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. 17-59). 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 (Fig. 17-59, B). Granulation tissue infiltrated by neutrophils is present on the ulcerated surface.

Hookworm dermatitis: Hookworm dermatitis is caused by cutaneous migration of the larvae of Ancylostoma or Uncinaria sp. Red papules that coalesce and develop into lichenified alopecic areas occur on the feet of dogs and less frequently, on other areas in contact with an unsanitary environment contaminated by hookworm larvae. Pawpads can become soft, the keratinized portion can separate, and secondary bacterial dermatitis and paronychia can develop. Hyperplastic spongiotic perivascular dermatitis with eosinophils, serocellular crusts, and migration tracks 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.

Filarial dermatitis: 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 (black flies, 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 pattern recognition receptors known to contribute to innate immunity. Wolbachia have been identified in a number of filarial parasites in animals, including Onchocerca gutturosa, Onchocerca lienalis, Onchocerca cervicalis, Dirofilaria immitis, and Dirofilaria repens. However, further research is needed to determine the role of these bacteria in filarial parasitic diseases in animals. 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 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.

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 US 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. 17-60). Microscopic lesions consist of superficial and deep perivascular dermatitis with eosinophils, epidermal hyperkeratosis, parakeratosis, acanthosis with spongiosis, eosinophilic microabscesses, and crusts. Adult parasites and microfilaria can be seen. Other causes of filarial dermatitis include Elaeophora sp., Parafilaria sp., Suifilaria sp., and rarely Dirofilaria sp. or Acanthocheilonema sp.

Type I Hypersensitivity Reactions: Type I hypersensitivity 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 17-10). 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 Hypersensitivity Reactions: Type II hypersensitivity reactions, also called cytotoxic reactions, depend on IgG antibodies formed against either normal or altered cell membrane antigens. The reaction engages Fc receptor and complement-mediated effector mechanisms. Cell damage occurs by either complement-mediated lysis, antibody-dependent cell-mediated cytotoxicity, or antibody-directed cellular dysfunction (see Table 17-10). The first two mechanisms are most common in type II reactions affecting the skin. Examples include deposition of autoantibody to desmoglein 1 and 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, a 180 kD hemidesmosomal transmembrane molecule in bullous pemphigoid (rare). The lesions vary with the location of the target antigen. In pemphigus foliaceous, 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 Hypersensitivity Reactions: 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 17-10). 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 Hypersensitivity Reactions (T Lymphocyte–Mediated Hypersensitivity Reactions): Type IV reactions are mediated by antigen-specific effector T lymphocytes. These include sensitized CD4⁺ lymphocytes (T_H1 or T_H2), or CD8⁺ lymphocytes (cytotoxic T lymphocytes) (see Table 17-10). The reaction mediated by sensitized CD4⁺ T_H1 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_H2 lymphocytes (T-helper lymphocytes), contact with soluble antigen bound to 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 associated with 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_H1 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.

Combination Hypersensitivity Reactions: 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.

Urticaria and Angioedema: Urticaria (hives) and angioedema occur most commonly in horses and dogs, and consist of multifocal 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, and insect stings) and nonimmunologic (heat, exercise, and stress) stimuli. Immunologic mechanisms involve type I and type III hypersensitivity reactions. 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 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. Occasionally, the intercellular epidermal edema (spongiosis) progresses to epidermal vesicles, serum exudation, and serous crusting.

Atopic Dermatitis (Atopy, Allergic Inhalant Dermatitis): 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 Host Defense Mechanisms Against Injury, disease example of barrier dysfunction.

