

Disorders of Eosinophils, 18

Disorders of Basophils, 20

Qualitative Disorders of WBCS, 21Congenital Disorders of Leukocytes, 21

Acquired Disorders of Leukocytes, 26

References, 26

CHAPTER TWONon-neoplastic Disorders of Platelets 31

Lija Joseph

Platelet Production Structureand Function, 31Production, 31

Structure and Function, 31

Quantitative Disorders of Platelets, 33Thrombocytopenia, 33

Thrombocytopenia in Adults, 36

Qualitative Disorders of Platelets, 39Congenital Causes of Defects in Platelet

Function, 39

Acquired Defects in Platelet Function, 41

Laboratory Tests used to Assess PlateletFunction, 41

References, 43

CHAPTER THREEApproach to Disorders of Red Blood Cells 45

Jason C. Ford

Introduction, 45The Anemias, 45

The Complete Blood Count, 46

The MCV Approach to Anemia: Three Lists ofCauses, 46

The Pathogenetic Approach to Anemia: TwoPossible Mechanisms, 47

vii

viii | CONTENTS

Peripheral Smear Morphology: The Most ImportantTest, 49

Poikilocytosis and Its Clinical Associations, 50

The Approach to Anemia, 50The Approach to Microcytic Anemia, 51

The Approach to Normocytic Anemia, 53

The Approach to Hemolysis, 54

The Approach to Macrocytic Anemia, 60

The Polycythemias, 63References, 63

CHAPTER FOURMicrocytic, Normocytic, and MacrocyticAnemias 65

Reza Setoodeh and Loveleen C. Kang

Microcytic Anemias, 65Iron Deficiency Anemia (IDA), 66

Anemia of Chronic Disease (ACD), 68

Thalassemia, 70

Sideroblastic Anemia, 72

Lead Poisoning, 74

Normocytic Anemias, 74Hemolytic Anemia, 75

Enzymopathies, 77

Acquired Membrane Defect, 79

Extracorpuscula Defects, 80

Nonhemolytic Normocytic Anemia, 81

Macrocytic Anemias, 81Megaloblastic Anemia, 82

Nonmegaloblastic Macrocytic Anemia, 85

References, 86

CHAPTER FIVEDisorders of Hemoglobin 89

Parul Bhargava

Overview, 89Historical Background, 89

Structure, 89

Synthesis, 89

Genetics, 89

Quantitative Disorders of Hemoglobin, 89Alpha Thalassemia, 89

Beta Thalassemia, 93

Delta Thalassemia, 94

Gamma Thalassemia, 95

Delta-Beta Thalassemias, 95

Hereditary Persistence of Fetal Hemoglobin, 96

Qualitative Disorders of Hemoglobin, 97Hemoglobin S, 97

Hemoglobin C, 98

Hemoglobin E, 100

Hemoglobin D, 101

Mixed–Quantitative Qualitative Disorders ofHemoglobin, 104

Double Heterozygous States, 105Thalassemia-Hemoglobinopathy, 105

Hemoglobinopathy—Hemoglobinopathy DoubleHeterozygosity, 105

Thalassemia—Thalassemia DoubleHeterozygosity, 105

Approach to Diagnosis of HemoglobinDisorders, 106Lab Diagnosis of Thalassemias, 106

Lab Diagnosis of Hemoglobinopathies, 107

Additional Laboratory Testing Methods in theEvaluation of Hemoglobinopathies, 110

References, 111

PART II Infectious Aspects ofHematology 113

CHAPTER SIXApicomplexal Parasites of PeripheralBlood, Bone Marrow, and Spleen: TheGenera Plasmodium, Babesia, andToxoplasma 115

Lynne S. Garcia

Plasmodium, 115Life Cycle, 115

Epidemiology, 116

Clinical Disease, 118

Pathophysiology, 118

Diagnosis, 122

Treatment and Drug Resistance, 125

Drug and Vaccine Development, 125

Babesia, 125Life Cycle, 126

Epidemiology, 126


CONTENTS | ix


Diagnosis, 127

Treatment, 127

Toxoplasma, 128Life Cycle, 128

Epidemiology, 129



Diagnosis, 131

Evaluation, Interpretation, and ResultReporting, 134

Treatment, 134

References, 134

CHAPTER SEVENBlood and Tissue Flagellates of the ClassKinetoplastidea: The Genera Leishmaniaand Trypanosoma 139

Raul E. Villanueva and Stephen D. Allen

Leishmaniasis, 139Life Cycle, 139

Epidemiology, 139

Clinical Syndromes, 140

Differential Diagnosis, 142

Diagnosis, 142

Therapy, 145

Chagas’ Disease, 145Life Cycle, 145

Epidemiology, 146



Diagnosis, 148

Therapy, 149

African Trypanosomiasis, 150Life Cycle, 150

Epidemiology, 150



Diagnosis, 153

Therapy, 155

References, 155

CHAPTER EIGHTProteobacteria and Rickettsial Agents:Human Granulocytic Anaplasmosis andHuman Monocytic Ehrlichiosis 159

Sheldon Campbell and Tal Oren

Microbiology and Epidemiology of HGA andHME, 159

Clinical Syndromes, 160Differential Diagnosis, 160Diagnostic Approach, 161Prevention and Treatment, 163References, 163

