key: cord-0056548-0h9c3pkc
authors: Hargis, Ann M.; Myers, Sherry
title: The Integument
date: 2017-02-17
journal: Pathologic Basis of Veterinary Disease
DOI: 10.1016/b978-0-323-35775-3.00017-5
sha: 808199d802e776ac0a204ed1f66924b39117cfdc
doc_id: 56548
cord_uid: 0h9c3pkc

nan

The epidermis is divided into layers based on the morphologic features of the keratinocyte, the major cell type of the epidermis. The epidermis of haired skin consists of four basic layers: stratum corneum, stratum granulosum, stratum spinosum, and stratum basale ( Fig. 17-3) . The epidermis of hairless skin has an additional layer, the stratum lucidum, which is located between the stratum granulosum and stratum corneum (see Fig. 17 -2). Keratinocytes originate from germinal cells in the stratum basale of the epidermis, ascend through the layers of the epidermis, changing in appearance and other characteristics in each layer until they reach the stratum corneum as fully cornified, dead corneocytes. Keratinocytes are continuously shed from the stratum corneum. The transit time for a keratinocyte from the stratum basale to shed in the stratum corneum is approximately 1 month, although this time can be accelerated in some disorders such as primary seborrhea characterized clinically by scaling.

The outermost layer of the epidermis is the stratum corneum, which consists of many sheets of flattened, cornified cells termed corneocytes. Keratin is an intracellular fibrous protein that is in part responsible for the toughness of the epidermis, enabling the epidermis to form a protective barrier. The next layer is the stratum granulosum, which consists of cells containing basophilic keratohyalin granules. In nonhaired skin the stratum corneum and stratum granulosum are separated by an additional layer of compacted, fully cornified cells, the stratum lucidum (see Fig. 17 -2), best seen in the pawpad. This layer has a translucent appearance due to the presence of eleidin, a protein similar to keratin, but with different staining affinity. Deep to the stratum granulosum is the stratum spinosum, a layer of polyhedral-shaped cells attached to one another by desmosomes. During fixation and processing for microscopic examination, the cells of the stratum spinosum contract, except for the desmosomal attachments. These attachment sites create the appearance of "spines" or intercellular bridges, leading to the name of this layer. The visibility of the intercellular bridges is enhanced when there is intercellular edema of the epidermis. The stratum spinosum in haired areas is thicker in horses, cattle, and pigs and is thinner in dogs and cats. The innermost layer of the epidermis is the germinal layer, or stratum basale, which consists of a single layer of cuboidal cells resting on a basement membrane. Intermixed within the basal cell layer are melanocytes, Langerhans cells, and Merkel cells.

Melanocytes, embryologically derived from neural crest cells, are also present in lower layers of the stratum spinosum and produce melanin pigment, giving skin and hair their color. Melanocytic granules are transferred to and become distributed in keratinocytes as a caplike cluster of granules between the nucleus and the external surface of the skin to help protect the nucleus from UV lightinduced injury. Langerhans cells are bone marrow-derived cells of monocyte-macrophage lineage that process and present antigen to sensitized T lymphocytes, thereby modulating immunologic responses of the skin. Langerhans cells are present in the basal, spinous, and granular layers of the epidermis but have a preference for a suprabasal position. Merkel cells are located in the basal layer, attach to keratinocytes via desmosomal junctions, and express keratin proteins 8, 18, 19, and 20. Merkel cells are located in haired and hairless skin, particularly in regions of the body with high tactile zone is composed of hemidesmosomes of basal cells (i.e., keratin intermediate filaments and attachment plaques), the lamina lucida (cell membrane, subdesmosomal dense plate, and anchoring filaments), and the lamina densa (i.e., type IV collagen), which also serve to anchor the epidermis to dermis (Fig. 17-4) . The importance of the basement membrane in anchoring function is noted in some immune-mediated diseases in which antibodies target, bind, and ultimately damage a component in the basement membrane and result in the formation of bullae (see the discussion on reactions characterized grossly by vesicles or bullae as the primary lesion and histologically by vesicles or bullae within the basement membrane [bullous dermatoses] in the section on Selected Autoimmune Reactions). The basement membrane zone also serves as a scaffold for migration of epidermal cells in wound healing and as an initial barrier to invasion of the dermis by neoplastic cells originating in the epidermis.

The dermis (corium) consists of collagen and elastic fibers in a glycosaminoglycan ground substance, and it supports hair follicles, glands, vessels, and nerves. By convention the dermis is generally subdivided into superficial and deep layers that blend together without a clear line of demarcation. The superficial dermis conforms to the contour of the epidermis and generally supports the upper sensitivity (digits and lips), and in the outer portion of hair follicles. When Merkel cells are associated with an axon, they form a Merkel cell-neurite complex and function as a slowly adapting mechanoreceptor. The specialized areas of the skin containing these Merkel cell-neurite complexes are known as tylotrich pads (hair disks, tactile pads). The axon associated with the Merkel cell is myelinated but near the epidermis, the myelin sheath is lost, and the nerve fibers terminate at the basal aspect of the Merkel cell. Merkel cells have granules that contain chemical mediators (metenkephalin, vasoactive intestinal peptide, chromogranin A, acetylcholine, calcitonin gene-related peptide, neuron-specific enolase, and synaptophysin). In addition to functioning as mechanoreceptors, Merkel cells may also influence keratinocyte proliferation, stimulate and maintain hair follicle stem cells, and alter blood flow and sweat production. The origin of Merkel cells is thought to be a primitive epidermal stem cell.

The epidermis and dermis are separated by a basement membrane. In hairless areas, such as the pawpads and nasal planum, this junction is irregular because of epidermal projections (e.g., rete pegs/also known as rete ridges or rete processes) that interdigitate with dermal papillae, thus strengthening the dermal-epidermal attachment by providing resistance to shearing. In densely haired areas the junction is smoother and has an undulating appearance because the dermalepidermal attachment is strengthened by the hair follicles. The more sparsely haired skin of pigs has more dermal-epidermal interdigitations (rete pegs) and fewer hair follicles. The basement membrane in haired skin has an undulating surface but lacks rete pegs (ridges or processes). The epidermis in haired skin has fewer nucleated cell layers than the epidermis in nonhaired (hairless) skin such as that on the nose and pawpads (see Fig. 17 -2); thus it is referred to as "thin" skin. Hair follicles (H), apocrine glands (A), and sebaceous glands (S) are present. Rete peg formation is not required because the hair follicles strengthen the attachment between the epidermis and dermis. The haired skin is thickest over the dorsal aspect of the body and on the lateral aspect of the limbs, and it is thinnest on the ventral aspect of the body and the medial aspect of the thighs. H&E stain. in hairless (nonhaired) skin has more nucleated cell layers, a thicker stratum corneum, and an additional layer termed the stratum lucidum (SL), than the epidermis in haired skin; thus it is referred to as "thick" skin. Note the dense zone of compact stratum corneum (SC) over the surface. The epidermal pegs (arrows) and dermal papillae in the superficial dermis (D) interdigitate and thus strengthen the attachment between the epidermis and dermis. Also note that in the pawpad of the dog, the contour of the cornified surface follows the epidermal contour and thus is papillated. H&E stain. (Courtesy Dr. Ann M. Hargis, DermatoDiagnostics.) SC E D SL CHAPTER 17 The Integument vessels then converge to form larger channels that eventually reach peripheral lymph nodes.

The skin is an important sensory organ containing millions of microscopic nerve endings that perceive itch (pruritus), pain, temperature, pressure, and touch . The nerve endings consist of Meissner's corpuscles, Pacini's or pacinian corpuscles, free sensory nerve endings, and mucocutaneous end organs (similar to Meissner's corpuscles but located in mucocutaneous skin). These nerve endings are minute, and the free sensory nerve endings are so delicate that they require special staining techniques, such as silver impregnation, to be visualized microscopically. The sensations of itch, pain, touch, temperature, and displacement of body hair are detected by the free sensory nerve endings. Itching, a form of mild pain that promotes the desire to scratch, is one of the most common reasons animals are presented to veterinarians. The sensations of pressure and touch are detected by Meissner's and Pacini's corpuscles. Sensations detected by free sensory nerve endings and by the corpuscles are transmitted to the spinal cord via the dorsal root ganglia. Sensory fibers to facial skin are supplied by the trigeminal nerve. Motor fibers (adrenergic and cholinergic) are supplied by the sympathetic component of the autonomic nervous system (see . Adrenergic fibers travel from the spinal cord through postganglionic fibers in peripheral nerves and arborize into plexuses that innervate blood portion of the hair follicle and sebaceous glands. It is composed of fine collagen fibers and is thicker in the skin of horses and cattle than in the skin of dogs and cats. The deep dermis supports the lower portion of the hair follicle and apocrine glands and is composed of collagen bundles larger than those in the superficial dermis. Smooth muscle fibers of the arrector pili muscle attach the connective tissue sheath of the hair follicle to the epidermis and are responsible for causing the hair to stand erect. Skeletal muscle fibers from the cutaneous muscle extend into the lower dermis and are responsible for voluntary skin movement. Mast cells, lymphocytes, plasma cells, macrophages, and rarely eosinophils and neutrophils can be found in normal dermis. These cells are bone marrow-derived cells and arrive via the blood vascular system; thus they are typically concentrated around small superficial blood vessels.

Cutaneous arteries give rise to three vascular plexuses: deep, middle, and superficial (see Fig. 17 -3). The deep plexus supplies the subcutis and deep portions of follicles and apocrine glands; the middle plexus supplies the sebaceous glands, midportion of follicles, and arrector pili muscles; and the superficial plexus supplies the superficial portions of follicles and epidermis. Lymph capillaries arise in the superficial dermis and connect with a subcutaneous plexus. The lymph . The next layer, the lamina lucida, is an electron-lucent zone composed of the basal cell membrane, subdesmosomal dense plate, and anchoring filaments. The deepest layer is the lamina densa, an electron-dense zone that consists of type IV collagen. Anchoring fibrils (type VII collagen), serve to attach the lamina densa and epidermis to the papillary dermis. The interconnecting layers of the basement membrane zone provide an important function in dermal-epidermal adhesion, serve as a barrier to invasion by malignant epidermal tumors, and may have reduced expression at birth (epidermolysis bullosa) or may be the site of deposition of immune reactants in subepidermal blistering cutaneous disease (see Table 17 These factors have been called adipokines and are thought to play a role in metabolism, and some may also contribute to adverse events associated with obesity.

Types of Hair Follicles. Hair follicles are classified into several types, primary or secondary, and simple or compound (Table 17-1) . Primary hair follicles are large and produce primary hairs or guard hairs. They have a hair bulb located deeply in the dermis or subcutis, a sebaceous and apocrine gland, and an arrector pili muscle. Secondary hair follicles are generally smaller than primary follicles and produce secondary hairs (also called undercoat hairs or wool fibers). They have a hair bulb located superficially in the dermis, may have a sebaceous gland but lack an apocrine gland and arrector pili muscle. Simple hair follicles have a single hair shaft that emerges from the follicle opening through the epidermis, and may be either a primary or secondary type of follicle. In contrast, compound hair follicles have multiple hair shafts, either one primary and more numerous secondary hairs, or multiple secondary hairs only, that emerge from one follicle opening through the epidermis (see Table 17 -1). The follicles forming a compound follicle each have their own lower segment, and they are joined at the level of the sebaceous duct to form a single common opening to the skin surface.

Tactile hairs include sinus and tylotrich hairs that function as mechanoreceptors (i.e., touch receptors). Sinus hairs, also termed whiskers or vibrissae, arise in simple follicles with a blood-filled sinus located between the inner and outer layers of the dermal sheath. Sinus hairs generally occur on the nose, above the eyes, on the lips and throat, and, in cats, on the palmar aspect of the carpus. Tylotrich hairs also arise in simple follicles and are scattered among the regular vessels, arrector pili muscles, and apocrine sweat glands. Stimulation by these adrenergic fibers causes vasoconstriction and piloerection (raising of the hair shafts). Cholinergic fibers travel from the spinal cord and arborize into plexuses that innervate the eccrine sweat glands. In the haired skin, equine sweat glands are considered to be the epitrichial (apocrine) type, where the duct opens into the follicular canal near the skin surface, but less commonly the duct may open in a depression near the follicle opening or directly on the skin surface. As in human beings, sweating in the horse is important in thermoregulation. However, the precise mechanisms that control sweating in the horse are unknown. The horse has a rich supply of vessels and nerves around sweat glands. It appears that equine sweat gland secretion is controlled by an interaction among neural, humoral, and paracrine factors. The only other domestic animal in which apocrine gland secretion is thought to play a thermoregulatory role is cattle, but sweating is not typically clinically visible except in horses. Dogs and cats lack eccrine glands in haired skin; however, cholinergic and to a lesser degree adrenergic fiber stimulation in dogs and cats causes sweating of the eccrine glands of pawpads at times of excitement or agitation.

The subcutis attaches the dermis to subjacent muscle or bone (with some regional exceptions where the subcutis may be absent such as involving the lip, cheek, eyelid, external ear, and anus) and consists of adipose tissue and collagenous and elastic fibers, which provide flexibility. Adipose tissue insulates against temperature variation and in the case of pawpads, serves in shock absorption. Adipose tissue also stores calories as triglycerides. In addition, there is recent evidence that fat cells secrete via autocrine, paracrine, and endocrine mechanisms a variety of cytokines, chemokines, and hormonelike factors such as adiponectin, leptin, resistin, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and acute phase proteins.

bulbs (growing hair bulbs) are in the mid-dermis, whereas in dogs and cats the anagen hair bulbs of primary follicles are at the dermalsubcutaneous junction. In all species the bases of telogen follicles (resting follicles) are more superficially located than the bases of anagen follicles. Development of Hair Follicles and Hair Shafts. The postnatal hair follicle and hair shaft form by proliferation and differentiation of the hair matrix cells of the hair bulb into various layers of the follicle wall, and subsequent keratinization with cornification centrally to form the hair shaft. Briefly, during the anagen stage of the hair cycle, the hair matrix cells in the hair bulb proliferate and differentiate to form multiple distinct, concentric cell layers or "sleeves" that eventually form the hair follicle wall (Table 17 -2). The structure of the follicle wall from the inside out includes the hair shaft, the inner root sheath (IRS), the companion layer, the outer root sheath (ORS), the basement membrane, and the connective tissue sheath (CTS). The most centrally located hair matrix cells of the hair bulb form the hair shaft. If melanocytes are present in the hair bulb, melanin is transferred to the hair matrix cells that form the cortex and medulla of the hair shaft. As the cells that form the hair cortex cornify, they harden and die and are pushed upward toward the skin surface as the hair matrix cells in the hair bulb continue to proliferate, and a hair shaft is produced. Keratin proteins constitute the majority of the hair shaft and are stabilized mostly by disulfide bonds. These strong bonds link the keratin proteins together and confer durability and strength to the hair shaft. The hair cuticle also provides durability to the hair shaft via sulfur-rich keratinocyteassociated proteins and hydrophobicity to the hair surface via longchain fatty acids. The cells of the hair cuticle flatten and resemble scales as they emerge from the hair bulb. Similar to the cells that form the hair cortex, as the cuticle cells cornify, they can no longer body hairs. Each tylotrich hair is associated with a tylotrich pad, and together they function as mechanoreceptors.

Structural Subdivisions within Hair Follicles. Fully developed hair follicles are traditionally subdivided into three anatomic segments: superficial, middle, and deep. The superficial segment, or infundibulum, extends from the follicular opening on the surface of the epidermis to the level where the sebaceous duct enters the follicle. The cells of the infundibulum are identical to and continuous with those of the epidermis. They keratinize slowly and form a granular cell layer before cornifying (through a process termed infundibular cornification). The middle segment, or isthmus, is quite short and extends from the level of sebaceous duct to the attachment of the arrector pili muscle. The cells of the follicular isthmus keratinize without forming a granular cell layer before cornifying (through a process termed trichilemmal cornification). The deep, or inferior, segment consists of the follicle below the attachment of the arrector pili muscle and includes the hair bulb, which consists of the hair matrix cells that partially enclose the follicular papilla, also called the dermal papilla. Two patterns of keratinization with cornification occur in the inferior portion of the follicle. One form is hair matrix (trichogenic) cornification, which occurs abruptly (does not form a granular layer), retains the nuclear outlines of keratinocytes, and produces the cortex of the hair shaft. The other form is inner root sheath cornification, which is compact and opaque and consists of Henle's and Huxley's layers, which contain red, trichohyalin granules. Cornification of viable keratinocytes is first recognized in an area termed Adamson's fringe, the upper margin of the keratogenous zone located between the mitotically active hair bulb and the hair shaft.

Depth of Hair Follicles/Hair Bulbs. The depth of follicles/hair bulbs varies among species. In horses and cattle the anagen hair function and also die. Some, but not all, hair shafts contain a medulla, the function of which is not completely understood. The medulla is usually absent in secondary hairs. The IRS extends from the hair bulb to the follicular isthmus. It differentiates into three layers and has a variety of functions (see Table 17 -2). The hair shaft and IRS are securely anchored together by the interlocking of cuticle cells, so that during growth the hair shaft and IRS move upward though the follicle concurrently. The IRS gives the hair shaft its surface shape and features and serves as a rigid protective covering around the developing hair. The keratin proteins of the IRS and of the hair cortex are of different composition. The proteins of the IRS are degraded by proteases from the sebaceous gland, but those of the hair shaft are not degraded, thus allowing the hair shaft to emerge as an independent structure from the follicular opening.

The companion layer (see Table 17 -2), located between the IRS and ORS, is tightly anchored to the IRS, but not to the ORS. It is thought to act as a slippage plane against which the IRS and hair shaft can move upward during hair growth, whereas the ORS remains stationary. The ORS extends from the hair bulb the entire length of the follicle and is continuous with the outer aspect of the sebaceous gland and with the overlying epidermis. The ORS also serves as a storage area for hair follicle stem cells. In addition, in the zone of the hair follicle where cornification occurs (the upper margin length of body hair in different anatomic sites, (2) shed fur to clean the body surface, (3) adapt and change hair coat in response to changing environment (winter to summer) or social conditions, or (4) protect against malignant transformation that might occur in a rapidly dividing tissue.

During the stages of the hair cycle, the infundibular and isthmus portions of the follicle are permanent because they remain structurally the same and do not visibly change. In contrast, the lower portion of the follicle below the isthmus regresses and is reconstructed during each cycle. The hair follicle stages include hair growth, regression, quiescence, shedding or loss of the hair shaft, and latency (Box 17-1 and see Fig. 17-7) . In the anagen stage of the hair cycle, mitotic activity and growth occur. The catagen stage is an apoptosis-driven regressing stage during which cellular proliferation ceases and the hair follicle cells are lost via programmed cell death. The hair follicle then enters a resting or relatively quiescent stage, telogen, after which mitotic activity and new hair production resumes. The kenogen stage refers to follicles that have lost their hair shaft and that remain empty for an indefinite period of time before anagen is reinitiated. This stage also has been referred to as "hairless telogen." In many hair loss disorders in domestic animals, increased numbers of kenogen follicles are evident histologically. Exogen is the stage in which the old hair shaft is shed. Exogen occurs independent of the hair cycle stage but often follows telogen.

All hairs of the body proceed through the hair cycle, but the duration of the cycle, duration of individual stages, and the length of hair shafts produced vary among animals and specific anatomic sites. In human scalp hair, each hair follicle has its own inherent rhythm, and thus hair cycles are asynchronous. Anagen is the longest stage of the cycle, and as a result human scalp hair grows almost constantly. In contrast, hair follicle growth occurs synchronously in many other mammals, resulting in periodic loss or shedding of the hair coat. Most mammals have a telogen-based hair cycle in which the hair shafts grow to a genetically predetermined length after which the follicle enters a prolonged stage of inactivity (telogen) and the hair shaft remains firmly attached to the follicle. The telogen-based hair cycle likely has an advantage in the conservation of protein and energy required for hair synthesis. There are exceptions to this general rule because some animals have continuously growing hair similar to scalp hair in human beings of the keratogenous zone, Adamson's fringe), the ORS cells have glycogen-rich cytoplasm that probably serves as a source of energy for the proliferative activities of the hair bulb and follicular cornification. The connective tissue sheath and its basement membrane provide physical support for the hair follicle, and the sheath may be a reservoir for mesenchymal stem cells.

Horses. Horses have simple hair follicles, both primary and secondary types, which are evenly distributed throughout the skin. Ruminants (Cattle, Sheep, and Goats) . Cattle have simple hair follicles, both primary and secondary types, which are distributed throughout the skin in subtle groups of three. Goats have primary follicles in groups of three, and each group usually has three to six secondary follicles. Compound follicles in goats are composed of secondary follicles. Hair follicles in sheep have been studied extensively because of the commercial importance in wool production. Sheep have mostly simple follicles in sparsely haired regions, including the face, distal legs, and pinnae, and mostly compound follicles in the densely covered wool-growing areas. The typical follicle group has 3 primary follicles and 15 to 16 secondary follicles. The compound follicles in sheep consist of multiple secondary follicles that originate in the region of the sebaceous gland by branching from an original secondary follicle. Selective breeding has substantially increased the number of secondary follicles in fine-wooled or medium-wooled sheep and goats.

Pigs. Pigs have sparse hair coats composed mostly of widely spaced simple primary follicles that occur in groups of two to four with the groups bordered by dense connective tissue.

Dogs and Cats. Dogs and cats have mostly compound follicles that are arranged in groups of one to six. The groups most often consist of three primary follicles associated with a greater number of smaller secondary follicles (see Table 17 -1). There is breed variation in the number of secondary follicles with some breeds such as German shepherd dogs having more secondary follicles than shortcoat breeds such as terriers. Cats have more secondary follicles (10 to 20) compared to dogs (2 to 15). Primary hair shafts may emerge independently through a single opening, whereas secondary hairs generally emerge through a common opening. The three larger primary follicles within a follicular group are located closer to the head, whereas the smaller secondary follicles are located caudal to the primary follicles . Within the follicular group the secondary follicles also become progressively smaller toward the caudal aspect (i.e., the tail) of the animal. This pattern of follicular group structure together with the slanted orientation of the hair shafts results in a hair coat that covers the surface of the epidermis smoothly with guard hairs on top of the finer undercoat.

open on the surface of the skin (e.g., meibomian gland, also known as tarsal gland). Well-developed sebaceous glands are found in the preputial glands of horses; the infraorbital, inguinal, and interdigital regions of sheep; the base of the horn of goats; the supracaudal gland of the base of the tail of dogs and cats; the anal sac glands of cats; and the submental organ of the chin of cats.

Anal sacs are specialized cutaneous structures that are especially prone to develop lesions. Anal sacs are bilateral diverticula located between internal and external anal sphincter muscles in dogs and cats and have ducts that open onto the anus at the level of the anocutaneous junction. Ducts and sacs are lined by stratified squamous epithelium. In dogs the wall has only apocrine glands, but in cats the sac wall has sebaceous and apocrine glands. The anal sacs can become distended with secretory products, rupture after trauma, and cause bacterial infection and chronic inflammation (foreign body reaction) in contiguous tissues. Carcinomas of the apocrine gland of the anal sac in dogs are often associated with tumor cell production of parathyroid hormone-related protein (PTH-rP) and humoral hypercalcemia of malignancy.

Hepatoid (i.e., circumanal or perianal) glands occur most commonly in the skin around the anus and are also present in skin near the prepuce, tail, flank, and groin. These glands are modified sebaceous glands that have nonpatent ducts and are composed of peripheral reserve cells that surround lobules of differentiated cells resembling hepatocytes, resulting in the name "hepatoid" glands. Adenomas of the perianal glands in male dogs are often testosterone dependent.

Hooves of horses consist of the wall, sole, and frog. The hoof wall comprises three structurally distinct cornified layers, which from the outside in include the stratum externum, stratum medium, and stratum internum. The stratum externum is a thin flaky cornified layer that arises from the germinal cells (basal cells) of the epidermis of the periople (an area of modified skin above the coronary band of the hoof). Toward the back of the foot the periople expands to form a broad cornified area or bulb (heel) supported by corium (dermis). The stratum medium consists of tubular and intertubular horn (the hard cornified component, stratum corneum) that arises from the basal cells of the epidermis lining the coronary band, or coronet, and is the thickest layer of the hoof wall and the main load support structure of the equine foot. The coronary epidermis is supported by the coronary dermis, which forms long papillae that extend into the epidermis and that are oriented parallel to the outer surface of the hoof wall. The coronary basal cells at the distal tip and along the sides of the dermal papillae form the tubular horn (or horn tubules), which also are parallel to the outer hoof wall. In cross section, the tubular horn may be circular, oval, or wedge shaped and consists centrally of a loosely arranged medullary area bordered by three layers of tightly or more loosely coiled cortical cells. The coiled (or springlike) pattern of tubular horn helps reduce compressive forces of the hoof. The coronary basal cells of the interpapillary dermis form the intertubular horn, which surrounds the tubular horn. The stratum internum (stratum lamellatum) of the inner hoof wall is present from the deep edge of the coronary region to the sole. It is a complex structure composed of approximately 600 parallel, The stem cells in the ORS also become activated but proliferate later and more slowly (within anagen) probably to sustain hair follicle growth throughout the anagen phase. In addition to hair follicle stem cells, melanocyte stem cells also reside in the ORS and the secondary germ. During fetal development the melanocyte stem cells migrate from the neural crest and colonize the developing follicle. The melanocyte stem cells and the hair follicle stem cells are activated concurrently during anagen. The melanocyte stem cells provide the hair bulb with mature melanocytes that produce and transfer melanin to hair matrix cells and result in the formation of a pigmented hair shaft.

Extrinsic factors are also important in governing the hair cycle and growth. For example, nutrition and health status have a significant influence on hair growth and quality. Hair is largely composed of protein, thus diets low in protein or disease states associated with severe protein loss, such as protein-losing enteropathy (see Chapter 7) result in poor-quality hair coat. Also, in disease states, cuticle formation can be defective, resulting in a dull or dry hair coat. Hair growth responds to photoperiods and to a lesser extent to ambient temperatures. Photoperiod effects act via the hypothalamus, pituitary, and pineal gland, which secrete tropic hormones, such as melatonin, prolactin, and the gonadal, thyroid, and adrenal hormones, that influence hair growth. Some hormones, such as thyroid and growth hormone, stimulate hair growth, whereas excessive concentrations of estrogen or glucocorticoids suppress hair growth. Intrinsic and extrinsic factors also interact. For example, cells in the dermal papilla (mesenchymal in origin) that mediate growthstimulating signals to hair matrix cells are thought to be the primary target cells that respond to these tropic hormones.

The arrector pili are smooth muscle bundles that are oriented almost perpendicularly to the wall of the follicle and are well developed on the back of animals, especially dogs. On one side the arrector pili muscle connects to the basement membrane of the epidermis, and on the other side inserts in the connective tissue sheath at the junction of the middle and inferior portion of the hair follicle. Muscle contraction causes erection of hairs and expression of the contents of sebaceous glands.

There are two basic types of sweat glands: apocrine glands and eccrine glands. Apocrine glands are located throughout haired areas of skin in domestic animals and are tubular-or saccular-coiled glands (see Fig. 17 -3). The ducts of the apocrine glands open in the superficial portion of the hair follicle; thus these glands are also called epitrichial glands. The glands are lined by secretory cuboidal to low columnar epithelium surrounded by contractile myoepithelial cells. Other apocrine glands include glands of the external ear canal and eyelids of domestic animals, the interdigital glands of small ruminants, the mental organ of pigs, and the anal sac glands of dogs and cats. Eccrine glands are merocrine in secretion. The ducts of eccrine glands, in contrast to apocrine glands, open directly onto the epidermal surface; thus eccrine glands are also called atrichial glands. They are tubular glands lined by cuboidal epithelium surrounded by myoepithelium and are confined mainly to the frog region of ungulates, nasolabial region of ruminants and pigs, the carpus of pigs, and pawpads of dogs and cats.

Sebaceous glands are simple, branched, or compound alveolar glands that undergo holocrine secretion, with ducts opening into hair follicles except at some mucocutaneous junctions where the glands 1019 CHAPTER 17 The Integument

The claws of dogs and cats shield the distal phalanx and consist of a wall (i.e., dorsal and lateral) and sole (i.e., distal), both of which are stratified squamous cornifying epidermis. The epidermis of the wall produces a hard, cornified layer (stratum corneum), whereas the epidermis of the sole produces a softer, flakier stratum corneum. The dermis of the claw consists of dense collagen, elastic tissue, and blood vessels that can bleed profusely if the claw is trimmed too short. The claw fold is a fold of skin that covers the wall laterally and dorsally for a short distance.

The digital pads of dogs and cats have a thick epidermis composed of all layers, including the stratum lucidum. The surface is covered by compacted layers of stratum corneum and is smooth in the cat; however, in the dog the surface is covered by conical papillae that conform to the outline of the epidermal surface (see Fig.  17 -2). The epidermis and dermis interdigitate via rete pegs and dermal papillae, thus providing resistance to shear forces. Eccrine (atrichial) glands are present in the dermis and the adipose tissue. Lobules of adipose tissue that act as a cushion are subdivided by collagenous stroma and elastic tissue.

Hair provides a variety of functions for animals, including thermal regulation, physical protection, sensory perception, and social interaction, and serves as a mechanism of camouflage (Box 17-2). The skin is not only the largest organ in the body, but one of the most important. Without the skin, terrestrial mammalian life could not exist. The skin prevents significant loss of fluid and electrolytes (e.g., the stratum corneum barrier), protects against physical and chemical injury (e.g., the stratum corneum barrier, keratin filaments, desmosomal and hemidesmosomal junctions, collagen, and elastic fibers), participates in temperature and blood pressure regulation (e.g., the hair coat, sweat glands, and vascular supply), produces vitamin D (e.g., ultraviolet [UV] light photolysis of dehydrocholesterol), serves as a sensory organ (e.g., tactile hairs, Merkel cells, and nerves), and stores fat, water, vitamins, carbohydrates, protein, and other nutrients (e.g., subcutaneous fat). Absorption, although not a primary function, also occurs. In addition, the keratinocyte, a major source of cytokines and antimicrobial peptides, is now considered to be an integral part of the innate and adaptive immune systems protecting against microbial injury and participating in inflammation and tissue repair.

A number of "new" terms commonly used to classify diseases of the skin are used throughout this chapter. For convenience and to provide quick reference, these terms are listed online in E-Glossary cornified primary epidermal lamellae that extend inward (toward the distal phalanx) from the stratum medium in which they are firmly incorporated or fused. Each primary epidermal lamella has approximately 150 to 200 outwardly radiating secondary epidermal lamellae, the dermal side of which orients toward the distal phalanx. The secondary epidermal lamellae consist of a central core of partially cornified spinous layer cells that attach at their apical surface to the sides of the primary epidermal lamellae, and a single layer of basal cells that attach to the subjacent secondary dermal lamellae via hemidesmosomes in the basement membrane (see Fig. 17-4) . The primary and secondary epidermal lamellae interdigitate with the primary and secondary dermal lamellae, providing a large surface area to the inner hoof wall. The blood vessels that nourish the epidermal cells are located in the dermal lamellae. On one side of the basement membrane the epidermal cells of the epidermal lamellae are firmly attached, and on the other side of the basement membrane the collagen fibers of the lamina densa and sublamina densa are tightly interwoven with the tendon-like connective tissue that is firmly attached to the parietal surface of the distal phalanx, thereby anchoring the inner hoof wall to the dermis that covers the distal phalanx. In this way the epidermal and dermal lamellae serve as the suspensory apparatus of the distal phalanx, and if the attachment of the epidermal and dermal lamellae fails, the shearing forces of body weight and movement can result in the separation of the distal phalanx from the inner hoof wall, which can lead to the painful condition of laminitis (also called laminopathy in some instances) most often seen in horses and cattle (see section on Cutaneous Manifestations of Systemic Disorders, Laminitis). The sole consists of epidermis that interdigitates with its supportive dermis, which blends with the periosteum of the distal surface of the distal phalanx. The sole epidermis forms the tubular and intertubular horn of the sole, the surface of which is loosely attached and can be easily removed as small flakes. At the junction of the sole epidermis and stratum lamellatum, the lamellar epidermis is redirected (changes orientation) toward the distal aspect of the foot, and the horn of the stratum lamellatum joins and interconnects with the tubular and intertubular horn of the sole epidermis. The horn from the lamellar epidermis has a different degree of compactness and orientation, which provides a different shade of color, and has been termed the white line or white zone. The color difference allows the hoof wall to be visually distinguished from the sole. The frog consists of tubular and intertubular horn that is softer than the horn of the sole and wall of the hoof, and that is supported by dermis that blends with the digital cushion, a wedge-shaped mass of collagen, elastic tissue, and adipose tissue that serves to help absorb the impact of walking and running. Eccrine (atrichial) glands are also present in the frog.

The chestnuts and ergots of the horse are considered to be vestiges of the first, second, and fourth digits. Chestnuts are located in the supracarpal and tarsal area on the medial surface of the limbs, and the ergot is located at the flexion of the fetlocks (metacarpophalangeal articulation). Chestnuts and ergots are histologically similar, and each consists of a thick layer of tubular and intertubular horn covering thick cellular layers of the epidermis. The rete pegs are long and interdigitate with long dermal papillae.

The hooves of ruminants and pigs are cloven or divided into two parts, each of which consists of a wall, sole, and prominent bulb (also called the heel). The histologic characteristics of the wall and sole are similar to those of the horse; however, the interdigitating lamellae are smaller and less well developed, and only primary lamellae are present. Instead of a frog, ruminants and pigs have a prominent bulb lined by soft, thin cornified epidermis that is continuous with the skin and forms a large part of the distal hoof surface. 17-1. Although there are many new terms to learn, it should be realized that the system used to form these terms is similar to that used for other anatomic systems. Basically, prefixes and suffixes are added to word roots to create specific terms that define the pathology of the skin. For example, the prefix "epi" (meaning on or above) combined with the word root "dermat(o)" (referring to skin) creates the word "epidermis," which simply means the portion of the skin above the dermis. Likewise, the term hypodermis refers to the portion of the skin below the dermis, also called the subcutis or panniculus. Suffixes are used in the same way. For example, the suffix "itis" (meaning inflammation) combined with the word root "dermat(o)" forms the word "dermatitis," which simply means inflammation of the skin. Similarly, terms referring to inflammation predominantly within the epidermis, follicles, or the panniculus are epidermitis, folliculitis, and panniculitis, respectively. The suffix "osis" refers to a disease process, often noninflammatory. Thus combining dermat(o) and osis forms the word "dermatosis," which means any disease of the skin, especially one not characterized by inflammation. The term "dermatoses" is the plural of dermatosis and thus typically means noninflammatory skin diseases. However, the term "dermatoses" is also used less specifically to refer to a group of skin disorders of a variety of types, such as immune-mediated dermatoses.

Numerous endogenous and exogenous factors can potentially cause injury of the skin ( Fig. 17-8) . Determining a definitive diagnosis of a skin disorder often depends on obtaining a complete history, including age, breed, and sex of the animal; conducting a thorough physical examination, paying particular attention to the distribution of skin lesions; and performing additional diagnostic tests, such as skin scrapings, surface cytologic examination, a complete blood cell count, serum chemistry panel, fecal examination (e.g., for hookworm parasite ova), skin biopsy sampling, and microbiologic cultures. Results from cutaneous biopsy sampling are often useful and can be necessary to establish a definitive diagnosis for skin diseases. Although the skin has a limited range of responses to injury, the distribution and types of inflammatory cells in the lesion often represent a recognizable pattern that can be used to (1) formulate a list of specific etiologic agents that could cause the lesion or (2) suggest categories of disease with similar lesions and a common pathogenesis. Algorithms (i.e., a set of directions for accomplishing some task that has a recognizable end point) have been developed for the recognition of histopathologic patterns in veterinary dermatopathology (Table 17-3) . Recognition of patterns, both clinically and histologically, can facilitate differential diagnoses of skin disease . Patterns of responses to injury are illustrated by changes in the epidermis, dermis, adnexa, and panniculus and are discussed in the next sections.

Alterations in Epidermal Growth or Differentiation. The basal cells (i.e., basal epidermal cells) in their postmitotic state migrate outward from the basal layer, eventually forming the cornified layers (stratum corneum) of the epidermis. In the normal epidermis, balance is established between the rate of proliferation of the basal cells (germinal cells) and the rate of loss of differentiated cells (corneocytes) from the surface, resulting in the constant thickness of the epidermis and each of the layers. The orderly proliferation, differentiation, and cornification of epidermal cells is regulated by cytokines (e.g., epidermal growth factor, fibroblast growth factors [FGFs] , insulin-like growth factors [ILGFs] , interleukins, and TNF), hormones (e.g., cortisol and vitamin D 3 ), and nutritional factors such as protein, zinc, copper, fatty acids, vitamin A, and B vitamins. The cytokines that regulate keratinocyte growth and differentiation are produced by a variety of cell types in the skin, including endothelial cells, leukocytes, fibroblasts, and keratinocytes. Thus keratinocytes also have a self-regulatory role (i.e., autocrine) in their growth and differentiation, and inflammatory cells, among others, can influence keratinocyte growth and differentiation.

Disorders of Cornification. Disorders of cornification (i.e., alterations in the formation of the stratum corneum) can be primary, such as occurs in primary seborrhea, but more often are secondary to a variety of factors such as inflammation, surface trauma, environmental conditions (e.g., low humidity), or metabolic or nutritional disorders. A disorder of cornification called hyperkeratosis is characterized by an increase in the thickness of the stratum corneum. There are two forms of hyperkeratosis, orthokeratotic and parakeratotic hyperkeratosis, which are distinguished by the completeness of the cornification process and whether the keratinocytes ultimately lose or retain their nucleus. In orthokeratotic hyperkeratosis (also referred to as hyperkeratosis), the keratinocytes undergo complete cornification and thus lose their nucleus to become anuclear, whereas in parakeratotic hyperkeratosis (also referred to as parakeratosis), the keratinocytes undergo only partial or incomplete cornification and thus retain their nucleus. Subtypes of hyperkeratosis include basket weave (exaggerated undulating pattern of layers of CHAPTER 17 The Integument A pattern consists of two parts: a component of the skin (e.g., epidermis) + a histologic reaction of that component to injury (e.g., hyperkeratosis) = pattern (hyperkeratotic diseases of the epidermis). Some of these disorders could be placed in different patterns. For instance, disorders characterized by vesicles or bullae may develop into an ulcerative pattern after the vesicles or bullae rupture. *Hyperkeratotic disorders may also affect the nasal planum and pawpads; see stratum spinosum, and is also referred to as acanthosis. Hyperplasia is a response common to a variety of stimuli, often chronic, and occurs in a variety of types, including regular, irregular, papillated, and pseudocarcinomatous (pseudoepitheliomatous) (Fig. 17-11 ). Some forms of epidermal hyperplasia (regular, irregular, and pseudocarcinomatous) can develop in sequence. In early stages of epidermal hyperplasia, the dermal-epidermal interface is mildly undulating, but as the hyperplasia progresses, there often is an elongation of the rete pegs that extend into the dermis and interdigitate with dermal papillae, and that can be regular or irregular. In regular epidermal hyperplasia the rete pegs are approximately evenly sized and shaped, whereas in irregular epidermal hyperplasia the rete pegs are less uniform. Pseudocarcinomatous hyperplasia is a chronic and late stage of epidermal hyperplasia that develops after milder forms (regular or irregular). It refers to marked hyperplasia of the epidermis, resulting in many branching and anastomosing epidermal projections (rete pegs) that deeply interdigitate with dermal collagen fibers. Mitotic figures can be numerous in proliferating basal cells, but in contrast to squamous cell carcinoma, the keratinocytes the normal stratum corneum), compact (compacted layers of basket weave stratum corneum), and laminated (layers of stratum corneum that are more even and linear, and less undulating). Both parakeratosis and hyperkeratosis are common nonspecific responses to chronic stimuli (e.g., superficial trauma, inflammation, or sun exposure) and also occur as primary lesions. For example, hyperkeratosis is a feature of the cornification disorder, primary seborrhea, of the cocker spaniel ( Fig. 17-9) , ichthyosis, and vitamin A deficiency. Diffuse parakeratosis is a feature of zinc-responsive dermatosis and superficial necrolytic dermatitis (hepatocutaneous syndrome) . Hyperkeratosis and parakeratosis can be accompanied by alterations in the thickness of the granular cell layer (stratum granulosum). Generally hyperkeratosis is associated with an increased thickness of the granular cell layer (hypergranulosis), and parakeratosis is associated with a decreased thickness of the granular cell layer (hypogranulosis). Epidermal Hyperplasia. Epidermal hyperplasia is an alteration in epidermal growth or differentiation characterized by an increase in the number of cells within the epidermis, most often within the CHAPTER 17 The Integument Stratum corneum maintain normal polarity, are not atypical, and do not penetrate the basement membrane. Pseudocarcinomatous hyperplasia develops subsequent to chronic injury, as seen with chronic dermal suppurative or granulomatous dermal inflammation or at the edges of persistent, nonhealing ulcers. Psoriasiform epidermal hyperplasia is an exaggerated type of regular epidermal hyperplasia in which the epidermis forms elongated rete pegs that are of similar length and width and that interdigitate with similarly elongated dermal papillae. This type of hyperplasia has very regular or uniform histologic appearance and is a feature of certain disease syndromes, such as psoriasiform lichenoid dermatitis of the springer spaniel and porcine juvenile pustular psoriasiform dermatitis (pityriasis rosea). Papillated epidermal hyperplasia is a unique form of epidermal hyperplasia in which fingerlike (papillary) projections of epidermis develop above the skin surface; it is a feature of some papillomas, hamartomas, and calluses and occasionally develops in response to cyclosporine drug therapy in dogs.

Apoptosis. Apoptosis refers to programmed cell death (see Chapter 1 for mechanisms of development), an important, normal physiologic process that contributes to embryologic development, wound healing, the removal of damaged cells, and adult tissue homeostasis and remodeling and is responsible for regression of the lower segment of the hair follicle during the catagen stage of the hair cycle. Apoptosis is tightly regulated because too little or too much may lead to pathologic processes. Neoplasia may develop when there is increased proliferation and inadequate apoptosisdriven removal of DNA-damaged cells. In contrast, the presence of numerous apoptotic keratinocytes is a feature of some immunemediated diseases such as erythema multiforme (Fig. 17-12 ) and more rare conditions, including toxic epidermal necrolysis and graftversus-host disease. Apoptotic cells typically condense and fragment into small bodies that are phagocytosed by adjacent parenchymal cells or tissue macrophages. However, keratinocytes, in contrast to other cells in the body, contain tonofilaments that provide structure and some rigidity to the cell. Thus the fragmentation into small bodies is less complete in apoptotic keratinocytes than other cells in the body. This is particularly so for keratinocytes that have accumulated more filaments through the process of maturation in the epidermis. The terms dyskeratosis or filamentous degeneration have been used to describe these keratinocytes. The fragmented (apoptotic) bodies in dyskeratotic keratinocytes are usually larger than in other cells, and they tend to resist phagocytosis. Dyskeratotic keratinocytes are separated from adjacent keratinocytes and have a pyknotic nucleus and brightly eosinophilic cytoplasm. Apoptosis differs significantly from necrosis, in which cell lysis liberates cellular contents into the extracellular space and elicits an inflammatory response. The development of an acute inflammatory response is prevented in apoptosis through phagocytosis of apoptotic keratinocytes, by adjacent keratinocytes, before their cellular disintegration.

Necrosis. Necrosis refers to the death of cells and is characterized by nuclear pyknosis (shrunken and dense nucleus), karyorrhexis (nuclear membrane rupture with fragmentation and release of contents), or karyolysis (complete dissolution of the nucleus with loss of chromatin material), organelle swelling, cell membrane rupture, and release of cytoplasmic elements into the extracellular space accompanied by an acute inflammatory response. Causes of epidermal necrosis include physical injury (lacerations, thermal burns), chemical injury (irritant contact dermatitis), and injury as a result of ischemia and infarction (vasculitis, thromboembolism) . Necrosis of the epidermis can result in erosion (partial-thickness loss of an area of epidermis) or ulceration (full-thickness loss of epidermis and a portion of the dermis and sometimes deeper tissue).

Dysplasia. Dysplasia is defined as abnormal development of tissues or organs. The term is used in two different situations: (1) in association with a congenital or inherited abnormality of development and (2) in association with an abnormality in maturation of cells within a tissue (e.g., preneoplastic) . In this second situation, it refers to an alteration in size, shape, and organization of adult cells (keratinocytes). Dysplasia is a stage of abnormal development that precedes the formation of a noninvasive (in situ) carcinoma. This is the stage of carcinoma that occurs before the abnormal epidermal cells penetrate the basement membrane. The histologic features of dysplasia include lost stratification of keratinocytes, variation in cell and nuclear size, increase in number of mitoses, and large hyperchromatic nuclei.

Epidermal Atrophy. Atrophy is a decrease in the number and size of the cells within the epidermis and occurs as a consequence of sublethal cell injury. Cutaneous atrophy can affect the epidermis, follicles, sebaceous glands, and dermal collagen and occurs in response to hormonal imbalances, such as hyperadrenocorticism in dogs and cats, partial ischemia, and severe malnutrition and may also develop as a consequence of aging.

Edema and Intracellular Fluid Accumulation. Edema refers to fluid accumulation between cells. Intercellular edema of the epidermis is called spongiosis because as the intercellular space expands with fluid, the epidermis develops a "spongy" appearance . The term "spongiosis" is used in other chapters of this book to describe responses to injury that are unique to other tissues or organ systems, and in those circumstances the term "spongiosis" has different meanings. Severe intercellular edema of the epidermis results in the formation of spongiotic vesicles, which are variably sized clefts or spaces in the epidermis. The spongiotic vesicles often blend with intercellular spaces that are also widened but to a lesser degree; thus intercellular bridges are often prominent between keratinocytes bordering spongiotic vesicles. Spongiosis is common in epidermal inflammation (epidermitis) caused by staphylococci or Malassezia sp.

Intracellular fluid accumulation results in cytoplasmic swelling of keratinocytes, and if the swelling is severe, the swollen keratinocytes can burst, forming microvesicles supported by the walls of the ruptured cells. This type of epidermal damage is termed reticular Figure 17 -13 Edema, Skin, Dog. A, Intercellular epidermal edema. The epidermis appears "spongy" and the "spines" between keratinocytes (arrows) are accentuated from edema that widens the intercellular spaces. The keratinocytes remain connected to each other via desmosomal attachment sites (see Fig. 17 A A B Figure 17 -12 Erythema Multiforme, Skin, Dog. A, Apoptotic keratinocytes (arrows) are present in multiple layers of the epidermis. The increased staining intensity of apoptotic keratinocytes is a result of condensation of cytoplasmic organelles and nuclei. H&E stain. B, Skin of abdomen, inguinal region, and scrotum. Note the circular and linear erosions. The clinical lesions resulting from apoptotic keratinocytes depend on the prevalence and location of the apoptotic cells in the epidermal strata. Numerous deeply located apoptotic keratinocytes can lead to partial-or full-thickness loss of the epidermis, resulting in erosions and ulcers. C, Scrotum, erythema, ulceration, and crusting are present. Crusts form because the ulceration (injury) results in the release of inflammatory mediators, leading to the accumulation of fluid and cellular exudate that covers and dries on the ulcerated surface. 

CHAPTER 17 The Integument to splitting of the extracellular core of the desmosomes. Subsequently the desmosomal plaques dissolve, and intermediate filaments retract to the perinuclear region of the keratinocytes. Acantholysis occurs with immune-mediated injury, as seen in pemphigus (type II cytotoxic hypersensitivity), with release of exfoliative toxins by staphylococci as seen in superficial pyoderma, and uncommonly with some Trichophyton sp. infections, presumably because of secretion of proteases by the fungi. The microscopic lesions vary with the location of acantholysis within the various layers of the epidermis. In pemphigus foliaceus (PF), acantholysis occurs in the subcorneal epidermis, resulting in release of freefloating keratinocytes in subcorneal vesicles and pustules . In pemphigus vulgaris (PV), acantholysis occurs in the epidermis, just above the basal layer, resulting in the separation of the upper epidermis from the basal cells (which are often referred to as a row of tombstones) attached to the dermis via the basement membane ( Fig. 17-16 ). Fluid accumulating between the separated layers of the epidermis forms vesicles of varied sizes and shapes.

Vesicles. Vesicles are fluid-filled cavities within or beneath the epidermis ( Fig. 17-17 ). If the cavity is less than 1 cm in diameter, it is called a vesicle; if it is greater than 1 cm in diameter, it is called a bulla (pl. bullae). Vesicles can develop in any layer of the epidermis or beneath the epidermis and can form as the result of acantholysis, epidermal or dermal edema, degeneration of basal cells and keratinocytes, or other processes, such as immune-mediated targeting of components of the basement membrane, or frictional trauma and burns that damage proteins and lead to a lack of cohesion between the epidermal cells or between the epidermis and dermis, resulting in the accumulation of fluid within a cavity. The location of vesicles or bullae within the layers of the epidermis is suggestive of certain diseases. For instance, intraepidermal vesicles can occur in viral infections, subcorneal vesicles in pemphigus foliaceus, panepidermal vesicles in panepidermal pustular pemphigus, suprabasilar vesicles in pemphigus vulgaris, and subepidermal vesicles in bullous pemphigoid or thermal burns .

Inflammatory Lesions of the Epidermis. Acute inflammation of the epidermis actually begins in the dermis with active hyperemia, edema, and migration of leukocytes, often neutrophils (see Inflammatory Disorders of the Dermis). The edema fluid arises from dilated venules and can move intercellularly through the epidermis, widening the intercellular spaces and causing spongiosis (see . In thermal burns of the skin, larger quantities of fluid accumulate within or below the epidermis, forming vesicles (see ; the fluid reaching the epidermal surface dries to form a largely acellular crust. The leukocytes (often neutrophils in acute inflammation) migrate from the superficial dermal vessels, through the superficial dermis, and into the intercellular spaces of the deep and then superficial layers of the epidermis. The aggregation of migrating leukocytes in the epidermis is termed exocytosis. Exocytosis of leukocytes is common in inflammation and is usually accompanied by spongiosis. If the inflammation progresses, the migrating leukocytes form pustules within the epidermis or the stratum corneum. Pustules usually dry rapidly and become crusts ( Fig. 17-19 ). The type of leukocyte recruited into the epidermis is influenced by complex interactions of cytokines involved in the pathogenesis of the disease and can be useful in classifying and ultimately diagnosing the disease. For instance, intraepidermal eosinophils can be seen in association with ectoparasite bites. Lymphocytic infiltrates into the epidermis are often seen with immune-mediated diseases such as lupus erythematosus. Malignant lymphoma that predominantly affects the epidermis is also characterized by intraepidermal lymphocytes. Erythrocytes can also be present in the epidermis, usually degeneration. Intracellular fluid accumulation limited to the basal layer of the epidermis is termed hydropic or vacuolar degeneration and can result in the formation of intrabasilar vesicles. Hydropic degeneration is a consequence of damage to basal keratinocytes when the basal keratinocytes cannot maintain normal homeostasis, and fluid accumulates within the cells (Fig. 17-14) . Rapid cytoplasmic swelling leads to cell membrane rupture and organelle breakdown typical of cell necrosis and is referred to as oncosis. Examples of diseases commonly resulting in hydropic degeneration include lupus erythematosus, dermatomyositis, and drug eruptions. Ballooning degeneration, a form of intracellular fluid accumulation of keratinocytes in more superficial layers of the epidermis, such as the stratum spinosum, is characterized by swollen cells losing their intercellular attachments. This type of degeneration can result in the formation of a fluid-filled vesicle. Viruses that infect cells of the epidermis, such as the pox and parapox viruses, can cause lysis of cytoplasmic keratin and a buildup of excessive fluid, resulting in ballooning degeneration (see section on Pathologic Reactions of the Entire Cutaneous Unit).

Acantholysis. Acantholysis is the disruption of intercellular junctions (desmosomes) between keratinocytes of the epidermis. The process is initiated by damage to transmembrane glycoproteins belonging to the cadherin family of adhesion molecules and leads Pustules in pemphigus foliaceus are located in the superficial epidermis, such as this subcorneal pustule that contains neutrophils and numerous acantholytic cells, which are epidermal cells separated from each other as a result of the loss of desmosomal attachments. Acantholytic cells may shed as individual cells (arrows) or in clusters. The roof of the pustule is the stratum corneum, and the base of the pustule is the stratum spinosum. Superficial pustules can rupture to form erosions and crusts. Forceful clipping or scrubbing of the surface of the pustule can lead to rupture and thus can make the sample nondiagnostic. H&E stain. B, Inguinal region, dog. Multiple pustules (circumscribed accumulations of pus in the epidermis visible as irregularly ovoid, slightly elevated yellowish tan areas) are present in the sparsely haired skin of the inguinal region. The skin within the black ellipse has been injected with local anesthetic in preparation for biopsy sampling. C, Face, dog. Erythema, alopecia, focal erosion, crusting, and depigmentation are present on medial surface of the pinnae, periocular skin, and dorsum of the muzzle and the nasal planum. Crusts develop as the result of upward growth of the epidermis and disruption of pustules. Erosions develop as the result of loss of stratum corneum and pustular exudate, which exposes the stratum spinosum. Depigmentation can result from inflammation and damage to pigment-containing epidermal cells. D, Pawpad, dog (same dog as in C). A B 1027 CHAPTER 17 The Integument be filled with eosinophils. Small pustules containing neoplastic lymphocytes (Pautrier's microabscesses) are present in epitheliotropic lymphoma.

Crusts. Crusts are composed of dried fluid and cellular debris (i.e., dried exudates) located on the epidermal surface; thus crusts are indicative of a previous exudative process. Crusts are not specifically diagnostic but can hold the key to diagnosis in some diseases. For example, in dermatophilosis, the most diagnostic portion of the skin sample is the crust, which is multilaminated (or stratified) and contains the Gram-positive, branching coccoid organism Dermatophilus congolensis. Similarly, crusts formed through aging of pustules in pemphigus foliaceus are multilaminated because of numerous episodes of pustular eruption, and the crusts frequently contain numerous acantholytic cells. Crusts can also contain hair shafts infected with spores and hyphae of dermatophytes.

Alterations in Epidermal Pigmentation. Pigmentary alterations include hyperpigmentation, hypopigmentation, and pigmentary incontinence. Melanin is produced by melanocytes located in the basal and lower spinous layers of the epidermis, in the ORS and hair matrix of follicles, and perivascularly in the dermis. Melanocytes have surface receptors for hormones, such as melanocytestimulating hormone, and these hormones regulate melanogenesis. Other factors that influence the amount of melanin pigment in skin and hair are genes, age, temperature, and inflammation.

Hyperpigmentation. Hyperpigmentation results from an increased production of melanin from existing melanocytes or an increase in the number of melanocytes. An example of hyperpigmentation caused by an increased number of melanocytes is a lentigo, a rare localized nonneoplastic proliferation of melanocytes confined to the epidermis and resulting in formation of a black macular circumscribed lesion that is usually less than 1 cm in diameter. Most hyperpigmentation of the epidermis results from increased production of melanin from existing melanocytes. Possible mechanisms of increased melanin production include increases in the rate of production of melanosomes (i.e., granules within melanocytes that contain tyrosinase and synthesize melanin), in melanosome size, and in rates of melanosome transfer to keratinocytes and increased survival of melanosomes in keratinocytes. Examples of epidermal hyperpigmentation by increased production of melanin include chronic inflammatory diseases (most common cause), such as chronic allergic dermatitis, and endocrine dermatoses, such as A, Subcorneal vesicle (as in impetigo or pemphigus foliaceus) is located between the stratum corneum and the superficial layers of the stratum spinosum. B, Panepidermal vesicle (as in panepidermal pustular pemphigus in the dog) extends through multiple levels of the stratum spinosum, and the stratum corneum may form the roof of the vesicle. C, In a suprabasal vesicle, a portion of the epidermis (stratum spinosum) forms the roof (as in pemphigus vulgaris). D, In a subepidermal vesicle, the entire epidermis separates from the dermis and forms the roof (as in bullous pemphigoid). The roof of the vesicle may be missing in biopsy specimens. Dermis associated with trauma, or circulatory disturbances, such as marked vasodilation and vasculitis.

Pustules. Pustules (microabscesses) are accumulations of inflammatory cells (pus) within the epidermis (see Fig. 17-15 ). Epidermal pustules vary in inflammatory cell content and location in the epidermis, depending on the pathogenesis of the disease. The pustules of superficial bacterial infections generally contain degenerate neutrophils and coccoid bacteria and are often located beneath the stratum corneum (subcorneal). In ectoparasitic hypersensitivity, pemphigus foliaceus, and feline eosinophilic plaque, the pustules can Fibrosis. Fibrosis (fibroplasia) develops in response to various injuries, particularly ulceration of the epidermis. It consists of proliferation of fibroblasts and newly formed collagen fibrils (extracellular matrix). In the early stage of fibroplasia (called granulation tissue), the long axis of the fibroblasts and collagen fibrils are parallel to the surface of the skin and are oriented perpendicular to vertically aligned proliferative vessels. Clinically, the capillaries are seen on the surface as minute red dots that create a "granular" appearance, thus the name "granulation tissue." Microscopically, the orientation pattern provides a "latticework" appearance to the tissue . Fibrosis refers to the gradual deposition and maturation of collagen to form a scar. During fibrosis, collagen production increases and fibroblast and capillary numbers decrease, resulting in less cellular dense collagen oriented in thick hyaline bundles in parallel arrangement (e.g., a scar), which grossly appear white and glistening.

Collagen Dysplasia. Collagen dysplasia is generally an inherited abnormality of collagen that results in decreased tensile strength and an increased ability of the skin to stretch beyond normal limits. Because the tensile strength is reduced, even minor trauma can cause the skin to tear. Healing results in formation of scars. Microscopic features vary among the different types of collagen dysplasia disorders and may include collagen bundles that vary in size and shape and consist of tangled fibers with an abnormal organizational pattern; however, in some of these disorders the skin has no detectable microscopic alterations. Solar Elastosis. Solar elastosis is caused by chronic exposure of the skin to the UV spectrum of sunlight. UV radiation (UVR) consists of UVA (400 to 315 nm), UVB (315 to 280 nm), and UVC (280 to 100 nm). As sunlight passes through the atmosphere, the UVC and approximately 90% of UVB are absorbed. The UVA spectrum is less influenced by the atmosphere, so most UVR reaching the surface of the earth is UVA and a small amount of UVB. UVB penetrates into the epidermis and superficial dermis and is the portion of UV light most damaging to the skin. UVA penetrates deeper into the dermis, but its role in causing cutaneous injury is less well understood. Both UVB and UVA are thought to contribute to photoaging and carcinogenesis. The amount of UVR reaching the skin is dependent on a variety of host and environmental factors that can greatly influence the geographic incidence and anatomic locations of solar damage.

Environmental factors include quantity of ozone, smog, and cloud cover that tend to absorb and scatter some of the UV rays.

hyperadrenocorticism. Hyperpigmentation secondary to inflammation is thought to result from release of melanocyte-stimulating factors from keratinocytes. It is thought that these factors are present in normal epidermis, but that their level or activity is increased in response to stimulation or keratinocyte stress.

Hypopigmentation. Hypopigmentation can be congenital or hereditary and develops because of a lack of melanocytes, failure of melanocytes to produce melanin, or failure of transfer of melanin to epidermal cells. Hypopigmentation can also be acquired via a loss of existing melanin or melanocytes (depigmentation). Because copper is a component of tyrosinase, production of melanin pigment depends on copper, and copper deficiency can result in reduced pigmentation. In addition to providing color to the skin, hair, and eyes, melanocytes are also important in the inner ear where they function to control ion transport necessary for the function of the inner ear. Thus animals without melanocytes in the inner ear are often deaf.

Pigmentary Incontinence. Pigmentary incontinence refers to the loss of melanin pigment from the basal layer of the epidermis or ORS or bulb of the hair follicles caused by damage to the cells of the basal layer or of the follicular components and the accumulation of the pigment in macrophages in the upper dermis or perifollicular regions, respectively. Basal layer pigmentary incontinence can be a nonspecific lesion associated with inflammation; however, it is also seen with diseases that specifically damage basal cells or melanocytes such as lupus erythematosus or vitiligo. Perifollicular pigmentary incontinence occurs in diseases in which inflammation targets the follicular wall, such as demodicosis, or when there is abnormal growth or development of hair follicles, such as in some types of follicular dysplasia. Leukotrichia and leukoderma refer to decreased pigmentation of hair and skin, respectively.

Dermal Atrophy. Dermal atrophy results from a decrease in the quantity of collagen fibrils and fibroblasts in the dermis and leads to a decrease in the thickness of the dermis noted clinically by thin, translucent skin with more visible vasculature. The principal causes of dermal atrophy in domestic animals are catabolic diseases associated with protein degradation, such as hyperadrenocorticism (particularly in dogs and cats), and starvation. In cats with hyperadrenocorticism, collagen loss is sufficient to increase fragility of the skin, which tears with normal handling. Severe CHAPTER 17 The Integument

Altitude and latitude are also very important. The atmosphere at high altitude is thinner, so there is less oxygen and particulate matter to absorb and scatter the UV rays. Latitude is also critically important. The incidence of sunlight-induced cancer is estimated to double for every 265 miles closer to the equator that human beings reside. At high latitudes the path of sunlight through the ozone layer is longer than at lower latitudes, so the ozone absorbs more of the harmful UV light. The path of sunlight through the ozone layer is also one of the reasons that sunlight has more damaging UV rays in summer months and at midday. Increased wind velocity has also been shown to have an enhancing influence on damaging effects of UV light on the skin. Local environmental factors can influence the quantity of UV light reaching an animal's skin. Such factors include availability of shelter from sunlight in the form of trees, shade panels, or indoor housing, and color of the ground material (lightly colored sand) that can increase exposure to UV light through reflection. Host factors include quantity of hair, degree of pigmentation, thickness of stratum corneum, and other difficult-to-define genetic factors. Therefore solar damage is more prevalent in high-altitude, low-latitude parts of the world and in animals residing outside for long periods of time. Lesions generally develop in poorly haired and lightly pigmented sites. Solar elastosis develops in the superficial dermis of chronically sun-exposed skin, and consists of increased numbers of thick, interwoven, basophilic fibers with the staining characteristics of elastin (thus the name "solar elastosis"). In the nonpigmented abdominal skin of dogs, solar elastosis may develop intermixed with or below a linear band of dermal scarring parallel to the epidermal surface (laminar fibrosis). The pathogenesis of the development of solar elastosis is complex and not fully understood and may vary with species. Current evidence involving studies in human beings and mouse models supports the view that a majority of the elastotic material (elastin, fibrillin, and glycosaminoglycans) is newly formed as the result of altered function of sun-damaged fibroblasts, but that degradation of preexisting dermal matrix proteins, including elastin and also most likely collagen, seems to be involved as well. Solar elastosis is less prominent in the skin of domestic animals than in human beings but is often prominent in lightly pigmented, poorly haired sun-exposed skin and eyelids of horses and in the lower eyelids of Hereford cattle residing in sunny locations.

Degenerative Collagen Disorders of the Dermis. The term collagen degeneration has been used to refer to an altered histologic appearance of collagen fibers in hematoxylin and eosin (H&E)stained sections, whereby there is brightly eosinophilic granular to amorphous material bordering the fibers and somewhat obscuring the fiber detail. The collagen fibers and bordering eosinophilic material have also been referred to as flame figures, due in part to the irregular, sometimes radiating edges and brightly eosinophilic staining intensity. Electron microscopic studies in cats and human beings indicate that the collagen fibers can be disrupted, but they are not "degenerate." Instead, the brightly eosinophilic granular and amorphous material consists of aggregates of many eosinophils and eosinophil granules that border slightly disrupted but otherwise normal collagen fibers. These flame figures are seen in conditions in which eosinophils are prominent, including reactions to insect bites, mast cell tumors, and eosinophilic granulomas (collagenolytic granulomas) (Fig. 17-22 ). Collagen lysis refers to dissolution of collagen fibrils morphologically consisting of amorphous, lightly eosinophilic material lacking fibrillar detail. Collagen lysis is likely a secondary event caused by proteolytic enzymes released by a variety of cells, including eosinophils (collagenase) and neutrophils (collagenolytic proteinase, collagenase). A, Injury to the epidermal pigmentcontaining cells (predominantly melanocytes) has caused loss of melanin pigment in the epidermis (leukoderma). The pigment from the damaged melanocytes has been phagocytosed by dermal macrophages (pigmentary incontinence) (arrows). Mild to moderate lymphocytic inflammation is present along the epidermal dermal interface. H&E stain. B, Nose and lips. Areas of the normally black skin of the planum nasale and lips have been partially (bluish gray) or totally (pink) depigmented. The bluish-gray areas are in the process of becoming depigmented. Biopsy samples should be collected from the bluish-gray areas (arrow) to identify active inflammation and diagnostic lesions. Biopsy samples from black skin or from already totally depigmented skin will likely only show normal-appearing black or nonpigmented skin, respectively, with no evidence of inflammation. C, Leukotrichia, body. This dog is the same one depicted in B. He was a black Labrador retriever mix. More than 90% of the black hair coat became white (leukotrichia). Biopsy samples from white-haired areas may be normal because the inflammatory event that caused the pigment loss is likely gone by the time nonpigmented hair shafts emerge from the hair follicles. A, Note vertically oriented capillaries (C) and horizontally oriented fibroblasts and a few collagen fibers providing a "latticework" appearance to the granulation tissue. B, Leg. Note ulcerated area filled with granulation tissue. C, Exuberant granulation tissue, leg. Granulation tissue is a normal component of wound healing. However, excessive or exuberant granulation tissue can develop as a pathologic process. This condition occurs, especially in horses, when an ulcer fails to become reepithelialized. Although this process is commonly called "exuberant granulation tissue," at the stage depicted in this photograph, most of the granulation tissue has been converted to fibrous connective tissue. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) B A A C C has a thick, puffy appearance. In cases of severe mucinosis, the skin, when pricked with a needle, can exude mucin (a stringy fluid material). In histologic sections, much of the water is lost, and mucin appears as fine amphophilic granules or fibrils that separate dermal collagen. Examples of disorders with dermal mucin deposition are termed myxedema in hypothyroidism and mucinosis (hereditary cutaneous hyaluronosis) in the Chinese Shar-Pei dog.

Calcium Deposits. Mineralization is a general term for the deposition of insoluble, inorganic minerals in the cutaneous tissue and usually consists of calcium in combination with phosphate or carbonate. Because the mineral most often deposited is calcium, the terms mineralization and calcification are often used interchangeably. Mineralization can occur in four basic forms: (1) dystrophic, (2) metastatic, (3) idiopathic, and (4) iatrogenic. Mineralization can also occur in tissues that have been traumatized, which may encompass more than one of these pathogenic mechanisms. Dystrophic mineralization occurs as a result of injury or degeneration of cellular and extracellular components of the skin, with normal serum calcium concentrations, and without abnormalities in calcium metabolism. Examples include deposition of mineral in granulomas and calcinosis cutis seen in some cases of hyperadrenocorticism. In metastatic mineralization the calcium deposits develop without preceding tissue injury or degeneration and in association with hypercalcemia, usually the result of abnormal metabolism of calcium, phosphorus, or vitamin D. Examples include deposition of calcium salts in soft tissues in chronic renal disease and in poisoning with cholecalciferol (vitamin D 3 ). Mitochondria have a high affinity for calcium and phosphate and participate in both dystrophic and metastatic calcification by concentrating intracellular calcium and phosphate to concentrations that allow crystallization. Mechanisms leading to calcium deposition in dystrophic mineralization involve reduced pH of injured tissue, the influx of calcium into injured cells, and then into mitochondria. Metastatic calcification may be the result of increased extracellular calcium concentrations and the failure of the cell's normal ability to strictly regulate intracellular calcium with resultant accumulation within mitochondria.

Amyloid. Amyloid is an abnormal proteinaceous substance that can be deposited in a localized site in the body (organ limited) or can be "systemic," in which multiple organs are involved. In the systemic form, amyloid deposition can be the result of a primary abnormality of plasma cells (primary amyloidosis), in which case the amyloid is derived from components of immunoglobulin light chains (AL amyloid), or as a result of chronic inflammatory conditions (secondary amyloidosis), in which case the amyloid is derived from serum amyloid-associated protein (SAA protein), an acute phase reactant produced by the body in response to inflammation. Cutaneous amyloid deposition can occur in association with systemic amyloidosis, but visceral involvement is more common and clinically important. Cutaneous deposition of amyloid is rare but is seen in horses, dogs, and cats. In horses it can occur in association with secondary systemic amyloidosis or in a localized (organ-limited) form. In organ-limited amyloidosis the skin and/or upper respiratory tract are typically involved, the condition is not associated with recognized triggering causes, and the amyloid is produced from immunoglobulin light chains (AL amyloid). Clinical lesions vary from papules and plaques to nodules that usually are covered by a normal hair coat. Similar nodules can also develop in the respiratory mucosa and regional lymph nodes. Histologic lesions include nodular to diffuse granulomatous dermatitis and panniculitis with deposition of amyloid, an eosinophilic hyaline material. Cutaneous deposition of amyloid in dogs and cats is usually the localized type and is seen in association with extramedullary plasma cell tumors (AL amyloid). However, cutaneous deposition of amyloid in dogs also can be triggered by a monoclonal gammopathy (AL amyloid). Clinical and histologic lesions reflect the triggering disease.

