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Histology for Pathologists FIFTH EDITION Published April 2019

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Histology for Pathologists FIFTHEDITION ISBN 978-1-4963-9894-9

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Filled with more than 1,000 images, the latest edition of this award-winning comprehensive classic written by anatomic pathologists for anatomic pathologists—has been updated with new information on surgical principles and techniques. Like previous editions, the book is designed to bridge the gap between normal histology and pathologic alterations.

Published April 2019 Sample Chapter Preview

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Features include: Unique among pathology textbooks in using human—as opposed to animal—tissues for discussions on histology. Now featuring the latest developments and advances made since the previous edition five years ago. Essential reading for all anatomic pathologists, and particularly helpful for pathology residents throughout their training. NEW NEW

Chapters and sections organized by biological system as well as body region.

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Contributors

Sylvia L. Asa, MD, PhD Professor Department of laboratory Medicine and Pathobiology University of Toronto Toronto, Ontario Kristen A. Atkins, MD Professor Department of Pathology University of Virginia School of Medicine Charlottesville, Virginia Hikmat Al-Ahmadie, MD Assistant Attending Department of Pathology Memorial Sloan Kettering Cancer Center New York, New York Leomar Y. Ballester, MD, PhD Assistant Professor Department of Pathology and Laboratory Medicine University of Texas Health Science Center at Houston Houston, Texas Karoly Balogh, MD Associate Professor of Pathology Harvard Medical School Beth Israel Deaconess Medical Center Boston, Massachusetts José E. Barreto, MD Attending Pathologist Instituto de Patología e Investigación Asunción, Paraguay Kurt Benirschke, MD † Emeritus Professor Department of Pathology UC San Diego School of Medicine San Diego, California Gerald J. Berry, MD Professor of Pathology Director of Cardiac and Pulmonary Pathology Director of Anatomic Pathology

John S.J. Brooks, MD Chair Department of Pathology Pennsylvania Hospital of University of Pennsylvania Health System Philadelphia, Pennsylvania Sofía Cañete-Portillo, MD Research collaborator Instituto de Patología e Investigación Asunción, Paraguay Maria Luisa Carcangiu, MD Director UO 1 Anatomic Pathology Department of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Italy J. Aidan Carney, MD, PhD Emeritus Department of Laboratory Medicine and Pathology Mayo Clinic College of Medicine and Science Rochester, Minnesota Darryl Carter, MD Professor Emeritus Department of Pathology Yale School of Medicine New Haven, Connecticut William L. Clapp, MD Director, Renal Pathology Professor, Department of Pathology, Immunolgy and Laboratory Medicine University of Florida School of Medicine Gainesville, Florida Laura C. Collins, MBBS Vice Chair of Anatomic Pathology Director of Breast Pathology Beth Israel Deaconess Medical Center Professor Department of Pathology Harvard Medical School Boston, Massachusetts Julian Conejo-Mir, MD, PhD Head Professor and Chairman Medical & Surgical Dermatology Department Hospital Universitario Virgen del Rocio University of Sevilla Spain

Stanford University Stanford, California

† Deceased

iii

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Contributors

James R. Conner, MD, PhD Assistant Prof Laboratory Medicine and Pathobiology University of Toronto Pathologist Mt Sinai Hospital Toronto Ontario, Canada Antonio L. Cubilla, MD Emeritus Professor Of Pathology Universidad Nacional de Asuncion Director Instituto de Patología e Investigación Asunción, Paraguay Thomas J. Cummings, MD Professor Department of Pathology Duke University School of Medicine Durham, North Carolina Gerald R. Cunha, PhD Professor of Anatomy, Professor of Obstetrics & Gynecology, Professor of Urology Department of Urology University of California San Francisco School of Medicine San Francisco, California Ronald A. DeLellis, MD

C. Blake Gilks, MD Professor

Department of Pathology and Laboratory Medicine University of British Columbia Faculty of Medicine

Vancouver, British Columbia Joel K. Greenson, MD Professor of Pathology Department of Pathology University of Michigan Medical School Ann Arbor, Michigan Krisztina Z. Hanley, MD Associate Professor Department of Pathology Emory University School of Medicine Atlanta, Georgia

Ralph H. Hruban, MD Baxley Professor and Director Department of Pathology The Johns Hopkins University School of Medicine Baltimore, Maryland Seung-Mo Hong, MD, PhD Professor Department of Pathology Asan Medical Center University of Ulsan College of Medicine Seoul, Republic of Korea Muhammad T. Idrees, MD Associate Professor Director immunohistochemistry Department of Pathology Indiana University Indianapolis, IndianaBest Andrew Kanik, MD Medical Director of Histopathology and Director of Dermatopathology Department of Dermatopathology CBLPath, Inc. Rye Brook, New York Darcy A. Kerr, MD Assistant Professor Department of Pathology University of Miami Miller School of Medicine Miami, Florida David S. Klimstra, MD Chairman Department of Pathology Memorial Sloan Kettering Cancer Center New York, New York

Consultant Pathologist Department of Pathology Lifespan Academic Medical Center Providence, Rhode Island Javier Dominguez-Cruz, MD Dermatologist, Investigation Unit Dermatology Department Hospital Universitario Virgen del Rocio Sevilla, Spain

Samson W. Fine, MD Associate Attending Pathologist Department of Pathology Memorial Sloan Kettering Cancer Center New York, New York Gregory N. Fuller, MD, PhD Professor Department of Pathology University of Texas MD Anderson Cancer Center Houston, Texas Patrick J. Gallagher, MD, PhD, FRCPath Senior Clinical Lecturer Centre for Medical Education Bristol University Medical School Bristol, United Kingdom

