SAUNDERS An Imprint of Elsevier ‘The Curtis Center Independence Square West Philadelphis, Pennsylvania 19106 Library of Congress Cataloging.n-Publication Data Mule, George {Small animal dermatlogy} Mules & Kets small animal deatology—8h ed /Danny W. Scot. Wiliam H, Miler, J, Craig E- Gat, bem ISBN-13: 978-0-7216-7610-0 ISBN. 0-7216-7616-9 1.Dogs—Diseases, 2. Cals—Diseases. 3 Pets—Diseasos. 4 Vetorinary domatology. |. Ki, Robert Warren, 1882. I Scot, Danny We I Mil, WitanH. (iar Howard), 1988- IV. Goffin, Craig EV. Te '5F092.855 MBS 2001 696 089'65—de21 0.030088 ISBN-13: 978-0-7216-7618-0 ISBN-10: 0-7216-7618-9 Acquisitions Bator: Ray Kersey ‘Book Designer: Jonel Soian Production Manager: Norman Stellandet Manuscript Elitor: Carol DiBerardino Mustration Specialist: Lis Lambert MULLER & KIRK'S SMALL ANIMAL DERMATOLOGY Copyright © 2001, 1995, 1989, 1983, 1976, 1969 by Saunders Allrights reserved. No part ofthis publication may be reproduced or transmitted in any frm or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher Permissions may be sought dtctl from Elsevier's Health Sciences Rights Department in Philadephia, USA. phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail healthpermissions@elsevier com. You may a0 ‘complete your request onine via the Elsevier homepage (tp:/www elseviet.com), by selecting “Support and contac’ and then ‘Copyright and Permision” Printed in China Lastdigit isthe print number, 9 8 7 6 5Preface and Acknowledgments Each time we gear up to do another edition of Small Animal Dermatology, we optimisti- cally—yet with the trepidation born of familiarity—tell ourselves that this rewrite will be less involved, less time consuming, less intimidating than the last. After all . . . we just did a total rewrite for the previous edition... . so this one couldn't possibly bé as extensive. . . could it? ‘Well, once again we have found the task daunting . . . just shy of stifling. In fact, for the first time in the history of the book, we came in 6 months late. Oof! One convenient explanation for our struggles and tardiness —one that admittedly attempts to deflect some portion of the blame fiom where it clearly should land, right smack-dab on our Bdgeting selves—is the staggering amount of new information that has surfaced in the last 5 years in the field of veterinary dermatology. Good examples of this prodigious proliferation include the more than 70 “new” conditions described herein, and the numerous veterinary dermatology textbooks published during this time span (see Chap. 22) In veterinary medicine, very litle information is available concerning the demograph- ies of canine and feline skin disorders. It has been estimated that between 20% and 75% of the small animals seen in the average practice have skin problems as a chief or ‘concurrent owner complaint.'“* A 1978 Ralston Purina Company survey indicated that 25% of all small animal practice activity was involved with the diagnosis and treatment of problems with the skin and haircoat.® A nationwide survey by the Alpo Company in 1985 ‘of 2540 small animal practitioners in the United States revealed that skin disorders were the most common reason for patient visits to the veterinarian’s office.’ Dermatologic disorders accounted for 188% of the dogs and 15.2% ofthe cats examined at a univers teaching hospital.” Using data gathered from 17 North American veterinary teaching hospitals for the year 1983, Sischo and associates reported that the 10 most commonly diagnosed canine ‘skin disorders were, in decreasing order of frequency, flea bite hypersensitivity, skin cancer, bacterial pyoderma, seborrhea, allergy, demodicosis, scabies, immune-mediated dermatoses, endocrine dermatoses, and acral lick dermatitis® Significant differences were noted in the frequency of those skin diseases in the various geographic regions studied. A survey conducted in 1981 by the American Academy of Veterinary Dermatology revealed the most common feline dermatologic disorders to be, in decreasing order of frequency, rasitie dermatoses, miliary dermatitis, eosinophilic granuloma complex, endocrinolo Esorders, fungal diseases, hypersensitivity reactions, bacterial disease, pychogente derma: toses, sebortheic conditions, neoplastic tumors, and autoimmune dermatoses." During a I-year period at a university teaching hospital,® the most common dermato- ses in dogs and cats were as follows: Dogs—bacterial folliculitis and furunculosis (25.3% of the cases), atopy (12.7%), food ‘hypersensitivity (4.7%), flea bite hypersensitivity (3.4%), hyperadrenocorticism (3.4%), and hypothyroidism (2.7%). Cats—abscesses (18.5%), otodectic mange (12.9%), cheyletiellosis (8.1%), flea bite hypersensitivity (6.5%), atopy (6.6%), flea infestation (4.9%), neoplasia (4.9%), and food hypersensitivity 47),vi * Preface and Acknowledgments Clearly, dermatology is a “big ticket item” in small animal practice; bacterial infec- tions, ectoparasitisms, allergies, fungal infections, and neoplasia are common problems. ‘We cannot overstate our appreciation for those who have contributed to this sixth edition of Small Animal Dermatology. We couldn't have done it without yout Held up for special praise and recognition are those who have given so much in terms of love, patience, and support during this production: Kris, Travis, and Tracy (DWS); Kathy, Steven, Julia, and Andrew (WHM); and Laura, Trevor, Kyle, and Taylor (CEG). And last, but not least, we sincerely thank the whole crew at W.B. Saunders Company—especially Ray Kersey—for their patience, support, and terrific effort And now ... it's time to open up our labor of love for your serutiny. In the words of Bob Seger (and the Silver Bullet Band, of course), we invite you to “Turn the Page.” © REFERENCES 1, Schwartzman RM, Orkin M: A Comparative 7, Alpo Veterinary Panel. Dermatologica problems Sty of Skin Diseaes of Dog and Man, Charles hhetd problem ist. DVM Magazine,” August, C Thomas, Springfeld, CT, 1962 1985, 2, Uhrke PJ, Frant’ CE: Breed as a risk ctor asto- 8, Scott DW, Paradis M: A survey of canine and ciated with skin diseases in dogs seen in northem feline skin disorders soon in « university practice: California, Calf Vet 39:13, 1985, Small “Animal Clinic, University. of Montréal 3, Neshitt GH: Canine and Feline Dermatology: Saint-Hyacinthe, Québec (1987-1988). Can Vet j Systematic Approach. Lea & Febiger, Philadel 31:830, 1990. phia, 1989, 8. Sischo' WM, et ali Regional distibution of 10 4, Wilkinson GT: Color Atlas of Small Animal Der common skin diseases in dogs. ] Am Vet Med rmatclogy. Willams &e Wilkins, Baltimore, 1985 Assoc 195,752, 1989 5. Grant Di: Skin Diseases in the Dog and Cat. 10, Nesbitt GH: Incidence of feline skin disease: a Blackwell Scentie Publications, Oxford, 1985, survey. Proc Am Acad Vet Dermatol, Las Vege 6, Ralston Paria Company. An Tntrodvetion to the 1982, Nutiton of Dogs and Cats. Veterinary Learning Systems, Trenton, NJ, 1980 D.W. Scott W. HL Miller, Jr C. E. GriffinThe Last Time ‘The greatest professional honor I have ever received was being asked to join “the book.” Yo! George Muller . . . the legendary father of “the book”... and Bob Kirk . . . the ‘most famous veterinarian on the planet. I mean . . . T had contributed bits and pieces to the second edition but now I was coauthor of “the bible.” T have always taken “the book” very seriously: as a clinical dermatologist and educator, I could do no fess. “The book” is an enormous commitment, an awesome responsibility. When it is to be “reborn,” it demands your all: all your knowledge, all your experience, all your sifting and analysis of our vast literature, all your energy. Getting “the book” ready for its next viewing is all about enthusiasm, conviction, dedication, perseverance, several very short or sleepless nights, curtailed family time, a number of “Advil moments” and, when it is done, a feeling of having given all you had. . . of numbness. T no longer have what it takes to do “the book” the way it needs to be done . . . and 1 love this book too much to do anything less than give it the very best there is. So, this will be my last edition. It has been a great ride, a true honor and blessing to be associated with “the book.” And Ray Kersey with W.B. Saunders and my wife, Kris, have been with me for the whole 25 years. As much as it aches to say good-bye . . . it is time. I am comforted in the knowledge that—in Bill and Craig—Small Animal Dermatology will be left in knowledgeable, experienced, dedicated, and loving hands. And now Tam reminded of a great old song by Mick and the boys, which T have often found myself humming as I worked on this sixth edition! The Last Time (Mick Jagger and Keith Richard, 1965) Thanks, George. Thanks, Bob. Thanks, Ray. Thanks, Kris. Thanks, Bill. Thanks, Craig. Thanks to everyone out there. May “the book” be with you! Danny Ithaca, New York—2000NOTICE Companion animal practice is an ever-changing field. Standard safety precautions must be followed, but as new research and clint espeence gow. changes In Geatment and drug therapy become. necessary or appropriate. The authors and editors of this work have carclily checked the generic und trade drug names and veriBed drag dosages to ensure that dosage information is precise and in accord with standards accepted at the time of publication. Readers are advised, however, to check the product information currently rovided by the manufacturer of each drug to be administered to be certain that changes ave not been made in the recommended dose or in the contraindications for administra- tion. This is of particular importance in regard to new or infrequently used drugs Recommended dosages for animals are sometimes based on adjustments in the dosage that would be suitable for humans. Some of the drugs mentioned here have been given experimentally by the authors. Others have been used in dosages greater than those recommended by the manufacturer. In these kinds of cases, the authors have reported on their own considerable experience. It is the responsibility of those administering a drug, relying on their professional skill and experience, to determine the dosages. the best treatment for the patient, and whether the benefits of giving a dug justify the attendant risk. The editors cannot be responsible for misuse or misapplication of the material in this work ‘THE PUBLISHERChapter 1 Structure and Function of the Skin WwW hat a glorious organ it is! The skin is the largest and most visible organ of the body and the anatomic and physiologie barrier between animal and environment, It provides protection from physical, chemical, and microbiologic injury, and its sensory components perceive heat, cold, pain, pruritus, touch, and pressure. In addition, the skin is synergistic with internal organ systems and thus reflects pathologic processes that are either primary elsewhere or shared with other tissues. Not only is the skin an organ with its own reaction patterns; it is also a mirror reflecting the miliew interieur and, at the same time, the capricious world to which it is exposed. The skin, hair, and subeutis of @ newborn puppy represent 24% of its body weight.!