CHAPTER NINEClinically Significant Fungal Yeasts 165

Ramon L. Sandin

Introduction, 165Histoplasma capsulatum var. capsulatum

(H. capsulatum), 166Definition, 166

Synonyms, 167

Epidemiology, 167

Clinical Aspects and Pathophysiology, 167


Treatment of Choice and Prognosis, 168

Approach to Diagnosis, 168

Newer Diagnostic Modalities, 169

Blastomyces dermatitidis, 170Definition, 171

Synonyms, 171

Epidemiology, 171





Coccidioides immitis, 174Definition, 174

Synonyms, 174

Epidemiology, 174



x | CONTENTS



Cryptococcus neoformans, 178Definition, 178

Synonyms, 178

Epidemiology, 178





Candida albicans and other Candida Species, 183Definition, 184

Synonyms, 185

Epidemiology, 185





Malassezia furfur, 188Definition, 188

Synonyms, 188

Epidemiology, 188





References, 193

CHAPTER TENHematologic Aspects of Tropical Infections 195

Deniz Peker

Anemia in Tropical Infections, 195Malaria, 195

Babesiosis, 196

Visceral Leishmaniasis (Kala-Azar), 197

Trypanosomiasis, 197

Amoebiasis, 198

Giardiasis, 198

Tuberculosis, 198

Human Immune Deficiency Virus, 199

Hookworms, 200

Schistosomiasis, 201

Trichuriasis, 202

Vascular Purpuras, 202Viral Hemorrhagic Fever—Yellow Fever, 202

Defective Platelet Function—Lassa Fever, 203

References, 203

PART III Non-neoplastic Lymph NodePathology and Infections 205

CHAPTER ELEVENClassification of ReactiveLymphadenopathy 207

Hernani D. Cualing

Introduction, 207Definition, 209

Synonyms, 209

Epidemiology, 210

Processing of a Lymph Node, 211

Gross Appearance, 212

Morphologic Approach, 214

Normal Lymph Node Histology, 216

Patterns of Reactions, 224

References, 229

CHAPTER TWELVELymph Node Biology, Markers and Disease 231

Hernani D. Cualing

Peripheral Lymphoid Tissue, 231Pathophysiology, 231Cortex, 232

Generation of Germinal Centers, 232

Cytology, 232

Immunophenotypic Markers, 235

Mantle Zones, 237

Monocytoid B Cell and Marginal ZonesB Cells, 237

Germinal Center T Cells, 239

Follicular Dendritic Cells, 239

Paracortex, 240T-Cell Reaction, 240

Perivenular Sinus, 240

Dendritic Cells, 241

Pathogens and Dendritic Cells, 241

NK Cells, 241

Plasmacytoid Dendritic Cells, 241

CONTENTS | xi

Sinus Histiocytes, 242Foamy Histiocytosis, 242

Signet Ring Histiocytosis, 242

Pigmented Histiocytes, 242

Parasitophorous Vacuoles, 242

Epithelioid Histiocytesand Granulomas, 243

Nodal Framework, 243The Composite Nodule and Extranodular

Compartment Concept, 243

Transformation in Extranodule, 243

Granulomas, 244

Extranodal or Ectopic LymphoidTissue, 245

References, 246

CHAPTER THIRTEENLymphadenopathy with PredominantFollicular Patterns 249

Shohreh Iravani Dickinson, Jun Mo, andHernani D. Cualing

Germinal Center Hyperplasia, 249Florid Follicular Hyperplasia, Nonspecific, 249

Immunophenotyping, 252

Regressive Transformation of Germinal Center(Atrophic) Pattern, 256Castleman’s Hyaline Vascular Pattern, 256

Immunophenotyping/Cytochemistry, 262

Atrophic Follicular or Germinal Center Pattern inPrimary Immunodeficiency Diseases, 265

Progressive Transformation of Germinal CenterPattern, 267

Marginal Zone Hyperplasia and Mantle CellHyperplasia, 273Mantle Cell Hyperplasia, 273

Marginal Zone Pattern, 274

Reactive Follicular Pattern, Mixed with OtherPatterns, Specific Entities, 276HIV-Persistent Generalized Lymphadenopathy and

Involuted Phase of HIV-RelatedLymphadenopathy, 276

Regressed (Atrophic) Germinal CentersPattern, 277

Mixed Pattern with Follicular Hyperplasia,Microgranulomas, MonocytoidHyperplasia, 278

Toxoplasmic Lymphadenopathy, 278

Follicular Hyperplasia with Capsular Fibrosisand Plasmacytosis-Syphilis, 282

References, 284

CHAPTER FOURTEENReactive Lymphadenopathy withParacortical Pattern, NoninfectiousEtiology 291