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Contributors

Günter Klöppel, MD Professor Emeritus Department of Pathology Consultation Center for Pancreatic and Endocrine Tumors Technical University Munich Munich, Germany S.H. Kroft, MD Professor and Interim Chair Department of Pathology Medical College of Wisconsin Milwaukee, Wisconsin Takeshi Kurita, PhD Associate Professor of Cancer Biology and Genetics Steven H. Lewis, MD, FCAP, FACOG Clinical Professor of Pathology and Faculty Associate Bioethics and Humanities Department of Pathology University of Colorado Anschutz Medical Campus Aurora, Colorado Megan G. Lockyer, DO Staff Pathologist Department of Pathology AmeriPath Cleveland Oakwood Village, Ohio M. Beatriz S. Lopes, MD, PhD Professor of Neuropathology and Neurological Surgery Department of Pathology University of Virginia School of Medicine Charlottesville, Virginia Fiona Maclean, MBBS Clinical Associate Professor Department of Clinical Medicine Macquarie University, Sydney Deputy Director Department of Anatomical Pathology Douglass Hanly Moir Pathology Macquarie Park, Sydney Shamlal Mangray, MBBS Director, Pediatric Pathology Department of Pathology Lifespan Academic Medical Center Providence, Rhode Island Fernando Martínez-Madrigal, MD Pathologist Department of Pathology Instituto Mexicano del Seguro Social Morelia, Mexico Department of Cancer Biology and Genetics Ohio State University College of Medicine Columbus, Ohio

Jesse K. McKenney, MD Pathologist Department of Pathology Cleveland Clinic Cleveland, Ohio Ozgur Mete, MD, FRCPC Associate Professor

Department of Pathology University Health Network University of Toronto

Toronto, Ontario, Canada Stacey E. Mills, MD W.S. Royster Professor of Pathology Chief of Anatomic Pathology Director of Surgical Pathology and Cytopathology University of Virginia Health System Charlottesville, Virginia Attilio Orazi, MD, FRCPath Professor and Chairman Department of Pathology Texas Tech University Health Care Sciences P.L. Foster School of Medicine El Paso, Texas Carlos Ortiz-Hidalgo, MD Professor of Histology Department of Tissue and Cell Biology Universidad Panamericana Escuela de Ciencias de la Salud Mexico City Histopathologist Department of Anatomical Pathology Hospital y Fundación Medica Sur Mexico City, Mexico Christopher N. Otis, MD Professor of Pathology Department of Pathology University of Massachusetts Medical School—Baystate Springfield, Massachusetts David A. Owen, MB, BCh, FRCPC Professor Emeritus Pathology and Laboratory Medicine University of British Columbia Faculty of Medicine Vancouver, British Columbia Liron Pantanowitz, MD Professor of Pathology Department of Pathology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

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Contributors

Robert E. Petras, MD Managing Director AmeriPath Institute of Gastrointestinal Pathology and Digestive Disease

Mercedes Sendín-Martín, MD Dermatologist Department of Dermatology Hospital Universitario Virgen del Rocio Sevilla, Spain Carlie S. Sigel, MD Assistant Attending Pathologist Department of Pathology Memorial Sloan Kettering Cancer Center New York, New York Edward B. Stelow, MD Professor of Pathology Department of Pathology University of Virginia School of Medicine Charlottesville, Virginia Kyle C. Strickland, MD, PhD Assistant Professor of Pathology Department of Pathology Duke University School of Medicine Durham, North Carolina

AmeriPath Cleveland Oakwood Village, Ohio Meredith E. Pittman, MD Assistant Professor

Department of Pathology and Laboratory Medicine NewYork-Presbyterian Hospital/Weill Cornell Medicine New York, New York Miriam D. Post, MD Associate Professor Department of Pathology University of Colorado Anschutz Medical Campus Aurora, Colorado Alan D. Proia, MD, PhD Professor Department of Pathology Duke University School of Medicine Durham, North Carolina Victor E. Reuter, MD Vice Chairman Department of Pathology Memorial Sloan Kettering Cancer Center New York, New York Robert H. Riddell, MD, FRCPC, FRCPath Prof Laboratory Medicine and Pathobiology University of Toronto Pathologist Mt Sinai Hospital Toronto Ontario, Canada Stanley J. Robboy, MD Professor of Pathology and Professor of Obstetrics and Gynecology Department of Pathology Duke University School of Medicine Durham, North Carolina Andrew E. Rosenberg, MD Professor, Vice Chair Director of Bone and Soft Tissue Pathology Department of Pathology Miller School of Medicine University of Miami Miami, Florida Stuart J. Schnitt Chief of Breast Oncologic Pathology Dana-Farber/Brigham and Women’s Cancer Center Senior Pathologist Brigham and Women’s Hospital Professor of Pathology

Arief A. Suriawinata, MD Section Chief of Anatomic Pathology Department of Pathology and Laboratory Medicine Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire David Suster, MD Pathologist Department of Pathology Massachusetts General Hospital

Harvard Medical School Boston, Massachusetts Saul Suster, MD Professor and Chairman

Department of Pathology & Laboratory Medicine Froedtert and the Medical College of Wisconsin Froedtert Hospital Milwaukee, Wisconsin

Swan N. Thung, MD Director of Liver Pathology Department of Pathology

Mount Sinai Hospital New York, New York Arthur S. Tischler, MD Professor Department of Pathology Tufts University School of Medicine & Tufts Medical Center Boston, Massachusetts

Harvard Medical School Boston, Massachusetts

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vi i

Contributors

Satish K. Tickoo, MD Attending Pathologist Department of Pathology Memorial Sloan Kettering Cancer Center New York, New York Humberto E. Trejo Bittar, MD Assistant Professor of Pathology Department of Pathology/Thoracic and Autopsy Pathology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Lawrence True, MD Professor Department of Pathology University of Washington School of Medicine Seattle, Washington Thomas M. Ulbright, MD Lawrence M. Roth Emeritus Professor of Pathology & Laboratory Medicine Indiana University School of Medicine Indianapolis, Indiana Paul van der Valk, MD, PhD Professor Department of Pathology University of Amsterdam Medical Centers