™ By the time of maturity, these structures constitute only 12% of body weight: © GENERAL FUNCTIONS AND PROPERTIES OF THE SKIN The general functions and properties of animal skin are as follows" 1. Enclosing barrier. The most important function of skin is to make possible an internal eovironment for all other organs by maintaining an effective barrier to the loss of water, electrolytes, and macromolecules. 2, Environmental protection. A corollary function is the exclusion of external injuri- fous agents—chemical, physical, and microbiologie—from entrance into the inter- nal environment. 3, Motion and shape. The flexibility, elasticity, and toughness of the skin allow motion and provide shape and form. 4. Adnexa production. Skin produces keratinized structures such as hair, claws, and the homy layer of the epidermis. 5. Temperature regulation. Skin plays a role in the regulation of body temperature through its support of the hair coat, regulation of cutaneous blood supply, and sweat gland function. 6. Storage. The skin is a reservoir of electrolytes, water, vitamins, fat, carbohydrates, proteins, and other materials. 7. Indicator. The skin may be an important indicator of general health, internal disease, and the effects of substances applied topically or taken internally. It contributes to physical and sexual identity 8, Immunoregulation. Keratinocytes, Langerhans’ cells, and lymphocytes together provide the skin with an immunosurvellance capability that effectively protects against the development of cutaneous neoplasms and persistent infections. 9. Pigmentation. Processes in the skin (melanin formation, vascularity, and. keratini- zation) help determine the color of the coat and skin. Pigmentation of the skin helps prevent damage from solar radiation. 10. Antimicrobial action. The skin surface has antibacterial and antifungal properties. *See references 57, 65, 102,150, 166, 172, 180, 187, and 196.2 + Structure and Function of the Skin 11, Sensory perception. Skin is a primary sense organ for touch, pressure, pain, itch, heat, and cold. 12, Secretion, Skin is a secretory organ by virtue of its epitrichial (apocrine), atrichial (eccrine), and sebaceous glands. 13, Exeretion, The skin functions in a limited way as an excretory organ. 14, Vitamin D production, Vitamin D is produced in the skin through stimulation by solar radiation. In the epidermis, vitamin D, (cholecaleiferol) is formed from ovitamin Dy (7-dehydrocholesterol), via previtamin D,, on exposure to sun- light The vitamin D—binding protein in plasma translocates vitamin Dy from the skin to the circulation. Vitamin Dy is then hydroxylated in the liver to 25- hydroxyvitamin D, and again hydroxylated in the kidney to form 1,25-dihydroxyi- oan De ‘which is important In the regultion of epidermal potiention and differentiation © % © ONTOGENY Skin is a complex multicellular organ in which endoderm, neural erest, and ectoderm contribute to form a three-dimensional unit in a spatially and temporally defined manner. ‘Skin morphogenesis involves the aetion of multiple genes in a coordinated fashion, Hom eobox genes are a gene family that encode information critieal for normal embryologi development and that likely play a very important role in the development of skin adnexa, pigment system, and stratified epithelium during embryogenesis." Epithelial-mesenchymal interactions regulate tissue homeostasis, the balanced reguil- tion of probiferation and differentiation maintaining normal tissue architecture and func- tion.!!° Multiple circuits of reciprocal permissive and instructive effects exist between epithelial and mesenchymal cells and extracellular matrices. Initially, the embryonic skin consists of a single layer of ectodermal cells and a dermis containing loosely arranged mesenchymal cells embedded in an_ interstitial ground substance. The ectodermal covering progressively develops into two layers {the basal cell layer, or stratum germinatioum, and the outer periderm), three layers (the stratum intermedium forms between the other two layers), and then into an adult-like structure 57 1.°§ Melanocytes (neural crest origin) and Langerhans’ cells (bone marrow origin) become identifiable during this period of ectodermal maturation. Dermal development is characterized by an increase in the thickness and number of fibers, a decrease in round substance, and the transition of mesenchymal cells to fibro- blasts. This process of building a fiber-rich matrix has been referred to as a ripening of the dermis, Elastin fibers appear later than do collagen fibers. Histiocytes, Schwann cells, and dermal melanocytes also become recognizable. Fetal skin contains a large percentage of Type HI collagen compared with the skin of an adult, which contains a large propor tion of Type I collagen Lipocytes (adipocytes, fat cells) begin to develop into the subeutis from spindle-shaped mesenchymal precursor cells (prelipoblasts) in the second half of gestation, ‘The embryonal stratum germinativum differentiates into hair germs (primary epithelial germs), which ve rise to halt follicles, sebaceous glands, and eptichtal (apocrine) sweat slands.+ ™.177 Hair germs initially consist of an area of crowding of deeply basophilic cells in the basal ayer of the epidermis. Subsequently, the areas of crowding become buds that protrude into the dermis. Beneath each bud lies a group of mesenchymal cells, from ‘which the dermal hair papilla is later formed. As the hair peg lengthens and develops into @ hair follicle and hair, three bulges appear. The lowest (deepest) of the bulges develops into the attachment for the arrector pili muscle, the middle bulge differentiates into the sebaceous gland; and the uppermost Balge evolves into the epitrichal sweat gland. These appendages develop on the ental side of primary hair folliles secondary har olicles develop on the extal ste, In general, the first hairs to appear on the fetus are vibrissae and tactile or sinus hairs that develop on the chin, eyebrows, and upper lip as white, slightly raised dots on otherwise smooth, bareStructure and Function of the Skin * 3 skin 17 The general body hair appears first on the head and gradually progresses caudally. Atrichial (eccrine) sweat gland germs also begin as areas of crowding of deeply basophilic cells in the basal layer of the epidermis, They initially differ from hair germs only slightly by being narrower and by showing fewer mesenchymal cells at their base. Cell interaction plays a central role in the formation of skin appendages.!"® Monpho- gens are substances that control the development of the hair follicle." ®” In addition, several new adhesion molecule families that mediate cell-to-cell and cell-to-substrate adh sion have been identified: (1) neural cell adhesion molecules (N-CAM), which belong to the immunoglobulin (IgG) gene superfamily; (2) cadherins, which mediate adhesion in the presence of calcium: (3) tenascin, which is a unique matrix molecule similar to the epidermal cell growth factor (EGF); (4) fibronectin, fibrinogen, and syndecan; and (5) integrins, which serve as cellular receptors for fibronectin, collagen, and other extracellular ‘matrix molecules. ®-*%. 1 Thus, in each step of the morphogenesis of skin appendages, different adhesion molecules are expressed and are valved in diferent functions induc tion, mesenchymal condensation, epithelial folding, and cell death ‘AIL vessels in fetal skin develop first as capillaries ® They have been suggested to organize in situ from dermal mesenchymal cells into single-layered endothelial tubes. Branches from large subcutaneous nerve trunks extend into the dermis and organize into deep and superficial plexuses related to the vascular plexus. © GROSS ANATOMY AND PHYSIOLOGY At each body orifice, the skin is continuous with the mucous membrane located there (digestive, respiratory. ocular, urogenital). The skin and haircoat vary in quantity and quality among, species, among breeds within a species, and among individuals within a breed; they also vary from one area to another on the body, and in accordance with age and sex. In general, skin thickness decreases dorsally to ventrally on the trunk and. proximally to distally on the limbs." 