Ling Zhang and Jeremy W. Bowers

Paracortical Hyperplasia, 291Definitions, 291

Synonyms, 292

Epidemiology, 292

Clinical Aspects, 293


Dermatopathic Lymphadenopathy, 297Definition, 297

Synonyms, 297

Epidemiology, 297



Morphologic Aspects, 298

Reactive ImmunoblasticProliferation, 301Definition, 301

Synonyms, 301

Epidemiology, 301



Postvaccinal Lymphadenitis, 307Definition, 307

Synonyms, 307

Epidemiology, 307



Drug-Induced Lymphadenopathy, 309Anticonvulsant (Phenytoin)-Related

Lymphoproliferative Disorder, 309Definition, 309

Synonyms, 309

Epidemiology, 310



xii | CONTENTS

Methotrexate-Related LymphoproliferativeDisorder, 312Definition, 312

Epidemiology, 312



References, 315

CHAPTER FIFTEENReactive Lymphadenopathy with DiffuseParacortical Pattern—Infectious Etiology 323

Jeremy W. Bowers and Ling Zhang

Introduction, 323Infectious Mononucleosis

Lymphadenitis, 323Definition, 323

Synonyms, 324

Epidemiology, 324


Pathogenesis, 326


Cytomegalovirus Lymphadenitis, 329Definition, 329

Synonyms, 329

Epidemiology, 329


Pathogenesis, 331


Herpes Simplex Virus Lymphadenitis, 333Definition, 333

Synonym, 333

Epidemiology, 333


Pathogenesis, 334


Varicella Zoster Lymphadenitis, 337Definition, 337

Synonyms, 337

Epidemiology, 337


Pathogenesis, 338


References, 340

CHAPTER SIXTEENReactive Lymphadenopathy with SinusPattern 347

Hernani D. Cualing

Sinuses and Vascular Supply, 347Sinus Histiocytosis, Nonspecific, 347

Definition, 348

Synonym, 348

Incidence, 348

Normal Histology and Function, 348

Relation to Cancer and Sinus HistiocytosisGrading, 349

Immunohistochemistry, 350

Special Types of Sinus Reaction, 350

Differential Diagnosis of Sinus Histiocytosis, 351

Signet Ring Histiocytosis, 354Definition, 354

Incidence, 354

Histology, 354

Cytochemistry/Immunohistochemistry, 355


Sinus Histiocytosis with MassiveLymphadenopathy (or Rosai–DorfmanDisease), 355Definition, 355

Synonyms, 355

Epidemiology, 355

Etiology, 355

Pathogenesis, 355


Immunohistochemistry/Cytochemistry, 356



Pigmented Sinus Histiocytic Pattern Secondary toIron Overload from Hemochromatosis,Transfusion, or Hemolysis, 357Definition, 357

Epidemiology, 357

Pathogenesis, 358

Clinical Features, 358


Treatment, 359

Histiocytic Reaction to Foreign Matter, 359

CONTENTS | xiii

Definition, 359

Lymphangiographic Effect, 359

Morphology, 359


Hip Replacement Adenopathy, 360

Sinus Pattern from ExtramedullaryHematopoiesis, 361Definition, 361

Epidemiology, 361

Etiology, 361


Morphology, 362


Immunohistochemistry, 363

Treatment, 363

Immature ‘‘Sinus Histiocytosis’’ or MonocytoidB-Cell Hyperplasia, 363Location of Marginal Zone Cells, 363

Location of Monocytoid B Cells (MBCs), 364


Relationship of MBCs and Marginal ZoneHyperplasia, 364

Reactive Hemophagocytic Syndromes, 365Definition, 365

Synonyms, 365

Etiology, 365

Morphology, 365

Pathogenesis, 365

Vascular Transformation of Sinuses (VTS), 366Definition, 366

Synonyms, 366

Epidemiology, 366

Etiology, 366



Sites of Involvement, 366






Whipple’s Disease (WD) Lymphadenopathy, 368Definition, 368

Synonyms, 368

Epidemiology and Geolocation, 368

Etiology, 369

Pathogenesis, 369








References, 370

CHAPTER SEVENTEENMixed Lymph Node Patterns: Stromal andHistiocytic Reactions, NonInfectious 375

Hernani D. Cualing

Proteinaceous Lymphadenopathy IncludingImmunoglobulin DepositionLymphadenopathy, 375Definition, 375

Synonyms, 375

Etiology, 375

Morphology, 375



Treatment, 377

Lymph Node Fibrosis or Fibrotic Changes,Nonspecific, 377Definition, 377


Pathogenesis, 377

Morphology, 378


Treatment, 378

Inflammatory Pseudotumor of LymphNodes, 379Definition, 379

Synonyms, 379

Etiology, 379

Laboratory Findings, 380






xiv | CONTENTS


Fatty Replacement or Fatty Changes,Nonspecific, 383Definition, 383

Synonyms, 383

Etiology, 383




Tumor Reactive Granulomatas, 384Definition, 384

Synonym, 384

Epidemiology, 384

Clinical Associations, 384

Morphology, 384


Treatment, 386

References, 386

CHAPTER EIGHTEENMixed Lymph Node Patterns: IncludingGranulomatous Lymphadenopathy,Noninfectious 389

Xiaohui Zhang and Hernani D. Cualing

Mixed Pattern with Follicular Hyperplasia andEosinophilia, 389Kimura’s Disease, 389

Allergic Granulomatosis/Churg–StraussSyndrome, 393

Mixed Nonnecrotizing ‘‘Dry’’ Granulomas, 396Sarcoidosis, 396

Berylliosis, 401

Crohn’s Disease, 401

Primary Biliary Cirrhosis, 402

Mixed Pattern with Hemorrhage andInfarction, 404Fine Needle Associated Changes, 404