Mucin. Mucin (glycosaminoglycan [GAG]), a normal component of the ground substance of the dermis, consists of protein bound to hyaluronic acid and can be deposited in increased quantity in focal areas or diffusely. Because hyaluronic acid has a great affinity for binding water, the skin in cases of mucin deposition (mucinosis) CHAPTER 17 The Integument Inflammatory Disorders of the Dermis. Dermatitis is inflammation of the dermis. Acute dermatitis begins with active hyperemia (increased blood flow), edema, and migration of leukocytes and results from release of cytokines and other mediators of acute inflammation (see Chapter 3). Active hyperemia is caused by vasodilation of arterioles, which causes increased blood flow at reduced velocity to capillary beds and postcapillary venules. Edema is caused by increased vascular permeability. Fluid leaves vessels mostly through widened interendothelial cell junctions. With a mild increase in vascular permeability, the edema fluid is clear (serous) because there are very few plasma proteins in the fluid. With increasing vascular permeability or endothelial cell injury, larger protein molecules, such as fibrinogen, escape from vessels, and the edema fluid becomes more eosinophilic and amorphous to fibrillar (fibrinous). The next step in acute dermatitis is migration of leukocytes from vessels into the perivascular dermis. The slowing of the blood flow and the endothelial cell expression of adhesion molecules that bind circulating leukocytes permit the migration of leukocytes in acute inflammation. The slowing of the blood flow allows leukocytes to move from the center of the vessel, where blood flow is fastest, to the margin, where they contact and attach to the activated endothelial cells.

After attaching to activated endothelial cells, leukocytes migrate between the endothelial cells into the perivascular dermis. The type of leukocyte that migrates and the sequence of cellular influx depend on activation of different adhesion molecules and chemotactic factors in the different phases of inflammation. In many types of acute inflammation, neutrophils are one of the first cells to arrive. Neutrophils predominate in the first 6 to 24 hours of injury and are generally replaced by macrophages in 24 to 48 hours. This sequence of cellular exudation can vary. For example, in reactions mediated by immunoglobulin E (IgE) cross-linking, such as type I hypersensitivity responses, mast cells (located in the perivascular dermis) are stimulated to release contents of granules (occurs in seconds) and synthesize and release inflammatory mediators (prostaglandins, leukotrienes, and cytokines), resulting in the influx of eosinophils, basophils, CD4 + T helper type 2 (T H 2) lymphocytes, and macrophages. Mast cell degranulation and T H 2 lymphocyte activation cause eosinophils to accumulate in large numbers. Thus eosinophils often constitute the majority of leukocytes in inflammatory reactions against parasites and other allergic reactions.

Acute dermatitis typically results in one of four outcomes. First, there can be complete resolution, which occurs when the inciting stimulus has short duration and there is little tissue damage that is completely repaired. Second, an abscess can form, which occurs with pus-producing (pyogenic) bacterial infections. Third, healing occurs by replacement of the injured area by fibrous connective tissue (e.g., scarring), which occurs when there is significant tissue destruction (such as a deep burn) in which the parenchymal tissues are lost and thus cannot regenerate. Fourth, there is progression of acute dermatitis to chronic dermatitis.

Chronic dermatitis is inflammation of the skin that lasts weeks or months. Histologic features of chronic dermatitis include accumulation of macrophages, lymphocytes, and plasma cells; tissue destruction in part caused by the inflammatory cells; and a reparative host response of fibrosis and angiogenesis. Chronic dermatitis is usually caused by persistent infections often associated with delayed hypersensitivity and the formation of granulomas (e.g., Mycobacteria sp.), presence of foreign material in the skin (e.g., embedded suture), or autoimmune reactions in which self-antigens provoke an ongoing immunologic inflammatory response against host tissue (e.g., lupus erythematosus). Macrophages are a key cell in chronic dermatitis. They arise from monocytes in the peripheral Mineralization can affect individual or groups of collagen fibers, resulting in increased basophilia and fragmentation of fibers in H&E-stained sections. The causes of idiopathic mineralization are not known; it occurs in the absence of tissue injury or abnormalities in calcium or phosphorus metabolism. Calcinosis circumscripta is a form of tissue mineralization in which calcium is deposited as amorphous nodular aggregates in the soft tissues of the tongue and in the subcutis of the pawpads of dogs. The pathogenesis is not defined, but some cases are considered idiopathic, whereas others may be the result of tissue trauma. Calcium deposits can elicit a granulomatous inflammatory response, a foreign-body reaction to the deposits. Iatrogenic mineralization develops via direct exposure to calcium salts such as occurs with topical exposure to calcium chloride deicing solutions. This is the least specific pattern because all inflammatory patterns are at one stage, perivascular. B, Vascular (vasculitis): Leukocytes target the vessel wall, resulting in necrosis, inflammation, leakage of fibrin and red blood cells, and if severe, thrombosis and infarction. C, Interface, cell poor: Mild, often lymphocytic, inflammation located along the dermal-epidermal interface with vacuolar or apoptotic degeneration of basal cells. D, Interface, cell rich: Dense band of inflammation along the dermal-epidermal interface, obscuring the basilar layer of the epidermis, and with vacuolar or apoptotic degeneration of basal cells. E, Nodular to diffuse with or without microorganisms. Inflammation, typically granulomatous to pyogranulomatous, which partially effaces the architecture of the dermis may be associated with infectious agents or may be sterile. ( C without infectious agents ( Fig. 17-23 ). For example, perivascular dermatitis with eosinophils is suggestive of hypersensitivity associated with parasites or other antigens; interface dermatitis with lymphocytes is suggestive of an immune response directed toward epidermal cells, such as lupus erythematosus or erythema multiforme; and nodular dermatitis with macrophages (granulomatous dermatitis) indicates a persistent stimulus, such as infection with acid-fast bacteria or fungi. Thus patterns of inflammation combined with cellular composition of infiltrates are useful in microscopic diagnosis.

The term adnexa refer to appendages or adjunct parts, which in the skin includes hair follicles and glands. The major clinical and histologic changes involve the hair follicles, and thus follicular lesions are emphasized in the next discussion.

Atrophy. Atrophy refers to gradual reduction (involution) in size and can be physiologic or pathologic. Physiologic atrophy is related to the normal progression of the hair follicle cycle (i.e., the hair cycle stages of transition [catagen], rest [telogen], shed [exogen], and latency [kenogen]). Pathologic atrophy occurs when the degree of atrophy is greater than that expected for a given stage of the hair cycle and may involve a greater frequency and duration of kenogen. Causes of follicular atrophy include hormonal abnormalities, blood and mature to macrophages whose primary function is phagocytosis. Macrophages also become activated by a variety of chemical mediators, including the cytokine interferon-γ (IFN-γ) secreted by sensitized T lymphocytes. When activated, macrophages also secrete many mediators of tissue injury (toxic oxygen metabolites, proteases, and coagulation factors) that contribute to chronic inflammation and fibrosis (growth factors, angiogenesis factors, and collagenases). The presence of lymphocytes and plasma cells in chronic inflammation is indicative of a host immune response.

The inflammatory milieu in the progression of acute and chronic dermatitis can be further complicated by other superimposed factors, notably physical injury from self-trauma, secondary bacterial infection of traumatized surface, injury from insect bites attracted by odor or exudate, and moderation by the host immune response or therapy. Thus dermal inflammatory responses to different stimuli often have overlapping histologic features, providing a diagnostic challenge for the dermatopathologist. Even so, the distribution of leukocytes often evolves into recognizable patterns that, when combined with the inflammatory cell type and other morphologic changes, suggest a group of differential diagnoses or the cause or pathogenesis of a specific disease (see Tables 17-3 and 17-4). Dermal patterns of inflammation that have been used in histologic diagnosis include perivascular dermatitis, vasculitis, interface dermatitis (inflammation affecting the basilar epidermis and superficial dermis that often obscures the dermal-epidermal interface), nodular to diffuse dermatitis with infectious agents, and nodular to diffuse dermatitis CHAPTER 17 The Integument However, as many animals have telogen-based hair cycles with fewer hair follicles in the anagen stage of growth, the degree and pattern of hair loss in anagen effluvium are variable, and animals with anagen-dominant cycles (such as poodles) may be predisposed to this side effect. Diagnosis is usually made based on history of drug therapy or illness, examination of affected hairs, in conjunction with sudden onset of alopecia. Histopathologic evaluation is rarely performed.

Other animals with hair cycle abnormalities have gradual but progressive loss of hair shafts associated with an arrested hair cycle such as the endocrine disease termed hyperadrenocorticism. Follicular Dysplasia. Follicular dysplasia refers to incomplete or abnormal development of the structure of follicles and hair shafts that ultimately leads to alopecia. Structure refers to the permanent physical structure of the hair follicle in contrast to temporary changes that may occur cyclically. Follicular dysplasia is usually an inherited abnormality of the hair follicles in which there is production of defective hair shafts, failure to maintain hair within follicles, or failure of hair growth. Follicular dysplasia may be congenital (present at birth) or tardive (later onset in life). Different types of follicular dysplasia syndromes are described in animals, but most are poorly characterized. Clinical features include reduced, absent, or poor-quality hair coat. Microscopic features vary but include abnormal keratinocytes in the hair matrix or abnormally formed components of the follicular wall. In contrast to the follicular dysplasia syndromes that are not associated with coat color, the color-linked follicular dysplasia syndromes such as color mutant alopecia (color dilution follicular dysplasia, color dilute alopecia) and black (dark) hair follicular dysplasia ( Fig. 17-24 ) have more obvious microscopic lesions in which melanin pigment abnormalities serve as a marker for the dysplasia. These pigment abnormalities include abnormally clumped melanin pigment granules in keratinocytes and melanocytes in the epidermis and hair bulb; melanin pigment clumps that are of irregular size, shape, and distribution in hair shafts that may cause the hair to weaken and break above the epidermal surface; nutritional abnormalities, inadequacy of blood supply, inflammation, and general state of health, including stressful events or systemic illness. Some types of pathologic atrophy can be reversed when the underlying cause is corrected. Damage to germinal epithelial cells can result in destruction or total loss of the adnexa with replacement by a scar. Examples include extensive inflammation and disruption of the follicle (folliculitis and furunculosis) and bordering glands and dermis that destroys a significant portion of the adnexal germinal epithelium, thermal burns sufficiently deep to involve the adnexa and dermal vessels, thrombosis causing infarction (i.e., diamond skin disease in pigs), and severe physical trauma such as lacerations that remove components of the skin, including adnexa.

Hypertrophy. Hypertrophy is an increase in the unit size of a structure or an individual cell. Follicular hypertrophy, which results in follicles that are longer and wider than normal for the site, develops secondary to repeated surface trauma such as in acral lick dermatitis. Hyperplasia is an increase in the number of cells in a structure. Enlargement of adnexa, a common response to injury, usually involves both hypertrophy and hyperplasia and is observed in follicles and sebaceous and apocrine glands associated with chronic allergic dermatitis.

Abnormalities of Hair Cycle Stages. Abnormalities of hair cycle stages occur when there is disruption in the normal progression from the anagen, catagen, telogen, exogen, and kenogen stages of the hair cycle (see Fig. 17 -7). Clinical and histopathologic lesions can vary. Telogen effluvium is associated with a sudden noticeable shedding of the hair coat (telogen hairs) that may result in a bilateral, patchy to more diffuse alopecia. In domestic animals no scientific studies regarding cause or pathogenesis have been performed. Anecdotal reports usually associate the condition with a past episode of systemic illness or severe stress such as high fever, pregnancy and lactation, or anesthesia and surgery. The illness or stressful event is thought to cause synchronization of the hair cycle leading to many of the hair follicles eventually entering anagen simultaneously with subsequent sudden loss of telogen hairs. It is unclear if there are differences in telogen effluvium between animals with an anagendominant hair cycle (as occurs in animals with continuously growing hair coats such as poodles) versus a telogen-dominant hair cycle (as occurs in most domestic animals). In most cases the hair loss typically does not develop until several weeks or months after the systemic illness or stress, and it eventually resolves as the new hair shafts emerge from the follicles and the new hair coat becomes visible. Diagnosis is usually made clinically with the history of rapid, often widespread hair loss after a systemic illness or severe stress. Examination of epilated hair shafts reveals telogen hair bulb (usually straight, rough surfaced, club or spear shaped, and without pigment). Most clinical cases have biopsy samples collected during the late stages (during the stage of excessive shedding), when the majority of follicles are in the anagen stage of the hair cycle (recovery stage). Histopathologic evaluation is most useful in ruling out other disorders that may also cause alopecia.

Anagen effluvium has been studied the most in human beings and is associated with sudden hair loss that occurs within days of insult to the anagen hair follicle that impairs its mitotic or metabolic activity. The hair loss is usually associated with chemotherapeutic agents used to treat cancer, especially combination drugs at higher doses. Damage to the hair matrix cells of the follicle can result in failure to produce a hair shaft or production of a narrow fragile hair shaft susceptible to breakage. Examination of the affected hair shaft reveals a fracture at a narrowed area. Histopathologic lesions include apoptosis and fragmented nuclei of hair matrix cells of the anagen hair bulbs. Anagen effluvium has been reported in animals that have had fever, infectious disease, metabolic disease, or antimitotic drugs. A, Melanin pigment granules in hair shafts and hair matrix cells are large and variably sized, shaped, and distributed (arrows). Perifollicular macrophages (arrowheads) that are most prominent near hair bulbs have phagocytosed melanin pigment presumably released from damaged hair matrix cells. H&E stain. B, The hair coat is normal in white-haired areas. Alopecia affects black-haired areas only but is difficult to recognize from a distance because the skin in affected areas is also black. 

atrophy and dysplasia that develop after or secondary to the sebaceous gland lesions.

Folliculitis. Folliculitis, inflammation of the hair follicle, affects most domestic animals. It is histologically classified according to the affected component of the hair follicle, the type of leukocytes in the inflammatory infiltrate, and the severity of the inflammation . The types of follicular inflammation include perifolliculitis, mural folliculitis, luminal folliculitis, and inflammation of the hair bulb (bulbitis). The inflammation of hair follicles begins in the perifollicular blood vessels with the same hemodynamic, permeability, and leukocytic changes that constitute dermal inflammation. Leukocytes migrate from perifollicular blood vessels to the dermis, resulting in perifolliculitis (inflammation around but not involving the hair follicle). Perifolliculitis is not specific for any category of disease but is an initial event in the development of folliculitis. Perifolliculitis also often coincides with folliculitis of a variety of causes. The perifollicular inflammatory cells then migrate into the follicular wall, resulting in mural folliculitis (inflammation limited to the wall of the follicle). Depending on the cause of the inflammatory process, the leukocytes can remain localized to the follicular wall or can progress into the follicular lumen.

Mural. In mural folliculitis, leukocytes remain largely confined to the follicular wall. Mural folliculitis is further subdivided by the location, type, or severity of involvement of the follicular wall such as interface (outer aspect of the follicular wall), infiltrative (more and perifollicular melanophages that are most prominent near hair bulbs and that have phagocytosed melanin pigment presumably spilled from damaged hair matrix cells. The pathogenesis of the abnormal hair coat appears to involve weakened hair shafts that break at areas of aberrantly large pigment deposits, abnormal cuticle development, and possibly abnormal hair shaft development caused by damaged hair matrix cells. The dysplastic follicles may also become atrophic with time, contributing to the alopecia.

It should be noted that not all dogs that have coat color dilution have concurrent follicular dysplasia because the prevalence of follicular dysplasia varies among breeds with dilute coat colors. The propensity to develop follicular dysplasia is high in some breeds with coat color dilution such as the Doberman. For example, it is estimated that follicular dysplasia develops in approximately 93% of blue and 75% of fawn Dobermans.

Sebaceous Gland Dysplasia. Abnormal development of sebaceous glands is rare, is presumed to be genetic in origin, and has been reported in dogs and cats. The pathogenesis is unknown. Histologically, in early stages there are increased numbers of small epithelial reserve cells compared with mature sebaceous gland cells. The number of mature sebaceous gland cells may be reduced, cytoplasmic vacuolization may be irregular, and the orderly differentiation of reserve cells to mature cells is lost or absent. In the late stage there is subtotal atrophy, in which only a few reserve cells and a few mature sebaceous gland cells remain. Clinical lesions consist of adherent scales, poor hair coat, and progressive alopecia. The poor hair coat and alopecia are presumed to be the result of follicular There are subtypes of mural folliculitis that vary with level of involvement (superficial versus inferior), type of inflammation (pustular versus necrotizing), and the degree or severity of penetration into the follicular wall (interface versus infiltrative). C, Luminal folliculitis: Inflammatory exudate is present in the follicular lumen, and inflammation also usually involves the wall, often a response to follicular infection. D, Furunculosis: Disruption of the follicular wall, resulting in release of luminal contents into the bordering dermis. E, Bulbitis: Inflammation targeting the inferior segment or hair bulb of the hair follicle. F, Sebaceous adenitis: Inflammation targeting the sebaceous glands. For simplicity, a simple hair follicle is illustrated in parts B, C, and D. ( and around growing (anagen) hair bulbs up to the level of the isthmus. The cellular infiltrates within the hair bulb are mostly cytotoxic CD8 + lymphocytes and CD1 + antigen-presenting dendritic cells, whereas CD4 + lymphocytes dominate the peribulbar T lymphocyte infiltrate. The role of circulating autoantibodies that target trichohyalin, hair keratins, and other components of the hair follicle remain unresolved; however, their appearance before the onset of clinically apparent alopecia in many cases of alopecia areata suggests these autoantibodies are not simply produced as a secondary response to hair follicle damage. The inflammation associated with the anagen hair bulb is thought to disrupt the function of the follicles, which subsequently enter the catagen and then telogen stages of the hair cycle. Alopecia areata can spontaneously resolve, but the newly growing hairs can be white instead of pigmented, probably as a result of damage to melanocytes in the hair bulb. In some instances the inflammation disappears, but the hair matrix cells do not fully recover, and instead follicles develop abnormal shapes or contours infiltration into the follicular wall), pustular (presence of pustules in the follicular wall), or necrotizing (necrosis and disruption of the follicular wall). The subtype of mural folliculitis can provide insight into the pathogenesis of folliculitis (e.g., disease process). For example, pustular mural folliculitis is a feature of pemphigus foliaceus, and interface mural folliculitis is a feature of demodicosis ( Fig. 17-26) .

Bulbitis. Bulbitis refers to inflammation directed to the deepest portion of the hair follicle, the hair bulb. Alopecia areata is a specific example of bulbitis that develops in horses, cattle, dogs, and cats. Inflammation and subsequent damage to the hair matrix cells in the growing hair bulb ultimately result in alopecia. Although alopecia areata is recognized as an immune-mediated disorder, its precise etiopathogenesis is uncertain. In horses and dogs, antifollicular cellmediated immunity and humoral immunity may participate. In some cases of alopecia areata, the hair bulb melanocyte also may be a target. Microscopic lesions consist of lymphocytic infiltrates within Figure 17 -26 Demodicosis, Skin, Dog. A, Note mites deep in the follicle lumens (arrow) and also inflammation in the outer wall of the follicle (interface mural folliculitis) and in the perifollicular dermis (perifolliculitis). H&E stain. B, Note the mite in the follicular lumen. A few lymphocytes border the follicular wall, and there is mild vacuolar degeneration of basal cells (arrows) (lymphocytic interface mural folliculitis) of the follicular wall. H&E stain. C, Localized demodicosis, periocular. Skin is alopecic and lichenified, with mottled hyperpigmentation and hypopigmentation that are likely caused by inflammation, initiated by an immune response to mite infestation and possibly secondary bacterial infection, that results in damage and sometimes disruption of the follicular wall (furunculosis). (Courtesy Dr. A.M. Hargis, DermatoDiagnostics.)

C release of follicular contents into the dermis. There are other causes of furunculosis, including trauma to the surface of the skin resulting in epidermal hyperplasia at the opening of the follicle, plugging of the follicle by stratum corneum, and accumulation of follicular contents, including glandular secretions (comedo formation). The gradual accumulation of this luminal material can cause distention of the follicle and thinning of the follicular wall, leading to rupture. Regardless of the cause of furunculosis, the presence of hair fragments, keratin proteins, sebum, and possible infectious agents in the dermis leads to a suppurative inflammatory response that progresses to more long-standing chronic pyogranulomatous inflammation and scarring. Perifolliculitis, luminal folliculitis, and furunculosis often follow in sequence ( Fig. 17-29) . The inflammation can resolve with appropriate therapy, can extend into the deep dermis and panniculus, and/or can form sinuses that drain to the surface of the skin and are difficult to resolve. Severe inflammation can lead to complete destruction of adnexal units and replacement by scar tissue that diminishes the likelihood of hair regrowth and complete recovery by the skin. Sebaceous Adenitis. Sebaceous adenitis is a specific inflammatory reaction of unknown cause that targets sebaceous glands and results in alopecia and epidermal and follicular hyperkeratosis. It is largely a disease of dogs but rarely is seen in horses and cats. Early histologic lesions are characterized by accumulations of lymphocytes around sebaceous ducts or glands. Fully developed lesions consist of lymphocytes, neutrophils, and macrophages that efface sebaceous glands. Chronic lesions have total loss of sebaceous glands (atrophy), scarring, epidermal and follicular hyperkeratosis, and follicular atrophy. The inflammation of sebaceous glands is thought to be the result of a cell-mediated immune response, but the pathogenesis of alopecia and scaling is incompletely understood. Sebaceous gland inflammation also can occur secondary to folliculitis, demodicosis, uveodermatologic syndrome, or leishmaniasis, in which the inflammation primarily targets other areas of the skin (follicles, epidermal cells, or dermis) and involves the neighboring sebaceous glands because of their proximity to the inflammation.

Hidradenitis. Hidradenitis, which is inflammation of apocrine glands, has rarely been studied in detail in domestic animals. Suppurative hidradenitis has been described in dogs in which most cases developed in conjunction with staphylococcal folliculitis and furunculosis, either affecting the same or other follicular units. It is speculated, because of the physical connection between the apocrine gland and hair follicle in dogs, that suppurative hidradenitis is most often an extension of hair follicle infection and is the result of the bacteria that cause the folliculitis. There are no clinical signs that are unique to or suggest the presence of hidradenitis other than the association with follicular bacterial infection. Histologically, dogs with hidradenitis associated with bacterial folliculitis and furunculosis have suppurative inflammation of the apocrine gland and surrounding dermis.

Vasculitis, inflammation of vessels (see Fig. 17 -23, B) in which the vessels are the primary target of injury, can be the result of infection by microbes, immunologic injury, toxins, photodynamic chemicals, UV light, or disseminated intravascular coagulation (DIC) or can be idiopathic. The species most commonly presenting with vasculitis are the horse and the dog, and most cases are idiopathic in that a specific cause cannot be determined. Histologic diagnosis of vasculitis is often challenging because it is difficult to differentiate between vessels taking part in inflammation simply by providing a conduit for inflammatory cells to reach a site of injury in the epidermis or dermis or vessels that are destroyed by their proximity to and produce defective hair shafts. In the past these noninflamed but abnormal hair follicles and hair shafts were mistakenly thought to represent a primary form of follicular dysplasia, but it is now realized that these abnormal follicles are the result of previous hair bulb inflammation and hair matrix cells that do not fully recover function.

Luminal. Luminal folliculitis refers to inflammation predominantly involving the lumen and usually the wall of the follicle. It develops when leukocytes migrate from the wall into the lumen because they are attracted by various intraluminal stimuli, such as a follicular infection with bacteria (staphylococci), dermatophytes (Microsporum, Trichophyton), or infestation with parasites (Demodex, Pelodera) ( Fig. 17-27) . The inflammation can weaken the follicular wall, leading to rupture, known as furunculosis (Fig. 17-28) , and A, The wall of the follicle is disrupted, resulting in the release of follicular contents (a hair shaft, stratum corneum of the follicle, and exudate) into the dermis. The follicular lumen also contains numerous coccoid bacteria (arrow). Note that the hair shaft has variably sized and shaped melanin pigment granules, indicating that this dog also has coat color dilution, which may increase susceptibility to folliculitis. H&E stain. B, A circular area of erythema, scaling, and crusting (center of image) is caused by follicular inflammation and rupture (furunculosis). The exudate in the perifollicular dermis has extended into the surrounding dermis and onto the skin surface through a draining sinus, and dried to form a crust. (Courtesy Dr. A.M. Hargis, DermatoDiagnostics.) A A B Figure 17 -29 Progression of Folliculitis. Inflammation begins with migration of leukocytes (black dots) from perifollicular dermal vessels into the perifollicular dermis (perifolliculitis). Inflammation progresses to involve the follicular wall (mural folliculitis) and then the lumen (luminal folliculitis). If the inflammation continues, the follicular wall is weakened and ruptures, and follicular contents are released into the dermis (furunculosis surrounding inflammation that is severe and those vessels that are actually the target of injury. Also, the type of inflammatory cell that participates in the vasculitis reaction can vary more with the age of the vascular lesion than with the type of disease process inciting the stimulus. Histologic lesions in vasculitis include damage to the vessel wall such as the presence of few necrotic cells or foci of fibrinoid necrosis, mural infiltrates of leukocytes, and intramural or perivascular edema, hemorrhage, or fibrin exudation. Vascular injury leads to the clinical lesions of edema and hemorrhage and, if severe, can include ischemic necrosis and cutaneous infarction. Ulceration with or without sloughing of the skin can occur. Sustained partial ischemia can lead to atrophic changes in the components of the skin. Classic examples include immune-complex deposition in vessel walls (systemic lupus erythematosus and equine purpura hemorrhagica), vasculitis and ischemic dermatopathy associated with subcutaneous rabies vaccination, infection with an endotheliotropic organism (Rickettsia rickettsii), and septicemia with bacterial embolism and infarction in pigs (Erysipelothrix rhusiopathiae).

Panniculitis. Panniculitis, inflammation of the subcutaneous adipose tissue, affects most domestic animals and can be caused by infectious agents (bacteria, fungi), immune-mediated disorders (systemic lupus erythematosus), physical injury (trauma, injection of irritant material, foreign bodies), nutritional disorders (vitamin E deficiency), or pancreatic disease (pancreatitis, pancreatic carcinoma) or can be of undetermined cause (idiopathic). Panniculitis can be primary or secondary. In primary panniculitis the SECTION II Pathology of Organ Systems

CHAPTER 17 The Integument predominantly neutrophilic, predominantly lymphocytic, predominantly granulomatous to pyogranulomatous with infectious agents, predominantly granulomatous to pyogranulomatous without infectious agents, and fibrosing.

Skin diseases uncommonly affect just one component of the skin (e.g., only the epidermis or only the lumens of hair follicles). More often, multiple components of the skin are involved in the disease process. In addition, lesions evolve through different stages; some lesions can resolve, and there can be secondary lesions, such as self-induced trauma, complicating the initial lesions. Therefore multiple biopsy samples collected from different areas of the skin are often necessary to help illustrate the range of lesions necessary to reach a diagnosis. Multiple biopsy samples provide a more representative picture of the disease process than a single biopsy sample could. Even so, evaluation of multiple biopsy samples does not always lead to a specific diagnosis, but the pattern of lesions identified often suggests categories of disease and rules out other differential diagnoses.

The involvement of multiple components of the skin in a disease process can be illustrated by a poxvirus infection ( Fig. 17-32) . When a poxvirus invades the epidermis, the virus replicates in the cells of the stratum spinosum and causes cytoplasmic swelling (ballooning degeneration) and rupture (reticular degeneration) of some of the epidermal cells. Cytoplasmic viral inclusions form in some cells. Cellular constituents released from damaged epidermal cells act as chemical mediators of the acute inflammatory response and are chemotactic for leukocytes. These chemical mediators and chemotactic factors (1) increase blood flow to the site of viral invasion by dilation of arterioles, (2) cause margination of leukocytes in capillaries and postcapillary venules in the dermis, (3) increase vascular permeability (dermal edema), and (4) cause migration of leukocytes out of vessels into the tissue, creating the formation of macular lesions. The epidermal degeneration, dermal edema, and perivascular inflammation can progress to exudative lesions. Ballooning and reticular degeneration of keratinocytes result in the formation of intraepidermal vesicles. Leukocytes in perivascular sites under the influence of inflammatory mediators from the epidermis migrate to the epidermis and enter the vesicle to form pustules. Some poxviruses also cause epidermal hyperplasia by stimulating host cell DNA synthesis, presumably by a viral gene product similar to epidermal growth factor, resulting in pseudocarcinomatous hyperplasia. The pustule enlarges and eventually ruptures, releasing the exudates onto the skin surface. The exudates dry and form a crust (scab). The primary lesions of vesicles and pustules are fragile and often transient, lasting only hours, and so are difficult to identify and collect in biopsy samples. The secondary lesions of crusting and scarring are typical lesions at clinical presentation because they are more long-standing, but these older (late stage) lesions are less subcutaneous adipose tissue is the target of the disease process ( Fig.  17-31 ). An example of primary panniculitis is feline pansteatitis, which occurs in cats fed diets high in polyunsaturated fatty acids and low in antioxidants, such as vitamin E. Lack of vitamin E leads to oxidation of lipids (free radical-induced membrane lipid peroxidation) of the subcutaneous adipose tissue, inciting a pyogranulomatous inflammatory response. In secondary panniculitis the subcutis is affected by inflammation primarily involving the contiguous dermis; the inflammation extends down into the subcutis. For example, deep bacterial folliculitis with furunculosis can lead to a secondary panniculitis, as can a penetrating wound contaminated with microbial agents or a foreign body. Animals with panniculitis clinically have palpable nodules that can ulcerate and drain an oily or hemorrhagic material (see Fig. 17 -31). Lesions are most often on the trunk and proximal limbs and can be solitary or multifocal. Solitary lesions may be cured by excision, whereas multiple lesions may resolve with specific therapy or result in scar formation. In animals, panniculitis is subdivided based on cell type and presence or absence of microorganisms into the following basic categories: Figure 17 -30 Sebaceous Adenitis, Skin, Haired, Dog. A, The inflammation in this fully developed sebaceous adenitis lesion forms a band of inflammatory cells parallel to the epidermis at the level of the sebaceous glands (arrows), which are absent. Epidermal and infundibular hyperkeratosis are present. H&E stain. B, The inflammation in this early or mild sebaceous adenitis lesion is beginning to efface the sebaceous glands. A few sebaceous glands are visible within the area of inflammation (arrows). H&E stain. C, Normal curly hair coat before development of sebaceous adenitis (face and paws are more closely clipped). D to F, Hair coat after development of sebaceous adenitis. Much of the hair coat of the entire body gradually shed. The poodle was treated with therapy, some of the hairs regrew, but the hair coat that remains is thinner than normal, and the hair shafts are darker, straighter, and coarser. The skin of the dorsal lumbar area is visible through the hair coat (F). (A to C courtesy Dr. A.M. Hargis, DermatoDiagnostics. D to F courtesy Dr. D. Duclos, Animal Skin and Allergy Clinic.) and cats seem to be predisposed to develop particular autoimmune diseases.

Type I reactions are mediated by preformed or newly synthesized pharmacologically active substances released by mast cells and basophils after reaction between foreign antigen and specific antibody (usually IgE) bound to high-affinity IgE receptors on the membrane of the mast cells or basophils (see Table 17 -5). Preformed substances released from mast cells include histamine, factors chemotactic for eosinophils and neutrophils, prostaglandins, serine esterases, and TNF-α. Substances synthesized on mast cell stimulation include leukotrienes, cytokines, and platelet-activating factor. Type I hypersensitivity can be systemic (anaphylaxis), localized to the skin, or both. In the skin the reaction results clinically in pruritic, circumscribed wheals with raised, erythematous borders. The reaction occurs in two phases, immediate (15 to 30 minutes) and late (6 to 12 hours), and is generally referred to as an immediate hypersensitivity reaction. The eosinophil products, major basic protein and eosinophil cationic protein, are toxic to epithelial cells and contribute to tissue damage in the late phase reaction. The production of IgE is genetically controlled, and therefore inherited predispositions to type I hypersensitivity occur. Cutaneous type I hypersensitivity reactions include atopic dermatitis (most common), urticaria, angioedema, hypersensitivity resulting from bites of flies such as Culicoides sp. and mites such as Sarcoptes sp., the presence of gastrointestinal parasites, and ingested dietary components (e.g., proteins, grains, preservatives). This type of reaction is characterized microscopically by mast cell degranulation, capillary dilation, edema, and infiltrates of eosinophils.

Type II reactions, also called cytotoxic reactions, depend on IgG or IgM antibodies formed against either normal or altered cell membrane antigens. The reaction engages Fc receptor and diagnostic histologically. In this way, multiple components of the skin participate in the development of the lesions and are responsible for the clinical stages of macule, papule, vesicle, pustule, crust, and scar.

Diseases associated with excessive or aberrant immunologic responses are classified as either hypersensitivity (allergy) or autoimmune. Hypersensitivity is a mild to severe reaction that develops in response to normally harmless foreign compounds, including antiserum, pollen, and insect venoms. In contrast, autoimmune diseases develop when antibodies or T lymphocytes react against self-antigens when mechanisms of self-tolerance fail. Typically the immune system randomly generates millions of lymphocytes that can each respond to a different foreign protein and subsequently also removes any lymphocytes that may also respond to a selfantigen. Failure to remove or cull lymphocytes that respond to self-antigens may result in autoimmune disease. Autoimmune disease in this section is a general term referring to a spectrum of diseases in which autoimmune mechanisms appear to participate in lesion production. Four basic immune reactions, types I, II, III, and IV, mediate the tissue damage in both hypersensitivity and autoimmune diseases (Table 17 -5). Most cutaneous hypersensitivity reactions are mediated by either type I or type IV reactions, or by a combination of one or more of the four reactions. In contrast, most autoimmune reactions tend to be mediated by type II or III reactions, although more than one mechanism can be involved. Hypersensitivity reactions are common in horses and dogs, less common in cats, and uncommon in food animals. Autoimmune diseases with cutaneous manifestations are uncommon in domestic animals, accounting for 1% to 2% of dermatoses in most species. Of the cutaneous autoimmune disorders, pemphigus foliaceus is the most prevalent, followed in incidence by discoid and systemic lupus erythematosus. In domestic animals, certain breeds of horses, dogs, CHAPTER 17 The Integument 

The strict categorization of hypersensitivity reactions is an oversimplification. Categories and lesions can overlap, and there are species differences. Hypersensitivity to fleas, ticks, Staphylococcus sp., hormones, and drugs are mediated by a combination of types I, II, III, or IV reactions. Therefore histopathologic examination may provide the general category of inflammatory reaction pattern and rule out other disease processes but may not lead to a diagnosis of the specific type of hypersensitivity present.

Information on this topic is available at www.expertconsult.com.

Information on this topic is available at www.expertconsult.com.

Information on this topic is available at www.expertconsult.com.

There are two basic causes or types of cutaneous aging, the first is called intrinsic (or natural) aging and is controlled by the animal's genome and specific genes (life span of telomeres [see Chapter 1). Genetic disorders in human beings, including progeria (LMNA gene mutation) and wrinkly skin syndrome (mutations in PYCR1 gene), that accelerate the process of aging are included in this category. The second type of aging is called extrinsic aging and is caused by external or outside factors such as chronic exposure to the sun (UV light), mechanical trauma, diet, and others that are less well understood.

The effects of aging on the skin are manifested by a loss of normal structure and function such as the loss of barrier systems, collagen and elastin, lipids, sebaceous and sweat gland secretions, cutaneous microvasculature, reparative and regenerative capacity (wound healing), and nerve sensory function. These occur together with thinning of the skin, reduced strength and resiliency of the skin, thinning and graying of the hair, and increased prevalence of neoplastic transformation.

Chronologic aging of the skin in domestic animals has not been seriously investigated but is likely similar to some aspects of aging reported in human beings and experimental laboratory animals. Aging changes are perhaps more obvious in those domestic animal species that share a close relationship with their human caretakers, live out their natural lives, and thus age alongside human beings. Disease outcomes of aging in domestic animals are discussed later and illustrated in Box 17-3. The more clinically obvious aging changes in the skin of domestic animals include neoplastic transformation and thinning and graying of the hair. With few exceptions, most cutaneous tumors, benign or malignant, develop in mature adult to older animals. In human beings, many age-related changes in the skin, including the development of selected neoplasms, arise via the extrinsic mechanism of chronic environmental exposure to UV light from the sun. Although the same is true for the sparsely haired and sparsely pigmented skin of domestic animals, such as the skin around the eyes, nose, lips, genitalia, or on the ventral abdomen, chronic sun exposure poses less of a problem for most domestic animals due to the usual protection of the hair coat. For further discussion, see the section on Solar (Actinic) Dermatosis, Keratosis, and Neoplasia.

The overt visibility of the hair coat and regenerative nature of the hair follicles may explain why thinning and graying of the hair, common to many species, are notable features of aging. Thinning and graying of hair with age have been studied most extensively in complement-mediated effector mechanisms. Cell damage occurs by complement-mediated lysis, antibody-dependent cell-mediated cytotoxicity, or antibody-directed cellular dysfunction (see Table  17 -5). The first two mechanisms are most common in type II reactions affecting the skin. Examples include deposition of autoantibody to desmoglein 1, desmocollin 1, or desmoglein 3, transmembrane proteins found in desmosomes that provide physical connections between keratinocytes and are present in pemphigus (uncommon), and autoantibody to bullous pemphigoid antigen 2 (also called collagen XVII), a 180-kD hemidesmosomal transmembrane molecule in bullous pemphigoid (rare). The lesions vary with the location of the target antigen. In pemphigus foliaceus, desmosomal damage leads to formation of superficial epidermal vesicles that rapidly become pustules and crusts, whereas in bullous pemphigoid the deeper hemidesmosomal damage leads to formation of subepidermal vesicles that rapidly become ulcers.

Type III reactions are mediated by soluble immune complexes mostly of the IgG class formed in the circulation or in tissues. The antigen can be exogenous (e.g., bacterial) or endogenous (organ specific as in systemic lupus erythematosus). Immune complexes are often deposited in vessel walls and result in complement fixation and in the generation of cytokines and leukotactic factors, leading to vasculitis (see Table 17 -5). Tissue damage results from lysosomal enzymes released from neutrophils, activation of complement and coagulation systems, platelet aggregation, and free oxygen radicals. Immune-complex vasculitis is believed responsible for the purpura seen in infections in horses with Streptococcus equi and is responsible for some of the lesions of systemic lupus erythematosus. Clinical lesions associated with immune-complex vascular damage include hemorrhages and edema with serum exudation. In severe cases, vascular damage leads to ischemic necrosis and ulceration of the skin. Microscopic lesions consist of the vascular wall disrupted by neutrophils (neutrophilic vasculitis), perivascular edema, hemorrhage, and fibrin exudation.

Type IV reactions are mediated by antigen-specific effector T lymphocytes. These include sensitized CD4 + lymphocytes (T H 1 or T H 2) or CD8 + lymphocytes (cytotoxic T lymphocytes) (see Table 17 -5). The reaction mediated by sensitized CD4 + T H 1 lymphocytes develops after contact with a specific persistent or nondegradable antigen (such as tuberculin), causing the release of cytokines and recruitment of other lymphocytes and macrophages. The reaction largely depends on IFN-γ or other cytokines, including IL-2. IFN-γ activates macrophages that work to eliminate the targeted antigen. In reactions mediated by CD4 + T H 2 lymphocytes (T-helper lymphocytes), contact with soluble antigen bound to major histocompatibility complex class II (MHC II) results in inflammatory responses in which eosinophils predominate. This type of reaction is believed to participate in the pathogenesis of atopic dermatitis. In the cytotoxic reaction the CD8 + T lymphocytes kill the targeted host cell directly. This is the mechanism of damage in allergic contact dermatitis associated with antigens such as poison ivy and can also participate in graft-versus-host disease. Type IV reactions take many hours to develop and are initiated by antigens bound to host cell major histocompatibility molecules. Type IV reactions mediated by CD4 + T H 1 lymphocytes are used in the diagnosis of diseases such as tuberculosis, histoplasmosis, and coccidioidomycosis. The skin reaction typically develops 24 to 48 hours after exposure to the specific antigen and consists of perivascular mononuclear cell accumulations and dermal edema.

Regeneration and repair constitute a host defense mechanism to injury (E-Box 17-1). The details of tissue regeneration and repair are covered in Chapter 3, whereas the basic mechanisms involved in healing of cutaneous wounds are summarized here. Two common types of cutaneous wounds are used as examples, and these include wounds with opposed edges, such as surgical incisions, and larger wounds in which the edges cannot be opposed, such as broad ulcers, necrosis associated with deep burns, or large areas of trauma in which portions of the skin have been lost. Recall that regeneration and repair are dynamic processes involving multiple and overlapping stages. These stages include (1) blood clotting and inflammation (12 to 24 hours after injury), (2) reepithelialization, fibroplasia, and angiogenesis (3 to 7 days after injury), and (3) wound contraction and collagen production (1 to 2 weeks after injury).

The simplest healing involves the clean, uninfected surgical incision in which the edges of the wound are closely opposed by sutures so that the wound space is narrow. Healing of these wounds is called primary union or healing by first intention (see Fig. 3 -34). These wounds cause minimal necrosis of cells of the epidermis, dermis, and adnexa and minimal disruption of the basement membrane. Thus they heal quickly without significant architectural change, although a thin scar remains and the adnexa destroyed by the incision are permanently lost.

The first stage of wound healing is blood clotting and inflammation and begins within the first 12 to 24 hours of injury. The process begins with blood vessel disruption, platelet aggregation, blood

The second stage of wound healing consists of reepithelialization, fibroplasia, and angiogenesis and is maximal between 3 and 7 days of injury. The process of reepithelialization begins within hours of injury from basal cell keratinocytes adjacent to the incision. For the basal cells to become mobile, they retract intercellular tonofilaments, dissolve desmosomes and hemidesmosomes, and form cytoplasmic actin filaments. In addition to mobility, within 24 to 48 hours from injury, there is mitosis of basal cells at the edges of the wound. The mitosis is induced by growth factors from epidermal cells, macrophages, and dermal parenchymal cells. Basal cells from both sides of the wound migrate along the cut edges of the dermis separating nonviable tissue from viable tissue by using the expression of various surface integrin receptors on viable cells and through the production of collagenase, which débrides dead tissue. The basal cells join at the midline of the wound, and as reepithelialization develops, the nonviable tissue above this newly united epidermis is sloughed. Basal cells also produce extracellular matrix, such as fibronectin, to facilitate reestablishment of the basement membrane. The basal cells revert to a nonmigratory normal phenotype, form hemidesmosomes, and firmly reattach to the newly formed basement membrane, thus beginning the reestablishment of the epidermis over the wounded skin.

Fibroplasia and angiogenesis begin with the formation of granulation tissue, which is the term applied to a specialized type of tissue composed of proliferative fibroblasts and vascular endothelial cells produced in healing of soft tissue injury. Granulation tissue is the hallmark of healing and is named for its clinical appearance of soft pink to tan tissue with minute red foci consisting of capillaries that resemble granules. However, it is the histologic appearance that is diagnostic, a latticework array of proliferative capillaries (angiogenesis) oriented perpendicular to proliferative fibroblasts (fibroplasia). The fibroblasts produce extracellular matrix, which is remodeled, ultimately resulting in scar formation (i.e., cicatrix formation).

The process of forming granulation tissue begins approximately 3 days after injury. Fibroplasia (fibrosis) is induced when cytokines (IL-1, TNF-α) and growth factors (transforming growth factor [TGF-β], platelet-derived growth factor [PDGF], epidermal growth factor [EGF], FGF) from inflammatory cells (especially macrophages), platelets, and endothelial cells stimulate fibroblasts to proliferate, migrate, and ultimately produce extracellular matrix. As in reepithelialization, the ability of fibroblasts to migrate into the clot or provisional matrix requires alteration in expression of surface receptors and production of proteolytic enzymes to provide a path for migration. When fibroblasts have migrated into and filled the wound space, growth factors and cytokines (TGF-β, PDGF, FGF, IL-1, IL-13) direct fibroblasts to switch from migration to protein (collagen) production, providing the structural protein that

Clot forms in vessel and wound space, provides matrix for cell migration, and dries to form scab over wound Platelets and coagulation and complement cascade recruit inflammatory cells Neutrophils and macrophages phagocytize pathogens and foreign debris Macrophages secrete collagenase, facilitating tissue débridement, and transition between inflammation and repair

Epithelial cells produce proteases to dissect between viable and nonviable tissue, migrate and proliferate to cover wound, and reestablish basement membrane

Fibroblasts produce proteolytic enzymes to provide path for migration, migrate and proliferate in wound site, and produce extracellular matrix to form connective tissue

Endothelial cells form tubular structures that become blood vessels and reestablish blood flow

Fibroblasts produce collagen and contractile microfilaments that link to matrix Newly formed collagen bundles link to each other and to collagen bundles at wound edge to contract the wound Inflammation, edema, and vascularity gradually disappear

Injury: Regeneration and Repair coagulation, and clot formation in the vessel and wound space. Dehydration of the surface of the clot forms the scab that covers the wound. The clot in the wound space provides the matrix for migration of inflammatory cells, endothelial cells, and fibroblasts. Plateletderived factors and factors associated with the coagulation and complement cascades facilitate recruitment of inflammatory cells, such as neutrophils and macrophages, to phagocytose pathogens, foreign particles, and debris. Many of the cytokines and chemokines that govern inflammation in regeneration and repair are the same as those participating in inflammatory processes of other causes. Neutrophils, the first cells to arrive at the margins of the incision, phagocytose pathogens and debris, then either slough with desiccated tissue, are phagocytosed by macrophages, or undergo apoptosis. Macrophages replace neutrophils, secrete collagenase (facilitates tissue débridement), and release growth factors initiating the formation of granulation tissue.

Concurrent with fibroblast migration into the wound space, angiogenesis, which is the formation of new blood vessels in an area of tissue injury, is also occurring (see Chapters 2 and 3; and see . Angiogenesis develops from preexisting vessels and also from endothelial precursor cells (angioblast-like cells) from the bone marrow. Many growth factors play a role in angiogenesis, but vascular endothelial growth factor (VEGF) is considered to be the most important. In angiogenesis from preexisting vessels, macrophages and injured cells in the wound site release cytokines (such as FGF and VEGF), causing endothelial cells to release proteinases (e.g., procollagenase). The proteinases degrade components of the endothelial cell basement membrane. The disruption of the endothelial cell basement membrane removes the barrier otherwise confining endothelial cells, thereby permitting endothelial cells to migrate into the injured site in response to cytokines and growth factors released from injured or stimulated cells (e.g., FGF from macrophages, VEGF from keratinocytes, and heparin from mast cells). The migratory endothelial cells form tubes that express α v β 3 integrin, facilitating endothelial cell adhesion and migration. The endothelial cells deposit provisional matrix of fibronectin and proteoglycans and eventually form new basement membrane.

The growth factors continue to stimulate endothelial cell proliferation, ensuring a supply of endothelial cells for the extension of capillary tubes so that blood flow to the area of soft tissue injury can be reestablished. In angiogenesis from endothelial precursor cells, VEGF stimulates the mobilization of endothelial cell precursors from the bone marrow and proliferation and differentiation of these cells at the site of injury; however, the mechanism whereby these cells are directed to the site of injury is unclear. Once at the site of injury, these endothelial cell precursors form a delicate capillary plexus that eventually links to existing capillaries, facilitating formation of a capillary network. The newly formed vessels, whether produced by sprouting from preexisting capillaries or from endothelial precursor cells, are provided structural support by pericytes (recruited by angiopoietin 1 interacting with Tie 2, an endothelial cell receptor) and smooth muscle cells (recruited by PDGF) and by production of extracellular matrix proteins (stimulated by TGF-β).

Angiogenesis is a well-regulated process. More than 20 molecules present in tissue act as angiogenesis inhibitors and modulate the reparative process. By the end of the second stage of wound healing, the incision is filled with granulation tissue, neovascularization is maximal, collagen fibrils bridge the incision, and reepithelialization has been completed. By day 7, the usual time to remove sutures, the tensile strength of the incision site is approximately 10% that of unwounded skin.

principally affects large wounds that heal by second intention and is described later. Production of collagen and proliferation of fibroblasts (directed by cytokines, such as TGF-β) progress fairly rapidly in this phase of wound repair. In contrast, inflammation, edema, and increased vascularity disappear. The proliferation and maturation of endothelial cells, fibroblasts, and inflammatory cells that contribute to wound repair depend on complex feedback control mechanisms between cells, cytokines, enzymes, and the extracellular matrix microenvironment. This complex interaction has been called dynamic reciprocity. As the wound space is bridged by granulation tissue and fibroblasts produce collagen, the endothelial cells undergo apoptosis, thus reducing capillary numbers. Similarly, fibroblasts and macrophages also undergo apoptosis. The reduction of endothelial cells, fibroblasts, and inflammatory cells leads to formation of an acellular scar. By the third week of wound repair, the wound has approximately 20% the tensile strength of normal skin. Over the ensuing months, collagen production is reduced, but there is continued slow remodeling of the extracellular matrix, leading to a healed wound that at maximum strength is only 70% to 80% that of unwounded skin.

Healing of wounds with separated edges (healing by second intention) occurs when there is more extensive loss of skin tissue (see Fig. 3 -34). Healing by this process is more difficult and time consuming, and larger scars result and replace the cutaneous architecture. The principal differences between healing by primary intention and healing by second intention include the following: (1) in healing by second intention, inflammation is usually more extensive because there is more tissue damage that must be removed, and secondary infection is more likely; (2) granulation tissue is more extensive because the wound has wider edges so there is a larger gap to fill; and (3) wound contraction occurs, reducing the size of the wound to a fraction of the original size (experimentally, it has been shown that large wounds in rabbits are reduced to 5% to 10% of their original size in approximately 6 weeks).

Wound contraction begins during the second week of healing when fibroblasts develop phenotypic characteristics of smooth muscle cells. These consist of cytoplasmic bundles of actincontaining microfilaments, and formation of cell-cell and cellmatrix linkages. Fibroblasts link to the extracellular fibronectin matrix and collagen matrix by fibronectin (e.g., α 5 β 1 ) and collagen (e.g., α 1 β 1 , α 2 β 1 ) receptors and to each other through direct adherens junctions. Also, newly synthesized collagen bundles form covalent cross-links with themselves and with collagen bundles at the wound edge. These linkages thus provide a conduit across the wound space so that the traction of fibroblasts on the matrix can contract the wound, substantially reducing its size and facilitating healing by second intention. eventually contributes to wound strength. Collagen production begins by days 3 to 5 and persists for several weeks, depending on the size of the wound.

The third and final phase of wound repair involves collagen production and wound contraction. However, wound contraction CHAPTER 17 The Integument

The mechanisms of hair graying are incompletely understood. Perhaps the most relevant and most studied time sequence of hair graying occurs in human beings, in whom the regeneration of an intact hair follicle pigmentary unit, which is formed from the pigment-producing melanocytes anchored to the basement membrane above the dermal papilla and the hair shaft-producing keratinocytes in the hair bulb, occurs optimally only during the first 10 hair cycles, or until approximately 40 years of age. Thereafter there is gradual reduction in the melanin pigment production of each hair follicle, resulting in the growth of gray and white hair shafts, suggesting an age and genetically regulated exhaustion of the pigment production potential of each individual hair follicle. This biologic process appears to be associated with the loss of melanocytes in the hair bulb and loss of the melanocyte stem cells in the isthmus region of the ORS. The endogenous oxidative stress that develops from the hydroxylation of tyrosine and the oxidation of dihydroxyphenylalanine (DOPA) to form melanin may to contribute to the reduction of pigment by causing selective premature aging and apoptosis of melanocytes. In addition, studies using aged human hair follicles and transgenic mice have shown loss of maintenance of melanocytic stem cells, which may involve premature differentiation of stem cells or activation of a senescence program. If stem cells differentiate prematurely, they lose the ability to retain their stem cell capabilities. Other factors that may damage melanocyte stem cells include reduced or inefficient antioxidant systems and oxidative stress from exogenous sources such as inflammation, UV light, psychoemotional stress, and others. Ionizing radiation, experimentally in mice, also has been shown to cause irreparable DNA damage that eliminates renewal of melanocyte stem cells. Oxidative injury, in particular a high degree of endogenous oxidative stress from melanin pigment production, may play a more important role in human beings, who have an anagen-based hair cycle with a long growing phase resulting in production of long and often heavily pigmented hair shafts. In contrast, many domestic animals have a telogen-based hair cycle and thus shorter lengths of hair, which theoretically should result in less oxidative damage to the follicular melanin unit following melanin production and may explain why there is less extensive and less generalized graying of the hair coat of aged animals. Alternatively, animals may have more efficient or enhanced antioxidant systems or may be less susceptible to the various causes of melanocyte or melanocytic stem cell damage. For example, in horses and dogs, the two domestic species in which age-related hair coat graying are reported, the graying occurs predominantly on the face around the muzzle and eyes, although scattered gray hairs are also noted in other anatomic areas of the body. A genetic component may play a role in hair graying in dogs because certain breeds (e.g., German shepherd dogs, Irish setters, Labrador retrievers, golden retrievers) are more likely to develop gray muzzle and chin hairs at a relatively younger age.

The mechanisms underlying hair loss in aging individuals are not clearly understood but may involve progression to a telogen-based hair cycle in addition to senescent hair loss that may be related to reduction of hair follicle epithelial stem cells associated with reduced renewal, premature differentiation, apoptosis, or cellular senescence. Age-related hair loss in human beings is thought to result from a defective hair cycle that causes a shortened anagen (or growth) stage, increased ratio of telogen to anagen follicles, and persistence of telogen follicles. Studies in mice also have shown the duration of the telogen stage increases with each hair cycle, and the entire hair cycle slows considerably with aging. Similarly, it is generally believed that the hair cycle of many animals becomes increasingly telogenic with age. Interestingly, similar changes to those described in human beings and mice have been observed in some aging dogs with human beings and mouse models. Although similar hair coat changes occur in aged domestic animals, little has been investigated or published regarding these changes, which may in part be due to the perceived irrelevance of these changes in animals compared with human beings, or that most domestic animals are unlikely to be a good model for the human condition due to the differences in the type of hair follicles (e.g., compound versus simple), the length of the hair cycle (telogen based versus anagen based), and stronger seasonal and nutritional influences on the hair cycle and the hair coat in animals.

Graying of hair on face around muzzle and eyes and sometimes other anatomic locations Genetic breed-related hair coat graying and melanoma formation Dull, dry hair coat Loss of dorsal muscle mass, resulting in "swayback" Depressed grooves above eyes Excessively long, curly hair coat or failure to shed; related to pars intermedia pituitary gland tumor as seen in aged horses Reduced or absent stratum externum of hoof wall

Graying of hair on face around muzzle and eyes, sometimes also other anatomic locations Dull, dry hair coat, sometimes with hair coat thinning Alopecia and callus formation over pressure points Nodular sebaceous gland hyperplasia Nasodigital hyperkeratosis Brittle and malformed claws

Hyperkeratosis of epidermis and hair follicles Atrophy of the epidermis Increased numbers of telogen and kenogen follicles Mineralization of hair follicle basement membrane Reduced cellularity plus degeneration of collagen bundles Occasional reduction or degeneration of elastic fibers Cystic apocrine glands (apocrine cystomatosis) may be senile degenerative change

Thick, brittle, sometimes overgrown claws Hair matting, skin odor, and inflammation (less frequent or effective grooming) Thinner, less elastic skin, more prone to infection and with reduced blood circulation

Variable epidermal and follicular hyperkeratosis Atrophic follicles (occasional) Granular, fragmented collagen fibers (occasional) Sebaceous glands atrophied and vacuolated (occasional) Arrector pili muscle may appear fragmented and more vacuolated and eosinophilic than normal (occasional) Cystic ceruminous glands (ceruminous cystomatosis) may be senile change in some cats

exposure if the body's natural defenses, such as the hair coat and melanin pigments, are not present or are inadequate. The lesions of solar (actinic) dermatosis (see section on Disorders of Physical, Radiation, or Chemical Injury; Solar (Actinic) Dermatosis, Keratosis, and Neoplasia) typify the effects of chronic exposure to UVR. In addition to solar dermatosis, squamous cell carcinomas, hemangiomas, and hemangiosarcomas have an increased tendency to develop in skin chronically damaged by UVR. Cutaneous melanomas also have been reported in UVR-exposed Angora goats. Doberman pinscher dogs with autosomal recessive oculocutaneous albinism also develop melanomas in the skin, lips, eyelids, and iris, but the melanomas develop in sun-exposed and non-sun-exposed sites, so the role of UV light in tumor induction in these dogs is unclear.

The dermal capillaries can be a portal of entry to the skin via the hematogenous route. Embolization of infectious agents, such as bacteria (E. rhusiopathiae [diamond skin disease]) or fungi (systemic infection with Blastomyces dermatitidis), can damage the skin via this route during hematogenous dissemination. Tumor cells (hemangiosarcoma) can also embolize to the skin and lead to metastatic tumor foci or possible cutaneous infarction. The hematogenous route to the skin is also one of the most common delivery systems for drugs (adverse cutaneous reactions to the administration of trimethoprimpotentiated sulfonamides; photosensitization dermatitis that occurs with phenothiazine ingestion) and toxins (gangrenous ergotism caused by the mycotoxin of Claviceps purpurea).

Rarely, an infectious agent that is neurotropic can migrate from a ganglion along sensory nerves via axonal flow to the skin and cause dermatitis. An example is reactivation of feline herpesvirus 1 (FHV-1) infection that results in feline herpesvirus dermatitis. The skin can also be secondarily infected or traumatized or damaged by extension of pathologic processes affecting adjacent tissues or support structures such as bone, muscle, lymph nodes, or glands (locally invasive mammary gland carcinoma resulting in cutaneous ulceration).

The skin is a complex organ composed of many integrated components that are structurally and functionally designed to protect the host. Host defenses against injury principally consist of three broad mechanisms: (1) physical defense, (2) immunologic defense, and (3) repair mechanisms. The most critical defense is the barrier derived from the more superficial layers of the skin, which include the stratum corneum, epidermis, basement membrane, and superficial dermis. Without these outer layers of the skin, animals cannot survive (consider, for example, the deleterious effects of extensive burns and ulcerative immune-mediated diseases such as pemphigus vulgaris). One of the most important cells in the skin is the keratinocyte that terminally differentiates to form the stratum corneum, the outermost barrier of the skin. Keratinocytes produce keratin filaments, desmosomes, and hemidesmosomes, providing structural integrity to the cytoplasm and an interconnecting network that anchors the keratinocytes to each other and the basement membrane. Keratinocytes produce cytokines (including IL-1, IL-6, IL-8, IL-3, TNF-α, colony-stimulating factors) and growth factors (including transforming growth factor-α [TGF-α], TGF-β, platelet-derived growth factor [PDGF], FGF), thus participating in innate and adaptive immunity and in the communication between the two. Keratinocytes also dissolve desmosomes and hemidesmosomes and form actin filaments so they can migrate to cover skin wounds and then proliferate to regenerate the wounded skin. Keratinocytes thus not anagen-based hair cycles, such as poodles. These changes histologically include a gradual increase in the number of telogen stage hair follicles with age, and the hair coats of some of these aged poodles become less dense over time. However, because most dogs and other mammals have a telogen-based hair cycle and there are seasonal influences associated with the hair cycle, it is difficult to clinically or histologically assess an insidious prolongation of the telogen stage of the cycle in most domestic species. Nevertheless, prolongation of the telogen phase with aging could theoretically result in the presence of older, more worn hair shafts similar to what is observed in some hair cycle arrest disorders (such as endocrine-based alopecia). In fact, aged horses and dogs tend to have a dull, dryer hair coat, which could be associated with prolongation of telogen. Although a telogen-based hair coat may be of lesser quality, telogen stage follicles with retained hair shaft may be the most beneficial for the aging animal because it is thought to be the most energy efficient hair follicle stage (does not require protein production to form a hair shaft), and the inactive telogen bulb that lacks the mitotic activity may also reduce the risk for malignant transformation.

Normal intact skin has many natural defenses and barriers that render it impenetrable to most organisms and protect the body from a variety of insults that include pressure, friction, mild mechanical trauma, temperature extremes, UV light exposure, and chemical absorption (see Defense Mechanisms/Barrier Systems).

In order to initiate disease, most infectious agents must first gain entrance into the body via routes termed portals of entry . The skin becomes an efficient portal of entry for microorganisms only when the barrier is first damaged by trauma; excessive moisture, heat, or cold; or disruption of the normal flora of the integument; however, a few pathogens, such as hookworm and Cuterebra larvae, are able to penetrate intact normally functioning skin. Some organisms may also use more than one portal; for example, Cuterebra larvae also gain entrance via ingestion during grooming by the host, or they can migrate over skin to natural body openings such as the nares, where they can more easily penetrate a less defensive barrier, the mucosa. Dermatophytes are able to colonize the nonviable cornified structures such as hair, claws, and the stratum corneum and cause disease without ever entering living tissue. Clinical disease, or dermatophytosis, results from the host's reaction to the organism and its by-products. A number of microorganisms (e.g., Staphylococcus pseudintermedius, Streptococcus sp., Corynebacterium pseudotuberculosis, Pasteurella sp., Proteus sp., Pseudomonas sp., and Escherichia coli) gain entrance to the body by entering through natural pores, such as hair follicles or glands with ducts that traverse the epidermis, or by the parenteral route, which includes all types of breaks in the skin, including injections, insect bites, and other types of wounds. Organisms that are able to inhabit hair follicles, such as mites or bacteria, gain entry to the body when the wall of the follicle is ruptured, leading to emptying of follicular contents into the dermis. Similarly, rupture of glands or ducts can lead to entry for some of those microorganisms. Once in the dermis, infectious agents can stimulate a robust host immune response or possibly spread to other areas of the body by gaining entry to the bloodstream or traveling to regional and distant lymph nodes via lymph flow.

Intact skin with its waterproof barrier provides some protection against weak acids and alkali substances and water-soluble compounds, but certain lipid-soluble compounds can be absorbed directly through intact skin as can some artificially engineered gases developed for chemical warfare. UVR can damage the skin by direct CHAPTER 17 The Integument and minor trauma. Tail hairs of horses can also be used to swat at insects and thus reduce insect bite-related injury. The hair coat also sheds water as a result of the lipids provided by sebaceous gland secretion. Vibrissae, or tactile hairs, and sensory neurons provide awareness of the physical environment, allowing the animal to make appropriate reactions for survival such as reflex responses to heat and other noxious stimuli. Claws, especially on cats, serve as quite an effective barrier against predators by providing traction for only orchestrate the activities of the skin but also serve as many members of the orchestra.

Barriers of the skin against physical injury are listed in Box 17-4. The hair coat, particularly the long dense hair coat of some dogs and cats, serves as a physical barrier to temperature extremes, UVR, 

Migration from ganglion along sensory nerves via axonal flow to epithelial cells

Penetrating trauma from bone fracture Extension of tumor or infection from adjacent lymph node, gland, muscle, or bone phospholipid cell membrane of the keratinocyte when the membrane-bound enzymes (e.g., transglutaminases) cross-link proteins from the keratohyalin granules (e.g., loricrin) and the cytoplasm (e.g., involucrin) in isopeptide bonds. Other proteins (including trichohyalin and small proline-rich proteins) are similarly cross-linked, and eventually the entire cell membrane consists of cross-linked proteins. The proteins of the cornified envelope compose 7% to 10% of the protein mass of the epidermis. The corneocytes are joined together by desmosomes that are modified from those joining keratinocytes in lower layers of the epidermis by the addition of a protein called corneodesmosin. These stratum corneum desmosomes are referred to as corneodesmosomes.

The mortar is formed when lipids, from the lamellar bodies in the stratum granulosum, are released into the intercellular space. These intercorneocyte lipids (glycosyl ceramides, cholesterol, cholesterol esters, and long-chain fatty acids) are hydrophobic and prevent transepidermal water loss. Lamellar bodies have other important functions: (1) they provide enzymes that generate ceramides and free fatty acids that are incorporated into the lipid membranes; (2) they provide proteases and antiproteases that regulate digestion of corneodesmosomes and shedding of cornified cells to the exterior; and (3) they secrete antimicrobial peptides, including defensins, into the intercellular compartment of the stratum corneum. The lipid component of the stratum corneum surrounds the protein component to which it is covalently bound and provides adhesion of the cornified cells (i.e., bricks) to the intercellular lipids (i.e., mortar). Layers of the corneocytes and their corneocyte envelope (i.e., bricks) and intercellular lipids (i.e., mortar) form a tough and resilient protective barrier. The keratinocyte and sebum-derived lipids help make the stratum corneum water repellant.

Other barrier functions of the skin include defense against antioxidant injury provided by vitamin E in sebaceous gland secretion and defense against UV light provided by the hair coat and also by melanin pigment in keratinocytes. The cap of melanin pigment over the nucleus scatters and absorbs UV light rays and protects against UV light-induced injury to DNA. The basement membrane zone serves as an initial barrier to invasion of the dermis by neoplastic epidermal cells. The panniculus serves as insulation against temperature extremes, and secretion from apocrine glands (sweating) in cattle and horses provides defense against excessive heat.

Anatomic features of the skin that provide resistance to physical injury are listed in Box 17-4. Hair follicles help anchor the epidermis to the dermis, as do dermal-epidermal interdigitations; thus these interdigitations are most numerous in nasal planum and pawpad, where hair follicles are absent and resistance to shearing force is necessary. Host defense against mechanical injury is also provided by the tightly bundled keratin filaments of the corneocyte, the resilience of the cornified envelope, the adhesion of the cornified envelope and intercellular lipids, and the corneodesmosomes. In addition, the keratinocytes contain keratin filaments and form desmosomal junctions with adjacent cells (see Fig. 17 -4). The keratin filaments perform a structural role (i.e., cytoskeletal) in the cells, and the desmosomes promote adhesion of epidermal cells and resistance to mechanical stresses. The basement membrane anchors the epidermis to the dermis via hemidesmosomes, providing structural integrity against trauma. Dermal collagen and elastic tissue provide resilience and tensile strength to the skin and support for the vessels, nerves, and adnexa. The panniculus protects against surface trauma by providing some shock absorption (e.g., pawpads), by facilitating movement, and by anchoring the dermis to fascia. Thus the various components of the epidermis, dermis, adnexa, and panniculus climbing and serve as weapons to be used against aggressors. Hooves and claws may also function as "shields" that cover and protect underlying bone from trauma or fracture. Hooves, soles, and pawpads also permit ambulation over surfaces that are rough or uneven, or hot or cold. The planum nasale of dogs has a thick stratum corneum that provides additional protection against minor trauma.

The stratum corneum is an exceedingly important component of the barrier, imparting protection from the exterior and preventing water loss from the interior. The stratum corneum is composed largely of keratins, a family of proteins called intermediate filaments.

Keratin proteins are the major structural proteins of the skin, hair, and claws. The stratum corneum is considered to be the "bricks and mortar" of the barrier. The bricks are the flattened cornified cells (corneocytes) with their resistant cell envelopes and keratin microfibrils, and the mortar consists of intercorneocyte lipids.

The bricks are formed at the level of the stratum granulosum when the keratinocytes are transformed into the flattened corneocytes. The transformation occurs when (1) the nucleus is digested, (2) the keratin intermediate filaments aggregate into microfibrils oriented parallel to the skin surface, (3) the lipids are released into the intercellular space, and (4) the cell membrane is converted into a resilient cell envelope consisting of cross-linked protein with lipids covalently bound to its surface. Filaggrin (which is an acronym for filament-aggregating protein) from the keratohyalin granules in the stratum granulosum plays a significant role in formation of the bricks by participating in the aggregation of keratin filaments into tight bundles. The keratin intermediate filaments and filaggrin compose 80% to 90% of the protein mass of the epidermis. Later filaggrin is digested by proteolytic enzymes to produce components of amino acids that form the "natural moisturizing factor" of the stratum corneum, which serves to help maintain hydration, flexibility, and orderly desquamation that preserve the epidermal barrier. Concurrent with the aggregation of the keratin filaments, the resistant cornified envelope is transformed from the water-permeable 

provide a flexible and strong interconnecting framework to protect the host against mechanical injury.

Information on this topic, including E- Table 17 -1 and E- Fig. 17 -1, is available at www.expertconsult.com.

Information on this topic, including E- Table 17 -2, is available at www.expertconsult.com.

Atopic dermatitis serves as an example of a common disease associated with impaired function of the epidermal barrier and immunity. It is a multifactorial, chronic and relapsing, often severely pruritic skin disease that affects human beings, horses, dogs, and cats. It can cause severe discomfort, including sleeplessness from pruritus, and is associated with secondary skin infections. Although the etiopathogenesis of atopic dermatitis has been studied most extensively in human beings, many similarities with the human disease have been identified in atopic dogs. Advances in the knowledge of canine atopic dermatitis have occurred through the recent development and validation of animal models of the disease; these models have allowed more in-depth investigative studies in dogs and more precise comparisons of the disease between human beings and dogs. Atopic dermatitis is a common problem in dogs; the prevalence varies with survey, but it is estimated to affect up to 27% of the population in the United States ( Fig. 17-34) . It is also a common human disease estimated to affect 10% to 20% of children. Similarities of the disease in human beings and dogs include young age of onset; genetic inheritance; similar clinical lesion distribution; similar histopathologic lesions, including infiltration of IgE + CD1c + dendritic cells; dry skin with increased transepidermal water loss; decreased stratum corneum ceramides (lipids); decreased epidermal filaggrin (in some subsets of dogs); increased colonization of surface staphylococci; positive atopy patch test; increased IgE-specific responses most commonly directed against environmental allergens; in acute disease T H 2-dominated immune responses; and in chronic disease a switch from T H 2 to T H 1 immune responses. A major difference in the disease is that children with atopic dermatitis often develop asthma and allergic rhinitis, whereas dogs affected with atopic dermatitis do not; the reason for this difference is currently unknown.