8 2% The skin is thickest on the forehead, dorsal neck, dorsal thoras, rump, and base of the tail. It is thinnest on the pinnae and on the axillary, inguinal, and perianal areas. ‘The reported average thickness of the general body skin of cats is 0.4 to 2.0 mm! ™; of dogs, it is 0.5 to 5.0 mm. ™ The haircoat is usually thickest over the dorsolateral aspects of the body and thinnest ventrally, on the lateral surface of the pinnae, and on the undersurface of the tail, The skin surfaces of haired mammals are, in general, acidic. The pH of normal feline and canine skin has been reported to range from about 5.5 to 7.5: 12.19% 155 186.17 In a dynamic study of skin surface pH in dogs,’ the following observations were made: pH values varied at different sites on the skin and varied from day to day; males had significantly higher pH values than females on all sites; spayed females had significantly higher pHT values at all sites than intact females; black Labrador retrievers had significantly higher pH values than yellow Labrador retrievers, and Labrador retrievers and miniature schnauzers were significantly different from English springer spaniels and Yorkshire terri ers, Clearly, skin surface pH appears to vary with site, day, coat color, sex, gonadal status, and breed. In addition, it has been reported that the skin surface pH of an excited dog can inerease by greater than 1 unit within 1 minute! The metabolism of the skin is not well understood. All of the enzymes of the Aycolstic pathway and those of the tricarboxylie acid cyele have been demonstrated in Skin. but actual glucose metabolism ‘seems to be anomalous ™ ©." °!™ Glace is preferentially metabolized to lactate, rather than fully oxidized to CO,. The skin is an active site of fatty acid metabolism (see Chap. 3) Studies of the surface markings of the muzzle and nose have shown that there are individual, genetically determined differences similar to those of human fingertips." It has been’ suggested that imprints (“fingerprints”) of these special skin areas (termed labiograms or nasolabiograms) could be used for the identification of animals,4+ Structure and Function of the Skin Hair Hair, which is characteristic of mammals, is important in thermal insulation and sen- sory perception and as a barrier against chemieal, physical, and microbial injury to the skin "177" Hair is photoprotective. The ability of a haircoat to regulate body temperature correlates closely with its length, thickness, and density per unit area, and with the medullation of individual hair bers. in general, haircoats composed of long, fine, poorly medullated fibers, with the coat depth increased by piloerection, are the ‘most efficient for thermal insulation at low environmental temperatures. Coat color is also of some importance in thermal regulation; light-colored coats are more efficient in hot, sunny weather. The glossiness of the haircoat is important in reflecting sunlight. Transghutami- tue a murder of early agen blr Flleoy, and ts imported ln ie protein cross- linking that contributes to the shape and remarkable physical strength of hair: The diameter of the hair shaft is largely determined by the volume of the hair matrix epithe- lium, and the final length of the hair shaft is determined by both the rate of hair growth and the duration of anagen Both primary (outercoat, guard) and secondary (undercoat) hairs are medullated in dogs and cats; thus, the term lanugo, meaning nonmedalated, is incorrect when applied to nonletal dogs and cats. In cats, secondary hairs are far more numerous than primary hairs Uioat dorsal, 241 ventrally). The haits of the cat have been divided into three types Jased on gross appearance: (1) guard hairs (thickest, straight, evenly tapered to a fine tip), (2) awn hairs (thinner, possessing subapical swelling below the hair tip), and (3) dawn hairs (thinnest, evenly erimped or undulating).'®.1% 7 In general, the shape of the hair fiber is determined by the shape of the hair follicle, with straight follicles producing straight hairs and curly follicles producing curly hairs." "77 in general, no new hair follicles are formed after birth. Puppies do not actually “lose” their puppy coat; rather, they gain an adult coat. Puppies have simple hair follicle produce secondary hairs for the first 12 weeks of life." All hair follicles grow obliqu to 60 degrees) in relation to the epidermis, The direction of the slope of the hairs, which varies from one region of the body to another, gives rise to the hair tracts." The study of hair tract patterns is called trichoglyphics. The true significance and the origin of hair tracts are unknown. With the hair slope generally running caudally and ventrally, benefits include minimal impediment to forward motion and the ability of water to flow off the body to the ground without soaking the haircoat, which would reduce its thermal-insulat- ing properties. ‘Adult shorthaired cats produced a yearly amount of hair growth of 32.7g/kg."> Dogs produced 60 to 180 g/kg, depending on the breed." Hair Cycle Analysis of the factors controlling or influencing hair growth is complicated by evolution- ary history *® The pelage changes as a mammal grows, and that of the adult often differs markedly fom that ofthe juvenile, reflecting different requirements for heat regulation, camouflage, and sexual and social communication. In addition, the eyclic activity of the hair follicles and the periodic molting of hairs have provided a mechanism by which the ppelage can be adapted to seasonal changes. in ambient temperature or environmental background. This mechanism is influenced by changes in the photoperiod, which acts through the hypothalamus, hypophysis, and pineal gland, altering levels of various hor- tones (incudig melatonin, prolactin, and those of gonadal, thyrowdal, and adrenocortical origin) and modifying the inherent rhythms of the hair follicle Hair growth cycles involve the repeated induction of hair follicle anlagen and their concurrent downward growth and invasion through the dermis: 8 Signals controlling, hair follicle induction, development, regression, and reactivation have not been identified: however, multiple growth factors or their receptors (e.g., EGF, transforming growth factor (TGF]-61, TGF-B2, neurotrophin-3) have been localized to’ hair follicles and the sur- rounding mesenchyme, These grovith factors control cellular proliferation and collagenaseStructure and Function of the Skin * release from cultured hair follicles. In addition, an interplay between class I major Bstocompatbilty complex (MIIC) expression, condltin proteoglycans, and aetiated macrophages is involved in the regulation of hair growth, especially during the eatagen phase.* Neural mechanisms of hair growth control in mice have revealed that the sensory and autonomic innervation of hair follicles, the substance P content of skin, and the cutaneous nerve~mast cell contacts show changes during the hair cycle." The hair follicle is a source and a target of neurotrophins, and neuropharmacologic manipulations alter hair cycling. The trophic effects of cutaneous nerves on follicular growth are exerted via regulation of vascular tone (nutrient and oxygen supply), neuropeptide stimulation of receptors on follicular keratinocytes and dermal papilla fibroblasts, and modulation of ‘macrophage and mast cell activities. In dogs, hair growth retardation (follicular atrophy) has occurred after experimental sectioning of peripheral nerves and dorsal roots."® How- ever, peripheral nerve damage can also induce increased hair growth, as seen in the unilateral hypertrichosis (“hemitrichosis”) following major unilateral thoracic surgery in Hairs do not grow continuously but rather in eyeles (Fig. 1-1). Each cycle consists of ‘4 growing period (anagen), during which the follicle is actively producing hair, and a resting period (telogen), during which the hair is retained in the follicle as a dead (or club) hte that ts absoquently lost. There i also a trantiona) period (catagen) between these two stages. Tt is often stated that certain breeds of dogs, such as poodles, Old English sheepdogs, and schnauzers, have continuously growing hair coats, but there has boon no sclontfe investigation that would substan such a statoment, The relative duration of the phases of the eycle varies with the age of the individual, the region of the ody, the breed, and the sex, and it can be modified by a variety of physiologic and pathologie factors. ‘The hair cycle, and thus the haircoat, are controlled by photoperiod, ambient temp ature, nutrition, hormones, general state of health, genetics, and poorly understood intr sic factors?-4 #728 65 04 15, 11, 66 1.77. 18186 Tntrinsie factors include growth factors and cytokines produced by the follicle, the dermal papilla, and other cells (lymphocytes, FIGURE 1=1, The fair eye. x, Anagen: Daring tht growing stage, ha is produced by mixin cell of the dermal pupils. tary eager: In the tance sage a cotton occu othe ale tn. The Bair above ths wil Boome s "dub, Catage: ‘The dtl fllle boomer thik and Corrupted tnd pushes the hale outward: Telogen ‘Thies the vexing stage. The, dermal papa ‘separates and an epithelial strand shortens to form a secondary eer ce, Early anagen: The seconc " germ grows down to enclose the dermal papilla and a new hair bulb forms. ‘The old “club” ts Tot Anagen: The hai elongates as growth continues,6 + Structure and Function of the Skin macrophages, fibroblasts, mast cells) in the immediate environment, In cats, there was no effect of repeated clipping on hair growth.” Hair replacement in’ dogs and cats is mosaic in pattem because neighboring hair follicles are in different stages of the hair cycle at any one time. Replacement is unaf- fected by castration; it responds predominantly to photoperiod and, to a lesser extent, to tae opera Dogs and eats in temperate latitudes such as the northem United States and Canada may shed noticeably in the spring and fall. Hair follicle activity, and thus hair growth rate, are maximal in summer and minimal in winter. For example, up to 50% of hair follicles may be in telogen in the summer, but this proportion may increase to 90% in the winter. Maximum hair follicle inactivity is reached earlier in female cats than in male cats. Catagen hairs always constitute a small proportion of the total number of hairs, usually accounting for 4% to 7% of the total: Many dogs and cats exposed to several hours of artificial light (e.g., animals housed indoors) shed, sometimes profusely, ughout the year. 1% Sinus hairs are not subject to a seasonal shedding, and are shed rously as single hairs.!”" Hair grows until it attains its preordained length, which varies according to body region and is genetically determined: it then enters the resting phase, which may last for a considerable amount of time. Each region of the body has its own ultimate length of hair beyond which no further growth occurs. This phenomenon is responsible for the distin tive coat lengths of various breeds and is genetically determined. In mongrel dogs, it was shown that hair growth rates varied at different sites and that the speed of growth was related to the ultimate length of the hair in each particular site. For example, in the shoulder region, where ultimate hair length was about 30 mm, the average rate of hair growth was 6.7 mnvwk, whereas in the forehead region, which had ultimate hair length of about 16 mm, the growth rate was 2.8 mmAvk. Other investigators have reported daily hair growth rates in dogs of 0.04 to 0.18 mm (Greyhound)* ™ and 0.34 to 0.40 mm (beagle)? In the cat, daily hair growth rate has been reported to be 0.25 to 0.30 mm"? or 62 to 289 ayem’.