Hannes Vogel, MD Professor Department of Pathology

Stanford Medicine Stanford, California Roy O. Weller, MD, PhD, FRCPath Emeritus Professor of Neuropathology Clinical Neurosciences University of Southampton School of Medicine Emeritus Consultant Neuropathologist Cellular Pathology (Neuropathology) Southampton University Hospitals Trust Southampton, United Kingdom Bruce M. Wenig, MD Senior Member Department of Anatomic Pathology H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida Maria Westerhoff, MD Associate Professor Department of Pathology University of Michigan Medical School Ann Arbor, Michigan Rhonda K. Yantiss, MD Professor of Pathology and Laboratory Medicine Chief, Gastrointestinal Pathology Service New York-Presbyterian Hospital/Weill Cornell Medical Center New York, New York Samuel A. Yousem, MD E. Leon Barnes Professor of Anatomic Pathology Department of Pathology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Hala El-Zimaity, MD Pathologist

VU University Medical Center Amsterdam, The Netherlands Allard C. van der Wal, MD, PhD Professor Faculty of Medicine University of Amsterdam Clinical Pathologist Academic Medical Center Amsterdam, The Netherlands J. Han J.M. van Krieken, PhD Professor Department of Pathology Radboudumc Nijmegen, The Netherlands Elsa F. Velazquez, MD Vice President and Director Department of Dermatopathology Inform Diagnostics Needham, Massachusetts Clinical Assistant Professor of Dermatology Tufts University School of Medicine Boston, Massachusetts

Dynacare Laboratories University of Brampton Toronto Ontario, Canada

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Contents

Contributors iii Preface ix Preface to the First Edition xi Acknowledgments xiii

SECTION IV Nervous System 9 Central Nervous System 219 10 Pituitary and Sellar Region 270 M. Beatriz S. Lopes 11 Peripheral Nervous System 300 Carlos Ortiz-Hidalgo and Roy O. Weller Gregory N. Fuller and Leomar Y. Ballester

SECTION I Cutaneous Tissue

1 Skin 3

Andrew Kanik

2 Nail 31 Julian Conejo-Mir, Javier Dominguez-Cruz, and Mercedes Sendín-Martín

SECTION V Head and Neck 12 Eye and Ocular Adnexa 335

SECTION II Breast

Alan D. Proia and Thomas J. Cummings

13 The Ear and Temporal Bone 362 Bruce M. Wenig 14 Mouth, Nose, and Paranasal Sinuses 396 Liron Pantanowitz and Karoly Balogh 15 Larynx and Pharynx 424 Stacey E. Mills 16 Major Salivary Glands 440 Fernando Martínez-Madrigal

3 Breast 69

Laura C. Collins and Stuart J. Schnitt

SECTION III Musculoskeletal System

4 Bone 87

Darcy A. Kerr and Andrew E. Rosenberg

SECTION VI Thorax and Serous Membranes

5 Joints 113 Fiona Maclean

6 Adipose Tissue 133 John S.J. Brooks 7 Skeletal Muscle 166 Hannes Vogel

17 Lungs 469

Humberto E. Trejo Bittar and Samuel A. Yousem

18 Thymus 506

David Suster and Saul Suster

19 Heart 529 Gerald J. Berry 20 Serous Membranes 551

8 Blood Vessels 190 Patrick J. Gallagher and Allard C. van der Wal

Darryl Carter, Lawrence True, and Christopher N. Otis

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xvi

Contents

35 Prostate 964

SECTION VII Alimentary Tract

Samson W. Fine and Jesse K. McKenney

36 Testis and Excretory Duct System 981 Muhammad T. Idrees and Thomas M. Ulbright

21 Esophagus 573

James R. Conner, Hala El-Zimaity, and Robert H. Riddell

37 Penis and Distal Urethra 1009

22 Stomach 601 David A. Owen 23 Small Intestine 615

Elsa F. Velazquez, José E. Barreto, Sofía Cañete-Portillo, and Antonio L. Cubilla

Megan G. Lockyer and Robert E. Petras

SECTION X Female Genital System

24 Colon 640

Maria Westerhoff and Joel K. Greenson

38 Vulva 1031

25 Appendix 664

Krisztina Z. Hanley

Megan G. Lockyer and Robert E. Petras

39 Vagina 1047

26 Anal Canal 677

Stanley J. Robboy, Gerald R. Cunha, Takeshi Kurita, and Kyle C. Strickland

Meredith E. Pittman and Rhonda K. Yantiss

27 Liver 692

40 Normal Histology of the Uterus and Fallopian Tubes 1059 Kristen A. Atkins

Arief A. Suriawinata and Swan N. Thung

28 Gallbladder and Extrahepatic Biliary System 719 Edward B. Stelow and Seung-Mo Hong 29 Pancreas 738

41 Ovary 1107 C. Blake Gilks

42 Placenta 1137

Carlie S. Sigel, Ralph H. Hruban, Günter Klöppel, and David S. Klimstra

Steven H. Lewis, Miriam D. Post, and Kurt Benirschke

SECTION VIII Hematopoietic System

SECTION

Endocrine 43 Thyroid 1175

30 Lymph Nodes 783 Paul van der Valk 31 Spleen 799

Maria Luisa Carcangiu

44 Parathyroids 1201

J. Han J.M. van Krieken and Attilio Orazi

Sylvia L. Asa and Ozgur Mete

32 Bone Marrow 813 S.H. Kroft

45 Adrenal 1225 J. Aidan Carney

46 Neuroendocrine 1249

SECTION IX Genitourinary Tract

Ronald A. DeLellis and Shamlal Mangray

47 Paraganglia 1274

Arthur S. Tischler and Sylvia L. Asa

33 Kidney 855 William L. Clapp 34 Urinary Bladder, Ureter, and Renal Pelvis 949 Victor E. Reuter, Hikmat Al-Ahmadie, and Satish K. Tickoo