The predominant clinical sign of atopy 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 Web Fig. 17-2) and paw licking. Severely affected dogs may be restless and may not be able to sleep because of frequent 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 atopy vary and include pruritus of the face, neck, or ears, or generalized pruritus manifested as self-induced trauma or alopecia. Miliary dermatitis, eosinophilic granuloma complex, and symmetric alopecia are often features of feline atopic dermatitis. Primary clinical lesions are rare, and most lesions are the result of self-inflicted trauma such as excoriations, erythema, and alopecia. More chronic lesions include lichenification and hyperpigmentation. Microscopic lesions collected from nontraumatized skin in atopic dermatitis consist of superficial perivascular accumulations of lymphocytes, mast cells, variable numbers of eosinophils, and cells with a histiocytic morphologic appearance. Immunohistochemistry of atopic dog skin has revealed that the lymphocytes are T lymphocytes and the cells with the histiocytic appearance are dendritic antigen-presenting cells. Some animals, particularly horses, have deep perivascular inflammation as well. Eosinophils are seen less frequently in dogs than other species but are the predominant inflammatory cell in horses and cats, which can also develop eosinophilic folliculitis. The epidermis in atopic dermatitis is hyperplastic, and sometimes epidermal intercellular edema (spongiosis) progresses to small foci of parakeratosis (see Web Fig. 17-2, B). In dogs, epitheliotropic mononuclear cells identified as T lymphocytes and Langerhans’ antigen-presenting cells are present. Langerhans’ cells can occur in clusters. Uncommonly, intraepidermal eosinophils and subcorneal eosinophil microabscesses have been observed in 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. Diagnosis of atopy is based on clinical signs, physical examination, intradermal skin testing, and the use of the radioallergosorbent test (RAST) and the ELISA for elevated allergen-specific IgE.

Insect Bite Hypersensitivity:

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 shampoo, and historically to plastics in food dishes. These chemical substances contain low molecular 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 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 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, have acanthosis and foci of parakeratotic cellular crusts. Lesions associated with self-induced trauma can also be seen.

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 trimethoprim-potentiated 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, necrotizing dermatitis, perforating folliculitis (i.e., furunculosis), or panniculitis.

Reactions Characterized Grossly by Vesicles or Bullae as the Primary Lesion and Histologically by Acantholysis: Pemphigus represents a group of diseases clinically characterized by transient vesicles or bullae and histologically by acantholysis (Table 17-11). This group of diseases is caused by a type II response and involves autoantibodies produced against proteins responsible for keratinocyte cell-to-cell adhesion (desmosomes, in particular desmoglein-1 and desmoglein-3). 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 on epidermis in the section on Morphology of the Skin).These desmosomal protein antigens are found in various stratified squamous epithelia, including skin, mucocutaneous junctions, oral mucosa, esophagus, and vagina. Damage to desmosomes results in acantholysis, which leads to the formation of vesicles or bullae within varying levels of the epidermis according to the location of the target antigen. The pathogenesis of acantholysis is not fully understood and is an active area of investigation. However, the autoantibodies themselves induce acantholysis and thus are considered pathogenic. The pathogenesis of acantholysis may differ between the superficial form of the disease (pemphigus foliaceous) versus the deeper form (pemphigus vulgaris). For both pemphigus foliaceous and pemphigus vulgaris, accumulating experimental evidence suggests that antibody binding to specific desmoglein proteins initiate acantholysis by triggering intracellular signaling pathways, which indirectly results in loss of desmoglein-mediated binding. The signaling pathways involve p38MAPK (mitogen-activated protein kinase) and RhoA (a small protein known to regulate the actin cytoskeleton). In pemphigus vulgaris, plakoglobin (a protein in the desmosomal plaque that is thought to be part of a receptor complex required to transfer the signal from autoantibody-bound desmoglein-3 into the cell) also contributes. In addition, in pemphigus vulgaris direct inhibition of desmoglein-3 binding and desmoglein-3 depletion from desmosomes, as well as activation of other signaling pathways (involving the transcription factor c-Myc, phospholipase C, protein kinase C, and others) appear to contribute to the pathogenesis of acantholysis, but their role in pemphigus foliaceous is uncertain. Other factors, such as desmoglein proteolysis, mechanical stress, and secondary changes such as altered extracellular calcium concentration, may also play a role in acantholysis.

The severity of clinical disease is in part related to the depth of the formation of the vesicles. The more severe signs are caused by separations deep within the epidermis and or oral mucosa, and the more mild signs are caused by separations in the subcorneal epidermis. The reasons that blisters develop in the superficial versus deeper epithelium are controversial. One theory, the compensation theory, suggests that different histologic sites of blister formation in superficial versus deep forms of pemphigus are the result of different distribution patterns of desmoglein-1 and desmoglein-3 within the skin and mucous membranes and the ability of these desmoglein proteins to compensate for the loss of each other in regard to the adhesion of keratinocytes. However, other studies using mouse models and in vitro systems have suggested that this compensation theory does not fully explain the difference in depth of blister formation and that various signaling pathways required for the maintenance of desmosomal adhesion in the specific epidermal layers may play a role, but these pathways have not been fully elucidated.