* Because hair is predominantly protein, nutrition has a profound effect on its quantity and quality (see Chap. 17). Poor nutrition may produce a dull, dry, brittle, or thin haircoat with or without pigmentary disturbances Under conditions of ill health or generalized disease, anagen may be considerably shortened; accordingly, a large percentage of body hairs may be in telogen at one time. Because telogen hairs tend to be more easily fost, the animal may shed excessively. Disease states may also lead to faulty formation of hair cuticle, which results in a dull, Iusterless hair coat. Severe illness or systemic stress may cause many hair follicles to enter synchronously and precipitously into telogen. Shedding of these hairs (telogen defluxion; see Chap. 11) thus occurs simultaneously, often resulting in visible thinning of the coat oF actual alopecia ‘The hair eycle and haircoat are also affected by hormonal changes.** © 7 1° In general, anagen is initiated and advanced and hair growth rate is accelerated by thyroid hormones and growth hormone. Conversely, excessive amounts of glucocorticoids or estro- gens inhibit anagen and suppress hair growth rate. Dermal papilla cells, which are mesenchymal component of the hair bulb, are considered to play a fundamental role in the induction of epithelial differentiation. These cells are morphologically and funetionally Aifferentiated from dermal fibroblasts and are thought to be the primary target cells that respond to hormones and mediate growth-stimulating signals to the follicular epithelial cells. ‘Obviously, the details of the regulation of hair follicle cycling and growth are extraor- inary complex an sil poorly understood. The factors that control the hur fle ote are, in general, different from the factors that control hair follicle structure. Alterations in factors (eg, hormones) controlling the hair follicle cycle result in follicular atrophy, Alterations in factors (e.g, morphogens) that control hair follicle structure result in follcu- lar dysplasia. Hlair growth is a confusing subject that needs much research. It should be remem- bered that the haircoat of pet animals is a cosmetic or omamental feature. Every effortStructure and Function of the Skin * 7 should be made to minimize procedures (clipping and shaving) that may affect the animal's appearance for many weeks. Although generalizations ean be misleading, normal or short coats usually take about 3 to 4 months to regrow after shaving and long coats ‘may take as Tong as 18 months." Occasionally, an unexplained and extremely frustrating failure to regrow hair in an area of skin occurs, usually following clipping and surgical scrubbing. The skin in affected areas appears grossly normal, but biopsy reveals cata- genization, or occasionally telogenizaton, of the hair folcles, This frustrating follicular arrest disappears spontaneously in 6 months to 2 years after clipping (see Chap. U1). ‘Attention has’ been focused onthe usefulness of hair, analysis as diagnostic tool. 2 It is well recognized by most dermatologists and nutritionists in human. medi- cine that mineral and trace element analysis of hair samples is not a clinically useful tool in the assessment of nutitional status The reasons for variability and unreliability inchude environmental effects (topical agents, geographic location, occupational exposures), differ- ing hair growth rates (health, drugs, age, sex), and lack of standardization in analysis techniques. Until and unless ‘adequate scientific documentation of the validity of such multielement analysis is performed, it is necessary for both health professionals and the public to be aware of the very limited value of hair analysis and of the potential to be confused and misled by it, Scientifically oriented nutritionists do not use hair analysis as a primary method of detecting nutritional problems. Cautious consumers and health profes- sionals should regard practitioners who rely solely on this test with suspicion 2! Small (0.16 to 0.42 mm in diameter), hairless, knoblike structures are present in the haired skin of cats and dogs." 1% 18 These tylotrich pads serve as slow-adapting mecha noreceptors. ell proliferation kinetic values have been establis of normal beagles and Cocker spaniels. These values were established by intradermal pulse-labeling injections of tritiated thymidine, examination of skin biopsies, and autoradi- ‘ographs. The basal cell labeling index was 146 + 0.78% in beagles and 107 + 0.42% in Cocker spaniels. 1d for the hair follicle epithelium Hair Colors and Types Do Although hair types in dogs are extremely diverse, various authors have attempted to cea tes nthe bests of color length, pe of brite, and charectenstis of the medulla and cortex." Hair types among dogs can be divided into normal (intermediate Tength) shor and long coats ae Normal Coat ‘The normal coat is typified by that seen in the German shepherd, the Welsh corgi, and wild dogs such as wolves and coyotes. It is composed of primary hairs (coarse guard hairs or bristles) and secondary hats (fine has or undercoat)” A high proportion of the hairs, by number but not by weight, are secondary hairs. The next two classes of hair coats are also made up of primary and secondary hairs, but the relative sizes of the hairs and their numbers vary markedly from those of the normal coat be classified as coarse or fine. The coarse short coat is typified by the Rottweiler and many of the terriers. This type of coat has a strong growth of primary hairs and a much lesser growth of secondary hairs. The total weight of hair is lower, and the secondary hairs, especially, weigh less and are fewer in number than those in the normal coat. The fine short coat is exemplified by boxers, dachshunds, and miniature pinschers. This type of coat has the largest number of hairs per unit area. The secondary hairs are numerous and well developed, and the primary hairs are reduced in size as compared with those of the normal coatStructure and Funetion of the Skin Long Coat The long coat can also be arranged into two subdivisions: the fine long coat and the ‘woolly or coarse long coat. The fine long coat is found in the Cocker spaniel, the Pomeranian, and the Chow Chow. This coat has a greater weight of hair per unit area than does the normal coat, except in the toy breeds (in which the weight of the hair may be less because it is finer). The woolly or coarse long coat is found in the poodle and in the Bedlington terrier and the Kerry blue terrier. Secondary hairs make up 70% of the total weight of these coats and 80% of the number of hairs; compared with other secondary-type hairs, these are relatively coarse. The three breeds mentioned have less tendency to shed hair than do many breeds. The genetic aspects of coat color in dogs constitute a complex subject." Pigmen- tation in individual hairs may be uniform throughout the length of the shaft, or it may vary. In the agouti-type hair (German shepherd, Norwegian elkhound), the tip is white or light, the heavy body’ is pigmented brown or black, and the base is a light yellow or red- brown. Pigment cells in the bulb of the hair deposit pigment in or between the cortical and medullary hair cells. The amount of pigment deposited in the hair and its location there produce different optical effects; however, there are only two types of pigment. The black-brown pigment is called eumelanin, and the yellow-red pigment is called pheomel- nin. In addition, the melanocytes of the follicle may or may not produce pigment throughout the period of growth. In black hair, pigment production obviously remains active throughout the period CAT ‘The colors and types of hair coat in cats have been studied in some detail 2% 15215 4 self (solid) cat is a single color throughout. No patterning, shading, ticking, or other variation of color is observed, although it is common for kittens to have slightly tabby markings and scattered white hairs that disappear with maturity. Whatever their coloring, all cats are genetically tabbies, possessing the Abyssinian, mackerel, or blotched tabby genes, or a combination of two of these types. Solid white is dominant over all colors but may be associated with various abnormalities; for example, white cats with blue eyes ofte cochlear degeneration and deafness. The tabby is the basic type of cat, the wild type from which all others evolved. The complex tabby coloration arises from two component patterns governed by two separate sets of genes. The underlying pattem is agouti, which is characterized by hairs with a bluish base and black tip separated by yellow banding. The tabby genes determine whether a cat has narrow, vertical, gently curving stipes (mackerel), larger patches (blotch), or an Abyssinian pattern. Tipped hair coats are characterized by hairs that have colored tips (e,, blue, red, Back) verhing a paler eolor. Differences inthe degree of tipping are grat with the