Diagnostic Electron Microscopy A TEXT/ATLAS

Second Edition Springer New York Berlin Heidelberg Barcelona Hong Kong London Milan Paris Singapore Tokyo G. Richard Dickersin, M.D.

Associate Professor of Pathology Harvard Medical School

Associate Professor of Pathology Massachusetts Institute of Technology

Pathologist Head of Diagnostic Electron Microscopy Unit Massachusetts General Hospital Boston, Massachusetts

Diagnostic Electron Microscopy A TEXT/ATLAS

Second Edition With 894 Illustrations G. Richard Dickersin, M.D. Pathologist and Head, Electron Microscopy Unit Department of Pathology Massachusetts General Hospital Boston, MA 02114-2617 USA and Associate Professor of Pathology Harvard Medical School Boston, MA 02115-6092 USA and Associate Professor of Pathology Massachusetts Institute of Technology Cambridge, MA 02139 USA

Library of Congress Cataloging-in-Publication Data Dickersin, G. Richard. Diagnostic electron microscopy : a text/atlas / G. Richard Dickersin. — 2nd ed. p. cm. Includes bibliographical references and index. ISBN 0-387-98388-0 (hardcover : alk. paper) 1. Diagnosis, Electron microscopic. 2. Tumors—Diagnosis. I. Title. [DNLM: 1. Microscopy, Electron—methods Atlases. 2. — ultrastructure Atlases. 3. Cytodiagnosis—methods Atlases. 4. Kidney Glomerulus—ultrastructure Atlases. 5. Metabolic Diseases—pathology Atlases. 6. Neuromuscular Diseases—pathology Atlases. QZ 17 D549d 1999] RB43.5.D55 1999 616.07Ј58—dc21 DNLM/DLC 99-32439

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ISBN 0-387-98388-0 Springer-Verlag New York Berlin Heidelberg SPIN 10656887 To my wife, Barbara; my daughters, Kay, Gail, Leslie, and Amy; and my son, Ged. Ten years have elapsed since the appearance of the first edition of this book, and since then a number of ad- vances have been made in the field of diagnostic pathol- ogy. New and improved techniques have contributed to our diagnostic armamentarium and to our general understanding of various disease processes. In the field of neoplasia, immunohistochemistry has become a rou- tine procedure in most departments of pathology. Flow cytometry has become an efficient technique for meas- Preface uring ploidy, and molecular biological methods such as DNA and RNA hybridization and polymerase chain re- action (PCR) have made it possible to identify specific genetic markers for various hereditary, neoplastic, and infectious diseases. The importance of these innova- tions in pathology is duly recognized, but, at the same time, they have limitations, and traditional morpho- logical studies still comprise the backbone of the pathologist’s work. In this latter group of studies we in- clude electron microscopy, which has continued to be used selectively in diagnostic workups of neoplastic, re- nal, neuromuscular, infectious, hereditary, and meta- bolic diseases. In our own experience, electron micro- scopy has been especially valuable in complementing immunohistochemistry or in superseding immunohis- tochemistry when the latter is equivocal or nonspecific. Aside from the practical application to diagnostic work, electron microscopy has been a valuable tool for educating residents and staff. It reveals cells and tissues at very high magnification, making cell surfaces and in- teriors visible beyond the limits of light microscopy, a seemingly important experience in the study of normal and diseased states. The omission of this basic mor- phological step in the training and continuing educa- tion of pathologists would be, in our opinion, a serious deficiency. In this second edition, we have retained the style and core components of the first edition but have updated the text and bibliography, added new topics, and re- placed and supplemented photographs appropriately. The result has been a larger book and, we hope, one of broader applicability.