Reactions Characterized Grossly by Vesicles or Bullae as the Primary Lesion and Histologically by Vesicles or Bullae within the Basement Membrane (Bullous Dermatoses): Bullous dermatoses are a rare group of disorders caused by autoantibodies directed toward one or more antigens within the basement membrane zone (see the discussion on the basement membrane zone in the section on Morphology of the Skin and Table 17-11) and characterized clinically and histologically by vesicles and bullae. The disorders include bullous pemphigoid (autoantibodies against bullous pemphigoid antigen 2 [BPAG2; BP180], which is type XVII collagen, a hemidesmosomal transmembrane molecule), epidermolysis bullosa acquisita (autoantibodies against type VII collagen in the anchoring fibrils), linear IgA bullous dermatosis (autoantibodies against the 120-kD linear IgA bullous dermatosis antigen [LAD-1] in the upper lamina lucida), mucous membrane pemphigoid (laminin-5, collagen XVII, and integrin alpha-6 beta-4), and bullous systemic lupus erythematosus (autoantibodies against the noncollagenous amino terminus of type VII collagen) reported in one dog. Bullous pemphigoid is described as it affects the greatest number of species. Basic features of the other subepidermal bullous dermatosis are listed in Table 17-11.

Reactions Characterized Grossly by Depigmentation, Pleomorphic Papular to Macular Eruptions, or Ulceration and Histologically by Basal Cell or Keratinocyte Degeneration:

Reactions Characterized Grossly by Hemorrhage, Edema, Necrosis, Ulceration, Infarction, or by Alopecia and Scarring and Histologically by Vasculitis or Thrombosis: The 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 physiologically to reach 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., SLE), infections (e.g., Rickettsia rickettsii, Erysipelothrix 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 include direct invasion of vessels by infectious agents (e.g., Rickettsia, herpesvirus) and immune-mediated mechanisms (e.g., 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. 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 most 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.

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 usually in the telogen stage of the hair cycle, generally without hair shafts (hairless telogen follicles). Follicular infundibular hyperkeratosis with plugging of the follicular opening is also present. Other histologic changes seen in some dogs with hypothyroidism include acanthosis of epidermis and follicular infundibular epithelium. 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 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 levels of thyroxine and triiodothyronine. The reduced levels 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 Valley, and the Pacific Coast region. Paradoxically, maternal diets high in iodine can also result in congenital hypothyroidism. High blood iodine also interferes with one or more steps of thyroid hormone production, leading to low blood thyroxine levels, 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: 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. 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. 17-65). Dystrophic calcification of the dermis of the dorsal cervical region, inguinal, and axillary areas can occur in dogs, particularly in iatrogenic hyperadrenocorticism (calcinosis cutis) (Fig. 17-66). Grossly, lesions of calcinosis cutis are firm, thickened, sometimes gritty, often ulcerated and alopecic crusted plaques or nodules (see Fig. 17-66). In cats, 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. 17-65), and follicular hyperkeratosis. Hair follicles are in the telogen stage of the hair cycle and have lost their hair shafts (hairless telogen). In cats, the atrophic hair follicles often have brightly eosinophilic keratin (trichilemmal keratin) in the lumens, a feature considered highly suggestive of hyperadrenocorticism. Calcinosis cutis may develop in dogs (see Fig. 17-66). A foreign body reaction (granulomatous inflammation) and draining sinuses can develop in association with the calcium deposits.

Pituitary Dysfunction in the Horse: 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 proopiomelanocortin (POMC), which is processed into high levels of various pars intermedia–derived peptides, including corticotropin-like intermediate lobe peptide, melanocyte-stimulating hormone, and beta endorphin, and much smaller levels of adrenocorticotropin. The combination of hypothalamic dysfunction and differential expression of pars intermedia–derived peptides over that of adrenocorticotropin result in a unique syndrome of hyperpituitarism in horses that differs from functional pituitary tumors in dogs and cats, which usually are associated with high levels 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.