Atopic dermatitis in human beings is a multifactorial, heterogeneous genetic disease that arises in association with environmental factors. Defects in three groups of genes important in epidermal barrier function in atopic human beings have suggested that in most cases alterations in the epidermal barrier contribute to the development of atopic dermatitis and may represent the primary event. The type and degree of genetic defect plus interaction with environmental factors appear to influence the severity or probability of developing the disease. A defective epidermal barrier facilitates penetration of allergens though the skin, as well as the interaction of the allergens with the local antigen-presenting and immune effector cells (E- Fig. 17 -2). Changes in genes encoding for structural proteins (especially filaggrin), epidermal proteases, and protease inhibitors have been identified in human beings with atopic dermatitis. These defects serve to reduce stratum corneum hydration and increase transepidermal water loss, increase cleavage of corneodesmosome junctions, reduce lamellar body secretion and thus stratum corneum lipids, increase pH, and reduce antimicrobial properties of the stratum corneum. These alterations to the barrier favor population by pathogenic versus nonpathogenic bacteria and sustain allergen entrance through the barrier. The allergens are phagocytosed by dendritic cells, which present the allergen to T H lymphocytes and recruit other CD4 + T lymphocytes to the site. The activated dendritic cells and the cytokines produced by the CD4 + T lymphocyte (particularly IL-4) lead to switching from a T H 1 to T H 2 response (in early lesions) and release of proinflammatory cytokines and production of IgE, which in the presence of allergen activates mast cells. In atopic dermatitis there is a complex interaction between the immune system and the nervous system that can promote the sensation of itch. For example, at least one of the T H 2 proinflammatory cytokines, IL-31, binds to receptors on neurons to stimulate itch; thus it significantly contributes to pruritus, a hallmark of atopic

Innate immunity is a primitive, highly conserved response that quickly detects and impairs pathogens and harmful environmental stimuli encountered daily in life and does not require antigenspecific receptors. Innate immunity protects the host during the first 7 days of exposure to a pathogen before development of an adaptive immune response and also initiates and assists the adaptive immune response (E-Table 17-1). The diversity of microorganisms requires equal diversity in host defense responses. The first phase of innate host defense consists of the barrier of the stratum corneum, which prevents pathogen adhesion and provides an antimicrobial surface consisting of antimicrobial peptides and fatty acids. The antimicrobial peptides (e.g., β-defensins and cathelicidins) are effective against many organisms, including viruses, bacteria, protozoa, and insects, and probably kill some of these pathogens by damaging their lipid membranes. The surface barrier also includes normal flora of nonpathogenic bacteria that competes with pathogenic microorganisms for nutrients and for attachment sites on cells. The normal flora also produces antimicrobial substances that prevent pathogen colonization. Because the dry cornified surface is such an effective barrier to pathogens, a wound or abrasion is usually necessary for a pathogen to gain entrance. E- Fig. 17 -1 provides an illustration of how the innate and adaptive (acquired) immune systems participate in host defense against bacterial pathogens that have gained entrance into the skin through a wound in the epidermis. When injured, keratinocytes release a variety of antimicrobial peptides, chemokines, and cytokines, which activate endothelial cells and attract macrophages, neutrophils, and lymphocytes to the site of injury. Early key cells that play a role in innate immunity are the tissue macrophages that contact, bind, phagocytose, and thereby eliminate many types of pathogens. Pathogen recognition is mediated by pattern recognition receptors (PRRs), including Toll-like receptors and others, that recognize repeating patterns of molecular structures common to broad classes of pathogens and efficiently differentiate pathogen antigens from self-antigens. The repeating patterns of molecular structures on pathogens are called pathogenassociated molecular patterns (PAMPs).

Recognize broad classes of pathogens, differentiate pathogen antigens from self-antigens, initiate Toll signaling pathway, and secrete cytokines, facilitating inflammation and innate immunity Toll signaling pathway Promotes expression of large numbers of genes, resulting in production of cytokines, chemokines, and adhesion molecules important in inflammation and innate immunity Macrophages and neutrophils Recognize, ingest, and destroy pathogens Endothelial cells Express adhesion molecules and trigger kinin and coagulation systems, facilitating influx of plasma proteins and migration of leukocytes (cell trafficking) necessary to control infection Coagulation system

Forms blood clot in case of injury to control blood loss and prevents microorganisms from entering the bloodstream Complement enzyme cascade Recruits inflammatory cells, opsonizes pathogens, and kills some pathogens Lipid mediators Increase vascular permeability and induce influx and activation of leukocytes sustaining inflammatory responses

Innate immunity protects the host in the first 7 days of exposure and does not require antigen-specific receptors but does not provide protection to later reexposure.

self-antigens from pathogen antigens. The important outcomes of pathogen-receptor binding include the activation of phagocytic and other immune effector cells and release of cytokines, chemokines, adhesion molecules, and other inflammatory mediators initiating an acute phase response. The acute phase response proteins can opsonize a broad range of pathogens and can also activate the complement cascade, making pathogens more susceptible to phagocytosis and killing by macrophages and neutrophils. Once initiated, the innate immune response helps to start the antigen-specific immune response (i.e., adaptive immunity). Innate immunity is crucial to protecting the host in the early days of infection; however, pathogens can evade innate immunity, and innate immunity does not lead to immunologic memory characteristic of adaptive immunity.

A few examples of PAMPs include lipopolysaccharide (most Gram-negative bacteria), peptidoglycan (Gram-positive bacteria), CpG motifs (mostly bacterial pathogens), lipoarabinomannan (mycobacteria), mannans and zymosan (yeast), double-and singlestranded RNA (viruses), and heat shock proteins (bacteria, fungi, algae, protozoa). These PAMPs have been conserved during evolution and allow the innate immune system to broadly distinguish Whereas innate immunity works immediately to detect and destroy microorganisms, acquired or adaptive immunity develops later because the lymphocytes that contribute to adaptive immunity specific for the invading pathogen must first increase in number by clonal expansion (E- Table 17 -2). The major components of the cutaneous adaptive immune system include keratinocytes, dendritic antigen-presenting cells (Langerhans cells and dermal dendritic cells), lymphocytes, and endothelial cells (see E- Fig. 17 -1).

The adaptive immune response is initiated by a stimulus (in this example, the epidermal injury, microbial invasion, and signals provided from the innate immune system), at which time the bone marrow-derived antigen-processing and antigen-presenting cells (Langerhans cells in the epidermis and dendritic cells in the perivascular dermis) ingest and process the antigen. Pathogen recognition is mediated through PAMPs as described previously. The major function of Langerhans cells and dermal dendritic cells is antigen processing and presentation; thus these cells are referred to as "professional antigen processing and presenting cells." Langerhans and dermal dendritic cells reexpress the ingested and processed antigen on their cell surfaces and migrate via afferent lymphatic vessels to the paracortical areas of skin-associated lymph nodes, where they arrive as mature and powerful antigen-presenting cells. These skinderived dendritic cells then initiate a pathogen-specific protective immune response by presenting antigen to the naïve T lymphocytes. Langerhans cells also produce cytokines (e.g., IL-1 and TNF-α), thus participating in upregulation of inflammatory and immune responses in the skin.

The T lymphocytes activated by antigen presentation in the skin-associated lymph nodes are also known as sensitized or memory 1047.e2 SECTION II Pathology of Organ Systems E- Figure 17 -1 Interactions between the Innate and Acquired Immune Systems in Response to Bacterial Infection of the Skin. In response to bacteria that have breached the epidermal barrier, keratinocytes synthesize antimicrobial peptides, chemokines, and cytokines. These factors lead to activation of the dermal capillary endothelium, inducing the migration of innate leukocytes and memory T lymphocytes into the skin and additionally guiding these cells via chemotactic gradients. These factors and bacterial antigens activate innate phagocytes to kill ingested organisms and activate dendritic cells to migrate to the local skin lymph nodes. In the lymph nodes, dendritic cells present bacterial antigens to naïve and central memory T lymphocytes, leading to stimulation of pathogen-specific lymphocytes. Effector CD8 + T lymphocytes exit the lymph node, home to inflamed skin, and kill pathogens. Helper CD4 + T lymphocytes provide help to B lymphocytes, inducing the production of antibodies that directly neutralize pathogens and lead to additional targeting of innate responses. Antibody-directed phagocytosis by innate cells leads to enhanced antigen presentation, further enhancing acquired responses. 

Ingest and process antigen, present antigen to naïve T lymphocytes in lymph nodes, present antigen to sensitized T lymphocytes at site of injury, and produce cytokines that upregulate inflammation and immune responses T lymphocytes After stimulation by antigen-presenting cells in lymph node, migrate back to the site of injury CD8 + (cytotoxic lymphocytes)

Recognize antigen expressed on the cell surface and kill the cell (cytotoxic lymphocytes); responsible for killing neoplastic cells, some bacteria and parasites, and all viruses that replicate inside cells CD4 + T H 1 lymphocytes Activate macrophages, helping to control infection by intracellular bacteria CD4 + T H 2 lymphocytes Activate B lymphocytes, helping eliminate extracellular pathogens B lymphocytes Secrete immunoglobulin, providing defense against pathogens (often bacteria) in extracellular spaces Endothelial cells Express adhesion molecules and bind to stimulated T lymphocytes Keratinocytes

Produce cytokines and growth factors upregulating or downregulating inflammation and immune responses Cytokines, chemokines, and adhesion molecules

Contribute as in innate immune response Adaptive (acquired) immunity develops after innate immunity because the lymphocytes that contribute to adaptive immunity specific for the invading pathogen must increase in number by clonal expansion and provides protection on later reexposure to pathogen.

Lymphocytes recognize pathogens (i.e., antigens) via cell surface receptors. The B lymphocytes have immunoglobulin molecules as the receptors for antigen, and on activation, B lymphocytes secrete immunoglobulin, which provides defense against pathogens (often bacteria) in the extracellular spaces. Antibody facilitates pathogen neutralization, complement activation, and enhanced endocytosis by phagocytes. In contrast, T lymphocytes have receptors that recognize foreign antigens expressed as peptide fragments bound to MHC proteins (see Chapter 5 for a review). One class of T lymphocytes expresses the CD8 molecule on their surface (i.e., CD8 + T lymphocytes). These CD8 + T lymphocytes recognize peptide Another class of T lymphocytes expresses the CD4 molecule on their surface. This class of T lymphocyte is divided into subclasses. One subclass, the CD4 + T lymphocyte subset (T H 1 [helper]), recognizes peptide fragments (e.g., microbial antigen) bound to MHC II and releases cytokines, including IFN-γ, resulting in an inflammatory response via macrophage activation. A second subclass, CD4 + T lymphocyte subset (T H 2 [helper]), recognizes peptides (including allergens) bound to MHC II and releases cytokines, including IL-4, IL-5, and IL-13, resulting in inflammatory responses in which eosinophils predominate and stimulates B lymphocytes to secrete immunoglobulin. Another subclass, the T regulatory lymphocyte, acts to suppress responses of other T lymphocytes. Most antigens require an accompanying signal from helper T lymphocytes before they can stimulate B lymphocytes to proliferate and differentiate into antibody-secreting plasma cells. Thus T lymphocytes are crucial to adaptive immunity by destroying pathogen-infected cells, by activating macrophages, and by activating B lymphocytes.

T lymphocytes. These memory T lymphocytes are subdivided into two types, central memory and effector memory T lymphocytes. The central memory lymphocytes generally circulate between the blood and lymph nodes, serve mostly as long-term reservoirs of immunologic memory, and when stimulated by antigen give rise to both central memory and effector memory T lymphocytes. The effector memory T lymphocytes express skin-associated homing receptors (e.g., cutaneous lymphocyte antigen [CLA] ) that interact with adhesion molecules (E-selectin, P-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1) on cytokineactivated endothelial cells in the dermal vessels at the site of initial injury, thus providing a way for the effector memory T lymphocytes to find their way back to the site of the injury and pathogen entrance. Once in the skin and after receipt of a renewed antigenic stimulus by the professional antigen-presenting cells, the effector memory T lymphocytes undergo clonal expansion, resulting in the generation of protective effector mechanisms. Most of the lymphocytes in the skin are T helper lymphocytes, but various types of T and B lymphocytes contribute to adaptive immunity.

Thus complex interactions between host cells, pathogens or other antigens, and inflammatory mediators of the innate and adaptive immune system typically result in appropriate host defenses, the removal of the inciting pathogen, and the generation of differentiated memory lymphocytes through clonal expansion, allowing faster specific immune responses in future encounters with the same offending antigen. Impaired host defense mechanisms can lead to increased susceptibility to infection, to development of neoplasia, or to chronic inflammatory or autoreactive disorders such as atopic dermatitis, contact hypersensitivity, or lupus erythematosus. fragments bound to MHC I, then kill the cell, and thus are also called cytotoxic T lymphocytes. The epidermal barrier is formed by the lower layers of the stratum corneum and is composed of differentiated keratinocytes, termed corneocytes (beige rectangles), held together with corneodesmosomes (purple spheres). The hyperactivity of degradative proteases (light red hexagons) found within the epidermis and contributed to by exogenous proteases (red hexagons), from house dust mites and Staphylococcus spp. bacteria for example, facilitates the cleavage of the corneodesmosome junctions. This is just one event in the breakdown of the epidermal barrier that permits the penetration of allergens. Dendritic cells (green) found in the dermis take up and present these allergens (red stars) to helper T lymphocytes type 1 (T H 1) (purple) and recruit more CD4 + T lymphocytes (blue). Activated dendritic cells and interleukin dermatitis. Other itch-promoting inflammatory mediators such as neurotrophins or neuroactive peptides also contribute. Langerhans cells also contribute in early lesions because they prime naïve T lymphocytes into the T H 2 type (with high IL-4 production). IL-4 may also be produced by mast cells, basophils, or eosinophils. Exogenous factors also contribute. For example, proteases from house dust mites can facilitate cleavage of corneodesmosomes and additionally contribute to epidermal barrier damage. The resulting inflammation causes pruritus, which stimulates scratching, further damaging the epidermal barrier (and keratinocytes, resulting in release of additional proinflammatory cytokines, including IL-1), and creating a vicious cycle that perpetuates the disease and that is difficult to control. Secondary infections with Staphylococci and Malassezia also contribute because proteins from these infections more readily pass through the impaired epidermal barrier and can result in development of IgE-mediated bacterial and yeast hypersensitivity. Approximately 25% of human beings with severe atopic dermatitis have IgE antibody directed toward self-proteins. These antibodies may develop after intracellular proteins from keratinocytes are released when the keratinocytes are damaged by scratching. These keratinocyte proteins may mimic microbial structure and induce IgE autoantibodies that further perpetuate the disease. In summary, atopic dermatitis is a complex, multifactorial, heterogeneous disease in which altered epidermal barrier function appears to contribute to the pathogenesis by facilitating penetration of allergens though the skin, as well as the interaction of the allergens with the local antigen-presenting and immune effector cells. It serves as an example of the importance of the epidermal barrier in protecting the host against injury from allergens, microbial infections, and autoreactive disorders.

Knowledge of the clinical appearance of skin lesions, distribution of lesions, and correlation between the gross and histologic lesions is often critical in formulating differential and final diagnoses. In skin diseases the clinical lesions represent the gross lesions and are typically examined by a practitioner, not the pathologist; thus the practitioner essentially serves as the eyes for the pathologist. It is therefore important for the practitioner to develop the ability to accurately recognize clinical lesion morphologic features and translate that information to the pathologist. To facilitate this process, Table 17 -6 is provided to illustrate the morphologic characteristics of the various clinical lesions and provide examples of the disease processes in which those lesions occur.

Important tips for biopsy sampling of the skin are listed in Table  17 -7. Biopsy do's and don'ts are listed in Boxes 17-5 and 17-6, respectively.

Knowing when to collect biopsy samples helps obtain the most diagnostic samples; facilitates obtaining samples early so acute, serious, or neoplastic disorders are diagnosed quickly; and prevents the frustration and economic loss when samples are inappropriately collected, such as when concurrent therapy might alter diagnostic lesions, when lesions are in a quiescent stage and might not be diagnostic, and when clinical dermatologic evaluation would have been a better method of achieving a diagnosis. Knowing when biopsy is not the best course of action is equally important. Biopsy should not be viewed as a substitute, or equivalent option, for referral to a veterinary dermatology specialist. If in regional proximity, referral to a veterinary dermatology specialist may be recommended before and instead of collecting biopsy samples. Biopsy sampling is recommended when the following are present: 1. The therapy for the skin disorder is associated with significant side effects (to confirm the clinical diagnosis before starting therapy). 2. A nodular lesion, ulcer, or nonhealing wound might represent a tumor (so that surgical excision of the tumor can be performed as early as possible). 3. Lesions develop suddenly, are severe, or are unusual (to help identify a serious disease so that therapy can be instituted early). 4. Lesions develop during the course of therapy (to identify a potential adverse reaction to drug therapy). 5. Lesions are active and before use of therapy that might alter the histologic appearance of the lesions, and there are multiple clinical differential diagnoses, and the thorough clinical dermatologic examination does not differentiate the conditions. 6. A skin disorder fails to respond to apparently appropriate therapy, or the disorder responds to therapy but recurs when therapy is stopped (to establish the correct diagnosis, or evaluate for predisposing factors). Recall that antiinflammatory therapy can alter lesions.

Multiple cutaneous sites representative of the range of lesions should be selected for biopsy. Fully developed nontreated primary lesions, such as macules, papules, pustules, nodules, neoplasms, vesicles, and wheals, are often the most useful for diagnosis (see Table 17 -6). However, primary lesions may not be present at the time the animal is examined, so secondary lesions, such as scales, crusts, ulcers, comedones, or scars then need to be sampled and evaluated (see Table 17 -6). These secondary lesions can be diagnostic or contribute substantially to the diagnosis when multiple cutaneous sites are selected for biopsy. One of the most useful secondary lesions is the crust because acantholytic cells from drying pustules in pemphigus foliaceus and organisms, such as D. congolensis or dermatophytes, may be identified in crusts, providing the information necessary for diagnosis. Also, the margin of a chronic ulcer may represent a squamous cell carcinoma, or the scale at the edge of an epidermal collarette (i.e., peripherally expanding ring of epidermal scales) may represent superficial spreading pyoderma, thus providing the key to diagnosis.

Excisional biopsy samples (entire lesions) are recommended for large pustules or vesicles that can be damaged by use of a smaller punch biopsy instrument. Deeper excisional biopsy samples are generally necessary for diagnosis of lesions, such as panniculitis, that are deep to the epidermis and dermis. Digital amputation can be required, particularly in dogs, for the diagnosis of claw bed lesions. Electrocautery or laser should not be used for small biopsy samples because the samples can be damaged and rendered nondiagnostic. Tissue forceps (small toothed) should grasp, if at all, only one nonaffected margin, preferably in the subcutis.

Generally the skin at a punch biopsy site should not be surgically prepared because the procedure may remove a diagnostic portion of the sample. Gentle clipping of hair is acceptable, and surgical preparation of the skin is acceptable for an excisional biopsy of lesions deep to the epidermis. For collection of biopsy samples in areas of alopecia, drawing a line with a fine-tipped permanent marking pen in the direction of the hair coat helps laboratory personnel orient Text continued on p. 1055 CHAPTER 17 The Integument Collect multiple samples representative of the range of lesions. If crusting is significant, collect crust, wrap in lens paper, and place in formalin. For alopecic conditions: Collect samples from the most alopecic areas; draw a line on the sample in the direction of the hair coat. For ulcers or depigmenting lesions (junction important): Use incisional or excisional method or use an 8-mm biopsy punch instrument, and draw a line on the sample perpendicular to the junction between lesion and normal skin. Punch samples Use 6-or 8-mm punch instruments for haired skin. Use 4-mm punch for periocular skin, pawpads, or nasal planum. Incisional and excisional samples

Use incisional or excisional methods if smaller punch would damage large pustule or vesicle. Gently place thin incisional or excisional samples, subcutis side down, on a piece of cardboard; let adhere for approximately 30 seconds, then place in formalin (prevents warping). note: Do not let sample dehydrate. For lesions in the panniculus, use incisional or excisional method to ensure that the sample is of sufficient size and depth for diagnosis. Fixation

Fix samples in 10% buffered formalin with 10 times the volume of formalin for the volume of samples. For diagnosis of autoimmune skin disease or tumors, begin with standard histopathologic evaluation; selected immunohistochemical stains can usually be done later on the formalin-fixed samples if desired. Important finale Submit a history with differential diagnoses or specific conditions you would like to rule out.

Consider whether referral to a veterinary dermatologist may be a better option than biopsy sampling. Be gentle. Biopsy early. Collect multiple samples representative of the range of lesions. Include crusts (additional crust may be peeled from lesions and immersed in formalin with biopsy samples). Biopsy before using antiinflammatory therapy. Use the correct biopsy procedure for the type of lesion. Promptly immerse samples in formalin. Label samples from different areas. Prevent samples from temperature extremes during shipping. Submit a history and photographs if available.

Don't surgically prepare the site if lesions are in the epidermis or dermis. Don't use electrocautery or laser for small biopsy samples. Don't grasp the punch biopsy samples or lesion areas of larger samples with a tissue forceps. Don't use a biopsy instrument that is too small (4 mm is the minimum useful diameter). CHAPTER 17 The Integument be placed in 10% NBF, fixed overnight, and then transferred into 70% alcohol for shipment to reduce the chance of freezing of specimens during transport.

Accurate histopathologic diagnosis and interpretation require knowledge of the gross features of the lesions. Therefore it is essential to include with biopsy samples the following information: (1) age, breed, and sex of the animal; (2) location, gross appearance, and duration of the lesions; (3) presence or absence of lesion symmetry (i.e., the distribution on the patient); and (4) presence or absence of pruritus affecting the animal (Box 17-7). Clinical information, including results of laboratory evaluations (i.e., hemogram, serum biochemical analysis, urinalysis); results of skin cultures, scrapings, or cytologic evaluation; current medications; and response to therapy, should be included along with a list of clinical differential diagnoses. History can be critical to reaching a diagnosis. For example, presence of luminal and mural folliculitis with no apparent follicular infectious agents in H&E-stained sections in conjunction with the history of lack of response to appropriate antibiotic therapy would suggest to the pathologist that a fungal stain to evaluate for occult dermatophyte infection should be performed. Without the history of lack of response to appropriate antibiotic therapy, the folliculitis pattern could easily be presumed to be of bacterial origin, and a fungal infection may be overlooked.

Other diagnostic procedures can supplement information gained from histologic examination of biopsy samples. These procedures include aspiration of pustule contents or exudates for cytologic evaluation, performing touch imprints of the cut surface of suspected neoplastic or infectious lesions for cytologic evaluation, aseptically the sample ( Fig. 17-35 , A). In the laboratory the sample is cut along the line so that the hair follicles are oriented longitudinally (see B) . If the line is not drawn on the sample, the sample might be cut so that the follicles are in cross or tangential section rather than longitudinal section (see Fig. 17 -35, C), which reduces histologic value of the sample when evaluating for follicular disease. For collection of ulcers, depigmented lesions, or other lesions in which the junction between normal and affected skin is critical to diagnosis, use of incisional or excisional samples collected from affected skin and contiguous normal skin is often preferable. However, a large (8-mm) biopsy punch instrument can be used to collect the junction between normal and affected skin if a line with a fine-tipped permanent marking pen is drawn perpendicular to the junction between the normal and affected tissue before sample collection ( Fig. 17-36 ). The line instructs laboratory personnel how to trim the sample to ensure that the critical areas are present for dermatopathologic evaluation. For lesions suspected of being invasive tumors, complete excision of the mass, including a 3-cm margin of clinically normal skin around all borders, is recommended ( Fig. 17-37) .

Punch biopsy specimens should be placed in 10 times the volume of 10% neutral buffered formalin (NBF). To prevent warping in the fixative, thin excisional biopsy specimens should be gently attached to a flat object, such as a piece of cardboard or tongue depressor, and permitted to dry for 20 to 30 seconds. Twenty to 30 seconds is all that is necessary for the sample to adhere to the flat object. The specimen and flat object are then immediately immersed in formalin. Care should be taken not to let the sample become dehydrated (i.e., remain unfixed for longer than 20 to 30 seconds), which could damage the morphologic features of small samples and the lesions. In cold climates during winter months, punch biopsy samples should in some cases. The formalin-fixed tissue submitted for histopathologic evaluation also can be used for most routine immunohistochemical procedures, because most use immunoperoxidase staining rather than immunofluorescence (IF). Unfortunately, immunostaining techniques for immunemediated skin diseases can give false-positive or false-negative results; thus they must be done in conjunction with standard histopathologic evaluation. For autoimmune diseases, should IF evaluation be desired, specimens can be fixed in Michel's medium, which preserves immunoglobulin and complement. If immunohistochemical (immunoperoxidase) staining is desired, formalin-fixed samples are used; however, for best results, samples should not remain in formalin longer than 48 hours. Prolonged fixation in formalin results in cross-linking of proteins and false-negative results. For autoimmune disease, newer techniques that detect more specific antigens, such as desmoglein (transmembrane glycoproteins found in desmosomes that provide physical connections between keratinocytes), use of "salt-split" skin sections (a technique used in immunostaining of the skin in which sodium chloride splits the epidermis from the dermis through the lamina lucida, allowing better differentiation of subepidermal bullous dermatoses), use of better substrates for indirect immunostaining, and use of immunoblotting and enzyme-linked immunosorbent assay (ELISA) techniques may improve diagnostic accuracy of immune-mediated skin diseases in the future.

Identification of cell surface or cytoplasmic proteins can help identify the cell type in poorly differentiated tumors (Table 17-8) . However, there can be anomalous expression of proteins in some tumors (e.g., anomalous expression of cytokeratin in melanoma); thus evaluation of a series (panel) of antibodies is preferred because the pattern of staining with a panel of antibodies is more reliable than staining with one or two antibodies. In addition, some laboratories also offer "prognosis panels" for some tumors (e.g., mast cell tumors and melanomas), which may help direct therapy. Formalin-fixed specimens are acceptable for most procedures, but for others, fresh or frozen specimens are better. Discussion with a pathologist is recommended regarding when to use immunostaining procedures.

The terms congenital and hereditary are not synonymous. Congenital lesions develop in the fetus (in utero), are present at birth, and have a variety of causes. An example is hypotrichosis in the fetus associated with maternal dietary iodine deficiency. Inherited conditions are transmitted genetically and are not always manifested phenotypically in utero or at birth but may develop later in life. An example is sebaceous adenitis, which may not develop until 1 to 2 years of age or later. E-Box 17-2 lists selected cutaneous inherited diseases in animals (also see E-Box 1-1). There are many other diseases (e.g., cutaneous and renal glomerular vasculopathy in greyhounds, atopic dermatitis in selected breeds) that may also be inherited, but the mode of inheritance has not been documented.

Congenital alopecia or atrichia (absence of hair from skin where hair is usually present) and hypotrichosis (less than the normal amount of hair) have been reported in most species of domestic animals. In most instances, congenital hypotrichosis is a hereditary condition caused by spontaneous genetic mutations affecting genes responsible for or influencing the normal development and/or maintenance of hair follicles or other components of the skin. In most cases the exact mutation has not been identified. In some of these collecting a tissue sample for microbiologic culture, and collecting biopsy samples of suspected immune-mediated diseases or poorly differentiated tumors for immunostaining. Cytologic evaluation is a potentially more rapid and sensitive test for detection of infectious agents than histopathologic evaluation, and early diagnosis via cytologic evaluation may help guide further testing or therapy. Use of immunostaining for identification of cell surface or cytoplasmic proteins (to aid in diagnosis of tumors) or for identification of immunoglobulin, complement, or other antigens (to aid in the diagnosis of immune-mediated skin disease, such as pemphigus) can be helpful When collecting the junction of a lesion and normal skin for the evaluation of ulcers or depigmenting lesions using a large punch biopsy instrument (8 mm), it is necessary to draw a line on the sample from normal into affected skin to direct laboratory personnel to cut and embed the sample so that the junction between the normal and affected skin is present for microscopic examination. Without this line, the sample could be cut at a right angle to the desired line and thus miss the junction between normal and affected skin essential for histologic examination of the area most likely to have diagnostic changes.

Lesional (affected) 

Irish terrier and Dogue de Bordeaux, suspect autosomal recessive Irish terrier and Kromfohrländer, mutation in FAM83G gene (family with sequence similarity 83 member G gene)

Shar-Pei, regulatory mutation close to HAS2 (hyaluronan synthase 2 gene)

German shepherd, autosomal dominant

Rottweiler, suspect X-linked

Labrador retriever, monogenic autosomal recessive, suspect SUV39H2 gene mutation (suppressor of variegation 3-9 homolog 2)

Waardenburg-like syndrome, bull terrier, collie, Dalmatian, Sealyham terrier, and Great Dane, autosomal dominant with incomplete penetrance Coat color dilution in some dog breeds, mutation within or near the melanophilin gene Coat color dilution and cerebellar degeneration, Rhodesian ridgeback, autosomal recessive Albinism, autosomal recessive Oculocutaneous albinism, Doberman pinscher, partial gene deletion of SLC45A2 (solute carrier family 45, member 2) White skin and hair, boxers, semidominant

Primary seborrhea, West Highland white terrier and others, suspect autosomal recessive

Standard poodle, currently undefined Havanese, currently undefined Akita, possible autosomal recessive component

Lethal acrodermatitis, white bull terriers, autosomal recessive Zinc-responsive dermatosis, Alaskan malamute, Siberian husky, presumed inherited predisposition

Congenital hypotrichosis, Siamese and Birman, autosomal recessive Hairlessness, Canadian sphynx cat, monogenic recessive Hairlessness, Russian hairless cat, presumed semidominant with other gene interactions

Primary seborrhea, Persian cat, autosomal recessive

Waardenburg-like syndrome, autosomal dominant with complete penetrance for the loss of pigmentation, and an incomplete penetrance for the inner ear degeneration Chédiak-Higashi syndrome, Persian cats, autosomal recessive Maltese coat color dilution, autosomal recessive, melanophilin (MLPH) gene deletion CHAPTER 17 The Integument alopecia and hypotrichosis disorders from the nongenetic congenital alopecic disorders. The latter includes congenital hypotrichosis caused by maternal iodine deficiency in foals, calves, lambs, and pigs; in utero infection with bovine virus diarrhea or hog cholera virus; and defects in other systems such as adenohypophyseal hypoplasia in some breeds of cattle (Table 17 -9). Differential diagnosis of these conditions is usually made by a combination of clinical or gross examination (e.g., thyroid glands, pituitary gland, or dental abnormalities), microscopic examination (e.g., presence of absence of hair follicles or other adnexa), and in some instances evaluation for infectious agents (e.g., immunohistochemical evaluation of hair follicles for bovine virus diarrhea virus in calf skin). For best results in microscopic evaluations, it is important to collect skin samples from the most alopecic areas as well as the most haired areas in similar anatomic locations on the body if possible and to submit the samples in separate and labeled containers.

Collagen dysplasia (cutaneous asthenia, hyperelastosis cutis, dermatosparaxis, Ehlers-Danlos-like syndrome) occurs in most domestic animals and comprises a clinically, genetically, and biochemically heterogeneous group of diseases that are rare. In each, skin tears easily and is hyperextensible and loose, but the severity of these lesions varies among species. Specific enzyme defects affecting collagen synthesis or processing are the cause of most collagen dysplasia syndromes. Abnormal synthesis or processing of collagen leads to structurally abnormal dermal collagen that has decreased tensile strength. The cause of some collagen dysplasia syndromes has not been established. Gross lesions consist of cutaneous hyperextensibility and laxity ( Fig. 17-39) , seromas or hematomas, frequent skin wounds that result even from normal handling and activity, and numerous scars, which are the result of previous tearing of the dermal connective tissues. Microscopic features vary among the different types of collagen dysplasia syndromes, and in some the skin is histologically normal. If microscopic lesions are present, the collagen bundles can vary in size and shape, can be separated by wide spaces, have laminar splits in various levels of the dermis, or have a haphazard arrangement. Electron microscopy or biochemical analyses are sometimes required to make a definitive diagnosis.

animals the alopecia or hypotrichosis has been recognized as standard for the breed (e.g., Mexican hairless pig, Chinese crested dog, Mexican hairless dog, and sphynx cat), and the mutation is purposefully propagated. The congenital alopecia and hypotrichosis syndromes have been considered to be forms of congenital follicular dysplasia because there is an abnormal development of the hair follicles. Animals with congenital hereditary hypotrichosis can have defects in other body systems, including brachygnathism (abnormal smallness of the mandible) and dental, thymic, and genital abnormalities. When the condition involves the hair follicles plus adnexal glands and teeth, which all arise from the ectoderm, the condition is also termed ectodermal dysplasia. In addition to health problems created by oral, dental, or thymic defects (inability to efficiently chew or graze and immune deficiency that can lead to death), animals with hypotrichosis are more susceptible to sunburn, temperature extremes, and bacterial and fungal infections. The degree, location, and age of onset of hairlessness or hypotrichosis vary. Hair that is present is usually abnormally coarse or fine and easily broken or epilated. Morphologic changes in the skin and hair follicles vary from species to species, most likely representing differences in mutations. A useful example is congenital hypotrichosis with anodontia in German Holstein calves . In this condition, hypotrichosis, lack of most teeth, and complete absence of eccrine nasolabial glands is inherited as a monogenic X-linked recessive trait. Because the condition affects the hair follicles, some adnexal glands, and teeth, it is also classified as an ectodermal dysplasia. The condition varies in severity, with some calves more affected than others. Affected calves have reduced numbers of hairs per surface area in various anatomic locations (especially head, pinnae, neck, back, and tail), and also have reduced length and numbers of eyelashes and vibrissae. The alopecia and hypotrichosis are most severe in newborn calves because the number of fine hairs increases with age. There are no defects in the horns, endocrine glands, genital organs, or other internal organs. Histologically, hair follicles and adnexal glands are absent in the skin on the back of the ears. Hair follicle density is often reduced in other areas. When present, hair bulbs are small and poorly developed. In some areas the apocrine glands are reduced in quantity, and eccrine nasolabial glands are absent. Especially for purposes of herd health management and disease prevention, it is important to differentiate the congenital inherited 

GFAP, Glial fibrillary acidic protein; CD, cluster of differentiation.

osteoarthritis, and a higher-than-expected incidence of corneal ulcers. Clinical lesions usually develop within the first 2 years of life and include cutaneous swellings (seromas and or hematomas), open wounds or sloughing skin, loose easily stretched skin that does not return to original position, scars, and white hairs (possibly associated with follicular damage during dermal tearing). Histologic lesions are most obvious in the deep dermis and consist of thin and short collagen fibers arranged in clusters separated by clear spaces sometimes accompanied by granulation tissue and fibrosis, presumably from previous injury, but lesions are subtle and may be inconclusive. It is important to include deep dermis in biopsy samples, because samples from more superficial areas (such as samples of skin from seromas, hematomas, or wounds) may only include superficial dermis above the pathologic dermal separation and thus may be nondiagnostic. Ultrastructural evaluation fails to consistently differentiate between control and affected samples and is thus considered insensitive. Therefore definitive diagnosis rests with genetic testing.

Although rare, one of the more common of the collagen dysplasia syndromes, hereditary equine regional dermal asthenia (HERDA), is an autosomal recessive disease that occurs in young quarter horses and horses of quarter horse ancestry. This syndrome is caused by a genetic mutation on equine chromosome 1 in equine cyclophilin B, and a genetic test is available for diagnosis. It has been shown that affected horses have altered cyclophilin B-protein interactions, and that collagen folding is affected, presumably leading to the clinical lesions, which tend to develop in the skin of the dorsal trunk when young horses begin saddle training, initially suggesting that the collagen defect was only regionally present. However, other areas of the body can develop lesions, and additional studies have indicated that the collagen abnormality is uniformly present in skin of affected horses, but that other factors such as trauma, heat, or UV light-associated injury may influence lesion development. Although internal organ collagen dysfunction has not been noted, affected horses may have hyperextensible joints, weaker tendons and ligaments, an increased risk for developing The hair coat is sparse and short. Eyelashes and tactile hairs are also sparse and very short. The tail switch (not in this photograph) was approximately one-third the normal length. B, Radiograph, skull. Note that most of the teeth are missing (i.e., anodontia). When congenital hypotrichosis involves the hair follicles plus adnexal glands and teeth, which all arise from the ectoderm, the condition is also termed ectodermal dysplasia. C, Affected skin. Note the lack of hair follicles and other adnexa. Animals with hypotrichosis are susceptible to extremes of temperature, and the skin is more likely to sustain traumatic injury and secondary infection because of the lack of the protective hair coat. Absence of sweat glands may complicate the ability of affected animals (horses and cattle with ectodermal dysplasia) to thermoregulate. H&E stain. 1. Clinically manifested endocrine disease in cats is usually caused by hyperadrenocorticism in which marked dermal atrophy leads to tearing of the skin with normal handling procedures. Alopecia can be a feature, but skin fragility is a more significant problem. 2. Clinically manifested endocrine disease in horses is usually caused by hyperadrenocorticism and is typified paradoxically by hypertrichosis rather than alopecia (possibly because of production of adrenal androgens, other hormones, or pressure of the pituitary on thermoregulatory areas of the hypothalamus). † Prolonged alopecia postclipping: The pathogenesis of this condition is undetermined, but because hair regrowth may take a year or more, an arrest in the hair cycle is suspected. Collagen dysplasia syndromes other than HERDA have developed in various other breeds of horses, including the quarter horse, and in particular, warmbloods. Unlike HERDA, however, lesions develop in young foals, there is more generalized clinical lesion distribution, and the genetic test for HERDA, when performed, has been negative, indicating that more that one type of collagen dysplasia disorder is present in horses.

Chronic Progressive Lymphedema of Draft Horses. Chronic progressive lymphedema is a disabling disorder of the peripheral lymphatic system that has been described in a variety of breeds of draft horses. Early clinical lesions consist of skin thickening, pitting edema, and scaling that progress to more moderate and extensive areas of permanent thickening (fibrosis) with skin folding and nodules, scaling, ulceration, exudation, and enlarged leg diameter. The lesions are often hidden by the long hair coat, so they may be inapparent until they have become more chronic and extensive. Bacteria and parasites often secondarily infect lymphedematous skin, and the inflammation associated with the secondary infections further aggravates the lymphedema, eventually leading to mechanical impairment, lameness, and sometimes euthanasia. The cause and pathogenesis of this condition are not fully understood but are thought to be multifactorial with an underlying genetic component (see Chapter 10).

Congenital Lymphedema. Congenital lymphedema, also a disorder of the peripheral lymphatic system, has been reported in cattle, pigs, dogs, and cat. The onset of lesions is usually at birth or within the first few months of life. Clinical lesions consist of generalized or regional swellings that vary in severity depending on the species. The condition is often inherited (see Chapter 10).

Epidermolysis bullosa refers to a group of mechanobullous diseases resulting in development of cutaneous blisters (bullae) in response to minor mechanical trauma. Blisters develop as a result of poor cohesion of the epidermis and dermis as a result of structural defects at the basement membrane zone. The structural defects are the result of mutations in genes responsible for the synthesis of a variety of structural components of this anatomic region of the skin and include abnormalities in keratin intermediate filaments, proteins associated with hemidesmosomes, and anchoring fibrils such as type VII collagen. The diseases vary in mode of inheritance, clinical manifestations, and anatomic location of the blisters. Animals affected with the diseases usually die because of their inability to obtain nourishment, loss of fluid and protein, and secondary infection leading to bacteremia. Epidermolysis bullosa has been reported in horses, cattle, sheep, dogs, and cats. Lesions can be present at birth or develop shortly thereafter and are located where epithelial surfaces are subjected to minor mechanical trauma, such as oral mucosa, lips, and extremities, and can include sloughing of claws, hooves, or pawpads. Shearing forces that normally cause no problem are sufficient to cause injury in these animals. Microscopic lesions are those of an epidermal vesicular disease in which vesicles form in different locations (subepidermal, dermal-epidermal junction, or intraepidermal), depending on the specific disease. The vesicles progress to ulcers or if secondarily infected, become pustules. As healing occurs, the reepithelialization causes sloughing of the dried exudates over the ulcer, and the pustules dry to form crusts.

Epitheliogenesis imperfecta results from the failure of the stratified squamous epithelium of skin, adnexa, and/or oral mucosa to develop completely. The disease varies in severity and has been reported in most domestic species. It is the result of inherited genetic mutations in some species, but inheritance is not proved in other species. Additional information regarding the pathogenesis is not known. Without the protective covering of the stratified squamous epithelium, the underlying tissue is easily traumatized, can become infected, and bacteremia can develop. Grossly, lesions consist of sharply demarcated areas devoid of the epidermis and adnexa or mucosa, exposing the underlying red, moist dermis or submucosa. Lesions are located most often on the face, extremities, or mucous mediators, such as cytokines, from radiation-damaged keratinocytes, or from direct damage to endothelial cells of superficial dermal capillaries by UV light. Chronic sun exposure, particularly to UVB, causes damage primarily in the epidermis leading to the development of neoplasia. The damage occurs in three broad categories, as follows: 1. One of the most detrimental changes occurs when UVB radiation contacts the nucleus and causes the formation of "photoproducts," which are abnormal covalent or single bonds between two adjacent pyrimidine bases in a strand of DNA. The two major UVB-induced photoproducts are pyrimidine dimers (covalent bonds between two thymine or two cytosine bases) and 6-4 photoproducts (single bond bridging carbon 4 in one cytosine and carbon 6, either in a cytosine or a thymine). These photoproducts form in keratinocyte DNA (and also in DNA of Langerhans cells and dermal dendritic cells). The damage can be easily and accurately repaired before the cell undergoes mitosis by the nucleotide excision repair enzyme system that removes the damaged area and synthesizes a new strand of DNA. However, if the cell undergoes mitosis before the damage is repaired, a gap in the DNA strand is left at the location of the photoproduct. The gap is repaired by a postreplication repair method that is thought to be error prone and may lead to mutations and the development of neoplasms. Factors that irritate the skin and increase the rate of cell division increase the number of cells repaired by the postreplication repair method and therefore can enhance development of neoplasms. 2. Chronic exposure to UVB radiation also causes damage to DNA in the form of mutations to tumor-suppressor genes, in particular to the p53 gene. Normally, UVR-induced DNA damage causes keratinocyte induction of the p53 gene, which leads to cell cycle arrest, thus allowing the UVR-caused DNA damage to be corrected by the nucleotide excision repair system before the cell undergoes mitosis, and a functional p53 gene also facilitates apoptosis (programmed cell death) of cells with excessive unrepaired damaged DNA so that those defective cells are removed. The p53 gene mutations develop when UVR-induced photoproducts are not repaired before keratinocyte mitosis. The photoproducts form small structural abnormalities in the DNA strand that can result in faulty base paring (i.e., mutations) during replication. The mutations are characterized by the replacement of a cytosine with a thymine (C to T) or double-base membranes and can be small (1 cm) or involve extensive regions such as the entire distal limb ( Fig. 17-40 ). Small lesions can heal with scarring and not interfere with life. With extensive involvement the entire skin can be affected, including hooves, ears, lips, and eyelids, and may result in abortion of the affected fetus. Animals born alive with extensive lesions usually die from infection or dehydration and electrolyte abnormalities from extensive fluid loss through nonepithelialized surfaces.

See Disorders of Ruminants (Cattle, Sheep, and Goats).

See Disorders of Pigs.

The majority of ultraviolet radiation (UVR) reaching the surface of the earth is UVA and a small amount of UVB (see Responses of the Dermis to Injury, Alterations in Growth, Development, or Tissue Maintenance, Solar Elastosis). UVB penetrates into the epidermis and superficial dermis and is the portion of UV light most damaging to the skin because it is absorbed by and damages DNA. UVA penetrates deeper into the dermis but is less efficient in causing DNA damage because it is not significantly absorbed by native DNA. However, UVA can act indirectly by causing secondary photoreactions of existing UVB-induced DNA damage or alternatively damage DNA via indirect photosensitizing reactions. For example, if photodynamic chemicals are present in the skin, they can chemically react with the longer wavelengths (UVA and sometimes visible light), thus releasing energy and leading to the formation of reactive oxygen intermediates that initiate a chain of reactions resulting in cutaneous damage (photosensitization, phototoxicity). Solar (Actinic) Dermatosis, Keratosis, and Neoplasia. The damage to skin by UV light can be acute (sunburn) or chronic (solar dermatosis, neoplasia). An early transient erythema may be caused by the heating effect of the light rays and possibly by photochemical changes. The later developing erythema is called "sunburn erythema," and the skin is warm, tender, and swollen. The pathogenesis of sunburn erythema may involve diffusion of inflammatory 

recently have been identified in mucosal and cutaneous in situ and invasive squamous cell carcinomas, including invasive squamous cell carcinomas arising in sun-exposed skin in cats. However, it is currently not known if the papillomavirus identified within the tumor is merely infecting the tumor or if the virus could have a role in tumor induction. Some papilloma viral gene products have been shown to bind p53 tumor-suppressor gene protein products in cervical squamous cell carcinomas in women, leading to disruption of the cell cycle regulation. The lesions of sun-induced injury occur in all domestic animals. In horses, lesions occur on the eyelids and nose and around the prepuce. The eyelids of Hereford cattle are also prone to development of lesions. In lightly colored dairy goats, lesions can develop on the lateral aspects of the udder and teats. Lightly pigmented young pigs are also susceptible to more acute solar injury, and the pinnae and tip of the tail can slough if injury is severe. In dogs, lesions develop most commonly in nonpigmented, sparsely haired skin of the ventral abdominal, inguinal, and perianal areas . In cats, gross lesions occur where there is little or no hair and little pigment, particularly on external ear tips, eyelids, nose, and lips, and are most severe in white cats. Grossly, lesions begin as changes in which a cytosine dimer is replaced by two nondimerized thymine bases (CC to TT). Although p53 gene mutations occur in a variety of tumors, those mutations caused by UVR (the C to T or CC to TT mutations) are unique and do not occur with other types of DNA damage or in tumors unassociated with UVR; thus they are termed signature mutations. 3. UVB causes immunosuppression by depressing host cell-mediated immune reactions that normally serve to eliminate or destroy mutated proliferating cells. A variety of mechanisms contribute and involve UVB-damaged keratinocytes, Langerhans cells, dendritic cells, and others. Mechanisms include release of immunosuppressive cytokines such as IL-10 and IL-4, reduction in the number of Langerhans cells (antigen-presenting cells), a switch in Langerhans cell antigen presentation from T H 1 lymphocytes (involved in immune response against tumors) to T H 2 lymphocytes (which release immunosuppressive cytokines), induction of suppressor T lymphocytes, and release of cytokines and other biologic response modifiers that downregulate the immune response.

Other factors may also contribute to the development of solarassociated squamous cell carcinomas. For example, papillomaviruses The nonpigmented and lightly pigmented spots are affected, but the densely pigmented black spots are clinically unaffected. The nonpigmented and sparsely haired skin is erythematous, has comedones and crusts, and is palpably thickened. Comedones can rupture (furunculosis), releasing follicular contents that cause a foreign body inflammatory response and secondary bacterial infection (arrows). Clinically, the inflammation is prominent (erythema and furuncles) and can be misinterpreted as primary. Clinically, the distribution pattern of affected nonpigmented sparsely haired skin and unaffected haired or pigmented skin is supportive of the diagnosis of solar dermatosis. B, Ventral abdomen. Solar dermatosis with a solar (actinic) keratosis that has formed a cutaneous horn. Cutaneous horns are keratoses formed from multiple layers of compacted stratum corneum. They may arise from benign or malignant lesions in the epidermis (solar actinic keratosis, squamous cell carcinoma) or adnexa (infundibular keratinizing acanthoma). C, The epidermis is thickened by acanthosis, and three comedones (follicular distention and hyperkeratosis) are present. If comedones rupture, a large amount of endogenous foreign material (stratum corneum, hair shafts, and sebum) is released into the dermis, causing a foreign body inflammatory response. Bacteria are also released and cause a secondary bacterial infection. 1063 CHAPTER 17 The Integument proteins, and organelles. The photodynamic agent usually enters the dermis via the systemic circulation. However, direct contact and absorption of some photodynamic agents, such as occurs in phytophotodermatitis, can result in localized contact photosensitization, and although most cases occur in nonpigmented sun-exposed skin, uncommonly, sun-exposed darkly pigmented skin can be affected.

Photosensitization can occur in several forms. Type I or primary photosensitization is often caused by ingestion of preformed photodynamic substances contained in a variety of plants; thus herbivores are most commonly affected. The plants causing photosensitization usually contain helianthrone or furocoumarin pigments. The helianthrone pigments are red fluorescent pigments such as hypericin (found in Hypericum perforatum [St. John's wort]) and fagopyrin (found in Fagopyrum esculentum [buckwheat] ). Photosensitization attributed to furocoumarin pigments is caused by the presence of psoralens, photodynamic agents found in a variety of plants, including Cymopterus watsonii (spring parsley), Ammi majus (bishop's weed), and Thamnosma texana (Dutchman's breeches). Furocoumarin pigments also form phytoalexins, a group of compounds formed in plants in response to fungal infection or other injury and that inhibit or destroy the invading agent. The phytoalexins formed in fungus-infected parsnips and celery have caused phytophotodermatitis when they are absorbed into the skin and react with UV light.

Primary photosensitization can also occur with the administration of drugs such as phenothiazine, which is converted to a photoreactive metabolite in the intestinal tract. This metabolite is usually converted to a nonphotoreactive compound in the liver by mixedfunction oxidases, but occasionally either the reactive metabolite bypasses the liver or mixed-function oxidase activity in the liver is compromised or insufficient and the reactive metabolite reaches the skin.

Type II photosensitization develops because of abnormal porphyrin metabolism, leading to the blood and tissue accumulation of photodynamic agents. These diseases usually are inherited as an enzyme deficiency, resulting in abnormal synthesis of photodynamic agents, including uroporphyrin and coproporphyrin. Examples include bovine congenital porphyria and bovine erythropoietic (hematopoietic) protoporphyria. Photosensitization caused by abnormal porphyrin metabolism has also been reported in pigs and cats.

Type III or hepatogenous photosensitization is caused by impaired capacity of the liver to excrete phylloerythrin, which is formed in the alimentary tract from the breakdown of chlorophyll. This is the most common type of photosensitization and occurs most commonly in herbivores, but any animal with generalized hepatic disease on a chlorophyll-rich diet that is exposed to sufficient solar radiation can develop hepatogenous photosensitization. Hepatogenous photosensitization occurs secondary to primary hepatocellular damage, inherited hepatic defects, or bile duct obstruction. Toxic plants, including but not limited to Lantana camara (lantana) and Tribulis terrestris (puncture vine), and mycotoxins, such as sporidesmin, are the most common cause of this type of photosensitization. Other plants that cause hepatic damage (such as those that contain pyrrolizidine alkaloids) can also contribute to the development of hepatogenous photosensitization.

Most forms of photosensitization cause lesions that are located on areas of the body with nonpigmented skin and hair and on parts of the body exposed to the sun such as the face, nose, and distal extremities in horses. In cattle, lesions occur in white-haired areas and on the teats, udder, perineum, and nose. In sheep with heavy fleeces, lesions occur on the pinnae, eyelids, face, nose, and coronary band, but in shorn sheep, lesions can occur on the back. Sheep can have extensive edema of the head, prompting terms that are erythema, scaling, and crusting. After years of exposure the skin becomes wrinkled and thickened secondary to epidermal hyperplasia, hyperkeratosis, fibrosis, and in some species, elastosis. One or more papular or plaquelike foci covered with thick scale (hyperkeratosis) known as solar (actinic) keratoses may develop, some of which progress to invasive squamous cell carcinoma. Occasionally the hyperkeratosis is dense and compact and resembles a "horn" (see Fig. 17-41, B) . Hemangiomas and hemangiosarcomas have developed in the nonpigmented conjunctiva of horses and dogs and in the dermis of sparsely pigmented and sparsely haired skin of dogs, and a few goats and cats. The cutaneous hemangiomas and hemangiosarcomas are often seen on the abdomen and flanks of dogs that spend time resting in the sun. The difference in type of neoplasm can be a result, in part, of thickness of the epidermis, which influences the depth of penetration of the UV rays. UV light may also play a role in the development of melanomas in goats. Melanomas also develop in the skin, lips, eyelids, and iris in Doberman pinscher dogs with autosomal recessive oculocutaneous albinism. However, the melanomas develop in sun-exposed and non-sun-exposed sites, so the role of UV light in tumor induction in these dogs is unclear.

Microscopically, in early UV-induced injury, the number of apoptotic cells (sunburn cells) scattered in the epidermis can be so numerous as to form a band of these cells along with intercellular edema, vacuolation of keratinocytes, and loss of the granular cell layer. By 72 hours, hyperkeratosis, parakeratosis, and acanthosis are present along with dermal lesions of hyperemia, edema, perivascular mononuclear infiltrates, capillary endothelial cell swelling, and hemorrhage. Hyperkeratosis, parakeratosis, and acanthosis can persist. Comedones (hair follicles dilated with a plug of follicular stratum corneum and sebum) develop in some dogs (see Fig. 17 -41, C). Affected follicles are often surrounded by a thin layer of fibrosis. In dogs, superficial dermal vessels may have hyalinized or sclerotic walls, and endothelial cells may be missing (solar vasculopathy). In some animals and in some anatomic locations, elastic tissue and collagen are damaged by solar radiation, and the dermis may be thickened by a zone of fibrosis parallel to the epidermal surface (laminar dermal fibrosis). Solar elastosis characterized by deposits of wavy basophilic elastin fibers in the superficial dermis is often present in horses and sometimes dogs. With continued UV exposure, solar keratoses develop. The epidermal surface is thickened by compact hyperkeratosis or parakeratosis. The acanthotic epidermis has atypical keratinocytes starting in the basal layer and progressing into the spinous layer. Keratinocytes are irregularly stratified and irregularly sized and shaped. Nuclei are large and often vary in size. Nucleoli may be large. There may be increased mitoses and apoptotic keratinocytes. The keratinocytes may form downward proliferations, usually as short buds, but occasionally as branching and anastomosing epidermal pegs. However, in solar keratoses the basement membrane remains intact. Invasive squamous cell carcinoma can develop in the site of solar keratoses when atypical keratinocytes breach the basement membrane and invade the contiguous dermis and, less often, subcutis. In some instances the atypical keratinocytes invade lymphatic channels and can metastasize to lymph nodes, lungs, and can more widely disseminate.

Photosensitization. Photosensitization is a disorder caused by long-wavelength UV (UVA), or less frequently by visible light, absorbed by a photodynamic chemical in the skin or by a complex of a photodynamic molecule and a biologic substrate. This process results in a release of energy that produces reactive oxygen molecules, including free radicals. Generation of reactive oxygen molecules leads to mast cell degranulation and the production of inflammatory mediators, which causes damage to cell membranes, nucleic acids,

Chemical injuries to the skin can result from local application directly onto the skin or from absorption of chemicals via the gastrointestinal tract and subsequent distribution to the skin. For a chemical to cause injury via local application, it must penetrate the hair and protective epidermal layers. Penetration is enhanced by physical damage to the stratum corneum, especially that caused by excessive moisture. Chemical injuries of the skin include contact irritant dermatitis (local application), systemically distributed chemicals, such as arsenic, mercury, thallium, iodine, and organochlorines and organobromines, and poisonings by fungalcontaminated plants and plants containing selenium, mimosine, and trichothecenes. Externally applied agents that produce irritant contact dermatitis induce cutaneous damage by altering the waterholding capacity of the epidermis or by penetrating the epidermis and directly damaging cells. Systemically absorbed and distributed chemical agents cause lesions by a wide variety of mechanisms, some of which are not known. An example is toxicity caused by systemic absorption of some organochlorine and organobromine compounds, such as highly chlorinated naphthalenes, which were used as additives in lubricants for farm machinery such as feed pelleting equipment. As a result, highly chlorinated naphthalenes were frequent feed contaminants. Toxicosis occurred most commonly in cattle, the most susceptible species, and was known as X-disease or bovine hyperkeratosis. Fortunately, this toxicosis is largely historically interesting, because highly chlorinated naphthalenes have not been used in machinery lubricants since the 1950s. Lesions of chlorinated naphthalene toxicity are the result of the interference of the conversion of carotene to vitamin A and result in vitamin A deficiency. Vitamin A is necessary for normal differentiation of stratified squamous epithelium. Clinical lesions consist of alopecia and lichenified, fissured plaques of scale that spare only the legs. Histologic lesions consist of marked hyperkeratosis of the epidermis and follicles. Squamous metaplasia of the epithelial lining of the glands and ducts of the liver, pancreas, kidneys, and reproductive tract also develop.

There are two forms of contact dermatitis. One form is allergic contact dermatitis, which is immunologically mediated and requires prior exposure (sensitization) to the offending agent in a hypersensitive individual (see the discussion on allergic contact dermatitis in the section on Selected Hypersensitivity Reactions). The other form is irritant contact dermatitis, most cases of which are nonimmunologic in origin, and are instead caused by direct contact with substances such as acids, alkalis, soaps, detergents, body fluids (urine or diarrhea scald), wound secretions, some plants, and some topical medications. These substances overwhelm the protective mechanisms of the skin and directly injure cells. It is important to realize that the two types of contact dermatitis can produce very similar histologic lesions, thus differentiation between immune-mediated and irritant contact dermatitis largely depends on history, clinical signs, and anatomic distribution of the lesions. Horses develop lesions on the nose, ventrum, lower limbs, and where riding tack contacts the body, and on the perineum and caudal aspect of the rear legs. In dogs and cats, lesions of irritant contact dermatitis develop on the glabrous (sparsely haired) skin of the abdomen, axillae, flanks, interdigital spaces, perianal area, ventral tail, ventral chest, legs, eyelids, and feet. Grossly, erythematous patches, papules, and rarely, vesicles develop, but self-inflicted trauma can lead to ulcers and crusts. Microscopically, lesions consist of spongiotic dermatitis, neutrophilic vesicopustules, and superficial dermal perivascular neutrophilic inflammation. Chronic lesions consist of epidermal hyperplasia, hyperkeratosis, sometimes confluent parakeratosis, and superficial perivascular inflammation. Lesions synonyms: "swelled head" and "facial eczema." Onset of lesions may take only hours and initially include erythema and edema, followed by blisters, exudation, necrosis, and sloughing of necrotic tissue. The microscopic lesions consist of coagulative necrosis of the epidermis and possibly hair follicle, adnexal glands, and superficial dermis. Subepidermal vesiculation can occur. Endothelial cells of the superficial, middle, and deep dermal vessels are swollen and necrotic, and fibrinoid degeneration and thrombosis can result in edema; infarction; sloughing of the epidermis, dermis, and adnexa; and secondary bacterial infection.

Advances in the treatment of cancer in companion animals have made the possibility of radiation-induced skin injury more likely. Ionizing radiation consists of electromagnetic radiation (x-rays, γrays) and particulate radiation (e.g., electrons, neutrons, protons) and is most damaging to highly proliferative cells, such as those of the anagen hair matrix, but epidermal basal cells and vascular endothelial cells are also affected. Available radiation modalities offer differing degrees of tissue penetration and thus differing potential for tissue injury. Some forms of radiotherapy penetrate deeper tissues while sparing the skin, and others are more concentrated in the superficial tissues or are preferentially absorbed by specific tissues. The type of radiation therapy and the source, dose, intensity, and duration of exposure dictate the range of possible side effects. Ionizing photons disrupt chemical bonds in cells, leading to injury or cell death. Some cells are not lethally damaged but sustain DNA damage to the extent that replication and/or replacement are not possible. The effects of radiation damage can be divided into acute and chronic forms.

Acute radiation injury to the skin is a result of damage to rapidly dividing cells. Damage is self-limiting, and recovery is associated with rapid cell turnover. Clinical lesions of radiation dermatitis appear 2 to 4 weeks after exposure. Initially there is erythema, pain, edema, and heat, followed several weeks later by dry or moist desquamation depending on the degree of injury. Histologically, the lesions resemble a second-degree burn, with suprabasilar or subepidermal bullae formation, dermal edema with fibrin exudation, and a marked leukocytic infiltrate. Reepithelialization occurs over a period of 10 to 60 days. The damage sustained to germinal cells of hair follicles and sebaceous glands leads to alopecia within 2 to 4 weeks after exposure. Hair regrowth follows over the next several months, but damage to sebaceous glands is not reversible and leads to permanent scaling manifesting histologically as hyperkeratosis. The chronic lesions of radiation injury are evident months to years after treatment and are primarily the result of damage to the microvasculature. Chronic changes include pigmentary alterations (hyperpigmentation with lower doses and hypopigmentation with higher doses), leukotrichia (depigmentation of hair shafts because of loss of follicular melanocytes), dermal scarring, epidermal atrophy, and ulceration. The epidermis is thin, friable, and in some areas hyperplastic and can become neoplastic. Squamous cell carcinomas can develop in some sites of severe radiation damage because of sublethal DNA damage. Chronic nonhealing exudative ulcers can develop, but granulation tissue does not form. The dermis is fibrotic with atypical fibroblasts, telangiectasia, and possibly deep arteriolar changes. Endothelial swelling, necrosis, and thrombosis lead to occlusion and excessive endothelial proliferation, which, when combined with the effects of vascular leakage, leads to vascular collapse. This condition of progressive vessel abnormalities is referred to as obliterative endarteritis and is known to form a "histohematic" (tissue-blood) barrier to surrounding tissue, leading to continued anoxia and nutrient shortage. rabies antigen in the vessels and cells of the hair follicles. A lowgrade, immune-mediated vasculitis with resultant tissue hypoxia leading to the atrophic changes in the adnexa has been suggested as the pathogenesis. Vascular lesions are characterized by hyalinization of the vessel wall, lack of endothelial cells, intramural karyorrhectic debris, and perivascular lymphocytic infiltrates. Rarely, small numbers of lymphocytes are found within the walls of affected vessels.

Injection site eosinophilic granulomas with necrotic centers have been reported to occur in horses 1 to 3 days after injections of various substances using silicone-coated needles. The reaction is suspected to be a form of delayed hypersensitivity. Snake and Spider Bites (Envenomations). The families Elapidae (coral snake) and Viperidae (rattlesnake, water moccasin, and copperhead) contain the majority of the poisonous snakes in the United States. The genera Latrodectus (e.g., black widow) and Loxosceles (e.g., brown recluse) are the most common venomous spiders causing cutaneous injury. Effects depend on composition of the venom, individual victim response, anatomic location of the envenomation, and specific characteristics of the offending snake or spider, which can be influenced by season of the year, geographic location, time since last inflicted bite or sting, depth of injury, and so forth. Different species of animals respond differently to the same venom.

Spider bites occur most often on the face and legs. The brown recluse spider (Loxosceles reclusa) is the spider most known to induce dermal necrosis, although there are a number of others. Brown recluse venom contains numerous enzymes, including lipase, hyaluronidase, and sphingomyelinase-D, which degrade tissue. A blister with a surrounding pale halo and more peripheral erythema characterizes initial reactions documented in human beings and some experimental animals. Necrosis and eschar formation occur within 5 to 7 days. Ulceration can be extensive. Histologically, there is hemorrhage and edema, neutrophilic vasculitis, and arterial wall necrosis. The epidermis and dermis undergo infarction, which can extend into the subcutis and underlying muscle. Panniculitis can be present. Eventually there is dermal scarring and replacement of the subcutis and muscle by hypocellular connective tissue. Brown recluse spider bites in human beings can also lead to massive hemolysis. Differentials include other venomous bites, vasculitis, slough can be obscured by self-inflicted trauma, making histologic diagnosis difficult. Corrosive substances (strong acids or alkalis) can cause epidermal necrosis.

Injection Site Reactions. Injections of vaccines or therapeutic drugs into the subcutis can incite a local and persistent (chronic) immunologic response resulting in granulomatous nodules that are palpable. There are no reported histologic descriptions of the acute or subacute inflammatory responses to such injected materials. Histologic changes represented by these chronic post-injection site nodules consist of a localized area of deep dermal or subcutaneous necrosis containing foreign material bordered by macrophages and multinucleated giant cells with a peripheral zone of lymphocytes and variable numbers of plasma cells and eosinophils (foreign body granuloma). Macrophages usually contain amphophilic granular foreign material. Lymphoid follicular development at the margins of these lesions can be extensive. Although many injection site lesions heal without serious consequences, in some cats there is a causal relationship with injections and development of sarcomas such as fibrosarcomas, myxosarcomas, osteosarcomas, rhabdomyosarcomas, chondrosarcomas, and histiocytic sarcomas. The injected substance, inflammation, and eventual fibroblastic proliferation are thought to be important factors predisposing some cats to sarcoma formation. It is speculated that during tissue repair, fibroblasts or myofibroblasts at the injection site are stimulated, and this response, in combination with other factors such as oncogene alterations or unidentified carcinogens, leads to malignant transformation of cells. Tumor development can take months to years, with eventual neoplastic transformation of mesenchymal cells. Any type of vaccine, other injectable materials, microchips, nonabsorbable suture, or other trauma has the potential to contribute to sarcoma formation. It is currently unknown how to identify cats that are at risk for the development of these types of sarcomas. Uncommonly fibrosarcomas have developed in dogs in cutaneous sites of presumed previous vaccination.

In small, often soft-coated, breeds of dogs, especially poodles, subcutaneous injection of killed rabies vaccine can result in localized lymphoplasmacytic panniculitis, subtle vasculitis, and localized ischemia leading to severe follicular atrophy in overlying dermis ( Fig. 17-42 ) that is clinically apparent as a focal area of alopecia and hyperpigmentation. Immunofluorescence staining has identified A B P complete antigen that sensitizes lymphocytes and evokes the cellmediated immune response upon repeat exposure. Initial lesions in cattle consist of a rough coat with papules and crusts affecting the skin of the udder, teats, escutcheon (back of udder and perineum), and neck, followed by involvement of the trunk, face, and limbs. The skin becomes alopecic, lichenified, and less pliable. Marked pruritus leads to excoriations from self-induced trauma. The dermis has perivascular to diffuse infiltrates of monocytes, lymphocytes, plasma cells, multinucleated giant cells, and eosinophils. There is marked hyperkeratosis and dermal and epidermal edema.

The clinical syndrome begins 2 or more weeks after consumption and consists of pruritic dermatitis, diarrhea (possibly bloody), and wasting. Morbidity is low, and mortality is high. Holstein and Angus cattle and cattle 3 years or older are more often affected. Death in cattle occurs approximately 10 to 20 days after illness begins. At autopsy (syn: necropsy), yellow nodular infiltrates of mononuclear leukocytes are seen that disrupt the architecture of a wide range of organs but are most severe in myocardium, kidney, lymph nodes, thyroid, and adrenal glands. In cattle, other species of Vicia and additional compounds are capable of inducing disease indistinguishable from vetch toxicity. These include feed additives such as di-ureido isobutane and citrus pulp.

Hairy vetch toxicosis in horses resembles that in cattle, except for the infrequent finding of eosinophils in the infiltrate and lack of heart involvement. Conditions very similar to vetch toxicosis also have been reported in horses with no vetch exposure. These cases have been variably referred to as equine sarcoidosis; equine idiopathic, generalized, or systemic granulomatous disease; or equine histiocytic disease/dermatitis (see Nodular Granulomatous Inflammatory Disorders without Microorganisms, Equine Sarcoidosis). These idiopathic conditions in the horse are fairly indistinguishable and are a differential diagnosis for hairy vetch toxicosis.

The diagnosis of vetch toxicity or vetchlike disease is a diagnosis by exclusion. It is made after review of the herd history, the character and distribution of the lesions, and ruling out other causes of granulomatous inflammation such as infectious agents. 

A callus is a raised, irregular, patch of thickened skin that develops because of friction, usually over pressure points on bony prominences or on the sternum (see Table 17 -6). Callosities can develop in all domestic animals but are particularly common in pigs and giant breed dogs kept on concrete or other hard flooring without adequate bedding. Secondary folliculitis, furunculosis, and ulceration can develop. Microscopically, the epidermis and follicular infundibulum are thickened by hyperkeratosis and acanthosis. Regular epidermal hyperplasia (rete peg and papillary dermal interdigitation) also occurs. Comedones are present in some lesions. The follicular openings can be widened by excessive keratin. Dilated follicles can rupture (furunculosis), releasing bacteria, keratin proteins, and sebum, resulting in secondary pyoderma and an endog-caused by iatrogenic injection of irritating substances, thermal burns, necrotizing fasciitis or other cutaneous infection, septic embolization, or trauma. Some putative spider bites (and possibly wasp and bee stings) in the dog develop as acute, painful, swollen areas on the dorsal or lateral nose that histologically consist of severe eosinophilic folliculitis and furunculosis (see the discussion on eosinophilic furunculosis of the face in dogs in the section on Disorders Characterized by Infiltrates of Eosinophils and Plasma Cells, Disorders of Dogs), leading to the theory that these lesions are probably caused by hypersensitivity reactions to injected venom.

Snakebites are common in the horse and dog and to a lesser degree in cats and most often inflicted on the head or legs. Snake venom contains various enzymes, proteins, peptides, and kinins. Of the five genera of venomous snakes in the United States, crotaline venom (rattlesnake, copperhead, cottonmouth, and others) contains the highest concentration of proteolytic enzymes. Snakebite envenomation produces pain, edema, and erythema that, if severe, are followed by necrosis and sloughing of tissue, and sometimes death of the animal. Variable systemic effects occur, including paralysis, coagulation disturbances, shock, increased capillary permeability, myocardial damage, rhabdomyolysis, and renal failure.

