PC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
August 2022
I-M02

Signalment (JPC# 21474-17):  Dog, breed unspecified

HISTORY:  This dog presented with pruritus and alopecia that was most severe in the skin of the lower back and base of tail.

HISTOPATHOLOGIC DESCRIPTION:  Haired skin (2 sections):  Multifocally, primarily within the mid-dermis but extending into the panniculus, surrounding adnexa and occasionally vessels, minimally infiltrating follicular epithelium, and separating adipocytes and collagen fibers are moderate numbers of neutrophils, macrophages, lymphocytes, plasma cells, and eosinophils.  Multiple hair follicles and apocrine glands are mildly ectatic. Hair follicles contain keratin and cellular debris and, occasionally, low numbers of degenerate neutrophils and scattered 1 to 2 um diameter cocci (luminal folliculitis). Diffusely, there is epidermal hyperplasia characterized by acanthosis forming short, broad rete ridges, prominent intercellular bridging (spongiosis), and moderate orthokeratotic hyperkeratosis.  There is focal epidermal erosion, and the remaining epidermis and subjacent dermis contain few macrophages, eosinophils and neutrophils admixed with cellular debris (necrosis), hemorrhage, fibrin, and edema.  Diffusely, the superficial dermis is mildly expanded by clear space, dilated lymphatics (edema) and vascular congestion. There is mild sebaceous gland hyperplasia.

MORPHOLOGIC DIAGNOSIS:  Haired skin:  Dermatitis, periadnexal and perivascular, subacute, eosinophilic and lymphoplasmacytic, multifocal, moderate, with focal erosion, epidermal hyperplasia, and folliculitis, breed unspecified, canine.

ETIOLOGIC DIAGNOSIS:  Allergic dermatitis

GENERAL DISCUSSION:

• Allergic skin disease is caused by hypersensitivity to environmental antigens that are inhaled, ingested, or come in contact with skin, as well as to drugs and antigens from parasites
• Atopic dermatitis (AD) is the most common allergic skin disease
  • Atopy is defined as an inherited tendency to produce IgE antibodies and develop clinical allergy to pollens and other environmental allergens  
• In animals, atopy most often manifests in the skin and is a complex disease involving multiple genetic, immunological, and environmental factors
• Affects 10% of canine population
  • Breed predilections: Several small terrier breeds, Labrador and golden retrievers, West Highland white terriers, springer spaniels, Chinese shar-peis, bull terriers, bichon frises, Tibetan terriers, Dalmatian, French bulldog, boxer, among others
  • Strong genetic component but precise basis unclear

PATHOGENESIS:

• Atopic dermatitis in dogs is multifactorial: Allergen sensitization, immune dysregulation, skin barrier defects, environmental conditions, altered microbial flora (Staphylococcus, Malassezia)
• Dogs with AD have altered skin barrier including abnormal lipid composition in the stratum corneum, ultrastructural changes in the stratum corneum, and increased water loss through the epidermis
  • Transdermal allergen exposure more important than inhalation
• The current, most widely-accepted theory for pathogenesis of AD: A primary skin barrier defect, in association with aberrant immunological responses to common allergens, causes AD.
• Skin barrier defect:
  • Filaggrin, an important part of the cornified envelope, plays a role in forming natural moisturizing factors for the stratum corneum and preventing transepidermal allergen migration/sensitization; derived from profilaggrin in keratohyaline granules of stratum granulosum
    • Local disruption of skin barrier may occur due to Th2 inhibition of filaggrin production or altered epidermal filaggrin mRNA expression and protein distribution
  • Aberrant immunologic responses:
  • Th2 lymphocyte cytokine immunoregulatory imbalances and production of IL-4, I-L5 and IL-13 incite an IgE-mediated reaction and promote IgE class switching (Th2 response is very important in the early phase of AD; becomes a primarily Th1 response in chronic phase)
• All four types of hypersensitivity can be involved in the pathogenesis of allergic skin disease (see chart below for review).
  • In atopic dogs, T cells are the primary component of the cutaneous inflammatory infiltrate

TYPICAL CLINICAL FINDINGS:

• The following factors are significantly correlated with atopic dermatitis in dogs:
  • Onset prior to 3-years of age
  • Living indoors
  • Pruritis prior to onset
  • Lesions on forepaws and concave pinnae
• Pruritus which begins seasonal, but becomes year-round
• Alopecia and dermatitis
• Non cutaneous manifestations such as conjunctivitis, rhinitis, asthma and gastrointestinal disorders

TYPICAL GROSS FINDINGS:

• Clinical lesions are usually due to self-trauma, secondary bacterial or Malassezia infections, or seborrhea
• Face, paws, distal extremities and ventrum
• Erythema, alopecia, salivary staining, and secondary infections are common
• Lichenification and hyperpigmentation in chronic cases
• Pruritic crusting, papules, or nodules
• Atopic otitis externa often occurs

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Nonspecific findings; diagnosis of AD in dogs is based on historical findings, gross lesions, response to treatment, and exclusion of other conditions such as sarcoptic mange, flea bite hypersensitivity, and food hypersensitivity
• Epidermal hyperplasia with elongation of rete ridges
• Hyperkeratosis
• Perivascular and periadnexal inflammatory infiltrates of lymphocytes, plasma cells, eosinophils and mast cells
• Hyperplastic sebaceous glands and dilated apocrine glands

ADDITIONAL DIAGNOSTIC TESTS:

• Intradermal skin test
• Serology: RAST, ELISA

DIFFERENTIAL DIAGNOSIS:

Types of allergic skin diseases:

• Flea-bite (insect) hypersensitivity:
  • Pruritic, crusted papular dermatitis in animals sensitized to antigens in flea saliva
  • No breed predilection
  • Type I and type IV hypersensitivity reactions

• Atopy (allergic inhalant dermatitis):
  • Onset usually between 1 and 3-years of age
  • Type I hypersensitivity reaction
  • Breed predisposition includes small terriers, golden retrievers, boxers, Chihuahuas, Irish and English setters, Chinese shar-pei, and others

• Food allergy:
  • Now termed “CARF” (cutaneous adverse reaction to food)
  • Clinical signs virtually indistinguishable from AD; histo lesions are variable and not diagnostic

• Allergic contact dermatitis (ACD):
  • Rare, variably pruritic, maculopapular dermatitis affecting sparsely haired skin
  • Type IV hypersensitivity reaction
  • Antigens (low molecular weight substances that penetrate the skin) are not immunogenic until conjugated with a carrier protein 
  • Carrier is an epidermal protein, or surface molecule on the Langerhans cells

• Intestinal parasite hypersensitivity:
  • Type I hypersensitivity
  • Skin lesions clear up after intestinal parasitism resolved
  • Seen in association with: hookworms, tapeworms, whipworms, ascarids, coccidia

• Canine scabies (I-P06):
  • Evidence of hypersensitivity includes concurrent proteinuria and immune complex glomerulonephritis

• Dirofilariasis:
  • Hypersensitivity to microfilaria

• Tick bite hypersensitivity:
  • Involves type II and type IV hypersensitivity responses

• Drug eruptions:
  • Rare, variably pruritic, cutaneous or mucocutaneous reaction in dogs and cats, most often in response to penicillins and sulfonamides
  • Involves types I, II, III, and IV hypersensitivity reactions
  • Erythema multiforme (I-M29), toxic epidermal necrolysis

• Bacterial hypersensitivity:
  • Uncommon, severely pruritic pustular dermatitis associated with a presumed hypersensitivity reaction to staphylococcal antigen (S. aureus)
  • Type III and type IV reactions

• Hormonal hypersensitivity:
  • Rare, pruritic, crusted papular dermatitis
  • Hypersensitivity to endogenous gonadal hormones
  • Types I and IV hypersensitivity
  • Intact females develop skin lesions with irregular estrus or pseudopregnancy

COMPARATIVE PATHOLOGY:

• Urticaria and angioedema:
• Urticaria is most common in horses, less common in cattle, dogs, and cats
• Variably pruritic, edematous skin disorders due to mediators (i.e. histamine) released by mast cells and basophils > increased vascular permeability > edema
• Immunologic: Type I (primarily) and type III hypersensitivity reactions
• Nonimmunologic: Physical forces (pressure, sunlight, heat, cold, exercise), psychological "stresses," genetic abnormalities, and various drugs and chemicals (aspirin, doxorubicin, radiographic contrast material, narcotics, foods, and food additives)
• Angioedematous reactions involving nasal passages, pharynx, and larynx may be fatal
• Normal epidermis with prominent dermal edema, mild perivascular lymphocytic inflammation, and dilated lymphatics
• Reaction is superficial in urticaria and superficial to deep in angioedema
• Feline:
• Atopic dermatitis: Diagnosis of AD in cats similar to dogs with historical findings, gross lesions and exclusion of other causes of allergic dermatitis (ectoparasites etc.); Devon Rex and Abyssinian breeds may be predisposed
• Miliary dermatitis:
  • Non-specific cutaneous reaction pattern in cats composed of numerous crust covered papules
  • Common feline reaction to various antigens: fleas, food, atopy
  • Concurrent miliary dermatitis and eosinophilic plaques are fairly common
  • Superficial and deep perivascular infiltrates of eosinophils, mast cells
  • Epidermis is spongiotic, eosinophils may be present in the epidermis, and intraepidermal eosinophilic micropustules are common
• Nonhuman primates
  • Atopic dermatitis has been recognized in several species of NHPs, including Japanese and rhesus macaques.
  • Typical presentation is pruritus, regional alopecia, and hyperkeratotic skin with lichenification. Shoulders, axillary and inguinal regions, neck, and upper chest are common locations.
  • Histology shows acanthosis with perivascular mononuclear cell infiltration in the superficial dermis with variable numbers of eosinophils and mast cells. May also see dermal edema and fibrosis and thickening of walls of superficial blood vessels.
• Horses
  • Culicoides hypersensitivity (type I and IV hypersensitivity)
• Suffolk ewes
  • Seasonal dermatoses similar to AD is described

REFERENCES:

1. Kramer JA, Bielitzki J. Integumentary system diseases of nonhuman primates. In: Bennett BT, Abee CR, and Henrickson R. Nonhuman Primates in Biomedical Research: Diseases. 2nd ed. London, UK: Academic Press; 2012:578.
2. Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier Saunders; 2021:204-215.
3. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016: 590-599. 

 

Type	Prototype Disorder	Immune Mechanisms	Pathologic Lesions
Body_ID: T006002.50
Immediate (type I) hypersensitivity	Anaphylaxis; allergies; bronchial asthma (atopic forms)	Production of IgE antibody → immediate release of vasoactive amines and other mediators from mast cells; recruitment of inflammatory cells	Vascular dilation, edema, smooth muscle contraction, mucus production, tissue injury, inflammation
Body_ID: T006002.100
Antibody-mediated (type II) hypersensitivity	Autoimmune hemolytic anemia; Goodpasture syndrome	Production of IgG, IgM → binds to antigen on target cell or tissue → phagocytosis or lysis of target cell by activated complement or Fc receptors; recruitment of leukocytes	Phagocytosis and lysis of cells; inflammation; in some diseases, functional derangements without cell or tissue injury
Body_ID: T006002.150
Immune complex- mediated (type III) hypersensitivity	Systemic lupus erythematosus; some forms of glomerulonephritis; serum sickness; Arthus reaction	Deposition of antigen-antibody complexes → complement activation → recruitment of leukocytes by complement products and Fc receptors → release of enzymes and other toxic molecules	Inflammation, necrotizing vasculitis (fibrinoid necrosis)
Body_ID: T006002.200
Cell-mediated (type IV) hypersensitivity	Contact dermatitis; multiple sclerosis; type I, diabetes; rheumatoid arthritis; inflammatory bowel disease; tuberculosis	Activated T lymphocytes → (i) release of cytokines → inflammation and macrophage activation; (ii) T cell-mediated cytotoxicity	Perivascular cellular infiltrates; edema; cell destruction; granuloma formation

 

Table 6-1 of Robbins and Cotran, 10^th ed., 2021, Chapter 6, pg 204

 

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