Hyperestrogenism: 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. Iatrogenic estrogen administration has also caused hyperestrogenism in male dogs (Fig. 17-67). In addition to endocrine alopecia, 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 without hair shafts (hairless telogen) (see Fig. 17-67).

Hypersomatotropism: Hypersomatotropism rarely occurs in adult dogs and is a result of excess levels 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 levels 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 about a third of cases.

Hyposomatotropism: 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. Microscopically, the features are consistent with endocrine alopecia (e.g., hyperkeratosis of superficial epidermis and of hair follicles; normal or atrophic epithelium; follicular dilation from hyperkeratosis; increased numbers of telogen hair follicles; lack of hair shafts in follicles; and increased epidermal pigmentation). The numbers of dermal elastic fibers are reduced in the skin of some dogs.

Cyclical or Seasonal Flank Alopecia (Idiopathic Flank Alopecia): Cyclical or seasonal flank alopecia develops more commonly in dogs living in northern latitudes. The cause of cyclical flank alopecia 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 seasonally or cyclically in the skin of the flank, usually bilaterally (Fig. 17-68). Histologically, follicles are in the telogen stage of the hair cycle, generally without hair shafts (hairless telogen), and primary follicles are markedly dilated and distorted by follicular 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 upside-down “footprint” (see Fig. 17-68, B). The condition, as the name suggests, is often transient but can be recurrent.

Postclipping Alopecia: Postclipping alopecia 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. It is thought 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 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 prominent trichilemmal keratin resembling flame follicles but in which the hair shafts are retained.

Telogen Effluvium: Telogen effluvium develops when an animal is systemically ill or is severely stressed such as occurs with high fever, pregnancy and lactation, or anesthesia and surgery. The illness or stressful event triggers a sudden termination of the growth stage of follicles. This causes a majority of the hair follicles to synchronously enter the catagen and then telogen stages of the hair cycle. Gross lesions do not develop until about 1 to 3 months after the systemic illness or stress resolves, and the telogen (or inactive) follicles synchronously enter into the anagen stage of the hair cycle. When the new anagen hair shafts emerge from the follicle, the old telogen hair shafts are suddenly shed. The alopecia resolves as the new hair shafts emerge from the follicles, and the new hair coat becomes visible. Histologic changes vary with the time of biopsy sampling. In late stages (during the stage of excessive shedding), the skin and follicles are essentially normal and consist of the majority of follicles in the anagen stage of the hair cycle. In early stages (before shedding), telogen follicles predominate.

Chemotherapy-Associated Alopecia: Chemotherapy-associated alopecia is best documented in humans 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 epithelial cells in the hair bulb, which have the greatest proliferative activity. The abrupt cessation of mitotic activity is thought to lead to weakening of the partially keratinized proximal portion of the anagen hair shaft, which subsequently breaks at its narrowest 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 about 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 narrow or pointed ends 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 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. Chemotherapy-associated alopecia 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 longer haired 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 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 symmetrical involvement of facial skin). Hair 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 haircoat may be altered. Diagnosis is based on clinical history, physical examination, and 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 humans.

Feline Psychogenic Alopecia: Psychogenic alopecia occurs in cats of the more emotional 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 thigh, or abdominal areas. Microscopically, the skin is generally normal, but there may be trichomalacia (twisted or broken hair shafts within hair follicles). The principal differential diagnosis is alopecia resulting from hypersensitivity (see next discussion). Endocrine-associated alopecia is rare in the cat.

Alopecia Caused by Hypersensitivity Reactions in the Cat: 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 of a variety of causes (food allergy, parasitism, or atopy). 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.

Follicular Dysplasia Syndromes: Follicular dysplasia syndromes, defined as incomplete or abnormal development of follicles and hair shafts, comprise a group of generally poorly characterized disorders recognized most commonly in dogs but occasionally in horses, cattle, and cats. Clinical lesions are alopecia or hypotrichosis, and consequently, there is clinical resemblance to the endocrine disorders. Some of the more common follicular dysplasia syndromes are associated with coat color dilution (color dilution follicular dysplasia, color mutant alopecia) or occur in black versus white haired areas (black hair follicle dysplasia) (see Fig. 17-23). Microscopic features of follicular dysplasia vary with the syndrome. The conditions associated with coat color dilution or those that occur in black-haired areas have densely clumped melanin pigment in the hair bulb, hair shafts, and also in the basal layer of the epidermis (see Fig. 17-23). Lesions in other conditions include lipid distention of hair matrix cells, abnormally formed follicles or hair bulbs, and abnormal hair shafts. The microscopic features help to differentiate syndromes of follicular dysplasia from the endocrine dermatosis.