greatest in the smokes and least in the chinchillas (silver). Pointed hair coats are charac- terized by pale-colored hair on the body with darker hairs on the extremities or points (nose, ears, feet, tail. Points arise through a temperature-dependent mechanism present in breeds such as Siamese, Himalayan, Balinese, and Birman, In these breeds, the dark hair color (acromelanism) is due to a temperature-dependent enzyme that converts mela- nin precursors into melanin by a process of oxidation." With higher temperatures, the hair is light colored; with low temperatures, it is darker. Thus, kittens are light at birth, ‘and cats kept indoors or in tropical climates are lighter than those kept outdoors or in cold climates. Inflammation and hyperemia result in more lightly colored new hair. The poor peripheral circulation that accompanies senility and shaving to remove hair often result in more darkly colored new hair. Multicolored coats include the tortoiseshell and piebald spotting pattems. The arche- typal tortoiseshell is a patchwork of black and orange, but there is range of color variation among torties. The hair may be chocolate (chestnut), cinnamon, blue, or lilac (lavender) in the nonorange areas. The tortoiseshell pattern occurs in females or in males with two X chromosomes. White spotting in piebald cats varies in degree from white gloves on the feet, a nose smudge, or a white bib, to extensive white over most of the body. haveStructure and Function of the Skin + 9 ‘The Maltese dilution, which dilutes black to blue (gray), orange to eream, and seal point (Siamese) to blue-point, is inherited as an autosomal recessive trait!" In_ non: Maltese cats, small melanin granules of uniform shape and size are scattered uniformly throughout the cortex and medulla of the hair shaft, hair follicle epithelium, and epider mis, In the skin and hair from Maltese dilution eats, a nonuniform distribution of very waped melanin granules results from the clumping of small large, irregularly sized and In a typical shorthaired cat, the longest primary hairs average about 4.5 cm in length By contrast the sly cout ofa good show eat has primary hare that may exceed 12.5 in length. The shorthair is the fundamental wild type and is dominant to the others Various mutant halt coat types have Occurred that have been perpetuated as a breed characteristic. The rex mutant is characterized by curly hairs and occurs in two major breeds, the Devon rex and the Comish (German) rex. The Comish rex lacks primary hairs, and the Devon rex has primary hairs that resemble secondary hairs, Comish rex whiskers are often short and curly, but Devon rex whiskers are often absent or stubbled. Tn some Devon rexes, the coat is completely absent on the chest, belly, and shoulders, a fault many breeders try to eliminate, Comish and Devon rexes may partially or completely molt, especially during estrus or pregnancy, resulting in a symmetric alopecia that may be mistaken for an endocrine dermatosis.* These breeds are occasionally recommended as hypoallergenic cats to humans with animal dander hypersensitivities, but there appears to bbe no scientific documentation for this claim, ‘The wire-hair mutation, seen in the American wirchair, is characterized by a coat that looks and feels wiry because it is coarse, crimped, and springy. All hairs are curled in an irregular fashion, and the awn hairs resemble a shepherd's erook. ‘One survey attempted to relate feline coat color to personality. Results suggested that cats with solid black, black and white, or gray tabby coats tended to have good personalities, to handle stress well, and to make excellent pets. By contrast, calicos were most likely to be aggressive and to have litter pan problems. There are a number of cutaneous patterns or lines that are evoked to explain certain distributions of skin lesions encountered clinically!" Voight's lines are the boundaries of the areas of distribution of the main cutaneous nerve stems. Langer’s lines reflect the course of blood vessels or lymphatics. Blaschko’s lines form the pattern assumed by many different nevoid and acquired skin diseases, Blaschko’s lines reflect a mosaic condition deriving either from a single mutated clone of cells originating from postzygotic muta- tion or from an X-linked mutation made evident by lyonization." These lines follow a V- shape over the spine, an S-shape on the abdomen, an axial distribution on the limbs, and 1 wavy pattern down the forchead, over and below the eyes, over the upper lip, and behind the ear. Tension lines are determined by muscle action, connective tissue fiber orientation and traction, and gravity ® Footpads ‘The canine and feline footpad is a specialized area of integument. "1 The thick epidermis protects against mechanical trauma, and the large fat deposits provide shock- absorbing elasticity. A copious nerve supply provides an important sensory function. Nu- merous atrichial sweat glands produce a secrction that may improve traction during running and climbing and may aso be important in scent marking @ MICROSCOPIC ANATOMY AND PHYSIOLOGY The microscopic anatomy and physiology of the skin of dogs and cats have been the subjects of numerous studlies.* "See references 7, 102, 117, 118,195,138, 16, 168, 170,172,180, 88, 202, and 21.10 + Structure and Function of the Skin Epidermis ‘The outer layer of the skin, or epidermis, is composed of multiple layers of cells defined by position, shape, polarity, morphology and state of differentiation of the keratinocytes (Figs. 1-2, 1-34, 1-4, 1-5, and 1-6; see also Fig. 1-16). There are four distinct cell within the epidermis: Keratinocytes (about 85% of the epidermal cells), melanocytes 5%), Langerhans” clls (3% to 8%), and Merkel eels about 2%), which are associated with tylotrich pads. '*.®% For purposes of identification, certain areas of the epidermis are classified as layers and are named, from inner to outer, as follows: basal layer (stratum basale), spinous layer (stratum spinosum), granular layer (stratum ganulosum), lear yer (stratum lucidum, and omy leer (sau omen). In gen teal, the epidermis of cats and dogs is thin (two to three nucleated cell layers, not counting the homy layer) in haired skin, ranging from 0.1 to 05 mm in thickness or in depth.!'8 "18.85.22 The thickest epidermis is found on the footpads (see Fig. 1—4) and nasal planum (see Fig. 1-5), where it may measure 1.5 mm. The surface of the footpad epidermis is smooth in cats but papillated and irregular in dogs. Rete ridges (projections FIGURE 1-2. A, Normal canine shin, B, Norma feline skin. Note the thin epidermis and il ha fol Hole srangement of bath spocies.FIGURE 1-2. 4 Norn canine int & E an) 2, Elsi (end olan ak ers (AOC stain) C, Min (Whe) separating dermal collagen bundles (pink) (H&E stan), Melanin granes (black) sn keratinocytes and melano- cores (lear cell") (H & E sain). E, Keratohyalin granules (dark blue) below stratum comeum (Hf & E-stin) F. ‘eichobyalin granules (red) nthe Inver rot sheath ofa hat follicle (H & E stain). Note vacuolated (glycogen) appearance of enter root sheath Keratinogtes. G, Tichilemmal keratnation (ee) of central hat Talide (H&E stan) H, Basement ‘membrane zone (oll) (PAS stan).12 + Structure and Funetion of the Skin FIGURE 1-4. 4, Histologic section of eanine forpad. Note papilated sie face. B, Histologic section of feline footpat. Note smooth surface,FIGURE 1-5. Histologic section of ‘the nasal plamuen, Note the thick ris, dende stratum comoum, and rete of the epidermis into the underlying dermis) are not found in the normal hair-bearin skin of eats and dogs. Rete “ee however, may be found in normal footpad and nas planum cpiderm and in the lightly haired serotum (see Fig. 16). BASAL LAYER ‘The stratum basal is a single row of columnar to cuboidal cells resting on the basement ‘membrane zone that separates the epidermis from the dermis (see Figs. 1-5, 1-7, and 1-10). 18.1% Most of these cells are keratinocytes, which are constantly reproducing and pushing upward to replenish the epidermal cells above. The daughter cells move into the ‘outer layers of the epidermis and are ultimately shed as dead horny cells. Mitotic figures and apoptotic Keratinocytes are occasionally seen, especially in areas of skin with thicker epidermis (e.g,, nasal planum, footpad, mucocutaneous junction). There is morphologic and factional heterogeneity in basal Keratinocytes sone populations serve primarily to anchor the epidermis, and others serve a proliferative and Foparative (stem cel) function The tips of the deep epidermal rete ridges (in glabrous skin) and the bulge (Wulst) region of the hair follicle (site of attachment of the arrector pili muscle) are the presumed sites of the epidermal and hair follicle stem cells in humans and rodents. "5 Dogs and eats do not have a hair follicle bulge-*. Hemidesmosomes are junctional complexes distributed along the inner aspect of basal Keratinocytes, whose major role is epidermal-dermal adhesion. ¥ The linkage of the keratin intermediate filament (cytokeratin) network to the hemidesmosome and the basal keratinocyte plasma membrane involves several components, including the plaque proteins bullous pemphigoid antigen I (BPAG I or BP 230) and plectin, the transmembrane proteins ‘1664 integain and BPAG TT (collagen XVID, and lannin 32" Various inherited dofects in the hemidesmosome-anchoring filament components are known to produce vari avs aed pklermelyss bulls and tabs to some ofthe components are invaed in pathogenesis of pemphigoid and bullous systemic lupus erythematosus.2 Tntogeins aru large family of cel surface adhesive receptors These cell surface lycoproteins are important int cell-cell and cell-matrix interactions, and also act as signal Sorelucen through which extracellular and intracellular compartments can influence and modify each hee Each integrin consists of a heterodimer of an a and a subunit, which are noncovalently associated. In the epidermis, integrin expression is normally confined to the basal layer. The integrin subunits that are most abundant in the epidermis are a, @, By, a, and ,. Examples of keratinocyte integrin functions include: asB, which14 + Structure and Function of the Skin FIGURE 1-6, Histologic section of ‘canine scrotal skin, Note muscle bundles (arrow) imedats keratinogte adhesion to fbronectin, cy, which mediates Keratinoet alhesion to colagens type T and TV and laminin: a, which i a receptor for epigin and is ion to laminin; ay6,, which mediates keratinocyte adhesion to vitronectin; and ag which mediates keatinoge adhesion fo laminin (see Table 22)” MELANOCYTES AND MELANOGENESIS Melanocytes, the second type of cell found in the basal layer of the epidermis, are also found in the outer root sheath and hair matrix of hair follicles, in the ducts of sebaceous and sweat glands, and to a lesser extent in the superficial dermis.