Lymph Node Infarction, 405

Mixed Necrotizing Pattern with No or MinimalGranulomas, 406Lupus Erythematosus, 406

Kawasaki’s Disease, 409

Necrotizing Nonsuppurative Granulomatas, 410Kikuchi–Fujimoto’s Lymphadenitis/Kikuchi

Disease, 410

Necrotizing Suppurative Granulomatas, 413Chronic Granulomatous Disease of Children, 413

Granulomatous Change within GerminalCenters, 415Henoch–Schonlein Purpura, 415

Children with Shock or Bacteremia, 417

Mixed Pattern with Plasmacytosis, 418Rheumatoid Arthritis Lymphadenopathy, 418

Plasma Cell (Mott Cell) Granuloma, 419

References, 420

CHAPTER NINETEENMixed Patterns in Lymph Node,Suppurative Necrotizing GranulomatousInfectious Lymphadenopathy 427

Hernani D. Cualing and Gary Hellerman

Cat-Scratch Disease, 427Definition, 427

Synonyms, 427

Epidemiology, 427

Etiology, 428



Diagnosis, 428

Laboratory Findings, 428

Morphology, 428



Course and Prognosis, 431

Tularemia, 431Definition, 431

Synonyms, 431

Epidemiology, 431

Etiology, 431



Lymphogranuloma venereum, 433Definition, 433

Synonyms, 433

Epidemiology, 433

Etiology, 433

Pathogenesis, 433

Sites of Infection, 433


CONTENTS | xv

Treatment, 434

Chancroid, H. ducreyi, 434Definition, 434

Synonyms, 434

Epidemiology, 434

Etiology, 434


Site of Infection, 435

Treatment, 435

Yersinia enterocolitica/pseudotuberculosisLymphadenitis, 435Definition, 436

Synonyms, 436

Epidemiology, 436

Etiology, 436


Site of Infection, 436



Treatment and Prognosis, 437

Brucellosis, 437Definition, 437

Synonyms, 437

Epidemiology, 438

Etiology, 438

Pathogenesis, 438



Treatment and Prognosis, 439

Melioidosis, 439Definition, 439

Synonyms, 440

Epidemiology, 440

Etiology, 440

Pathogenesis, 440





Typhoid Lymphadenitis (Salmonella typhi), 442Definition, 442

Synonyms, 442

Epidemiology, 442

Etiology, 443

Pathogenesis, 443



Treatment, 444

References, 444

CHAPTER TWENTYMixed Patterns: Emergent/TropicalInfections with CharacterizedLymphadenopathy 447

Hernani D. Cualing

Mixed Pattern with Granulomatas and DiagnosticMicroorganisms, 447Filariasis, 447

Lymphadenopathy Secondary to LocalizedFilariasis, 449Dirofilaria spp. in Subcutaneous Lymph Node, 449

Bancroftian spp. Lymphadenopathy, 451

Brugia spp. Lymphadenopathy, 452

Loa Loa Lymphadenitis, 452

Tropical (Filarial) Eosinophilia Diagnosed by TissueBiopsy, 453

Schistosomiasis, 453Leishmaniasis, 454Mixed Pattern with Granulomas and Foamy

Macrophages, 457Leprosy, 457

Mixed Pattern with Deposition of InterstitialSubstance, 459Pneumocystiis jiroveci Lymphadenitis, 459

Mixed Pattern with Caseation Necrosis, 461Mycobacteria tuberculosis, BCG Lymphadenitis,

and Systemic Fungal Lymphadenitis, 461

Mixed Pattern Atypical Mycobacterial Infectionsin AIDS, 463Bacillus Calmette–Guarine Lymphadenopathy, 466

Mixed Pattern with Angiomatoid Change, 467Bartonella bacilliformis Bacillary

Angiomatosis, 467

Mixed Pattern with Spent Granulomas andExtracellular Organisms, 470Histoplasmosis Secondary to H. capsulatum, 470

Subclinical Histoplasmosis: FibroticGranulomas, 470

xvi | CONTENTS

Acute Histoplasmosis, 471

African Histoplamosis Secondaryto H. capsulatum var duboisii, 474

References, 476

CHAPTER TWENTY-ONECytopathology of Non-neoplastic andInfectious Lymphadenopathy 481

Sara E. Monaco, Liron Pantanowitz,and Walid E. Khalbuss

Technical Components, 483Approach to Cytomorphologic Evaluation of

Lymph Nodes, 484FNA Reporting Terminology, 485Intraoperative Touch Preparation, 487Reactive Lymphoid Hyperplasia, 487


Inflammatory and Infectious Causes ofLymphadenopathy, 488Acute Suppurative Lymphadenitis, 488