G. Richard Dickersin, M.D. Boston, Massachusetts

vii It goes without saying that a book of this type cannot be produced by one person, at least not within a prac- tical time frame and while simultaneously carrying out routine “service work” in a busy department of pathol- ogy. Thus, there are a number of persons who deserve special acknowledgment for their roles in making this work possible. First, Cheryl Nason and Martin Selig were at the core of the daily labor of the book. Cheryl’s mastery of the computer allowed for rough drafts, Acknowledgments countless additions and revisions, and literature searches to be accomplished in a timely manner. Her work was always outstandingly prompt and accurate, and I am most appreciative of it. Martin was a steady, consistent, right-hand man in the “rescoping,” photog- raphy, and assembly of illustrations. His skills went be- yond the purely technical ones, of which he is such a master, and included an academic familiarity with the particular morphology we were attempting to capture and portray. As will be noticed, Martin is listed as a con- tributing author of the chapter on renal glomerular dis- ease, but he also approached a similar level of involve- ment on several of the other chapters. I wish to acknowledge and thank him for the high quality of his work and for his commitment to the project. An “unsung hero” in the evolution of this book was a person whose skillful and reliable performance of rou- tine technical chores kept our electron microscopy serv- ice viable and efficient. That person is Robert Holmes. To Rob, our emphatic expression of gratitude and ap- preciation. Special appreciation also goes to the authors of Chapters 12 and 13, Shamila Mauiyyedi, Alain P. Mar- ion, Robert B. Colvin, Umberto De Girolami, and Dou- glas C. Anthony. Their expertise and contributions round out this book, making it more comprehensive and authoritative than I could possibly have hoped to accomplish myself. Finally, as for the first edition, I want to thank my wife, daughters, and son for their tolerance during weekends and vacations, when I would usually put in a few hours on “the book.”

G. Richard Dickersin, M.D. Boston, Massachusetts

ix Contents

Preface vii Acknowledgments ix Contributors xix

CHAPTER 1 Normal Cell Ultrastructure and Function 1 Cytoplasmic Organelles 1 Cytoskeleton (Cytoplasmic Matrix Structures) 4 Cytoplasmic Inclusions 4 Nuclear Organelles 4 Organization of Organelles Within the Cell 5 Cell Attachment Sites 5

CHAPTER 2 Selective Embryology 7 Embryogenesis from Fertilization Through Three Weeks 7 Differentiation of the Paraxial Mesoderm 9 Differentiation of the Intermediate Mesoderm 10 Differentiation of the Lateral Mesoderm 11 Comparison of Embryonic Mesodermal Differentiation with Embryonal Rhabdomyosarcoma, Wilms’ Tumor, and Mesothelioma 11

CHAPTER 3 Large Cell Neoplasms 27 Carcinoma 27 Adenocarcinoma (and Adenoma) 27 Squamous Cell Carcinoma 65

xi XII CONTENTS

Transitional Cell (Urothelial) Carcinoma 65 Undifferentiated Carcinoma 88 88 Mesothelioma 88 Lymphoma 89 Histiocytic Disorders 116 Macrophagic Lesions 116 Dendritic Cell Lesions 117 Mastocytosis and Mastocytoma 124

CHAPTER 4 Small Cell Neoplasms 147 Neuroendocrine Carcinoma 147 Neuroblastoma 147 Ewing’s 161 Primitive Neuroectodermal Tumor 161 Embryonal and Alveolar Rhabdomyosarcoma 169 Rhabdoid Tumor 169 Nephroblastoma (Wilms’ Tumor) 169 Lymphoma (Small Cell) 197 Plasmacytoma 197 Desmoplastic Small Round Cell Tumor with Divergent Differentiation 197 Small Cell Osteosarcoma 197 Mesenchymal Chondrosarcoma 209

CHAPTER 5 Leukemias 217 Myelocytic Leukemia 217 Monocytic and Myelomonocytic Leukemia 227 Lymphocytic Leukemia 227 Erythrocytic Leukemia 227 Megakaryocytic Leukemia 234 Hairy Cell Leukemia (Leukemic Reticuloendotheliosis) 234

CHAPTER 6 Spindle Cell Neoplasms and Their Epithelioid Variants 247 Fibrous Neoplasms 247 Malignant Fibrous Histiocytoma 264 CONTENTS XIII

Cartilaginous Neoplasms 278 Osteoblastoma and Osteosarcoma 278 Synovial Sarcoma 295 Adipose Neoplasms 295 Smooth Muscle Neoplasms 320 Skeletal Muscle Neoplasms 320 Vascular Neoplasms 341 Hemangiopericytoma 341 Schwannoma and Malignant Schwannoma 359 Granular Cell Tumor 359 369 Sarcomatoid (Spindle Cell) Carcinoma 369 Sarcomatous Thymoma, Melanoma, and Mesothelioma 369