Index 1297

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SECTION

Cutaneous Tissue

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Skin Andrew Kanik

EMBRYOLOGY 3 Epidermis 3 Dermis 4

HISTOLOGIC VARIATIONS ACCORDING TO ANATOMIC SITES 18

PATHOLOGIC CHANGES FOUND IN BIOPSIES AND INTERPRETED AS “NORMAL SKIN” 20

Epithelial Skin Appendages 4

SPECIMEN HANDLING 21

HISTOMORPHOLOGY 5 Epidermis 5 Dermis 15

ARTIFACTS 21

Subcutaneous Tissue 16 Blood Vessels, Lymphatics, Nerves, and Muscle 16 HISTOLOGIC DIFFERENCES OF SKIN WITH AGE 18 Newborns and Children 18 Elderly 18

STAINING METHODS 22

Histochemical Stains 22 Immunofluorescence 23 Immunohistochemical Stains/Molecular Studies 23 REFERENCES 27

The skin accounts for about 15% of the total body weight and is the largest organ of the body. It is composed of three layers: (a) epidermis, (b) dermis, and (c) the subcutaneous adipose tissue. Each component has its unique and com- plex structure and function (1–3), with variations accord- ing to age, gender, race, and anatomic location. Functions of the skin are extremely diverse. It serves as a mechanical barrier against external physical, chemical, and biologic noxious substances and as an immunologic organ. It par- ticipates in body temperature and electrolyte regulation. It is an important organ of sensuality and psychological well-being. In addition, it is a vehicle that expresses not only primary diseases of the skin, but also diseases of the internal organs. An understanding of the skin’s normal histology is essential to the understanding of pathologic conditions.

The ectoderm gives rise to epidermis and its append- ages. The mesoderm provides the mesenchymal elements of the dermis and subcutaneous fat (4). Developmental abnormalities in the ectoderm produce among others a variety of syndromes grouped under the umbrella term of ectodermal dysplasias (5). Initially, the embryo is covered by a single layer of ectodermal cells which by the 6th to 8th week of develop- ment differentiates into two layers, the basal layer and an overlying second layer called periderm. Because of mitotic activity, the basal layer becomes the germinative layer and additional rows of cells develop from this proliferating layer, forming a multilayer of cells between the ectoderm and periderm (4). By the 23rd week, keratinization has taken place in the upper stratum, and the cells of the periderm have already been shed (4,6,7). Of interest is that the CD30 antigen, considered to be restricted to tumor cells of Hodgkin disease and anaplastic large cell lymphoma, par- ticipates in the terminal differentiation of many fetal tissues including the skin (8). Cell junction proteins are expressed in the early two- layered embryonic epidermis and as early as the 8th week of estimated gestational age (9). By the end of the first

EMBRYOLOGY

Epidermis Basic knowledge of the embryology of the skin is important because it helps to understand some postnatal pathology.

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SECTION I : CutaneousTissue

trimester, the dermoepidermal junction with its compo- nents is ultrastructurally similar to that of mature skin (10). Thus, the characteristic neonatal epidermis is well devel- oped by the 4th month. Keratinocytes constitute 90% to 95% of the cells in the epidermis. The rest of the epidermal cells are nonkerati- nocytes, and they include melanocytes, Langerhans cells, and Merkel cells. The nonkeratinocytes are seen in the epidermis of 8- to 10-week-old embryos. The precursor cells of melanocytes migrate from the neural crest to the dermis and then to the epidermis, where they differentiate into melanocytes during the first 3 months of development. During this migration, melanocytes can reside in other organs and tissues. Ultrastructurally, recognizable melano- somes in melanocytes may be seen in the fetal epidermis at 8 to 10 weeks of gestational age (11). Langerhans cells are derived from the CD34 + hema- topoietic precursor cell of the bone marrow. The charac- teristic cytoplasmic marker, the Birbeck granule, is seen ultrastructurally in 10-week-old embryos (12). The expres- sion of a more characteristic immunohistochemical marker, CD1a, is completed by 12 to 13 weeks of estimated gesta- tional age (12,13). Merkel cells can also be seen in the epidermis of 8- to 10-week-old embryos. The origin of Merkel cells is debat- able. Some have suggested a neural crest derivation (14), whereas others suggest epidermal origin through a process of differentiation from neighboring keratinocytes (15,16,17). Merkel cells in the epidermis are initially numerous and later diminish with increasing gestational age (18). Dermis The dermis is derived from the primitive mesenchyme underlying the surface ectoderm. The papillary and reticu- lar dermis are recognized by 15 weeks of intrauterine life (19,20). As described by Breathnach (19), three types of cells are recognized in 6- to 14-week-old embryos. Type I cells are stellate-dendritic cells with long, slender processes. These are the most numerous primitive mesenchymal cells and probably give rise to the endothelial cells and the pericytes. Type II cells have less extensive cell pro- cesses; the nucleus is round and the cytoplasm contains large vacuoles. They are classified as phagocytic macro- phages of yolk-sac origin. Type III cells are round with little or no membrane extension, but they contain numer- ous vesicles, some with an internal content suggestive of granule secretory type of cells. These cells could be mela- noblasts on their way to the epidermis, or they could be precursors of mast cells; Schwann cells associated with neuroaxons, but lacking basal lamina, are also identified during this period. The type II mesenchymal cells are rarely seen after week 14 of development. However, another cell type with ultrastructure of histiocyte or macrophage is frequently