Cat-Scratch Lymphadenitis, 489

Granulomatous Lymphadenitis, 489

Mycobacterial Lymphadenitis, 491

Fungal Lymphadenitis, 492

Sarcoidosis, 493

Toxoplasma Lymphadenitis, 494

Herpes Simplex Virus Lymphadenitis, 494

Infectious Mononucleosis Lymphadenitis, 495

HIV-Associated Lymphadenopathy, 496

Leishmania Lymphadenitis, 497

Other Causes of Lymphadenopathy, 497Histiocytic Necrotizing Lymphadenitis, 497

Kimura Disease, 498

Sinus Histiocytosis with MassiveLymphadenopathy, 498

Dermatopathic Lymphadenitis, 499

Castleman Disease, 500

Extramedullary Hematopoiesis, 500

Foreign Body or Iatrogenic Related Changes inLymph Nodes, 501

Non-neoplastic Inclusions in Lymph Node, 502

Autoimmune Lymphoproliferative Syndrome, 502

Lymphadenopathy in Autoimmune Diseases, 503

Lymphadenopathy in the Pediatric Patient, 504Use of Ancillary Studies, 504

Flow Cytometry, 504

Microbiology Culture, 504

Immunohistochemistry and Special Stains, 505

In-situ Hybridization, 506

Fluorescence Microscopy, 506

Molecular Studies, 506FISH, 506

PCR, 506

References, 506

CHAPTER TWENTY-TWOMixed Patterns In Lymph Node: TropicalInfectious Lymphadenopathy andHematopathology, Not OtherwiseCharacterized 511

Hernani D. Cualing

Introduction, 511Hemorrhagic Lymphadenopathy, 511

Anthrax, 511

Rocky Mountain Spotted Fever, 515

Sinus Pattern, 517Bubonic Plaque, 517

Leptospirosis, 520

Scrub Typhus, 523

Diffuse Pattern with Depletion and AtypicalImmunoblastic Reaction, 525Dengue, 525

Human Monocytic EhrlichiosisLymphadenopathy, 527

Human Granulocytotropic (or Granulocytic)Anaplasmosis, 529

Lassa Hemorrhagic Fever, 530

Nipah Virus, 531

Unusual Granulomas Q Fever, 531References, 533

PART IV Non-neoplastic Findings inBone Marrow Transplantation 537

CHAPTER TWENTY-THREENon-neoplastic Hematopathology of BoneMarrow Transplant and Infections 539

Taiga Nishihori and Ernesto Ayala

Introduction, 539Fundamental Principles of Hematopoietic Cell

Transplantation (HCT), 539

CONTENTS | xvii

Characteristics of Pretransplant BoneMarrow, 542

Hematopoietic Regeneration, 542Chimerism, 543Post-Transplantation Marrow, 543

First Week after Transplant, 543

Second Week after Transplant, 545

Third Week after Transplant, 545

First Month after Transplant, 545

Second Month after Transplant, 546

Beyond Third Month after Transplant, 546

Complications of HematopoieticRegeneration, 547

Dyshematopoiesis, 547

Hypocellular or Acellular Marrow, 547

Pure Red Cell Aplasia, 547

Residual Neoplastic Marrow, 548

Recurrent Disease, 548

Graft-versus-Host Disease (GVHD), 549

Granulomas and Infectious Disease in theMarrow, 549

Conclusion, 551References, 552

Index, 559

CONTRIBUTORS

Stephen D. Allen, MDJames Warren Smith Professor of Clinical

MicrobiologyProfessor, Department of Pathology and Laboratory

MedicineIndiana University School of MedicineIndiana University HealthIndianapolis, IN

Ernesto Ayala, MDAssistant ProfessorBone Marrow Transplant Division, Department of

Oncologic ScienceMoffitt Cancer Center and Research InstituteTampa, FL

Parul Bhargava, MDMedical Director, Hematology Laboratory at Beth

Israel Deaconess Medical CenterAssistant ProfessorBeth Israel Deaconess Medical Center—Needham

CampusMember of Harvard Medical Faculty Physicians

(HMFP)Boston, MA

Jeremy W. Bowers, MDHematopathology FellowDepartment of Hematopathology and Laboratory

MedicineMoffitt Cancer Center and Research InstituteDepartment of Pathology and Cell BiologyUniversity of South Florida, College of MedicineTampa, FL

Sheldon Campbell, MD, PhD, FCAPDepartment of Laboratory MedicineYale University School of MedicinePathology and Laboratory MedicineVA Connecticut, West Haven, CT

Hernani D. Cualing, MDJoint Associate Professor, Department of Pathology

and Cell BiologyUniversity of South Florida, College of MedicineMedical Director, IHCFLOW, Inc.Consultant Hematopathologist, Specialty:

Hematopathology, Cutaneous Lymphomas, andImaging Science

Post-Director of HematopathologyFellowship-Moffitt Cancer Center and ResearchInstitute

Shohreh Iravani Dickinson, MDAssistant Professor, Moffitt Cancer Center and

Research Institute, Department of Pathology andCell Biology, University of South Florida, COM

Anatomic Pathologist and Hematopathologist

Jason C. Ford, MD, FRCP(C)Head, Division of Hematopathology, Children’s

and Women’s Health Centre of BCAssociate Professor, Faculty of MedicineUniversity of British ColumbiaBC, Canada

Lynne Garcia, MS, MT, FAAMClinical MicrobiologistDirector, LSG & Associates, Santa Monica, CA

xix

xx | CONTRIBUTORS

Gary Hellermann, PhDAssistant ProfessorDivision of Allergy and ImmunologyDepartment of Internal MedicineUniversity of South Florida College of MedicineTampa, FL