Selenium. Selenium poisoning is caused by an overdose of a selenium supplement or ingestion of seleniferous plants that have accumulated toxic concentrations of selenium. Some plants selectively accumulate selenium, regardless of soil selenium content. These selective accumulators (obligate accumulators; e.g., Astragalus, Stanleya) require selenium for growth, generally are not palatable, and are eaten only when other plants are unavailable. Many other plants (facultative accumulators; e.g., Aster, Atriplex) do not require selenium for growth but will accumulate toxic concentrations of selenium if grown in soil with high selenium concentrations. These facultative accumulator plants are commonly eaten by livestock and more often are the cause of poisoning. The mechanism by which selenium is thought to exert its effects on the integument and appendages is through its competitive replacement of sulfur, which modifies the structure of keratin, a sulfurcontaining molecule. Replacement of sulfur by selenium in other molecules can also contribute to toxicity. Acute or chronic selenium poisoning has developed in most domestic animals, although susceptibility to selenium poisoning varies with species, dosage, diet, rate of consumption, chemical form, and other factors. In acute poisonings, signs relate to involvement of multiple organ systems. Chronic selenium toxicity usually develops in livestock (horses, cattle, and sheep) consuming seleniferous forages. It occurs worldwide but is more frequent in Nebraska, Wyoming, and the Dakotas in the United States and in areas of western Canada. Animals with chronic selenium intoxication are emaciated, have poor-quality hair coat, and have partial alopecia. Horses lose the long hair of the mane and tail, develop hoof deformities, and shed the hooves.

Vetch Toxicosis and Vetchlike Diseases. Vetch toxicosis is most commonly seen as a syndrome characterized by dermatitis, conjunctivitis, diarrhea, and granulomatous inflammation of many organs. It occurs in cattle and to a lesser extent in horses after consumption of vetch-containing pastures. Hairy vetch (Vicia villosa Roth) is a cultivated legume used as pasture, hay, and silage in most of the United States and other countries. Toxicity from vetch seeds is known to be a result of the presence of prussic acid. The cause of the granulomatous inflammation in this syndrome remains unclear. One proposed pathogenesis is that ingestion of vetch or another substance leads to antigen formation in the form of a hapten or a 1067 CHAPTER 17 The Integument are rare anecdotal reports of poxvirus infection in the skin of cats in North America, but with the exception of one case, the poxvirus or viruses involved have not been characterized. In the single case in which the virus was identified, polymerase chain reaction (PCR) and gene sequencing identified raccoonpox, an orthopoxvirus, in enous foreign body inflammatory response to released follicular contents (callus pyoderma).

Intertrigo is superficial dermatitis occurring on apposed skin surfaces. It occurs in cows with large pendulous udders and develops between the udder and the medial thigh (udder-thigh dermatitis). Intertrigo also occurs in dogs in the skin of the facial fold (brachycephalic breeds), lower lip fold (breeds with large lips such as the Saint Bernard), body fold (Shar-Pei breed), vulvar fold (obese female dogs with a small vulva), and tail fold (dogs with corkscrew tails such as English bulldogs) ( Fig.  17-43) . The cause and pathogenesis involve the presence of closely apposed skin surfaces, frictional trauma between the skin surfaces, accumulated moisture (from tears, saliva, cutaneous glandular secretions, urine, or water after drinking, swimming, or bathing), and bacterial infection. The moisture and frictional trauma predispose to bacterial or yeast overgrowth and subsequent infection. Early gross lesions of intertriginous dermatitis typically consist initially of erythema and edema. Later, pustules, ulcers, and crusts can develop. Late lesions in cows can be severe, with occasional sloughing of skin and subcutis. Microscopically, in early stages there is congestion and edema with early perivascular inflammation that progresses to a more diffuse band of inflammation in the superficial dermis, parallel to the epidermis, but often sparing the dermal-epidermal junction. Inflammatory cells include plasma cells, fewer lymphocytes, neutrophils, and macrophages. In more severe cases there can be exocytosis of neutrophils into the epidermis, epidermal pustules, crusts, ulcers, and in cows, necrosis that leads to sloughing of tissue. If the cause is corrected, early and mild chronic lesions heal without scarring (most cases). However, when there is ulceration or necrosis and sloughing of tissue (minority of cases), lesions heal by second intention with the formation of granulation tissue, wound contraction, and scarring.

Information on this topic is available at www.expertconsult.com.

Cutaneous infections develop when there is disruption in the defense mechanisms of the skin (see section on Defense Mechanisms/ Barrier Systems). Predisposing factors to skin infections involve compromised epidermal barrier integrity caused by friction, trauma, excessive moisture, dirt, matted hair, chemical irritants, freezing or burning, irradiation, and parasitic infestation. Suppressed immune function resulting from inadequate nutrition, therapy with glucocorticoids, and other acquired or inherited immunologic abnormalities can also contribute to increased susceptibility to microbial and parasitic infections. Infectious agents enter the body via their specific portal of entry (see Portals of Entry/Pathways of Spread), which includes traversing the epidermal surface, entering via hair follicles or the ducts of glands, and migrating via nerves or sometimes via the hematogenous route.

Poxviruses. See Disorders of Horses, Disorders of Ruminants (Cattle, Sheep, and Goats), and Disorders of Pigs for species-specific poxviruses.

Poxviruses are DNA viruses that infect most domestic, wild, and laboratory animals and birds (Table 17 -10). Dogs and cats are rarely infected with poxviruses, although infection with a parapoxvirus (contagious ecthyma of sheep) has been reported in dogs, and cutaneous infection with a poxvirus of the Orthopoxvirus genus (cowpox in cattle) has been reported in cats and rarely dogs in Europe. There 

Exposure to cold temperatures can cause tissue damage, or frostbite. The severity of injury varies with the magnitude of the temperature extreme and duration of exposure. The pathogenesis involves two basic mechanisms: (1) vascular damage leading to tissue anoxia and (2) actual tissue freezing leading to cellular injury.

The most important mechanism of tissue injury in frostbite is loss of blood supply to the tissues (damage to the microvasculature). This occurs via the loss of the microvasculature and thus the oxygencarrying capacity to the cells, resulting in tissue anoxia. In addition, endothelial damage in surviving vessels leads to increased vascular permeability, resulting in reduced blood volume, reduced blood flow, increased blood viscosity, and blood clotting. The clotting further obstructs blood flow, leading to loss of circulation and tissue anoxia resulting in coagulation necrosis. Cutaneous lesions caused by cold temperatures are uncommon in well-nourished healthy animals but can develop in an animal recently moved from a warm to a cold climate, sick or debilitated animals, or in neonates that are hypoglycemic or inadequately dried at birth. Lesions are located in the extremities, such as the ear tips, tail, and teats of cattle, scrotum of bulls and dogs, and ear tips of cats. Grossly, lesions consist of infarction (dry gangrene) and sloughing of necrotic tissue.

With actual freezing of the tissue, the initial injury results in the formation of extracellular ice crystals that physically disrupt cells. The ice crystals grow by extracting water from cells, leading to a shift in intracellular water to the extracellular space, causing cellular dehydration and increased intracellular sodium concentration. The resultant osmotic and chemical imbalances also lead to cell damage. Intracellular ice crystal formation, much more damaging to cells, usually requires much faster freezing than occurs with frostbite.

Thermal burns are caused by exposure to excessive heat. Examples of heat sources include hot liquids, flames, friction, electricity, heating pads, blow dryers, drying cages, and lightning. Longer exposure to lower temperatures is more damaging than shorter exposure to higher temperatures. Dry heat causes desiccation and carbonization, whereas moist heat causes coagulation of tissue. In less severe burns, damage is caused by accelerated cellular metabolism, inactivation of enzymes, and vessel injury. Burns are categorized as partial (first-or second-degree) or full-thickness (third-degree) relative to the layers of skin that are affected. In first-degree burns, only the epidermis is affected, whereas in second-degree burns the epidermis and part of the dermis are damaged. In third-degree (full-thickness) burns, there is coagulation of the epidermis and all dermal components, including connective tissue, blood vessels, and adnexa. Fourth-degree burns are similar to third-degree burns, but damage from these burns extends into the subcutaneous fascia and underlying tissue. Gross lesions of burns vary from erythema and edema caused by capillary dilation and increased capillary permeability (first-degree burn) to vesicle formation as a result of fluid accumulation at the dermal-epidermal junction, which produces the "burn blister" (second-degree burn), to desiccation and charring of the epidermis, with underlying amorphous accretion of connective tissue representing the coagulated dermis and adnexa (third-and fourth-degree burn). Microscopically, partial-thickness burns consist of coagulation necrosis of the epidermis, subepidermal vesicles as a result of accumulation of fluid from superficial capillaries (see Fig.  17 -18), necrosis of superficial portions of follicles and sebaceous glands, and degeneration of the subepidermal collagen. In partialthickness burns there is preservation of part of the epidermis or dermal portions of adnexa from which epithelial regeneration develops. Full-thickness (third-and fourth-degree) burns are represented by coagulation of all components of the skin accompanied by acute inflammation. Subcutaneous vasculitis can be present. Partialthickness burns involving the epidermis (first-degree burns) heal completely, because remaining epidermis and epithelium from adnexa reepithelialize the surface, and the dermis and adnexa are intact, so there is no scarring. However, partial-thickness burns that also involve the superficial dermis and superficial adnexa (seconddegree burns) can result in superficial dermal scarring, but the adnexa are preserved. In full-thickness burns, over time, histiocytes infiltrate the tissue, the necrotic tissue sloughs, and the defect is filled in by granulation tissue. Permanent scarring with loss of adnexa results unless skin grafts are performed, and if much of the body is affected, the lesions are life threatening because of fluid loss and possible sepsis from lack of the skin's protective barrier. In human beings the prognosis in severe burn injury can be roughly calculated by adding the patient's age plus the percentage of the body with full-thickness burns (third-degree). If the total is 100, the likelihood of survival is low.

Moderate heat dermatitis (erythema ab igne) is an uncommon disorder reported in dogs and cats and is caused by repeated chronic (weeks to months) exposure to moderate heat, too low to cause a thermal burn. Heat sources that have caused moderate heat dermatitis include heating pads, heated kennel mats, electric blankets, plant warmers, heat registers, and concrete driveways. When the heat source is in direct contact with the skin, conduction probably plays a role in mediating the injury, but the mechanism at the cellular level by which conductive heating causes moderate heat dermatitis has not been investigated. In dogs and cats the cutaneous lesion distribution typically reflects chronic exposure to moderate heat during lateral or sternal recumbency. Clinical lesions consist of irregular areas of erythema, alopecia, and sometimes hyperpigmentation. Histologic lesions include keratinocyte karyomegaly, atypia, and degeneration; mixed dermal mononuclear inflammation, endothelial degeneration, dermal edema, and focal hemorrhage, a variable number of dermal, wavy, strongly eosinophilic elastic fibers; and adnexal atrophy. Hyperpigmentation is caused by accumulation of melanophages and hemosiderophages in the dermis. Recall that exposure to moderate heat sources (e.g., heating pads on low temperature setting) can also cause thermal burns. Therefore lesions of thermal burns (e.g., coagulation of the epidermis) can coexist with those of moderate heat dermatitis. the skin lesions. There are major differences between different poxviruses and in the range of species they infect; some are species specific and others are zoonotic. Many poxviruses of animals, such as the contagious ecthyma parapoxvirus, can cause skin lesions in human beings. Poxviruses induce lesions by a variety of mechanisms. Lesions develop secondary to poxviral invasion of epidermis, by ischemic necrosis caused by vascular injury, and by stimulation of host cell DNA, resulting in epidermal hyperplasia (see Fig. 17 -32). Hyperplasia may be explained by a gene, present in several poxviruses, including molluscipoxvirus (the cause of molluscum contagiosum), whose product has significant homology with epidermal growth factor. Poxviruses also encode for functions that may counteract host defenses. These include genes related to those encoding the serpins (a superfamily of related proteins important in regulating serine protease enzymes that mediate kinin, complement, fibrinolytic, and coagulation pathways) and genes encoding antiinterferon activities. The severity of poxviral infection varies, depending on whether the infection is localized (cutaneous) or systemic and whether there are secondary infections.

The sequence of the cutaneous lesions is macule, papule, vesicle (varies in severity), umbilicated pustule, crust, and scar (see Fig.  17 -32). Histologically, pox lesions begin as keratinocyte cytoplasmic swelling and vacuolation, usually first affecting the cells of the outer stratum spinosum. Rupture of the damaged keratinocytes produces multiloculated vesicles, so-called reticular degeneration. The early dermal lesions include congestion, edema, vascular dilation, a perivascular mononuclear cell infiltrate, and a variable neutrophilic CHAPTER 17 The Integument

Papillomaviruses gain access through defects in the epithelium and enter the basal layer epithelial cells. Once in the cell, there are three possible outcomes: (1) the virus can remain within the basal cell nucleus outside of the chromosomes in a circular DNA episome where the virus replicates synchronously with the host cell, causing a latent infection without morphologic changes in keratinocytes;

(2) as the basal cells mature, the virus can convert from latent to productive infection with the formation of complete infectious virions and with morphologic changes recognized as viral cytopathologic changes, including epithelial hyperplasia, keratinocytes with clear cytoplasm and pyknotic nuclei, and sometimes with cytoplasmic or intranuclear inclusion bodies; or (3) the virus can become integrated into the genome of the host cell, resulting in malignant transformation and the morphologic changes of neoplasia. Malignant transformation occurs because the viral genes that remain after integration into the host cell are those associated with cellular regulation. These viral genes promote keratinocyte cell growth by inactivating tumor-suppressor proteins such as p53 and pRb. These events lead to uncontrolled cell proliferation, inability to repair DNA damage, and eventual malignant transformation.

All domestic animals are affected by one or more papillomaviruses (see Table 17 -10), and some cross-species infections have been detected, particularly with the bovine papillomaviruses, and there are rare reports of human papillomavirus infections in cats. The specific type or types of papillomaviruses involved in some infections have yet to be determined. Papillomavirus infections cause diverse clinical and histologic lesions, including papillomas, viral plaques, and fibropapillomas, including sarcoids. Papillomavirus DNA has also been identified within in situ and invasive squamous cell carcinomas in animals. However, because papillomaviruses can be found in normal skin as well as inflamed skin of a variety of different causes, simply identifying papillomaviruses in lesional tissue of some of the proliferative lesions such as viral plaques, sarcoids, and squamous cell carcinomas, does not prove papillomavirus is the cause of the lesions. Therefore further work is necessary to prove a causeand-effect relationship for some of these presumptive papillomavirusassociated lesions.

A common type of cutaneous papillomavirus infection (papilloma, wart) consists of clinical lesions that may be exophytic (proliferating to the exterior) or endophytic (inverted) papilliferous benign masses. Other papillomas may be flat, plaquelike lesions that lack the prominent papilliferous projections. Histologically, stratified squamous epithelium is covered by thickened orthokeratotic or parakeratotic stratum corneum, is acanthotic, and in the exophytic and endophytic papillomas, has elongated dermalepidermal interdigitations that project outwardly or inwardly, depending on the type. In some papillomas, keratinocytes, especially of the upper stratum spinosum, are swollen, have clear cytoplasm or a perinuclear halo, and a pyknotic nucleus; these keratinocytes are termed koilocytes (meaning hollow or concave). Keratohyalin granules are often large and irregular. Also, pale basophilic intranuclear inclusion bodies, located in degenerating cells in the outer layers of the stratum spinosum and granulosum in which virion production is taking place, occur in some but not all papillomas. Many papillomas spontaneously regress, and in regressing stages, there is reduced epidermal hyperplasia, increased proliferation of fibroblasts, deposition of collagen, and infiltration of T lymphocytes at the dermal-epidermal interface and in the epithelium. Some papillomas, such as those on the genitalia or concave pinnae (also called ear papillomas or aural plaques) of horses and some affecting the teats of cattle, often do not regress. Viral plaques have been described in dogs and cats. Canine pigmented viral plaques are associated with papillomavirus infection infiltrate. Neutrophils migrate into the epidermis and aggregate in vesicles to form microabscesses. Large intraepidermal pustules can form and sometimes extend into the superficial dermis. There is usually marked epidermal hyperplasia and sometimes pseudocarcinomatous hyperplasia of the adjacent epidermis. This contributes to the raised border of the umbilicated pustule. Rupture or drying of the pustule produces a crust, often colonized on its surface by bacteria. Poxvirus lesions often contain characteristic intracytoplasmic eosinophilic inclusion bodies. These are single or multiple and of varying size and duration. The inclusions are primarily composed of proteins. Sheeppox and goatpox are the most pathogenic poxviruses, and infection causes significant mortality, especially in young animals as a result of systemic disease. Sheeppox and goatpox do not occur in the United States or Canada.

Herpesviruses. Herpesviruses are DNA viruses that only occasionally produce cutaneous lesions (see Table 17 -10). Cutaneous lesions have rarely been reported in nondermatotropic herpesvirus infections, such as infectious bovine rhinotracheitis (bovine herpesvirus 1) and equine coital exanthema (equine herpesvirus 3), and in cats with FHV-1 infection. Two dermatotropic herpesvirus infections with economic importance are bovine herpesvirus 2 and bovine herpesvirus 4. Herpesviruses can be latent, with inactive virus persisting in tissue such as the trigeminal nerve ganglia. It is speculated that up to 80% of adult cats recovered from FHV-1 infection as kittens or young cats have latent FHV-1 infections. During times of stress the virus is reactivated, and lesions can recur. Herpesviruses infect epithelial cells and replicate in the nucleus, leading to lysis of nuclear contents. As immature viral particles enter the cytoplasm, there is degeneration of cytoplasmic organelles, accumulation of cytoplasmic lipid, and precipitation of protein. Death of keratinocytes leads to spread of virus to neighboring cells, leading to rapid necrosis of focally extensive areas of the epidermis. Gross lesions consist of vesicles that rupture to form ulcers that are then covered by crusts. Microscopic lesions in herpesvirus infections depend on the stage, but early degenerative changes include ballooning and reticular degeneration, the sequelae of degeneration of epidermal cells and acantholysis. Syncytial cells may be seen. Intranuclear inclusions develop, but because of rapidly developing necrosis may not be found except at the margins of ulcers. The appearance of the viral inclusions varies with the specific herpesvirus. Some herpesviruses produce large, hyaline amphophilic inclusions that fill the nucleus (FHV-1), whereas others (dermatotropic bovine herpesvirus 2) produce typical Cowdry type A inclusions, which are also intranuclear but smaller and eosinophilic.

Bovine Herpesvirus 2 and Bovine Herpesvirus 4. See Disorders of Ruminants (Cattle, Sheep, and Goats).

Feline Herpesvirus Dermatitis. See Disorders of Cats.

Papillomaviruses. Papillomaviruses are typically species-and site-specific pathogens that infect the squamous epithelium and may infect fibroblasts, and that cause benign proliferative masses and less commonly malignant tumors. As more precise methods of papillomavirus identification have been developed, including in situ hybridization, PCR, and DNA sequencing, increasing numbers of papillomaviruses and papillomavirus-associated lesions have been identified. Papillomavirus may infect squamous epithelium and fibroblasts; however, with the rare exception of bovine papillomavirus 2, reproduction occurs exclusively in keratinocyte nuclei, and complete virions are produced only in squamous epithelium. It has recently been shown that bovine papillomavirus 2 can replicate in other epithelia such as transitional epithelium of bladder and chorionic epithelium of placenta, and possibly also in lymphocytes.

has been identified in these lesions in cats, suggesting a nonproductive infection promotes the epithelial hyperplasia characteristic of this disease. The papillomaviruses identified in some of these lesions have homology with human papillomaviruses, but feline papillomavirus 2 is thought to be the most likely and most common etiologic agent. Multicentric squamous cell carcinoma in situ clinically consists of sharply demarcated single, or more often multiple, scaly verrucous or irregular plaquelike lesions 0.5 to 3.0 cm in diameter that may develop in pigmented or nonpigmented skin. Histologically, the epidermis and follicular infundibulum are thickened by proliferation of basal keratinocytes that tend to stream together, providing a "windblown" appearance to the epidermis. Nuclei are often varied in size with hyperchromatic nuclei, large nucleoli, and numerous mitoses, some of which are located above the basal layer. The basement membrane, at the time of histologic examination, is intact. Most lesions remain as "in situ" carcinomas indefinitely, but an occasional lesion has progressed to invasive basal cell carcinoma or invasive squamous cell carcinoma.

Some types of papillomaviruses, particularly bovine papillomaviruses 1 and 2, can infect fibroblasts and cause fibropapillomas, flat, verrucous, or nodular masses in which the proliferation of dermal fibroblasts is the prominent feature, often surpassing that of the epidermal hyperplasia ( Fig. 17-45 ). Fibropapillomas occur in horses, mules, donkeys, cattle, sheep, and cats. These lesions in horses are called sarcoids, which are thought to represent a nonproductive infection by bovine papillomaviruses 1 and 2. Equine sarcoids are locally aggressive, nonmetastatic fibroblastic skin tumors of horses, in certain breeds of dogs (miniature schnauzers, pugs, and Shar-Peis) or in other breeds of dogs that are immunosuppressed. Numerous novel papillomaviruses have been detected in some of these plaques. Clinical lesions occur most commonly on the ventral abdomen, groin, ventral thorax, or neck and consist of variably irregular, pigmented macules, or plaques. Histologically, the lesions are sharply demarcated, hyperkeratotic foci, or plaques with pigmented, acanthotic epidermis, and large keratohyalin granules. Canine viral plaques do not regress, are slowly progressive, and occasionally develop into a squamous cell carcinoma. Feline viral plaques are usually multiple, ovoid, slightly raised pigmented or nonpigmented, and slightly scaly and rough plaques less than 8 mm in greatest dimension. Papillomaviruses have been detected in the lesions, and feline papillomavirus 2 is the virus most often identified, suggesting this papillomavirus is the likely etiologic agent. Histologically, there is an abrupt transition between normal epithelium and the plaque, which consists of epidermis thickened by hyperkeratosis, hypergranulosis, and acanthosis. Keratohyalin granules may be enlarged, and koilocytes (keratinocytes with clear cytoplasm and pyknotic nuclei) and cytoplasmic pseudoinclusions may be present. Malignant transformation commonly occurs; lesions resemble the bowenoid in situ carcinoma (see next paragraph).

Papillomavirus infection also has been implicated in the development of another syndrome in cats and less often in dogs termed multicentric squamous cell carcinoma in situ (bowenoid in situ carcinoma, Bowen's disease). Although not all the factors contributing to lesion formation have been documented, papillomavirus DNA C CHAPTER 17 The Integument slower growing, less aggressive forms of sarcoid can become more proliferative and aggressive if traumatized, including the trauma of biopsy sampling, and can transform into a more aggressive clinical form. Therefore it is usually recommended before considering biopsy sampling, that a treatment plan be established if the diagnosis of equine sarcoid is confirmed histologically. No treatment protocol has been universally effective, so it is not possible to ensure that the lesion will remain harmless or can be successfully treated.

Histologically, sarcoids are typically biphasic tumors composed of both epidermal and dermal components; however, the epidermal component may be minimal or absent in some tumors, especially those with extensive ulceration. When the epidermis is intact, hyperkeratosis, parakeratosis, and acanthosis with thin rete pegs extending deep into the dermis are common features. The dermal component consists of fibroblasts and collagen in various proportions. The fibroblasts have plump nuclei, and nucleoli may be prominent. The mitotic index is usually low. Fibroblasts at the dermal-epidermal junction are frequently oriented perpendicular to the basement membrane in a "picket fence" pattern, which is a distinctive histologic feature seen in most sarcoids. The cells are arranged in whorls, interlacing bundles, or haphazard arrays of variable density. Tumor margins are typically indistinct, and adequacy of excision is frequently difficult to determine histologically. Spontaneous remission is uncommon. The tumors are characterized by a high rate of recurrence, up to 50%, after surgical excision alone, and additional therapies (e.g., cryotherapy, chemotherapy, immunotherapy, and others) are often recommended or necessary in an attempt to prevent recurrence. Feline fibropapillomas (also called sarcoids) are similar morphologically to the equine lesion and also likely represent a nonproductive infection with a papillomavirus resulting from a cross-species infection by a bovine papillomavirus. Affected cats often live in rural areas and have had exposure to cattle. Bovine fibropapillomas are caused by bovine papilloma virus 1 (teats, penis) or bovine papillomavirus 2 (head, neck, shoulder, legs, and teats) and occur in young animals. The lesions generally spontaneously regress within 1 to 12 months.

Papillomaviruses, some as yet to be identified by type, have been found in equine, canine, and feline invasive squamous cell carcinoma. However, the presence of the virus in the tumors does not allow differentiation between actual induction of the tumor and mere infection of the tumor. Further work to characterize the types of papillomaviruses and the role the viruses play in epidermal hyperplasia and neoplasia is necessary.

Information on this topic is available at www.expertconsult.com.

The portals for entry of bacteria into the skin include pores (follicular openings), hematogenous spread, or direct entry through damaged skin. Cutaneous bacterial infections vary in location (e.g., epidermis, dermis, subcutis, adnexa, or systemic), morphologic characteristics (e.g., pyogenic, granulomatous, or necrotizing), distribution (e.g., focal, multifocal, regional, mucocutaneous, haired skin, or interdigital), and severity (e.g., mild and asymptomatic to severe with systemic signs). The variation is caused by the specific organism involved, predisposing or coexisting factors, and host-immune response. The so-called superficial and deep bacterial infections are frequently pus-producing infections (pyogenic) and are thus referred to as pyodermas. In contrast, bacterial granulomas are characterized by an abundance of macrophages and are usually caused by traumatic implantation of bacteria that generally are saprophytes of low virulence. Systemic bacterial infections or localized infection with mules, and donkeys. They are the most common skin tumor of horses, accounting for 35% to 90% of tumors in numerous surveys, and occur in any breed, sex, or age. Young adult horses 3 to 6 years of age are most commonly affected. Although sarcoids do not metastasize and typically are not life-threatening lesions, they compromise the value of horses because of their infectious and progressive nature, and depending on their anatomic location, can compromise the use of the horse. Sarcoids frequently develop in areas subjected to trauma or at sites of wounds that occurred 3 to 6 months previously, and they develop anywhere but are most common on the head, legs, and ventral trunk. They can be single or multiple. Sarcoids are clinically subclassified as occult, verrucous, nodular, fibroblastic, mixed, or a more aggressive type (called malignant or malevolent). The occult form consists of a slow-growing, slightly thickened area of skin with slight surface roughening and alopecia that remains static for a long period. The verrucous type is usually a slow-growing, small wartlike growth, often measuring less than 6 cm in diameter, with a dry, irregular (verrucous) surface and variable alopecia. Nodular sarcoids are firm dermal or subcutaneous, often circumscribed masses with a nonulcerated surface. The fibroblastic type of sarcoid (referred to as "proud flesh sarcoid") usually has a raised ulcerated surface prone to hemorrhage and resembles exuberant granulation tissue. The mixed sarcoid has more than one clinical form and is often seen in long-standing lesions or those subject to repeated trauma. The mixed sarcoids can become more clinically aggressive as more fibroblastic transformation occurs. The "malignant or malevolent" sarcoid is deeply invasive and aggressive. The 

Cutaneous lesions are seen with foot-and-mouth disease (picornavirus), vesicular stomatitis (rhabdovirus), swine vesicular disease (picornavirus), vesicular exanthema (calicivirus), and malignant catarrhal fever (herpesvirus) (see Table 17 -10; see also Chapters 4 and 7). A few cats with FeLV infection have developed dermatitis characterized by epidermal and follicular infundibular acanthosis with epidermal giant cells and individually shrunken and degenerate keratinocytes suggestive of apoptotic cells. Hyperkeratosis, crusts, and secondary bacterial infection may develop. In addition, a few FeLV-infected cats have also developed one or more localized areas of marked compact hyperkeratosis of the pawpads that clinically resemble "horns" (cutaneous horns). In immunohistochemically stained sections the hyperplastic epidermis in cases with epidermal giant cells is strongly positive for FeLV antigens. Both FeLV and feline immunodeficiency virus (FIV), because of their immunosuppressive capabilities, can cause cats to be susceptible to chronic skin infections, including abscesses, paronychia, and demodicosis.

Feline calicivirus, usually the cause of upper respiratory infection and oral ulcers with high morbidity but low mortality, rarely produces cutaneous ulcers. More recently, hypervirulent systemic strains of feline calicivirus with mortality rates between 30% and 60% have been reported to affect kittens, and adult cats vaccinated against feline calicivirus. These strains cause alopecia, cutaneous ulcers, and subcutaneous edema. The pathogenesis involves lysis of epithelial cells of the epidermis, follicles, oral mucosa, bronchioles, alveoli, and exocrine pancreas, in addition to lysis of endothelial cells. The lysis of epithelial and endothelial cells leads to necrosis, edema, Multifocal cutaneous papular to nodular lesions are rarely reported in cats affected with the clinical syndrome of feline infectious peritonitis (FIP). Although the pathogenesis of FIP remains unclear, essential requirements for development of FIP lesions include infection with a virulent (mutated) form of feline coronavirus (virulent FCoV), replication of the virus in monocytes, and activation of virus-infected monocytes. Host-associated factors including age, breed, sex, reproductive status, and immunologic response also play a significant role in the development of the disease. Histologic lesions consist of multifocal pyogranulomatous to mixed cellular perivasculitis, sometimes vasculitis or phlebitis, and folliculitis. Immunohistochemical evaluation for FCoV within intralesional macrophages confirms the diagnosis. fibrin exudation, and thrombosis from vascular injury and release of inflammatory mediators from damaged cells. Clinical lesions include ulcers of the nose, lips, pinnae, feet, and oral mucosa; variable alopecia of limbs and ventrum; and subcutaneous edema, especially of the limbs and face. Systemic signs of fever, anorexia, icterus, red and swollen conjunctival mucosa, and nasal or ocular discharge are present. The most consistent microscopic lesions are epithelial necrosis with subsequent ulceration of the skin and oral and nasal mucosa. Vascular injury consists of edema, microthrombosis, and fibrin exudation. Bronchointerstitial pneumonia and necrosis of the liver, pancreas, spleen, and lymph nodes are present in some cats. In contrast to infection with the more common and less virulent field strains of feline calicivirus, the systemic hypervirulent strains cause more severe disease in adult cats than kittens.

folliculitis is discussed in the section on Superficial and Deep Bacterial Folliculitis and Furunculosis and Deep Pyoderma.

Superficial Pustular Dermatitis. Superficial pustular dermatitis, typically caused by staphylococci, encompasses several syndromes, including impetigo in a variety of animal species, exudative epidermitis in pigs (see Disorders of Pigs), and superficial pyoderma in dogs (see Disorders of Dogs). Pathogenicity may correlate with various proteins and toxins produced by the bacteria and thought to act as virulence factors. One of the factors that has come under recent scrutiny includes the exfoliative toxins. These toxins have been isolated from strains of S. aureus in human beings with impetigo, an acute contagious superficial bacterial skin infection that usually affects children and is characterized by vesicles and pustules that form yellowish crusts. In addition, similar exfoliative toxins have been identified as a source of another skin condition usually affecting infants and children, termed staphylococcal scalded-skin syndrome, that is typified by generalized blisters and superficial exfoliation of the stratum corneum. In impetigo and staphylococcal toxin-producing bacteria are often most severe because of vascular damage or the presence of endotoxins or exotoxins that have systemic consequences. The most common bacterial infections of the skin are listed in Box 17-8.

Bacterial skin disease is seen much more frequently in dogs than other domestic species, possibly the result of the thin stratum corneum with small amount of lipids, lack of a protective lipid seal at opening of the canine hair follicles, and the relatively high pH of canine skin. Until recently Staphylococcus intermedius had been considered the cause of most cases of pyoderma in dogs. However, recent molecular studies involving multilocus gene sequencing have revealed that bacterial isolates phenotypically consistent with S. intermedius consist of three separate species (considered to be the S. intermedius group), which include S. intermedius, S. pseudintermedius, and Staphylococcus delphini. S. pseudintermedius is now considered to be responsible for most cases of pyoderma in dogs, which presents most often as inflammation of the superficial segment of the hair follicle. Coagulase-positive staphylococci are also the most common bacteria isolated from pyoderma in horses (Staphylococcus aureus, S. intermedius), in cattle and sheep (S. aureus), and in goats (S. aureus). Molecular studies will likely be required to identify the species involved in some of these infections, particularly those of the S. intermedius group. Staphylococcus hyicus causes exudative epidermitis in piglets and has been associated with superficial pyoderma in several other species. Many other bacteria can cause skin infections. D. congolensis is responsible for superficial pyoderma in many species. Many Gram-negative bacteria are opportunistic pathogens that can invade already diseased or compromised skin.

Staphylococci, especially in dogs, but also in other domestic animals, including horses, have become increasingly resistant to a variety of antibiotics (methicillin-resistant and multidrug resistant), which has led to a limited range of treatment options, resulting in increased morbidity, mortality, and cost of therapy. In addition, concern is developing regarding potential transmission of antimicrobial-resistant strains of bacteria from animals to human beings and vice versa. Therefore it is important to recognize bacterial infections early and manage them appropriately to avoid increasing the prevalence of antimicrobial-resistant strains of bacteria that adversely affect animal and human health and to which treatment options are becoming limited. Superficial Bacterial Infections (Superficial Pyodermas). Superficial bacterial infections (superficial pyodermas) involve the epidermis and the upper infundibulum of hair follicles, usually heal without scarring, and usually do not involve the regional lymph nodes. Gross lesions include erythema, alopecia, papules, pustules, crusts, and peripheral expanding rings of scale also called "epidermal collarettes" (see Table 17 -6). The early microscopic feature of superficial bacterial infection that involves the epidermis is intraepidermal pustular dermatitis. The intraepidermal pustules are fragile and can rupture, leading to crust and superficial scale formation. The major microscopic feature of superficial bacterial infection that involves the follicles is superficial suppurative luminal folliculitis. The cellular infiltrate in and around hair follicles plus dermal congestion and edema correspond to the clinically evident papules and follicularly oriented pustules. Follicular injury leads to alopecia. Although Gram-positive cocci, such as Staphylococcus spp., are usually the cause of the superficial bacterial infections, the bacteria are not always demonstrable histologically, but their presence is often suspected when pustular or luminal exudates contain poorly preserved neutrophils. Predisposing factors, such as allergy, seborrhea, and immune deficiency, and other causes of follicular inflammation or dysfunction often play a role. Superficial bacterial Box 17-8 Cutaneous Bacterial Infections CHAPTER 17 The Integument epidermis by the Dermatophilus "zoospore." The organism also synthesizes various products, including enzymes such as proteases, keratinases, and ceramidase, that may have a role in virulence and pathogenesis.

When D. congolensis overcomes the barriers of the skin, the invasive filamentous form grows by subdividing longitudinally and transversely in the ORS of the hair follicle and superficial epidermis (see Fig. 17-46) . These bacteria stimulate an acute inflammatory scalded-skin syndrome, the exfoliative toxins produced by virulent forms of S. aureus cause the loss of adhesion of keratinocytes in the superficial epidermis. These toxins are glutamate-specific serine proteases that cleave a single peptide bond in desmoglein 1, present in the extracellular protein core of the desmosome. The separation of these superficial keratinocytes results in intraepidermal splitting and initiation of lesion development in these infections. In impetigo the S. aureus that produces exfoliative toxins can be isolated from the intact pustules. In contrast, in staphylococcal scalded-skin syndrome, cultures from intact vesicles usually are negative for exotoxinproducing S. aureus, and it appears that the exfoliative toxins are produced in a distant area of infection and reach the skin via the bloodstream (a process called toxemia). Investigative studies in two domestic species (pigs and dogs) suggest that a similar pathogenic mechanism involving exfoliative toxins may play a role in development of superficial pustular dermatitis caused by staphylococci. For example, it has been shown that S. hyicus, which causes exudative epidermitis in piglets, produces an exfoliative toxin that can cleave pig desmoglein 1 and produce cutaneous exfoliation similar to that in pigs with exudative epidermitis. Similarly, an exfoliative toxin isolated from strains of S. pseudintermedius from dogs with pyoderma has caused cutaneous exfoliation when injected into the skin of dogs. In addition, the exfoliative toxin gene has been identified in S. pseudintermedius isolated from skin, wound, and ear infections in dogs, suggesting a role for the toxin in pathogenicity. Although the exfoliative toxins in canine pyoderma have not been fully characterized, these findings suggest that some strains of Staphylococcus spp. in dogs and S. hyicus in pigs may cause superficial bacterial infections via a pathologic mechanism involving exfoliative toxins. Further studies are necessary to determine if exfoliative toxins or other virulence factors contribute to the development of superficial pyoderma in other species.

Impetigo. Impetigo is observed most commonly in cows, ewes, does, and dogs and is usually caused by coagulase-positive Staphylococcus sp. Predisposing factors, such as cutaneous abrasions, viral infections, increased moisture, and poor nutrition, may contribute. Lesions of impetigo in cows, does, and ewes occur predominantly on the ventral abdomen, perineum, medial thigh, vulva, ventral tail, teats, and udder. In dogs, lesions are largely in nonhaired ventral skin. Prepubescent puppies are usually healthy otherwise, but older dogs with impetigo often have underlying disease, including immunosuppression associated with hyperadrenocorticism. Gross lesions consist of nonfollicular pustules that develop into crusts. The microscopic lesion is a nonfollicular neutrophilic subcorneal pustule. In bullous impetigo, a more severe condition occurring in older dogs with underlying disease, the lesions are large interfollicular flaccid pustules (bullae) that when ruptured lead to more extensive loss of the superficial epidermis. Acantholytic cells may be present in the pustules, probably the result of the cleavage of desmoglein 1 by the exfoliative toxin, thus requiring differentiation between impetigo and pemphigus foliaceus (see Fig. 17-15 ). The presence of coccoid bacteria within intact pustules can help provide support for a bacterial origin of the lesions. Perivascular to interstitial neutrophilic to mixed mononuclear dermal inflammation is present.

Dermatophilosis (Streptothricosis). Dermatophilosis, caused by D. congolensis, is characterized by crusty cutaneous lesions (Fig.  17-46) and occurs in horses, cattle, and sheep more often than goats, pigs, dogs, or cats. The bacterium is transmitted by carrier animals and is more common in tropical and subtropical climates and during wet weather, thus the layman's term rain rot. Lesions tend to develop on the dorsum of the back and distal extremities and after epidermal irritation from ectoparasites, trauma, or prolonged wetting of the skin, hair, or wool, which allows penetration of the damaged 

Pastern Dermatitis). Early thorough clinical evaluation and sometimes microbiologic or histopathologic evaluation may be required to differentiate staphylococcal folliculitis affecting the skin of the pastern from equine pastern dermatitis and other conditions that may affect the skin of the pastern area.

In adult sheep, lesions develop on the face, especially around the eyes, or on the limbs or teats. In otherwise healthy lambs, mild lesions develop most commonly on the lips and perineum and usually spontaneously regress. In goats the face, pinnae, distal limbs, and glabrous areas of the udder, ventral abdomen, medial thighs, and perineum are most commonly affected.

In dogs, lesions are localized or generalized and develop on the dorsal nose, pressure points, interdigital areas, and chin. Other cutaneous areas can also be affected, especially if predisposing conditions (e.g., follicular dysplasia, cornification disorders, or demodicosis) are present. Deep pyoderma of adult German shepherd dogs (German shepherd folliculitis, furunculosis, and cellulitis) is a unique deep pyoderma with an apparent genetic predisposition. Lesions are located on the dorsal lumbosacral, ventral abdominal, and thigh areas. Hypersensitivity to the bites of fleas or alterations in immune or neutrophil function have been proposed as predisposing causes, but most of these potential causes have been discounted. Deep folliculitis and furunculosis, especially on the cheek area or neck of some large-breed dogs (golden and Labrador retriever, Saint Bernard, and Newfoundland), can clinically resemble superficial pyotraumatic dermatitis (acute moist dermatitis), belying the deep nature of the lesions.

Postgrooming furunculosis is an uncommon but acute, severe, and painful form of furunculosis in the dog that is believed to be associated with grooming. A variety of bacteria have been cultured from lesions, including S. pseudintermedius, Pseudomonas aeruginosa, E. coli, and Proteus sp.

Grossly the lesions of superficial folliculitis include papules, crusted papules, pustules, epidermal collarettes, and alopecia. Hair follicle involvement by pustules may be difficult to appreciate macroscopically. Multifocal to coalescing patches of alopecia resulting in a "moth-eaten" appearance to the hair coat may be the only visible lesions of superficial bacterial folliculitis, especially in shortcoated breeds of dog. Deep folliculitis can have similar lesions plus hemorrhagic bullae, nodules, and draining sinuses. The microscopic patterns include superficial or deep luminal folliculitis, pyogranulomatous furunculosis, draining sinuses, and occasionally panniculitis. Microscopic lesions include suppurative luminal folliculitis with follicular distention often in conjunction with furunculosis. Pyogranulomatous dermatitis in response to release of follicular contents is often severe and may efface the dermal architecture, extend into the deep dermis and panniculus, and form sinuses that drain to the surface. Scarring can lead to loss of adnexal structures and permanent alopecia localized to affected skin. Subcutaneous Abscesses. Subcutaneous abscesses are localized collections of purulent exudate located within the dermis and subcutis. Abscesses are common in cats because of the frequency of bacterial contamination of puncture wounds. Abscesses also are common in large animals. In addition to puncture wounds, other predisposing causes include foreign bodies, injections, and shearing and clipping wounds. Granulation tissue or mature fibrous connective tissue borders the exudate. Subcutaneous abscesses frequently rupture and drain spontaneously, and heal by scarring. A wide variety of bacteria can cause subcutaneous abscesses. Commonly isolated bacteria include Pasteurella multocida (dog and cat bite wounds), C. pseudotuberculosis (horses, sheep, and goats), and Trueperella (Arcanobacterium) pyogenes (cattle, sheep, goats, pigs). Other response in which neutrophils migrate from superficial vessels into the dermis and through the epidermis to form intraepidermal microabscesses. The inflammation inhibits further penetration of the bacterium into the dermis. However, residual bacterial organisms subsequently invade the newly regenerated epidermis. Thus repeated cycles of bacterial growth, inflammation, and epidermal regeneration result in the formation of the stratified pustular crusts. Grossly, lesions consist of papules, pustules, and thick crusts that can coalesce and mat the hair or wool (see Fig. 17-46) . The microscopic lesions consist of hyperplastic superficial perivascular dermatitis with stratified crusts of alternating layers of stratum corneum, proteinaceous fluid, and neutrophils covering the skin surface. Samples of crusts obtained by biopsy are necessary to identify organisms and make a definitive diagnosis. Human infections have been reported after contact with affected animals, so dermatophilosis may be considered a potential zoonosis.

Ovine In horses, lesions develop most commonly in association with tack, especially on the skin of the saddle area, the tail, or the caudal aspect of the pastern (proximal interphalangeal articulation) or fetlock (metacarpophalangeal articulation). Staphylococcal folliculitis and furunculosis of the pastern or fetlock may involve one or more legs and is a differential diagnosis for the multifactorial syndrome of equine pastern dermatitis (see Disorders of Horses, Equine CHAPTER 17 The Integument Mycobacterial infection is more common with the rapidly growing opportunistic mycobacteria (also called atypical mycobacteria), and infections are more common in cats, in which lesions are characterized by recurrent nodules, with draining sinuses frequently located in the dermis and subcutis of the inguinal area. The microscopic lesions are characterized by pyogranulomatous inflammation. Organisms are more often found extracellularly in vacuoles sometimes lined by neutrophils (Fig. 17-47) . Infections with the slowgrowing, opportunistic mycobacteria are more commonly disseminated (not limited to the skin) and resemble those caused by M. tuberculosis.

In cattle, cutaneous infections with opportunistic mycobacterial organisms, historically called skin tuberculosis, occur as single or multiple nodules 1 to 8 cm in diameter in the dermis and subcutis, particularly of the lower legs. But lesions can spread to the thighs, frequently isolated bacteria include β-hemolytic streptococci, Fusobacterium sp., Peptostreptococcus sp., Bacteroides sp., Staphylococcus sp., and Clostridium sp. Less often, abscesses can develop from a noninfectious cause such as injection of sterile material.

Cellulitis. Bacterial cellulitis, in contrast to an abscess, is a poorly delineated suppurative bacterial infection of the dermis and subcutis that dissects and spreads through surrounding soft tissues. The affected skin is often swollen, erythematous, and warm and may become devitalized and slough. The bacteria can cause a foul odor and some, such as Clostridium sp., can produce subcutaneous gas bubbles (subcutaneous emphysema). Cellulitis may be accompanied by fever and enlargement of regional lymph nodes. Histologic lesions consist of poorly delineated areas of purulent to pyogranulomatous inflammation that may include hemorrhage, necrosis, and thrombosis. Bacteria may be visible histologically. As with subcutaneous abscesses, the source of the infection is usually a penetrating wound in the area of infection. A variety of bacteria, including those found in subcutaneous abscesses, can cause cellulitis. A rare but particularly severe subtype of cellulitis, termed necrotizing fasciitis, has been described most often in the dog in association with Streptococcus canis infection (see later discussion of infection with toxinproducing bacteria).

Bacterial granulomatous dermatitis is usually caused by traumatic implantation of bacteria, which are generally saprophytes of low virulence. Causative organisms usually stimulate a strong cellmediated immune response by persisting as an antigen in the tissue. Grossly, lesions are slowly progressive, nodular or diffuse, and can ulcerate and drain through the surface of the skin via sinuses. Microscopic lesions consist of mixed populations of inflammatory cells, especially macrophages; thus lesions are granulomatous to pyogranulomatous. Multinucleated giant cells and caseous necrosis are present in some lesions. Causal agents can be present in macrophages, exudate, or in clear spaces or fat vacuoles within tissue but are often in such low numbers that they are difficult to identify in histologic sections.

Mycobacterial Granulomas. Mycobacterial organisms produce granulomatous to pyogranulomatous dermatitis and panniculitis in many species of animals, particularly cats and less frequently in other diagnoses of botryomycosis include infections with filamentous bacteria that cause similar nodular masses (actinomycotic mycetomas) and nodular masses caused by fungi (eumycotic mycetomas). Filamentous bacteria also cause bacterial granulomatous dermatitis with granules bordered by Splendore-Hoeppli material and are differentiated from botryomycosis by Gram staining and culture. The bacteria are introduced through traumatic injury; are Grampositive, filamentous, and branching; and include various species of Nocardia and Actinomyces. Other actinomycetes (e.g., Actinomadura, Streptomyces) can also contribute. The granules contain mycelial filaments that are 1 µm or less in diameter. Nocardia spp. have a limited tendency to clump together; thus they typically do not form granules. The clinical lesions are progressive nodular cutaneous and subcutaneous masses, often with draining sinuses, which can extend into and involve underlying bone. These nodular masses are called actinomycotic mycetomas. Histologic lesions are nodular areas of granulomatous inflammation with abundant fibrosis and embedded bacterial colonies bordered by Splendore-Hoeppli material. Histologic differential diagnoses include botryomycosis and mycetomas caused by fungi (see the discussion of eumycotic mycetomas in the Subcutaneous Mycoses). A classic example of actinomycotic mycetoma in cattle is the so-called lumpy jaw, wherein the infection begins via traumatic implantation of Actinomyces bovis into the mandibular mucosa (rather than skin), which progresses to involve mandibular bone (see Chapter 16).

or Infection with Toxin-Producing Bacteria. Systemic bacterial infections can cause skin lesions in animals by bacterial embolization to the skin during sepsis, toxin production, direct infection of vascular endothelial cells, or precipitation of immune-complex disease. In some infections, more than one mechanism is involved. Lesions often reflect vascular damage, specifically vasculitis and thrombosis. Cutaneous lesions caused by E. rhusiopathiae (erysipelas) and septicemic salmonellosis are discussed under Disorders of Pigs.

Toxic Shock Syndromes. Recently conditions that resemble toxic shock syndrome in human beings have been described rarely in dogs and more rarely in other domestic species. In human beings, toxic shock syndrome is an acute febrile illness that results in hypotension, shock, an extensive cutaneous rash, and involvement of three or more visceral organ systems. The pathogenesis involves the release of bacterial exotoxins (e.g., toxic shock syndrome toxin 1 and enterotoxins) produced by certain strains of S. aureus that usually cause minor or occult infections. The exotoxins act as superantigens and thus do not need to be processed by antigen-presenting cells to cause T lymphocyte activation. As a result, substantial numbers of T lymphocytes are activated in a short period of time, subsequently causing release of proinflammatory cytokines, including TNF-α, IL-2, IL-1, and INF-γ, which are thought to cause the tissue damage and signs of toxic shock syndrome. Less commonly, group A streptococci are the cause of toxic shock syndrome. However, in contrast to the minor or occult infections associated with S. aureus toxic shock syndrome, the streptococcal toxic shock syndrome is usually associated with bacteremia and severe necrotizing fasciitis (inflammation of the subcutaneous fat and fascial planes). The involved streptococci produce pyrogenic exotoxin A, which has similarities to toxic shock syndrome toxin 1 and is thought to contribute to the development of the syndrome.

As in human beings, two types of toxic shock-like syndrome occur in dogs. In one, S. canis is usually the cause of a severe localized infection in the skin or another site (e.g., lung or urogenital tract) with presumed release of bacterial toxins that cause severe secondary systemic shock. Clinically, the skin lesion, termed proximal forelimbs, shoulders, and abdomen through skin lymphatics. The skin of the udder is sometimes involved. The lymph nodes are unaffected. The causative organisms are thought to be saprophytic atypical mycobacteria that probably enter through cutaneous abrasions. In most of these infections, the specific mycobacteria have not been identified by culture, but M. kansasii has been identified in a few cases. A more appropriate name for this condition is bovine cutaneous opportunistic mycobacteriosis. Clinical lesions are either firm or fluctuant nodules connected by thin cords of tissue that represent inflamed lymphatic channels (lymphangitis). The firm nodules consist of pyogranulomatous inflammation with fibrosis and sometimes mineralization. The fluctuant nodules are thickwalled abscesses that can ulcerate, rupture, and drain thick, tan exudate. Small lesions can spontaneously resolve, but larger lesions are persistent. This disease became apparent during the time of intense tuberculosis eradication efforts because infection with these opportunistic mycobacterial organisms can cause false-positive reactions to bovine tuberculin tests. Bovine cutaneous opportunistic mycobacteriosis is much less commonly identified now, partly because the prevalence of and thus testing for bovine tuberculosis has been reduced.

Feline leprosy (see Disorders of Cats), caused by M. lepraemurium and probably other mycobacterial organisms (see later discussion) develops in cats living in cold, wet areas of the world, including the northwestern United States and Canada.

Rarely, a nodular granulomatous dermatitis caused by acid-fast bacilli develops on the head, dorsal pinnae, or other distal extremities in dogs, often with short hair coats (canine leproid granuloma syndrome). Saprophytic mycobacterial organisms transmitted via the bites of flies are thought to be the cause of the syndrome. The dogs are healthy otherwise, and cultures are negative.

Cutaneous infections caused by M. tuberculosis and M. bovis are rare; alimentary and pulmonary infections are more common, but skin infections can develop alone or in combination with disseminated infection. Tentative diagnosis of mycobacterial infections is made by considering the animal species affected, clinical lesion appearance and location, and cytologic or histopathologic detection of acid-fast bacilli. In the past, culture was required for definitive identification of the organism involved. The acid-fast bacilli can be rare in tissue sections, especially with the saprophytic opportunistic agents, and some organisms, such as those in feline leprosy and canine leproid granuloma syndrome, are exceedingly difficult to grow on culture media; thus diagnosis is challenging. Fortunately, the need for cultural identification is being reduced by use of immunohistochemical evaluation and PCR techniques that can identify the organisms or their genetic material in tissue and can be completed within a few days. The use of genetic techniques is enhancing studies of mycobacterial diseases in human beings and animals. It is likely that taxonomy of mycobacterial diseases will be refined, based on the use of the genetic techniques.

ria. Botryomycosis is a term for a granulomatous dermatitis caused by nonfilamentous bacteria, typically Staphylococcus spp., Streptococcus spp., P. aeruginosa, Actinobacillus lignieresii, and Proteus spp. In botryomycosis, these bacteria form small yellow "sulfur" granules, which consist of centrally located bacterial colonies surrounded by radiating club-shaped bodies of homogeneous eosinophilic material termed Splendore-Hoeppli material (see Fig. 7-51) . This material is considered to be antigen-antibody complexes, tissue debris, and fibrin. Clinically, the lesions are progressive nodular masses located in cutaneous or subcutaneous areas that are composed of granulomatous inflammation with the embedded bacterial colonies bordered by the Splendore-Hoeppli material. Histologic differential develop secondary to gastrointestinal or respiratory systemic infections or as a primary disease that begins in the skin (cutaneous anthrax). The cutaneous lesions that develop secondary to gastrointestinal or respiratory anthrax result from systemic vascular damage and include extensive edematous swellings and hemorrhages that occur in dependent areas of the neck, ventral thorax and abdomen, perineum, external genitalia, and shoulders in more susceptible species such as ruminants and horses, and in face and neck regions of less susceptible species such as pigs and carnivores.

Cutaneous anthrax, in contrast to the other forms, results from the introduction of infective material via penetrating mechanical injury of the skin through abrasions, wounds from grass seeds, or biting flies. Horses appear to be particularly susceptible to anthrax infections introduced by biting flies. Cutaneous anthrax may develop in conjunction with outbreaks of gastrointestinal or respiratory anthrax because during outbreaks, vegetative bacteria from exudates or blood of sick or dead animals contaminate the environment and form spores. Spores (or the vegetative form) serve as an available source of infective material that may contact wounds or be transferred by biting flies. Damage to the skin is thought to be important in initiating cutaneous anthrax, which appears clinically in two basic patterns: (1) edematous swellings (horses, cattle, sheep) or (2) rarely as discrete, necrotic areas termed "carbuncles" that resemble the more typical lesions of cutaneous anthrax in human beings (cattle, rarely dogs). In domestic animals, edematous swellings in the skin may therefore develop secondary to systemic disease or from primary skin infection. Because the route of infection is not always established, the pathogenesis and significance of cutaneous lesions of anthrax in domestic animals are not always clear. However, in cattle, both edematous swellings and carbuncles of the skin have developed in immunized animals when the herd's resistance to anthrax is waning. Carbuncles also have been reported in the jowl area of dogs, a species considered to have some natural resistance to anthrax. In this example the anthrax bacillus may have been introduced into the skin during ingestion of blood containing the anthrax bacillus. Thus cutaneous carbuncles appear to develop in animals that have cutaneous contact with the anthrax spore or bacillus, and that have partial immunity to anthrax, either natural immunity or that provided via vaccination. In addition, carbuncles in cattle, when present in conjunction with edematous swellings, may help clinically to differentiate cutaneous anthrax from other diseases that cause edematous swellings in this species. Support for the hypothesis that damage to the skin facilitates cutaneous infection comes from experimental murine models of anthrax that revealed spores have limited ability to penetrate nonlesional skin, and that damage to the epidermis results in more intense infections. Damage to the epidermis appears to increase susceptibility of infection of hair follicle contents and residual epidermis, although direct dermal invasion can also occur. Subsequent invasion and proliferation of the organism in the hair follicles and epidermis is thought to facilitate the development of deeper infections.

In contrast to domestic animals, cutaneous anthrax is the most common form of the disease in human beings and accounts for over 95% of cases. Most human infections result from cutaneous contact with infective material from sick or dead animals or animal by-products. In naturally occurring cutaneous anthrax in human beings, the initial lesion is a pruritic papule that arises 3 to 5 days after infection. Edema is often extensive during early stages of the development of the lesion. The papule progresses to a hemorrhagic vesicle that ruptures and undergoes central necrosis and drying, resulting in a dark eschar (hard crust) with peripheral erythema, termed a carbuncle. The eschar dries and sloughs over a period of 1 necrotizing fasciitis, is painful, hot, and swollen, and pain is disproportionately severe relative to the size of the lesion. The subcutaneous fat, fascia, and overlying skin can become necrotic and can slough. The swelling is caused by necrosis of fat and exudate accumulating between the fascial planes (fasciitis and/or cellulitis). Histologic lesions include edema, hemorrhage, necrosis, suppurative inflammation, and thrombosis. Occasionally vasculitis and colonies of cocci are seen. The condition can rapidly lead to sepsis, multiorgan failure, and death if not treated early and aggressively. Fever or shocklike symptoms are present. With the exception of the area with necrotizing fasciitis, the skin is not otherwise affected. The diagnosis of necrotizing fasciitis is clinical and consists of severe pain disproportionate to degree of skin lesions, necrotic fascia, lack of bleeding from fascia, and lack of resistance of fascia to blunt dissection during surgery.

The second type of toxic shock-like syndrome has been described in dogs without concurrent necrotizing fasciitis. This syndrome has distinct clinical and histologic similarities to the staphylococcal toxic shock syndrome in human beings, but the site of infection and production of exotoxin have not yet been documented. The dogs are depressed, febrile, and anorectic. The clinical skin lesions include generalized macular erythema predominantly involving the head, trunk, and legs. Some dogs also have edema of the limbs. Vesicles or pustules are seen in some dogs and can progress to crusts. Ulcers may be seen in advanced lesions. The histologic lesions are identical to those seen in the human staphylococcal toxic shock syndrome. The dogs have superficial to mid-dermal perivascular to periadnexal and interstitial neutrophilic to mixed cellular dermatitis with dermal congestion, edema, and sometimes hemorrhage. A unique feature is the presence of apoptotic keratinocytes in multiple layers of the epidermis and superficial hair follicles bordered by neutrophils or occasional eosinophils. Superficial epidermal pustules and crusts may be seen. Apoptosis may become confluent, resulting in full-thickness necrosis and ulceration of the epidermis. The syndrome can be fatal without early therapy with appropriate antibiotics.

Cutaneous Anthrax. Anthrax is caused by Bacillus anthracis, a Gram-positive, spore-forming bacterium. The mechanism of injury is acute coagulative necrosis of cells caused by bacterial toxins. Spores germinate into vegetative bacteria that develop a capsule and produce a deadly three-part exotoxin (AB toxin) that acts on cell membranes to cause vascular injury, edema, hemorrhage, thrombosis, and infarction (see Chapter 4). The capsule is a major virulence factor, the primary role of which is to establish infection. It does this by protecting the bacterium against various host bactericidal factors and phagocytosis, or if phagocytosed, against phagocyte-mediated killing. Once infection is established, anthrax toxins are produced. Anthrax toxins have three antigenic components that individually lack significant biologic activity, but when two or three of these components are combined together, the new grouping becomes highly potent.

In general the outcome of exposure to the anthrax bacterium depends on the susceptibility of the host to infection and toxins, virulence of the organism, infective dose, and route or site of infection. In natural infections of domestic animals, ruminants are considered the most susceptible animal followed by horses and pigs; dogs and cats are considered quite resistant. In domestic animals, anthrax infections occur in gastrointestinal (see Chapter 7), respiratory (see Chapter 9), and cutaneous forms. Most infections are gastrointestinal, and the usual route of infection is ingestion of soil, food, water, or animal byproducts that contain infective material (spores or vegetative bacteria). Respiratory anthrax is rare but can result from inhalation of dust contaminated with spores. Cutaneous lesions may CHAPTER 17 The Integument systemic diseases, such as diabetes mellitus or neoplasia, or in animals treated with glucocorticoids or other immunosuppressive agents or with long-term, broad-spectrum antibiotics. Superficial Mycoses. Superficial mycoses are infections restricted to the stratum corneum or hair with minimal or no dermal reaction. Piedra is a rare superficial mycosis caused by Trichosporon spp. and has been reported in horses and dogs. Lesions consist of minute swellings restricted to the extrafollicular portion of the hair shaft.

Cutaneous Mycoses. Cutaneous mycoses (also included as superficial mycoses by some authors) are infections of cornified tissue, including hair, claws, and epidermis. The fungi are usually restricted to the cornified layers and only very rarely are found in the dermis or subcutis, but tissue destruction and host response can be extensive. Infections in animals include dermatophytosis, cutaneous candidiasis, and Malassezia dermatitis.

Dermatophytoses. Dermatophytoses are fungal infections of the skin, hair, and claws of animals caused by taxonomically related fungi known as dermatophytes. Pathogenic genera include Epidermophyton, Microsporum, and Trichophyton. Dermatophytosis occurs worldwide, is the most important cutaneous (superficial) mycosis, and is common in human beings and animals, especially cats. Superficial and cutaneous mycoses (dermatophytosis) are acquired by contact with infected animals or by contact with infective material such as shed scales or hair in the environment or on fomites (e.g., combs, brushes, clippers, equine tack). Dermatophytes are able to colonize the cornified structures (hair, claws) and the stratum corneum and cause disease without ever entering living tissue. Clinical disease in a dermatophyte infection is the result of the host's reaction to the organism and its by-products. Dermatophytes are more contagious than other fungal infections, are more common in hot, humid environments, and young animals are more susceptible than adults. Animals kept in overcrowded, dirty, or damp areas and those with inadequate nutrition, or those that are immunosuppressed, are also more susceptible. It is thought that cell-mediated immune response is the principal means of resolving the infection. Fungal species that more commonly infect domestic animals are included in the genera Microsporum and Trichophyton. Epidermophyton is adapted to human beings (anthropophilic) and rarely infects animals. Zoophilic dermatophytes (e.g., Microsporum canis and Trichophyton mentagrophytes) are primary animal pathogens but can infect human beings. M. canis is so well adapted, especially in longhaired, purebred cats that inapparent infections occur. Yorkshire terriers and Persian and Himalayan cats appear to be predisposed to M. canis dermatophytosis. The source of M. canis infections is usually an infected cat. Trichophyton spp. infections are usually acquired by contact with reservoir hosts, which in the case of T. mentagrophytes are rodents or their immediate environment. Geophilic dermatophytes (e.g., Microsporum gypseum) occur in the soil as saprophytes but under favorable conditions can infect human beings and animals if the integrity of the skin is broken or the host immune system is compromised.

Dermatophytes invade cornified tissues (stratum corneum, hair shafts, and claws) by producing proteolytic enzymes (e.g., keratinase, elastase, and collagenase), which help them penetrate the cornified surface and hair cuticle, but other factors such as mechanical injury and increased humidity may facilitate penetration. Arthrospores are the typical infective portion of the organism and form by segmentation and fragmentation of fungal hyphae. They adhere strongly to keratin and germinate within hours of contact with the skin and invade the cornified tissue, and as a result, infection of the hair to 2 weeks. Histopathologic evaluation of the eschar reveals an ulcer covered by necrotic debris that replaces the epidermis and superficial dermis. The subjacent dermis and subcutis are markedly edematous with vasculitis, hemorrhage, and variable numbers of mixed leukocytes. Large rods typical of the anthrax bacillus may be identified.

The diagnosis of anthrax is generally made in animals with systemic disease, living or dead, when typical organisms are found in impression smears of hemorrhagic exudates from orifices or from blood obtained from a peripheral vein. Bacteria collected from a peripheral vein are less likely to be damaged by putrefaction. Animals suspected of having died from anthrax should not be autopsied (syn: necropsied) to avoid contamination of the environment with bacteria that rapidly form spores in favorable environmental conditions. Anthrax spores are extremely resilient and are a source of infection for animals and human beings.

Toxin-Producing Bacterial Infections from Direct Extension. Bacterial infections can also develop from direct extension of infections of deeper tissue, such as clostridial myositis and cellulitis. Clostridium novyi can cause severe cellulitis, toxemia, and death in young rams whose heads have been traumatized by butting during the breeding season. Spores in the soil gain entrance through cutaneous lacerations at the base of the horns, germinate, produce toxins (including α-toxin), and result in cellulitis and toxemia. C. novyi α-toxin causes loss of integrity of vascular endothelium with resulting severe local, painful edema, hypotension, organ failure, and death. Swelling of the head and neck result in the common term big head or swelled head. Clostridium chauvoei is a secondary invader of wounds, where spores can germinate, proliferate, and produce necrotizing and hemolytic exotoxins leading to extensive necrosis of the skin and underlying tissue (gas gangrene).

Infection with Rickettsia rickettsii. Rocky Mountain spotted fever, the most important rickettsial disease associated with cutaneous lesions, is caused by R. rickettsii, an organism that infects endothelial cells. This organism is transmitted by ticks, mainly Dermacentor andersoni and Dermacentor variabilis. The disease is seasonal, corresponding with the increased activity of ticks and contact with ticks. In addition to systemic signs, affected dogs have cutaneous, ocular, genital, and oral erythema with petechiae, edema, necrosis, and ulceration as a result of the direct endothelial cell damage and vasculitis caused by the rickettsia. 

Mycotic infections have been classified into four basic categories: superficial, cutaneous, subcutaneous, and systemic (Box 17-9). Ability to mount an inflammatory response is paramount to clearing the infection. Mycotic infections tend to occur more often in animals with compromised resistance because of debilitating Gross lesions in haired skin are often circular or irregularly shaped, scaly to crusty patches of alopecia (Fig. 17-48) , which can coalesce to involve large portions of the body. Fungi tend to die in areas of inflammation in the center of lesions but are viable at the periphery, thus giving rise to the peripheral red ring and the term ringworm. Hair loss is caused by breakage of hair shafts and loss of hair shafts from inflamed follicles. Follicular papules and pustules can be present. In animals with severe furunculosis, the inflammation can extend into the deep dermis and subcutis, leading to draining sinuses. Microscopic patterns include perifolliculitis, luminal folliculitis, or furunculosis and epidermal hyperplasia with intracorneal microabscesses. In many lesions, septate hyphae or spores are present in hair shafts and in the stratum corneum of the epidermis or follicles (see Fig. 17-48, B) . Culture and evaluation of macroconidia from the cultured mycelial surface identify the organism involved. Although infections in many animals spontaneously resolve in 3 months, specific therapy is often recommended for affected animals to decrease infective material (scales and hairs) shed into the environment.

Candidiasis. Candidiasis is a yeast infection caused by Candida sp., normal inhabitants of the skin and gastrointestinal tract (see Figs. 7-7 and 7-8). Infection occurs when host resistance is compromised. Infections with Candida sp. are rare in domestic animals and usually occur on mucous membranes and at mucocutaneous junctions. Gross lesions consist of exudative and pustular to ulcerative inflammation of the lips (cheilitis), oral mucosa (stomatitis), and external ear canal (otitis externa). Microscopic lesions consist of spongiotic neutrophilic pustular inflammation, parakeratosis, and ulceration with exudation. The yeast organisms are present in the superficial exudates. Culture identifies the organism involved.

Malassezia Dermatitis. Malassezia infections are seen most commonly in dogs and cats and are usually caused by Malassezia pachydermatis (Pityrosporum canis), a lipophilic, but non-lipiddependent yeast that is considered to be a commensal organism in dogs and cats and can be isolated from the normal external canal, skin, anal sacs, and mucosal surfaces. M. pachydermatis lives in the stratum corneum and becomes a pathogen when predisposing factors alter host cutaneous microenvironment, epidermal barrier, or immune system. These include increased heat and humidity,

Trichosporon spp.

Dermatophytes Microsporum canis Microsporum gypseum Trichophyton mentagrophytes Candida spp. Malassezia spp. in furunculosis. Bacterial infection increases the severity of the folliculitis and furunculosis. Gross and microscopic lesions are highly variable and range from an asymptomatic infection to an eruptive nodular mass (kerion), to deep granulomatous nodular dermal and subcutaneous masses containing distorted fungal hyphae (pseudo-dermatitis with or without thymoma, diabetes mellitus, and FIV infection.

Because surface scale and Malassezia spp. can be lost during tissue processing, cytologic evaluation is often a more reliable method of detecting and enumerating yeasts, and culture is rarely needed. Because Malassezia spp. can be identified in normal skin and because they may be seen in association with other disease processes, the role of Malassezia spp. in causing or contributing to the skin disease must be interpreted in regard to clinical findings and may ultimately rest with response to treatment. Subcutaneous Mycoses. Subcutaneous mycoses are caused by fungi that, after traumatic implantation, invade cutaneous and subcutaneous tissue. Some infections remain localized, but others spread to the lymph vessels. Diseases in this category include eumycotic mycetomas, dermatophyte pseudomycetoma, subcutaneous phaeohyphomycosis, subcutaneous hyalohyphomycosis, sporotrichosis, subcutaneous entomophthoromycosis, and oomycosis (pythiosis and lagenidiosis, not true fungi). The gross appearance of subcutaneous mycoses and deep granulomatous infections caused by bacteria are similar, usually one or more ulcerative nodules, sometimes with draining sinuses. Microscopically the lesions of subcutaneous mycoses consist of nodular to coalescing, suppurative, pyogranulomatous, or granulomatous inflammation. Culture identifies the organism involved; however, some fungi, especially those that are considered "dimorphic," meaning they grow as molds at room temperature and yeast at human body temperature, can be dangerous to culture in routine microbiology laboratory settings because the mycelial phase is infective to human beings. Examples of dimorphic fungi include some species in the genera Sporothrix, Histoplasma, Blastomyces, and Coccidioides. If these organisms are suspected clinically, laboratory personnel should be notified when cultures are submitted.

Eumycotic Mycetomas. Eumycotic mycetomas develop most often in horses and dogs and are rare fungal infections resulting in progressive cutaneous and subcutaneous nodular enlargements of granulomatous inflammation that can have draining sinuses and that resemble botryomycosis and actinomycotic mycetomas. The portal of entry is through traumatic injury into the dermis or subcutis, and most of the fungi involved in these infections are saprophytes. Curvularia geniculata is the most commonly isolated fungus alterations in the amount of composition of surface lipids in response to changes in hormones, cornification disorders, nutritional disturbances, the presence of allergic skin disease such as atopic dermatitis, or disorders associated with immune compromise such as feline immunodeficiency virus (FIV) or paraneoplastic dermatoses in cats. Some dog breeds (basset hounds, West Highland white terrier, cocker spaniels, and others) and cat breeds (sphynx, Devon rex) appear to be predisposed to infection.