seen during this time. Well-formed mast cells are also seen in the dermis. In 14 to 21 weeks of development, fibroblasts are numer- ous and active. Fibroblasts are recognized as elongated spin- dle cells with abundant rough endoplasmic reticulum. They are the fundamental cells of the dermis and synthesize all types of fibers and ground substance (1). Type III collagen fibers are abundantly present in the matrix of fetus, whereas type I collagen fibers are more prominent in adult skin (20). Elastic fibers appear in the dermis after the collagen fiber during the 22nd week of gestational age; and, by week 32, a well-developed network of elastic fibers is formed in the dermis. Initially, the dermis is organized into somites, but soon this segmental organization ends and the dermis of the head and neck and extremities organizes into dermatomes along the segmental nerves that are being formed (21). From the 24th week to term, fat cells develop in the subcutaneous tissue from the primitive mesenchymal cells. Epithelial Skin Appendages Most epithelial cells of skin appendages derive from fol- licular epithelial stem cells localized in the basal layer of epidermis at the prominent bulge region of the develop- ing human fetal hair follicles. Furthermore, such multipo- tent stem cells may represent the ultimate epidermal stem cell (22). In 10-week-old embryos, mesenchymal cells of the developing dermis interact with epidermal basal cells. These epidermal cells grow both downward to the dermis and upward through the epidermis to form the opening of the hair canal. As the growing epithelial cells reach the subcutaneous fat, the lower portion becomes bulbous and partially encloses the mesenchymal cells descending with them to form the dermal papillae of the hair follicle, this structure plays an important role in the future processes of hair follicle regeneration (23). The descending epider- mal cells around the dermal papillae constitute the matrix cells from which the hair layers and inner root sheath will develop. The outer root sheath derives from downward growth of the epidermis. The first hairs appear by the end of the 3rd gestational month as lanugo hair around the eyebrow and the upper lip. The lanugo hair is shed around the time of birth. The developing hair follicle gives rise to the sebaceous and apocrine glands. The sebaceous glands originate as epithelial buds from the outer root sheath of the hair follicles and are developed at approximately the 13th to 15th gestational weeks (24). Differentiated sebaceous glands with a hair protruding through the skin surface are present at the 18th week of gestational age (25). They respond to maternal hormones and are well developed at the time of birth. The apocrine glands also develop as epithelial buds from the outer sheath of the hair follicles in 5- to 6-month- old fetuses (21) and continue into late embryonic life as long as new hair follicles develop.

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CHAPTER 1: Skin

The eccrine glands develop from the fetal epidermis independent of the hair follicles (21). Initially, they are seen as regularly spaced undulations of the basal layer. At 14 to 15 weeks, the tips of the primordial eccrine glands have reached the deep dermis, forming the eccrine coils (26). At the same time, the eccrine epithelium grows upward into the epidermis. The primordial eccrine epithelium acquires a lumen by the 7th to 8th fetal month, and thus the first eccrine unit is formed. Both ducts and secretory portions are lined by two layers of cells. The two layers in the secre- tory segment undergo further differentiation; the luminal cells into tall columnar secretory cells, and the basal layer into secretory cells or myoepithelial cells. The first glands are formed on the palms and soles by the 4th month, then in the axillae in the 5th month, and finally on the rest of the hairy skin (27). Epidermis The epidermis is a stratified and keratinizing squamous epi- thelium that dynamically renews itself maintaining its nor- mal thickness by the process of desquamation. The cells in the epidermis include (a) keratinocytes, (b) melanocytes, (c) Langerhans cells, (d) Toker cells (in certain anatomic locations), and (e) Merkel cells. In addition, the epidermis contains the openings for the eccrine ducts (acrosyringium) and hair follicles. Recent immunohistochemical studies have demonstrated that the epidermis contains free nerve axons in association with Langerhans cells (28). Keratinocytes The keratinocytes of the epidermis are stratified into four orderly layers from bottom to top: (a) the basal layer (stratum basale, germinativum), (b) the squamous layer (prickle cell layer or stratum spinosum), (c) the granular layer (stratum granulosum), and (d) the cornified or horny layer (stratum corneum) (Fig. 1.1). In histologic sections, the dermoepi- dermal junction has an irregular contour because of the upward extension of the papillary dermis to form the dermal papillae. The portion on the epidermis separating the dermal papillae are the rete ridges (Fig. 1.2). The transcription factor p63 plays an important role in this orderly arrangement and continuous development of the pre- and postnatal skin (29). ❯ T he B asal L ayer Basal cells are the mitotically active cells that give rise to the other keratinocytes. Histologi- cally, basal cells are seen as a single layer of cells above the basement membrane that show minor variations in size, shape, and melanin content. Basal cells are columnar or cuboidal, with a basophilic cytoplasm. The nucleus is round or oval, with coarse chromatin and indistinct nucleolus. Basal cells contain melanin in their cytoplasm as a result HISTOMORPHOLOGY

FIGURE 1.1 Electron micrograph of normal epidermis and portion of papillary dermis ( × 2,100) ( 1 , papillary dermis; 2 , basal cells; 3 , squamous layer; 4 , granular layer; 5 , cornified layer).

of pigment transfer from neighboring melanocytes. Basal cells are connected to each other and to keratinocytes by specialized regions (known as desmosomes) located in the plasma cell membranes. They are aligned perpendicular to the subepidermal basement membrane and attached to it by modified desmosomes, hemidesmosomes. Certain dermatitides involving the basal layer produce vacuolar alteration of the basal cells, which may progress to the formation of subsequent subepidermal vesicles as seen in diseases such as graft-versus-host disease, lupus erythe- matosus, and erythema multiforme. ❯ T he S quamous L ayer The squamous layers are com- posed of approximately 5 to 10 layers of cells with keratino- cytes larger than the basal cells. The suprabasal keratinocytes are polyhedral, have a somewhat basophilic cytoplasm, and a round nucleus. Again, melanin is seen scattered in many of these keratinocytes, where it provides protection from the damaging effect of ultraviolet light. The more superficial

FIGURE 1.2 Normal skin showing stratified epidermis with rete ridges, papillary dermis, and reticular dermis (H&E). Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this content is prohibited.