Vandita Johari, MDDepartment of PathologyDivision of Clinical PathologyDirector, Hematology Laboratory and Flow

CytometryAssistant Professor of PathologyTufts University School of Medicine

Lija Joseph, MDStaff HematopathologistLowell General HospitalAdjunct Associate ProfessorBoston University School of MedicineBoston, MA

Loveleen C. Kang, MDAssociate ProfessorDepartment of PathologyUniversity of South FloridaCollege of MedicineStaff PathologistJames A. Haley VAMCTampa, FL

Walid E. Khalbuss, MD, PhD, FIACAssociate ProfessorDirector of Cytopathology-UPMC Shadyside

HospitalDepartment of PathologyUniversity of Pittsburgh Medical Center (UPMC)UPMC-Shadyside, Pittsburgh, PA, USA

Rebecca Levy, MDDepartment of PathologyBaystate Medical CenterSpringfield, MA, USA

Jun Mo, MDAssociate ProfessorPediatric HematopathologyDivision of Pathology

Cincinnati Children’s Hospital Medical CenterCincinnati, OH, USA

Sara E. Monaco, MDAssistant ProfessorDirector of Fine Needle Aspiration Biopsy

Service-UPMC Children’s Hospitalof Pittsburgh

Department of PathologyUniversity of Pittsburgh Medical Center (UPMC)UPMC-Shadyside, Pittsburgh, PA, USA

Taiga Nishihori, MDAssistant MemberDepartment of Blood and Marrow TransplantationMoffitt Cancer Center, Tampa, FL

Tal Oren, MD, PhDDepartment of PathologyStamford HospitalSuffern, NY, USA

Liron Pantanowitz, MDAssociate ProfessorDirector of Fine Needle Aspiration Clinic-UPMC

Shadyside HospitalDepartment of PathologyUniversity of Pittsburgh Medical Center (UPMC)UPMC-Shadyside, Pittsburgh, PA, USA

Deniz Peker, MDClinical Fellow, Hematopathology Fellowship

ProgramMoffitt Cancer Center and Research InstituteDepartment of Pathology and Cell BiologyUniversity of South Florida College of Medicine

Ramon L. Sandin, MD, MS, FCAP, ABP–MMClinical PathologistMedical Director, Clinical Microbiology and

VirologySenior Member and Professor Department of

Hematopathology and Laboratory Medicine,and Blood and Marrow Transplant Program

Moffitt Cancer Center

Betram Schnitzer, MDProfessor Department of PathologyUniversity of Michigan Ann ArborAnn Arbor, MI

CONTRIBUTORS | xxi

James W. Smith, MDNordschow Professor Emeritus

of Tropical MedicineVan Nuys Medical ScienceFormer Chair Dept. of Pathology & Laboratory

MedicineIndiana Univ. School of MedicineIndianapolis, Indiana

Raul E. Villanueva, MDClinical PathologistPuget Sound Institute of PathologySeattle, WA

Dr. Reza Setoodeh, MDDepartment of Pathology and Cell

Biology

University of South Florida Collegeof Medicine

Ling Zhang, MDAssistant ProfessorHematopathologistDepartment of Hematopathology and Laboratory

MedicineMoffitt Cancer Center and Research InstituteDepartment of Pathology and Cell Biology,

USF

Xiaohui Zhang, MD, PhDResident-Fellow, Hematopathology FellowshipMoffitt Cancer Center and Department of Pathology

and Cell BiologyUniversity of South Florida College of Medicine

FOREWORD

Many years ago, when I began my residency inpathology, there seemed to be few, if any, textbooksdealing exclusively with the topic of hematopathol-ogy. The general pathology texts then available usu-ally contained only short, cursory chapters on lymphnode and bone marrow findings in such diseases aslymphomas and leukemias. However, only multiplerudimentary classifications of these two neoplasticdisease entities were described. Ever since the AFIPfascicle on Classification of Lymphomas by Dr. HenryRappaport appeared in 1966, however, numerousbooks on the subject of hematopathology have beenpublished.

With the exception of the now out-of-datemultiple-volume set by William St. Clair Symmers,there are, to my knowledge, no other textbookscombining the fields of hematopathology andWestern or tropical infectious diseases. Now, inthis book, Dr. Cualing and his fellow contributors

have successfully combined these two areas ofexpertise.

The current volume is especially timely in thisera of globalization when people from all over theworld travel into our midst, bringing with them dis-eases that we are unfamiliar with. In other instances,pathologists from other countries send slides forconsultation from patients who have a variety of dis-orders. Thus, more than ever, there is a pressing needfor the development of a closer interaction betweenhematopathology and microbiology in the investiga-tion of infectious and benign reactive diseases partic-ularly those involving lymph nodes, blood, and bonemarrow. This book has as its mission the integrationof these two disciplines leading to further collabora-tion and understanding between hematopathologistsand microbiologists.

