CONTENTS

1. General Immunology of and ...... 1 Overview of the Immune System and Immunologic Responses ...... 1 Lymph Nodes ...... 1 Anatomy ...... 1 Primary Immune Response...... 1 B Lymphocytes...... ` 3 T Lymphocytes...... 8 Natural Killer Cells...... 9 Dendritic Cells ...... 10 Spleen ...... 11 Anatomy ...... 11 White Pulp ...... 11 Marginal Zone...... 13 Red Pulp...... 14 2. Embryology and Histology of the Lymph Node and Spleen...... 19 Embryology of the Spleen ...... 19 Embryologic Abnormalities of the Spleen...... 19 , Ectopic Spleen, and ...... 19 ...... 22 Abnormal Fusion: Splenogonadal, Splenorenal, Hepatolienal Fusion...... 23 ...... 24 Embryology of the Lymph Nodes ...... 24 Ectopia in Lymph Nodes ...... 25 Histology of Lymph Node (Normal Architecture and Function of Lymph Nodes) . . 35 Capsule and Subcapsular Sinus...... 36 Cortex ...... 36 Paracortex ...... 40 Medulla ...... 43 Vasculature...... 43 Histology of the Spleen ...... 45 General Microanatomy...... 45 Vasculature...... 45 Red Pulp...... 47 White Pulp ...... 50 3. Technical Evaluation and Overview of Lymph Node and Spleen...... 57 Indications for Lymph Node Biopsy ...... 57

xi Benign and Reactive Conditions of Lymph Node and Spleen

Indications for ...... 58 Sampling and Handling the Fresh Lymph Node ...... 58 Sampling and Handling the Fresh Spleen...... 61 Fixation and Processing...... 61 Routine and Histochemical Stains ...... 64 Evaluation of the Lymph Node...... 65 Evaluation of the Spleen ...... 71 4. Ancillary Studies for Evaluation of Lymph Node and Spleen...... 75 Basic Concepts...... 75 Immunohistochemistry Techniques...... 75 Antigen Retrieval ...... 76 Antibodies: Clusters of Differentiation (CD) Groups...... 76 Immunohistochemistry of Lymphoid Tissues ...... 77 B Cells ...... 77 T Cells ...... 79 Reactive Conditions Versus Malignancies...... 80 Reactive Conditions Versus Lymphomas ...... 82 Reactive Conditions Versus B-Cell ...... 83 Reactive Conditions Versus T-Cell Neoplasms ...... 85 Reactive Conditions Versus ...... 86 Histiocytic and Myelomonocytic Antibodies...... 87 Myeloid Cell Antibodies ...... 87 Dendritic Cell Antibodies ...... 88 Potential Pitfalls in Immunohistochemistry...... 89 Immunohistochemistry of the Spleen ...... 91 Flow Cytometry...... 93 Flow Cytometry of the Spleen...... 93 Ultrastructural Examination of the Lymph Node and Spleen...... 94 5. General Reactive Conditions in Lymph Node and Spleen ...... 97 Follicular Hyperplasia...... 97 Interfollicular/Immunoblastic Hyperplasia ...... 105 Mantle Zone (Primary Follicle) Hyperplasia ...... 107 Marginal Zone (Monocytoid B-Cell) Hyperplasia...... 109 T-Cell Hyperplasias including Nodular Paracortical T-Cell Hyperplasia and other T-Cell Nodules...... 112 Mixed Pattern Hyperplasia...... 116 Atypical Lymphoid Hyperplasia...... 117 Sinus Histiocytosis...... 119 Granulomatous Inflammation ...... 119