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cells are larger, flattened, eosinophilic, and oriented parallel to the surface. The keratinocytes contain one or two con- spicuous nucleoli and tonofilaments within the cytoplasm. The squamous layer is also called the spinous or prickle cell layer because of the characteristic appearance by light microscopy of short projections extending from cell to cell. These projections are the result of retraction of the plasma membrane during tissue processing, whereas the desmosomes remain relatively fixed and correlate with intercellular bridges. Desmosomes are composed of a variety of polypeptides, desmogleins and desmocollins as transmembrane constitu- ents and the desmoplakin, plakoglobin, and plakophilin as cytoplasmic components. In addition, other intercellular junctions (such as gap junctions and adherens junctions) are distinct from desmosomes in composition and distribution and provide alternative cell-to-cell adhesion mechanisms (30). An intercellular space of constant dimension is present between each cell; acid and neutral mucopolysaccharides are present in the intercellular spaces as indicated by spe- cial stains. The pemphigus antigens are localized in the cell membranes (31) or in the desmosomes of these cells (32). Occasionally, Toker cells with clear or pale cyto- plasm are seen in the squamous layer. It is important to distinguish these cells from the neoplastic cells of Paget disease. Benign clear cells have a pyknotic nucleus sur- rounded by a clear halo and a narrow rim of clear cytoplasm (Fig. 1.3). They lack the pleomorphism, nuclear morphol- ogy, and intensity of the chromatin staining seen in Paget cells (Fig. 1.4). Regardless of gender (33), these benign

FIGURE 1.4 Paget cells in extramammary Paget disease.

clear cells are often seen in the epidermis of the nipple, the accessory nipple (34,35), and the pubic regions or in the milk-line distribution (36). In the nipple, these clear cells, also called Toker cells, have been considered to be non- neoplastic ductal epithelial cells, although some authors hypothesized that these cells might be the precursors of mammary or extramammary Paget diseases (35,37). Those outside of the nipple are considered to be the result of either abnormal keratinization or aberrant derivatives of eccrine or apocrine sweat gland epithelial cells (38–40). They may present as hypopigmented macules or papules in a rare dis- order called clear cell papulosis. The immunohistochemical staining pattern of benign clear cells may resemble that of Paget cells in that they react with the cytokeratin 7 (CK7) but differ from Paget cells in that they are usually negative for GCDFP-15. However, emphasis should be made that morphologic distinction is the most important manner to differentiate both cells. Common inflammatory changes seen in the squamous layer are (a) spongiosis—intercellular edema (e.g., allergic con- tact dermatitis), (b) acanthosis—thickening of the epidermis (e.g., psoriasis), (c) atrophy—thinning of the epidermis (e.g., discoid lupus erythematosus), (d) acantholysis—detachment of keratinocytes because of changes involving intercellular junctions (e.g., pemphigus), and (e) dyskeratosis—abnormal keratinization (e.g., squamous carcinoma). ❯❯ T he G ranular L ayer The granular layer is composed of one to three layers of flattened cells lying parallel to the skin surface. The cytoplasm contains intensely basophilic- stained granules known as the keratohyalin granules. In contrast, trichohyalin granules (produced by the inner root sheath of hair follicles) are stained red on routine hema- toxylin and eosin (H&E)-stained sections. The keratohya- lin granules are histidine rich and are the precursors to the protein filaggrin, which promotes aggregation of keratin filaments in the cornified layer.

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Histologic observation of this layer can provide key find- ings in certain entities such as increase (e.g., lichen planus) and decrease (e.g., psoriasis) in the thickness of the granular layer. Keratinocytes, located between the squamous layer and the granular layer, contain small membrane-coating gran- ules known as lamellar granules (also called Odland bodies or keratinosomes). They are composed of the acid hydro- lase and neutral sugars conjugated with proteins and lipids. These granules, present both intra- and extracellularly, are approximately 300 nm in diameter and are not visible by light microscopy. Their functions are to provide epidermal lipids, increase the barrier property of the cornified layer against water loss, and aid in the desquamation process. This interface between the squamous and the granular layer is also the site of synthesis and storage of cholesterol (41). ❯❯ T he C ornified L ayer The cornified layer is composed of multiple layers of polyhedral eosinophilic keratinocytes that lack a nucleus and cytoplasmic organelles. These cells are the most differentiated cells of the keratinization system. They are composed entirely of high–molecular-weight kera- tin filaments. In formalin-fixed section, the cornified layers are arranged in a basket-weave pattern (Fig. 1.5). These cells eventually shed from the surface of the skin. The process of keratinization takes 20 to 45 days. In histologic sections taken from the skin of the palms and soles, a homogenous eosinophilic zone, known as the stratum lucidum is present in the lowest portion of the cor- nified layer (above the granular layer). This additional layer is rich in extracellular elements such as energetic enzymes and SH groups adding to the normal functional barrier of the skin (42). Common abnormalities of the cornified layer are (a) hyperkeratosis—increased thickness in the cornified layer (e.g., ichthyosis), (b) parakeratosis—presence of nuclei in the cornified layer (as usually seen in actinic keratosis), and (c) presence of fungal organisms (superficial dermatophytosis).