Malassezia dermatitis is much more common in dogs than cats and is most often found in dogs with concurrent dermatoses, especially hypersensitivity dermatitis or staphylococcal bacterial folliculitis. M. pachydermatis is thought to have a symbiotic relationship with staphylococci, both organisms producing mutually beneficial factors that facilitate their growth. Lesions can be regional (ventral neck, interdigital, otic, perianal, paronychial, or intertriginous) or more generalized (Fig. 17-49) . Grossly, the lesions are erythematous, alopecic, often lichenified, and may be hyperpigmented. The lesional surface is often greasy and may be malodorous. Affected claws and paronychial hairs may have red-brown discoloration. Lesions are variably pruritic. Because M. pachydermatis does not invade below the stratum corneum, it is likely that animals with intense pruritus associated with Malassezia dermatitis have a hypersensitivity reaction to yeast products or antigens. Microscopic lesions consist of hyperkeratosis, focal parakeratosis, variable spongiotic pustular dermatitis, lymphocytic exocytosis, acanthosis, perivascular and interstitial mixed cellular dermatitis, and the presence of M. pachydermatis within the surface keratin. Lesions associated with the concurrent disease may also be present.

In otherwise healthy cats, Malassezia dermatitis may be regional and seen in association with chin acne, facial dermatitis, or otitis externa. In otherwise healthy cats bred for congenital hairlessness (e.g., sphynx, Devon rex), Malassezia spp. (often M. pachydermatis) are also commonly found in association with varying degrees of dark brown, greasy exudate on the claws, claw fold, palmar and plantar interdigital areas, axillae, groin, and sometimes ears. These breeds of cats also frequently develop a more generalized greasy dermatitis in which Malassezia spp. (often M. pachydermatis) are isolated from multiple skin sites. In contrast, more generalized dermatitis in association with Malassezia spp. in cats without congenital hairlessness suggests the concurrent presence of underlying systemic disease such as feline pancreatic paraneoplastic alopecia, feline exfoliative 

ing organisms is infectious to human beings if introduced into cutaneous wounds.

Oomycosis (Pythiosis and Lagenidiosis). Oomycosis refers to dermal and subcutaneous infection by Pythium insidiosum or Lagenidium sp., which are both aquatic dimorphic water molds and members of the class Oomycetes. Pythiosis most often affects the skin of the limbs and trunk of horses, cattle, dogs, and cats. Lagenidiosis has been reported only in dogs. Many infections develop in conjunction with exposure to free-standing water. Contamination of minor skin wounds is thought to be necessary for infection to occur. Infections are more common in tropical or subtropical climates, including the Gulf coast of the United States, and are characterized clinically by erythematous, sometimes necrotizing, nodular lesions that ulcerate and drain (Fig. 17-51 ). There can be extensive tissue destruction by inflammation and necrosis. A unique gross feature of pythiosis in the horse is the presence of yellow, friable fragments of necrotic tissue and hyphae, which can be dislodged from the lesions. Pythiosis in the dog is a rapidly progressive, debilitating, and often fatal disease seen most often in young, large-breed dogs. Although cutaneous pythiosis is most common, gastric pythiosis also occurs in dogs of this same signalment. Lagenidiosis in the dog is also a very aggressive disease, and dogs may have lesions in organs other than the skin and lymph nodes. Histologically, hyphae or hyphal-like structures are in areas of eosinophilic to pyogranulomatous dermal or subcutaneous inflammation. Organisms may not be readily visible in H&E-stained sections; thus special stains, such as Gomori's methenamine silver stain, may be required to identify the organisms. Although pythiosis and lagenidiosis have hyphal morphologic features similar to fungi, they are aquatic water molds and do not respond to antifungal therapy; thus they need to be differentiated from fungi, especially entomophthoromycosis (zygomycosis; see discussion in the next section). Definitive diagnosis of pythiosis can be made by serologic testing (ELISA), culture, or molecular diagnosis using PCR, but for culture, specific specimen handling and culture techniques are required. Diagnosis of lagenidiosis is made by culture of fresh tissue followed by ribosomal RNA (rRNA) gene sequencing.

Entomophthoromycosis (Zygomycosis). Entomophthoromycosis refers to dermal and subcutaneous infections caused by Basidiobolus sp. and Conidiobolus sp., which are saprophytic fungi that gain entry to the body by inhalation or traumatic implantation by wounds or insects. Most Basidiobolus sp. infections have been reported in the horse. Infections with Conidiobolus sp. have been reported in horses, in animals; other fungal genera include Madurella, Acremonium, and Pseudallescheria. Histologic lesions are nodular masses of granulomatous inflammation with fibrosis and exudate in which there are embedded granules composed of masses of septate, branching fungal hyphae measuring 2 to 4 µm in diameter. The granules vary in size, shape, color, and texture and are bordered by Splendore-Hoeppli material. Culture identifies the organism involved.

Dermatophytic Pseudomycetoma. See Disorders of Cats. Phaeohyphomycosis. Phaeohyphomycosis is a mycotic infection caused by species of pigmented fungi (dematiaceous) of a variety of genera that have dark-walled, septate hyphae. Genera include Alternaria, Drechslera, Exophiala, Phialophora, and others. These fungi are plant pathogens, soil saprophytes, or in some instances, normal flora that enter the skin at sites of trauma. Most of these infections remain localized to the skin and subcutaneous tissue, but they can spread to other tissue via lymphatic drainage in immunocompromised hosts. Grossly, lesions consist of alopecic or haired cutaneous nodules that can ulcerate and drain (Fig. 17-50) . Microscopically, lesions consist of foci of granulomatous, pyogranulomatous, or lymphocyte-rich granulomatous inflammation containing pigmented fungal organisms. Culture is necessary for specific identification of the fungus involved. Subcutaneous phaeohyphomycosis occurs in horses, cattle, cats, and rarely dogs. Hyalohyphomycosis (paecilomycosis) is similar to phaeohyphomycosis except that the fungal hyphae in tissue are nonpigmented (nondematiaceous). Organisms include Pseudallescheria sp., Acremonium sp., Fusarium sp., Paecilomyces sp., and Geotrichum sp.

Sporotrichosis. Sporotrichosis, caused by the Sporothrix schenckii complex, is an uncommon mycosis that occurs in cutaneous, cutaneolymphatic, and disseminated forms in horses, mules, cattle, cats, and dogs. The medically important species in the S. schenckii complex are Sporothrix brasiliensis, S. schenckii, Sporothrix globosa, and Sporothrix luriei. The most important species in North America is S. schenckii, a saprophytic dimorphic fungus found in moist organic debris, and entry into the body is by traumatic implantation. Ulcerated cutaneous nodules and draining sinuses develop at the site of inoculation and along lymph vessels (lymphangitis), but visceral dissemination is uncommon. Deep dermal to subcutaneous pyogranulomatous inflammation develops. Organisms are ovoid to elongate (cigar-shaped) bodies, which are often sparsely distributed and difficult to find in histologic sections but may be detected in cytologic preparations. Immunohistochemical evaluation or culture or both may be required to document infection. The exudate contain- 

Ectoparasites include mites and ticks (which have eight legs as adults), and lice, fleas, and flies (which have six legs as adults) (Box 17-10). The presence of these ectoparasites is called an infestation. Endoparasites causing cutaneous lesions include nematodes, trematodes, and protozoa, and their presence is called an infection. Parasites cause a number of untoward effects, including damage to hides and predisposition to secondary infection. Arthropod parasites (jointed limbs) also serve as vectors of bacterial, spirochetal, helminthic, rickettsial, protozoal, and viral infections. The cutaneous reaction to parasites varies with parasite number, location, feeding habits, and host immune response. The cutaneous reaction is often mediated in part by immune mechanisms (hypersensitivity). Diagnosis of parasitic infestations and infections requires identification of the specific parasite involved, and this may not be possible with skin biopsy evaluation alone. The only mites that are routinely expected to appear in skin biopsy samples of domestic animals are Demodex spp.

Mites. Mite infestations can cause serious cutaneous lesions in domestic animals and economic loss in food animals. Mite infestations are rare in horses, except for Chorioptes sp., which produce dermatitis of distal limbs in heavy breeds. Cattle can be infested with a variety of mites, including Sarcoptes, Psoroptes, and Chorioptes, which are reportable diseases in the United States. Sheep in the United States are free of mite infestation except for Demodex sp. Mite infestations can also cause serious cutaneous diseases in dogs (Demodex canis, Sarcoptes scabiei, Otodectes cynotis), cats (Demodex cati, Demodex gatoi, O. cynotis, Notoedres cati), and pigs (S. scabiei). In S. scabiei infestation, mites can be difficult to find, except for infestation of the skin of the external ears of pigs.

Most species of Demodex mites live their entire life cycle in the lumens of hair follicles or sebaceous glands as part of the normal fauna of the skin of most mammals. It is only when the normal equilibrium between the host and the parasite is changed to favor proliferation of the mite that skin lesions of demodectic mange are produced. Thus identification of large numbers of adult mites or an increased number of immature mites in skin scrapings or biopsy samples is required for diagnosis of demodicosis. Demodicosis is llamas, sheep, and dogs. Systemic dissemination of Conidiobolus sp. has developed in the sheep and dog. As in oomycosis, infections are more common in tropical or subtropical climates. Clinical and histologic features are similar to those of oomycosis. Differentiation between entomophthoromycosis and oomycosis requires culture (pythiosis, entomophthoromycosis, lagenidiosis), PCR or ELISA (pythiosis), or rRNA gene sequencing following culture (lagenidiosis) and is therapeutically important because infections with Zygomycetes (true fungi) can be responsive to antifungal treatment, whereas infections with Oomycetes are not. Systemic Mycoses. The respiratory tract, especially the lung, is almost invariably the primary portal of entry and infection in the systemic mycoses, but cutaneous and subcutaneous infections can occur as part of the disseminated disease or by direct implantation of fungi by trauma. Systemic mycoses include Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, and Histoplasma capsulatum. Infections with these fungi can occur in animals with apparently normal immune function but are more extensive in immunocompromised animals. Grossly, one or more nodular areas in the skin can ulcerate and have draining sinuses. Histopathologically, there are nodular areas of granulomatous or pyogranulomatous inflammation in the dermis and possibly subcutis. C. neoformans can cause a granulomatous response, but generally the inflammation is less severe than with the other fungi. The cryptococcal organisms have a mucinous capsule that does not stain with H&E. When inflammation is mild, the capsules of the numerous organisms in a lesion give the tissues a multicystic appearance microscopically. Cytologic or microscopic examination is required for diagnosis. The morphologic features of the organisms (including mucicarminepositive capsule of C. neoformans) are usually sufficient for diagnosis; however, culture may be needed in cases when capsule formation is minimal. There are morphologic overlaps between the systemic mycoses, and cultures may be needed to confirm any of these infections when organisms are in low number. See the section on subcutaneous mycoses regarding precautions when submitting cultures for dimorphic fungi.

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Protothecosis is a rare infection of animals caused by achloric (colorless) algae of the genus Prototheca. Prototheca organisms inhabit sewage, animal waste, and slime flux of trees. They enter the body via ingestion of contaminated water or food (see Chapters 4 and 7) or traumatic implantation. The organisms are usually of low pathogenicity, but severe or even disseminated infections occur in immunologically compromised hosts. Infection is most often reported in the dog and cat. Cell-mediated immunity is considered vital to controlling or eliminating the infection. Grossly, the lesions are nodular, and the microscopic pattern is nodular to diffuse granulomatous dermatitis and panniculitis. The organisms can be identified in tissues by the characteristic endospores, especially when stained with Gomori's methenamine silver stain or with immunohistochemical techniques. Prototheca sp. can also be identified by culture. CHAPTER 17 The Integument and coronary bands can also be affected. Demodex aries is located in sebaceous glands of the vulva, prepuce, and nostrils and can cause papular, rarely pustular, or nodular lesions.

Demodex phylloides of pigs causes scale-covered papules progressing to nodules that are filled with keratinaceous debris and mites and that damage the hide. Lesions develop in the ventral body skin, eyelids, and snout.

Demodicosis is one of the most common skin disorders of dogs in North America. Several different demodectic mites have been identified in dogs, D. canis (most common), Demodex injai (rare), and Demodex cornei (rare), a short-bodied mite. D. canis and D. injai live in hair follicles and can be found in sebaceous glands. D. cornei is found on the skin surface. Mixed infections with D. canis and D. injai and D. canis and D. cornei have been reported. D. injai has been associated with generalized demodicosis and a clinically greasy hair coat. D. cornei has been associated with generalized and localized demodicosis. Most cases of canine demodicosis are caused by D. canis, and occur in two clinical forms, localized and generalized, both of which are more common in juvenile dogs. Transmission from mother to offspring occurs via close skin contact, as occurs during suckling. Purebred dogs of many breeds are predisposed to infestation, suggesting an inherited basis for the disease related to a primary deficit in cell-mediated immunity. Research studies suggest the defect is one of T lymphocyte helper dysfunction, resulting in damage by cytotoxic T lymphocytes. Active lesions of demodicosis result in lymphocytic mural folliculitis with lymphocyte-mediated damage to the keratinocytes of the follicular wall. It is speculated that follicular keratinocytes express altered self-antigens or Demodex antigens, which leads to immune-mediated destruction of the follicular wall. Secondary immunodeficiency, caused by T lymphocyte suppression, is also associated with demodicosis, particularly if a secondary S. pseudintermedius infection is present. The secondary immunodeficiency improves as the demodicosis resolves. Results of studies conflict as to whether the secondary immunodeficiency is caused by the accompanying bacterial infection or the mite infestation. Demodicosis occurs in adult dogs with underlying metabolic disorders (hypothyroidism, hyperadrenocorticism) or that are given drugs (glucocorticoids or cytotoxic drugs) that can compromise the immune system. Idiopathic cases also occur.

Gross lesions of localized demodicosis in the dog consist of one to several small scaly, erythematous, alopecic, areas on the face or forelegs (see Fig. 17 -26). Canine generalized demodicosis usually involves large areas of the body; lesions consist of larger coalescing patches of erythema, alopecia, comedones, scales, and crusts. The early microscopic lesions include epidermal hyperkeratosis, perifolliculitis, and lymphocytic interface mural folliculitis, including mild degeneration of follicular basal cells, follicular pigmentary incontinence, and intraluminal mites (see Fig. 17-26) . Follicles can become plugged with large numbers of mites, keratin, and sebum. Secondary bacterial infection leads to neutrophilic folliculitis that in conjunction with mite proliferation and follicular hyperkeratosis progresses to follicular rupture. Mites, bacteria, keratin, and sebum spill into the dermis, stimulating a granulomatous to pyogranulomatous dermatitis. Perifollicular granulomas with portions of mites are often seen. Gross lesions in dogs with severe secondary bacterial infection include papules, pustules, edema, and draining sinuses. In severe demodicosis, inflammation and organisms spread into the subcutis, and lymphadenitis and septicemia can develop. Severe chronic lesions consist of dermal fibrosis with effacement of adnexal structures.

In cats, demodicosis is rare and is typically caused by two species of mites, one (D. cati) lives in follicles and sebaceous glands, and the other (D. gatoi) resides on the skin surface within the stratum caused by host-specific mites; it is a major problem in dogs but is uncommon in other animals.

Demodicosis. Demodectic mange is rare in the horse. Demodex caballi is commonly present in pilosebaceous units of eyelids and muzzle, generally without producing lesions. In contrast, Demodex equi is distributed over the body. Clinical lesions are rare, but when present, develop on the face, neck, shoulders, or forelimbs and consist of localized to diffuse alopecia and scaling or of papules, nodules, and pustules.

Demodicosis in cattle (Demodex bovis, Demodex tauri, and Demodex ghanaensis) and goats (Demodex caprae) is of little clinical significance, but extensive infection can damage hides by development of multifocal nodules in the skin of shoulders, neck, and face or in a more generalized distribution. Nodules correspond to follicular cysts that are filled with mites and keratinaceous material. Rupture of the cysts leads to severe granulomatous dermatitis and damage to the hide.

Sheep have two species of mites. Demodex ovis is located in hair follicles or sebaceous glands distributed over the body and can cause alopecia, erythema, scaling, pustules, and matted fleece. Lesions develop on the face, neck, shoulders, and back, but the ears, limbs, 

Hookworms, Habronema sp., Pelodera sp., Necator sp., Strongyloides sp., Gnathostoma sp., Bunostomum sp.

Onchocerca sp., Stephanofilaria sp., Elaeophora sp., Parafilaria sp., Suifilaria sp., Dirofilaria sp., Acanthocheilonema sp.

Leishmania sp. Rarely other genera

characterized initially by an erythematous papular rash followed by scales, crusts, and alopecia, and when chronic, with lichenification. Lesions begin on the neck and pinnae and extend to the head, face, and paw and can become generalized. Microscopic lesions consist of a hyperplastic, perivascular eosinophilic dermatitis with mild spongiosis and crusts. In cats, mites are readily found in the stratum corneum in tissue sections or in skin scrapings. Otodectic Mites. Otodectic mite infestation caused by O. cynotis occurs in the external ear canals of dogs and cats and occasionally can be present on other parts of the body. The mite lives on the skin surface and can be seen by direct visualization. Because Otodectes mites can be present in areas of the body other than ears, it is important to differentiate them from Sarcoptes and Notoedres mites, which can be identified in microscopically examined skin scrapings or sometimes in tissue sections.

Psoroptic Mites. Psoroptic mite infestation in horses, cattle, sheep, goats, rabbits, and other animals is caused by several species of host-specific mites. Psoroptes cuniculi live on the surface of the skin, feeding on lipids and later on serous and hemorrhagic crusts that exude from the traumatized skin. It infests the external ear canals of horses, sheep, goats, and rabbits. Psoroptes equi infests the base of the mane and tail and skin under the forelock of horses. Psoroptes ovis causes serious disease in cattle and sheep, producing parasitic lesions of thickened skin and dry scales and crusts that begin on the withers and spread because of persistent self-inflicted trauma. In sheep, psoroptic mite infestation is called sheep scab. Lesions develop on the withers and sides. The wooled areas are chiefly involved with crusts that become adherent to the matted fleece and in time expand and coalesce. Damage is the result of self-inflicted trauma, caused by the pruritus associated with irritation and hypersensitivity reactions. The microscopic lesion is a spongiotic, hyperplastic, hyperkeratotic, or exudative superficial perivascular dermatitis with eosinophils. Self-trauma leads to erosions, ulcers, and exudation of serum and leukocytes. No cases of P. ovis have been reported in sheep in the United States since 1970.

Chorioptic Mange. Chorioptic mange, caused by Chorioptes bovis, affects cattle, horses, goats, and in some countries, sheep. The mite is not host specific. Mites on the skin surface cause irritation corneum. A third species of demodectic mite in the cat (Demodex sp. unnamed) resembles, but is larger than, D. gatoi, but the significance of this mite has not been determined. Unless the immune response is compromised, lesions associated with D. cati are usually localized to the chin, eyelids, head, or neck. When the immune response is compromised, as in feline retroviral infections, generalized lesions of erythema, scaling, alopecia, pustules, and crusts develop. Histologically, cats with D. cati have epidermal and follicular hyperkeratosis and follicular atrophy. Inflammation is minimal. The most common sign associated with the presence of D. gatoi is pruritus, resulting in excessive grooming and symmetric alopecia. D. gatoi is contagious between cats, and there is an asymptomatic carrier state.

Scabies. Scabies is caused by S. scabiei. This highly contagious and zoonotic mite is the most important ectoparasite of pigs, is common in dogs, and is uncommon to rare in horses, cattle, sheep, goats, and cats. The mites burrow in tunnels in the stratum corneum and cause intense pruritus principally as a result of hypersensitivity reactions, although irritation from secretions also plays a role. Lesions begin on the external ears, head, and neck and can become generalized. Early gross lesions include erythematous macules, papules, crusts, and excoriations. Chronic lesions are scaly, lichenified, and hairless ( Fig. 17-52) . Microscopically, early lesions consist of superficial perivascular dermatitis with eosinophils, mast cells, and lymphocytes. Mild focal spongiosis can be seen. Small parakeratotic crusts can develop as spongiotic lesions age. Chronic lesions are associated with epidermal acanthosis with marked rete peg formation, compact hyperkeratosis, parakeratosis, crusting, and perivascular dermatitis with eosinophils, mast cells, and lymphocytes. In areas of excoriation, neutrophils-and with time, dermal scarring-may be evident. Mites, mite eggs, or feces may be found in tunnels in the stratum corneum (see Fig. 17-52 , B) but are not commonly seen in tissue sections because of small numbers of mites; thus microscopic examination of skin scrapings is usually required for diagnosis.

Notoedric Mites. Notoedric mite infestation is caused by N. cati. This mite infests cats, rabbits, and occasionally foxes, dogs, and human beings. It is a rare but highly contagious pruritic disease 1087 CHAPTER 17 The Integument section of skin (from epidermis to panniculus), these lesions can be triangular with the apex at the panniculus. Some lesions comprise granulomas (arthropod bite granulomas) in which the inflammatory cells efface the tissue architecture and lymphoid follicles form.

Lice. Pediculosis is infestation with lice and is caused by two orders of lice: Mallophaga (biting lice) and Anoplura (blood-sucking lice). Infestations are relatively host specific, are spread by direct contact, and are relatively easy to control because the life cycle takes place entirely on the host. Pediculosis occurs more commonly in winter, when temperatures are cooler, the wool or hair coat is longer, animals are congregated, and the plane of nutrition is lower. Thus heavy infestations are usually an indication of underlying problems, such as overcrowding, poor sanitation, or poor nutrition. Generally pediculosis is not a significant threat to the host, and animals with low infestations may not have clinical signs or lesions. Most problems are related to skin irritation and resultant pruritus. However, the Anoplura have piercing mouthparts and suck blood; thus heavy infestations can cause anemia. In addition, Haematopinus suis, a sucking louse that parasitizes pigs, is economically important because the lice transmit Mycoplasma (Eperythrozoon) suis and the viruses of swinepox and African swine fever. The Mallophaga cause less severe signs because they feed on epithelial cellular debris. Primary lesions caused by lice are few, and most are secondary to scratching, rubbing, or biting. The cause of the pruritus is not known but is thought to be a result of more than mechanical irritation alone. Gross lesions consist of papules, crusts, excoriations, and self-induced damage to hair and wool. Lice and eggs are visible on hair or wool. Animals infested with sucking lice can be anemic. Weight loss and reduced production of milk can result from the constant irritation associated with some infestations.

Ctenocephalides felis is the most common flea causing infestation, and it also transmits Dipylidium caninum. Infestation can occur with Ctenocephalides canis and less commonly with fleas that parasitize other mammals and birds. Fleas can cause severe skin irritation because of frequent biting and release of enzymes, anticoagulants, and histamine-like substances; hypersensitivity reactions to saliva; and secondary host-inflicted trauma from scratching and biting. Severe infestations can cause blood loss (anemia), especially in puppies, kittens, or small debilitated adults. Lesions occur over the dorsal lumbosacral region (Fig. 17-53) , caudomedial thighs, ventral abdomen, flanks, and the neck area in cats and consist of multiple red papules and secondary excoriations (see the section on Insect Bite Hypersensitivity).

Flies. Cutaneous reactions caused by fly bites range from minor to severe and are caused by bites from adult flies and myiasis by larvae. Reactions to the bites of flies vary and include irritation, anemia, direct toxicity, and hypersensitivity. Biting flies include Haematobia irritans (horn fly), Stomoxys calcitrans (stable fly), and horseflies, deerflies, blackflies, biting gnats, mosquitoes, and the sheep ked (Melophagus ovinus), which is a common wingless fly that sucks blood. Lesions of biting flies are due to local irritation and include wheals and papules centered around a puncture wound that can bleed. Such lesions can persist with hair loss, scales, hemorrhagic crusts, erythema, and secondary excoriations because of selfinflicted trauma, especially if the animals are hypersensitive to the bites. Such hypersensitivity occurs with Culicoides sp. in horses (Queensland itch, sweet itch; see the discussion on Culicoides hypersensitivity in the section on Selected Hypersensitivity Reactions) and mosquitoes in cats (see the discussion on mosquito and pruritus leading to self-trauma and the gross lesions of erythematous, papular, crusted, scaly, hairless, thickened skin on the lower hind limbs, scrotum, tail, perineum, udder, and thigh of cattle; lower limbs and tail of horses; scrotum and lower hind limbs of sheep; and lower limbs, hindquarters, and the abdomen of goats. Microscopic lesions are similar to those seen in other surface-dwelling mite infestations.

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Ticks. Ticks comprise two families, Ixodidae (hard ticks that have a scutum, a hard chitinous plate on the anterior dorsal surface) and Argasidae (soft ticks that lack the scutum). Most of the pathogenic ticks are in the family Ixodidae. An exception is Otobius megnini, the spinose ear tick, which is parasitic to all domestic animals and causes severe otitis externa. Heavy tick infestations, particularly by adult argasid ticks that engorge repeatedly, can cause anemia. As obligate blood-sucking ectoparasites, ticks also serve as vectors for many potentially severe blood-borne diseases, including, but not limited to, Rocky Mountain spotted fever, borreliosis, babesiosis, anaplasmosis, and ehrlichiosis. Tick bites also cause direct damage to the skin at the site of attachment, which predisposes to secondary bacterial infection leading to abscesses or septicemia and to myiasis. Adverse reactions to ticks depend in part on the content of salivary secretions. Tick saliva has been shown to contain factors that are antihemostatic, antiinflammatory, and immunosuppressive. These factors are thought to facilitate feeding and the transmission of tick-borne diseases. In addition, salivary secretions of several species of ixodid ticks (e.g., Dermacentor andersoni and Dermacentor variabilis in North America) contain neurotoxins that can cause an acute ascending lower motor neuron paralysis of the host. If the tick is removed, symptoms disappear rapidly.

The severity and type of local cutaneous reactions vary not only with salivary secretions but also with host resistance and whether tick-bone illness is concurrent. In experimental studies it has been shown that in nonsensitized hosts the inflammatory response to tick mouthparts embedded deeply in the dermis develops in the immediate site of the bite, is composed largely of neutrophils, and is minor even approximately 2 days after the tick attaches. In contrast, previously sensitized hosts develop more rapid and intense local reactions (as early as 1 hour after attachment). Cutaneous lesions are present a greater distance from the site of attachment, and basophils, eosinophils, and neutrophils are present in the epidermis and dermis. Cutaneous basophil hypersensitivity, a form of delayed-type hypersensitivity, plays an important role in immunity to ticks.

In naturally occurring cases, gross lesions include red papules that progress to circular erythematous areas up to 2 cm in diameter. Lesions progress to foci of necrosis, erosions, ulcers, crusts, and in some animals, nodules. Lesions heal with scarring and alopecia. Histologic lesions include congestion, edema, and sometimes hemorrhage with an intradermal cavity below which the tick mouthparts may be present. Inflammation consists of perivascular to diffuse accumulations of neutrophils, eosinophils, and basophils, although basophils may be difficult to identify histologically. Later-developing lesions include epidermal and dermal necrosis, the granulocytic leukocytes of more acute lesions plus accumulations of lymphocytes and macrophages at the margin of the necrotic dermis. In a vertical

Cheyletiellosis, caused by infestation with Cheyletiella sp., occurs in dogs, cats, rabbits, wild animals, and human beings. The mite lives on the surface of the skin and induces hyperkeratosis. In dogs and cats, lesions consist of hyperkeratosis manifested as dry, white, scaly dandruff along the dorsal midline of the back. Some infestations are asymptomatic. Cats can have focal, multifocal, or generalized red papules or crusts, characterized microscopically by superficial perivascular dermatitis with eosinophils. The diagnosis requires identification of the mites via skin scrapings, acetate tape, or brush techniques because mites are not usually seen in tissue sections.

Psorergatic mite infestation, caused by Psorergates (Psorobia) ovis, occurs in sheep in Australia, New Zealand, South Africa, and Argentina. Sheep in the United States have been free of these mites since 1973. Suspected cases of psorergatic mange should be reported to the state veterinarian. The infestation initially results in papules and scales along the trunk. Over time the fleece becomes ragged because severe pruritus leads to secondary crusts, lichenification, and hyperpigmentation with alopecia.

Trombiculiasis is infestation by larvae of trombiculid (harvest) mites also known as chiggers. Eutrombicula (Trombicula) alfreddugesi (North American chigger), and Eutrombicula (Trombicula) splendens are some of the species implicated in trombiculiasis in horses, dogs, and cats. Neotrombicula (Trombicula) autumnalis, the European harvest mite, attacks most domestic species. Eutrombicula (Trombicula) sarcina, an Australian species known as the leg-itch mite, is an important parasite of sheep, although its principal host is the gray kangaroo. The larvae tunnel into the epidermis and inject saliva that gels to form a characteristic stylostome used to obtain digested tissue fluids. Grossly, small red papules or crusts containing several orange to red larvae develop on parts of the skin in close contact with plants or the ground. Lesions are intensely pruritic. The microscopic lesions are a hyperplastic, superficial perivascular dermatitis with eosinophils, mast cells, and intraepidermal mites. Identification of a stylostome microscopically is pathognomonic.

canal (H. bovis), where they develop into second-stage larvae. These second-stage larvae then migrate to the subcutis of the back, become established in subcutaneous nodules similar to those of Cuterebra sp. with an opening for respiration, and mature to third-stage larvae (Fig. 17-54) . Microscopically, these larvae are located in a cavity filled with fibrin, blood, and a few eosinophils and bordered by granulation tissue containing clusters of eosinophils.

Screwworm myiasis is caused by two species of Diptera larvae, Cochliomyia hominivorax (Coquerel), the New World screwworm, and Chrysomyia bezziana (Villeneuve), the Old World screwworm. C. hominivorax occurs in tropical and semitropical regions of the Western Hemisphere, including Central and South America and some Caribbean islands. It has been eradicated in the United States, Mexico, and Panama. C. bezziana (Villeneuve) is found in tropical and semitropical regions of the Eastern Hemisphere, including bite hypersensitivity in cats in the section on Disorders of Cats). Microscopic lesions associated with fly bites vary, depending on the fly involved. Dermal hemorrhage and edema with a central area of epidermal necrosis are early lesions seen with bites of some flies. Hemorrhagic crust covers areas of necrosis, and perivascular neutrophilic, eosinophilic, and mixed mononuclear inflammation can be seen. Intraepidermal eosinophils, including eosinophilic pustules, are sometimes identified, and eosinophilic folliculitis and furunculosis can be present in reactions to mosquito bites. Epidermal hyperplasia, hyperkeratosis, parakeratosis, and crusting are associated with self-trauma.

Myiasis is infestation of tissues by the larvae of dipterous flies (flies with two wings or winglike appendages) and is a disease of neglect. Lesions develop in skin kept moist and soiled by urine, feces, or body secretions. Flies are attracted by the odor of such areas. Sheep, largely with ovine fleece rot (see section on Bacterial Infections, Disorders of Ruminants [Cattle, Sheep, and Goats]) are most commonly affected. In myiasis caused by blowflies (Calliphoridae) and flesh flies (Sarcophagidae), eggs are deposited in wounds or on soiled hair or wool. Gross lesions consist of matted hair or wool and multiple irregular cutaneous holes or ulcers with an offensive odor. Secretion of proteolytic enzymes by larvae causes lesions to spread. Death can result from septicemia or toxemia.

In Cuterebra myiasis, eggs of Cuterebra sp. are deposited on stones or vegetation near the burrows of rabbits and rodents, the natural hosts. Less often, cats or dogs become infested. The eggs hatch to first-stage larvae on the vegetation, and when the host contacts the vegetation, larvae attach to the hair coat and move to the skin. Once on the skin, larvae move to natural body openings such as the nares, where they penetrate the mucosa. Other portals of entry are direct penetration of the skin or ingestion by the host during grooming. The larvae migrate to the subcutis, produce a cystlike subcutaneous nodule in which the larvae mature and cut a hole in the skin for respiration. The larvae feed on tissue debris. Wounds heal slowly after larvae are removed or released, but secondary bacterial infection can develop.

In Hypoderma myiasis, larvae of Hypoderma lineatum and Hypoderma bovis penetrate the skin of the legs of cattle and less frequently horses and migrate proximally in the subcutis of the leg. The larvae can be found in many areas of the body. After weeks to months, first-stage larvae reach the esophagus (H. lineatum) or vertebral 1089 CHAPTER 17 The Integument or localized areas of edema. In urticaria the edema involves the superficial dermis, whereas in angioedema the edema involves the deep dermis and subcutis. There are immunologic (foods, drugs, antisera, insect stings, plants such as stinging nettle, and exposure to chemicals) and nonimmunologic (pressure, sunlight, heat, cold, exercise, and stress) stimuli. Immunologic mechanisms involve type I and type III hypersensitivity reactions. Pruritus is not always present, particularly in the horse. A unique form of urticaria has been described in Jersey and Guernsey cattle because of a type I hypersensitivity reaction to casein in their milk. Urticarial lesions are wheals that typically arise suddenly and remain a few hours, although chronic urticaria (lasting weeks or longer) has been described. In sensitive animals, particularly short-haired dogs or purebred horses, pressure applied to the skin can result in linear urticarial lesions called dermographism. In some animals, serum oozes from the wheals matting the hair coat. Angioedema is a localized or generalized area of extensive deep dermal and subcutaneous edema. Histologic lesions in urticaria and angioedema are subtle and consist of vascular dilation and edema with or without perivascular eosinophilic to mixed mononuclear dermatitis and can be overlooked because the edema fluid may be removed during tissue processing. Occasionally the intercellular epidermal edema (spongiosis) progresses to epidermal vesicles, serum exudation, and serous crusting. The prognosis is generally favorable. Fatalities are rare and probably due to anaphylaxis or associated angioedema involving the respiratory passages.

Atopic dermatitis is defined as a genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features associated most commonly with IgE antibodies to environmental allergens. It is an example of a type I hypersensitivity reaction, although type IV mechanisms also participate. The skin is the major target organ in horses, dogs, and cats. There is increasing evidence that the major route of allergen exposure is percutaneous and that epidermal barrier dysfunction contributes to the development of atopic dermatitis. A discussion of the pathogenesis of atopic dermatitis can be found in the section on Disease Example of Barrier Dysfunction.

The predominant clinical sign of atopic dermatitis is pruritus. Horses can have pruritus of the head, pinnae, ventrum, legs, and tail head, or recurrent urticaria. Pruritus causes horses to bite themselves, rub against objects, stomp their feet, and switch their tails. In dogs, pruritus is often manifested as face rubbing (see Fig. 17-34) , ear scratching, and paw licking. Severely affected dogs may be restless, may not be able to sleep, and may lose weight because of frequent or persistent scratching. Pruritus may affect the face, distal extremities, ears, and ventrum or may be generalized. Pruritus of the distal extremities and otitis externa are frequent features of dogs with atopic dermatitis. Clinical signs of feline atopic dermatitis vary and include pruritus of the face, neck, or ears or generalized pruritus manifested as self-induced trauma or alopecia. In general, atopic dermatitis is considered a disorder without the presence of primary cutaneous lesions. In horses, urticaria may accompany pruritus. In some dogs, papular, macular, or plaquelike eruptions have been reported. Multifocal crusted papules termed "miliary dermatitis," eosinophilic granuloma complex, and symmetric alopecia are often features of feline atopic dermatitis but are not specific to feline atopic dermatitis because they may be seen in other allergic conditions as well. Most cutaneous lesions are secondary, the result of self-inflicted trauma such as excoriations, erythema, and alopecia. More chronic lesions include lichenification and hyperpigmentation. Microscopic lesions have been studied most in affected dogs, Africa, India, and southern Asia. Screwworm flies deposit eggs in wounds or near mucocutaneous junctions of living animals. The eggs develop into first-stage larvae that burrow into tissue headdownwards in a screwlike fashion using sharp, pointed mouth hooks that tear living tissue. Larvae feed on tissues liquefied by secretions of proteolytic enzymes. Screwworm myiasis is an important disease in domestic and wild animals because the larvae develop only in living tissue and thus destroy viable tissue. Grossly, malodorous wounds contain larvae, shreds of tissue, and copious amounts of reddish-brown fluid. Once an animal is infested, death is almost inevitable unless the larvae are removed. Screwworm myiasis is a reportable disease in some countries, including the United States. When it is necessary to differentiate screwworm myiasis from cutaneous myiasis caused by other flies, larvae can be preserved in 70% alcohol and submitted for identification.

Larvae of the tropical warble fly or human botfly, Dermatobia hominis, cause cutaneous myiasis in human beings and numerous species of mammals, most commonly and importantly in cattle in South and Central America. It has been suggested that they surpass all other cuterebrines in terms of economic and public health importance. Adult D. hominis attaches its eggs to the legs of other insects that then transport the eggs to the mammalian hosts. This unique egg dispersal strategy is responsible for the more generalized host range of D. hominis compared with other botfly species. While the insects feed, the eggs are deposited on the skin, hatch into larvae, and quickly penetrate the skin of the host mammal. The larvae grow in subcutaneous nodules sometimes referred to as "warbles," which are similar to those of Cuterebra sp., with an opening on the skin surface for respiration, after which they leave the nodule and drop to the ground to complete their life cycle. Individual cattle may be infested by thousands of larvae. Dermatobia myiasis is of economic importance because it predisposes the skin to myiasis by other flies, results in losses from cattle mortality or renders the animal as unfit for slaughter, and causes condemnation of hides.

Helminths. Cutaneous infections with helminths are generally not life threatening but can be unsightly and irritating in companion animals and cause hide damage in food animals. Infections are caused by migration of helminth larvae, which live in noncutaneous sites as adults, or by filarial infections (filarial dermatitis), in which adults or microfilaria spend some time in the skin or subcutis. Causes of filarial dermatitis include Onchocerca sp., Stephanofilaria sp., Elaeophora sp., Parafilaria sp., Suifilaria sp., and rarely Dirofilaria sp. or Acanthocheilonema sp. 

Information on this topic is available at www.expertconsult.com.

For a detailed description of mechanisms, see section on Hypersensitivity and Autoimmune Reactions-Mechanisms of Tissue Damage.

Urticaria and Angioedema. Urticaria (hives) and angioedema occur most commonly in horses and dogs and consist of multifocal

In the United States, cutaneous protozoal infections develop as part of systemic infections, principally with members of the genus Leishmania. Rarely, cutaneous infection with Caryospora sp., Neospora sp., Sarcocystis sp., Toxoplasma sp., or Hepatozoon sp. has been reported. Leishmaniasis occurs in human beings, horses, dogs, cats, and other mammals, but severe disease is usually seen in human beings and dogs. Members of the Leishmania donovani complex (Leishmania donovani and Leishmania infantum [also known as Leishmania chagasi], an intracellular parasite of the mononuclearphagocytic system, cause most infections. Sand flies serve as the vector for infection of animals. Dogs, cats, and rodents serve as reservoirs of infection for human beings. Leishmaniasis is endemic in Mediterranean countries and some parts of Africa, India, the Middle East, Asia, and Central and South America. L. infantum infection is endemic in foxhounds in many states in the eastern United States and in Canadian provinces. It is thought that importation of infected foxhounds to North America led to the breedspecific endemic status of leishmaniasis. There is likely a genetic susceptibility to infection. L infantum can be transmitted directly from dog to dog venerally, transplacentally, and directly by contamination with blood and secretions. Transmission by the sand fly might also occur. Infection and clinical disease do not always correlate. Clinical disease in the foxhound breed is often precipitated by other stressors such as pregnancy or concurrent disease. The disease, which can occur in cutaneous, mucocutaneous, or visceral forms, is otherwise rare in animals in the United States except in endemic areas in Oklahoma, Texas, and Ohio. However, visceral leishmaniasis has been identified in approximately 22 states in the United States and in 2 provinces of Canada, indicating an increase in the prevalence of this disease. Infections in animals in the United States also have been associated with foreign travel of human beings and their animals.

Innate immunity is evaded by the organism, so adaptive immunity plays the major role in host defense. Protective immunity is thought to be due to activated T lymphocyte release of cytokines (e.g., TNF-α, IL-2, and IFN-γ) that upregulate macrophage killing of the organisms. Infected macrophages are also killed by CD8 + cytotoxic T lymphocytes. Clinically, ill dogs infected with Leishmania sp. have reduced T lymphocyte-mediated immunity and increased B lymphocyte proliferation that is thought to be detrimental and responsible for hyperglobulinemia and generation of autoantibodies that can lead to disease (e.g., thrombocytopenia) or that form immune complexes that deposit in tissue and cause disease (e.g., glomerulonephritis, arthritis, uveitis). The leading cause of death in affected dogs is immune complex deposition in glomeruli, which causes chronic protein-losing nephritis that may progress to end-stage kidney disease, nephrotic syndrome, and/or systemic hypertension. The skin is one of the main organs affected in systemic leishmaniasis in dogs. Dogs with the alopecic form of the cutaneous disease have fewer organisms and a more robust cellular immune response, including larger numbers of antigen-presenting Langerhans cells, MHC II-positive keratinocytes, and infiltrating T lymphocytes. In contrast, dogs with the nodular form of cutaneous disease have fewer antigen-presenting cells and greater numbers of macrophages and larger numbers of organisms. Therefore it has been suggested that the clinical and histologic lesions can be useful in establishing a prognosis for remission, in that the character of the lesions reflects immune competence. Cutaneous lesions in dogs consist of generalized alopecia with silvery white scales or more severe lesions of nodules and ulcers. Lesions occur chiefly in anatomic areas in which sand flies feed-around the muzzle (nose), ears, and eyes. Paronychia and deformed claws have also been reported. Microscopically, lesions include hyperkeratosis, parakeratosis, crusts, and granulomatous nodules in the dermis, including periadnexal regions. Accumulations of macrophages, lymphocytes, and plasma cells can efface sebaceous glands. Leishmania spp. are most commonly identified within macrophages; however, they can occasionally be found within other leukocytes, endothelial cells, or fibroblasts. In areas of necrosis the organisms can be free within the interstitium. Leishmania sp. can be distinguished from other protozoa via light microscopy by recognizing the kinetoplast oriented perpendicular to the nucleus. Cytologic examination, histopathologic evaluation, immunohistochemical evaluation, PCR, and serologic testing can help confirm the diagnosis.

Fibropruritic nodules consist of a core of coarse thick collagen bundles covered by a hyperplastic epidermis; the end result of chronic inflammation associated with flea bites. In cats, the inflammatory lesions are in the superficial and deep perivascular dermis, and eosinophilic folliculitis and furunculosis also can be a feature. The overlying epidermis is often acanthotic.

Allergic Contact Dermatitis. Allergic contact dermatitis, an example of a type IV hypersensitivity reaction, is primarily the result of contact with chemicals such as aniline dyes in carpets, plant resins, chemicals in shampoos and medications, and historically to plastics in food dishes. These chemical substances contain lowmolecular-weight haptens that require binding to cell-associated proteins before they are recognized by cytotoxic T lymphocytes (CD8 + ). Lesions develop on reexposure to the antigen. The lesions are pruritic, result in self-inflicted trauma, vary in severity, and, importantly, are located in regions in contact with the antigen, typically in areas of glabrous (smooth and bare or hairless) skin unless the antigen is a liquid or aerosol. Grossly, lesions consist of erythema, papules with or without vesicles, and exudates that develop into crusts. Chronic lesions are nonspecific and consist of lichenification, hyperpigmentation, and alopecia. Early microscopic lesions are spongiotic superficial perivascular dermatitis with lymphocytes, macrophages, and usually, infrequent eosinophils. However, some lesions have many perivascular eosinophils and eosinophilic epidermal pustules. More chronic lesions, often those identified in biopsy samples, are nonspecific and consist of acanthosis and foci of parakeratotic cellular crusts. Lesions associated with self-induced trauma can also be seen. The location of lesions to contact sites typically affecting poorly haired skin is important diagnostically, because the histologic lesions of allergic contact dermatitis can be present in other types of skin allergy.

Hypersensitivity Reactions to Drugs. Hypersensitivity reactions to drugs are uncommon in dogs and cats, are rare in other domestic animals, and can result from any of the four types of hypersensitivity reactions. The drugs most commonly associated with hypersensitivity reactions include penicillins and trimethoprimpotentiated sulfonamides, but many drugs can cause a hypersensitivity reaction. Gross and microscopic lesions vary greatly. Microscopic lesions have different histopathologic patterns and include perivascular dermatitis, interface dermatitis, epidermal necrosis, vasculitis, vesiculopustular dermatitis, cytotoxic dermatitis, perforating folliculitis (i.e., furunculosis), or panniculitis. The presence of more than one histologic pattern may strongly suggest a hypersensitivity response to a drug.

Reactions Characterized Grossly by Vesicles or Bullae as the Primary Lesion and Histologically by Acantholysis. Pemphigus represents a complex group of diseases clinically characterized by transient vesicles or bullae and histologically by acantholysis (Table 17 -13). A variety of factors appear to predispose to development of some cases of pemphigus in human beings, including genetic influences, drug intake, viral infections, UVR, emotional stress, and others. In dogs and cats, drug administration has been shown to contribute to some cases of pemphigus, and a few breeds of dogs appear predisposed to developing pemphigus, suggesting that genetic factors may contribute in some dogs. The pemphigus group of diseases is caused by a type II response thought to involve autoantibodies produced against desmosomal proteins (e.g., desmogleins, desmocollins, and plakins), but autoantibodies to nondesmosomal and lesions collected from nontraumatized skin consist of superficial perivascular accumulations of lymphocytes, mast cells, variable numbers of eosinophils, and cells with a histiocytic morphologic appearance. Immunohistochemical evaluation of atopic dog skin has revealed that the lymphocytes are T lymphocytes and the cells with the histiocytic appearance are dendritic antigen-presenting cells. The epidermis is hyperplastic, and sometimes epidermal intercellular edema (spongiosis) progresses to small foci of parakeratosis (see Fig. 17-34, B) . Uncommonly, intraepidermal eosinophils and subcorneal eosinophil microabscesses have been observed in affected dogs. Lesions of self-trauma, such as excoriations, and secondary infections with staphylococci and Malassezia sp. with the accompanying perivascular inflammation and exocytosis of leukocytes into the epidermis, sometimes associated with epidermal or follicular pustules, can mask mild lesions of atopic dermatitis. The inflammation in horses and cats is often deeper than in dogs and consists of perivascular dermatitis with eosinophils as the predominant inflammatory cells. Horses and cats with atopic dermatitis may also develop eosinophilic folliculitis or eosinophilic granulomas. There is no definitive test for atopic dermatitis, so diagnosis is often based on history, clinical signs, physical examination, and ruling out other pruritic diseases with similar presentation (e.g., hypersensitivity to parasites or food). Histopathologic evaluation can be useful in a supportive capacity. Intradermal skin testing and serologic evaluations for elevated levels of allergen-specific IgE are not diagnostic tests but may be considered if immunotherapy is planned.

Culicoides Hypersensitivity. Culicoides hypersensitivity in horses is a common worldwide pruritic dermatitis, caused principally by type I and type IV hypersensitivity reactions to salivary antigens from bites of Culicoides sp. Signs can be seasonal or nonseasonal depending on climate and thus the prevalence of Culicoides. Signs usually develop in horses more than 2 years of age that reside in geographic areas in which Culicoides live, and signs usually worsen with age. Gross lesions depend on the stage of disease and severity of pruritus. Initial lesions are papules. Later-developing lesions are pustules and nodules. Self-trauma can cause excoriations, erosions, and sometimes ulcers, crusts, alopecia, and lichenification. Common sites are the tail base, withers, and head. Microscopic lesions include superficial and usually deep perivascular dermatitis with numerous eosinophils. Some horses also have eosinophilic folliculitis, intraepidermal pustules, crusts, erosions or ulcers, and eosinophilic granulomas. Older lesions are nonspecific and consist of epidermal hyperplasia, hyperkeratosis, cellular crusts, and dermal fibrosis, usually the result of ulceration or folliculitis and furunculosis.

Flea Bite Hypersensitivity. Flea bite hypersensitivity is the most common hypersensitivity dermatitis in dogs and cats. It is mediated by type I and type IV reactions, including cutaneous basophil hypersensitivity. Flea bite hypersensitivity is pruritic. In dogs, cutaneous lesions occur principally along the dorsal lumbosacral area (see Fig.  17 -53), ventral abdomen, caudomedial aspects of the thighs, and flanks. In cats, lesions occur around the neck but can be generalized, especially in highly sensitive animals. Secondary lesions are caused by self-inflicted trauma. Grossly, there is a papular dermatitis with secondary excoriations. Chronic lesions include lichenification, which is nonspecific (see Table 17 -6), and some dogs develop multiple firm alopecic nodules (fibropruritic nodules) in the dorsal lumbosacral area. Microscopically, flea bite hypersensitivity in dogs consists of superficial perivascular dermal accumulations of mast cells, basophils, eosinophils, lymphocytes, and histiocytes. Occasionally, small foci of epidermal necrosis and eosinophils called nibbles are seen, which strongly suggest flea bite hypersensitivity. histologic disease. The pathogenesis of acantholysis is not fully understood and is an active area of investigation. However, the autoantibodies to desmogleins are considered pathogenic because they induce acantholysis when injected into neonatal mice and also cause keratinocyte disassociation in cell culture. There are multiple theories of how autoantibodies cause acantholysis, which may not be mutually exclusive. One theory suggests that the antibodies cause steric hindrance of the desmoglein adhesion site, interfering directly with adhesion. Another theory suggests that antibody binding to desmosomes triggers intracellular signaling pathways that cause disruption of desmosomes and loss of intercellular cohesion by inducing separation of the desmosomal plaque from the intermediate filament cytoskeleton and/or interfering with desmosome turnover. Another relatively recent theory, the multiple hit hypothesis, was developed in part due to discrepancies in correlation of autodesmoglein antibodies alone with type and severity of clinical disease in affected human beings, together with the discovery of other antigens that can be targeted by pemphigus autoimmunity, including not only the proteins may also play a role. Traditionally the most important protein antigens thought to contribute in various species are desmoglein 1 and desmoglein 3, and recently desmocollin 1 in dogs. Desmosomes are the sites where cells of the stratum spinosum attach to each other, and during fixation and processing for microscopic examination, the cells of the stratum spinosum contract, except for the desmosomal attachments, which provide the appearance of "spines" or intercellular bridges (see the discussion in the section on Structure, Epidermis). These desmosomal protein antigens are found in various stratified squamous epithelia, including skin, mucocutaneous junctions, oral mucosa, esophagus, and vagina. Damage to desmosomes is thought to result in acantholysis, leading to the formation of vesicles or bullae within varying levels of the epidermis and mucosal epithelia according to the location of the target antigen. Antibodies to more than one of the desmosomal proteins have been identified in affected human beings and dogs, and differences in the specific desmosomal protein or proteins targeted may contribute to some of the morphologic variations in clinical and distribution pattern of lesions. Antibodies targeting desmoglein 1 cause cutaneous, rather than oral, lesions, and the acantholytic process occurs at a superficial level in the epidermis, producing clinical lesions that are typically exfoliative (Fig. 17-55) . Pemphigus foliaceus in animals is thought to be similar to that in human beings. In fact, autoantibodies to desmoglein 1 have been identified in the serum of a small percentage of dogs with pemphigus foliaceus. However, autoantibodies to desmocollin 1, a desmosomal protein also located in the superficial epidermis, have been identified in the sera of a larger population of dogs with pemphigus foliaceus; thus desmocollin-1 is now thought to be a major autoantigen in canine pemphigus foliaceus. Thus it appears that pemphigus foliaceus is immunologically heterogeneous and that autoantibodies, including those directed toward desmosomal proteins, contribute to the pathogenesis of canine pemphigus foliaceus. Autoantibodies involved in the development of pemphigus foliaceus have not been studied in horses, goats, or cats. The gross lesions are similar in all species. The primary lesions consist of transient vesicles that rapidly become pustules, which can be localized to specific areas of the skin (nose, pinnae, periocular skin, pawpads, claw beds, and coronary bands) or can be more generalized and symmetric. The pustules are in the superficial epidermis, covered by only a small amount of stratum corneum or a few epidermal cells. Because the pustules are fragile, they quickly rupture from minor mechanical pressure on the surface, and this leads to secondary crusts, scales, alopecia, and superficial erosions desmosomal cadherins, but other adhesion molecules, cell membrane receptors, and mitochondrial proteins. Some of the autoantibodies to nondesmosomal antigens involved in cell adhesion (including the keratinocyte acetylcholine receptors) have induced pemphigus-like lesions when injected into neonatal mice, suggesting that these other autoantibodies contribute to acantholysis in some forms of pemphigus. The multiple hit hypothesis proposes that acantholysis in pemphigus is caused by the synergistic and cumulative effect of autoantibodies targeting keratinocyte cell membrane antigens of different kinds that include molecules that regulate cell shape and adhesion (e.g., acetylcholine receptors) and molecules that mediate cell-to-cell adhesion (e.g., desmosomal cadherins), and that the severity of disease depends on the ratio of different kinds of autoantibodies in each case. Future research may clarify the pathogenesis of acantholysis in pemphigus disorders and lead to more specific therapies.

Pemphigus Foliaceus. Pemphigus foliaceus is the most common and milder form of pemphigus and in domestic animals has been reported in the horse, goat, dog, and cat. The disease develops spontaneously and in dogs and cats, as an adverse reaction to drug therapy. In human beings, pemphigus foliaceus autoantibodies recognize the desmosomal protein, desmoglein 1, which is expressed predominantly in the upper layers of the epidermis. This expression pattern of desmoglein 1 in conjunction with expression patterns of other intercellular adhesion molecules and signaling pathways appears to play a role in location of the vesicles and the anatomic Y -Autoantibody CHAPTER 17 The Integument vulgaris (including desmoglein 1) and were thought to contribute in one horse with pemphigus vulgaris (desmoglein 1). It is thought that the distribution patterns of desmoglein 3 in conjunction with desmoglein 1 in skin and oral mucosa in combination with antibodies to other proteins involved in intercellular adhesion result in vesicular lesions deep in the epidermis, oral mucosa, or both. Thus some forms of pemphigus vulgaris largely affect the oral mucosa (mucosal-dominant pemphigus vulgaris), whereas others affect the skin and oral mucosa (mucocutaneous pemphigus vulgaris). The deep vesicular lesions lead to formation of vesicles or secondary erosions and ulcers in the oral mucosa, at mucocutaneous junctions, and/or skin subject to mechanical stress such as in the axilla or groin. Animals can be febrile, depressed, and anorectic and have leukocytosis. Drooling is often a presenting complaint, because involvement of the oral mucosa is almost always present. Microscopic lesions consist of separation of keratinocytes of the lower epidermis owing to loss of intercellular attachments. However, basal cell keratinocytes remain attached to the basement membrane, resulting in a suprabasilar vesicle leaving a row of basal cells attached to the basement membrane ("row of tombstones") (see Fig. 17-16 ). There usually is accompanying superficial perivascular to interface mixed inflammation. Direct IF or IHC reveal immunoglobulin and sometimes complement in the intercellular epidermis. Indirect IF has revealed circulating antikeratinocyte antibodies, typically toward desmoglein 3. Paraneoplastic Pemphigus. Paraneoplastic pemphigus (PNP) is a rare, aggressive form of pemphigus, often but not always associated with solid or hematopoietic neoplasms (see Table 17 -13). Paraneoplastic pemphigus has been documented in human beings, dogs, and a putative case in one cat. Cutaneous lesions can precede detection of the neoplastic process and are resistant to treatment. Lesions consist of severe mucosal and mucocutaneous blisters and erosions. Histologically, lesions have a combined or blended pattern of erythema multiforme (a form of cytotoxic dermatitis) together with suprabasilar acantholysis resembling pemphigus vulgaris. Lymphohistiocytic cell-rich interface dermatitis with apoptosis of keratinocytes is present. In addition, lymphocytes border apoptotic keratinocytes (this is often called lymphocytic satellitosis). The pathomechanism for paraneoplastic pemphigus is unknown. Labeling of intercellular bridges is detected by IHC or IF. In human beings with paraneoplastic pemphigus serum autoantibodies targeting multiple cutaneous antigens, including desmoglein 3, desmoplakins, bullous pemphigoid antigens, envoplakin, periplakin, and others, have been reported. Similarly in paraneoplastic pemphigus-affected dogs, autoantibodies to envoplakin, periplakin, desmoglein 3, and desmoplakins have been reported; thus paraneoplastic pemphigus in dogs appears similar to paraneoplastic pemphigus in human beings and likely has an immunologic basis.

Pemphigus Subtypes. Subtypes of pemphigus include pemphigus erythematosus, pemphigus vegetans, and "facially prominent" pemphigus foliaceus. Pemphigus erythematosus occurs in dogs and cats and is considered to be a variant of pemphigus foliaceus with a facial lesion distribution. Currently, there is insufficient clinical, histologic, immunologic, or prognostic evidence to clearly separate pemphigus erythematosus from facially predominant pemphigus foliaceus.

Pemphigus vegetans has very rarely been reported in dogs. Original designations of pemphigus vegetans in dogs were based on similarities to pemphigus vegetans in human beings, a mucocutaneous condition in which pustules evolve into hyperplastic verrucous (vegetative) cutaneous lesions in conjunction with mucosal suprabasilar acantholysis as seen in pemphigus vulgaris. Antibodies to desmoglein 3 are identified in human patients, and sometimes, circulating (see Fig. 17-15 ). In horses, lesions often begin on the face or distal extremities or can be localized to the coronary bands. Most horses have multifocal to generalized crusting, scaling, and alopecia of the face, neck, trunk, and extremities. Some horses have been depressed and lethargic. In goats, pustules, crusts, scales, and alopecia develop on the face, abdomen, limbs, perineum, and tail, and in females, udder and teats. In most dogs, lesions are bilateral and symmetric and appear first on the dorsal muzzle, planum nasale, periocular skin, and ears. Pawpads are frequently involved, and claws may be affected and may slough. In more than half the cases, lesions become generalized. Mucosal lesions are rarely seen in dogs with pemphigus foliaceus. Pruritus is present in approximately onefourth of affected dogs. Systemic signs (anorexia, depression, fever, and weight loss) usually are seen in dogs with more generalized and erosive lesions. In the cat, lesions are similar to those in the dog and occur on the face, ears, and feet and consist of erosions and crusts, because pustules are exceptionally transient. Skin around the nipples may be affected. Pustular exudate and crusting may be seen in the skin of the claw folds. In any species, the lesions can become generalized.

Microscopically, lesions in all species are similar. Subcorneal and intragranular acantholysis result in the formation of very transient "vesicles" (in animals the vesicle stage is not a major clinical feature as it is in human beings because the vesicle stage in animals very rapidly progresses to the pustular stage). Pustules contain neutrophils, less often eosinophils, and acantholytic keratinocytes. The acantholytic keratinocytes may "cling" to the roof of the pustules or may lift from the base of pustules, and occur in clusters. In dogs, cells resembling apoptotic keratinocytes have been noted, but their significance is unknown. Pustules are often large, broad, and extensive and bridge multiple follicles. The pustules may affect the follicular infundibulum. Pustules progress to crusts. In the horse, subcorneal or intragranular pustules are observed, but in the dog, pustules may occur in the stratum spinosum. Crusts should be included in the biopsy sample, especially if well-developed pustules are no longer present because laminated crusts with acantholytic cells can help establish the histologic diagnosis. The laminated crusts are composed of multiple layers of dried pustules, one on top of the other, which result from previous episodes of vesicle and pustule formation at the site. The dermis contains perivascular to interstitial accumulations of mixed inflammatory cells. Eosinophils are the predominant inflammatory cell in approximately one-third of the canine and equine cases. Deposition of IgG at intercellular bridges in all layers of the suprabasilar epidermis or in the superficial epidermis demonstrated by IF or immunohistochemistry (IHC) is a feature of pemphigus foliaceus but is not specific for pemphigus foliaceus. With immunostaining there are frequent false-negative results (poor lesion selection or prior glucocorticoid or immunosuppressive therapy) and false-positive results (chronic skin lesions with plasma cells and secondary immunoglobulin diffusion into the epidermis); thus immunostaining must be interpreted carefully and in conjunction with clinical and histologic findings. Newer techniques that detect more specific antigens, such as desmocollin or desmoglein, and use of better substrates for indirect immunostaining may improve diagnostic accuracy of superficial forms of pemphigus in the future.

Pemphigus Vulgaris. Pemphigus vulgaris (PV) is a very severe form of pemphigus and has been reported in the horse, dog, and cat (see Table 17 -13). In the horse and dog, autoantibodies are formed against desmoglein 3, one of the prominent desmosomal proteins involved in adhesion of basal cells of the epidermis and mucosae. In addition, autoantibodies to other proteins involved in intercellular adhesion have been reported in some dogs with pemphigus SECTION II Pathology of Organ Systems pemphigus vulgaris). Prognosis of the autoimmune subepidermal blistering dermatoses is difficult to predict due to their rarity and the fact that immunologic studies have allowed more definitive diagnosis only in the past 15 years. However, reports indicate that for dogs treated with appropriate combination therapy, there may be complete remission during therapy, and there may be sustained remission after medication withdrawal in some cases. In domestic animals the autoimmune subepidermal blistering dermatoses include acquired junctional epidermolysis bullosa (dog), bullous pemphigoid (horse, pig, dog, cat), bullous systemic lupus erythematosus (dog), epidermolysis bullosa acquisita (dog), linear IgA bullous dermatosis (dog), mixed autoimmune subepidermal blistering dermatoses (dogs), and mucous membrane pemphigoid (dog, cat). In the dog, the species in which most autoimmune subepidermal blistering dermatoses have been documented, approximately 50% of the cases are mucous membrane pemphigoid, approximately 25% are epidermolysis bullosa acquisita, less than 10% are bullous pemphigoid, and the other disorders constitute the remainder. The basic features of subepidermal bullous dermatoses are listed in Table 17 -13. Bullous pemphigoid is described in the next section because it affects a wider range of species than the other autoimmune subepidermal blistering dermatoses.

Bullous Pemphigoid. Bullous pemphigoid (BP) is caused by autoantibodies directed against hemidesmosomal proteins. In human beings the autoantibodies are directed toward bullous pemphigoid antigen 1e (BPAG1e), a 230-kD intercellular antigen, and type XVII collagen (also called BPAG2), a 180-kD hemidesmosomal transmembrane molecule. In animals, type XVII collagen has been identified as the major antigen. Bullous pemphigoid has been reported in the horse, Yucatan minipig, dog, and cat. The pathogenesis of vesicle formation is thought to involve a type II immunologic response in which autoantibody binds to the target antigen, and complement activation develops (see Table 17 -5). This leads to mast cell degranulation, recruitment and activation of neutrophils and eosinophils, and release of a variety of proteolytic enzymes that result in loss of cell-to-matrix adhesion and in subepidermal vesiculation. It is also possible that autoantibodies might interfere directly with target antigen function or activate cellular signaling and induction of proinflammatory cytokines. Clinical lesions are similar between species and consist of vesicles, erosions, ulcers, and crusts. The location and severity of clinical lesions vary. In horses, lesions are severe and associated with systemic signs; involve the oral mucosa, the squamous lining of the esophagus, and the stomach in some cases; and are generalized in the skin (Fig. 17-56) . In Yucatan minipigs, lesions are usually limited to the skin of the back and rump. Dogs are usually mildly affected and have cutaneous lesions in the skin of the abdomen and axillae, concave pinnae, or mucocutaneous junctions. Oral lesions occur in approximately half the dogs. Cats usually have few lesions limited to the face and oral mucosa. Separation of the hemidesmosomes of the basal layer cells from the upper lamina lucida of the basement membrane leads to the microscopic lesions of vesicles and bullae, often with eosinophils and neutrophils in the superficial dermis or within the subepidermal vesicles. Lesions in dogs and pigs have more inflammatory cells than those in horses and cats. Direct IF staining most commonly reveals IgG and in some dogs complement, linearly distributed at the dermoepidermal junction. Evaluation of salt-split epithelial substrates with indirect IF reveals staining on the epithelial side of the artificial split, helping to differentiate bullous pemphigoid from epidermolysis bullosa acquisita, in which staining is located in the sublamina densa or dermal side of the artificial split. The presence of eosinophils is considered to be suggestive of bullous pemphigoid. autoantibodies to other proteins involved in intercellular adhesion have been identified. Some of the dogs diagnosed with pemphigus vegetans have not had oral lesions. In another dog with lesions suggestive of pemphigus vegetans, antibodies to desmoglein 1 rather than desmoglein 3 were identified; thus the rare cases of pemphigus vegetans diagnosed in dogs to date are not directly comparable to those in the human.

Panepidermal pustular pemphigus (PPP) refers to a form of pemphigus in the dog that has some of the features of pemphigus foliaceus, pemphigus vegetans, and pemphigus erythematosus. It appears to represent a variant of pemphigus foliaceus. The term was originally developed when a facially predominant form of pemphigus foliaceus was identified in Akitas, Chow Chows, and a few other breeds of dogs, and there appeared to be a need to reconsider the classification of pemphigus subtypes. The principal diagnostic feature used to distinguish dogs with panepidermal pustular pemphigus from those with pemphigus foliaceus is based solely on histopathologic evaluation: the presence of acantholytic cell-containing pustules that span all layers of the epidermis and the follicular infundibular ORS (e.g., pustules located in deeper epidermis than typical for pemphigus foliaceus [see Fig. 17-17, B] ). An explanation for the difference in pustule depth may simply reflect the regional variation in various antigens targeted by autoantibodies in different anatomic locations of canine skin. For example, it has been shown that desmoglein 1 can be identified on keratinocytes in all layers of the epidermis in skin from the dorsal muzzle, pinna, and pawpads, whereas desmoglein 1 is detected only in the upper layers of the epidermis in skin from the shoulder, groin, or abdomen. Thus the difference in desmoglein expression could influence pustule location. Further classification of subtypes of pemphigus requires in-depth studies, including immunopathology, as well as the results of therapeutic trials.

Bullous dermatoses are a rare group of autoimmune disorders clinically typified by vesicles or bullae in the skin and often oral mucosa, are caused by autoantibodies directed toward one or more antigens within the basement membrane zone, and are collectively termed "autoimmune subepidermal blistering dermatoses" (AISBDs) (see the discussion in the section on Structure, Basement Membrane Zone, and see Table 17 -13). The autoimmune subepidermal blistering dermatoses should be differentiated from the inherited/congenital bullous dermatoses (see section on Disorders of Domestic Animals, Congenital and Hereditary Disorders, Epidermolysis Bullosa [Red Foot Disease]), and from adverse reactions to drug therapy. Much of what is known about the autoimmune subepidermal blistering dermatoses has been borrowed from the human literature, where these diseases are classified based on clinical, histologic, and immunologic features that identify target antigens and autoantibodies. In domestic animals, due to the rarity of these diseases and difficulty and cost of producing stable recombinant antigens, in-depth immunologic classifications are typically limited to research laboratories and have been performed mostly in dogs; however, a few autoimmune subepidermal blistering dermatoses have been identified in the horse, pig, and cat. In the veterinary setting, diagnosis of these diseases is largely based on information obtained from previous research studies that have documented breed predispositions, clinical lesion distribution patterns, and histologic features that help identify lesions consistent with autoimmune subepidermal blistering dermatoses, and that rule out other diseases that can cause vesicles or bullae (e.g., vesicular cutaneous lupus erythematosus, dermatomyositis, and CHAPTER 17 The Integument superficial layers of the epidermis and/or hair follicles, hyperkeratosis and parakeratosis result in the clinical features of thick scale/crust and comedones.

Lupus Erythematosus Syndromes. Systemic lupus erythematosus (systemic lupus erythematosus ) is a multiorgan disease of dogs and rarely cats and horses. Factors involved in development include genetic predisposition, viral infections, hormones, and UV light. Systemic lupus erythematosus is a disease of immune dysregulation, with abnormalities in both cellular and humoral immunity, including defective T lymphocyte suppressor function and cytokine dysregulation. The defective T lymphocyte suppression function may be caused by anti-T lymphocyte antibodies or a primary suppressor T lymphocyte deficiency. The defective T lymphocyte suppression function results in B lymphocyte hyperactivity and in the formation of autoantibodies to a variety of membrane and soluble antigens, including nucleic acids. Antibodies are also directed to organspecific antigens, clotting factors, and cells (e.g., erythrocytes, leukocytes, and platelets). The antinuclear antibody titer should be positive. Although the autoantibodies can damage tissue, the principal mechanism of injury in systemic lupus erythematosus occurs via antigen-antibody binding (i.e., immune-complex formation), and deposition of the antigen-antibody complexes in a variety of tissues, including skin. The deposition of these immune complexes, which in the skin occurs at the basement membrane and in the walls of dermal blood vessels, results in a type III hypersensitivity response. Lesions are intensified by exposure to UV light. The enhanced damage may occur via UV-induced expression of nuclear antigens on the keratinocyte surface, autoantibody binding to the newly expressed antigens with resultant keratinocyte damage, and release of keratinocyte cytokines (e.g., IL-1, IL-6, and TNF-α). UV light may also act by inducing the expression of adhesion molecules, thus facilitating trafficking of leukocytes to the epidermis. Systemic signs are variable but can include polyarthritis, myositis, fever, anemia, proteinuria (from glomerulonephritis), and thrombocytopenia.

Cutaneous lesions are highly variable, can be localized or generalized, but commonly involve the face, pinnae, and distal extremities. Lesions consist of erythema, depigmentation, alopecia, scaling, crusting, and ulceration. Stomatitis or panniculitis can be present. Microscopic lesions include lymphohistiocytic interface dermatitis with basal cell apoptosis, pigmentary incontinence, and the presence of subepidermal vacuolization. The basal cell degeneration and subepidermal vacuolization can lead to formation of subepidermal vesicles, which can rapidly ulcerate and crust. Basement membrane thickening caused by accumulation of immune complexes and immune-complex vasculitis of small dermal vessels can also be seen.