Alopecia X: 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) alopecia-sparing head and distal extremities, (3) normal thyroid and glucocorticoid levels, and (4) skin biopsy samples with telogen follicles that retain their hair shafts (haired telogen), and often prominent flame follicles (follicles with prominent trichilemmal keratin 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. 17-69). Thyroid function testing, adrenocorticotropic hormone (ACTH) 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 (Fig. 17-69, 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 trichilemmal keratin spikes and with hair shafts retained are seen in normal plush-coated breeds of dogs and in post clipping alopecia. Epidermal hyperpigmentation and dermal atrophy are variable.

Acquired Pattern Alopecia (Pattern Baldness): Pattern alopecia develops in selected toy breeds of dogs (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.

Trauma-Associated Alopecia: 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 chronically 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 in the lower 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 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 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.

Dietary Zinc Deficiency in Ruminants: 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.

Hereditary Zinc Deficiency in Calves: 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, and shorthorn cattle in the US). 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, 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.

Zinc Deficiency in Pigs: 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.

Canine Zinc-Responsive Dermatosis: Canine zinc-responsive 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. 17-70), 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 trauma (e.g., elbows and hocks), the pawpads, and planum nasale. Microscopically, there is marked diffuse parakeratosis (see Fig. 17-70, B) that extends into the hair follicles, and an accompanying superficial perivascular lymphocytic and sometimes eosinophilic dermatitis. Another disorder, generic dog food dermatosis, a largely historic 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 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 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, 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.

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 3 or 4 times higher in cocker spaniels with seborrhea than in normal dogs. The hyperproliferation results in reduction in the epidermal turnover time to about 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, as 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 epithelium. 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.

Ichthyosis: The ichthyoses are a heterogeneous group of inherited skin disorders seen principally in cattle and dogs. 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 humans, 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 humans. Grossly, the skin in affected calves is covered by thick cornified plaques separated by fissures. 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. Follicular infundibular epithelium is also affected, and stratum corneum surrounds entrapped hairs. In the less severe form of ichthyosis in cattle (ichthyosis congenita), the defect has not been identified molecularly. Lesions may be mild at birth and progress with age. The skin becomes thickened, folded, and covered by platelike scales separated by shallow fissures and 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 humans, 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 the Jack Russell terriers include generalized adherent and loosely attached scales, as well as large, adherent white or tan scales in sparsely haired skin (Fig. 17-71). 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 uncertain, but an autosomal recessive mode of inheritance is suspected. Clinical lesions vary in severity and consist of large flat scales on the surface of the skin and within the haircoat. Pawpads and nasal planum are not affected. Histologic lesions consist of mild-to-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. 17-72). This condition is similar to epidermolytic hyperkeratosis in humans, caused by defects in keratin proteins 1 and 10. Keratin intermediate filaments are 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. 17-72). 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 and rarely is seen in cats and horses. The cause and pathogenesis are uncertain, but an inherited component of the disease is proposed for two breeds of dogs (Standard poodle and Akita) in which the disease has been studied more extensively. Clinical lesions are variable between breeds of dogs. In general, there is multifocal to coalescing or diffuse alopecia and scaling with fronds of keratin adherent to hair shafts. Similar lesions are reported in cats. 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 (see Fig. 17-29), 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).

Hyperkeratosis of Nasal Planum or Pawpads in Dogs: 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., PF 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 17-11). 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 Figs. 17-10 and 17-15). 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, 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: 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.

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.

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: 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 PF, 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.

Porcine Juvenile Pustular Psoriasiform Dermatitis (Pityriasis Rosea): 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. 17-73). 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 ridges of uniform length and width) and parakeratotic cellular crust.

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, fungal infection, 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.

Inherited Hypopigmentation: Hereditary hypopigmentation can be divided into melanocytopenic hypomelanosis, characterized by the absence of melanocytes in affected areas, and melanopenic hypomelanosis, in which melanocytes are present but defective. Hypopigmentation can be localized, focally extensive, or generalized.