Bertram Schnitzer, MD

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PREFACE

This book explores new material at the nexus ofhemic-lymphatic manifestations of Western and trop-ical infectious diseases. It attempts to expand on theclassic descriptions of the reactive and inflammatorymanifestations of infectious diseases in blood andother related organs. Because many agents seek entryand circulate in blood and lymphatic system, the bookbegins with the basics of hematology and follows withblood-borne infections. It adds in a survey of patternsof reactions in blood and lymph nodes and ends withhematopathology of bone marrow transplantation.Many of the agents of infections diseases, in additionto human to human transmission, are zoonotic, use anumber of vectors, and hence epidemiologic and geo-graphic aspects are included. Upon entry, a number ofthese agents commandeer blood elements includinglymphocytes and macrophages as mobile shuttles.Both blood and lymphatic disorders are thereforeelaborated since direct effect by these agents causered cell, platelets, leucocytes, and tissue immuno-logic disorders. All these disorders are illustratedwith pictures, tables, descriptive and text; illustratedas well are the range of non-neoplastic hematologicdisorders, and reactive patterns of noninfectious andinfectious agents, and the blood and lymphatic mani-festations of familiar infections and the more commoninfections in the tropics. The epidemiology, pathobi-ology, and clinical and pathologic manifestations inblood and lymphatic organs as well as the approach todiagnosis, treatment, and prognosis are described. Foruniformity of terminology, the book includes WHO-endorsed diagnostic codes based on the InternationalClassification of Disease (ICD-10). Since many infec-tious agents are also of tropical origin, and sincethe vast majority of these agents infect a large seg-ment of the world, including transient travelers andimmigrants, this book incorporates diseases found in

both Western and Eastern Hemispheres. Additionallythe microscopic criteria as well as the molecular andlaboratory tests provided in this code should proveuseful information even for laboratories practicing inresource limited settings besides those with access tomodern diagnostic modalities.

We divided the book into four parts. Part I pro-vides an overview of non-neoplastic hematology, PartII addresses blood-borne infections, Part III coverspatterns seen in noninfectious and infectious lym-phadenopathies, including those commonly seen intropical countries as well as cytomorphologic find-ings of reactive adenopathies, and Part IV deals withhematopathologic issues of bone marrow transplan-tation associated with common and rare infections.We begin the book with a section on the basicsof hematology and diagnosis based on peripheralblood findings, then go on to infections related tohematopathology, followed by tissue and pattern-based diagnosis, and finally cover the basics of bonemarrow transplantation. In tissue, we proffer anapproach using low-power recognition of the his-tology patterns and proceed from there. The basicsof hematology written by practicing experts in thefield is completely and succintly covered in PartI, detailing issues on leucocytes, platelets, and redcells disorders including thalassemias. Part II coversblood-borne infections written by well-known prac-ticing microbiologists and includes apicomplexas,flagellates, protobacterias, and fungal infections. InPart III, practicing hematopathologists discuss theissue of reactive lymphadenopathy and present atable detailing the entities under the classic four pat-terns: follicular, diffuse, sinus, and mixed patterns.The premise for this approach is that knowledge ofthe salient morphologic findings, the constellation of

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clinical presentation, the geographic or epidemiolog-ical background of the patient, and the key laboratoryand the morphologic manifestations will help in arriv-ing at a correct diagnosis. In other words, we begin atthe beginning: approach a disease from what we allsee under the microscope.

The difficulty in diagnosing reactive lym-phadenopathy rivals, if not exceeds, that of thelymphomas. The case of recognizing a reactivelymph node belies its complexity, and contributes tothe generally nonchalant attention it receives com-pared to its malignant cousin. Just as in the case oflymphomas, there is an approach that makes sense ofthese numerous complexities as well as a frameworkto formulate diagnoses. Historically the many waysto classify lymphadenopathies has been hinderedby the artifice of easy understanding and simplediagnosis. Partly to blame is the notion that ‘‘it is justbenign, who cares what kind’’ until the lymphoma ismistaken for a benign diagnosis, or a treatable infec-tion, or one that is highly contagious is missed. Oftenthe lack of clinical history compounds the limitedmicroscopic window that a pathologist initially sees.Hence we use the approach of hematopathologists:we widen the microscopic window to observe whatare the pitfalls, the clinical milieu, and the subtlehistologic features that differentiate rival entities.

Non-neoplastic hematopathology is a difficultdiagnosis not only because of the reactive lymphnode’s mimicry of lymphomas but also because thefield has received less studious attention than its neo-plastic counterpart. Inherently, reactive lymph nodesare also difficult to diagnose because lymph nodes,upon stimulation, display a dynamic variability thatdepends on the patient’s age, immune status, phase orduration of reaction, and whether the etiology is infec-tious or noninfectious. About 30 to 40% of reactivelymph nodes have specific histologic features leadingto a definite diagnosis: features in histology suggest apattern that requires ancillary serology, phenotypic,or serologic tests that may lead to a specific diag-nosis. The rest of lymph nodes seen in pathology

practice may show a nonspecific histology, but itspattern needs to be stated to initiate a pattern-baseddifferential diagnosis. Even for a nonspecific reactivehyperplasia, such as a mixed follicular and paracor-tical reaction, diagnosis is important because of theimplicit concern for a lymphoma is considered andnot favored. A specific reactive lymphadenopathydiagnosis, when suggested by a constellation of clues,needs to be given so that confirmatory tests can be per-formed. A diagnosis of infection would impel a ther-apy to commence, surveillance made for endemic andcommunicable disease, and malignancy ruled out.

