AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

INTEGUMENATRY SYSTEM

August 2019

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, spongiosis and prominent rete ridges, with orthokeratotic hyperkeratosis. There is focal epidermal erosion with few eosinophils and neutrophils admixed with cellular debris (necrosis), hemorrhage, fibrin and edema in the underlying dermis. 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 refers to an inherited predilection to develop IgE mediated allergy to environmental allergens, including pollen

·         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 at increased risk

·    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 spp., Malassezia)

·         Dogs with AD have altered skin barrier including abnormal lipid composition, changes in the stratum corneum and increased water loss through the epidermis

·    Transdermal allergen exposure more important than inhalation

·         Current, most widely-accepted theory for pathogenesis of AD (“outside-inside-outside” theory): A primary skin barrier defect, in association with aberrant immunological responses to common allergens > AD

·    Filaggrin is an important part of the cornified envelope and plays a role in forming natural moisturizing factors for the stratum corneum and prevent transepidermal allergen migration/sensitization

·       Derived from profilaggrin in keratohyaline granules of stratum granulosum

·       Recent study found altered epidermal filaggrin mRNA expression and protein distribution has been associated with development of AD in dogs

·       Local disruption of skin barrier may occur due to Th2 inhibition of filaggrin production

·       According to other references mutations in filaggrin gene not involved AD in dogs but altered expression may be present

·    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 and Th1 in chronic phase)

·    Periostin, an extracellular matrix protein expressed in dermal fibroblasts, and in some cases basal keratinocytes, is increased in chronically inflamed skin, at the epidermal-dermal junction, and may play a role in the pathophysiology of atopic dermatitis

·    A recent study showed that atopic dogs exhibit decreased staining for the tight junction proteins zonula oclcludens (ZO-1) and occludin, suggesting that altered expression of tight junction proteins may play a role in AD

·         All four types of hypersensitivity can be involved in the pathogenesis of allergic skin disease:

·       Type I (anaphylactic type): Formation of IgE (cytotoxic) antibody > immediate release of vasoactive amines and other mediators from mast cells (and basophils) > recruitment of other inflammatory cells

·       Type II (cytotoxic type): Formation of IgG, IgM > binds to antigen on target cell surface > phagocytosis of target cell or lysis of target cell by activated complement or antibody dependent cellular cytotoxicity

·       Type III (immune complex): Antigen antibody complexes form > activated complement > attracted neutrophils > release of lysosomal enzymes

·       Type IV (cell-mediated): Activated T lymphocytes > (i) release of cytokines and macrophage activation; (ii) T cell-mediated cytotoxicity

·      In atopic dogs, T cells are the primary component of the cutaneous inflammatory infiltrate

·      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

 

TYPICAL CLINICAL FINDINGS:

·      Pruritus

·      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 or 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

·    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:

  • Type I, type III and type IV reactions
  • Now termed “CARF” (cutaneous adverse reaction to food)

·      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:

  • 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, 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 > results in increased vascular permeability > edema

·      Immunologic: Type I 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 too deep in angioedema

·       Feline

·       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

·      Horses - Culicoides hypersensitivity (type I and IV hypersensitivity)

·      Suffolk ewes – Seasonal dermatoses similar to AD described

 

REFERENCES:

1.    Fanton N, Santoro D, Cornegliani L and Marsella R (2017), Increased filaggrinmetabolizing enzyme activity in atopic skin: a pilot study using a canine model of atopic dermatitis. Vet Dermatol, 2017; 28: 479-e111. doi:10.1111/vde.12443

2.    Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Diseases of the dermis. In: Skin Diseases of the Dog and Cat, Clinical and Histopathological Diagnosis. 2nd ed. Ames, IA: Blackwell; 2005: 200-211.

3.    Kim HJ, Cronin M, Ahrens K, Papastavros V, Santoro D, Marsella R. A comparative study of epidermal tight junction proteins in a dog model of atopic dermatitis. Vet Dermatol. 2016;27(1): 40-e11.

4.    Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2015:200-211.

5.    Santoro D, Marsella R, Ahrens K, Graves TK, Bunick D. Altered mRNA and protein expression of filaggrin in the skin of a canine animal model for atopic dermatitis. Vet Dermatol. 2013; 24(3):329-336.

6.    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: 590-598.

7.    Mineshige T, Kamiie J, Sugahara G, Yasuno K, et al. Expression of periostin in normal, atopic, and nonatopic chronically inflamed canine skin. Vet Pathol. 2015;52(6):1118-1126.

8.    Nuttall T, Marsella R, Rosenbaum M, Gonzales A, Fadok V. Update on pathogenesis, diagnosis, and treatment of atopic dermatitis in dogs. JAVMA. 2019; 254(11): 1291-1300.

9.    Nuttall T, Uri M, Halliwell R. Canine atopic dermatitis – what have we learned? Vet Rec. 2013;172(8):201-207.

 

 

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, 9th ed., 2014, Chapter 6, pg 201


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