Syndromes analogous to the human Waardenburg-Klein syndrome have been reported in horses, dogs, and cats. In this melanocytopenic hypomelanosis, there is failure of melanoblasts to migrate from the neural crest into the skin or failure to survive in the skin. 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 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 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 shortly after birth.

Piebaldism is also a form of genetic melanocytopenic 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 by 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 melanopenic hypomelanosis. In albino animals and humans, 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. In albino animals with white hair and skin and translucent irides, there is a mutation in the tyrosinase gene resulting in no residual enzyme activity.

Chédiak-Higashi syndrome in humans; 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. While 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 an autosomal recessive gene 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. The pale coat coloration is caused by clumping of large melanin granules in hair shafts, hair matrix cells, and sometimes in the epidermis. In cats, dilute coat color is thought to be a result of an autosomal recessive trait (Maltese dilution).

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 melanocyte-stimulating factors from surviving keratinocytes and subsequent increase in production of melanosomes. It is thought that these factors are preset 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 melanocytopenic hypomelanosis of humans and animals, which 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 shows an epithelium 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 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, but there are conflicting results regarding the role of humeral versus cell-mediated immune responses. Ocular lesions usually develop before cutaneous lesions. Clinical lesions consist of symmetrical 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).

In dogs, hypopigmentation can occur in immune-mediated diseases targeting the epidermal-dermal 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.

Secondary Hyperpigmentation: Hyperpigmentation can result from inflammation, irritation, and metabolic disorders. 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, as occurs after trauma.

Acanthosis Nigricans: 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 and include secondary seborrhea and pyoderma. Histologic examination reveals hyperplastic dermatitis with orthokeratotic and parakeratotic hyperkeratosis, acanthosis, and rete ridge 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 used to encompass a variety of chronic inflammatory and pruritic disorders that in their chronic form are manifested by axillary or more diffuse lichenification, alopecia, and hyperpigmentation. Consequently, the diagnosis of primary acanthosis nigricans requires clinical correlation together with the histologic findings to support the diagnosis in a young dachshund with compatible lesion distribution.

Eosinophilic Plaques: 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.

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. 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. 17-21). 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. 17-21). Collagen lysis develops in some lesions, likely a secondary event caused by the proteolytic enzymes (e.g., 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.

Nasal Eosinophilic Folliculitis and Furunculosis in Dogs: Nasal eosinophilic folliculitis and furunculosis develops primarily on the dorsal and lateral surfaces of the nose 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. At this time, microscopic lesions consist of ulceration, superficial and deep interstitial eosinophilic to mixed inflammation with eosinophilic folliculitis and furunculosis.

Hypereosinophilic Syndromes with Systemic Signs or Lesions:

Plasma Cell Pododermatitis: Feline plasma cell pododermatitis is an uncommon condition of undetermined cause or pathogenesis. Immunohistochemical staining with a polyclonal anti-Mycobacterium bovis antibody cross reactive to a broad spectrum of bacteria and fungi, and PCR for a variety of potential feline pathogens, including Bartonella spp., Ehrlichia spp., Anaplasma phagocytophilum, Chlamydophila felis, Mycoplasma spp., Toxoplasma gondii, and feline herpesvirus 1 (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 numbers of Russell body plasma cells, neutrophils, and lymphocytes. This condition is sometimes accompanied by plasmacytic stomatitis, immune-mediated glomerulonephritis, or renal amyloidosis.

Juvenile Sterile Granulomatous Dermatitis and Lymphadenitis (Juvenile Cellulitis, Juvenile Pyoderma, Puppy Strangles): 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. 17-74), 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. 17-74). Early lesions are adjacent to but do not involve follicles; however, lesions typically progress to folliculitis, furunculosis, panniculitis, cellulitis, and granulomatous to pyogranulomatous lymphadenitis. The lesions initially are considered to be sterile, but secondary bacterial infections develop and can lead to sepsis if not treated. About half of the puppies are lethargic, and anorexia, fever, and joint pain can also occur. This condition occasionally has been reported in adult dogs.

Idiopathic Sterile Granuloma and Pyogranuloma (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 cytology for organisms are negative. The lesions must be differentiated from those of the infectious granulomatous disorders and reactive histiocytosis in dogs.