* Traditionally, melano- gytes are structurally and functionally into two compartments: epidermal and follicular". 1 1% Because melanocytes do not stain readily with hematoxylin and eosin (H & E) and because they undergo artifactual cytoplasmic shrinkage during tissue pro- cessing, they appear as cler cls (se Fig, 1-78), In general, there is one melaooyte per 10'to 2) keatinoeytes in the basal cel layer. They are derived from the neural crest nd migrate into the epidermis in early fetal le. Although melanocytes ure of nondescript appearance, with special stains, they can be shown to have long cytoplasmic extensions *Sce references 51, 65, 77,111,150, 172, 180, and 206,Structure and Function of the Skin + 15 FIGURE 1-7. 4, Dondsitc metanoetes (arrow) inthe basal hyer of the epidermis. B, Melanceyes (lear cols) (arrchead) in the stratum basal.16 + Structure and Funetion of the Skin }. Pigmented epithelism from nasal plana, Note how melanin granules are offen clustered in ape” dorsal to keratinocyte nucle, (dendrites) (see Fig. 1-7A) that weave among the Keratinocytes. There is an intimate relationship between melanocytes and keratinocytes in which both cells interact and exist as epidermal symbionts in a functional and structural unit called the epidermal melanin unit. 115. 1% Ultrastructurally, melanocytes are characterized by typical intracytoplasmic melanosomes and premelanosomes and a cell membrane~associated basal layer lamina (see Fig. 1-9). Most of the melanin pigment in skin is located in the basal layer of the epidermis, but in dark-skinned animals, melanin may be found throughout the entire epidermis as well as within superficial dermal melanocytes (see Fig. 1-3D). Melanin granules are often clustered as “caps” dorsal to keratinocyte nuclei (Fig. 1-8), presumably 1 photoprotective localization. ‘Although the melanocyte accounts for only a small proportion of the epidermal cells, it has a vasety ‘of important functions: (1) a cosmetic entity, participating in protective coloration and in sexual attraction; (2) a barrier against ionizing radiation, especially Important in protection agaist utrvlet ght (UL) (8) a sonenge of titre rd ‘and intermediates; and (4) a participant in developmental and inflammatory proc- esses. 11.1 Although melanin absorbs UVL over a broad spectrum, including UVA and. UVB, itis not a particulaly eliient absorber of UVL. Tt probably photoproteets in other ways, possibly as a quencher of free radicals generated in response to UVL. Melanin’ pigments are chiefly responsi for the coloration of skin’ and halt. Skin pigmentation is considered to consist of two components. Constitutioe pigmentation is the pigmentation that is genetically determined in the absence of stimulatory influences, Facultative pigmentation is that which occurs with various stimuli (eg, UVL, inflamma- tion, hormones). Melanins embrace a wide range of pigments, including the brown-black cumelanins, yellow or rolbrown pheomelanns, and other pignents whose pliyscocherioal natures fre intermediate between the two. Pheomelanins differ from eumelanins by contain- ing a high proportion of sulfur. Despite the different properties of the various melanins,Structure and Function of the Skin + 17 they all arise from a common metabolic pathway in which dopaquinone is the key inter- mediate.*: Melanogenesis takes place exclusively within melanocytes and on the specialized or- ganelle, the melaosome:® " "® Here, the specie ene, tyrosinase, ‘ctalzs the conversion of tyrosine to dopa. Tyrosinsse is the rate-limiting enzyme in the melanin pathway. It is a copper-containing enzyme, is found exclusively in melanocytes, and is thus 1 good specific marker for these cells. Tyrosinase is an unusual enzyme in that it has three distinet catalytic activites. The most crite! is its yrosine hydrolase atv, converting tyrosine to dopa. However, it is also able to use dopa or 5,6-dihyroxyindole (DH) as substrates for oxidase activities. Mutations in the tyrosine structural gene are responsible for several types of albinism!!! ‘Once dopa is formed, it can spontaneously autooxidize to dopaquinone without tyrosi- nase (though at slower rates), and continue through the melanin pathway to dopachrome, 5,6-dihyclroxyindole-2-carboxylic acid (DHICA), DHI, and indole-5,6-quinone.® "8" An- other melanocyte-specific enzyme is dopachrome tautomerase, which converts dopachrome to DHICA."""™ This conversion requires the presence of iron, ‘The determination to produce eumelanins or pheomelanins is under genetic con- trol%-.10 19 If sulfhydryl groups are available, pheomelanins are produced. Tt has been proposed that the “switching” of melanin synthesis is mainly controlled by the levels of tyrosinase, with high levels producing eumelanins and low levels producing pheomel Mammalian pigmentation is regulated at many different developmental, cellular, and subcellular levels, and is influenced by many genes‘ "6°, Although melanocytes in the skin have characteristic basal levels of function that are particular to each individual, they are highly responsive cells that continually sample their environment and modulate their levels. of proliferation and melanogenesis. Classically, melanin production was thought to be under the control of geneties and melanocyte-stimulating hormone (MSH) from the pituitary gland.® ® ©". The main pigmenting hormones from the pituitary gland include a-MSH (a-melanocortin), adrenal cortical stimulating hormone (corticotro- in), and B-lipotropic hormone (B-lipotropin).""» !° These hormones are derived from a ee ee ie origin hormones in physiologic and pathologic pigmentation in mammals is largely un- mown. At present, rome Ba the: theory | that melanogenesis and m¢ lanocyte roliferation and differentiation are mostly regulated locally in paracrine and autocrine ashion. Melanocytes express a number of cell surface receptors (e.g. intercellular adhesion molecule 1 HANI} that allow interaction with other cells in their envionment includ ing keratinocytes, Langerhans’ cells, fibroblasts, lymphocytes, and macrophages." 19.6 They express receptors for and respond to (modifying their proliferation, differentiation, and melanogenesis) growth factor (e.,, 6 fibroblast growth factor) hormones, interferons, interleukins, eicosanoids, retinoic acid, vitamin Dy, and a host of other cytokines. In fact es are able to produce some of these themselves, thus acting in an autocrine . Melanocytes themselves secrete several cytokines (e.g. interleukin-8 [IL-8]) and ipate in inflammatory and immunologic reactions. Many of the precursors and inter- mediates of the melanin biosynthetic pathway are cytotoxic and could contribute to cellular injury and infammation. It can be appreciated that a highly complex interaction exists between the cellular components of the epidermis, their respective immune cyto- kines, and the inflammatory mediators released in response to injury. @-MSH is a neuroimmunomodulatory and ant-inflammatory peptide that is synthe- sized and released by keratinocytes, Langerhans’ cells, fbroblasts, and endothelial cells, as, well as melanocytes themselves." 815° q-MSH cell surface receptors can also be identi- fied on these cells. a-MSH can, hence, modulate Keratinocyte proliferation and differenti- ation, and endothelial cell and fibroblast cytokine and collagenase production. It also downregulates the production of proinflammatory cytokines and accessory molecules on antigen-presenting cells (monocytes and macrophages). MSH is an antagonist of IL-1, fn important cytokine in the cutaneous immune response. Thus, a-MSH is part of @18 + Structure and Function of the Skin mediator network that modulates eutancous inflammation and hyperprolifeative skin dis ‘eases. This may he far more important than any effect it has on skin pigmentation. Melanogenesis takes place in membrane-bound organelles called melanosomes,** 1 designated stages I through IV according to maturation (Fig. 1-9). It is often stated that the ultrastructural hallmark of the melanocyte is the melanosome, However, it is more accurate to say that stage I melanosomes are melanocyte specific, because later stage melanosomes may be found in keratinocytes and other phagocytic cells!!! Melanosomes FIGURE 1-9. siclinoote. \, nics of manos: rows, melansomes, C, lige in the dennis ter baal lmint (100) nt Meamomer in fran sag of past) eT) (erom Lew WE Tippett, Pdi, 10, int tage re net. Sage I oer nurgLeer 6: Hiepathg of SkinStructure and Funetion of the Skin + 19 originate fom the Gol epputus, where the tyrosinase ename i formed. Stage, 1 melanosomes contain no melanin and are electron lucent. As melanin is progressively laid down on protein matrices, melanosomes become increasingly electron dense. At the same time, they migrate to the periphery of the dendrites, where transfer of melanin to adjacent epidermal cells takes place. Transfer involves the endocytosis of the dendrite tips of the incorporated Stage IV melanosomes by the adjacent keratinocytes, Melanocytes eject melanosomes into keratinocytes by a unique biologic transfer process called cytocri- nia Dermal melanocytes are often referred to as continent melanocytes, because they do not transfer melanosomes as do the epidermal or secretory melanocytes. Skin color is determined mainly by the number, size, type, and distribution of melanosomes. ‘At present, there are no histochemical stains that can be performed on routinely processed skin biopsy specimens that exclusively stain melanin.” Argentafin stains rely n the ability of melanin to reduce silver from a silver solution (eg., silver nitrate) Examples of argentaffin stains include Fontana-Masson and Gomori’s methenamine silver These agents also stain neurosecretory granules and formalin pigment. Argyrophil stains ae similar to argentafin stains, but use an external silver reducer to produce elemental silver. An example of an argyrophil stain is Grimelius’ stain, Argyrophil stains also stain nerves, reticulum, and elastic fibers. MERKEL'S CELLS Merkel’s cells are dendritic epidermal clear cells confined to the basal cell layer, or just below, and occur predominently in tylotrich pads and hair follicle epithelium.