CHAPTER 7 Gonadal and Related Neoplasms 391 Surface Epithelial–Stromal Tumors of the Ovary 391 Serous Tumors 391 Mucinous Tumors 406 Endometrioid Tumors 406 Clear Cell Tumors 418 Transitional Cell Tumors (Brenner and Non-Brenner Types) 424 Squamous Cell Tumors ( and Squamous Cell Carcinoma) 424 Mixed Epithelial Tumors 424 Undifferentiated Carcinoma 424 Sex Cord–Stromal Tumors 424 Granulosa Cell Tumor 424 Thecoma 439 Fibroma 439 Signet-Ring Stromal and Related Tumors 439 Sertoli–Stromal Cell Tumors (Androblastomas) 439 Sex Cord Tumors with Annular Tubules 451 Gynandroblastoma 451 Sex Cord–Stromal Tumors Unclassified 451 Steroid (Lipid) Cell Tumors 451 Germ Cell Tumors 451 Dysgerminoma (Seminoma) 451 Yolk Sac Tumor (Endodermal Sinus Tumor) 462 Embryonal Carcinoma 462 Choriocarcinoma and Placental Site Tumor (and Normal Placenta) 462 Teratoma (Immature and Mature; Monodermal) 462 Gonadoblastoma 478 XIV CONTENTS

Adenomatoid Tumor 478 Tumors of Uncertain Origin and Miscellaneous Tumors 478 Ovarian Small Cell Carcinoma, Hypercalcemia Type 478 Small Cell Carcinoma, Pulmonary Type 478 Tumor of Probable Wolffian Origin 478

CHAPTER 8 Central Nervous System Neoplasms 488 Meningioma 488 Astrocytoma 499 Oligodendroglioma 499 Ependymoma (and Subependymoma) 510 Choroid Plexus Neoplasms 510 Neuronal and Mixed Neuronal Glial Neoplasms, Including Embryonal Forms 510 Gangliocytoma (Central Ganglioneuroma) 510 Ganglioneuroma (Peripheral) 510 Ganglioglioma 526 Central Neurocytoma 526 Neuroblastoma 526 Ganglioneuroblastoma 528 Ependymoblastoma 528 Primitive Neuroectodermal Tumor 528 Medulloblastoma 528 Germinoma (and Embryonal Carcinoma, Choriocarcinoma, and Teratoma) 528 Pineocytoma and Pineoblastoma 532 Hemangioma 532 Hemangioblastoma 532 Pituitary Adenoma 543

CHAPTER 9 Miscellaneous Neoplasms 560 Neuroendocrine Neoplasms 560 Carcinoid/Islet Cell Neoplasms 560 Medullary (C-Cell) Carcinoma of the Thyroid 569 Parathyroid Carcinoma and Adenoma 569 Paraganglioma (Chemodectoma), Extra-adrenal 569 Pheochromocytoma (Adrenal Paraganglioma) 569 Monomorphic Adenoma 569 Pleomorphic Adenoma 585 Adenoid Cystic Carcinoma 585 Mucoepidermoid Carcinoma 585 CONTENTS XV

Alveolar Soft-Part Sarcoma 604 Chordoma 604 Epithelioid Sarcoma 613 Hepatoblastoma 613 Embryonal Sarcoma of Liver 613 Gastrointestinal Stromal Tumor 613 Gastrointestinal Autonomic Nerve Tumor (Plexosarcoma) 628 Pulmonary Blastoma 628 Juxtaglomerular Cell Tumor 628

CHAPTER 10 Infectious Agents 648 Bacteria 648 Viruses 661 Protozoa 680 Pneumocystis carinii 680 Toxoplasma gondii 680 Cryptosporidium parvum 680 Trypanosoma cruzi 694 Microsporida (M. enterocytozoon bieneusi and M. septata intestinale) 694 Giardia lamblia 694 Fungi 702 Histoplasma capsulatum 702

CHAPTER 11 Genetic and Metabolic Diseases 710 Storage Diseases 710 Erdheim–Chester Disease (Fibroxanthomatosis) 738 Porphyria 738 Alpha-1-Antitrypsin Deficiency 738 Pulmonary Alveolar Proteinosis 738 Mitochondrial Abnormalities 747 Wilson’s Disease 747 Amyloidosis 747 Amiodarone Toxicity 757 Adriamycin Toxicity 757 Hemosiderosis 757 Cholestasis 757 “Melanosis” (Lipofuscinosis) Coli and Prostaticus 757 Primary Ciliary Dyskinesia 771 XVI CONTENTS