Discoid lupus erythematosus (DLE), also called localized or chronic cutaneous lupus erythematosus (CCLE) and photosensitive nasal dermatitis, is seen most commonly in the dog but is rare in the horse. Historically, discoid lupus erythematosus has been considered to be a mild variant of systemic lupus erythematosus in which there is no involvement of other organ systems and the antinuclear antibody titer is negative. Clinical lesions of discoid lupus erythematosus consist of depigmentation, erythema, scaling, erosion, ulceration, and crusting and generally occur in the skin of the nasal planum, dorsal surface of the nose, and less commonly, the pinnae, lips, periocular region, and rarely in the oral mucosa. The nasal planum may lose the normal surface architecture and become atrophic, scarred, and bleed easily when traumatized. Discoid lupus erythematosus can be exacerbated by sunlight. Microscopic lesions include accumulations of lymphocytes and plasma cells at the dermalepidermal interface. In early cases the infiltrate can be sparse, but in some cases the lymphocytes and plasma cells are arranged in a dense bandlike pattern that obscures the dermal-epidermal

Keratinocyte Degeneration (Cytotoxic Dermatitis). Interface dermatitis, more recently referred to as cytotoxic dermatitis, is a histologic pattern of inflammation that affects the dermal-epidermal junction (interface), and that is importantly associated with damage to basal cells (see Fig. 17-14) or in some instances, more superficially located keratinocytes. Basal cells are damaged by oncosis (hydropic or vacuolar degeneration) or apoptosis (shrunken cells due to programed cell death), whereas damage to more superficial keratinocytes is typically due to apoptosis (see Fig. 17-12) . The inflammation can be sparse and referred to as cell poor, or dense and referred to as cell rich. This type of dermatitis is referred to as cytotoxic because the pathogenesis in part involves T lymphocyte-mediated cytotoxicity of epidermal basal cells or keratinocytes. The clinical features of this histologic reaction pattern are quite variable, the cause of which is not completely understood; however, the location of the apoptotic keratinocytes correlates to a degree with the clinical lesions. For example, if the apoptosis or cellular damage is more prevalent in the basal layer of the epidermis, depigmentation, erosions, and ulceration result from loss of basal layer keratinocytes and melanocytes. In contrast, if apoptosis is more prevalent in the interface lymphocytic dermatitis with hydropic degeneration of basal cells, keratinocyte apoptosis, and extensive vesicles and bullae at the dermal-epidermal junction that progress to ulcers. Mixed inflammation is present in ulcerated lesions, and subepidermal fibrosis may be extensive.

Lupus panniculitis is a rare manifestation of lupus erythematosus and is seen in dogs. Clinical lesions consist of nodules occurring predominantly in the subcutis of the trunk and proximal aspects of the legs. Histologic lesions consist of nodular masses of lymphoplasmacytic and histiocytic inflammation, often with fat necrosis. Vasculitis can also be present. In addition, there may be apoptotic basal cell degeneration, pigmentary incontinence, and thickening of the basement membrane.

Immunostaining in cases of lupus erythematosus may reveal the presence of immunoglobulin and sometimes complement or both at the basement membrane.

Epidermal Necrolysis. Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are uncommon to rare conditions affecting the skin and sometimes mucous membranes. They have been reported in human beings, horses, cattle, pigs, dogs, and cats. They have been studied most extensively in the human and less so in the dog. Until recently the conditions were considered to represent different expressions or severity of the same clinical disease with erythema multiforme at the mild end and toxic epidermal necrolysis at the severe end of the spectrum. However, in-depth studies scrutinizing the character and extent of clinical and histologic lesions in correlation with the clinical history have prompted a modification. Currently erythema multiforme in human beings is considered to be a separate entity with approximately 90% of cases associated with herpesvirus infection, and now called herpes-associated erythema multiforme (HAEM), but only viral fragments, such as DNA polymerase, and not complete virions are detected in erythema multiforme lesions and thus herpes-associated erythema multiforme is not a productive or active viral infection. Less commonly erythema multiforme in human beings is associated with other infections or is drug associated. In contrast, Stevens-Johnson syndrome and toxic epidermal necrolysis most often represent adverse reactions to drug therapy. Classification of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis in animals is controversial. The results of one multicenter study aimed at better defining these conditions in dogs suggested that although Stevens-Johnson syndrome and toxic epidermal necrolysis were likely to be associated with drug exposure, erythema multiforme was not. A variety of causes for animal erythema multiforme have been proposed, but are usually not proven. These include infections, neoplasia, and adverse responses to dietary substances, drugs, or vaccinations. Virus infections have been implicated as a possible cause of erythema multiforme in animals, including herpesviruses (horses, pigs, cats) and parvovirus (dogs), but these infections either are not proven definitively as a specific cause or they differ from herpes-associated erythema multiforme by being active or productive infections. Most cases of animal erythema multiforme remain idiopathic. Drugs (sulfonamides, cephalexin, levamisole, and others) appear to be the main cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in animals, but drug causation is not usually proven because of the unwillingness to purposely reexpose a patient to the suspected offending drug. However, a new disease-specific algorithm, termed Assessment of Drug Causality in Epidermal Necrolysis, has been validated in human beings with Stevens-Johnson syndrome/toxic epidermal necrolysis. It has been used in a few dogs and shows promise in helping determine if a drug may have contributed to development of toxic epidermal necrolysis interface. In addition, there are apoptotic basal cells resulting in loss of epidermal pigment that is phagocytosed by dermal macrophages (pigmentary incontinence). As with systemic lupus erythematosus , the basal cell degeneration can, in more severe cases, lead to subepidermal vesicles, loss of the epidermis, and ulceration and crusting. The major differential diagnosis of DLE includes mucocutaneous pyoderma (see section on Superficial Bacterial Infections, Diseases of Dogs), which is differentiated from DLE by the succesful treatment of mucocutaneous pyoderma with antibiotic therapy.

Mucocutaneous lupus erythematosus (MCLE) in dogs is a newly described disorder thought to be a variant of DLE. The condition most often affects German shepherd dogs between 4 and 8 years of age, but other breeds and ages of dogs may be affected. Female dogs are overrepresented. As with DLE, clinical signs suggestive of SLE are absent. Gross lesions occur most commonly in genital, perigenital, anal, and perianal regions, but may also affect periocular, perioral, and perinasal regions and consist of symmetrical, well-demarcated erosions and ulcers, often accompanied by erythema, crusting, and hyperpigmentation. Microscopic lesions are consistent with those described for cutaneous lupus erythematosus, but are often patchy and secondarily infected with bacteria. Focal basement membrane deposition of IgG is the most common immunologic finding. Several disorders require differentiation from MCLE. They include: 1. Mucocutaneous pyoderma, which is differentiated by its complete response to antibiotic therapy and lack of prominent erosions or ulcers 2. Mucous membrane pemphigoid (see Reactions Characterized

Grossly by Vesicles or Bullae as the Primary Lesion and Histologically by Vesicles or Bullae within the Basement Membrane (Bullous Dermatoses), which is differentiated by the usual significant oral involvement and presence of vesicles and scars in mucous membrane pemphigoid 3. Erythema multiforme (see section on Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis), which is differentiated by the presence of skin lesions in other, nonmucocutaneous sites in erythema multiforme 4. Discoid lupus erythematosus, which is differentiated by the usual restriction of lesions to the skin of the face in DLE. Exfoliative cutaneous lupus erythematosus was formerly known as lupoid dermatosis of the German short-haired pointer. Lesions develop in German short-haired pointers between 3 months and 3 years of age. Clinical lesions consist of scaling and crusting first seen on the face, ears, and back. Lesions then become generalized. The lesions persist but wax and wane. Fever and lymphadenopathy can be present. Rarely there is a positive antinuclear antibody titer. Histologic lesions consist of lymphocytic interface dermatitis with hydropic degeneration of basal cells and apoptosis of keratinocytes. Interface inflammation also affects the basal cells of follicles and sebaceous glands, resulting in sebaceous gland atrophy. Vesicular cutaneous lupus erythematosus is a disorder formerly known as ulcerative dermatosis of the collie and Shetland sheepdog. Lesions develop in middle-aged to older dogs. The Shetland sheepdog, rough collie, and border collie appear predisposed to lesion development. Dogs with this form of lupus have a negative antinuclear antibody titer, but some have antibodies to extractable (soluble) nuclear antigens (e.g., Ro/SSA and La/SSB). Clinical lesions develop most commonly in the groin and axillary areas but may also occur in the mucocutaneous junctions around eyes, mouth, external genitalia, and anus. Lesions consist of vesicles and bullae that progress to ulcers. Lesions can be cyclic and worsen in association with estrus. Lesions also tend to occur in spring and summer; season plus location in less-haired areas has suggested a possible role for sunlight in the pathogenesis of lesions. Histologic lesions include CHAPTER 17 The Integument purpuric (purple or red, due to hemorrhage) macules and patches that rapidly progress into painful confluent erosions. The epidermis detaches easily (necrolysis means separation of tissue due to necrosis) and forms large areas of translucent sheets that peel from the dermis. Lesions are often present on the face, medial pinnae, and mucocutaneous junctions (especially periocular and perilabial) but can be more widespread. Interdigital skin can be affected, and pawpad involvement is reported in some cases. Histologically, lesions resemble those in erythema multiforme and Stevens-Johnson syndrome with apoptotic keratinocytes in all levels of the epidermis or mucosa, usually accompanied by lymphocytes (lymphocytic satellitosis), but the number and location of apoptotic cells can vary. Full-thickness coagulative necrosis of the epidermis is also a feature. Hair follicles, particularly the follicular infundibulum, are similarly affected. Dermal inflammation in the acute lesions may be minimal and only present in small areas. When present, lymphocytes are at the dermal-epidermal interface and in the superficial perivascular dermis. The coagulative necrosis lesions in toxic epidermal necrolysis are distinguished from thermal burns by the lack of dermal necrosis in toxic epidermal necrolysis. The diagnosis of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis requires both clinical and histologic findings because although there are some histologic differences, those differences may be subtle or evade detection in individual cases for various reasons that include low sample number or sample ulceration. Thus these conditions cannot be reliably differentiated by histopathologic evaluation alone. The presence of systemic signs and the extent of clinical involvement that includes the presence or absence of mucosal lesions are paramount. Similarly, there are other conditions in which keratinocyte apoptosis is present in multiple layers of the epidermis that may require differentiation from some cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. These include graft-versus-host disease in which bone marrow transplantation has occurred (usually experimentally), exfoliative dermatitis in cats with and without thymoma (see section on Disorders of Cats, Paraneoplastic Syndromes), and proliferative, lymphocytic, infundibular mural folliculitis and dermatitis with prominent follicular apoptosis and parakeratotic casts in dogs (see section on Disorders of Dogs).

Feline Exfoliative Dermatitis with or without Thymoma. See Disorders of Cats, Paraneoplastic Syndromes.

Casts. See Disorders of Dogs.

and Histologically by Vasculitis or Thrombosis. The histologic diagnosis of cutaneous vasculitis is challenging because it can be difficult to distinguish between inflammatory cells targeting a vessel from inflammatory cells simply migrating through a vessel en route to an area of inflammation elsewhere in the epidermis or dermis. Disproportionate numbers of inflammatory cells in the vessel wall in comparison to the surrounding dermis suggest the vessel is a target of the inflammation. Vasculitis can be primary or secondary to systemic processes such as drug ingestion (e.g., sulfonamides), connective tissue disease (e.g., systemic lupus erythematosus), infections (e.g., R. rickettsii, E. rhusiopathiae), or it may be incidental to a local process such as ulceration or a thermal burn. In many instances the cause of the vasculitis is unknown (idiopathic). Two principal mechanisms are thought to contribute to the pathogenesis of vasculitis; these are direct invasion of vessels by infectious agents (e.g., Rickettsia, herpesvirus) and immune-mediated mechanisms (e.g., lesions. The pathogenesis in erythema multiforme, as well as Stevens-Johnson syndrome and toxic epidermal necrolysis, is thought to involve a misdirected cell-mediated (type IV) immune response against antigens (foreign peptides that are components of infectious agents, drugs, or others) expressed on the surface of keratinocytes. The main effector cells are the cytotoxic T lymphocyte (CD8 + lymphocyte) (see Table 17 -5) and natural killer lymphocytes that recognize and bind to the foreign peptide-MHC I complex on the surface of keratinocytes, resulting in apoptosis. In erythema multiforme the apoptosis of keratinocytes is typically patchy and associated with lymphocyte-mediated direct cytotoxicity, which contrasts to Stevens-Johnson syndrome and toxic epidermal necrolysis, where apoptosis is usually more extensive and in some areas may be confluent. The pathogenesis for the more extensive apoptosis in Stevens-Johnson syndrome and toxic epidermal necrolysis is unclear, but the number of inflammatory cells in affected human beings is considered too few to cause such widespread keratinocyte apoptosis. Soluble mediators, such as granulysin released by cytotoxic T lymphocytes and natural killer lymphocytes, and perforin and Fas ligand are considered responsible for the widespread keratinocyte death. The role of soluble mediators in the pathogenesis of Stevens-Johnson syndrome and toxic epidermal necrolysis in animals is unknown.

In animals, erythema multiforme has been studied most extensively in dogs and is initially characterized clinically by polymorphous papules, macules, or plaques that are distributed bilaterally and may coalesce and form circular areas of erythema with firm borders. Although some early lesions of erythema multiforme may resemble urticaria, in contrast to true urticaria, erythema multiforme lesions are not transient. The erythema disappears centrally, producing target-like lesions that are most common on the trunk, axillae, and groin but may be seen on the inner pinnae, footpads, and mucocutaneous junctions. The erythematous areas may progress to vesicles, erosions, ulcers, serpiginous erythematous lesions (see Fig.  17-12) , or thick, scaly, or crusted plaques. Erythema multiforme can occur in minor or major forms, depending on the extent of clinical involvement. In erythema multiforme minor, usually either mucosal surfaces are not involved or lesions are restricted to one site. In contrast, more extensive mucous membrane and cutaneous involvement are seen in erythema multiforme major, referred to as Stevens-Johnson syndrome (SJS) by some authors, in which clinical lesions may be more extensive, hemorrhagic, vesiculobullous, and ulcerative. Erythema multiforme may have a mild, self-limiting clinical course, and lesions may resolve, especially if the triggering factor is identified and removed. However, especially in dogs and unlike most cases of herpes-associated erythema multiforme in people, the clinical course tends to be chronic or relapsing and may last for years. Systemic signs have been described and are more likely to occur in more severe cases (e.g., erythema multiforme major or Stevens-Johnson syndrome). Histologically, individual keratinocytes in all layers of the epidermis undergo apoptosis (see Fig. 17 -12) and are surrounded by lymphocytes (lymphocytic satellitosis). Apoptotic keratinocytes can coalesce, leading to the clinically visible erosions and possibly ulcers. There are perivascular mononuclear cells in the dermis with minor obscuring of the dermal-epidermal interface.

In animals, toxic epidermal necrolysis is seen principally in dogs and cats, is a much more serious condition than erythema multiforme, and may overlap in the spectrum of gross and histologic lesions with Stevens-Johnson syndrome. Both Stevens-Johnson syndrome and toxic epidermal necrolysis are considered clinical emergencies with a high mortality rate in all species. Toxic epidermal necrolysis in particular is a life-threatening disorder that begins clinically as widespread, irregularly shaped, erythematous or infundibular hyperkeratosis and increased trichilemmal cornification; reduced numbers of growing (anagen) follicles; increased numbers of resting (telogen) hair follicles, which may vary with breed; and increased numbers of follicles that lack hair shafts and may also be atrophic (kenogen follicles, also called hairless telogen follicles). Although these general features, including increased numbers of kenogen follicles, support the diagnosis of an endocrinopathic dermatosis, they are not usually diagnostic for a specific endocrine disorder. Also, inflammation caused by secondary seborrhea or pyoderma or previous glucocorticoid therapy for concurrent allergic dermatitis frequently complicates the microscopic changes. Selected clinical and histologic features of individual endocrine disorders (e.g., clinical evidence of epidermal, dermal, and muscle atrophy and histologic evidence of mineral deposition in the case of hyperglucocorticoidism) in conjunction with medication history and clinical testing are used to establish a more definitive diagnosis. Cutaneous endocrine disorders are more common in dogs than in horses, ruminants, or cats.

Hypothyroidism. See Disorders of Dogs.

Hyperestrogenism. See Disorders of Dogs.

Hyposomatotropism. See Disorders of Dogs. 

Excessive grooming, particularly in cats, can result in symmetric alopecia or hypotrichosis that clinically resembles endocrine dermatoses. Excessive grooming can be the result of pruritus (usually associated with cutaneous hypersensitivity reactions) or allegedly from psychogenic problems such as boredom or stress (feline psychogenic alopecia). Excessive grooming has also been reported in feline hyperthyroidism. Thus it is important to determine if the alopecia or hypotrichosis is the result of excessive grooming and if so, what the underlying stimulus is.

Cat. See Disorders of Cats.

Follicular Dysplasia Syndromes. Follicular dysplasia syndromes, defined as incomplete or abnormal development of the structure of follicles and hair shafts, comprise a group of generally allergic, antibody-mediated cytotoxic, immune complex, or cell mediated). The type of inflammatory cell may suggest the pathogenesis. For example, eosinophils may predominate in allergic reactions (arthropod bites or collagenolytic granulomas), neutrophils may predominate in immunologic reactions associated with immune complex deposition (lupus erythematosus, some drug reactions), and lymphocytes may predominate in cell-mediated immune responses (malignant catarrhal fever). However, the cell type may simply reflect stage of disease rather than the mechanism, and in many cases the cellularity is mixed. In animals, type III hypersensitivity reactions (immune complex-mediated processes) are thought to contribute to many cases of immunologic vasculitis, but it is likely that multiple immunologic mechanisms contribute. Evidence for the role of immune complex deposition is derived from experimental studies (Arthus phenomenon and serum sickness) and from identification of immune complexes in serum and tissues in patients with vasculitis caused by infectious agents and hypersensitivity reactions to drugs. Thus infectious agents can contribute to immune complex-mediated vasculitis. The immune complexes can form in the circulation, in the vessel wall, or both.

Small arterioles, capillaries, and postcapillary venules are the most commonly affected vessels. Involvement of the deep vascular plexuses suggests a systemic component is contributing to the vasculitis. Clinical lesions include edema and hemorrhage and in severe cases in which thrombosis can develop, ischemic necrosis and infarction. Ulceration and sometimes sloughing of the skin can occur. In some cases, partial ischemia leading to alopecia and scarring are the main features. Histologic lesions may include the presence of variable numbers of intramural inflammatory cells, intramural or perivascular edema, hemorrhage, or fibrin exudation. Necrosis and fibrin exudation (fibrinoid necrosis) can occur but are rarely seen in small animals. Thrombosis may develop. There is often significant overlap in the clinical and histologic lesions of vasculitis, depending on the severity and stage of disease at the time lesions are examined. Vasculitis is most common in horses and dogs and is rare in cattle, sheep, pigs, and cats.

Information on this topic is available at www.expertconsult.com. 

(see Table 17 -9)

Hair cycle disorders of endocrine origin are due to imbalances in hormones and generally are manifested as nonpruritic, bilaterally symmetric alopecia or hypotrichosis. The remainder of the hair coat is dull, dry, easily epilated, and fails to regrow after clipping. The epidermis is often hyperpigmented or scaly. These lesions are referred to as endocrine alopecia. In disorders associated with alterations in sex hormones, the alopecia often begins in the perineal and genital areas and can extend cranially. However, it is not uncommon for a cutaneous endocrine disorder to have asymmetric alopecia and epidermal hyperpigmentation along with secondary pyoderma or seborrhea. Microscopically, uncomplicated endocrine disorders of the skin consist of normal, atrophic, or hyperplastic epidermis; epidermal hyperkeratosis and increased epidermal pigmentation; follicular

Cold agglutinin disease is an autoimmune disease that has rarely been reported in dogs and cats but can be seen in other species and is caused by the presence of autoantibodies directed against erythrocytes. The autoantibodies precipitate at cool temperatures (0° to 37° C) and dissolve on warming. Clinical lesions include erythema, hemorrhage, cyanosis, necrosis, and ulceration of the distal extremities (pinnae, tip of tail, pawpads, and nasal planum). Histologic lesions include thrombosis, coagulation necrosis, ulceration, and later inflammation associated with secondary infection. Blood vessels may be filled with homogeneous eosinophilic material (cryoglobulin). Cryoglobulins sometimes develop in association with other diseases, including B lymphocyte lymphoma, myeloma, autoimmune and connective tissue diseases, and infection. degree of alopecia) the hair coats regrew normally. Histopathologic evaluation is not described.

Idiopathic winter alopecia develops in otherwise healthy adult beef cattle in well-managed herds located in western Canada. Thorough clinical evaluations, skin scrapings, and biopsy samples have not identified a cause. The only clinical lesion is alopecia, which occurs most commonly on the dorsal midline but may develop in any site. Multiple animals in the herd develop alopecia, but bulls are affected more often than cows. Alopecia develops during late winter and early spring and spontaneously resolves in late spring or early summer. Timing of skin biopsy in affected cattle often coincides with a resolving phase of the alopecia and, as such, reveals a predominance of growing hair follicles, but no other lesions. Skin biopsy can be used to rule out other causes of alopecia but is not diagnostic. Clinical history and evaluations to rule out other conditions are also required for diagnosis.

Idiopathic (also called cyclic or seasonal) flank alopecia develops more commonly in dogs living in northern latitudes. The cause of this condition is not known, but changes in the photoperiod and thus melatonin released from the pineal gland might play a role. Many breeds are affected, but English bulldogs, boxers, and Airedale terriers are among the more commonly affected breeds. Alopecia develops fairly rapidly, seasonally or cyclically in the skin of the flank (Fig. 17-57) . Alopecia usually has a bilaterally symmetric pattern, but there may be variation in severity from one side to another, and alopecia may also involve more cranial areas of the skin such as the shoulder. There may be patches of unaffected (fully haired) skin located within alopecic areas. Hyperpigmentation usually accompanies alopecia. Histopathologic evaluation of the most alopecic areas in the relatively early stages of the disease reveals follicles in the telogen stage of the hair cycle, generally without hair shafts (hairless telogen/kenogen), and follicles markedly dilated by hyperkeratosis. The follicular hyperkeratosis also distends the openings of secondary follicles as they enter the primary follicle, giving the follicles the distorted appearance of an upsidedown "footprint" (see Fig. 17 -57). The portions of the primary and secondary follicles below the infundibulum may be present in irregular wavy configurations. Biopsy samples collected late in the clinical course of disease or in the stage just before hair growth resumes have numerous anagen follicles, which indicates hair regrowth should be forthcoming. The condition, as the name suggests, is often transient but can be recurrent.

Alopecia Related to Trauma. Traction alopecia in dogs and posttraumatic alopecia in cats are presumed a result of interference with the local blood supply to follicles and adjacent skin. Traction alopecia develops in long-haired breeds of dogs in which rubber bands or other devices are used repeatedly or continuously to apply tension to the hair. Lesions usually occur on the top of the head or on the ears, the location where the traction devices are usually applied. Posttraumatic alopecia has been reported in cats that have suffered traumatic pelvic fracture. Alopecic lesions develop on the lower or caudal back several weeks after the fracture. The gross lesion in both conditions is alopecia, which is long term and generally permanent. Histologically, in both traction alopecia and posttraumatic alopecia, follicles are in hairless telogen, are atrophic, and may be partially or completely lost and replaced by dermal fibrosis. Adnexal glands are also usually atrophic and may be absent. In traction alopecia some follicles may contain damaged hair shafts (malacic hairs) or melanin pigment debris, indicating previous poorly characterized disorders recognized most commonly in dogs (Box 17-11) but occasionally in horses, cattle, and cats. Structure refers to the permanent physical structure of the hair follicle in contrast to temporary changes that may occur cyclically. The conditions can be congenital (present at birth; see the section on Disorders of Domestic Animals, Congenital and Hereditary Disorders) or tardive (develop months to years after birth) (see Table 17 -9). Clinical lesions are alopecia or hypotrichosis, and consequently in animals that develop tardive structural follicular dysplasia, there may be clinical resemblance to the endocrine disorders. The microscopic features help to differentiate syndromes of follicular dysplasia from the endocrine dermatoses. Color-associated follicular dysplasia is discussed in the section on Responses of the Adnexa to Injury, Follicular Dysplasia.

Seasonal or Cyclic Alopecia. Alopecia apparently associated with seasonal change occurs in horses, cattle, and dogs. Little is known about the cause or pathogenesis of seasonal alopecia in horses because most reports are anecdotal, but it has been reported in four different situations. Icelandic horses in Austria developed recurrent areas of hair loss and scaling at the base of the ears, ocular lateral canthus, dorsal neck, and occasionally cranial shoulder. The hair loss developed in November, resolved in May or June, and recurred in November. The horses were otherwise healthy. Histopathologic evaluation of affected skin revealed the follicles were in a regressing stage of the hair cycle and dermal inflammation was minimal. Although the nutrient content of the feed (hay and silage in this case) was normal, supplements with vitamins, iodine, cobalt, and selenium prevented recurrence. In another situation, different horses developed alopecia in the spring or early summer with resolution in fall or early winter. Lesions were limited to the skin of the face. Two additional situations of excessive hair loss have been reported in association with spring shedding in horses with straight hair coats and some horses with curly hair coats. In horses with straight hair coats, lesions developed on the face, shoulder, and rump. In curly-haired horses the trunk and sometimes the mane and tail areas are affected. After the excessive shedding (hair loss to the of the face, ears, neck, distal extremities, pressure points, and mucocutaneous junctions. In uncomplicated cases, microscopic lesions consist of parakeratosis and sometimes hyperkeratosis. 

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See Disorders of Cats.

See Disorders of Dogs.

Primary Idiopathic Seborrhea. Primary idiopathic seborrhea is a disorder of epidermal hyperproliferation that results in increased production of corneocytes and visible scale. It occurs most commonly in dogs and less commonly in horses and cats. Most experimental work has been performed in cocker spaniels. The pathogenesis of the disease involves hyperproliferation of the epidermis, hair follicle infundibulum, and sebaceous glands. The basal cell labeling indices are three or four times higher in cocker spaniels with seborrhea than in normal dogs. The hyperproliferation results in reduction in the epidermal turnover time to approximately one-third (e.g., from 22 days to 8 days in the cocker spaniel). In the cocker spaniel the disorder appears to be the result of a primary cellular defect in the keratinocyte, because the epidermal cells remain hyperproliferative when grown in culture and after being grafted onto the dermis of normal dogs. However, the molecular basis of the defect has not been studied. In seborrhea, quantitative studies on sebum production have not been performed, but it is known that there is a relative increase in free fatty acids and a relative decrease in diester waxes on the surface of the seborrheic skin of various breeds. In addition, there is a change from nonpathogenic resident bacteria to pathogenic, coagulase-positive staphylococci. Clinically, two forms of seborrhea have been described, a dry form (seborrhea sicca), with dry skin and white-to-gray scales that exfoliate (see Fig. 17-9) , and a greasy form (seborrhea oleosa), with scaling and excessive brown to yellow lipids that adhere to the surface of the skin and hair. An animal can have seborrhea sicca in some areas of the body and seborrhea oleosa in others. Microscopic lesions include marked hyperkeratosis of the epidermis and follicular infundibulum. The epidermis has a papillary appearance caused by widening of follicular ostia by the follicular hyperkeratosis (see Fig. 17-9) . Comedones (follicles dilated with a plug of follicular stratum corneum and sebum) are present in some animals. At the edges of follicular ostia, foci of parakeratosis form over a spongiotic epidermis containing a few scattered leukocytes. The superficial dermis is congested and edematous.

traction and fracture of hairs. In posttraumatic alopecia, the shearing force is severe and abrupt and results in degeneration of pannicular adipose tissue and more extensive dermal and superficial subcutaneous scarring.

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Zinc deficiency occurs chiefly in pigs and dogs and is of less importance in ruminants. It results from diets containing high concentration of phytic acid (binds zinc), low concentration of zinc, or high concentration of calcium (reduces absorption of zinc) or from inherited defective absorption or metabolism. In cattle, sheep, and goats, cutaneous lesions include alopecia, scaling, and crusting of the skin 

Malnutrition can be primary (dietary deficiency of proteins, fats, carbohydrates, vitamins, minerals, amino acids, or fatty acids) or secondary (diet is adequate, but malnutrition results from nutrient malabsorption, impaired nutrient use, increased nutrient loss, or increased nutrient needs such as pregnancy, neonatal growth, disease states, or cold weather). Inadequate diets can involve imbalances between dietary nutrients (e.g., copper deficiency and molybdenum excess, and vitamin E deficiency and excess dietary fatty acids). Diets inadequate in one nutrient may be inadequate in multiple nutrients, or there may be a greater deficiency in one nutrient relative to the others (e.g., starvation; the diet may be inadequate in protein, fats, carbohydrates, and vitamins and minerals, or there may be a greater deficiency in protein relative to other nutrients). A variety of nutritional deficiencies result in similar cutaneous lesions. The lesions heal when the animal is fed a balanced diet. Deficiencies affecting the skin include protein-energy malnutrition (starvation), fatty acid deficiency, vitamin deficiencies (A, C, E), and deficiencies of riboflavin, pantothenic acid, biotin, niacin, iodine, cobalt, copper, and zinc. A few selected deficiency conditions are described.

Protein-calorie malnutrition results in a range of clinical syndromes from inadequate dietary intake of protein and calories to meet the needs of the body. Often diets are deficient in multiple components, including protein, carbohydrates, and fats, which together are responsible for the total caloric intake. Deficiency of calories per se results in weight loss (adults) or retarded growth (young growing animals) and reduced subcutaneous fat and muscle, producing a thin, emaciated appearance. Increased energy demands, such as pregnancy or cold weather, can worsen the severity of the malnutrition, leading to ketosis in pregnant sheep, birth of weak neonates or dead fetuses, lack of estrus cycles, and death. A greater deficiency

Copper is an essential component of tyrosinase, an enzyme critical in melanogenesis. Animals with copper deficiency or depressed tyrosinase activity have depigmented hair or wool. Copper deficiency can be the result of simple deficiency or secondary to excessive dietary sulfate and molybdenum, which interfere with absorption. This pigmentary disorder is seen primarily in cattle and sheep. Affected cattle with normally black coats become rusty brown and develop "spectacle" lesions of depigmented hair around the eyes. Black sheep develop intermittent bands of light-colored wool corresponding to periods of restricted availability of copper. The deficiency of copper also affects the physical nature of the wool or hair. In sheep the wool has less crimp, prompting the colloquial name of "string" or "steely" wool. The straightness of the wool is the result of a disorder of keratinization, probably caused by imperfect oxidation of sulfhydryl groups in prekeratin, a process that involves copper.

of protein relative to calories also results in malnutrition, referred to herein as protein deficiency. In early stages, protein deficiency malnutrition resembles that from deficiency of calories and results in weight loss and reduced production (e.g., milk) in adults and reduced growth in young animals. In addition, prolonged protein deficiency also results in edema caused by the reduction in the concentration of the serum protein, albumin. Because of the requirement of protein for the production of hair coat, the hair coat of malnourished animals (protein-calorie malnutrition and protein deficiency) is thin and dull, with failure to shed or to complete the normal hair cycle. The epidermis, dermis, and adnexa are atrophic with reduced subcutaneous fat and muscle, and surface scales (hyperkeratosis) can be present. In long-standing severe protein deficiency, dermal and subcutaneous edema is present.

has not been identified. Lesions may be mild at birth and progress with age. The skin becomes thickened, folded, and covered by platelike scales separated by shallow fissures in which hairs are entrapped. More severe lesions are seen where hair is shorter, particularly on the limbs, abdomen, and nose. Microscopically, the epidermal surface is wrinkled, variably thickened by acanthosis, and covered by prominent laminated orthokeratotic hyperkeratosis.

Ichthyosis in dogs is usually divided into two basic subtypes, epidermolytic and nonepidermolytic, based on the presence or absence of vacuolization of the keratinocytes of the superficial stratum spinosum and granulosum in conjunction with hyperkeratosis. The molecular basis of canine ichthyosis rarely has been investigated; however, recently transglutaminase 1-deficient recessive lamellar ichthyosis, an autosomal recessive inherited disorder in Jack Russell terrier dogs, has been described. The disease is nonepidermolytic and resembles lamellar ichthyosis in human beings, which is associated with defects in the cornified cell envelope and is caused by mutations in the transglutaminase 1 gene. Transglutaminases catalyze cross-linking of proteins that form the cornified envelope. Clinical lesions in Jack Russell terriers include generalized adherent and loosely attached scales, as well as large, adherent white or tan scales in sparsely haired skin (Fig. 17-58) . Pawpads are moderately hyperkeratotic, and claws are soft. Secondary infection with coccoid bacteria and yeast are common, likely the result of the epidermal barrier defect. Histologic lesions consist of laminated to compact hyperkeratosis of the epidermis and follicular infundibulum without epidermolysis. Secondary infections result in inflammation. Ultrastructurally, many layers of corneocytes are present. Corneocytes have irregular margins and linear or oval lamellar inclusions and in comparison to control animals, thin or less prominent cornified envelopes.

Perhaps the most common form of nonepidermolytic hyperkeratosis in dogs occurs in young, otherwise healthy golden retrievers. The mode of inheritance is autosomal recessive, and the genetic defect is due to a mutation in the PNPLA1 gene. The protein encoded by this gene belongs to the patatin-like phospholipase (PNPLA) family, and is important in lipid metabolism. A genetic test is available that can detect carriers (heterozygous for the mutation) as well as affected dogs (homozygous for the mutation). PNPLA1 is important in formation of the epidermal lipid barrier. Clinical lesions vary in severity and consist of large flat scales on the surface of the skin and within the hair coat. Pawpads and nasal planum are not affected. Histologic lesions consist of mild to Ichthyosis. The ichthyoses are a heterogeneous group of inherited skin disorders seen principally in cattle and dogs (see E-Box 17-2). In severe forms of ichthyosis the skin is thickened by marked scaling and can crack into plates resembling fish scales; thus the disease is named "ichthys" from the Greek word meaning fish. Recently advances in molecular diagnosis have improved the understanding of the defects in some of these disorders. In human beings, most of the ichthyoses are associated with defects in the epidermal barrier, including the intercellular lipid layers, cornified envelope, and keratin proteins. These defects result in increased production of stratum corneum (scaling) characteristic of the disease and can result in an increased prevalence of secondary infections. Recently, molecular defects similar to those in the human ichthyoses have been identified as a cause of some forms of ichthyoses in cattle and dogs.

In cattle, two forms of the disease have been described; both are thought to have an autosomal recessive mode of inheritance. One (ichthyosis fetalis) is lethal, and most calves are stillborn or die within days of birth. Ichthyosis fetalis markedly resembles harlequin ichthyosis in human infants. Defects in a gene (ABCA12, a member of the adenosine triphosphate [ATP]-binding cassette family) have been identified as a cause of harlequin ichthyosis. The ABCA12 gene is involved in the production of a protein necessary for lipid transfer in lamellar granules, a process required for formation of intercellular lipid layers and epidermal barrier structure and function. Because of barrier dysfunction, infants with harlequin ichthyosis develop excessive loss of fluids (dehydration) and life-threatening infections in the first few weeks of life. A loss of functional ABCA12 protein disrupts the normal development of the epidermis, resulting in the hard, thick scales characteristic of harlequin ichthyosis. Recently a mutation in ABCA12 has been identified in Chianina cattle, one of the breeds of cattle known to develop ichthyosis fetalis, confirming the similarity of the genetic defect for the disease in cattle and human beings. Grossly, thick cornified plaques separated by fissures cover the skin in affected calves. Fissuring of the skin can lead to exudation of protein and secondary bacterial and fungal infections that often lead to death or euthanasia. The ears may be small, and there may be eversion of the eyelids, lips, and other mucocutaneous junctional areas. Microscopically, the epidermis is thickened by marked compact hyperkeratosis with variable parakeratosis. The follicular infundibulum is also affected, and stratum corneum surrounds entrapped hairs. In the less severe form of ichthyosis in cattle (ichthyosis congenita), the molecular defect 

important structural proteins in the epidermis, and defects can be associated with irregular keratin filament aggregation and loss of strength, resulting in disruption of keratinocytes, especially in association with trauma. In Norfolk terrier dogs the clinical lesions include scaling and epidermal fragility, and the superficial epidermis can slough after mild mechanical trauma. Pigmented scaling, especially in intertriginous areas, is present. Pawpads, claws, and hair are normal. Histologically, there is papillary epidermal hyperplasia with minimal to moderate hyperkeratosis, large keratohyalin granules, and disruption (epidermolysis) and clefting of granular cell keratinocytes (see Fig. 17-59) . Ultrastructurally, keratinocytes in the upper stratum spinosum and granulosum have a reduction of tonofilaments and abnormal filament aggregation.

Sebaceous Adenitis. Sebaceous adenitis, inflammation of sebaceous glands, occurs most commonly in dogs, rarely is seen in cats, and has been reported in one horse. Two basic types of clinical appearances of sebaceous adenitis have been reported in the dog and include the type seen in long-coated breeds and the type seen in short-coated breeds, but due to the distinctly different clinical presentation of lesions in the short-haired breeds of dogs, it has been suggested that sebaceous adenitis in these breeds is a separate entity. More commonly affected long-haired breeds include the standard poodle, Akita, English springer spaniel, Havanese, German shepherd, and Samoyed, but many other breeds may be affected. More commonly affected short-haired breeds include the vizsla, miniature pinscher, beagle, and dachshund. The cause and pathogenesis are uncertain, but an inherited component of the disease is proposed for the standard poodle and Akita. Immunohistologic studies have shown a predominance of antigen-presenting dendritic cells and T lymphocytes in areas of sebaceous gland inflammation, suggesting a cell-mediated immunopathogenesis. Clinical lesion severity and location vary between breeds of dogs, but in long-haired breeds, scaling with formation of fronds of keratin adherent to hair shafts (follicular casts) and a progressively poor, dry, brittle hair coat are consistently present. Hair loss often begins in more cranial and dorsal regions, but the tail may be severely affected in some cases. The hair coat may become lighter or darker, and in poodles hairs that develop after disease onset are wavy or straight rather than tightly curled (see Fig. 17 -30). Secondary bacterial folliculitis and otitis externa commonly develop. In the short-haired breeds of dogs, clinical lesions develop on the trunk and occasionally face and consist of focal, firm plaques and nodules with alopecia and adherent scale that may expand and coalesce. Hair casts may be present, but secondary bacterial folliculitis is rare. In some instances edematous swellings of the face or severe pinnal ulceration may develop, which are not a feature of the disease in long-haired breeds and suggest the short-haired form of sebaceous adenitis is a different entity. Cats have multifocal, circular areas of hair loss, scaling, crusting, and follicular keratin casts that begin on the head, pinnae, and neck and spread caudally. Progressive patches of nonpruritic scaling, crusting, alopecia, and leukoderma are reported in the horse. The reason scaling and alopecia develop in association with loss of sebaceous glands is speculative. Microscopic lesions include lymphocytes, neutrophils, and macrophages that efface sebaceous glands and sometimes form microscopic granulomas (see Fig. 17-30) , and in some dogs, extensive orthokeratotic hyperkeratosis. Chronically affected dogs have no remaining sebaceous glands, but mild residual inflammation and fibrosis are present in the perifollicular dermis near the isthmus (site normally occupied by sebaceous glands). Sebaceous gland inflammation or loss can occur in other conditions such as folliculitis, demodicosis, uveodermatologic syndrome, or leishmaniasis, in which the inflammation primarily targets other areas of the moderate compact orthokeratotic hyperkeratosis without epidermal acanthosis, epidermolysis, or dermal inflammation. Ultrastructurally, affected dogs have more cohesive corneocytes and more numerous corneodesmosomes, suggesting that the disorder may be caused by delayed degradation of corneodesmosomes.

The molecular basis of an autosomal recessive inherited form of epidermolytic hyperkeratosis recently has been described in Norfolk terrier dogs that have a mutation in the gene that encodes for keratin 10 (KRT10). Similar histologic lesions have been seen in a few other breeds of dogs (Fig. 17-59) . This condition is similar to epidermolytic hyperkeratosis in human beings, caused by defects in keratin proteins 1 and 10. Keratin intermediate filaments are 

Melanocytes produce melanin pigments that are responsible for the coloration of the hair, skin, and eyes and play an important role in photoprotection. In addition, melanocytes are also present in the inner ear, where they function to control ion transport and the function of the inner ear, and the absence of melanocytes can result in deafness. Melanin is synthesized by melanocytes, which are dendritic cells originating as melanoblasts in the neural crest. Melanoblasts develop in the neural crest and migrate to peripheral sites, including the basal and lower spinous layers of the epidermis, hair follicles, and dermis. Melanoblasts differentiate into melanocytes and synthesize melanosomes and melanin. Tyrosinase, a coppercontaining enzyme, plays a critical role in the synthesis of melanin. Genetic mutations affecting any of the steps in the formation of melanin can lead to hereditary hypopigmentation. Many types of exogenous influences, such as inflammation, UVR, endocrinopathies, autoimmune diseases, and nutritional status, can affect melanocytes in the skin, resulting in acquired hypopigmentation or hyperpigmentation.

Disorders associated with reduced pigment can (1) be inherited or acquired, (2) involve skin or hair, (3) be generalized or localized, or (4) be idiopathic or linked with other diseases. Reduction in pigmentation of the skin is leukoderma and of the hair is leukotrichia. Leukoderma and leukotrichia can occur independently. They can result from a decrease in melanin (hypomelanosis), a complete absence of melanin (amelanosis), or from a loss of existing melanin (depigmentation). These events result either from an absence of the pigment-synthesizing melanocytes or from a failure of melanocytes to produce normal amounts of melanin or to transfer it to adjacent keratinocytes. Because copper is a component of tyrosinase, production of melanin pigment depends on copper; thus copper deficiency can result in reduced pigmentation.

Hereditary hypopigmentation can be divided into hypomelanocytic/amelanocytic hypomelanosis, characterized by a reduction in or absence of melanocytes in affected areas, and hypomelanotic/amelanotic hypomelanosis, in which melanocytes are present but defective. Hypopigmentation can be localized, focally extensive, or generalized. Mutations that cause hypopigmentation can interfere with melanocytes at specific points in their development and function leading to specific syndromes, including: (1) melanoblast migrations (Waardenburg syndrome, piebaldism), (2) melanin synthesis in the melanosome (oculocutaneous albinism), (3) melanosome formation within melanocytes (Chédiak-Higashi syndrome), and (4) mature melanosome transfer to the tips of the dendrites (Griscelli syndrome in human beings as has been suggested for color-associated follicular dysplasia in Münsterländer dogs and possibly other dog breeds). Failure of melanocytes to migrate, differentiate, and survive can result in deafness, and thus animals with Waardenburg-like syndrome or piebaldism may be deaf.

Syndromes analogous to the human Waardenburg syndromes have been reported in horses, dogs, and cats. In this hypomelanocytic disorder, there is failure of melanoblasts to migrate from the neural crest to the skin, eye, and inner ear or failure to survive in those locations. Affected animals typically have white coats and blue or heterochromatic irides and are deaf. In dogs this syndrome has been described in breeds such as the Dalmatian, bull terrier, Sealyham terrier, collie, and Great Dane. In horses and dogs the condition is inherited as an autosomal dominant trait with incomplete penetrance. In the cat the inheritance is skin (follicles, epidermal cells, or dermis) and involves the neighboring sebaceous glands because of their proximity to the inflammation. Thus these conditions are histologic differential diagnoses for sebaceous adenitis predominantly in dogs.

Comedones (see Table 17 -6) occur in numerous skin disorders, including those associated with surface trauma (callus, solar dermatosis), endocrine dermatosis (especially hyperadrenocorticism), nutritional or inherited disorders of cornification (primary seborrhea, vitamin A-responsive dermatosis), and in some disorders associated with follicular infection (especially demodicosis). In addition, comedones are prominent in three conditions wherein the comedones are considered a major feature of the disease.

Acne. Feline acne develops in the skin of the chin, lower lip, and less commonly upper lip. Cats of a variety of ages, sexes, and coat lengths are affected. The cause and pathogenesis are unclear, but defects in follicular cornification and poor grooming habits have been suggested. Gross lesions consist of comedones that can progress to papules, crusts, nodules, and diffuse swelling. Histologic lesions begin as mild follicular hyperkeratosis and progress to comedones, which can become secondarily infected by bacteria, result in folliculitis, follicular rupture (furunculosis), and localized to diffuse dermatitis, panniculitis, and cellulitis. M. pachydermatis may contribute to cases of chin acne that are refractory to therapy.

Canine acne is a chronic disorder that develops in the skin of the chin and lips of young dogs, usually with short hair coats. The cause of the disorder is not known, but a follicular cornification disorder has not been definitively documented. Early lesions consist of follicular papules and comedones that with time enlarge to nodules that can ulcerate and drain. Histologically, early lesions consist of moderate to marked follicular hyperkeratosis (the papules and comedones) and later of folliculitis, furunculosis, and draining sinuses (the nodular, ulcerated, and draining lesions).

Equine Coronary Band Dystrophy. See Disorders of Horses.

Secondary Seborrhea. Secondary seborrhea is not a primary disorder of cornification; however, it clinically resembles the primary cornification disorders (dry exfoliative or greasy adherent scales) and thus needs to be differentiated from them. Secondary seborrhea is common and is caused by a variety of unrelated cutaneous disorders such as allergy; ectoparasitism; bacterial, demodectic, and fungal infections; dietary deficiency; endocrine disease; and internal diseases. The lesions of secondary seborrhea resolve completely if the underlying disease is eliminated. Microscopic changes include epidermal and follicular hyperkeratosis with or without parakeratosis plus the lesions associated with the underlying disease. Acquired Hypopigmentation. Acquired hypopigmentation follows damage to the epidermal melanin unit by various insults, including trauma, inflammation, radiation, contactants, endocrinopathies, infections, nutritional deficiencies, and neoplasia. In general the severity of the injury determines whether an insult will result in hypopigmentation or hyperpigmentation. Mild injury results in pigmentary incontinence and epidermal hypopigmentation from death of melanin-containing keratinocytes. However, hyperpigmentation can occur, possibly from release of melanocytestimulating factors from surviving keratinocytes and subsequent increase in production of melanosomes. It is thought that these factors are present in normal epidermis, but their level or activity is increased in response to stimulation or keratinocyte stress. In contrast, severe injury results in the death of melanocytes, which do not regenerate, and thus there is no repigmentation.

Vitiligo is a hypomelanocytic hypomelanosis of human beings and animals that is characterized by gradually expanding pale macules that are often symmetric or segmental in distribution. The immediate cause of vitiligo is the destruction of melanocytes. Theories regarding the pathogenesis of this disease include autoimmune destruction of melanocytes, a neurogenic theory involving release of a neurochemical from peripheral nerves that inhibits melanogenesis, a self-destruction theory that involves failure of protection of melanocytes against the toxic effects of melanin precursors, or a combination of factors. Vitiligo has been described in horses, cattle, dogs, and cats. The condition is best characterized in Belgian Tervuren dogs. The depigmentation in this breed occurs chiefly on the pigmented skin and mucous membranes of the face and mouth in young adult dogs. Histologic examination of affected skin reveals epidermis devoid of both pigment granules and DOPA-positive cells. Electron microscopy confirms the lack of melanocytes in the lesions, their place being taken by Langerhans or indeterminate dendritic cells.

Uveodermatologic syndrome (Vogt-Koyanagi-Harada [VKH]like syndrome) is a rare syndrome of histiocytic interface dermatitis and granulomatous uveitis in dogs, particularly Akitas, Chow Chows, Samoyeds, Alaskan malamutes, and Siberian huskies. The strong breed associations suggest there is an inherited basis for this disease. In fact, in the Akita, specific dog leukocyte antigen (DLA) class II gene alleles appear to predispose to the development of this disease. The pathogenesis is thought to involve an immune-mediated attack against melanin or melanocytes, particularly a T helper lymphocyte cell-mediated immune attack against melanocyte antigens, but humoral immune responses may also play a role. Ocular lesions usually develop before cutaneous lesions and are more important because they may lead to blindness. Clinical lesions consist of symmetric patchy to diffuse depigmentation of the skin of the nose, lips, eyelids, scrotum or vulva, anal skin, ears, and pawpads. Lesions are occasionally more widespread. Leukotrichia of adjacent hair can be present. Uncommonly, lesions are more severe and consist of erosion, ulceration, and crusting. Fully developed histologic lesions are cell-rich interface inflammation, primarily of histiocytic cells containing melanin pigment (pigmentary incontinence). The inflammation occurs parallel to the epidermal surface but usually does not obscure the interface and may extend around adnexa. Basal cell degeneration is uncommon.

Cutaneous depigmentation in horses and dogs can result from contact with rubber. The monobenzene ether of hydroquinone, a common ingredient in rubber, inhibits melanogenesis. In horses, lesions result from contact with equipment such as rubber bit guards, crupper straps, or with feed buckets (lips, buttocks, and face). In dogs, lesions result from contact with rubber dishes or toys (lips or nose).

autosomal dominant with complete penetrance for the loss of pigmentation and an incomplete penetrance for the inner ear degeneration.

Overo lethal white foal syndrome, analogous to human Waardenburg syndrome type 4 (Hirschsprung's disease), has been reported in American paint horses in which white foals from the breeding of two overo spotted paint horses are born with aganglionic colons. The condition has autosomal recessive inheritance and is the result of a genetic mutation in the endothelin signaling pathway, which is critical for correct development and migration of neural crest cells. Neural crest cells give rise to melanocytes and enteric neurons. These foals develop colic from greatly distended colons and die or are euthanized shortly after birth.

Piebaldism is also a form of genetic hypomelanocytic hypomelanosis resulting in multifocal white patches in which there is an absence of melanocytes because of either a congenital failure of melanoblasts to migrate from the neural crest to the skin or their inability to survive and proliferate in the skin. Piebaldism has been seen in many species, including horses, cattle, dogs such as the Dalmatian, and cats.

The various forms of albinism are examples of hypomelanotic hypomelanosis. In albino animals and human beings, melanocytes are present and normally distributed but are defective in function and fail to synthesize melanin. The extent of the biochemical defect varies, so that albinism covers a spectrum from amelanosis, oculocutaneous albinism, through graded pigmentary dilution. Oculocutaneous albinisms and pigment dilutions are inherited as autosomal recessive traits associated with a variety of gene mutations. A partial gene deletion of SLC45A2 has been reported to cause oculocutaneous albinism in Doberman pinscher dogs that develop melanomas in the skin, lips, eyelids, and iris.

Chédiak-Higashi syndrome in human beings; Hereford, Brangus, and Japanese black cattle; Persian cats; and various other animal species is an example of partial albinism and is inherited as an autosomal recessive trait. Although melanin is produced, there is a mutation of the beige gene, which plays a major role in generating cellular organelles. This results in a membrane defect leading to the formation of giant melanosomes that are transferred with difficulty to the keratinocytes. The clumping of these giant melanosomes produces the color dilution effect. Chédiak-Higashi syndrome is discussed with the hematopoietic system (see Chapter 13).

Cyclic hematopoiesis (cyclic neutropenia), a lethal hereditary disease of collie dogs, is caused by a mutation in the canine AP3B1 gene, which results in decreased neutrophil elastase enzymatic activity. This is an autosomal recessive genetic disorder with a pleiotropic effect on coat color dilution. Affected dogs are silver-gray. The abnormal hair pigmentation results from the diminished formation of melanin from its precursor tyrosine rather than from pigment clumping. The normal collie coat color is partially restored in animals receiving bone marrow transplants to correct cyclic hematopoiesis. The hematologic aspects of this disease are considered in the discussion on the hematopoietic system in Chapter 13.

Coat color dilution has been reported in many species. It occurs in many breeds of horses, cattle, dogs, and cats but is particularly common in Siamese cats. Clumping of large melanin granules in hair shafts and hair matrix cells is responsible for the pale coat coloration. Similarly clumped melanin granules occur in epidermal melanocytes. In cats, dilute coat color is thought to be a result of an autosomal recessive trait (Maltese dilution) due to a single-base deletion in melanophilin. One or more mutations within or near the melanophilin gene are also responsible for the coat color dilution in dogs. CHAPTER 17 The Integument collagenase). Some indolent ulcers on the upper lip of cats have areas of flame figures and granulomatous inflammation and are considered to be eosinophilic granulomas. 

Nodular granulomatous inflammatory disorders without microorganisms are listed in Box 17-14. The diseases in this category have traditionally been considered to be sterile because no microorganisms have been identified by microscopic examination, including with special stains or IHC for organisms, by electron microscopic examination, by cultures, or by cytologic evaluation for organisms. However, newer techniques, including PCR that detects minute amounts of DNA, suggest the potential for microbial participation in the pathogenesis of some of these seemingly sterile inflammatory disorders, especially in human beings. It is possible, for instance, for an abnormal immune response to an as yet unidentified microbial antigen to initiate a macrophage-dominated inflammatory response. Defective downregulation of the immune response to the organism could lead to a persistent granulomatous inflammatory process. Currently this issue remains unresolved, but as more of these lesions are probed for microbial agents, a better understanding of these so-called sterile inflammatory disorders will hopefully develop. It is considered important, when possible, to use newer techniques such as PCR in these cases before considering them to be sterile.

Pyogranuloma Syndrome). Idiopathic sterile granuloma and pyogranuloma, or sterile pyogranuloma syndrome, are seen most commonly in dogs and rarely horses and cats, are of unknown cause, and are characterized grossly by single or multifocal papules, plaques, or nodules most commonly in the skin of the head and extremities. Early microscopic lesions include periadnexal to coalescing nodular accumulations of leukocytes predominantly consisting of macrophages (histiocytes), neutrophils, and lymphocytes. Organized granulomas and pyogranulomas are present. Older lesions can efface adnexa and extend into the subcutis. Neither microorganisms nor foreign material are found microscopically, and cultures and cytologic evaluation for organisms are negative. The lesions must be differentiated from those of the infectious granulomatous disorders and reactive histiocytosis in dogs.

Canine Langerhans Cell Histiocytosis. See Disorders of Dogs.

In dogs, hypopigmentation can occur in immune-mediated diseases targeting the dermal-epidermal interface, such as lupus erythematosus and dermatomyositis, and in association with neoplastic conditions, such as epitheliotropic lymphoma (mycosis fungoides). The hypopigmentation develops from injury and subsequent loss of the melanin-containing keratinocytes or melanocytes. Leukotrichia (depigmentation of hair) can be seen in the healing stage of alopecia areata, an immune-mediated condition characterized clinically by alopecia and microscopically by lymphocytic inflammation of the hair bulb. Table 17 -3 and Box 17-12.

Acanthosis Nigricans. See Disorders of Dogs.

Secondary Hyperpigmentation. Hyperpigmentation can result from a wide range of stimuli, including inflammation, trauma, metabolic disorders, drug therapy (e.g., doxorubicin), subtotal injury to basal layer cells from irradiation, moderate heat, or immunemediated disorders, and some conditions for which the cause is unknown (alopecia X). Consequently, hyperpigmentation is seen in all species with epidermal melanin pigment. Hypermelanosis results from an increased rate of melanosome production, an increase in melanosome size, or an increase in the degree of melanization of the melanosome. It is usually associated with an accelerated melanocyte turnover with an increased number of melanosomes.

Disorders characterized by infiltrates of eosinophils or plasma cells are listed in Box 17-13. In addition to the syndromes discussed herein, eosinophils are often a prominent feature of hypersensitivity or parasitic dermatoses, especially in cats and horses, and are also often a feature in feline herpesvirus dermatitis.

Eosinophilic Granulomas (Collagenolytic Granulomas). Eosinophilic and granulomatous lesions with brightly eosinophilic, granular to amorphous material bordering collagen fibers and somewhat obscuring the fiber detail (flame figures) occur in horses, dogs, and cats. The causes of these syndromes are poorly understood. The tinctorial change can develop in any lesion with large numbers of eosinophils such as reactions to parasites, foreign bodies (including hair), or in mast cell tumors and in some cases of cutaneous lymphoma. Eosinophils congregate and degranulate near collagen bundles, causing the tinctorial change. Eosinophil degranulation results in release of a wide range of toxic granule proteins (e.g., major basic protein), enzymes (peroxidase, collagenase), cytokines (IL-3, IL-5, granulocyte-macrophage colony-stimulating factor [GM-CSF]), chemokines (IL-8), and lipid mediators (leukotrienes and platelet-activating factor) augmenting an inflammatory response. Gross lesions include papules, nodules, plaques (sometimes linear), and ulcers in the skin (see Fig. 17-22) . Nodular or ulcerated lesions can also develop in the oral mucosa of dogs and cats and in the pawpads of cats. Microscopically, nodular dermatitis (or stomatitis) consists of an inflammatory response with a prominence of eosinophils, flame figures, and macrophages, some of which are multinucleated (see Fig. 17-22) . Collagen lysis develops in some lesions, likely a secondary event caused by the proteolytic enzymes (e.g.,

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Sebaceous gland adenoma, skin, dog. This common tumor of sebaceous glands often protrudes above the epidermal surface. The tumors are hairless, greasy, and may be shiny due to the sebaceous gland secretion.

Lobules of well-differentiated sebaceous glands are present in the dermis and cause polypoid elevation of the overlying epidermis. A duct with sebaceous secretion is also present. H&E stain.

Note the close resemblance of the lobules of tumor cells to those of nonneoplastic sebaceous glands, a feature suggesting benign behavior. H&E stain.

Squamous cell carcinomas, skin, abdomen, dog. Note multiple ulcerated squamous cell carcinomas in nonpigmented, sparsely haired abdominal skin. These are solar-induced squamous cell carcinomas that developed in a beagle dog living outdoors in a high-altitude region where the level of UV light from the sun is increased.

Neoplastic cells that have arisen from the epidermis (above center) have invaded the dermis and formed irregular islands of cells with squamous differentiation. H&E stain. †

Islands of neoplastic cells with squamous differentiation have invaded the dermis and are surrounded by proliferating fibroblasts and collagen (desmoplasia). H&E stain. †

Cutaneous histiocytoma, skin, nose, dog. Circular raised alopecic tan nodule is present. Cutaneous histiocytomas frequently spontaneously regress. Inset, Section of cutaneous histiocytoma illustrating the nonencapsulated, solid dermal mass protruding above the epidermal surface.

Cutaneous histiocytoma, skin, dog. The histiocytoma elevates the epidermal surface and consists of a solid mass of histiocytic cells. H&E stain. † Cutaneous histiocytoma, skin, dog. Note the polyhedral to round cells in the dermis and the elongated down-growth of the epidermis (epidermal pegs) into the histiocytoma (a common feature of these tumors). Inset, Higher magnification of the histiocytic cells. H&E stain. Idiopathic Sterile Nodular Panniculitis. Idiopathic sterile nodular panniculitis develops in dogs, cats, and rarely horses. These lesions are of unknown cause and are characterized grossly by single or multifocal plaques or nodules in the subcutis and occasionally deep dermis of any anatomic site. Lesions can rupture and drain; thus they involve the dermis secondarily. Microscopic lesions consist of discrete, coalescing, or diffuse accumulations of macrophages (histiocytes), neutrophils, lymphocytes, and occasionally other leukocytes. The lesions must be differentiated from those of the infectious granulomatous disorders, sterile pyogranuloma syndrome, and reactive histiocytosis in dogs.

Xanthomas (Xanthogranulomas). Xanthomas are rare, usually multifocal, light tan to yellow papules, plaques, or nodules located in the skin of cats and more rarely horses and dogs. The lesions take their name from the Greek "xanthos," meaning yellow. Some xanthomas are associated with abnormalities in triglyceride or cholesterol metabolism and are thus seen in animals with hereditary defects in lipid metabolism or with metabolic disorders such as diabetes mellitus, hypothyroidism, or hyperadrenocorticism. Histologically, xanthomas associated with abnormalities in triglyceride or cholesterol metabolism consist of sheets of macrophages filled with foamy cytoplasm, scattered giant cells, and interstitial areas of granular to amorphous lipid material and cholesterol clefts. The lipids in the lesions impart a yellow to tan color to the clinical lesions, which is responsible for the name. Rarely, xanthogranulomas also have developed in apparently healthy cats and dogs.

A variety of terms are used to define diseases of the claw or claw bed. Onychitis refers to inflammation somewhere in the claw unit, onychodystrophy (onychodysplasia) to abnormal formation of the claw, onychomadesis to sloughing of claws, and paronychia to inflammation of the skin of the claw fold. Paronychia and disorders of multiple claws on multiple feet can occur in association with disease processes that also affect the skin, including infections (e.g., bacterial, fungal, parasitic), immune-mediated disorders (e.g., pemphigus, lupus erythematosus, bullous dermatoses), and systemic disease processes (e.g., hyperadrenocorticism, disseminated intravascular coagulation). However, diseases that affect only the claws are uncommon to rare. One exception is physical trauma to the claws, which is one of the more common causes of claw disease in dogs and cats. Lesions are usually asymmetric and limited to one or just a few claws but can affect all claws in dogs that, for example, have run excessively on hard surfaces or gravel.

Lupoid onychitis (also called lupoid onychodystrophy) is probably the most common cause of onychomadesis that leads to onychodystrophy of multiple claws involving multiple feet in dogs. The condition affects many breeds of dogs of varying ages, and the dogs are healthy otherwise. History includes pain manifested as lameness and sudden loss of one or more claws on multiple paws, eventually involving all claws on all paws. There is partial regrowth of misshapen, friable claws that continue to slough. Paronychia is usually absent. Diagnosis can require amputation of the distal phalanx and the adjacent skin proximal to the claw fold for histopathologic evaluation. Histologic lesions are more prominent on the dorsal aspect of the claw and claw bed skin and include interface lymphoplasmacytic inflammation with basal cell vacuolation and apoptosis and pigmentary incontinence. Secondary bacterial infection and osteomyelitis can develop. However, the histopathologic lesions may represent a nonspecific or stereotypic reaction pattern of the claw, so clinical history as well as other diagnostic tests may be required for diagnosis. Idiopathic onychodystrophy has also been described in dogs and is differentiated from lupoid onychitis by lack of onychomadesis preceding onychodystrophy.

The term laminitis technically refers to inflammation of the lamellar (laminar) structures of the hoof, but laminitis is a complex multifactorial syndrome that ultimately results in damage to the lamellae, and thus the suspensory apparatus of the distal phalanx, and in which lamellar inflammation may not always significantly contribute to the pathogenesis of the disease, at least initially. The lamellar region of the hoof consists of primary and secondary epidermal and dermal lamellae that interdigitate to form a significant component of the support system of the foot (see Adnexa, Specialized Structures) (Fig. 17-60) . Laminitis can be seen in any hoofed animal (ungulate) but in domestic animals is of greatest importance in horses and cattle. Clinical signs of laminitis may vary from mild to severe; typically include pain that is manifested as abnormal stance, lameness, and reluctance to move; and may lead to euthanasia.

In horses, laminitis traditionally is considered to progress through a series of stages, including developmental (prodromal, preclinical), acute, subacute, and chronic. The developmental stage occurs between the initial causative insult and the first appearance of acute lameness. The acute stage begins with the first appearance of acute lameness and lasts up to 72 hours without physical or radiographic evidence of mechanical collapse of the foot, or alternatively, the acute stage may terminate abruptly with digital collapse and thus proceed directly to the chronic stage. If there is no physical or radiographic evidence of digital collapse after 72 hours of acute lameness onset, the subacute stage begins and lasts a minimum of 8 to 12 weeks, but it may have a more protracted course depending 

Disorders without Microorganisms on disease severity. In severe laminitis (Fig. 17-61) , rotation can occur as early as 24 hours after the appearance of lameness. Chronic laminitis (also called founder) refers to the stage of laminitis associated with radiographic or physical evidence of rotational or vertical displacement of the distal phalanx relative to the hoof wall ( Fig.  17-62 ). In addition to the four traditionally recognized stages of laminitis, recent research suggests there is a subclinical form or stage of laminitis, in which repeated episodes of lamellar injury occur before the onset of easily recognizable pain or lameness, but gross lesions may be apparent in hooves of the subclinically affected animals, indicating lamellar injury has occurred (Fig. 17-63 ).

There are four broad categories of naturally occurring laminitis in horses (Table 17-14) : (1) sepsis-related or inflammatory laminitis, which is often associated with systemic disease such as carbohydrate overload, endotoxemia, septicemia, retained placenta, septic endometritis, enterocolitis, pleuropneumonia, or contact with black walnut (Juglans nigra) shavings; (2) endocrinopathic laminitis (or laminopathy), which is considered to arise from hormonal imbalances such as insulin resistance (including pasture-related laminitis Figure 17 -60 Normal Foot, Horse. A, Normal foot, midsagittal section. Note that the parietal surface of the distal phalanx is parallel to the epidermal lamellae of the inner surface of the hoof wall (arrows). No space is visible at this junction or at the junction of the distal surface of the distal phalanx and the internal surface of the hoof. B, Photomicrograph of normal primary and secondary epidermal and dermal lamellae of equine hoof. Primary epidermal lamella (PEL); primary dermal lamella (PDL); secondary epidermal and dermal lamellae in region closest to hoof wall (1), middle region (2), and region closest to the distal phalanx (3); dermis (corium) in region closest to the distal phalanx (d); epidermal stratum corneum in region closest to the hoof wall (c). H&E stain. C, Highmagnification photomicrograph of normal lamellae of equine hoof in the region closest to the distal phalanx. The collagen of the primary dermal lamellae (PDL) and the secondary dermal lamellae (arrows) stains blue, whereas the stratum corneum of the primary epidermal lamella (PEL) and the partially cornified core of the secondary epidermal lamellae stain red. A single primary epidermal lamella (one of approximately 600) is illustrated. Each primary epidermal lamella has approximately 150 to 200 outwardly radiating secondary epidermal lamellae the dermal side of which orient toward the distal phalanx. The secondary lamellar epidermal cells (arrowheads) are attached via hemidesmosomes to the basement membranes at the dermal/epidermal interface. The large number of interdigitating epidermal and dermal lamellae creates a large surface area for the inner hoof wall, which together with the strong hemidesmosomal attachments between the secondary epidermal and dermal lamellae (and ultimately the parietal surface of the distal phalanx) serves as the suspensory apparatus of the foot. Masson's trichrome stain. (3) supporting or contralateral limb laminitis (or laminopathy), which develops in the foot of the contralateral limb in horses with severe unilateral lameness that persists for more than several weeks and is due to excessive weight bearing on the contralateral limb; and (4) traumatic laminitis or "road founder," which occurs in association with intense training and the excessive contusion of repeated foot trauma.

In sepsis-related or inflammatory laminitis, bacterial toxins or other factors associated with changes in large intestinal microflora after carbohydrate overload or septic conditions gain access to the systemic circulation, and this form of laminitis tends to be temporally closely related to the inciting systemic disease. Various theories have been proposed to help explain how the hoof's lamellar structure is initially damaged by these factors, but none has been proven, some are controversial, and more than one mechanism may contribute. The vascular theory suggests that there are abnormalities in the hoof blood flow, including increased capillary pressure (which causes increased tissue pressure and edema), flow in arteriovenous CHAPTER 17 The Integument Figure 17 -61 Severe Laminitis with Lamellar Separation, Horse. A, Severe laminitis with lamellar separation and loss, foot, midsagittal section. Note that the parietal surface of the distal phalanx has separated from the inner surface of the hoof wall (arrows), leaving a large gap due to complete separation of the lamellae (a degloving injury), a feature that may be seen in severe septic inflammatory laminitis. The tip of the distal phalanx has sunk distally toward the sole, crushing the solear corium (a cause of intractable pain and distress). B, Photomicrograph of severe inflammatory laminitis in a horse. The lesions were sufficiently severe to result in euthanasia. There is neutrophilic inflammation with extensive loss of secondary epidermal lamellae and lysis and separation of the basement membrane shown here in the lamellar region closest to the distal phalanx. The epidermal stratum corneum to the left (closest to the hoof wall) is not shown in this image. H&E stain. C, Higher magnification illustrating displaced secondary epidermal lamellae (arrowheads 2) after separating from the basement membrane (arrows). There is loss of normal shape and arrangement of remaining epidermal cells (arrowheads 2). Inflammatory cells are present (arrowhead 1). The epidermal stratum corneum to the left (closest to the hoof wall) is not shown in this image. PAS stain. d, dermis (corium). anastomoses, and venoconstriction, which deprive the lamellae of oxygen/nutrients and can lead to ischemia. The enzymatic theory suggests that enzymes such as matrix metalloproteinases (MMPs) (especially MMP-2 and MMP-9) located in neutrophils and other tissues, including epidermis, may play a role because these enzymes have been shown to contribute to the separation of the lamellar epidermal cells from the basement membrane; however, new evidence indicates that these enzymes are either present in the inactive form or become activated hours after basement membrane degradation, so MMP-2 and MMP-9 may not be as important as originally thought. The role of other enzymes, including other MMPs and proteins, including proteoglycans, is under investigation. The inflammatory theory suggests that in the early stages of laminitis local digital cytokine (IL-1β, IL-6, and IL-8) and adhesion molecule (intercellular adhesion molecule 1 and E-selectin) gene expression is associated with infiltration of leukocytes into lamellar tissue, and the leukocytes create inflammation and tissue damage.