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Plasmacytoid Dendritic Cells ...... 126 Necrotizing Lymphadenitis...... 128 Progressive Transformation of Germinal Centers...... 129 Regressive Changes in Germinal Centers ...... 133 Fatty Transformation of Lymph Nodes...... 134 Hemorrhage and Infarction ...... 135 Perisplenitis (“Sugar-Coated” Spleen) ...... 137 6. Specific Clinical Entities...... 143 Dermatopathic Lymphadenitis ...... 143 Kimura ...... 145 Kawasaki Disease ...... 149 Kikuchi-Fujimoto Disease (Histiocytic Necrotizing Lymphadenitis)...... 150 (Angiofollicular Lymph Node Hyperplasia), Hyaline-Vascular Type, Plasma Cell Type, and Multicentric Type ...... 155 Angioimmunoblastic ...... 164 Rosai-Dorfman Disease (Sinus Histiocytosis with Massive Lymphadenopathy). . . . . 166 Hemophagocytic Syndromes ...... 169 Langerhans Cell Histiocytosis ...... 174 7. Congenital ...... 185 Severe Combined Immunodeficiency...... 188 Autoimmune Lymphoproliferative Syndrome ...... 193 Common Variable Immunodeficiency...... 197 Selective IgA Deficiency ...... 201 Hyper-IgM Syndrome...... 201 Hyper-IgE Syndrome (Job Syndrome) ...... 204 X-Linked Agammaglobulinemia (Bruton Agammaglobulinemia) and Hypogam- maglobulinemia...... 205 X-Linked Lymphoproliferative Disease (Duncan Syndrome)...... 207 Griscelli Syndrome and Chediak-Higashi Syndrome...... 210 Wiskott-Aldrich Syndrome...... 211 Ataxia-Telangiectasia (including Nijmegen Breakage Syndrome and Berlin Breakage Syndrome)...... 214 Chronic Granulomatous Disease ...... 216 Tuberous Sclerosis...... 219 8. Bacterial Infections...... 229 Gram-Positive Bacterial Infections...... 229 Staphylococcus and Streptococcus ...... 231 Corynebacterium...... 231 Listeria Monocytogenes...... 233

xiii Benign and Reactive Conditions of Lymph Node and Spleen

Actinomyces, Nocardia, and Rhodococcus Equi...... 233 Tropheryma Whipplei ...... 236 Bacillus Anthracis...... 237 Gram-Negative Bacterial Infections ...... 238 Bartonella Henselae and B Quintana: Cat-Scratch Disease ...... 240 Bartonella Henselae and B. Quintana: Bacillary Angiomatosis...... 243 Salmonella Typhi and Salmonella Enteritidis...... 246 Yersinia Pestis: Plague ...... 250 Other Yersinia Infections...... 250 Francisella Tularensis...... 251 Brucella ...... 252 Burkholderia Pseudomallei ...... 254 Mycoplasma, Treponema Pallidum, Borrelia, and Rickettsia Infections...... 255 Coxiella Burnetii...... 255 Chlamydia Trachomatis...... 257 Treponema Pallidum ...... 258 Rickettsia...... 261 Mycobacterial Infections...... 262 Mycobacterium Tuberculosis...... 262 Mycobacterium Avium-Intracellulare...... 266 Mycobacterium Leprae...... 270 Bacille Calmette-Guerin...... 273 Atypical Mycobacterial Infections...... 274 Postsplenectomy Infections ...... 276 9. Viral ...... 283 General Viral-Associated Lymphadenopathy...... 283 Infectious Mononucleosis/Acute Epstein-Barr Virus...... 283 Other Epstein-Barr Virus–Associated Lymphoid Proliferations...... 291 Cytomegalovirus ...... 295 Herpes Simplex Virus...... 298 Varicella-Zoster Virus...... 301 Human Herpesvirus-8...... 303 Human Herpesvirus-6...... 305 Measles Virus ...... 308 Rubella Virus...... 309 Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome ...... 309 Zoonotic Viruses...... 316 Parvovirus B19...... 317 Smallpox (Variola Virus), Cowpox, Monkeypox ...... 318

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Severe Acute Respiratory Syndrome...... 318 Poliovirus...... 319 Postvaccinial Lymphadenitis ...... 320 10. Fungal Infections...... 327 Cryptococcus Neoformans ...... 328 Histoplasma Capsulatum...... 328 Blastomyces Dermatitidis...... 332 Coccidioides Immitis...... 333 Paracoccidioides Brasiliensis...... 337 Pneumocystis Jiroveci...... 338 Penicillium Marneffei ...... 340 Candida, Torulopsis Glabrata, and Dermatophytes...... 341 Aspergillus...... 342 Zygomycetes (including Mucor and Rhizopus)...... 344 Chromoblastomycosis...... 344 Pseudoallerichia and Petriellidium ...... 345 Sporothrix Schenckii...... 345 11. Parasitic and Miscellaneous Infections ...... 347 Toxoplasma Gondii ...... 347 Entamoeba Histolytica...... 349 Other Protozoa (Microsporidium, Cryptosporidium, and Isospora Belli)...... 351 Filaria ...... 351 Nematode Infections (including Strongyloides) and Other Parasitic Worms...... 356 Echinococcus ...... 358 Leishmania Donovani...... 360 Trypanosoma Cruzi and T. Brucei...... 362 Schistosoma...... 363 Plasmodium...... 364 Babesia ...... 368 Rhinosporidium Seeberi...... 369 Prototheca ...... 369 Prions ...... 370 12. Systemic and Autoimmune Abnormalities ...... 375 Immune Thrombocytopenic Purpura ...... 375 Autoimmune Hemolytic Anemia...... 380 Sarcoidosis ...... 381 Systemic Lupus Erythematosus ...... 383 Rheumatoid Arthritis and Adult-Onset Juvenile Rheumatoid Arthritis (Still Disease). . . 388 Felty Syndrome...... 390