Canine Reactive Histiocytosis: Canine reactive histiocytosis is a poorly understood disorder that occurs in cutaneous and systemic forms in dogs of a variety of ages and breeds. Cultures and special stains fail to reveal causative agents, and the disorder is thought to be the result of immune dysregulation. The disorder typically has a slowly progressive, waxing and waning course but can respond favorably, at least for a time, to immunomodulatory therapy. The lesions require long-term 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 of histiocytic cells that are immunophenotypically identified as dermal perivascular activated dendritic antigen-presenting cells (CD1⁺, CD4⁺, CD11c⁺, MHC II⁺, and CD90⁺). Also intermixed with the histiocytic cells are CD3⁺, CD8⁺, TCRαβ⁺ T lymphocytes, and CD11b⁺ neutrophils. 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 head, neck, perineum, scrotum, and extremities. Histologically, there are single or multifocal infiltrates of large, round-to-oval histiocytes mixed with lymphocytes and neutrophils that, in early lesions, are periadnexal to elongate and are oriented vertically. Later, the infiltrates coalesce into larger deep dermal and subcutaneous masses. Vessels are often surrounded and invaded by the infiltrates, which can result in thrombosis and infarction.

Canine Langerhans’ Cell Histiocytosis: 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 (CD1⁺, CD11c⁺, CD90⁻, CD4⁻, MHC II⁺, and ICAM-1⁺, and usually E-cadherin⁺). Expression of E-cadherin may diminish as the Langerhans’ cells lose their connections with epidermal and follicular epithelial 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 epidermal dermal 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 peripheral T lymphocyte infiltrates and foci of necrosis (features of regression of typical 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.

Feline Dendritic Cell Histiocytosis: Feline dendritic cell histiocytosis is a rare condition in cats resulting in development of histiocytic masses. The cell of origin is immunophenotypically identified as a dendritic cell (CD 18, CD1⁺, MHC II⁺), but variable expression of E-cadherin in different cases prevents further identification as to whether this cell normally functions as an intraepithelial or dermal dendritic antigen-presenting cell. Gross lesions begin with the development of one or more dermal masses that may subsequently enlarge and coalesce into larger plaque-like 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 neoplasia 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 polyhedral cells with a large central vesicular nucleus. Mixed inflammatory cells, including numerous vacuolated macrophages, may be present. In some masses, the histiocytic cells are also present in the epidermis.

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.

Other syndromes, including equine generalized granulomatous disease (see the section on Vetch Toxicosis and Vetch-Like Diseases), and nutritional pansteatitis (see the section on Vitamin E Deficiency), are also categorized as sterile granulomatous disorders.

Paraneoplastic Alopecia Associated with Internal Malignancies in the Cat (Pancreatic Paraneoplastic Syndrome): Paraneoplastic alopecia associated with internal malignancies 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. 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 Malassezia pachydermatis is sometimes identified. In addition to the alopecia, the cats have systemic signs of anorexia, weight loss, and lethargy.

Exfoliative Dermatitis and 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 immune dysregulation probably plays a role in lesion development. 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 lesions are compatible with the diagnosis of erythema multiforme or a graft-versus-host-type reaction. Malassezia pachydermatis is sometimes identified. Cats with this syndrome may have clinical signs referable to an intrathoracic mass resulting in dyspnea.

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, or less commonly with a glucagon-secreting 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, but other conditions also have been present, including thymic amyloidosis and intestinal lymphoma. The pathogenesis of superficial necrolytic dermatitis is not completely understood and may vary with the underlying defect. When glucagon is elevated, persistent gluconeogenesis is thought to result in a negative nitrogen balance with protein degradation, including proteins in the epidermis. However, when glucagon is not elevated, as occurs in humans 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. In dogs, clinical lesions of scales, thick adherent crusts, erythema, alopecia, erosions, and ulcers develop 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): Pancreatic panniculitis (necrotizing panniculitis) is an acute rare disorder that has developed in dogs with pancreatic neoplasia and pancreatitis. It is seen less frequently in cats in which it has been associated with pancreatitis. 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.

Nodular Dermatofibrosis and Renal Disease in the Dog: 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 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.

Paraneoplastic Pemphigus: See the discussion on paraneoplastic pemphigus (PNP) in the section on Selected Autoimmune Reactions.