The endocrinopathic form of laminitis is the most common in horses and ponies, and the term laminopathy has been used for this form of laminitis because inflammation is not considered an early primary feature of lesion development. This form of laminitis is often associated with a slow onset of disease, is recurrent and difficult to treat, and research suggests that it is associated with repeated episodes of subclinical laminitis that occur before onset of clinically recognizable pain. Horses and ponies with metabolic/ endocrinopathic abnormalities are at increased risk for developing laminitis, and hyperinsulinemia appears to play a key role. The reasons for this are unclear, but it has been shown that laminitis can be induced in healthy ponies by maintaining superphysiologic circulating concentrations of insulin. Thus it has been hypothesized gross lesions include circumferential hoof rings (ridges, founder rings, divergent hoof rings) that are wider at the heel (see Fig. 17-63,  A) , altered foot shape, separation of the wall from the epidermis at the coronet, depression of the coronary band, a flattened sole, and in some cases, penetration of the distal phalanx through the sole. In horses, laminitis may affect one or more feet, but the front feet are most commonly affected, presumably due to increased weight bearing (in the standing horse, the body mass is divided between fore and hind limbs in an approximate ratio of 60 : 40). Gross evaluation of the external foot in horses or ponies at risk for the development of laminitis is considered an important strategy in prevention of some cases of laminitis, particularly the endocrinopathic form. For instance, the presence of divergent hoof rings (see Fig. 17-63 , A) in a horse or pony before the onset of clinically recognizable foot pain, suggests the presence of subclinical lamellar injury, which may allow for earlier implementation of management strategies to slow or prevent further lamellar injury.

In the carbohydrate overload and black walnut extract models, histologic lesions in acute laminitis include loss of normal shape and arrangement of lamellar basal and parabasal cells, and lysis and separation of the basement membrane. In addition, leukocytes are present in the developmental stage of the black walnut extract model and in the acute stage of the carbohydrate models and precede significant histologic changes, which suggests that leukocyte infiltration occurs early and may be a cause of basement membrane separation and structural failure of the foot (see Fig. 17-61 , B and C for an example of histologic lesions in acute laminitis). Histologic lesions 7 days after induction of laminitis in the carbohydrate overload model include significant alterations in the lamellar architecture. Lamellar basal cells that survive acute injury reconstruct basement membrane but are enclosed by it before they are able to reattach to the primary epidermal lamellae. This results in secondary epidermal lamellae that are irregularly sized and shaped and often separated from the primary epidermal lamellae. These changes reduce the surface area of dermal-epidermal interdigitations and weaken the suspensory apparatus of the distal phalanx. In addition, the primary epidermal lamellae elongate. In some instances, columns of abnormally cornified epidermal cells may surround the primary dermal lamellae in the region closest to the hoof wall. With time these mounds of abnormal stratum corneum enlarge, which reduces the structural integrity of the foot and thus complicates recovery. Histologic lesions in chronic naturally occurring endocrinopathic laminitis with hyperinsulinemia occur predominantly in lamellar regions closest to the hoof wall and include epidermal hyperplasia and apoptosis, and fusion and partial replacement of lamellar tissue by increased quantities of abnormal stratum corneum that may contain nuclear debris and pools of proteinaceous fluid. These lesions result Figure 17 -62 Severe Chronic Laminitis, Horse. A, Severe chronic laminitis, foot, midsagittal section. There is a wide space filled with abnormally cornified epidermal lamellae (arrows) between the parietal surface of the distal phalanx and the inner surface of the hoof wall. The tip of the distal phalanx has rotated distally toward the sole. The external surface of the sole horn has been altered, and the weight-bearing capacity of the foot compromised, leading to a turning up and irregular wear of the toe region, and thickening of the sole horn of the heel. B to D, Photomicrograph of chronic laminitis after carbohydrate overload. The primary epidermal lamellae are elongated (B), and columns of abnormally cornified epidermal cells surround the primary dermal lamellae in the region closest to the hoof wall (arrowheads, C). With time this mass of abnormal stratum corneum enlarges, which reduces the structural integrity of the foot and complicates recovery. Some of the secondary epidermal lamellae that appear as islands (arrows, D) have been shown by serial section analysis to be isolated from the primary epidermal lamellae. Isolated islands of secondary epidermal lamellae may develop when basal cells that survive acute injury reconstruct basement membrane but are enclosed by it before they are able to reattach to the primary epidermal lamellae. c, epidermal stratum corneum in region closest to the hoof wall; d, dermis (corium) in region closest to the distal phalanx. (A courtesy Dr. T. Boosinger, College of Veterinary Medicine, Auburn University; and Noah's Arkive, College of Veterinary Medicine, The University of Georgia. B to D courtesy Professor C. Pollitt and Dr. A. van Eps, School of Veterinary Science, The University of Queensland.) that laminitis can be triggered in an insulin-resistant horse or pony by conditions that further increase insulin resistance or hyperinsulinemia (e.g., diets high in carbohydrates, overfeeding, or administration of glucocorticoids).

For contralateral or supporting limb laminitis, also referred to as laminopathy, little is known about the early lesions. It occurs in less than 20% of at-risk adult horses, weeks to months after the injury or infection that caused the primary (or first) leg lameness. It is typically a localized disease process, not usually associated with a systemic disease, and the resulting lamellar injury is typically restricted to the overloaded foot. The mechanism of damage is hypothesized to involve load-associated compression of the vasculature in the lamellae, which may lead to poor lamellar blood flow with subsequent platelet activation and microthrombus formation, resulting in lamellar ischemia. Other factors such as secondary inflammation and enzymatic activation may occur. In addition, other as yet unknown factors that may be specific to an individual horse, may also contribute.

There are few detailed studies regarding traumatic laminitis. Historical reports indicate that excessive mechanical overload may directly lead to failure of the suspensory apparatus of the distal phalanx and traumatic lamellar damage.

Recent research also suggests there are interconnecting links between these various forms of laminitis, so they probably are not mutually exclusive, and more than one form of laminitis may be present concurrently in an affected animal. For example, a pony with obesity and insulin resistance that may have endocrinopathic laminitis may develop septic endometritis, which may contribute to sepsis-related lamellar inflammation, or a horse with sepsis-related lamellar inflammation may be forced to place excessive weight on one limb and may develop supporting limb laminitis.

Diagnosis of laminitis is based principally on clinical, radiographic, and gross findings. Histopathologic studies on naturally occurring laminitis are uncommon, and detailed histologic evaluations often have been performed in association with the various experimental models of laminitis to help advance understanding of the pathogenesis of the disease syndrome in an attempt to identify more specific therapeutic and preventative strategies. These experimental models include the carbohydrate overload models (starch overload, oligofructose overload), the black walnut extract model, and the insulin-induced model. The models have advanced the knowledge of the pathophysiology of laminitis, but they also have generated many new, and as yet, unanswered questions.

Gross findings of the external foot in acute laminitis can be minimal. Swelling or edema of the coronary band can be seen. Extravasation of serum through the skin above the coronary band is indicative of severe acute laminitis. In chronic laminitis, common in an irregular border between the cornified zone of the inner hoof wall and the lamellar tissue (see Fig. 17-63, B) . Acute separation may develop, often between epidermal and dermal lamellae but sometimes between primary epidermal and secondary epidermal lamellae. Primary and secondary epidermal lamellae also elongate. The most frequent change in the region closest to the distal phalanx is tapering of the epidermal lamellae. Minimal inflammation is noted, and basement membrane failure is not extensive in this form of laminitis.

A sequel of progression into chronic laminitis that may develop in some instances is irregular hyperplasia and abnormal stratum corneum production of the epidermal lamellae that form a triangularshaped mass called the lamellar thickening or lamellar wedge. The lamellar wedge is located between inner hoof wall and the proliferating lamellar epidermis and is evident in sagittal sections of the affected feet. The lamellar wedge forms subsequent to displacement of the distal phalanx and is associated with remodeling of this phalanx. The appearance of the lamellar wedge varies with disease severity, duration, and therapeutic interventions. Histologically the lamellar wedge consists of variable quantities of proliferative epidermis, abnormal stratum corneum, and sometimes resolving fluid accumulation and hemorrhage. Also present in chronic laminitis are changes in the distal phalanx, including increased porosity of cortical bone due to osteoclastic resorption that exceeds osteoblastic proliferation. Edema, proliferation of small-caliber blood vessels, inflammation, and proliferation of a fibromyxoid matrix may develop within the medullary spaces of the bone. The deep digital flexor tendon may develop neovascularization and fibroplasia associated with osteoclasis and bone modeling at the insertion to the distal phalanx.

Laminitis in cattle occurs in dairy and beef cattle, and unlike horses, the rear feet are more commonly involved, which may be due to the fact that the outside digits (claws) of the cow's rear legs bear the burden of the continuously changing weight load. Descriptions include four different stages of laminitis: acute, subacute, chronic, and subclinical. Acute laminitis is not common and is associated with diseases such as metritis, mastitis, or accidental consumption of large quantities of grain and is often an individual animal problem. Subacute laminitis occurs in beef bulls on feeding trials and feeder calves fed diets rich in carbohydrates. Thus acute and subacute laminitis are likely associated with systemic disease, including carbohydrate-induced gastrointestinal disease (ruminal acidosis), and subsequent release into the systemic circulation of inflammatory mediators that may affect the lamellae. A model of acute bovine laminitis confirms the association between dietary carbohydrate (oligofructose) overload and development of laminitis. Acute and subacute laminitis are associated with digital pain, and the claws may be warm with marked digital pulse. The histopathologic features of the more acute forms of laminitis in cattle have been studied using a carbohydrate overload model, in which it has been shown that early lesions are stretching of lamellae, dermal edema, hemorrhage, and basal cell morphologic changes, with white blood cells in the dermis and basement membrane detachment.

The most common form of laminitis in cattle has been described in dairy cows around the time of calving, and lameness may not be evident initially, so this form of laminitis has been referred to as subclinical laminitis. However, the role of inflammation and involvement of the lamellae in each case are unclear in this form of disease, and thus the etiopathogenesis of subclinical laminitis in dairy cattle is controversial. Multiple complex factors, including intense management systems, contribute to the development of this form of the disease. These factors include: (1) diet or nutrition such as vitamins (biotin) and minerals that influence the quality of the stratum Some consider pasture-associated laminitis to be a form of equine metabolic syndrome. Ponies appear to be particularly predisposed to metabolic syndrome and endocrinopathic laminitis.

corneum (horn), or factors associated with increased carbohydrate intake that may contribute to subacute ruminal acidosis; (2) hormonal changes at calving that alter the resilience of the feet to external stresses; (3) traumatic injury due to reduced digital cushion thickness, or increased trauma or wear on the sole due to maintenance of cattle on hard surfaces with inadequate time spent lying down; and (4) genetic predisposition. For example, it has been shown in dairy cattle that diets with a large proportion of rapidly fermentable carbohydrates and insufficient quantity and quality of fiber increase the prevalence of laminitis, possibly by influencing rumen metabolism that allows toxins or inflammatory mediators to enter the systemic circulation. Dairy cows housed on hard (concrete) flooring as opposed to rubber mats and cows that are unable to lie down and rest sufficiently have a higher prevalence of laminitis, possibly due to increased hoof trauma. In addition, the suspensory apparatus of cattle is less well developed than that of the horse, so the digital cushion (a structure consisting of adipose tissue under the distal phalanx) supports a greater amount of the body weight. Dairy cattle with a thinner digital cushion have a greater prevalence of lameness and conditions traditionally associated with subclinical laminitis such as ulcers of the sole, suggesting that these lesions are related to contusions within the hoof. Thus the pathogenesis of lesions in subclinical laminitis is multifactorial and may vary in individual animals depending on the degree of or type of contribution of the various nutritional, hormonal, mechanical, and genetic factors. Clinical lesions in affected dairy cattle before the onset of lameness include hemorrhage in the sole and white line (see the section on Structure, Specialized Structures), and yellow discoloration and softening of the sole horn. These lesions in dairy cows are thought to predispose to other foot conditions such as ulceration of the sole, white line separation and fissuring, and subsolar abscesses that can be the main causes of lameness in this form of laminitis in dairy cattle. If damage in the hoof in acute, subacute, or subclinical laminitis is subtotal, partial recovery may occur, but damaged lamellae, and possibly adjacent support structures, are less able to recover during repeat episodes of laminitis, and thus chronic laminitis may ensue. Chronic laminitis is associated with deformation of the claws, which become flattened and broad, with a concave and furrowed dorsal wall due to disruption and loss of integrity of the lamellae and displacement of the distal phalanx.

Cutaneous paraneoplastic syndromes are rare dermatoses that occur in association with internal malignancies (Box 17-15 ). Confirmation of a dermatosis as a paraneoplastic syndrome requires strict adherence to established clinical, histopathologic, and in some instances, immunologic criteria. Conditions meeting these criteria currently recognized in animals include paraneoplastic pemphigus (discussed in the section on Selected Autoimmune Reactions); paraneoplastic alopecia and internal malignancies in the cat; exfoliative dermatosis and thymoma in the cat, dog, and rabbit; and superficial necrolytic dermatitis in the dog and cat. Dermatofibrosis in the dog, pancreatic panniculitis, and multisystemic eosinophilic disease in the horse have also been associated with underlying neoplasia; however, they have not yet been proved to be true paraneoplastic syndromes. This list does not include the endocrine dermatoses associated with functional tumors of endocrine organs. Many other syndromes are documented in human beings, and it is likely more will be documented in animals in the future. The refractory nature of these syndromes and their significance as an indicator of systemic disease underscores the importance of their recognition. 

The skin is a common site of neoplastic growth in most animals; the neoplasms are of ectodermal, mesodermal, and melanocytic origin (see . Ectodermal neoplasms of the epidermis and adnexa are most often benign with the exception of the neoplasms of the apocrine sweat glands, apocrine glands of the anal sac, and neoplasms of the surface epidermis (squamous cell carcinomas).

Benign neoplasms do not metastasize or invade adjacent tissue. In general, benign neoplasms are circumscribed, grow by expansion, and are composed of well-differentiated cells that closely resemble the cells or tissue of origin (see Box 17-12). Malignant neoplasms are locally invasive and often metastasize. They are more often composed of anaplastic cells with a high mitotic index that no longer resemble the cells of origin. Anaplastic cells are pleomorphic (vary in cell size and shape) and typically have a large, vesicular nucleus with increased size and number of nucleoli (see Box 17-12). Malignant cells develop surface alterations such as altered antigenicity, decreased numbers or altered location of receptors for adjacent cells, and increased receptors for components of the extracellular matrix. Changes such as these allow malignant cells to detach from the primary site of tumor growth, move through tissues, and in some cases delay or escape detection by the host's immune system. A specific example is the loss of E-cadherins (proteins responsible for epithelial cell-to-cell attachment) by some types of carcinomas. E-cadherins are partially responsible for the "contact inhibition" that leads to density control and inhibits uncontrolled proliferation of epithelial cells.

Neoplasms of the skin develop secondary to the same basic molecular drivers that lead to the development of neoplasms of any tissue. The neoplastic transformation of a cell is the end result of a series of events that cause damage to the cell's DNA. Most agents that are known to be carcinogenic target and damage DNA. Solar Superficial necrolytic dermatitis Pancreatic panniculitis (necrotizing panniculitis) Nodular dermatofibrosis and renal or uterine tumors in dogs Paraneoplastic pemphigus Feline pancreatic paraneoplastic alopecia Feline exfoliative dermatitis with or without thymoma

radiation, x-radiation, viral infections, and continued trauma are important contributors to neoplastic transformation of components of the skin. Continued trauma contributes to tumor development by increasing cell turnover, which in turn increases the possibility of mutations. Not all factors that contribute to the development of cutaneous neoplasms are known. Four categories of genes encode for a large number of proteins responsible for regulation of cellular proliferation and differentiation. These categories are the tumor-suppressor genes, the protooncogenes, genes that regulate apoptosis, and genes that regulate DNA repair. Damage to these genes results in gain-or loss-offunction defects in proteins such as growth factors, growth factor receptors, signal-transducing proteins, cell cycle regulators, and nuclear transcription factors. The majority of malignant neoplasms have evidence of damage (mutation) of multiple genes within these categories. Mutations are often accumulated by cells in a stepwise manner that imparts increasing degrees of malignant potential. These molecular changes are known to correlate with morphologic changes and the clinical behavior of some neoplasms. For example, it is known that squamous cell carcinomas often develop in a stepwise manner and progress through several recognizable stages: hyperplasia (increased number of cells; no cellular atypia or tissue disorganization) → dysplasia (increased mitoses, cellular atypia, and tissue disorganization consisting of loss of polarity) → carcinoma in situ (increased tissue disorganization, mitoses, anaplastic nuclei, but no invasion of underlying basement membrane) → invasive squamous cell carcinoma (disruption of the basement membrane with dermal invasion by anaplastic carcinoma cells).

The progression of the disease from hyperplasia to an invasive carcinoma represents a series of molecular events whereby the population of cells harbors an increasing number of damaged genes (mutations) belonging to the four categories of genes listed. This series of changes takes place over long periods of time, often years, before a tumor reaches full malignant potential. Many of the genetic mutations are neutral (or passenger) mutations; however, others are considered to be "driver" mutations because they guide and sustain the selection and propagation of a malignant clone (malignant cells that arise from an individual parent cell with the genetic mutations). Under the influence of the driver mutations, clonal populations of malignant cells gain selection advantage over other cells and also gain control of various interactions with the tumor microenvironment, an essential part of tumor physiology, structure, and function that includes many nontumor cells and components such as endothelial cells, mesenchymal cells, immune cells, inflammatory cells, and extracellular matrix. The complex interactions of tumor cells and their adjacent microenvironment contribute to tumor growth and metastasis and are currently being investigated in an attempt to identify more effective anticancer therapies.

Most cutaneous neoplasms are primary because the skin is an uncommon to rare site for metastasis; however, the skin can be the site of secondary tumor growth. Examples include mammary gland neoplasms that invade into adjacent skin, feline pulmonary bronchogenic carcinomas that metastasize to multiple digits of the feet, and canine visceral hemangiosarcomas that can metastasize to the skin. E-Tables 17-3 to 17-6 provide a list of the salient features of the common neoplastic-like lesions and neoplastic lesions in domestic animals.

For disorders occurring in two or more species of animals, see the section on Disorders of Domestic Animals.

Poxviruses For more mechanistic detail, see the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Viral Infections, Poxviruses.

Information on this topic is available at www.expertconsult.com.

Proliferative Pododermatitis (Canker) Proliferative pododermatitis in horses, also known as canker (see Table 17 -12), is a painful, proliferative, and inflammatory condition of the hoof. The cause of proliferative pododermatitis in the horse is unknown, but the disease appears to be polymicrobial in nature. The condition has been associated with the presence of a variety of Gram-positive and Gram-negative bacteria and in some cases with tissue colonization of Treponema spp. spirochetes. Bacteroides sp. and Fusobacterium necrophorum have been isolated in some cases. Recently, bovine papillomaviruses 1 and 2 have been detected in affected tissue via PCR-based techniques, but it is not known if these viruses have a causative role. The pathogenesis of lesion formation is not yet known, but moisture and unclean environments often predispose to the condition. It most often affects the rear feet of draft horses but can affect any foot or multiple feet of any breed of horse and even those kept in dry, clean environments. Initial lesions consist of a focal raised pink lesion resembling granulation tissue that bleeds easily and is surrounded by a gray or brown zone located in the frog. This lesion will progress to excessive, soft, white filiform papillomatous-like proliferations emanating from the frog, bars, sole, and sometimes hoof wall of the affected foot. Some cases will be foul smelling and have surface collections of caseous white exudate. Microscopically, areas of marked papillary epidermal hyperplasia associated with hyperkeratosis and neutrophilic infiltrates of the epidermis are present. The outer stratum spinosum may have areas of marked ballooning degeneration. The dermis contains superficial neutrophilic to lymphoplasmacytic infiltrates. A mixed population of Gram-positive and Gram-negative bacteria can be identified on the surface epidermis, but the organisms are not consistently associated with the areas of inflammation. In some cases, spirochetes have been identified within the proliferative epidermis.

Necrotizing pododermatitis of the horse (see Table 17 -12), commonly known as thrush, is a painful, necrotizing condition of the frog and central and lateral sulci of the hoof. It is caused by the anaerobic bacterium, F. necrophorum. Trapping of moist and bacterial-ridden materials such as manure and mud leads to softening of the tissue of the frog and allows bacterial colonization. The condition most often affects the hind feet but can affect all hooves. Initial lesions consist of black discoloration and softening of the frog accompanied by a very foul odor. Over time the black discoloring and softening spread to involve deeper tissues and more areas of the frog. The lesions consist of foul-smelling black exudate and loss of frog tissue. In chronic severe cases the distal limb can be swollen and the frog becomes spongy and ragged, easily shreds, and can bleed. There can be long-term atrophy of the frog as tissue disintegration occurs. Gross characteristics are usually diagnostic, but microscopic lesions consist of degeneration, necrosis, and suppurative inflammation of the frog epidermis and sometimes of deeper tissues. Bacterial colonization of the tissues is usually present.

CHAPTER 17 The Integument E- Plaques of epidermal hyperplasia with increased numbers of melanocytes in the basal layer. The adjacent keratinocytes often contain increased melanin pigment granules, and the dermis has increased numbers of pigmentcontaining macrophages.

Epidermis of lips, eyelid, nasal planum, and pinna of cats; on nipples of dogs appear as flat pigmented macules usually < 5 mm in diameter.

Do not require therapy. Lesions are often not demarcated, progressive, and not amenable to resection; classification of these lesions is likely to evolve over time.

*Localized tumor-like malformation of mature cells and tissues that are normal components of the organ in which they arise, but that are disorganized, present in excess, and sometimes larger than normal (also referred to as nevi, usually one tissue element predominates). † Some of these lesions are likely congenital, but others may be secondary to trauma. ‡ May more accurately be considered an inherited condition in the German shepherd dog.

Equine molluscum contagiosum is a self-limiting cutaneous infection in the horse caused by a poxvirus from the genus Molluscipoxvirus (molluscum contagiosum virus), a virus closely related to, or possibly the same as, the human molluscipoxvirus. The equine lesions are small and often incidental and may be localized to the penis, prepuce, axillary and inguinal areas, and nose. However, the lesions may become widespread, and hundreds of lesions are present over the neck, shoulders, chest, and legs. The pathogenesis of lesion formation is typical of poxvirus infection. Commencing as multiple, circular, smooth-surfaced, gray-white papules 1 to 2 mm in diameter, the lesions become umbilicated and develop a central pore from which a caseous plug is extruded. The microscopic lesions of molluscum contagiosum consist of well-demarcated foci of epidermal hyperplasia and hypertrophy that form invaginated lobules of the epidermis in the superficial dermis. Keratinocytes containing inclusions exfoliate through a pore that forms in the stratum corneum and enlarges into a central crater. The individual keratinocytes are markedly swollen and contain large intracytoplasmic eosinophilic inclusions, known as molluscum bodies, which can be identified histologically and in cytologic preparations. There is usually no dermal reaction. Rarely, molluscum contagiosum has developed in dogs. *Trichoblastoma and solid-cystic apocrine ductal adenoma were previously considered to represent "basal cell tumors" in the older literature. Morphologic features and in some instances immunohistochemical techniques allow reclassification of these tumors. some horses. Microscopic cutaneous lesions vary from none to superficial and deep perivascular to interstitial dermatitis with eosinophils, lymphocytes, and microfilariae. Fibrosis is seen in older lesions.

Vasculitis Purpura Hemorrhagica. Purpura (from the Latin meaning purple) are red or purple macules or patches caused by hemorrhage in the skin or mucous membranes. Purpura hemorrhagica in the horse occasionally develops as a sequel to Streptococcus equi infection, often involving the respiratory tract with abscessation in an internal site. Less commonly purpura hemorrhagica is seen subsequent to other infections or vaccinations. Affected 

Helminth Larval Migrans Cutaneous Habronemiasis. Cutaneous habronemiasis (summer sores) occurs in horses and is caused by infection with the larvae of Habronema sp. or Draschia sp. deposited on the skin by house or stable flies. Larval deposition and lesions occur on parts of the body where the skin is either traumatized, such as the legs, or moist and soft, such as the prepuce and medial canthus of the eye (Fig. 17-64) . Larvae are unable to penetrate normal skin, but fly bites cause sufficient damage to allow larval penetration. Grossly, single or multiple, proliferative, ulcerated red to brown, nodular masses are present that on section have small, yellow to white, gritty foci. The microscopic lesion is a nodular dermatitis with eosinophils, epithelioid macrophages, and sometimes, giant cells bordering larvae or necrotic debris (see Fig. 17 -64). Granulation tissue infiltrated by neutrophils is present on the ulcerated surface.

Onchocerciasis is a filarial dermatitis principally affecting horses. Adult parasites are located in nodules in connective tissue and can be asymptomatic. Microfilariae are located in the dermis, particularly of the ventral midline, and are the source of the major lesions. Intermediate hosts, such as the Simuliidae (blackflies, gnats) and Ceratopogonidae (biting midges), transmit the microfilariae. Not all horses with microfilariae have clinical signs or lesions. In those horses with cutaneous inflammation attributed to microfilariae, dead or dying microfilariae induce the most intense inflammation, and inflammation can be enhanced by microfilaricidal therapy.

Differences in lesion severity between horses may reflect different degrees of hypersensitivity to microfilariae, different degrees of hypersensitivity to the bites of intermediate hosts, or possibly other factors. Recent evidence in human filarial disease has revealed that the acute inflammatory response in two important diseases, elephantiasis and river blindness, may largely be a result of the endosymbiotic bacteria (Wolbachia) harbored within the filarial parasites and released into the blood by living parasites or following death or damage of the adults or microfilariae. The inflammatory stimulus is thought to be induced by proinflammatory and chemotactic cytokines and depends on PRRs known to contribute to innate immunity. Wolbachia organisms have been identified in a number of filarial parasites in animals, including Onchocerca gutturosa, Onchocerca lienalis, Onchocerca cervicalis, Onchocerca ochengi, Dirofilaria immitis, and Dirofilaria repens. O. ochengi in cattle has been studied as a model of human onchocerciasis in which it has been shown that selective antibiotic therapy against Wolbachia results in reduced numbers of Wolbachia sp., reduced numbers of adult O. ochengi, and reduced numbers of microfilaria. These findings indicate that Wolbachia organisms have an important symbiotic relationship with O. ochengi (as well as many other filarial parasites) and may represent a new target against filarial and microfilarial parasites.

In equine onchocerciasis, clinical lesions related to microfilariae develop on the head, neck, medial forelimbs, ventral thorax, and abdomen and consist of patchy to diffuse alopecia, erythema, scaling, crusting, and pigmentary changes. Some horses have a characteristic, variably pigmented, circular area of dermatitis on the forehead. Keratitis, conjunctivitis, and uveitis are observed in 

Equine coronary band dystrophy is a condition of unknown etiology and pathogenesis. Clinically, the coronary band (coronary border of hoof) is thickened, crusty, and scaly. Cracks and fissures can lead to lameness. The chestnuts and ergots (cornified protuberances considered to be vestiges of the first, second, and fourth digits) are similarly affected and can be ulcerated. Usually all four limbs are affected; however, the lesion may not involve the entire coronary band. Histologically, the epidermis of affected areas has marked papillary epidermal hyperplasia (see Fig. 17 -11) and marked orthohyperkeratosis to parakeratotic hyperkeratosis. In some areas there is ballooning degeneration of keratinocytes. Dermal inflammation is minimal unless secondary infection is present. The diagnosis is made by ruling out the various differential diagnoses, including pemphigus foliaceus, hepatocutaneous syndrome, bacterial or fungal infection, selenium toxicosis, mite infestation, and eosinophilic exfoliative dermatitis. The condition is chronic and treatment palliative. Although the condition affects adult horses of any breed, draft breeds are considered predisposed.

See Disorders of Domestic Animals, Miscellaneous Skin Disorders, Disorders Characterized by Infiltrates of Eosinophils or Plasma Cells.

See Disorders of Domestic Animals, Miscellaneous Skin Disorders, Disorders Characterized by Infiltrates of Eosinophils or Plasma Cells, Eosinophilic Granulomas (Collagenolytic Granulomas).

Multisystemic Eosinophilic Epitheliotropic Disease in the Horse. Multisystemic eosinophilic epitheliotropic disease is a generalized, exfoliative dermatitis of horses that is of unknown etiology; however, one case report documents the coexistence of an intestinal T lymphocyte lymphoma and postulates a role for tumor cell overproduction of IL-5, a powerful eosinophilopoietin. Initial cutaneous lesions include dry scales and serous exudates of the epithelium of the skin of the head, coronary bands, and oral mucosa. The lesions progress to generalized excoriations with ulceration and alopecia. Secondary infections are common. Histologically, there is superficial and deep, perivascular to interstitial, eosinophilic lymphoplasmacytic, and sometimes granulomatous dermatitis with irregular epidermal hyperplasia and orthokeratotic and parakeratotic hyperkeratosis. Eosinophils, lymphocytes, and apoptotic keratinocytes can be prominent in the epidermis, and eosinophilic folliculitis, furunculosis, and flame figures are occasionally seen. The dermatitis is accompanied by a similar inflammatory response with fibrosis in other organs, including the alimentary tract, pancreas, liver, uterus, and bronchial epithelium. Clinically, most affected horses lose weight, become progressively debilitated, and either die naturally or are euthanized.

Equine sarcoidosis (equine idiopathic, generalized, or systemic granulomatous disease; equine histiocytic disease/dermatitis) is a horses may be febrile, anorectic, depressed, and reluctant to move. Lymph nodes may rupture and drain to the exterior. The clinical lesions of subcutaneous edema and petechial and sometimes ecchymotic hemorrhages of the skin and mucous membranes develop as a consequence of immune-complex vasculitis, which may also affect vessels of other organs such as the gastrointestinal tract. There may be serum exudation of distal extremities. Severely edematous skin may ooze serum and become necrotic and slough. Microscopic lesions consist of vascular wall disruption by neutrophils (neutrophilic vasculitis), perivascular edema, hemorrhage, and fibrin exudation.

Pastern Leukocytoclastic Vasculitis. Pastern leukocytoclastic vasculitis may represent a photoenhanced dermatosis; however, the cause and pathogenesis are unknown. Sun exposure appears to trigger lesion development in some horses, but lesions do not always resolve with removal from sun exposure. The disease is not considered a form of photosensitization because liver function is normal and exposure to photosensitizing chemicals has not been documented. Lesions typically develop in the white-haired legs, but rarely, similar lesions occur in legs covered with dark hair. Lesions initially consist of well-demarcated erythematous, moist, and crusted areas. More chronic lesions consist of plaques of epidermal acanthosis, hyperkeratosis, and crusting. Microscopically, lesions occur in small, thin-walled vessels of superficial dermal papillae. Early changes include vessel wall degeneration or necrosis and thrombosis. There is controversy regarding the presence of inflammation and true vasculitis. Although leukocytoclasia of neutrophils is described, the failure to demonstrate active vasculitis in many cases leads some veterinary dermatologists and pathologists to the preference of the term vasculopathy. Chronic changes include thickening and hyalinization of vessel walls. Epidermal changes include degeneration and hyperplasia, depending on stage of the disease. There may be mixed perivascular inflammation.

Tumors of the pars intermedia of the pituitary gland occur in older horses and can reach a large size, destroy the pituitary gland, and cause hypopituitarism and diabetes insipidus. The clinical signs in horses with pars intermedia pituitary tumors (polyphagia, polydipsia, polyuria, increased sweating, and an excessively long and thick hair coat) are largely mediated through dysfunction of the hypothalamus or neurohypophysis caused by an underlying expanding pituitary tumor. The long hair coat, also called hypertrichosis or hirsutism, is the result of failure to seasonally shed; cyclic shedding is mediated through the hypothalamus. Some tumors of the pars intermedia are functional and result in production of pro-opiomelanocortin (POMC), which is processed into high concentrations of various pars intermedia-derived peptides, including corticotropin-like intermediate lobe peptide, melanocyte-stimulating hormone, and β-endorphin, and much smaller concentrations of adrenocorticotropin. The combination of hypothalamic dysfunction and differential expression of pars intermedia-derived peptides over that of adrenocorticotropin results in a unique syndrome of hyperpituitarism in horses that differs from functional pituitary tumors in dogs and cats, which usually are associated with high concentrations of adrenocorticotropin. Some horses with large pituitary tumors also develop insulin-resistant hyperglycemia, which may be the result of downregulation of insulin receptors secondary to chronic polyphagia and hyperinsulinemia. Insulin resistance is associated with an increased prevalence of laminitis.

For disorders occurring in two or more species of animals, see the section on Disorders of Domestic Animals.

Congenital hypertrichosis refers to excessive growth of hair, which can be congenital or hereditary. Congenital hypertrichosis has developed in fetal lambs secondary to hyperthermia in pregnant ewes living in areas of high environmental temperature. In addition to the hypertrichosis, the lambs are small, and few survive the first 2 months of life.

In utero border disease virus infection of fetal lambs results in an abnormally hairy fleece at birth, muscle tremors, defective myelination of the brain and spinal cord, abnormalities of body conformation, poor growth, and reduced viability. The fleece abnormalities and the muscle tremors result in the name hairy shaker disease. Fleece abnormalities are noted only in fine-and medium-wooled (smooth-coated) breeds. Fetal infection before 80 days of gestation results in an initial phase of retardation of follicular growth, followed by an extended period of rapid growth of primary follicles. The altered growth rate of follicles results in production of larger, more heavily medullated primary hairs, and the clinical appearance of the "hairy" fleece. The exact mechanism controlling the exaggerated growth of primary follicles is unknown. It has been speculated that reduction in number of the later developing secondary fibers could be the result of impaired nutrition because of placentitis. Microscopically, primary follicles and hairs are enlarged, and the number of the secondary follicles and wool fibers is reduced (see the discussion on hair follicles in the section on Structure and also Fig. 17-6 ). Diagnosis can be confirmed in affected lambs by histopathologic evaluation of the CNS with immunohistochemical staining for the virus, by viral isolation using precolostral serum or buffy coat, by viral antigen detection ELISA using ethylenediaminetetraacetic acid (EDTA) or heparinized blood, and by reverse transcription PCR (RT-PCR) of clinical specimens.

Ergot poisoning is caused by the ingestion of toxic alkaloids produced by the fungus Claviceps purpurea. This fungus infects the seed heads of grasses and grains. The alkaloids, particularly ergotamine, cause direct stimulation of adrenergic nerves supplying arteriolar smooth muscle, resulting in marked peripheral arteriolar vasoconstriction and damage to capillary endothelium. Arteriolar spasm and damage to capillary endothelium lead to thrombosis and ischemic necrosis (infarction) of tissue. Cold temperatures increase the severity of the lesions. The species most commonly poisoned are cattle fed contaminated grain or cattle grazing pastures infected with the alkaloid-producing fungus. Lesions develop after approximately 1 week of consumption and begin as swelling and redness of the extremities, particularly the hind legs. Lesions begin at the coronary bands and extend to the fetlocks (metatarsophalangeal joints). The feet may become necrotic, with viable and nonviable tissue separated by a distinct line (dry gangrene). The front feet and tips of ears, teats, and tail can be affected and in severe cases can slough.

Lesions identical to those of ergot poisoning occur after the ingestion of tall fescue grass, a common pasture plant, infected by the endophytic fungus Neotyphodium coenophialum (formerly rare disorder usually with exfoliative dermatitis, wasting, and granulomatous inflammation in multiple organ systems, although occasional cases limited to the skin have been reported. The cause and pathogenesis are unknown, but an immunologic reaction to a component of an infectious agent or allergen is hypothesized. A variety of breeds of horses, usually over 3 years of age, have been affected. Although some studies report mares are overrepresented, others report geldings are more often affected. Dermatitis usually begins as scaling, crusting, and alopecia on the face and trunk, or legs and progresses to multifocal or generalized exfoliative dermatitis. Cutaneous nodules are rare, and lymph nodes may be enlarged. Although skin may appear to be the only organ affected, most horses progress to more systemic involvement, including many viscera, central nervous system (CNS), and bone, clinically manifested by weight loss, ventral edema, fever, and signs associated with visceral organ dysfunction. Prognosis varies because many horses experience progressive dermatitis and wasting over the course of weeks to months and eventually are euthanized; however, there are reports of positive response to therapy especially if initiated early in the course of the disease, and spontaneous recovery has been reported. Horses with few isolated lesions limited to the skin are usually otherwise healthy. Histopathologic lesions include nodular to diffuse granulomatous inflammation with multinucleated giant cells intermixed with small numbers of lymphocytes, plasma cells, and neutrophils. Electron microscopy, animal inoculation studies, IF, and immunohistochemistry have been negative for microorganisms. Diagnosis is made by histopathologic evaluation, ruling out infectious agents that can also cause granulomatous dermatitis, and evaluation of history for dietary exposure to toxins such as hairy vetch (Vicia sp.).

Equine pastern dermatitis (also known as grease heel, scratches, or grapes) is a complex syndrome in which secondary staphylococcal folliculitis is common and complicates the diagnosis. There may be a genetic predisposition, which includes a long hair coat on the pastern area as often occurs in draft horses. Other predisposing factors are numerous and include excessive moisture, trauma, and contact dermatitis. Also, many other conditions affect the pastern skin in horses, including immune-mediated diseases (pemphigus foliaceus, vasculitis, or photosensitization), other infections (dermatophilosis, dermatophytosis), chronic progressive lymphedema of draft horses, and mite infestation (Chorioptes sp.). Equine pastern dermatitis occurs in male or female adult horses of a variety of breeds, is usually bilateral, and most commonly affects the caudal aspect of the hind legs, but lesions may progress to involve the cranial aspect of the legs, and front legs may also be affected. Early clinical lesions include edema, erythema, and scaling, which rapidly progress to exudation, matting of hair, and crusting. Ulcers may be present. Chronic lesions are thickened and fissured skin, are often painful, and may result in lameness. Diagnosis is facilitated by obtaining a complete history and performing thorough physical, dermatologic, microbiologic, and histopathologic evaluations early in the course of disease. Histopathologic lesions vary with stage of disease and severity, and histopathologic evaluation is most helpful in ruling out other conditions that affect pastern skin. In severe chronic lesions, initiating causes may not be identifiable, and histologic lesions are often nonspecific and consist of ulceration, crusting, and scarring, with mixed inflammatory infiltrates. CHAPTER 17 The Integument length polymorphism (PCR-RFLP) techniques. These viruses are also considered potential agents of agroterrorism.

Sheeppox. Sheeppox is caused by the sheeppox virus and is the most serious of the pox diseases of domestic animals. Sheeppox causes extensive economic loss through high mortality; reduced meat, milk, or wool yields; commercial inhibitions from quarantine requirements; and the cost of disease prevention programs.

Transmission of infection is by direct contact with diseased sheep or indirect contact via contaminated environment. Sheeppox virus is resistant to desiccation and remains viable for up to 2 months on wool or 6 months in dried crust. There are breed differences in disease susceptibility. Fine-wooled Merino sheep are particularly sensitive, whereas breeds native to endemic areas, such as Algerian sheep, are comparatively resistant. Sheeppox occurs in all ages of sheep with high morbidity and mortality as high as 50%, but the disease is most severe in lambs, with mortality reaching 80% to 100%. A high level of background immunity, such as occurs in endemic areas of Kenya, is associated with low mortality, even in the young.

Sheeppox is a systemic disease. Infection is usually by the respiratory route but may occur through skin abrasions. The incubation period varies from 4 to 21 days and is followed by a leukocyteassociated viremia. The virus localizes in many organs, including the skin, where the virus concentration is highest 10 to 14 days after infection. The initial clinical signs are fever, lacrimation, drooling, serous nasal discharge, and hyperesthesia. Skin lesions develop in 1 to 2 days and have a predilection for the sparsely wooled areas and typically involve eyelids, cheeks, nostrils, vulva, udder, scrotum, prepuce, ventral surface of the tail, and medial thigh. There is usually a concurrent superficial lymphadenopathy.

The macroscopic lesions follow the typical pattern for pox infections. Erythematous macules progress to papules, which may be firm. Sheeppox lesions have a variably prominent vesicular stage. The pustule stage is characterized by the formation of a thin crust. In severely affected animals the lesions coalesce and form areas of edema, hemorrhage, necrosis, and induration, involving all layers of the skin and subcutis (Fig. 17-65) . These areas correspond to the development of vasculitis described later with microscopic lesions (see Fig. 17-65, B) . Highly susceptible animals often develop hemorrhagic mucosal papules early in the course of the disease, and ulcerative lesions in the gastrointestinal and respiratory tracts develop later. Approximately one-third of animals develop multiple pulmonary lesions that constitute foci of pulmonary consolidation. The kidneys have multifocal, circular, and fleshy nodules throughout the renal cortices.

Healing of the skin lesions is slow, taking up to 6 weeks, and a scar may remain. In the milder form of the disease, seen in endemic areas, the full range of pox lesions does not develop. Instead, epidermal proliferation produces papules covered by scale-crust, which heal with desquamation in a few days. Such lesions often occur on the ventral surface of the tail.

Sheeppox lesions have the typical microscopic poxviral epithelial lesions, including intracytoplasmic inclusion bodies. The lesions affect both surface epidermis and hair follicles. There are also marked dermal lesions reflecting the systemic route of cutaneous involvement and possibly implicating immune-mediated lesions in addition to those caused by direct viral damage. The initial dermal lesions, corresponding to the macroscopic erythematous macule, are marked edema, hyperemia, and neutrophilic exocytosis. During the papular stage, large numbers of mononuclear cells accumulate in the increasingly edematous dermis. These mononuclear cells are called sheeppox cells and are characteristic of the disease. The nuclei of sheeppox cells are vacuolated and have marginated chromatin. The Acremonium coenophialum). Lesions develop approximately 2 weeks after ingestion of the toxic plant and consist of necrosis (dry gangrene) of distal extremities. The ergot alkaloids, particularly ergovaline, are responsible for toxicity and act as peripheral vasoconstrictors.

See the section on Disorders of Domestic Animals; Disorders of Physical, Radiation, or Chemical Injury; Chemical Injury.

Poxviruses For more mechanistic detail, see the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Viral Infections, Poxviruses.

Cowpox. Cowpox virus infections occur rarely in cattle in the United Kingdom and other areas of Europe. There is increasing evidence that small wild rodents (i.e., mice, squirrels, voles) serve as a reservoir for infection and that cattle, cats, and rarely other mammals become infected through contact with the wild rodents. Cutaneous infections in cattle usually develop on the teats and udder of cows and on the muzzle of suckling calves. Lesions follow the typical sequence of cutaneous poxviral infections. For cowpox infections in the cat, see the section on Disorders of Cats.

Bovine Papular Stomatitis. Bovine papular stomatitis virus is distributed worldwide, and although it causes disease more commonly in cattle more than 2 years old, disease can occur at any age and in any breed. Lesions occur on the muzzle, nostrils, lips, and mouth, and cows with suckling calves can develop teat and udder lesions. The development and appearance of the lesions are similar to pseudocowpox, with resolution of lesions in days to weeks. A chronic form has been described in which exudative necrotic dermatitis involves the trunk, as well as the mouth, and in which the animals died in 4 to 6 weeks. Transmission to human beings induces lesions identical to "milker's nodule" caused by Pseudocowpox virus infection. The histologic appearance of lesions is typical of other poxviral infections. Capripoxviral Diseases. Capripoxviruses are the cause of sheeppox and goatpox. These viruses cause significant economic losses in countries where they are endemic, and the geographic distribution of these viruses is expanding. Sheeppox and goatpox are present in Africa, Asia, the Middle East, and most of the Indian subcontinent, where, despite attempts at vaccination, capripoxvirus is responsible for cycles of epidemic disease followed by periods of endemic maintenance with low morbidity. The disease is exotic to the Americas, Australia, and New Zealand. Although eradication measures eliminated the disease from Britain in the mid-nineteenth century, these measures have only recently been successful in eastern European countries. The diseases capripoxviruses cause lead to constraints on international trade of livestock and related products and can prevent the importation of new breeds of sheep or goats into endemic areas because fatality rates can be very high in nonindigenous breeds. Capripoxviruses are highly contagious and spread by the respiratory tract in times of close contact and mechanically by insect vectors and fomites. Virus is shed in saliva, conjunctival secretions, milk, urine, and feces, as well as in skin lesions and scabs. Vaccination of susceptible animals for sheeppox and goatpox provides lifelong immunity. The viruses share a high percentage of homology at the nucleotide and amino acid concentrations but are distinguishable phylogenetically using PCR-restriction fragment febrile, eruptive phase of the disease. Secondary bacterial infection and even septicemia and pneumonia can be the cause of death. Animals are also susceptible to fly strike.

Goatpox. Goatpox, caused by goatpox virus, occurs in the previously described geographic distribution, and a benign form of goatpox occurs in California and Sweden. The clinical signs of goatpox vary in different geographic areas. The disease is generally milder than sheeppox with a low mortality rate (5%), although generalized eruption with mortality rates approaching 100% may occur, with a course of disease similar to that of sheeppox infections in sheep. The cutaneous lesions have a predilection for the same areas as for sheeppox. In nursing kids, lesions may appear on the buccal mucosa or anterior nares. In animals with higher levels of resistance, the lesions may be confined to the udder, teats, inner aspects of thighs, or ventral surface of the tail.

Contagious Ecthyma. Contagious ecthyma (contagious pustular dermatitis, orf, sore mouth) is a common localized cutaneous infection of young sheep and goats caused by a parapoxvirus with worldwide distribution. Less commonly, human beings, cattle, wild ungulates, and dogs are infected. Morbidity in lambs is usually high, and although mortality is usually low, it can approach 15% in lambs. Lesions are initiated by abrasions; however, recent work has shown that active virus infection relies on proliferating keratinocytes that are in response to the cutaneous injury as opposed to the cutaneous injury itself. Cutaneous abrasions are typically acquired from pasture grasses or forage; begin at the commissures of the mouth and spread to the lips (Fig. 17-66) , oral mucosa, eyelids, and feet; and are susceptible to secondary bacterial infection. In contrast to other poxviruses, the orf virus infection is typically limited to the skin and does not have a systemic phase to the infection, which may explain why an antibody response is not particularly important or effective for immunity to infection. This contrasts to many other poxvirus infections, which also gain entrance through skin, but their spread to other organs can occur and be partly controlled by antibody response. The orf virus may persist for long periods of time in the environment from infected material such as shed scabs, which is important because past natural infection does not confer immunity to reinfection. Unlike other poxviruses for which attenuated vaccines can be used to protect against infection, protection against contagious ecthyma is best provided by use of fully virulent vaccines, which may result in outbreaks of disease caused by the vaccine. Lambs can transfer the virus to the teats of ewes, and the lesions can spread to the skin of the udder. Contagious ecthyma is economically important as the result of weight loss in lambs that are reluctant to eat because of the pain associated with oral and perioral lesions. Pathogenesis of lesion formation and gross and microscopic features are consistent with the typical cutaneous poxvirus lesions (see previous discussion and see Fig. 17-32) , except that the vesicle stage is very brief, the ulcer and crust stage persists and is clinically prominent, and the epidermis is markedly hyperplastic. Viral inclusion bodies are often not identified histologically because they are only briefly detectable during the earliest stages of infection.

For more mechanistic detail, see the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Viral Infections, Herpesviruses.

Bovine Herpesvirus 2. Bovine herpesvirus 2, a dermatotropic virus (Allerton virus), can cause generalized disease (pseudo-lumpy skin disease) or as seen in the United States, localized infection of the teat called bovine ulcerative mammillitis (bovine herpes vacuolated cytoplasm contains single, occasionally multiple, eosinophilic intracytoplasmic inclusion bodies. Sheeppox cells are virusinfected monocytes, macrophages, and fibroblasts, but not endothelial cells. Approximately 10 days after infection and corresponding with the most prominent epithelial lesions and peak of skin infectivity, severe necrotizing vasculitis develops in arterioles and postcapillary venules (see Fig. 17-65, B) . Virus particles have not been identified in endothelial cells, and the vasculitis may be the result of immune-complex deposition. Ischemic necrosis of the dermis and overlying epidermis follows. The pulmonary lesions are proliferative alveolitis and bronchiolitis with focal areas of caseous necrosis. Alveolar septal cells contain intracytoplasmic inclusion bodies. Additional histologic lesions, characterized by the accumulation of sheeppox cells, may involve heart, kidney, liver, adrenal gland, thyroid gland, and pancreas.

The course and outcome of sheeppox depend not only on the usual host-virus relationship but also on the nature and location of secondary infections. The virus itself may cause death during the 

CHAPTER 17 The Integument the fleece (wool), wets the skin, and causes proliferation of Pseudomonas spp. Approximately 1 week of continual wetting is usually sufficient to cause marked proliferation of the bacteria on the skin and in the fleece. This is followed by an acute inflammatory response with serum exudation and matting of the fleece. The fleece is also discolored because of production of pigments (chromogens) by the Pseudomonas bacteria and has a rotten odor. The condition may be complicated by other concurrent microbial infections such as dermatophilosis. Microscopic lesions include epidermal pustular dermatitis and superficial folliculitis. Ovine fleece rot is important economically because the malodor attracts flies, predisposing to myiasis (infestation of tissue by the larvae of dipterous flies), and the value of the affected wool is reduced.

Mycobacterial Granuloma. See Disorders of Domestic Animals, Microbial and Parasitic Disorders, Bacterial Infections, Bacterial Granulomatous Dermatitis (Bacterial Granulomas), Mycobacterial Granulomas. mammillitis). Mammillitis is inflammation of the teat or nipple. Localized infection occurs more commonly in lactating dairy cows but can develop in beef cows, pregnant heifers, and suckling calves. Trauma is implicated in the pathogenesis because normal skin is resistant to viral penetration. The pathogenesis of lesion formation is discussed earlier. Bovine ulcerative mammillitis is economically important because of decreased milk production and secondary bacterial mastitis. Lesions develop on the teats and skin of the nearby udder or occasionally the perineum. Suckling calves develop lesions on the muzzle (nose).

Bovine Herpesvirus 4. Bovine herpesvirus 4 (bovine herpes mammary pustular dermatitis) causes a similar but milder disease than the localized form of bovine herpesvirus 2.

Ovine fleece rot is a superficial bacterial dermatitis usually caused by excessive moisture (usually in the form of rain) that penetrates 

Contagious foot rot (benign foot rot, stable foot rot, interdigital dermatitis) (see Table 17 -12) is a slowly progressive, low-grade infection of the interdigital skin that is seen most commonly in intense dairy productions with poor hygiene. Moisture and trauma damage the interdigital epidermis and allow entrance of mixed bacterial populations of which the obligate anaerobic bacteria Dichelobacter

Papillomatous digital dermatitis (see Table 17 -12), also known as foot warts or hairy heel warts, is a painful, contagious dermatitis of the feet primarily of high-production dairy cattle. It occurs worldwide. The cause of papillomatous digital dermatitis is multifactorial and likely involves genetic predisposition, management conditions that allow the feet of cattle to remain wet for prolonged periods of time without access to air, in combination with multiple species of bacteria, including spirochetes belonging to the genus Treponema playing a predominant role. Papillomatous digital dermatitis most commonly affects the skin proximal and adjacent to the interdigital space at the caudal (plantar) aspect of the hind feet. Early gross lesions are well-circumscribed, round to oval, red plaques up to 6 cm in diameter with a moist granular surface prone to bleeding and with a very strong, pungent odor. Lesions are partially to completely alopecic and can be bordered by hypertrophied hairs two to three times longer than normal. Early microscopic lesions are largely limited to the epidermis, with minimal dermal involvement mostly consisting of minimal perivascular inflammation. Epidermal lesions consist of hyperplasia with foci of erosion, necrosis, ballooning degeneration, and microabscesses. Mixed bacteria can be present in the outer necrotic debris, but only spirochetes are present in the deeper viable epidermis. The lesions become progressively more proliferative and less painful with time. Mature lesions are irregular wartlike growths or filamentous papillae that measure 0.5 to 1.0 mm in diameter and 1 mm to 3 cm in length and are pale yellow, gray, or brown. Histologically the older lesions are composed of frondlike projections or plaques of markedly hyperplastic epidermis with parakeratosis and hyperkeratosis. Foci of necrosis and hemorrhage, ballooning degeneration, and aggregates of neutrophils are scattered throughout the hyperplastic epidermis ( Fig. 17-67) . At this later stage, inflammation is more intense in the dermis, and plasma cells can be numerous. Lesions are painful, forcing the animal to shift its weight to the toe of the affected foot, which results in a smooth contour to the toe (clubbing) and atrophy of the bulbs of the heels.

Papillomatous digital dermatitis is economically important because it frequently causes moderate to severe lameness that results in weight loss, decreased milk production, and poor reproductive performance. The vast majority of cases are in dairy cows, but the infection has also been reported in beef cattle. Although the disease occurs in cattle of all ages, the highest incidence appears to be in replacement dairy heifers.

Necrobacillosis (foul-in-the-foot, interdigital phlegmon, interdigital necrobacillosis, foot rot) (see Table 17 -12) of cattle is an infection originating in the interdigital skin that is caused by F. necrophorum and Prevotella melaninogenica (formerly Bacteroides melaninogenicus). Predisposing factors include interdigital trauma in combination with increased moisture, heat, and poor housing conditions that allow contact with manure and urine. F. necrophorum and P. melaninogenica are rumen microbes, are passed through the gastrointestinal tract, and thus readily contaminate the environment. F. necrophorum produces an exotoxin (leukotoxin) that causes necrosis and damages leukocytes. The infection usually involves both digits of a single foot in adult cattle, but several feet may be involved in calves. The disease progresses rapidly and is associated with a malodor. Early lesions are swelling and erythema of the soft tissues of the interdigital space and coronary band. The leukotoxin causes necrosis and exudation, which can progress to cellulitis that may extend into the deeper structures of the foot such as the distal phalanx, distal sesamoid bone, distal interphalangeal joint, and tendons. Extensive Contagious ovine digital dermatitis (CODD) (see Table 17 -12) is a severe infection of the ovine hoof reported in the United Kingdom, with initial reports occurring in 1997. The disease has spread widely in the sheep population and is of major animal welfare concern. It most commonly affects one foot, but multiple digits may be affected, and 80% of affected sheep are lame. The cause of this form of digital dermatitis in sheep is not yet completely defined but thought to be polymicrobial, with spirochetes belonging to the genus Treponema, including Treponema sp. phylogenetically identical to those associated with bovine digital dermatitis, frequently isolated from affected sheep. D. nodosus and F. necrophorum have also been isolated from affected sheep, but their role in the pathogenesis of the disease is uncertain. The condition differs from typical contagious foot rot in sheep in that the lesions have an acute onset, are more severe, and are characterized by ulcerative lesions of the coronary band and hoof wall in some cases (contagious foot rot lesions affect the heel and interdigital region). Select systemic antibiotic therapy improves likelihood of recovery and reduces the rate of new infection development. The pathogenesis of lesion formation is not yet known. Early gross lesions consist of ulcers at the coronary band and progress to loosening, and possible shedding, of the hoof wall or capsule. Interdigital lesions are not reported. Microscopic lesions have not been described.

Stephanofilariasis, a filarial dermatitis of cattle, buffalo, and goats, is transmitted by flies and caused by six species of parasites of the genus Stephanofilaria. Each species of Stephanofilaria causes lesions in a different body location. Cutaneous lesions are caused by a reaction to the parasites free in the dermis, to the bites of the flies serving as the vector, and self-inflicted trauma. Stephanofilaria stilesi occurs in cattle in the United States and causes lesions along the ventral midline that consist initially of small (1 cm) circular patches with moist erect hairs, foci of epidermal hemorrhage, and serum exudation. Such foci expand and coalesce into a large area covered by crusts, which, on healing, consist of thickened hairless plaques as large as 25 cm in diameter ( Fig. 17-68) . Microscopic lesions consist of superficial and deep perivascular dermatitis with eosinophils, epidermal hyperkeratosis, parakeratosis, acanthosis with spongiosis, eosinophilic microabscesses, and crusts, and adult parasites and microfilaria can be seen. In addition, adult parasites and microfilaria also can be identified in deep skin scrapings that are macerated in isotonic saline solution and examined microscopically.

Vasculitis is rare in cattle. It is seen with malignant catarrhal fever (see Chapters 4 and 7). Capripoxvirus causing lumpy skin disease in cattle causes damage to endothelial cells, resulting in vasculitis that is central to the pathogenesis of lesions in this condition. Systemic infection with Salmonella dublin can also cause gangrene of the distal extremities, tail, and pinnae as a result of venous thrombosis related to endotoxins.

Vasculitis in sheep and goats is also rare and is seen as part of systemic capripoxvirus infections (see section on Viral Infections).

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nodosus is considered to be the most important. Other bacteria, including F. necrophorum, may contribute. The infection is spread from infected to uninfected cows through the environment. The bacteria invade the epidermis but usually do not penetrate the dermis and may progress to erosions and ulcers that cause discomfort. Exudate may ooze from the commissures of the interdigital space and dry to form a crust. Diagnosis is usually made by clinical examination. The major differential diagnosis is papillomatous digital dermatitis.

Contagious foot rot in sheep (see Table 17 -12) is a serious, economically important disease occurring in most sheep-producing countries. The infection is caused by the Gram-negative anaerobe D. nodosus. Depending on climatic and host factors, and the virulence of the bacterial strain, lesions vary from mild interdigital dermatitis (benign foot rot) to severe separation of the horn of the hoof (virulent foot rot). The major virulence factors of D. nodosus are type IV fimbria (short fine appendages surrounding the bacterial cell that allow colonization of epidermis) and extracellular proteases that degrade tissue. The virulent form is caused by more virulent D. nodosus that produces significantly more proteolytic enzymes (proteases including elastase), allowing more bacterial penetration of the epidermis. The proteases in the virulent form also tend to be more heat stable. Virulent foot rot is more persistent (and can last for more than 1 year if not treated), affects a high percentage of sheep, affects more than one foot, and can result in death of sheep because of emaciation as a result of severe pain and reluctance to graze. Early lesions of virulent foot rot begin in the interdigital axial (inner) region, affect both digits, and consist of red, moist, and swollen eroded skin. The infection spreads to the epidermal matrix of the hoof and results in a malodorous exudate that separates the horn from the interdigital skin. Lesions progress to the bulb (heel) and sole, and finally to the abaxial (outer) surfaces of the hoof wall. The germinal epidermis is not destroyed, and although regeneration is attempted, the new horn is destroyed. In chronic infections, hooves can become long and misshapen. Benign foot rot in sheep is mild, confined to interdigital skin, and can have slight separation of the horn of the heel. The hoof can overgrow. Diagnosis of foot rot in sheep is often made by clinical evaluation of the flock and lesion severity and examination of smears or cultures for D. nodosus. However, culture and typing, as for other fastidious anaerobes, is difficult and laborious, is not widely offered in diagnostic laboratories, and culture alone may not distinguish between virulent and nonvirulent strains. More recently PCR testing has been developed that detects and differentiates virulent and nonvirulent strains of D. nodosus.

Necrobacillosis of the foot in sheep includes ovine interdigital dermatitis and foot abscesses (see Table 17 -12). Ovine interdigital dermatitis is an acute necrotizing dermatitis that is clinically similar to benign foot rot. Both benign foot rot and ovine interdigital dermatitis have been termed "foot scald." Ovine interdigital dermatitis can be differentiated from foot rot by the failure to demonstrate D. nodosus in smears or cultures of exudate, or with PCR from ovine interdigital dermatitis cases, but these differentiating tests are not always performed. Conditions similar to benign foot rot and ovine interdigital dermatitis occur in goats. In sheep, foot abscesses affect the heel (infective bulbar necrosis) or toe (lamellar abscesses). Foot abscesses are more common in wet seasons and in heavy adult sheep. In addition to F. necrophorum, Trueperella pyogenes (Arcanobacterium pyogenes) may be isolated from the lesions.

Dietary zinc deficiency has been reported in cattle, sheep, and goats. Cutaneous lesions include alopecia, scaling, and crusting of the skin of the face, neck, distal extremities, and mucocutaneous junctions. In uncomplicated cases, microscopic lesions consist of parakeratosis and sometimes hyperkeratosis. pneumonia characteristic of this disease. Skin lesions begin to resolve if the pig survives.

Poxviruses For more mechanistic detail, see the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Viral Infections, Poxviruses.

Swinepox. Pox lesions in pigs are caused by the host-specific poxvirus Suipoxvirus (swinepox). Normally swinepox is transmitted by contact, although transplacental infection has not been ruled out. The sucking louse Haematopinus suis often acts as a mechanical vector and assists infection by causing skin trauma. The virus persists in dried crusts from infected animals. The pathogenesis of lesion formation and morphologic features of the gross and histologic lesions are consistent with the typical pox infection. The gross lesions typically affect the ventral and lateral abdomen, lateral thorax, and medial foreleg and thigh. Occasionally lesions on the dorsum predominate. Lesions can be generalized and rarely involve the oral mucosa, pharynx, esophagus, stomach, trachea, and bronchi. The erythematous papules usually transform into umbilicated pustules without a significant vesicular stage (Fig. 17-69) . The inflammatory crust eventually sheds to leave a white scar. The disease occurs worldwide and is endemic to areas of intensive production of pigs. The disease affects young, growing piglets and is mild with very low mortality.

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For disorders occurring in two or more species of animals, see the section on Disorders of Domestic Animals.

Dermatosis vegetans is an inherited disorder of young pigs characterized by vegetating skin lesions, hoof malformation, and giant cell pneumonia. The condition is a simple autosomal recessive trait of Landrace pigs. The pathogenesis of lesion formation is unknown. Skin lesions can be present at birth but might not develop until 2 to 3 months of age. Lesions begin as erythematous papules on the ventral abdomen and medial aspect of the thighs and possibly the sides and back. The papules enlarge peripherally to form plaques with a depressed center filled with gray to brown-black granular brittle material. Each crusty plaque is sharply demarcated from normal skin by a hyperemic raised border. As lesions spread peripherally, they coalesce to form extensive horny, papilloma-like areas covered by black crusts. Hoof lesions, if they occur, are always present at birth. Usually all digits, including accessory digits, on more than one limb are affected. The coronary region is markedly swollen and erythematous, and a yellow-brown greasy material covers the skin. The wall of the hoof is thickened by ridges and furrows parallel to the coronary band. Histologically, fully developed cutaneous lesions have marked orthokeratotic and parakeratotic hyperkeratosis, prominent irregular epidermal hyperplasia, intercellular edema, and intraepidermal pustules and microabscesses containing eosinophils and neutrophils. Affected piglets frequently die of secondary infection when skin lesions reach the typical papillomalike stage (5 to 8 weeks of age) either from entrance of bacteria from skin lesions or a bacterial pneumonia complicating the giant cell 

Hereditary zinc deficiency (lethal trait A-46, hereditary parakeratosis, hereditary thymic aplasia) is an autosomal recessive inherited form of zinc deficiency that has been reported in young calves (Friesian and Black Pied Danish cattle of Friesian descent in Europe, Angus cattle in Australia, and shorthorn cattle in the United States). The disease is caused by intestinal malabsorption of zinc, and lesions resolve with zinc supplementation. The disease is multisystemic. Skin lesions usually begin at 1 to 2 months of age, and without zinc supplementation, calves usually die within a few months from secondary infections associated with immune dysfunction. Skin lesions begin on the nose and spread to periocular areas, pinnae, intermandibular space, and distal extremities, including coronary bands. Ventral abdominal, flank, and perineal skin can also be affected. Lesions consist of erythema, exudation, crusting, scaling, Zinc-responsive dermatosis in dairy goats rarely has been reported. Low serum zinc concentrations occur even though the diet has adequate concentrations of zinc. Clinical lesions include alopecic, firm, dry, scaly areas of the skin of the back, legs, udder, face, and ears. Histologic lesions include orthokeratotic and parakeratotic hyperkeratosis. Lesions respond to prolonged zinc supplementation, suggesting malabsorption of dietary zinc. and a rough hair coat that fades to lighter color. The calves have thymic hypoplasia, reduced humoral and cell-mediated immunity, and secondary infections. The major cutaneous histologic lesion is marked diffuse parakeratotic hyperkeratosis (parakeratosis). There also can be perivascular edema and dermatitis with neutrophilic exocytosis forming crusts colonized by cocci. CHAPTER 17 The Integument

For more mechanistic detail, see Disorders of Domestic Animals, Microbial and Parasitic Disorders, Bacterial Infections, Skin Lesions Secondary to Systemic Bacterial Infections or Infection with Toxin-Producing Bacteria.

Cutaneous lesions caused by E. rhusiopathiae (erysipelas) in pigs are a result of bacterial embolization to the skin during sepsis. Lesions consist of square to rhomboidal, firm, raised, pink to dark purple areas (Fig. 17-71) and are caused by vasculitis, thrombosis, and ischemia (infarction). The rhomboidal shape likely represents the area of skin no longer receiving blood supply from the now thrombosed vessel.

Septicemic Infection with Salmonella sp., Pasteurella multocida, or Escherichia coli Septicemic salmonellosis causes cyanosis of the external ears and abdomen because of capillary dilation, congestion, and thrombosis. The thrombosis leads to necrosis of distal extremities. The mechanism of vascular damage involves endotoxin-induced venous thrombosis. Systemic infection with P. multocida can cause similar lesions in pigs. E. coli production of Shiga toxin 2e (verotoxin 2e) causes edema disease that primarily affects healthy, rapidly growing nursery pigs. The Shiga toxin is produced in the intestine, is absorbed into the circulation, and targets vascular endothelium with high concentrations of the toxin receptor globotetraosyl ceramide. This results in vascular degeneration, necrosis, edema, and hemorrhage. Gross lesions of the skin in edema disease consist of accumulation of clear fluid (edema) in the subcutis of the snout, eyelids, submandibular area, ventral abdomen, and inguinal areas. Histologically, the subcutis is edematous, and there may be edema, hemorrhage, microthrombi, and smooth muscle necrosis and hyaline degeneration of the tunica media of small arteries and arterioles in the skin and other areas of the body.

For more mechanistic detail, see the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Bacterial Infections, Superficial Bacterial Infections (Superficial Pyodermas), Superficial Pustular Dermatitis.

Exudative epidermitis, usually caused by S. hyicus, is an acute, often fatal, dermatitis of neonatal piglets, but a mild disease in older piglets. Predisposing factors include cutaneous lacerations and poor nutrition. In piglets, brownish exudates develop around the eyes, pinnae, snout, chin, and medial legs and spread to the ventral thorax and abdomen, giving the animal an overall "greasy" appearance ( Fig.  17-70) . The lesions rapidly coalesce and become generalized, resulting in greasy, malodorous exudates covering an erythematous skin. If piglets survive, the exudate hardens, cracks, and forms fissures. Subacute disease develops gradually in older piglets, and lesions are generally localized to the skin of the face, pinnae, and periocular regions. Grossly, the epidermis is thickened with scaling. The early histopathologic lesion is subcorneal pustular dermatitis, which extends to the hair follicle, resulting in superficial suppurative folliculitis. In the fully developed lesion the epidermis is hyperplastic and has thick crusts of keratin, microabscesses, and cocci. The term exudative epidermitis is descriptive of this condition because the inflammatory changes largely involve the epidermis, and there is an accumulation of exudates on the surface. The dermis is congested and edematous. In the early stages the dermatitis is superficial and perivascular with neutrophils and eosinophils, and in the later stages it is perivascular and mononuclear.

See the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Bacterial Infections, Bacterial Granulomatous Dermatitis (Bacterial Granulomas), Mycobacterial Granulomas. reproductive and respiratory syndrome virus, or P. multocida. However, the role of these etiologic agents in porcine dermatitis and nephropathy syndrome has not been proven. Immune complex deposition is thought to play a role. Immunoglobulin and complement have been detected in cutaneous vessel walls and glomeruli. Clinical lesions consist of acute-onset cutaneous erythematous to hemorrhagic papules, macules, and plaques that progress to multifocal raised red crusts with black centers that are most severe on the hind limbs, ventral abdomen, flanks, and perineum. Necrosis and ulceration may develop. Histologic lesions are necrotizing neutrophilic vasculitis with hemorrhage, edema, and fibrin deposition affecting small-and medium-sized arteries of the skin, kidney, and other tissues, accompanied by thrombosis and infarction. Systemic signs include fever and lethargy, and the condition is commonly fatal.

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Porcine juvenile pustular psoriasiform dermatitis (pityriasis rosea) develops in suckling and young pigs (3 to 14 weeks of age), usually resolves spontaneously by 4 weeks of onset, and is thought to be inherited. A few piglets in the litter or entire litters can be affected. Lesions are symmetric and develop on the abdomen, groin, and medial thigh and begin as small papules covered by brown crusts. The lesions coalesce and spread and develop into umbilicated plaques with white centers and erythematous, scaly borders that can progress into mosaic patterns (Fig. 17-72) . These clinical lesions resemble those of dermatophytosis, swinepox, and dermatosis vegetans, from which they need to be differentiated, but otherwise the clinical lesions are of no significance. Microscopically, the early histologic lesions are superficial and deep perivascular neutrophilic, eosinophilic, and mixed mononuclear dermatitis. Epidermal spongiosis and leukocytic exocytosis result in spongiform pustules. Later, lesions consist of marked psoriasiform epidermal hyperplasia (regular epidermal hyperplasia with epidermal projections of uniform length and width) and parakeratotic cellular crust.

For disorders occurring in two or more species of animals, see the section on Disorders of Domestic Animals.

Also see the section on Disorders of Domestic Animals, Congenital and Hereditary Disorders.