* These specialized cells (slow-adapting mechanoreceptors) contain a large cytoplasmic vacuole that isplaces the cell nucleus dorsally. and their long assis usually parallel to the skin surface (Fig. 1-10). They possess desmosomes and characteristic dense-core cytoplasmic granules and paranuclear whorls on electron microscopic examination (Fig. 1-11). Merkel's cells also contain cytokeratin, neurofilaments, and neuron-specific enolase, suggesting a dual epithelial and neural differentiation, Current evidence suggests that Merkel's cells are derived from a primitive epidermal stem cell". ! Merkel’s cells may have other functions, such as influencing cutaneous blood flow and sweat production (via the release Of vasoactive intestinal peptide), coordinating keratinocyte proliferation, and maintaining eae a a ‘SPINOUS LAYER The stratum spinosum (prickle cell layer) is composed of the daughter cells of the stratum basale.®. "17218 2 Tn hairod skin, this layer is one or two cells thick, The stratum spinosum becomes much thicker at the footpads, nasal plamuro, and mucocutaneous jinetions, where it may occasionally approach 20 cell layers. The cells are lightly baso- philic to eosinophilic, nucleated, and polyhedral to flattened cuboidal in shape. The keratinocytes of the stratum spinosum appear to be connected by intercellular bridges (prickles), which are more prominent in nonhaired skin (Fig, 1~12) Keratinocyte adhesion is mediated by four major types of adhesive and communicative structures: desmosomes, hemidesmosomes, adherens junctions, and focal adhesions (Table 1-1).8%.! Hemidesmosomes and focal adhesions are located on the basal surface of basal calls and mediate adhesion to the underlying extracellular matrix, whereas desmosomes adherens junctions mediate adhesion between Keratinocytes in all epidermal layers Gap junctions serve primarily as intercellular routes of chemical communication." Because of the research efforts directed at defining the pathomechanism of pemy gus, mach has been learned concerning the structure and chetnical composition of ep mal desmosomes." Desmosomes are presently known to consist of keratin intermediate “See references 65,69, 77 110, 169,170, 172, 173, 180, and 20620 + Structure and Function of the Skin FIGURE 1-10. Mestots lls (arn) In a tylotich pad filaments and their attachment plagues, the keratinocyte plasma membrane, and the desmosomal core (desmoglea). which is interposed between two adjacent keratinocyte plasma membranes. Numerous desmosomal plaque proteins (desmoplakins I and II, plak- Eelobin, plakophilin) and desmosomal core yecprotens (desmogins 1, I, HT en des mocollins 1, Il, If) have been characterized. The immunohistochemical staining pattern seen with human pemphigus foliaceus antibody is identical to that seen with an antibody directed at desmoglein I (desmosomal core glycoprotein). Protein of the plkoglobin (plaogiobin, catenin), vineuln (vineuin, acatenin), and ‘ezrin (talin, radixin) families are found at desmosomal and adherens junction attach- rments.!* The keratinocyte cytoskeleton consists of three types of cytoplasmic filaments: cytoker- atin, actin, and ewoubules abut)! These. AlamentsTunetion in the oviitation, polarization, organelle sorting, motility, shape change, signal transduction, and structural resilience of keratinocyte Uleastructualyhertinoytes are characterized by keratin intermediate laments (ojtokeratin, tonoflaments) and desmosomes (Fig. 1-13} "Calum and calmodulin are crucial for desmosome and hemidesmosome formation, At least three keratinocyte- derived calmodulin-binding proteins participate in a flip-flop regulation (calcium concen- tration-dependent) of aloe caimodetin teractions elders deamon, tnd spec trin Immunohistochemically, keratinocytes are characterized by the presence of cytokeratins All epithelia express a keratin pair: one keratin chain from the acidic subfamily (Type I keratins, cytokeratins 9-20) and one chain from the neutral-basic sub-‘Structure and Function of the Skin * 20 Lad pte Fs FIGURE I-11. Merits col. N, cleus of a Merkel’ ell asterisk indicts basal lamina M, intochondsa, arous indlete specific games ofthe Meries cel, D wth pointer, desmenome between the Merkel cell and a keratnecyte (KC calligen with crosetiation 20,000) Inet specie membrane-bound granules at higher maison (% 73,000) (From Lever WF. Schaum ingLever G: Histopathology of the Skin, the) B. Lippnott Co, lial 1980, p, 863),22 + Structure and Funetion of the Skin FIGURE 1-12. Pride cells fom footpud showing iterelilar bridges (high power family (Type I keratins, cytokeratins 1-8).* The keratin pairs change with different epithelia and in the same epithelia st various stages of differentiation or proliferation Expression of a subset of these 20 different cytokeratins is more or less tissue specific. A number of workers have published electrophoretic patterns of proteins isolated from the eran of a variety of animals and on the bas of bsered difeences in banding patterns, have suggested that the technique might be useful as an aid to taxonomy, anima classification, and identifcation.® The Keratinocytes of the stratum spinosum synthesize lamellar granules (keratinosomes, membrane-coating granules, Odlund bodies), which are ‘important in the barrier function of the epidermis (see Epidermopoiesis and Keratogene- sis in this chapter). eninge are phagocytic (erythrocytes, melanin, melanosomes, cellular fragments, latex beads, inorganic substances) LANGERHANS’ CELLS. Langerhans’ cells are mononuclear, dendritic, antigen-presenting cells located basally or ‘suprabasally (Fig 1-14)$% 2. 124'26 19 20 They are epidermal clear cells that, like *See references 24a, $6, §5, 110, 148, 185, and 190-198, ‘@ Table 1-1 COMPONENTS OF ADHESION STRUCTURES, ADHESION TRANSMEMBRANE CYTOSKELETON FUNCTION AND STRUCTURE __PROTENS PLAQUE PROTEINS _ FILAMENTS Location Hemideanosome «6B itogin BPAGI Plt, BAGH ‘token Celkanhtate adhesion, “ealge Type cal elt and bas xvit membrane Foo adhesion intone (28, Tain vinci, arac= atin Callebatrat, bas 208 5B) ‘iin palin, min ‘cells Desmorome Dexmocoral adherns —Plaogichin: desma Cytckertin (cel adhesion; ll Dag hil it lskn LIV, entinogtes DeLinit Scsmocnin: pak Adhere juntion Case cadherins Pidgin, and Astin Cell ahesion; ll (sand Peadherins) catenin, cacti, ‘oratineyte (p-ca ‘ret hein asl els ooh) [BPAG, balls pemphigid antigen, Dag ~ desmoglein, Dac desmocainStructure and Funetion of the Skin + 23 FIGURE 1-13. Squamous col N, nucleus; NU, nucleolus: tonofiluments: D, desmesome: M, onde (12,50), Inet: Desmosomes at higher magnification (100,000), A’ desmesome con. Peso aig ents cos of nein. rede dese esa or he Incid fines. The two periperal dense, thick lines (lange asterisks) are the atachment plaques. The ‘single electron-dense linen the center of the desmosome (small asterisk) is the itercelllar contact, layer The two electron-dense lines between the lnterclllar contact layer and the two atachment plagues represent the cell surface coat together with the outer leaflet of the tlaminar plasma ‘membrane of each keratinoeyte (arrows). The two inner eleeton-lucid lies adjacent tothe intercela- Tar contact layer represent interellnlar cement, The two outer cleetro-ld ines are the conta lamina of the tlaminar plasma mombrane. (From Lever WF, Schaumberg- Lever G: Histopathology ofthe Skin, th ed. J.B. Lipincott Co, Philadelphia, 1990 p. 858.)24 + Structure and Function of the Skin FIGURE thie bps 1E 1-14, Epidermal Langerhans’ cells, They appear as suprabasilar epidermal “clear ells” (arr) in 3 fom an atopic dog Merkel’s cells, do not stain for melanin with dopa. The histochemical and immunopheno- type of Langerhans’ cells vary with. poder ger cells in many species—includ- ing cats and humans-—have_ charactestic intracytoplasmic organelles (Bitbecks or Lan- gethans’ granules), which are observed by means of electron microscopy (Fig. 1—15).®° #5 However, the Langerhans’ cells studied in dogs have inconsistently contained these gran- ules.'