We also take a lesson from a Family Circus cartoonby Bil Keane: kids looking over an adult reading abook say ‘‘Grown-up books are harder to read . . . theymake you think up your own pictures!!!’’ by incorporat-ing many color pictures. We try to fill in with moreguideposts a map of non-neoplastic hematopathol-ogy that is already dotted with classic landmarks.We are indebted to hematopathology pioneers whodescribed reactive lymphadenopathy and its clas-sic patterns. Bertram Schnitzer (1992) and LawrenceWeiss (2008). As we extend their work into the realmof the infectious diseases, we are indeed navigatinga wondrous terra incognita as the fictional sailors ofLewis Carroll: We hope the readers will be as excitedto fill in the blanks.

He had brought a large map representing the sea,Without the least vestige of land:And the crew were much pleased when they found it to beA map they could all understand.. . . ‘‘Other maps are such shapes, with their islands and

capes!But we’ve got our brave Captain to thank’’(So the crew would protest) ‘‘that he’s brought us the

best—A perfect and absolute blank!’’L. Carroll, Fit the Second, the Hunting of the Snark

Hernani D. CualingParul Bhargava

Ramon L. Sandin

ACKNOWLEDGMENTS

We, at the onset, would like to express our gratitudeto the staff of Wiley-Blackwell Publishers, andespecially to our ever gracious medical editor, ThomMoore. We also thank Ian Collins, Editorial Assistant,Dean Gonzalez, Illustration Manager, and DanielleLacourciere, Senior Production Editor, Maude Akagiand James Hastings of Wiley, as well as GowriVasanthkumar of Laserwords, India for their laborand patience in converting our texts to a book asflawless as possible. Since we may not be able tothank all the staff who made this book possible, weask leave for not including everyone. I would also liketo thank my former mentors who started me on thepath to hematopathology: Dr. Jen Lin of New Yorkand Drs. Dick Neiman and Atillio Orazi, formerlyof Indianapolis, where I had my hematopathologyfellowship. Since that time, I collected microscopicslides intending to use them and during my stintas faculty of University of Cincinnati, under Dr.Roger Smith and Dr. Fenoglio-Preiser, for teaching:my first cases of lymph node dirofilariasis andleishmaniasis of bone marrow came from thatfellowship and were augmented with pearls to manyslide boxes of reactive lymphadenopathies overthe years. For the book, additionally would liketo thank the following persons and are indebtedfor their contributions of images, comments, andsuggestions.

We are indebted to Dr. Betram Schnitzer for hissupport and for his endorsement of the book. Muchof our tropical infectious digital images were pro-vided by Dr. Wun-Ju Shieh, of the Infectious DiseasesPathology Branch, Division of High-ConsequencePathogens and Pathology, National Center for Emerg-ing and Zoonotic Infectious Diseases, Centers for Dis-ease Control and Prevention at Atlanta, and we could

not thank him and his colleagues enough. Dr. ElmerKoneman, a foremost microbiologist, provided uswith rare images of infections in tissues, and we alsoappreciate his comments on materials to include at thefront of the book. We thank Dr. Rito Zerpa Larrauri ofServicio de Microbiologıa, Instituto Nacional de Saluddel Nino, Lima, Peru for blood and tissue images ofleprosy, bartonellosis, and mycobacteria. We wouldalso like to thank Karen Goraleski, Executive Direc-tor of the American Society of Tropical Medicineand Hygiene for allowing us to use digital imagesof tropical diseases from Dr. Herman Zaiman collec-tions. We are encouraged by the vision and thrustof the ASTMH and support their mission to edu-cate and publish on tropical medicine of widespreademergent or neglected tropical infections. We thankDr. Fabio Fachetti of the Department of PathologySpedali Civili-University of Brescia, Italy, for theimage of CD123 and for personal communicationon plasmacytoid monocytes and lymphadenopathies.We additionally are indebted to Dr. James Smith ofIndiana University Medical Center, to Dr. Rodney C.Arcenas of Holywood, Florida, for reviewing mostof the manuscript, to Dr. Ronald Jaffe of PittsburghChildren’s Hospital, to Kathy White of Boston Medi-cal Center, and to Dr. J. Ford of Children’s Hospital,Vancouver, Canada. We thank Rodney C. ArcenasPhD, Ardeshir Hakam MD of Mofffitt Cancer Cen-ter, Antonio Hernandez MD of Quest Dx/AmeripathCenter for Advanced Diagnostics, and Dr. Steve Shawof NIH/NCI for providing scholarly materials dis-cussing the paracortical cords. We also thank Dr.Steve Swerdlow, chief hematopathologist at the Uni-versity of Pittsburg, for sharing digital images of CMLlymphadenitis. We thank Dr. Gary Hellerman forfacilitation of email communications at the beginning

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of the project and for editing parts of the manuscriptand also Gary Bentley for helping with line art figuresas well as to Dr. Peter Banks for his images onHerpes simplex Lymphadenitis. We are indebted toMs. Malou Domingo of Manila, the Philippines, forresearch in tropical pathology and to Dr. Sharon

Villanueva of Kyushu University Fukuoka, Japan, forarticles on leptospirosis and to Philip Yassin-Cualing,for research and editing work.

Hernani D. CualingLutz, Florida

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