FIGURE 1.6 PAS-positive basement membrane.

Basement Membrane Zone The basement membrane zone separates the epidermal basal layer from the dermis. It is seen by light microscopy as a continuous, undulating, and thin periodic acid–Schiff (PAS)-stained layer (Fig. 1.6). By electron microscopy, the basal cells are attached to the basal lamina by hemidesmo- somes. Ultrastructurally, the basement membrane zone is composed of four distinct structures, from top to bottom (Fig. 1.7) (43): 1. The plasma membrane of the basal cells containing the hemidesmosomes. Bullous pemphigoid antigen 1 is local- ized in the intracellular component of hemidesmosomes. 2. The lamina lucida, an electron-lucent area with anchoring filaments containing various laminin isoforms (44). Bullous pemphigoid antigen 2 (type XVII collagen) is associated with the transmembrane component of hemidesmosome- anchoring filament complexes in the lamina lucida. It is also the site of the blister in dermatitis herpetiformis (45). 3. The lamina densa, an electron-dense area composed of mainly type IV collagen. 4. The sublamina densa zone, or pars fibroreticularis, contains mainly the anchoring fibrils (46) (type VII col- lagen) that attach the basal lamina to the connective tissue of the dermis. Antibodies against epidermolysis bullosa acquisita react with the carboxy terminus of type VII collagen (47,48). Inflammatory conditions of the basement membrane can be seen by light microscopy as thickening (e.g., discoid lupus erythematosus) or by the formation of subepidermal vesicles (e.g., bullous pemphigoid). Melanocytes Melanocytes are dendritic cells that derive from the neu- ral crest. During migration from the neural crest, mela- nocytes may localize in other epithelia. In the epidermis,

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plasma membrane of these melanocytes to the basal lamina. Laminin-5, a component of anchoring filaments, may be a ligand for melanocyte attachment to the basement mem- brane in vivo (49). In addition, melanocytes that are close to the basal lamina have structures resembling hemidesmo- somes of basal keratinocytes (50). Melanocytes produce and secrete melanin. Melanin can be red (pheomelanin) or yellow-black (eumelanin). The most important function of melanin is to protect against the injurious effects of nonionizing ultraviolet irradiation. Melanin is formed through a complex metabolic pro- cess in which tyrosinase is the main catabolic enzyme, using tyrosine as substrate. The synthesis of melanin takes place in melanosomes, lysosome-related organelles. In the early stages of development, melanosomes are membrane-limited vesicles, located in the Golgi-associated endoplasmic reticu- lum. The maturation of melanosomes undergoes four stages. Stage I melanosomes are round without melanin. These are seen in balloon cell melanoma. Stage II through stage IV melanosomes are ellipsoidal with numerous longitudinal fil- aments. Melanin deposits start at stage II. In stage III, mela- nin deposits are prominent. Stage IV melanosomes are fully packed, with melanin obscuring the internal structures. The developing melanosomes, with their content of melanin, are transferred to the neighboring basal keratino- cytes and hair follicular cells. The mechanism of melanin transfer is a complex process (51,52), with the end result being phagocytosis of the tip of melanocytic dendrites by the keratinocytes (Fig. 1.9) in a process called pigment donation (53). The number of melanocytes in normal skin is constant in all races, the ratio being 1 melanocyte for every 4 to 10 basal keratinocytes. Alteration of this ratio is important in the diagnosis of certain pigmented lesions such as malig- nant melanoma of the lentigo maligna type and etiologies of clinical hypopigmentation such as vitiligo.

FIGURE 1.7 Ultrastructure of basement membrane ( × 37,800) ( 1 , hemides- mosome; 2 , lamina lucida; 3 , lamina densa; 4 , lamina reticularis; 5 , melanin; 6 , tonofilaments).

the melanocytes are localized in the basal layer, and their dendritic processes extend in all directions. The dendritic nature of normal melanocytes is usually not seen in routine H&E-stained sections. In H&E preparations, melanocytes are composed of elongated or ovoid nuclei surrounded by a clear space (Fig. 1.8). They are usually smaller than the neighboring basal keratinocytes. Melanocytes do not con- tain tonofilaments and do not attach to basal cells with des- mosomes. However, anchoring filaments extend from the

FIGURE 1.8 Melanocytes in the basal layer, composed of ovoid nuclei within a clear space. Copyright © 2020 Wolters Kluwer Health, I c. Unauthorized reproduction of this content is prohibited. FIGURE 1.9 Electron micrograph showing membrane-bound phagocy- tized melanin in keratinocyte ( × 19,200).