CHAPTER 12 Renal Glomerular Disease 782 Shamila Mauiyyedi, Martin K. Selig, Alain P. Marion, and Robert B. Colvin The Normal Glomerulus 782 Location of Electron-Dense Deposits 785 Diseases with Scant or No Glomerular Deposits 786 Minimal Change Disease (Lipoid Nephrosis) 786 IgM Nephropathy 787 Focal and Segmental Glomerulosclerosis (Primary and Secondary Types) 788 Focal Segmental Glomerulosclerosis, Collapsing Variant, Including HIV-Associated Nephropathy and Heroin Abuse Nephropathy 792 Congenital Nephrotic Syndrome 794 Diabetic Nephropathy 797 Thin Glomerular Basement Membrane Disease (Benign Familial Hematuria) 800 Alport’s Syndrome (Hereditary Nephritis) 803 Glomerular Diseases with Prominent Crescents 806 Wegener’s Granulomatosis 806 Anti-Glomerular Basement Membrane Nephritis (Goodpasture’s Syndrome) 806 Diseases with Prominent Amorphous Dense Deposits 809 Postinfectious Glomerulonephritis 809 Membranous Glomerulonephritis 811 Membranoproliferative Glomerulonephritis, Type I 815 IgA Nephropathy (Berger’s Disease) 819 Henoch–Schönlein Purpura 819 Systemic Erythematosus 823 Tubuloreticular Inclusions and Tubular Confronting Cisternae 836 Diseases with Distinctive Ultrastructural Deposits 839 Dense-Deposit Disease (Membranoproliferative Glomerulonephritis, Type II) 839 Amyloidosis 843 Fibrillary Glomerulonephritis 846 Immunotactoid Glomerulopathy 851 Cryoglobulinemic Glomerulopathy 851 Systemic Light Chain Deposition Disease 856 Monoclonal Gammopathy 856 Patella Syndrome (Hereditary Osteo-onychodysplasia) 859 Collagen Type III Collagenofibrotic Glomerulopathy 859 Fabry’s Disease 863 Cystinosis 865 Glomerulopathy of Sickle Cell Disease/Trait 865 Diseases with Endothelial Reaction 868 Thrombotic Microangiopathy (in Hemolytic Uremic Syndrome, Thrombotic , , Malignant Hypertension, Rejection, and Cyclosporine Toxicity) 868 Eclampsia/Preeclampsia 875 The Renal Allograft 877 CONTENTS XVII

Acute Allograft Glomerulopathy 877 Thrombotic Microangiopathy and the Renal Allograft 879 Acute Humoral Rejection 879 Chronic Allograft Glomerulopathy 885 Other Lesions in Renal Transplants 885 Diabetic Nephropathy 885 Membranous Glomerulonephritis 891 BK Virus (Polyomavirus) 891 Cyclosporine Nephropathy 891 Miscellaneous Lesions 896 Microparticles in Deposits 896 Gentamicin Bodies 896 Acute Tubular Injury 899

CHAPTER 13 Diseases of Skeletal Muscle and Peripheral Nerve 912 Umberto De Girolami and Douglas C. Anthony Skeletal Muscle 912 Muscular Dystrophy and Congenital Myopathy 920 Congenital Myopathies 927 Metabolic Myopathies 930 Mitochondrial Myopathies 937 Inflammatory Myopathies 937 Neurogenic Atrophy 949 Peripheral Nerve Disease 951 Axonal Degeneration and Regeneration 953 Specific Peripheral Neuropathies 963 Metabolic Neuropathies Associated with Diabetes Mellitus 966 Sensorimotor Neuropathies Associated with Hereditary Metabolic Disease 966 Hereditary Neuropathies 970 Amyloid Neuropathy 980 Immune-Mediated Neuropathies 982 Infectious Neuropathies 983 Neuropathy Associated with Paraneoplastic Syndromes and Dysproteinemias 986

Index 991 Douglas C. Anthony, M.D., Ph.D. Chief of Neuropathology Division, Department of Pathology, Children’s Hospital; Associate Professor of Pathology, Harvard Medical School, Boston, Massachusetts, USA Robert B. Colvin, M.D. Chief of Pathology, Department of Pathology, Massachusetts General Hospital; Benjamin Castleman Contributors Professor of Pathology, Harvard Medical School, Boston, Massachusetts, USA Umberto De Girolami, M.D. Chief of Neuropathology Division, Department of Pathology, Brigham & Women’s Hospital; Professor of Pathology, Harvard Medical School, Boston, Massachusetts, USA Alain P. Marion, M.D. Department of Pathology, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada Shamila Mauiyyedi, M.D. Renal Fellow in Pathology, Department of Pathology, Massachusetts General Hospital; Clinical Fellow in Pathology, Harvard Medical School, Boston, Massachusetts, USA Martin K. Selig, B.A. Senior Medical Technologist, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA

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