Dermal mucinosis occurs as an inherited dermal connective tissue disorder in the Chinese Shar-Pei dog in which the presence of the dermal mucin causes the thick, wrinkly skin that typifies this breed. The range in degree of dermal mucin deposition varies greatly with some Shar-Pei dogs having small quantities of dermal mucin and minimally wrinkly skin, whereas other Shar-Pei dogs have excessive quantities of dermal mucin, thick wrinkly skin, and "lakes" or pools of dermal mucin that can create clinically evident vesicles. The

Vasculitis is uncommon to rare in pigs and usually is seen in association with bacterial infection such as E. rhusiopathiae, and Gramnegative septicemias caused by Salmonella, Pasteurella, or E. coli. In addition, a condition called porcine dermatitis and nephropathy syndrome, predominantly affecting the vessels in the skin and kidneys, has been described. The incidence is usually low (less than 1%); however, epizootics in which the incidence reaches 10% to 20% or higher have been described. Mortality is high (80% to 90%). The cause and pathogenesis are unknown, but the condition may be associated with infection with porcine circovirus 2, porcine 

Zinc deficiency, although once common in pigs, occurs infrequently today because of dietary supplementation. Gross lesions are generally symmetric, circumscribed, reddened macules that develop first on the ventral abdomen and medial thighs and spread to the lower limbs, especially over joints, periocular areas, pinnae, snout, scrotum, and tail. The macular lesions progress to papules and plaques that become covered with scales and crust. The crusts thicken and develop fissures filled with debris, including soil and bacteria. The fissures provide a route of entrance for bacteria that can cause infection, including the development of subcutaneous abscesses. Microscopically, the lesions are parakeratosis, hypergranulosis, acanthosis, and pseudocarcinomatous hyperplasia. Secondary bacterial invasion results in epidermal pustular dermatitis and folliculitis. The fissures filled with debris can become infected by mixed populations of bacteria and lead to the development of subcutaneous abscesses. CHAPTER 17 The Integument

Acral lick dermatitis (lick granuloma, acral pruritic nodule, neurodermatitis) usually develops on an extremity (acral = extremity or apex) in dogs and is caused by persistent licking or chewing. The disorder is not uncommon and may be psychogenic in origin or associated with a disease process in the skin (e.g., localized infection or neoplasia) or underlying joint or bone. Boredom may play a role in some cases. The constant licking and chewing of the skin is a form of repeated trauma that leads to the gross and histologic changes. Usually a single lesion develops on the anterior surface of carpal, metacarpal, tarsal, metatarsal, tibial, or radial skin. Grossly, early lesions may be erythematous, haired or hairless, scaly to crusted ovoid to round, occasionally eroded macules or plaques (Fig. 17-73) . With time lesions become firm, hairless plaques or nodules that are often extensively or multifocally ulcerated. Ulcers are typically bordered by a raised edge. Microscopically, there is compact hyperkeratosis and acanthosis of the epidermis and follicular infundibulum. Erosions and ulcers may be present, the dermis is thickened by fibrosis, and capillaries and collagen fibers are oriented parallel to hair follicles, called vertical streaking, all the result of chronic irritation from licking. Sebaceous glands and hair follicles are hypertrophic, and there is perivascular and periadnexal plasmacytic dermatitis. Some lesions are complicated by secondary bacterial folliculitis and furunculosis, and severe scarring that may destroy the adnexa.

Pyotraumatic dermatitis, especially common in dogs, is secondary to irritation and principally the result of self-inflicted trauma from biting or scratching because of pain or itching caused by allergies, parasites, matted hair, or irritant chemicals. Dogs with long hair and dense undercoats are predisposed, and lesions develop more commonly in hot humid weather. Flea bite hypersensitivity is a common predisposing cause, and lesions can coalesce to involve large portions of dorsal lumbar and thigh skin (see Fig. 17 -53). Type I hypersensitivity reaction to flea bites leads to severe pruritus and self-trauma. Excoriated, moist skin is conducive to bacterial colonization. Grossly the lesions are hairless and red, exude fluid, and have circumscribed edges. Microscopically, affected dogs may have either superficial erosive to ulcerative exudative dermatitis or a deeper suppurative folliculitis (pyotraumatic folliculitis, deep pyoderma). The pyotraumatic folliculitis lesions are considered to represent a deep pyoderma and develop more commonly on the cheek and neck of young golden retriever, Saint Bernard, Labrador retriever, and Newfoundland dogs. Biopsy is required to differentiate the more superficial pyotraumatic dermatitis from the deeper suppurative folliculitis.

For more mechanistic detail, see the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Bacterial Infections, Superficial Bacterial Infections (Superficial Pyodermas).

For more mechanistic detail, see the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Bacterial Infections, Superficial Bacterial Infections (Superficial Pyodermas), Superficial Pustular Dermatitis. main component of dermal mucin is hyaluronic acid (hyaluronan), a glycosaminoglycan produced by many cutaneous cells, including fibroblasts and keratinocytes, and that has a marked ability to retain water, contributing to the dermal thickness noted clinically. The cause of excess hyaluronan in Shar-Pei dogs is thought to be the result of overactivation of the hyaluronan synthase 2 (HAS2) gene. Shar-Pei dogs have increased serum hyaluronic acid concentrations, which may occur as a result of drainage of hyaluronic acid into dermal lymphatic vessels, and subsequently into the blood. Histologically, dermal mucin is an amphophilic amorphous material that separates dermal collagen fibers, sometimes forming lakes of material. In these areas of mucin accumulation, there is a concomitant reduction in dermal collagen fibers, and lymphatic channels may be dilated. These areas of the skin are fragile, and if traumatized, thick, stringy clear or transparent mucin exudes from the dermis.

Mucin deposition, also consisting of glycosaminoglycans, notably hyaluronic acid, may also develop in association with myxedema of hypothyroidism. Myxedema is also present in approximately a third of dogs with hypersomatotropism. without basal cell degeneration. Other features include spongiosis and cellular exocytosis into the epidermis, neutrophilic pustular crusts, and folliculitis of adjacent follicles. Over time pigmentary incontinence develops. Although classic cases are said not to have basal cell degeneration, apoptotic keratinocytes above the basal layer can be present. In addition, there can be interface inflammation obscuring the dermal-epidermal interface. These features prevent definitive histologic differentiation from discoid lupus erythematosus. Mucocutaneous pyoderma may coexist with skin fold (intertriginous) pyoderma, and the lesions may appear similar histologically; however, lesions of mucocutaneous pyoderma do not originate in the skin folds. 

Hookworm dermatitis is caused by cutaneous migration of the larvae of Ancylostoma spp. or Uncinaria sp. Lesions develop in areas of the skin in contact with an unsanitary environment contaminated by the hookworm larvae, including distal limbs and feet, ventral thorax and abdomen, tail, and caudal thighs. Lesions begin as red papules that coalesce into erythematous areas that later become lichenified

Superficial spreading pyoderma is a common, often pruritic, superficial bacterial infection in dogs caused by S. pseudintermedius. Clinical lesions are most frequently recognized in the glabrous ventral thoracic and abdominal skin but can affect the haired skin of the dorsal and lateral trunk as well. Early clinical lesions include erythematous macules, papules, and transient pustules. Older clinical lesions include epidermal collarettes, crusts, alopecia, and hyperpigmentation. Early microscopic lesions are superficial, spongiotic epidermal pustules that rapidly crust and form basophilic debris, often with cocci, on the surface of the epidermis. This basophilic debris can dissect peripherally (laterally) between the epidermis and stratum corneum and is thought to form the rim of scale that clinically represents the epidermal collarette. In this way the lesions "spread" outwardly from the initial lesion. Occasionally, superficial spreading pyoderma can originate from superficial folliculitis in which follicular pustular formation is minor and epidermal collarette formation more prominent. Dermal lesions include superficial perivascular to interstitial accumulations of neutrophils, eosinophils, and mixed mononuclear cells. Some dogs have neutrophilic vasculitis involving superficial venules, possibly caused by immunecomplex deposition, a feature suggesting a hypersensitivity response to bacterial antigens. Dermal congestion and edema are usually present.

Mucocutaneous pyoderma is a putative bacterial infection of mucocutaneous junctional skin in dogs. Antibiotic responsiveness suggests that bacteria contribute; however, the etiology is likely more complex and may involve immunologic factors as well. A variety of breeds are affected, but the German shepherd breed is thought to be predisposed. The pathogenesis is unknown. Clinical lesions may be painful and consist of erythema, swelling, and crusting, and in severe cases, fissures and ulcers. Depigmentation may develop in chronic cases. Lesions are most common on mucocutaneous skin and commissures of the lips, but mucocutaneous skin in other sites, including the prepuce, vulva, anus, nares, and eyelids, can be affected. Histologic lesions include a dense band of lymphoplasmacytic inflammation with variable numbers of neutrophils at the dermal-epidermal junction (lichenoid inflammation), typically 1133 CHAPTER 17 The Integument and external ears, which progresses to involve the distal extremities, especially over bony prominences and the tip of the tail. Inflammation of the claw bed may lead to abnormal claw formation or sloughing of the claw. Myositis and atrophy of muscles of mastication, distal extremities, and sometimes of the esophagus develop after the dermatitis (see Fig. 17-74) . The myositis is variably severe and multifocal, but more prevalent in peripheral anatomic locations. and alopecic. Pawpads can become soft, the cornified portion can separate, and secondary bacterial dermatitis and paronychia can develop. Pawpad hyperkeratosis can also be a feature of chronic infection. Hyperplastic spongiotic perivascular dermatitis with eosinophils or neutrophils, serocellular crusts, and migration tracks (tunnels) are the microscopic lesions. Parasitologic evaluation of fresh tissue may allow larval identification.

Other helminth parasites associated with cutaneous larval migration include Pelodera, Necator, Strongyloides, Gnathostoma, and Bunostomum. Schistosome cercariae, especially of birds, can cause similar lesions.

Flea Bite Hypersensitivity. See the section on Disorders of Domestic Animals, Immunologic Skin Diseases, Selected Hypersensitivity Reactions, Insect Bite Hypersensitivity, Flea Bite Hypersensitivity.

Pemphigus. See the section on Disorders of Domestic Animals, Immunologic Skin Diseases, Selected Autoimmune Reactions, Reactions Characterized Grossly by Vesicles or Bullae as the Primary Lesion and Histologically by Acantholysis.

Parakeratotic Casts. A rare, recently described skin disorder in Labrador retrievers consists of variably extensive, multifocal, verrucous, crusted papules and plaques, and comedones or follicular casts. The lesions develop in haired skin. Histopathologic lesions consist of orthokeratotic and more prominent parakeratotic hyperkeratosis largely of the follicular infundibulum that result in follicular cast formation and a papillary epidermal surface. Histologically, apoptotic keratinocytes and CD3 + lymphocytes (cytotoxic dermatitis) are present in superficial strata of the follicular infundibulum and epidermis. The cause of the condition is unknown, but an immune response directed toward unidentified antigens expressed on the surface of keratinocytes is suspected. The lesions are indistinguishable from those of proliferative and necrotizing otitis externa in cats, which may also affect haired skin in other sites (see Chapter 20), and because of the intraepidermal lymphocytes and apoptotic keratinocytes, this condition histologically resembles erythema multiforme, especially when scales or crusts are prominent.

Vascular Lesions (Ischemic Dermatopathy). Dermatomyositis is an inherited disease with variable expressivity that occurs in juvenile and adult-onset forms in collies and Shetland sheepdogs ( Fig.  17-74 ). Other breeds are occasionally affected. The pathogenesis involves vasculitis of skin, muscle, and sometimes other tissues. The vascular lesions are subtle and include mild thickening of the vessel wall, occasionally pyknotic cells in the vessel wall, and occasionally lymphocytes within the wall; these changes are termed cell-poor vasculitis. Circulating immune complexes have been identified and likely play a role. Dermatomyositis develops in puppies as early as 8 weeks of age. Early lesions include vesicular dermatitis of face, lips, Figure 17 -74 Dermatomyositis, Skin, Dog. A, Face. Chronic lesions of hair loss, hyperpigmentation, and scarring are present in the skin around the eye and on the lateral side of the face. Interface dermatitis, myositis, and vasculitis have resulted in ischemic follicular atrophy, muscle atrophy, and scarring. The scarring and possibly also some muscle atrophy have contributed to the contraction of the skin of the eyelid and the inability to close the eyelids fully at the medial canthus (arrows). B, Lip. Erosion is present on the surface of the lip skin at the far right. Atrophy of the adnexa, not present here, and dermis can predispose to injury of the epidermis and superficial dermis by minor trauma. Muscle atrophy (arrows) and scarring around the muscle fibers are present. The diagnosis of dermatomyositis is strengthened if muscle atrophy or myositis is present in the skin biopsy sample. H&E stain. (Courtesy Dr. A.M. Hargis, DermatoDiagnostics.) A B dermatopathy. Puppies, approximately 1 to 2 months of age, are affected, and some puppies develop lesions after vaccination. The major clinical lesion is swelling of pawpads, and some puppies develop ulcers on the pawpads, ear margins, tail tip, and nasal planum with depigmentation of the nasal planum or nasal commissures. Histologically, early vessel lesions include neutrophil infiltration of small venules and arterioles, but more commonly, vascular lesions are subtle and consist of cell-poor vasculitis (mild thickening of the vessel wall with occasional pyknotic cells and lymphocytes within the wall). In addition, cutaneous lesions consist of mild interface dermatitis with pigmentary incontinence. The nodular lesions in pawpads are in the dermis and subcutis, and early lesions consist of focal collagen degeneration bordered by neutrophils and mononuclear cells. Chronic lesions have dermal and subcutaneous fibrosis sometimes accompanied by degeneration and fibrosis of skeletal muscle bundles.

Greyhound. Greyhounds with cutaneous and renal glomerular vasculopathy are typically from race track environments. The cause and pathogenesis are unknown; however, there is speculation that the disorder is similar to hemolytic-uremic syndrome in human beings in which a verotoxin (Shiga-like toxin) damages vascular endothelium. Most racing greyhounds eat raw meats, which could contain the E. coli-producing toxin. Clinical lesions include hemorrhagic macules that progress to deep ulcers of the tarsus, stifle, or inner thigh. Occasionally lesions develop on the front legs, groin, or trunk. Lesions heal slowly (usually over 1 to 2 months) by fibrosis. Histologically, capillaries, venules, and arterioles in the dermis and occasionally the subcutis have degenerate walls with pyknotic or karyorrhectic nuclei, as well as occasional fibrinoid necrosis. Fibrin thrombi can result in cutaneous infarction. Approximately 25% of the affected greyhounds also have systemic signs of renal failure because of glomerular arteriolar inflammation, necrosis, and thrombosis.

Hypothyroidism Deficiency of thyroid hormone develops most commonly in dogs and usually is caused by idiopathic thyroid atrophy and lymphocytic thyroiditis. Thyroid hormones play an essential role in normal growth and development of many organs, including the skin, and can result in a variety of systemic and cutaneous signs and lesions. In dogs the hair follicle is considered to be an important target for thyroid hormones, where the hormones are thought to be necessary for the initiation of the anagen stage of the hair cycle. Clinical lesions of thyroid deficiency consist of a dull, dry, easily epilated hair coat that fails to regrow after clipping. Alopecia develops in areas of wear, including the tail, elbows, hips, around the neck (wear from the collar), and on the dorsal surface of the nose. Symmetric truncal alopecia is not as common as once thought. Microscopically, in areas of advanced alopecia, hair follicles are in the telogen stage of the hair cycle or more commonly, have lost their hair shafts (kenogen). Follicular infundibular hyperkeratosis with plugging of the follicular opening is also present. Other histologic changes include acanthosis of epidermis and follicular infundibulum and a thicker dermis, features that help differentiate lesions of hypothyroidism from other endocrinopathies. Myxedema, an increase in dermal mucin resulting in dermal thickening, is a rare manifestation of canine hypothyroidism. Secondary staphylococcal infection can develop.

Hypothyroidism can also be the result of congenital iodine deficiency. Iodine deficiency develops in fetuses because of maternal The muscle inflammation consists of lymphocytes, plasma cells, histiocytes, and fewer neutrophils or eosinophils. Perifascicular myofiber atrophy (atrophy at the periphery of muscle fascicles) occurs occasionally. The rostral and most superficial portion of the temporalis muscle is the biopsy site of choice to confirm the myositis. Dermatomyositis varies in severity. Mild skin lesions heal without scarring, but moderate skin lesions heal with permanent foci of alopecia, hyperpigmentation or hypopigmentation, and scarring. The hypopigmentation develops from damage to melanin-containing cells in the basal layer of the epidermis. Skin and muscle lesions in dogs with severe disease are progressive and disfiguring, the result of severe scarring of the skin and atrophy of muscle. Microscopic skin lesions include cell-poor interface dermatitis with basal cell degeneration of the epidermis and follicular wall, variable epidermal vesicles and pustules, follicular atrophy, and dermal scarring. Cellpoor vasculitis, a major feature contributing to the lesions in dermatomyositis, is not always identified in small biopsy samples. The combination of interface dermatitis and mural folliculitis with follicular atrophy and cell-poor vasculitis has been considered to represent ischemic lesions and is referred to as ischemic dermatopathy.

Skin and vessel lesions indistinguishable from those in dermatomyositis (e.g., ischemic dermatopathy) have developed in other ages and breeds of dogs, sometimes in association with vaccination, and have been organized into the following groups: (1) juvenile dogs other than collies and Shetland sheepdogs without known breed predilection to dermatomyositis, and sometimes with temporal association with vaccination; (2) dogs with localized reactions to subcutaneous injection of killed rabies and sometimes other killed vaccines; (3) dogs with more generalized disease related to rabies vaccination; and (4) dogs with generalized ischemic dermatopathy in which correlation with previous vaccination cannot be documented.

Rabies vaccine-induced ischemic dermatitis develops as a localized form limited to the site of vaccination and as a more widespread form, both developing in the months after rabies vaccination. Poodles, Yorkshire and silky terriers, and other soft-coated breeds of dogs are predisposed to the localized form, but it can occur in any breed. In the localized form an alopecic, hyperpigmented patch of atrophic skin appears at the site of vaccination (see Fig. 17-42) .

Microscopically, in addition to lesions of ischemic dermatopathy, mild chronic lymphocytic cell-poor vasculitis, a mild diffuse increase in mononuclear cells throughout the dermis, and nodular lymphocytic panniculitis are present. Rabies antigen has been detected in hair follicles and in vessels in affected skin. In the widespread form, lesions are present at the site of vaccination, ear margins, periocular skin, and skin over bony prominences, tip of tail, and pawpads. Lingual erosions and ulcers also occur. In addition, some dogs develop perifascicular muscle atrophy and perimysial fibrosis, with complement components 5b-9 (C5b-9) in the microvasculature. The microscopic lesions are similar to the localized form with the addition of possible muscle lesions, but nodular lymphocytic panniculitis is absent in sites distant from the site of vaccination. The development of lesions after vaccination and the identification of rabies-virus antigen in the vessels and hair follicles in dogs with the localized form of rabies vaccine-induced dermatitis have resulted in the speculation that lesions might be a result of an idiosyncratic immunologic reaction to viral antigen in these sites in genetically predisposed dogs.

Familial Vasculopathy of German Shepherd Dogs. Familial vasculopathy of German shepherd dogs appears to have a genetic basis, but the underlying cause and pathogenesis are unknown. Cutaneous and vascular lesions have similarities to ischemic 1135 CHAPTER 17 The Integument female dogs have an enlarged vulva and abnormalities of the estrus cycle. Male dogs can develop gynecomastia, pendulous prepuce, or an enlarged prostate because of squamous metaplasia of prostatic ducts. Cutaneous microscopic lesions include orthokeratotic hyperkeratosis, follicular hyperkeratosis, and telogen follicles that have lost their hair shafts (kenogen) (see Fig. 17-77) .

Hypersomatotropism rarely occurs in adult dogs and is a result of excess concentrations of growth hormone (somatotropin). The excess growth hormone can arise from acidophil tumors of the anterior pituitary gland, injection of pituitary gland extracts, administration of progestins, or with the metestrus (luteal) phase of the estrous cycle in intact female dogs. Elevated concentrations of growth hormone result in increased production of connective tissue, bone, and viscera. Clinical lesions consist of acromegaly (enlargement of parts of the skeleton, especially distal extremities) and thick, folded myxedematous skin over the head, neck, and extremities. The hair coat can be long and thick, and the claws can be thick and hard. Histologic lesions include thickened dermis caused by increased production of glycosaminoglycans and collagen by dermal fibroblasts. Myxedema is present in approximately a third of cases.

ingestion of diets deficient in iodine or containing substances that interfere with production of thyroid hormones (goitrogens). These factors result in insufficient synthesis of thyroxine and reduced blood concentrations of thyroxine and triiodothyronine. The reduced concentrations of these hormones are detected by the hypothalamus and pituitary gland, stimulating secretion of thyrotropin and resulting in hyperplasia of the thyroid follicular cells. Regions of North America that are deficient in iodine include the Great Lakes basin, the Rocky Mountains, the northern Great Plains, the upper Mississippi River valley, and the Pacific Coast region. Paradoxically, maternal diets high in iodine can also result in congenital hypothyroidism. High blood iodine level also interferes with one or more steps of thyroid hormone production, leading to low blood thyroxine concentrations, hypothalamic and pituitary stimulation, and secretion of thyrotropin. Congenital iodine deficiency can occur in any domestic animal but usually is seen in large animals; it is associated with the birth of dead fetuses or weak neonates. These neonates can have alopecia, and thyroid glands are usually enlarged because of the follicular cell hyperplasia.

Hyperadrenocorticism results in cutaneous lesions principally in dogs, less often in cats, and rarely in other domestic animals. It is usually caused by bilateral adrenal cortical hyperplasia secondary to a functional pituitary neoplasm, and less often by a functional adrenal cortical neoplasm or a functional nodule of cortical hyperplasia. Particularly in dogs, the administration of exogenous glucocorticoids is also a cause. Rarely, accidental topical contact with glucocorticoids used on the skin of human beings may cause lesions, particularly in small dogs. In dogs, cutaneous lesions include endocrine alopecia that generally spares the head and extremities, thinning of the skin, comedones, increased bruising, poor wound healing, and increased susceptibility to infection ( Fig. 17-75) . Dystrophic calcification of the dermis of the dorsal neck region, inguinal areas, and axillary areas can occur in dogs, particularly in iatrogenic hyperadrenocorticism (calcinosis cutis) (Fig. 17-76) . Grossly, lesions of calcinosis cutis are firm, thickened, sometimes gritty, often ulcerated and alopecic, crusted plaques or nodules (see Fig. 17 -76). In cats affected with hyperadrenocorticism, calcinosis cutis typically does not develop; however, the dermal collagen fibers can be markedly thin and atrophic, resulting in extremely fragile skin that can tear with normal handling. Microscopically, the lesions of hyperadrenocorticism include epidermal, dermal, and follicular atrophy (see Fig.  17 -75) and follicular hyperkeratosis with the formation of comedones. Hair follicles are either in the telogen stage of the hair cycle or more commonly, have lost their hair shafts (kenogen). Calcinosis cutis may develop in affected dogs (see Fig. 17-76) , and foreign body reaction (granulomatous inflammation) and draining sinuses can develop in association with the calcium deposits. In cats the atrophic hair follicles often have brightly eosinophilic trichilemmal cornification, a feature associated with prolonged telogen and in the cat, considered highly suggestive of hyperadrenocorticism.

Hyperestrogenism can develop in male and female dogs. In females the estrogen originates from ovarian cysts, rarely an ovarian neoplasm, or from estrogen administration. In males, elevated serum concentrations of estrogen are usually derived from a functional testicular Sertoli cell tumor or less commonly a testicular interstitial cell tumor. Iatrogenic estrogen administration has also caused hyperestrogenism in male dogs (Fig. 17-77) . Rarely, accidental topical contact with estrogens used on the skin of human beings may cause lesions, particularly in small dogs. In addition to endocrine alopecia, Figure 17 -75 Truncal Alopecia, Hyperadrenocorticism, Skin, Dog. A, Note the alopecia, distended abdomen, and thin skin in which blood vessels are faintly visible (arrow). The distended abdomen and visibility of blood vessels are a result of protein catabolism and loss of muscle and dermal collagen, respectively. The distended abdomen and thin skin with greater visibility of blood vessels in conjunction with symmetric alopecia suggest that a catabolic endocrine disease, such as hyperadrenocorticism, is likely. B, Atrophy of dermal collagen fibers is so severe that the collagen has almost disappeared, and the adnexal glands and arrector pili muscles are readily visible. Hair follicles are in the telogen and kenogen stages of the hair cycle. Microscopically, the features are consistent with endocrine alopecia (e.g., hyperkeratosis of superficial epidermis and of hair follicles; normal or atrophic epidermis; follicular dilation from hyperkeratosis; increased numbers of telogen [haired] and kenogen [hairless] follicles; and increased epidermal pigmentation). The numbers of dermal elastic fibers are reduced in the skin of some dogs.

Prolonged alopecia postclipping is a failure of the hair to regrow in apparently normal dogs after close clipping. The condition usually occurs in long-haired or heavily coated (plush-coated) breeds of dogs such as the Chow Chow. The pathogenesis of this condition is undetermined, but because hair regrowth may take a year or more, an arrest in the hair cycle is suspected. Alternatively, it is possible that heavily coated breeds of dogs have a prolonged telogen stage of the hair cycle, possibly to conserve energy by avoiding frequent cycles of shedding. Thus clipping when the hair coat is in a prolonged inactive stage of the hair cycle would result in lack of quick regrowth of the hair coat. The hair coat may not regrow until there is another significant growth phase, which may take 6 to 12 months. Most affected dogs regrow the hair coat after they go through a cycle of heavy shedding. Histologic lesions consist of normal epidermis, dermis, and sebaceous glands, and hair follicles in the telogen stage of the hair cycle with retained hair shafts. The follicles may have prominent trichilemmal cornification and resemble flame follicles.

Alopecia X (adrenal sex hormone alopecia, castration-responsive dermatosis, growth hormone-responsive dermatosis) is seen most often in breeds of dogs with plush hair coats (e.g., Pomeranian, Chow Chow, Samoyed, keeshond, and Alaskan malamute). Toy and miniature poodles and sporadically other breeds of dogs are also affected. Dogs with this condition (or conditions) are grouped together by having in common (1) plush hair coats in the normal state (e.g., when not affected with this condition), (2) alopeciasparing head and distal extremities, (3) hypothyroidism and hyperglucocorticoidism ruled out, and (4) skin biopsy samples with telogen follicles that retain their hair shafts (haired telogen), and often prominent flame follicles (follicles that have prominent trichilemmal cornification that forms spikes into the follicular stratum spinosum). The alopecia often develops at 1 or 2 years of age in otherwise healthy dogs of either sex. The alopecia is symmetric and involves the perineum, caudal thighs, ventral abdomen and thorax, neck, and trunk. The head and distal extremities are spared. Hyperpigmentation is usually present (Fig. 17-78) . Thyroid function testing, adrenocorticotropic hormone response test, low-dose dexamethasone suppression test, and serum chemistry results are normal. Although abnormalities in a number of hormones have been detected, the cause of this condition remains unknown. Microscopic lesions include haired telogen follicles and prominent and diffuse formation of flame follicles (see Fig. 17-78, B) . Prominent diffuse flame follicle formation is suggestive of alopecia X, but flame follicles can be seen in other endocrine dermatoses (hyperestrogenism and hyperadrenocorticism, particularly in plush-coated breeds), and in follicular dysplasia of the Siberian husky. Follicles similar to flame follicles but with less exaggerated spikes of trichilemmal cornification and with hair shafts retained are seen in normal plush-coated breeds of dogs and in prolonged alopecia postclipping. Epidermal hyperpigmentation and epidermal and dermal atrophy are variable.

Deficiency of growth hormone in dogs younger than 3 months of age is usually the result of failure of the normal development of the pituitary gland, leading to cyst formation. Deficiencies of thyroid, adrenal, and gonadal hormones are frequent accompanying problems. Pituitary deficiency results in failure to grow, retention of the puppy hair coat, and development of endocrine alopecia. A, Dorsal neck. The skin is partially alopecic, ulcerated, crusted, and palpably thick and hard. B, Subcutis, the skin has been removed from the body and the subcutaneous surface exposed. Mineral deposits are visible as white papules and irregular plaques to nodules. C, Skin at the margin of a plaque is thickened by dermal mineralization and granulomatous inflammation (left half). H&E stain. D, Higher magnification of dermal mineralization (arrow) and granulomatous inflammation. loss can include vibrissae in both dogs and cats. With doxorubicin therapy, cutaneous hyperpigmentation is also present. Hair growth resumes after therapy is terminated, but the color or texture of the hair coat may be altered. Diagnosis is based on clinical history, physical examination, and microscopic examination of pulled hairs. Histopathologic examination has rarely been done and is not considered to be diagnostic. It has revealed a prominence of telogen follicles, which is more consistent with an early stage of telogen effluvium. The reason for this discrepancy is unknown but may reflect stage of hair loss at time of biopsy sampling (late in the course of hair loss) or differences in hair follicle cycling, response to chemical injury, or regenerative capabilities between dogs and human beings.

Acquired pattern alopecia develops in selected toy breeds of dogs with a short smooth hair coat (dachshund, Boston terrier, Chihuahua, Italian greyhound, and whippet). Breed predilections suggest a genetic basis. Generally, before 1 year of age, these dogs gradually develop a bilaterally symmetric thin hair coat in specific areas of the body such as the pinnae, skin caudal to the pinna, caudal thighs, perineal skin, or ventral neck, chest, and abdomen. The dogs are otherwise healthy. Histologic findings reveal miniaturized hair follicles and small (vellus) hair shafts.

Zinc-Responsive Dermatosis. Canine zincresponsive dermatosis occurs in two forms. One form occurs principally in Siberian huskies and Alaskan malamutes, but other large-breed dogs can be affected. Alaskan malamutes have an inherited reduced ability to absorb zinc from the intestine. Scaling and crusting develop in the skin around the mouth, chin, eyes (Fig. 17-79) , external ears, pressure points, and pawpads. The second form of zinc deficiency occurs in rapidly growing pups of large-breed dogs fed diets low in zinc or high in calcium or phytates, which can interfere with zinc absorption. Clinically dogs with this form have scaly plaques located on those areas of the skin subjected to repeated

Alopecia related to chemotherapy is best documented in human beings and occurs when there is a severe injury to the anagen (or growing) hair bulbs and is thus called anagen effluvium. It is usually diagnosed clinically by examination of pulled hairs, so scalp biopsy sampling is rarely performed. It is the result of an injury that interrupts the mitotic activity of the hair matrix cells in the hair bulb that have the greatest proliferative activity compared to other hair follicle cells. The abrupt cessation of mitotic activity is thought to lead to weakening of the developing anagen hair shaft nearest the hair bulb, which subsequently breaks at its narrowest or weakest point within the hair canal. The consequence of anagen effluvium is hair shedding that usually begins within a week or two after initiation of chemotherapy and is complete by 1 to 2 months after therapy. Because approximately 90% of human scalp hair is in the anagen phase, the hair loss is usually significant and alopecia obvious. Diagnosis can be made early in the course of hair loss by gently pulling out the damaged anagen hairs, which have irregularly narrowed or pointed ends that may contain melanin pigment when examined microscopically. Diagnosis can also be made late in the course of hair loss after anagen hairs have been lost. Because telogen hair follicles are immune to this injury, they remain intact. Thus microscopic examination of hairs pulled during the late stage of hair loss reveals a vast majority of telogen hairs, essentially confirming the presence of anagen effluvium (the anagen hairs have been lost). Alopecia related to chemotherapy also occurs in dogs and cats but has not been well studied. In dogs it has been reported most commonly with doxorubicin therapy and occurs in longer-coated breeds such as poodles and old English sheepdogs and also in some terrier breeds. The prolonged anagen hair phase in some of the longerhaired breeds may explain why they are predisposed. The degree of hair loss varies substantially and depends on drug, dose, method of administration, and treatment schedule, as well as individual animal variables (dogs with long versus short anagen hair cycle phases). Hair loss may begin within 7 to 10 days and is usually apparent within 1 to 2 months. The hair loss may be complete or partial (generalized thinning of the hair coat or loss of primary versus secondary hairs) and can affect different regions of the body (head and site of intravenous injection of the drug; skin of ventral trunk and medial legs; somewhat symmetric involvement of facial skin). Hair that more than zinc deficiency played a role in generic dog food dermatosis.

Lethal Acrodermatitis of Bull Terriers. Lethal acrodermatitis is an autosomal recessive inherited disease of defective zinc metabolism in white bull terriers. The exact cause or pathogenesis of the disorder is not known. Although defective zinc metabolism and/or absorption are thought to play a role, affected dogs do not respond to oral or parenteral zinc supplementation. The concentrations of serum zinc and copper are low in affected bull terriers compared with those of control dogs, suggesting that copper deficiency might Figure 17 -78 Alopecia X, Skin, Dog. A, Alopecia X in Chow Chow. Note the partial alopecia and hyperpigmentation of trunk. The alopecia is not diagnostic for a specific condition. The plush-coated breed of dog suggests that alopecia X should be considered as one of the differential diagnoses. B, Flame follicle, haired skin. The hair follicle is in the telogen stage of the hair cycle and has excessive trichilemmal cornification resembling the spikes of a flame (arrows) and is consistent with a "flame follicle." H&E stain. Periocular skin is thickened, alopecic, pigmented, and covered by tightly adherent scale. In Siberian huskies and Alaskan malamutes in particular, scaling and crusting develop in the skin around the mouth, chin, eyes, external ears, pressure points, and pawpads. B, Note the papillary epidermal hyperplasia (H) with marked parakeratosis (P). The parakeratotic hyperkeratosis and acanthosis form the thickened adherent scale. Although epidermal hyperplasia and parakeratosis are features of zinc-responsive dermatosis, they also occur in other conditions (such as superficial necrolytic dermatitis, chronic surface trauma, and nasal parakeratosis). Therefore breed, lesion distribution, and other features in the clinical history are important in differential diagnosis. trauma (e.g., elbows and hocks), the pawpads, and planum nasale. Microscopically, there is marked diffuse parakeratosis (see Fig. 17 -79) that extends into the hair follicles and an accompanying superficial perivascular lymphocytic and sometimes eosinophilic dermatitis. Another disorder, generic dog food dermatosis, a largely historical disease that occurred in the 1980s in dogs fed generic dog foods, has clinical and histologic lesions similar to those of canine zinc-responsive dermatosis. However, dogs with generic dog food dermatosis had a more rapid onset of lesions and also had systemic signs such as fever, depression, lymphadenopathy, and pitting edema of the dependent areas. The acute onset and systemic signs suggested CHAPTER 17 The Integument there is variable parakeratotic hyperkeratosis with intraepidermal serum and leukocytic exocytosis. The dermis has perivascular to interface or interstitial mixed inflammation. In familial pawpad hyperkeratosis, there is moderate to extensive epidermal acanthosis and marked diffuse orthokeratotic hyperkeratosis in which the surface stratum corneum forms many papillary projections.

Schnauzer comedo syndrome affects some miniature schnauzers and probably has an inherited basis. Gross lesions develop on the dorsum of the back and consist of comedones, papules, and crusts. Histologic lesions consist of follicles distended with a plug of follicular stratum corneum and sebum (comedones). Because the follicular opening is connected to the epidermis, the dilated follicles can contain coccoid bacteria. The dilated follicles can rupture (furunculosis) and release contents into the dermis, resulting in a foreign body response and bacterial infection.

Interdigital comedones and follicular cysts develop on the palmar and plantar skin of dogs and cause recurrent lameness, pain, nodules, or draining sinuses that erupt on the dorsal interdigital surface of the paw (see Table 17 -6). The lesions develop most commonly on the palmar and lateral interdigital webs of the front paws, where most weight bearing occurs. The pathogenesis is thought to result from external surface trauma to the palmar/plantar aspect of the haired interdigital skin, which causes follicular plugging and retention of follicular contents. Because canine hair follicles are mostly compound (see Fig. 17-6) , 15 or more secondary follicles can exit one common follicular opening, so narrowing or plugging of one follicular opening can result in the formation of multiple comedones or follicular cysts. The cystically dilated follicles can rupture and cause an inflammatory response to the material released from the contribute. Lesions generally begin between 6 and 10 weeks of age. Most affected dogs are dead by 15 months of age, usually because of bronchopneumonia. The thymus is small or absent, and T lymphocytes are deficient in lymphoid tissues, likely contributing to immunodeficiency and increasing the potential of infection. Cutaneous lesions begin between the digits and on pawpads and progress to involve mucocutaneous areas, especially of the face. Severe interdigital pyoderma, paronychia (inflammation of the skin around the claws), and villous thickening and fissuring of pawpad keratin ensue. Exfoliative dermatitis can also develop on pinnae, external nose, elbows, and hocks and in some dogs, can become more generalized, with crusting, ulceration, and secondary pyoderma. Microscopically, the principal lesions are extensive diffuse parakeratotic hyperkeratosis, responsible for the exfoliative dermatitis, and accompanying acanthosis. Lesions of secondary infection consist of epidermal pustular dermatitis and folliculitis.

Vitamin A-responsive dermatosis is a rare disorder primarily occurring in cocker spaniels, although a few other breeds of dogs have been affected. Because lesions respond to vitamin A therapy and relapse when treatment is withdrawn, vitamin A plays a role in the pathogenesis. However, vitamin A deficiency is not the cause of the lesions, because plasma concentrations of vitamin A are within the normal range. Vitamin A might contribute to lesion resolution by influencing epithelial differentiation. Gross lesions consist of generalized scaling, dry hair coat, and hyperkeratotic plaques with large "fronds" of stratum corneum extending from distended follicular openings (large open comedones). The plaques are most prominent in the ventral and lateral thorax and abdominal skin but can also occur on the face and neck. Microscopic lesions consist of mild orthokeratotic hyperkeratosis, mild irregular epidermal hyperplasia, and follicles markedly distended by hyperkeratosis.

Eosinophilic Dermatitis with Edema in the Dog. Eosinophilic dermatitis with edema affects adult dogs of a variety of breeds, although Labrador retrievers may be overrepresented. The cause is not known, but a hypersensitivity reaction to medications, arthropod bites, or other antigens is suspected. Gross lesions consist of extremely erythematous macules that progress and coalesce into arciform and serpiginous plaques. Facial or generalized pitting edema is often seen. Lesions involve the pinnae, ventral abdomen and thorax, and less often the extremities. Histologic lesions consist of diffuse, predominantly eosinophilic dermatitis, vascular dilation, and edema. Eosinophil aggregation and degranulation are seen in some lesions. Depression, hypoproteinemia, gastrointestinal diseases, and pyrexia are present in some dogs.

Juvenile sterile granulomatous dermatitis and lymphadenitis, also known as juvenile cellulitis, juvenile pyoderma, or puppy strangles, is a disorder of unknown cause that occurs in pups younger than 4 months ( Fig. 17-80) , with one or more of the pups of a litter developing pustular and nodular dermatitis and edema of the face, ears, and mucocutaneous junctions. The pustular and nodular lesions tend to rupture, drain, and crust. Microscopically, early lesions consist of multifocal granulomatous or pyogranulomatous perifolliculitis and dermatitis (see Fig. 17-80) . Early lesions are adjacent to but do not primarily involve follicles; however, folliculitis, furunculosis, panniculitis, cellulitis, and granulomatous to pyogranulomatous lymphadenitis develop with disease progression. The lesions initially are considered to be sterile, but secondary bacterial infections develop and can lead to sepsis if not treated. Approximately half of the puppies are lethargic, and anorexia, fever, and joint pain can also occur. This condition occasionally has been reported in adult dogs.

Canine reactive histiocytosis is a poorly understood disorder that occurs in cutaneous and systemic forms in dogs of a variety of ages and breeds, but Bernese mountain dogs, Rottweilers, Labrador retrievers, Irish wolfhounds, and a few other breeds of dogs appear predisposed to the systemic form. The cutaneous form is much more common than the systemic form, which is rare. Reactive histiocytosis is thought to be the result of immune dysregulation, and to be antigen driven, but cultures and special stains have failed to reveal etiologic agents, and no other antigen has been detected. The disorder typically has a slowly progressive, waxing and waning course but can spontaneously resolve and can respond favorably, at least for a time, to immunomodulatory therapy. The lesions require longterm management and often lead to death, particularly if there is systemic involvement. The cutaneous form consists of single or multifocal, nonpainful plaques or nodules composed predominantly of histiocytic cells that are immunophenotypically identified as activated dermal (interstitial) dendritic antigen-presenting cells that express CD1a, CD4, CD11c/CD18, CD90, MHC class II markers. Also intermixed with the histiocytic cells are T lymphocytes, mostly of the CD8 + type, and neutrophils. The role of the CD8 + lymphocytes is unknown. They may be involved in activation of the dendritic cells via release of cytokines such as GM-CSF and TNF-α known to be involved in the proliferation and differentiation of follicles, and a secondary bacterial infection. Exudate from the ruptured follicles can coalesce and form a draining sinus that ruptures on the dorsal surface of the paw, sometimes providing an erroneous opinion that lesions originate dorsally rather than ventrally. The palmar or planter interdigital skin is usually alopecic, may have callus-like thickening, and has prominent comedones from which follicular contents may be expressed. Histologic lesions consist of comedones and follicular cysts, some of which are ruptured, and pyogranulomatous inflammation containing hair shafts and follicular stratum corneum that form draining sinuses.

See Disorders of Domestic Animals, Disorders of Epidermal Growth or Differentiation, Predominant Follicular Hyperkeratosis (Comedones), Acne.

Primary idiopathic acanthosis nigricans is considered a genodermatosis (genetically determined skin disorder) of young dachshunds. The disease is manifested by bilateral axillary hyperpigmentation, lichenification, and alopecia, which can involve large areas of skin and also include secondary seborrhea and pyoderma. Histologic lesions are not highly specific, but include hyperplastic dermatitis with orthokeratotic and parakeratotic hyperkeratosis, acanthosis, and rete peg formation. All layers of the epidermis are heavily melanized. Spongiosis, neutrophilic exocytosis, and serous crusts can also be present. The dermal inflammatory reaction is mild, pleomorphic in cell type, and superficial perivascular in location. The term acanthosis nigricans has also been erroneously applied to a variety of inflammatory and pruritic disorders that in their chronic form are clinically manifested by axillary or more diffuse lichenification, alopecia, and hyperpigmentation, and thus overlap with the lesions of primary genodermatosis in young dachshunds. Consequently, the diagnosis of primary idiopathic acanthosis nigricans requires the expected clinical lesions, appropriate breed and age of dog, and histologic evaluation that can rule out other causes of acanthosis and hyperpigmentation.

Also see the section on Disorders of Domestic Animals, Miscellaneous Skin Disorders, Disorders Characterized by Infiltrates of Eosinophils or Plasma Cells.

See the section on Disorders of Domestic Animals, Miscellaneous Skin Disorders, Disorders Characterized by Infiltrates of Eosinophils or Plasma Cells, Eosinophilic Granulomas (Collagenolytic Granulomas).

Eosinophilic furunculosis develops primarily on the dorsal and lateral surfaces of the muzzle of young dogs and is thought to be a result of arthropod bites (bees, wasps, spiders). Lesions develop acutely and are often painful swollen areas that rapidly ulcerate and can drain bloody fluid. Lesions can progress to involve the periocular, pinnal, and sometimes the glabrous ventral abdominal skin. Because lesions develop rapidly and appear clinically severe, biopsy samples are typically collected early in the course of the disease, when microscopic lesions consist of ulceration, superficial and deep interstitial eosinophilic to mixed inflammation with extensive eosinophilic folliculitis and furunculosis. CHAPTER 17 The Integument dendritic cells. The systemic form is identical immunophenotypically but can also involve the nasal mucosa, eyelids, sclera, lung, spleen, liver, bone marrow, and multiple lymph nodes in addition to the skin. Gross lesions in the cutaneous form are restricted to the skin and subcutis, can be alopecic or haired, and are most often on the nose, face, neck, trunk, perineum, scrotum, and extremities, sometimes including pawpads. Histologically, there are single or multifocal nodular infiltrates of large, round to oval histiocytes mixed with lymphocytes and neutrophils that, in early lesions, are in the mid-dermal perivascular and periadnexal dermis and may be elongate and oriented vertically. Later, the infiltrates coalesce into larger deep dermal and subcutaneous masses. Vessels are often surrounded and invaded by the infiltrates (lymphohistiocytic vasculitis), which can result in thrombosis, necrosis, infarction, and ulcers.

Canine Langerhans cell histiocytosis is a rare condition in dogs resulting from progression of single or multiple persistent or recurrent canine cutaneous histiocytomas that spread to regional lymph nodes and subsequently to internal organs. The cell of origin is the Langerhans cell, a cell immunophenotypically identified as the intraepithelial dendritic Langerhans antigen-presenting cell that express CD1a, CD11c/CD18, CD45, MHC II, and usually E-cadherin markers. Expression of E-cadherin may diminish as the Langerhans cells lose their connections with the epidermal and follicular cells. The lesions begin with the development of one or more nodular, dome-shaped, often hairless masses (histiocytomas). In contrast to the majority of histiocytomas, the lesions fail to regress and become persistent, or they may recur after excision. The masses extend more deeply into the subcutis. There is enlargement of regional lymph nodes, the result of spread of Langerhans cells to the nodes. With time, infiltrative nodular masses of Langerhans cells develop in internal organs.

Histologically, the initial lesion consists of one or more circumscribed but nonencapsulated dermal to superficial pannicular masses that are broader at the surface than at the base. The masses consist of cords and sheets of round to polyhedral cells with a rounded, sometimes indented or folded nucleus (Langerhans cells). The epidermis may be acanthotic with exaggerated dermal-epidermal interdigitations. Langerhans cells are often present in the epidermis. Ulceration and secondary bacterial infection can develop. In the persistent lesions the cellular infiltrates extend more deeply into subcutis, become less well-differentiated, have increased mitotic index, and lack T lymphocyte infiltrates peripherally and foci of necrosis (features of regression of the typical and more common cutaneous histiocytomas). In addition, clusters of Langerhans cells are located within dermal lymphatic channels. These cells spread to efface architecture of regional nodes and form infiltrative nodular masses in internal organs. The condition has a poor prognosis. Immunomodulatory therapy is not effective and not recommended in cases of Langerhans cell histiocytosis.

Superficial Necrolytic Dermatitis (Diabetic Dermatopathy, Hepatocutaneous Syndrome, Necrolytic Migratory Erythema, Metabolic Epidermal Necrosis) Superficial necrolytic dermatitis (also known as diabetic dermatopathy, hepatocutaneous syndrome, necrolytic migratory erythema, metabolic epidermal necrosis) is an uncommon disorder reported primarily in older dogs with deranged nutrient metabolism associated with hepatic dysfunction, diabetes mellitus, hyperglucagonemia, malabsorption, or in a small percentage of dogs, glucagon-secreting A, The pustules on the muzzle are of 1-day duration. The mandibular lymph node (held between thumb and index finger) is markedly enlarged. B, The lesions, of 12-days' duration in the same dog as A, have progressed to include alopecia, thickening of the skin from edema, crusting, and ulceration. The mandibular lymph node (held between thumb and index finger) has at least doubled in size. C, Note the discrete nodular granulomatous dermatitis (arrows) that consists of a mixture of macrophages and fewer lymphocytes, plasma cells, and neutrophils is located below and adjacent to a hair follicle (HF A B HF C C of two independent conditions with a common hereditary linkage is undetermined. Gross lesions consist of firm dermal and subcutaneous nodules on legs, head, or ears. Histologic lesions consist of nodular dermal and subcutaneous aggregates of poorly cellular, mature dermal collagen bundles that are slightly thickened. In the dermis the collagen bundles blend often imperceptibly with bordering collagen, but in the subcutis the nodules are usually circumscribed. Adnexa are normal or hyperplastic. The cutaneous nodules are benign but serve as a marker for the more serious renal lesions.

For disorders occurring in two or more species of animals, see Disorders of Domestic Animals.

Feline ulcerative dermatitis syndrome is an uncommon disorder that may have more than one underlying cause. Previous injections and hypersensitivity are thought to initiate the syndrome in some but not all cats. The pathogenesis is not known, but self-trauma appears to significantly contribute to and perpetuate lesions. Lesions develop most commonly in the skin of the dorsal neck or interscapular regions and grossly consist of a nonhealing ulcer with serocellular exudate that can mat the adjacent hair. Microscopic lesions consist of an ulcer covered by fibrinonecrotic crust. The dermis subjacent to the ulcer contains components of necrotic epidermis and adnexa intermixed with degenerate neutrophils. Adnexal effacement by fibrosis is seen in severe cases. Inflammation in adjacent and deeper dermis is variable but often scant and consists of a few neutrophils, eosinophils, and mixed mononuclear cells. Chronic lesions consist of acanthosis of bordering epidermis with a linear band of fibrosis beneath and parallel to the adjacent intact epidermis. In those cases attributed to previous vaccination, nodular lymphoplasmacytic to histiocytic panniculitis is present.

Cowpox virus infection in cats is uncommon and usually occurs in outdoor cats living in rural areas, presumably because these cats hunt and have contact with rodents harboring the poxvirus. Primary cutaneous lesions typically develop on the face, neck, or forelegs and consist of an ulcerated or crusted macule or plaque. Lesions can develop into deep ulcers that heal with granulation tissue or less commonly develop into abscesses or cellulitis. Rarely, oral or mucocutaneous junctional areas are affected. Additional secondary cutaneous lesions can develop within approximately 2 weeks after viremic distribution to other cutaneous sites and less commonly to the upper or lower respiratory tract. The microscopic lesions are sharply demarcated, often deep ulcers covered by fibrinonecrotic exudate. Intracytoplasmic inclusion bodies in keratinocytes or follicular or sebaceous glandular cells help establish the diagnosis. Viral infectivity may remain for months in crusts. A variety of species may be infected, including human beings.

For more mechanistic detail, see the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Viral Infections, Herpesviruses.

Feline Herpesvirus Dermatitis. FHV-1is an uncommon cause of ulcerative, often persistent, facial dermatitis or stomatitis in cats of various ages and sexes. Less commonly, similar lesions have tumor usually within the pancreatic islets. Long-term anticonvulsant therapy and the rare ingestion of mycotoxins also have preceded the development of superficial necrolytic dermatitis. The disorder is rare in cats and has been associated in some instances with pancreatic carcinoma and/or hepatopathy, and in one cat a glucagon-producing primary hepatic neuroendocrine carcinoma. The pathogenesis of superficial necrolytic dermatitis is not completely understood and may vary with the underlying defect. When glucagon level is elevated, persistent gluconeogenesis is thought to result in a negative nitrogen balance with protein degradation, including proteins in the epidermis. However, when glucagon level is not elevated, as occurs in human beings with some types of hepatic or malabsorptive disease and in dogs with diabetes and multinodular vacuolar hepatopathy, it is thought that deficiencies of certain essential fatty acids, zinc, and amino acids play a role. Ultimately, low blood amino acid concentrations are thought to lead to the development of the cutaneous lesions. In dogs these lesions consist of scales, thick adherent crusts, erythema, alopecia, erosions, and ulcers on the mucocutaneous junctions, genitalia, pinnae, skin subjected to trauma (elbows, hocks), and ventral thorax. Pawpad lesions consist of crusting and fissuring or ulceration (see Fig. 17 -10) and result in lameness. In cats, alopecia and scaling of trunk and limbs have been seen; another cat had alopecia of the ventral trunk and medial thighs and ulceration and crusting of the oral mucocutaneous and interdigital regions. Microscopic lesions, when fully developed, are considered diagnostic and consist of trilaminar thickening of the epidermis in which the stratum corneum has marked parakeratosis, the upper stratum spinosum is pale with reticular degeneration, and the lower spinous and basal cell layers are hyperplastic (see Fig.  17 -10). Secondary infections with bacteria or yeast frequently complicate lesions, and secondary infection with dermatophytes also has been seen.

Pancreatic panniculitis (necrotizing panniculitis) is an acute rare disorder that has developed in dogs with pancreatic neoplasia or pancreatitis. It is seen less frequently in cats. The lesions are thought to be a result of the release of pancreatic enzymes (e.g., lipases) either from damaged pancreatic exocrine cells or from neoplastic exocrine cells. The lipases enter the systemic circulation and subsequently locate in the panniculus. Gross lesions are mostly truncal and consist of multiple, frequently ulcerated and hemorrhagic nodules or poorly defined swellings within the subcutis. Lesions may drain purulent, oily material. Histologically, there is necrosis of adipose tissue (caused by the lipases) with fine basophilic granularity (caused by mineralization of the necrotic fatty tissue). Suppurative to pyogranulomatous inflammation occurs at the periphery of the necrotic foci. Hemorrhage and fibrin exudation may be evident, and lesions may extend into the dermis and rupture through the epidermis.

In nodular dermatofibrosis, multiple cutaneous nodules composed of excessive collagen coexist with renal cystadenomas, cystadenocarcinomas, hyperplastic epithelial cysts, or uterine smooth muscle tumors. Renal lesions are often bilateral and may not be detectable clinically for months or years after the appearance of the cutaneous nodules. The syndrome has been described most commonly in the German shepherd but has been seen in a few other purebred dog breeds and mixed-breed dogs and is thought to have an autosomal dominant mode of inheritance in the German shepherd. Whether the condition is a true paraneoplastic syndrome with the renal neoplasm inducing dermal fibrosis or the simultaneous occurrence 1143 CHAPTER 17 The Integument developed in the skin of other sites. Glucocorticoid therapy or stresses, such as overcrowding, are thought to play a role in lesion development. Most lesions, particularly those affecting the face or oral cavity, develop under circumstances suggesting reactivation of latent herpesvirus infection. The pathogenesis is typical of that described for herpesviruses in the previous section. Gross lesions are ulcerative and crusted (see Table 17 -6). Histologically, there is extensive necrosis of the epidermis, follicles, and sometimes sebaceous glands accompanied by prominent mixed dermal inflammation that frequently includes numerous eosinophils. Hair follicles can be destroyed, and free keratin in the dermis is associated with eosinophils and foci of eosinophil degranulation bordering collagen fibers and collagen degeneration. Large amphophilic or hyaline intranuclear inclusions are present in the surface and adnexal epithelium. Inclusion bodies are often easily overlooked, variable in number, and sometimes present in small rafts of epithelial cells surrounded by necrotic debris or in crust. The lesions are different from those previously reported in domestic cats in that they persist and many are limited to the skin of the face or oral mucosa and often have significant eosinophilic inflammation. The inflammation in feline herpesvirus dermatitis overlaps with that of the hypersensitivity reactions, including mosquito bite hypersensitivity, and also with that of eosinophilic ulcers, thus warranting close scrutiny of eosinophilic necrotizing cutaneous lesions for intranuclear inclusion bodies or using more sensitive tests such as immunohistochemical staining for feline herpesvirus.

Mycobacterial Granuloma. See the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Bacterial Infections, Bacterial Granulomatous Dermatitis (Bacterial Granulomas), Mycobacterial Granulomas.

Feline Leprosy. Feline leprosy is usually caused by M. lepraemurium or Mycobacterium visibile, which are considered saprophytic organisms that typically do not grow in culture. Definitive diagnosis can be made by use of PCR and DNA sequencing, but not all laboratories perform these tests. Differential diagnoses include potentially zoonotic tuberculosis infections. Feline leprosy typically develops in cats living in cold, wet areas of the world, including the northwestern United States and Canada. Mode of transmission is not known, but bites of cats or rodents, soil contamination of cutaneous wounds, or possible transmission via biting insect vectors may be involved. Lesions develop most commonly on the head, neck, and limbs but can occur anywhere (Fig. 17-81) . Histologically, two distinct morphologic patterns of inflammation are present. In one there is diffuse granulomatous inflammation without necrosis and with large numbers of intracellular acid-fast bacilli; some of these infections have been caused by M. visibile. In the other pattern there are granulomas with central necrosis surrounded by a zone of lymphocytes. Few to moderate numbers of acid-fast bacilli are generally limited to the areas of necrosis. Some of these infections have been caused by M. lepraemurium. However, it has been suggested that the number of mycobacterial organisms may have more to do with the immune competence of the host than the mycobacterial agent itself, with infections in immunocompetent hosts having fewer mycobacteria than infections in hosts with immune compromise.

See the section on Disorders of Domestic Animals, Microbial and Parasitic Disorders, Fungal (Mycotic) Infections, Superficial Rarely, identical cutaneous lesions are recognized in cats without evidence of underlying neoplasia or internal disease, suggesting that the histologic lesions in this disease syndrome may represent a cutaneous reaction pattern associated with T lymphocyte immune dysfunction. Gross lesions begin as scaling and erythema of the head, neck, and ears and progress to generalized alopecia with scales, crusts, and ulcers. Histologically, the lesions include basal cell hydropic degeneration, lymphocyte exocytosis, and lymphocyte clustering around apoptotic keratinocytes of the epidermis and outer follicular root sheath. Sebaceous glands may be absent. The histologic lesions are similar, but generally milder, than those in the spectrum of erythema multiforme or a graft-versus-host disease reaction. Pruritus is variable but may be severe in some cats. M. pachydermatis is sometimes identified. Cats with this syndrome may have clinical signs referable to an intrathoracic mass resulting in dyspnea.

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in the cat (pancreatic paraneoplastic syndrome) is a rapidly progressive, largely ventrally distributed, symmetric alopecia that develops in older cats with metastatic pancreatic or biliary carcinomas. The pathogenesis of this condition is not known. The alopecia typically affects the ventral abdomen, thorax, and legs. The ears and periocular skin are less frequently involved. Alopecic skin is smooth, soft, and often has a shiny or glistening appearance. The pawpads are dry with circular rings of scale and may be painful. Histologically, affected skin has small inactive hair follicles with a reduction or absence of the stratum corneum. Some cats groom excessively, and it has been suggested that the smooth shiny appearance of the skin is caused by the absence of the stratum corneum. In other areas of the skin, there is variable orthokeratotic and parakeratotic hyperkeratosis in which M. pachydermatis is sometimes identified. In addition to the alopecia, the cats have systemic signs of anorexia, weight loss, and lethargy. Feline Exfoliative Dermatitis with or without Thymoma. A generalized exfoliative dermatitis has been documented as a paraneoplastic syndrome of older cats with thymomas. More recently the condition has been recognized in dogs and rabbits. T lymphocyte 1146.e1 CHAPTER 17 The Integument Suggested Readings VETERINARY DERMATOLOGY

Hair loss disorders in domestic animals

Muller & Kirk's small animal dermatology

Color atlas of farm animal dermatology

Equine dermatology

VETERINARY DERMATOPATHOLOGY

Practical veterinary dermatopathology for the small animal clinician

Skin diseases of the dog and cat: clinical and histopathologic diagnosis

Palmer's pathology of domestic animals

Tumors of the skin and soft tissues

HUMAN DERMATOPATHOLOGY

Lever's histopathology of the skin

Weedon's skin pathology

Color atlas of veterinary histology

Box 17-12 Examples of Tumors of the Skin-cont'd Hemangioma Hemangioma, skin, hind leg, dog. Note raised red to dark red circumscribed mass in nonpigmented and sparsely haired skin.Hemangioma, skin, dog. Well-defined mass of proliferative, blood-filled, vascular channels in the dermis has elevated the epidermis. H&E stain.Hemangioma, skin, dog. The dermis is expanded by a circumscribed mass of blood-filled vascular channels lined by well-differentiated endothelial cells. The flattened well-differentiated endothelial cells form a single uniform layer. H&E stain. †

Hemangiosarcoma, skin, dog. Note multiple raised red masses in nonpigmented and sparsely haired skin of whippet.Hemangiosarcoma, skin, dog. Note poorly demarcated margin between tumor (mostly on the right) and normal tissue (mostly on the left). H&E stain. 

Nasal and/or digital hyperkeratoses have a variety of underlying causes, including infectious disease (e.g., canine distemper [see Chapter 14], leishmaniasis), immune-mediated disorders (e.g., pemphigus foliaceus and lupus erythematosus), familial or inherited disorders (e.g., idiopathic seborrhea, familial pawpad hyperkeratosis of Irish terriers and Dogue de Bordeaux, ichthyosis, nasal parakeratosis of the Labrador retriever, and acrodermatitis of bull terriers), metabolic or nutritional disease (e.g., superficial necrolytic dermatitis, zinc-responsive dermatosis), adverse reaction to drug therapy, and neoplasia (e.g., cutaneous lymphoma) (Box 17-16). In some cases an underlying cause is not determined; thus the condition is considered to be idiopathic (occurs most commonly in old dogs). Some of the disorders in which nasal or digital hyperkeratosis is a feature also have skin lesions in other sites, and systemic disease can be present. Gross lesions on the pawpads or nasal planum include a dry, thick, irregular, and rough surface in which crusts, fissures, or erosions can develop (see . The edges of the pawpads and non-weight-bearing pads are more severely affected because friction on weight-bearing surfaces wears through some of the excessively thick stratum corneum. Histologic lesions of nasal and/or digital hyperkeratoses may reflect the underlying cause (e.g., infectious, immune mediated, metabolic, or neoplastic). In the idiopathic nasodigital hyperkeratosis of old dogs, irregular epidermal hyperplasia with marked orthokeratotic to parakeratotic hyperkeratosis is present. In familial nasal parakeratosis of Labrador retrievers, 

Dermatophytic pseudomycetoma is a rare, deep dermal and subcutaneous infection, usually caused by Microsporum canis, that develops predominantly in Persian cats, suggesting the possibility of a specific genetic deficit in innate or adaptive immunity in this breed. It is presumed that follicles rupture, releasing dermatophytes into the subfollicular dermis. Gross lesions are similar to other subcutaneous mycoses. Microscopic lesions are in the subfollicular dermis or subcutis and consist of a granulomatous inflammatory response and intermixed aggregates of fungal hyphae with irregular dilations. Hair shafts within adjacent follicles contain Microsporum canis hyphae and spores.

Flea Bite Hypersensitivity. See the section on Disorders of Domestic Animals, Immunologic Skin Diseases, Selected Hypersensitivity Reactions, Insect Bite Hypersensitivity, Flea Bite Hypersensitivity.

Mosquito bite hypersensitivity develops in cats hypersensitive to mosquito antigens, presumably present within the injected mosquito saliva. Experimental studies using intradermal skin tests and Prausnitz-Küstner tests in cats indicate that these lesions are initiated by a type I hypersensitivity reaction. A delayed hypersensitivity reaction also may occur but has not been fully characterized. Mosquito bite hypersensitivity develops primarily on the haired skin of the nose, but lesions can involve nasal planum, periocular skin, pinnae, and less commonly the flexor surface of the carpi and margins of pawpads. Lesions begin as erythematous papules and progress to crusts, erosions, ulcers, and alopecia ( Fig. 17-82 ). Inactive lesions can be hypopigmented or hyperpigmented, presumably from damage to or regenerative hyperplasia of melanin-containing cells in the epidermis. Histologic lesions include extensive superficial and deep, perivascular and interstitial eosinophilic to mixed dermatitis, occasionally with foci of degranulated eosinophils (flame figures) and eosinophilic folliculitis and furunculosis. The epidermis is acanthotic with foci of erosion, ulceration, and cellular crusting (see Fig.  17 -82).

Pemphigus. See the section on Disorders of Domestic Animals, Immunologic Skin Diseases, Selected Autoimmune Reactions, Reactions Characterized Grossly by Vesicles or Bullae as the Primary Lesion and Histologically by Acantholysis.

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Hyperadrenocorticism See Disorders of Dogs.

Psychogenic alopecia occurs in cats of the more sensitive or attention-demanding breeds, including Siamese and Abyssinian, and possibly others. A partial alopecia is the result of the breaking of hairs from gentle but persistent licking. Linear or symmetric areas of alopecia are found along the caudal dorsal midline or in the perineal, genital, caudomedial or caudolateral thigh, or abdominal areas. Microscopically, the skin is generally normal, but there may be trichomalacia (twisted or broken hair shafts within hair follicles). The 

Vasculitis is rare in cats. It can develop in association with the clinical syndrome of feline infectious peritonitis (FIP), caused in part by infection with the virulent form of feline corona virus. In FIP, multifocal cutaneous papules and nodules are due to granulomatous to pyogranulomatous vasculitis with leukocytoclasia.Vasculitis has also developed in cats infected with virulent systemic strains of feline calicivirus. Infection with this virus has caused facial and limb edema, oral ulceration, and variable alopecia, crusting, and ulceration of the nose, lips, pinnae, and pawpads, in addition to lesions in visceral and internal organs. Virus has been identified in keratinocytes, mucosal and follicular epithelium, and endothelium of small dermal vessels, where it causes epithelial cytolysis and endothelial injury. Virus-induced vascular injury is associated with edema and microthrombi and fibrin accumulation.

Hypereosinophilic Syndromes with Systemic Signs or Lesions Feline Hypereosinophilic Syndrome. Feline hypereosinophilic syndrome is a rare multisystemic and progressive disorder of unknown cause that is associated with moderate to marked peripheral eosinophilia and infiltrates of mature eosinophils in multiple organ systems, sometimes including the skin. Middle-aged female cats are more often affected. Gross lesions of the skin include erythema and excoriations associated with severe pruritus. Histologically, there is superficial and deep, perivascular dermatitis with prominent eosinophils. Clinical signs include anorexia, diarrhea, weight loss, and vomiting.

Feline plasma cell pododermatitis is an uncommon condition of undetermined cause or pathogenesis. Immunohistochemical staining with a polyclonal anti-Mycobacterium bovis antibody crossreactive to a broad spectrum of bacteria and fungi, and PCR for a variety of potential feline pathogens, including Bartonella spp., Ehrlichia spp., Anaplasma phagocytophilum, Chlamydia (formerly Chlamydophila) felis, Mycoplasma spp., Toxoplasma gondii, and FHV-1 have been negative. However, some cats have tested positive for FIV. Affected cats have hypergammaglobulinemia and a response to immunomodulating therapy, leading to the hypothesis that feline plasma cell pododermatitis is an idiopathic immune-mediated disease. It is characterized clinically by soft, painless swelling of multiple pawpads that can lead to collapse of the pawpad and ulceration, hemorrhage, and lameness. Histologically, the skin of the pawpad is heavily infiltrated by plasma cells with variable quantities of intracytoplasmic immunoglobulin (Russell bodies), neutrophils, and lymphocytes. This condition is sometimes accompanied by plasmacytic stomatitis, immune-mediated glomerulonephritis, or renal amyloidosis.

Feline Progressive Histiocytosis. Feline progressive histiocytosis is a rare condition in middle-aged to older cats resulting in development of cutaneous histiocytic masses most often on the head, distal extremities, or trunk. Immunophenotyping of the histiocytic cells has revealed expression of CD1a, CD11/18, MHC II, and usually a lack of E-cadherin expression. These features are most consistent with interstitial dendritic cells. Also present are reactive lymphocytes that express CD3 and CD8. Feline progressive histiocytosis behaves as a low-grade histiocytic sarcoma. Gross lesions begin with the development of one or more dermal masses that may subsequently enlarge and coalesce into larger plaquelike areas that may remain limited to the skin. In some cases there may be spread to regional lymph nodes. In addition, some masses may become poorly differentiated and develop invasive features of histiocytic sarcoma with spread to one or more internal organs.Histologic lesions consist of circumscribed, but nonencapsulated masses in the dermis and panniculus that are broader at the surface than the base. The masses consist of large rounded to polyhedralshaped histiocytic cells with a large central vesicular nucleus. Less than half of the cases have epitheliotropism (extension of the histiocytic cells into the epidermis). In addition to lymphocytes, neutrophils and vacuolated macrophages may be present.

Feline Pancreatic Paraneoplastic Alopecia. Feline pancreatic paraneoplastic alopecia associated with internal malignancies principal differential diagnosis is alopecia resulting from hypersensitivity (see next discussion). Alopecia related to endocrine disease is rare in the cat but has been seen in association with persistent licking in cats with hyperthyroidism.

Clinical signs of alopecia caused by hypersensitivity reactions are often identical to those of feline psychogenic alopecia. Pruritus typically is the result of hypersensitivity reactions to a variety of causes (food allergy, parasitism, or atopic dermatitis). Histologically, there is perivascular dermatitis, usually with eosinophils, mast cells, and lymphocytes. The inflammation helps to distinguish alopecia associated with hypersensitivity from that of feline psychogenic alopecia.

Cats fed diets containing an excess of dietary polyunsaturated fatty acids, such as canned red tuna, can develop inflammation of the subcutaneous and abdominal fat (pansteatitis). This condition develops when the diet is high in fat and when food processing or oxidation inactivates vitamin E. Vitamin E has a number of functions that contribute to its role as an antioxidant that stabilizes lysosomes. Affected cats may be anorexic, lethargic, and painful on palpation or movement. Grossly, the subcutaneous fat contains firm, nodular, yellow to orange masses. Microscopic lesions consist of fat necrosis that stimulates a lobular to diffuse neutrophilia followed by granulomatous inflammatory response. Macrophages and multinucleated giant cells contain ceroid pigment, which is responsible for the yellow to orange color of the affected fat.

Acne See the section on Disorders of Domestic Animals, Disorders of Epidermal Growth or Differentiation, Predominant Follicular Hyperkeratosis (Comedones), Acne.

See the section on Disorders of Domestic Animals, Miscellaneous Skin Disorders, Disorders Characterized by Infiltrates of Eosinophils or Plasma Cells.

Eosinophilic plaques are common lesions of the skin of cats that occur on the abdomen and medial thigh and are thought to be associated with hypersensitivity reactions. Lesions consist of raised, variably sized erythematous, pruritic, and eroded to ulcerated plaques. Microscopically, epidermal lesions include acanthosis, variable spongiosis, erosion, and ulceration, accompanied by superficial and deep, perivascular to diffuse, predominantly eosinophilic dermatitis.

See the section on Disorders of Domestic Animals, Miscellaneous Skin Disorders, Disorders Characterized by Infiltrates of Eosinophils or Plasma Cells, Eosinophilic Granulomas (Collagenolytic Granulomas).