xv Benign and Reactive Conditions of Lymph Node and Spleen

Large Granular Lymphocytosis ...... 391 Behcet Disease ...... 394 Thrombotic Thrombocytopenic Purpura...... 394 Vasculitides (Wegener Granulomatosis, Polyarteritis Nodosa, Churg-Strauss Disease, Henoch-Schonlein Purpura)...... 396 13. Hematologic Disorders ...... 405 Hereditary /Elliptocytosis...... 405 ...... 406 Hemoglobinopathies Associated with Unstable Hemoglobins...... 410 Syndromes ...... 410 Erythrocyte Enzyme Deficiencies...... 411 Pyruvate Kinase Deficiency...... 411 Extramedullary Hematopoiesis ...... 412 14. Medication and Treatment Effects...... 419 Rituximab Therapy and Other Monoclonal Antibody Therapies for Lymphoma . . . 419 Corticosteroid Therapy...... 421 Methotrexate ...... 422 Anticonvulsant Medications ...... 424 Granulocyte-Colony Stimulating Factor and Other Cytokines...... 427 Ionizing Radiation Effects ...... 430 Sulfasalazine ...... 433 Clofazimine Crystal Deposition...... 434 Bone Marrow Transplantation and Graft-Versus-Host Disease...... 434 Gold Therapy (Chrysotherapy) ...... 435 15. Foreign Bodies and Chemicals ...... 439 Proteinaceous Lymphadenopathy ...... 439 Extracellular Immunoglobulin Deposits...... 440 Amyloid Deposits/Amyloidosis...... 445 Tamm-Horsfall Protein Deposits ...... 449 Lipid Deposits...... 450 Lymphangiogram Effect...... 450 Silicone Deposits ...... 454 Histiocytic Lymphadenopathy after Joint Prosthesis ...... 456 Berylliosis...... 458 Asbestos Deposits ...... 459 Silicosis ...... 460 Hemochromatosis ...... 462 Thorotrast Deposition ...... 463 Talc Deposition...... 464

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Synthetic Polymer Deposition ...... 466 Tattoo Pigment/Anthracosis/Lipofuscin Deposition...... 466 16. Metabolic Diseases...... 477 Overview...... 477 Gaucher Disease...... 481 Niemann-Pick Disease ...... 484 Sea-Blue (Ceroid) Histiocytosis...... 486 17. Physical and Vascular Abnormalities ...... 491 Splenic Rupture (Traumatic and Atraumatic) ...... 491 Fibrocongestive (including Portal Hypertension) ...... 494 Infarction of Lymph Node and Spleen ...... 497 Changes Associated with Fine Needle Aspiration/Biopsy...... 501 Vascular Transformation of Lymph Node Sinuses (Nodal Angiomatosis)...... 502 and Peliosis...... 505 Lymphangioma and Lymphangiomatosis...... 507 Other Vascular Tumors...... 508 Splenic Artery Aneurysms ...... 516 18. Benign Disorders of Unclear Etiology and Neoplasms ...... 523 Splenic Hamartoma...... 523 Inflammatory Pseudotumor (Lymph Node and Spleen) ...... 528 Palisaded Myofibroblastoma ...... 537 Lipomatosis, Lipoma, and Fatty Replacement of Lymph Node ...... 539 Angiomyolipoma...... 541 Angiomyomatous Hamartoma, Lymphangiomyoma, Leiomyomatosis, and Leiomyoma ...... 542 Metastatic Tumors of Spleen ...... 547 19. Splenic Cysts...... 553 Nonparasitic Cysts...... 553 Pseudocysts ...... 553 True Cysts: Splenic Mesothelial, Epidermoid, and Epithelial ...... 554 True Cysts: Splenic Dermoid...... 557 Parasitic Cysts...... 557 Index ...... 561

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