# 82:5 Birbeck granules are variously described as being zipper, rod, flask, or tennis racket lie in appearance. They form by invagination of the plasma membrane and bound antigen, thus providing the morphologic description of the mechanism by which Langerhans’ cells internalize surface-bound antigen for processing and representation at the surface. ans’ cells are aureophilie (:e., they stain with gold chloride). Unlike Langherhans’ cells in humans, those in dogs and cats are $-100 protein and ATPase negative. They have Fe fraginent (Fe)-IgG and complement 3 (C3) receptors, high affinity receptors for IgE, and they synthesize and express antigens associated with’the immune response gene. In the dog, Langerhans’ cells are CDlabe, CDilac, CD18, CD45, ICAM-1, MHC class II, and vimentin positive." They are CD4 and CD90 (Thy-1} negative, which distinguishes them from dermal dendrocytes. In the cat, Langerhans’ cells are CDla, CD4, CD18, and MHC class IT positive." These cells are of bone marrow origin, of monocyte-histioeyte lineage, and serve antigen-processing and alloantigen-stimu- lating’ functions. Following ultraviolet light exposure, epidermal’ Langerhans’ cells are decreased in density and altered morphologically, resulting in an. immunosuppressive environment and antigen-specific tolerance." Topical or systemic glucocorticoids are Known to depress Langerhans’ cell numbers and function as well as other eutaneous and systemic immune responses. The areas of photoimmunology and photocarcinogenesis are receiving much attention, especially beeause they are relevant to the pathogenesis of skin cancer Studies in humans, dogs, and cats have shown that the number of Langerhans’ cells per unit of skin varies from one area of skin to another in the same individual,Structure and Function of the Skin * 25 FIGURE 1-15. lation micuraph of an epdemal Langa’ call (om Eley D ‘et ak Levers Histopathology of | ‘Skin, Sth ed. Lippincott Raven, Philadelphia, 1965, 021) emphasizing the need to use adjacent normal skin as a control when counting Langerhans’ cells im skin lesions % 125 13 126 THE SKIN AS AN IMMUNOLOGIC ORGAN The epidermis functions as the most peripheral outpost of the immune system (see Chap. 8). Langerhans’ cells, keratinoytes,epidermatropie mphexytes, and draining periph26 + Structure and Funetion of the Skin FIGURE 1-16. tomy layer), ranula layer (2), and prcle cll layer (6) fom the nasal planum (high power) eral Iymph nodes are thought to form collectively an integrated system of skin-associated lymphoid tissue that mediates cutaneous immunosurvellace = Langerhans ells (see previous discussion) stimulate the proliferation of relevant helper T lymphocytes by the presentation of antigen; they also induce cytotoxic T lymphocytes directed to allogeneic and modified self-determinants, produce IL-1 and other cytokines, contain numerous. enzymes, and are phagocytic. "0.1% ‘The keratinocyte also plays an active role in epidermal immunity: 1. Keratino- cytes (1) produce IL-1, (2) produce various cytokines (e.g., IL-3, prostaglandins, leukotri- nes, and interferon), (3) are pl and (4) ean express antigens associated with the immune response gene in a variety of lymphocyte-mediated skin diseases (presumably as a result of interferon-y secretion by activated lymphocytes): 1 Gamma and delta T lymphocytes are rare in normal canine skin but common in various immune-mediated and inflammatory dermatoses. GRANULAR LAYER ‘The stratum granulosum is variably present in haired skin: it ranges fom one to two cells in areas where it occurs." 8 2% In nonhaired skin or at the infundibulum of hair follicles, the stratum granulosum may be four to eight cells thick (Fig. 1-16). Cells in this layer are flattened and basophilic, and they contain shrunken nuclei and large, de basophilic heratohyain gramiles in their extoplm (se Fig, 1~3E). ‘erate ame are not true granules; they lick a membrane and are more accurately described as insoluble aggregates. Keratohyain granules are the morphologic equivalents of the struc tural protein profilaggrin, which is the precursor of flaggrin® and is synthesized in the stratum granulosum. The function of keratohyalin granules is incompletely understood, but it is thought to be concerned with keratinization and barrier function, The sulfur-rich ‘component of keratohy inules has been implicated as a precursor to the comified tcl envelope. Fibgara hse Teast two functions, Fist, it aggregates, packs, and aligns Feratin filaments and produces the matrix between the keratin Blaments in the comeo- cytes. Second, it is a source of free amino acids, which are important for the normal hydration of the stratum comeum, Loricrin is synthesized in the stratum granulosum in association with keratohyalin ‘granules and is involved in the binding of keratin filaments together in the comeoeyte and.Structure and Function of the Skin * 27 FIGURE 1-17. Stratum lucidum (ar ‘ro in fopad epithelium. in anchoring them to the crosslinked envelope. Another ultrastructural feature that characterizes granular cells are clustered lamellar granules at the margins of the cells. In rodents, two morphologic forms of keratohalin granules occur. The P-P granule {s irregularly shaped and contains profilaggrin, whereas the L-granule is smaller, rounded, and contains loririn. CLEAR LAYER The stratum Incidum is a fully keratinized, compact, thin layer of dead cells.!%: 95 2 This layer is anuclear, h s, and hyaline like, and it contains refractile droplets and a semifiuid substance called eleidin (Fig. 1-17). It differs histochemically from the stratum corneum by being rich in protein-bound lipids. The stratum lucidum is best developed in the footpads itis less developed inthe nasil planum and is absent from al other areas of normal skin, ‘The stratum lucidum has also been called the stratum ‘conjunctum, HORNY LAYER, ‘The stratum comeum is the outer layer of terminally differentiated keratinocytes that is constantly being shed." ". 188.2 Tt is a multilayered zone of corneocytes suspended in an extracellular lipid matrix, often likened to a series of bricks (comeocytes) bonded by mortar (lipids).!"” This layer, which consists of flattened, anuclear eosinophilic cells (cor28 + Structure and Function of the Skin neocytes), is thicker in lightly haired or glabrous skin (see Figs, 1-4, 1-5, 1-7B, and 1— 16). Its gradual desquamation is normally balanced by proliferation of the basal cells, ‘which maintains a constant epidermal thickness. Comeocytes contain a variety of humec- tants and natural sunsereens that are synthesized from proteins." “The terminally differentiated comeocyte has a highly specialized structure in the cell periphery. the cal! encelope, which assumes protective fnetions*™ ™™ t_ dovelops beneath the plasma membrane of strated epidermal cells, cells of the inner root sheath and medulla of the hair follicle, and the cuticle of the claw. The comeocyte has no true cell membrane because it contains no phospholipids, Cell envelope formation is associated with the increased activity of ealcium-dependent epidermal or hair follicle transglutami- nases that catalyze the cross-linking of soluble and particulate protein precursors into large, insoluble polymers, Major cytoplasmic protein precursors of the cell envelope synthesized in the stratum spinosum inelude involucrin, keratolinin, pancornulin, cornifin, and loricrin. #84 16", Us. 86.188 The impermeable comified envelope provides structural Support to the cell and resist invasion by microcrgansms and deleterious environmental agents. The stratum comeum has also been called the stratum dysjunctum. In routinely processed sections, the stratum corneum varies in thickness from 3 to 35 um in cats and from 5 to 1500 jum in dogs. However, clipping and histologic preparation Involving faation, dehydration, and paraffin embedding result inthe loss of about one hall of the stratum comeum. The stratum comeum of canine truncal skin, when measured in cexyostat sections, was found to have a mean thickness of 47 cell layers that measured 13.3 um." The loose, basketweave appearance of the stratum comeum is an artifact of Fixation and processing, 116 1" Transglutaminases are a superfamily of enzymes that are important in apoptosis, keratinization, and hair follicle formation.” Two members of the superfamily—keratino- «jte transglutaminase and epidermal transglutaminase—mediate the sequential eross-link- ied cell envelope precursor proteins, such as involucrin, eytostan A, elafin, rransghutaminases are chiefly expressed in the stratum granulosum and upper stratum spinosum, and require catalytie amino acids and calcium, Faulty keratinocyte transglutaminase expression is one cause of ichthyosis in humans.” Topographic studies have shown that the epidermal surface varies from gently undu- lating on the densely haired skin of the back to heavily folded on the skin of the abdomen.!'® " The hairs arise from the follicle infundibula, which are seen as pits in the skin. At their bases, the hairs tend to be joined by amorphous material that can also be seen around the squames adhering to hairs. The surface of the stratum comeum is uneven, especially in the hairy areas (see Fig. 1-19). It is covered with a homogeneous film that tends to conceal the structure of the squames and their intercellular junctions. Globular masses that are partially concealed by this film can be seen, On closer examina- tion, the surface can be seen to be composed of hexagonal cells and an amorphous substance that appears to be oozing to the surface of the margins of the cells. The bases Of the hair flide infundibula are sealed by an amorphous substance (sebaceous and cutaneous lps) and squames. No evidence wns found to suggest that sebum Bows from the hair pore to the interfollicular region, which suggested that rubbing and grooming ‘were important in spreading this emulsion over the skin. Hair growth may be important in “pushing” the sebum out of the pilar canal. Recent microautoradiographic studies of the dlsposition of topical prot! in dogs have shown that sebum does, deed, move over the epidermal surface.™ It has been suggested that the thinner, more compact canine stratum comeum with less intercellular lipid material—compared with other species—may par- tially explain the higher incidence of bacterial pyoderma in dogs in comparison with other Pe Tipids play an important role in the differentiation, structure, and function of the cepidermis.*" 5% 5 1°T Epidermal lipid composition changes dramatically during keratiniza- ton, heginning with large amounts of phospholipids and ending with predominantly ceramiges, cholesterol, and fatty acids, Epidermal surface lipids onginate fom maturing comeocytes, which contain about six times the amount of intracellular lipid as Keratino- cytes in the stratum basale. Skin surface lipids of cats and dogs were studied by thin-layer