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CHAPTER 1: Skin

The color of the skin is determined by the number and size of melanosomes present both in keratinocytes and melanocytes—and not by the number of melanocytes. The number of melanocytes decreases with age. As a result, the availability of melanin to keratinocytes diminishes, so the skin becomes lighter in color and the incidence of skin can- cer increases because of the lack of protection that melanin provides. Melanin is both argentaffin and argyrophilic. It can be recognized by Fontana–Masson silver stains. In addition, melanocytes and their dendritic processes are identified by the dopa reaction in histologic slides prepared from frozen sections and in paraffin-embedded sections with immuno- histochemical stains with S100 protein. The latter is highly sensitive but not specific for cells of melanocytic lineage. The S100 protein can be detected in various types of cells, such as Langerhans cells, Schwann cells, eccrine, and apocrine gland cells. Melanocytes can also be identified with monoclonal antibodies Melan-A/MART-1 (Melanoma Antigens Recog- nized by T cells-1), a melanocytic differentiation marker. The Melan-A/MART-1 antigen is expressed in normal melano- cytes, common nevi, Spitz nevi, and malignant melanoma. Under normal conditions, the melanoma-associated antigen HMB-45 does not react with adult melanocytes (54). It is expressed in embryonic melanocytes, hair bulb melanocytes and activated melanocytes (55). It is usually seen reacting with most melanoma cells, Spitz nevi, the junctional compo- nent of common nevi, and dysplastic nevi. An absence or significant decrease in the number of melanocytes is seen in vitiligo. In albinism, there is a defect in the synthesis of melanin, but the number of melanocytes is normal in a skin biopsy. Melanocytic hyperplasia is seen in lentigo, benign, and malignant melanocytic neoplasms, and as a reaction pattern in a variety of neoplastic and non- neoplastic conditions (e.g., dermatofibroma). In a freckle, there is an increase in pigment donation to adjacent kerati- nocytes rather than melanocytic hyperplasia. Langerhans Cells Langerhans cells (LCs), discovered by Paul Langerhans in 1868, are mobile, dendritic, antigen-presenting cells pres- ent in all stratified epithelium and predominantly in the mid to upper parts of the squamous layer. In H&E-stained sections, LCs can be suggested as they appear to lie within lacunae having darkly stained nuclei with indented, reni- form shape at high magnification (Fig. 1.10). As with mela- nocytes, their dendritic nature cannot be seen in routine sections. Langerhans cells can be recognized by histoen- zymatic stains for adenosine triphosphatase (ATPase); they can also be detected in formalin-fixed, paraffin-embedded tissue using immunoreactivity for S100 protein and, more specifically, the antibody to the CD1a antigen (Fig. 1.11). With histoenzymatic and immunohistochemical stains, the extensive dendritic nature of LCs becomes evident. By electron microscopy, LCs show no desmosomes, tonofilaments, or melanosomes. They contain small vesicles,

FIGURE 1.10 H&E section of possible Langerhans cells composed of elongated nuclei surrounded by a clear space in the mid epidermis.

multivesicular bodies, lysosomes, and the characteristic Birbeck granule (Fig. 1.12) (56), a rod-shaped organelle varying in size from 100 nm to 1 μ m (57). It has a centrally striated density and an occasional bulb at one end with a unique tennis-racket appearance. Langerhans cells are also present in epithelia, lymphoid organs, and dermis and are increased in the skin in a variety of inflammatory conditions, such as contact dermatitis, where they can be seen as min- ute nodular aggregates in the epidermis. Langerhans cell granulomatosis is a reactive lesion most commonly seen in bones but also appearing at other sites. Merkel Cells Merkel cells (MCs), first described by F.S. Merkel in 1875, are scattered and irregularly distributed in the basal cell layer in the epidermis. They may group together in clusters coupled with enlarged terminal sensory nerve fibers to form slowly adapting mechanoreceptors; within the epidermis, they mediate tactile sensation (58–60). They are located in higher concentration in the glabrous skin of the digits, lips, and oral cavity, in the outer root sheath of hair follicles (61), and in the tactile hair disks (62).

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FIGURE 1.12 Electron micrograph of a Langerhans cell containing Birbeck granules ( arrows ) and multisegmented nucleus ( × 8,000).

FIGURE 1.13 Cytokeratin 20 staining a Merkel cell in the basal layer of the epidermis.

Merkel cells are not recognized in routine histologic preparations. Electron microscopy and immunostaining are required for their identification. By electron microscopy, MCs are attached to adjacent keratinocytes by desmosomes. They have scant cytoplasm, invaginated nuclei, a parallel array of cytokeratin filaments in the paranuclear zone, and the characteristic membrane-bound dense core granules that are often, but not always, related to unmyelinated neurites. By immunostaining techniques, normal and neoplastic MCs may express neuron-specific enolase, chromogranin, synaptophysin, neural cell adhesion molecule, and various neuropeptides and other substances (63–65). However, the expression of these substances in MCs is heteroge- neous and variable. The constant pattern seen in MCs is the presence of paranuclear aggregates of cytokeratins (15,65,66), which include low–molecular-weight keratins 8, 18, 19, and 20. The most specific cytokeratin is CK20 because, in addition to MCs, they are expressed in simple epithelial cells and not in adjacent keratinocytes (67,68) (Fig. 1.13). Pilar Unit The pilar unit is composed of the hair follicle, sebaceous gland, arrector pili muscle, and (when present) eccrine and apocrine glands. ❯❯ H air F ollicle The hair follicle is divided into three segments from top to bottom: (a) the infundibulum,

which extends from the opening of the hair follicle in the epidermis to the opening of the sebaceous duct; (b) the isthmus, which extends from the opening of the sebaceous duct to the insertion of the arrector pili muscle; and (c) the inferior segment, which extends to the base of the follicle. The inferior segment is bulbous and encloses a vascularized component of the dermis referred to as follicular (dermal) papilla of the hair follicle (Fig. 1.14). The microanatomy and function of the hair follicle are very complex. The cells of the hair matrix differentiate along six cell linings. Beginning from the innermost layer, they are (a) the hair medulla; (b) the hair cortex; (c) the hair cuticle; and (d) three concentric layers of the inner root sheath, which are the cuticle of the inner root sheath, Huxley layer, and Henle layer. The inner root sheath of the hair follicle is surrounded by the outer root sheath (Fig. 1.15), which is composed of clear cells. These glycogen-rich cells are seen in some of the neoplasm with hair follicular differentiation (e.g., trichilem- moma). A PAS-positive basement membrane separates the outer root sheath from the surrounding connective tissue. Thus, the hair shaft is formed from the bulb region that occupies the hair follicular canal. Dendritic melanocytes are present only in the upper half of the bulb, whereas inactive (amelanotic) melanocytes are present in the outer root sheath. These melanocytes can become active after injury, migrating into the upper portion of the outer root sheath and to the regenerating epidermis.

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