JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2022

I-M28

 

Signalment (JPC 2602974): Dog.

 

HISTORY: Tissue from the nose of a dog with proteinuria.

 

HISTOPATHOLOGIC DESCRIPTION: Planum nasale, mucocutaneous junction:  Diffusely within the superficial dermis, surrounding blood vessels and adnexa, multifocally obscuring the dermal-epidermal junction, and forming a lichenoid band is a dense infiltrate of predominantly plasma cells, lymphocytes, fewer macrophages, and rare neutrophils (interface dermatitis). Inflammatory cells, predominantly neutrophils, often transmigrate the epidermis, frequently forming variably sized intracorneal and rare intraepidermal pustules. Superficial layers of epithelium are multifocally lost (erosion) and replaced by a serocellular crust composed of necrotic and fewer viable neutrophils, hemorrhage, fibrin, and necrotic cellular debris. Subjacent to areas of erosion are increased small caliber blood vessels arranged perpendicular to fibroblasts (granulation tissue). Diffusely the epidermis and superficial follicular epithelium are moderately spongiotic and hyperplastic with acanthosis and anastomosing rete ridges, and there is moderate parakeratotic hyperkeratosis. Within the stratum basale there is occasional hydropic degeneration and apoptosis (Civatte bodies), and basal keratinocytes are often disorganized with loss of orientation toward the basement membrane. Within the superficial dermis, there is free melanin as well as within scattered macrophages (pigmentary incontinence). Multifocal apocrine glands are mildly dilated and lymphatics are mildly ectatic (draining edema).

 

Lymph node:  Diffusely, the medullary sinuses are mildly expanded by increased numbers of histiocytes that often contain phagocytized erythrocytes and hemosiderin, and extravasated erythrocytes (draining hemorrhage).  There are moderate numbers of plasma cells within the medullary cords.

 

MORPHOLOGIC DIAGNOSIS:  1. Planum nasale, mucocutaneous junction:  Dermatitis and mucositis, interface, lymphoplasmacytic, diffuse, severe, with scattered basal cell apoptosis (Civatte bodies), moderate epidermal and follicular hyperplasia, and parakeratotic hyperkeratosis, breed not specified, canine.  

2.  Lymph node:  Draining hemorrhage, diffuse, mild.

 

ETIOLOGIC DIAGNOSIS:  Immune-mediated dermatosis

 

CONDITION:  Systemic lupus erythematosus (SLE)

 

GENERAL DISCUSSION:  

• Lupus erythematosus (LE) refers to a continuum of inflammatory disorders that varies from mild conditions limited to the skin to life-threatening systemic disease (e.g. systemic lupus erythematosus (SLE)); cutaneous lupus erythematosus (CLE) refers to the skin-specific effects of LE, regardless of systemic involvement; similar pathogenic mechanisms suspected regardless if the disorder remains localized to the skin
• SLE: 

• Rare, multisystemic immune-mediated disease that affects dogs, cats, horses, humans, nonhuman primates, mice, snakes, and iguanas 
• Characterized by high levels of circulating antigen-antibody complexes; the main tissue damage is caused by antigen-antibody complexes that deposit at various sites throughout the body and incite a type III hypersensitivity reaction; type II and type IV hypersensitivities play a lesser role 
• No age or sex predilection for SLE; collies, Shetland sheepdogs, poodles, German shepherd dogs, and Siamese, Himalayan and Persian cats appear to be predisposed  

• CLE: 

• Historically, LE restricted to skin was termed discoid lupus erythematosus (DLE);  however, DLE in domestic animals is not comparable to that in humans, and the term CLE is now preferred
• CLE in domestic animals generally does not precede the onset of SLE 
• Well-described CLE disorders in dogs are often breed specific and presumed hereditary 

• Localized (facial) discoid lupus erythematosus (DLE)
  • Also known as photosensitive nasal dermatitis
  • Chronic form of CLE; median age of onset is 7 years (1-12)
  • Lesions restricted to face; symmetrically affect nasal planum and dorsal muzzle and rarely extend to pinnae, lips, and periocular region
  • Multiple breeds affected; German shepherd dogs overrepresented
  • Exacerbated by ultraviolet light
• Generalized discoid lupus erythematosus
  • 2 reported cases (Chinese crested and Spitz)
  • Focal to multifocal thin round to ovoid plaques with central loss of pigmentation, crusting, erosion and/or ulceration with hyperpigmented margin; lesions typically distributed on ventral and dorsal trunk, and lateral extremities, +/- nasal planum and bridge of nose
• Exfoliative cutaneous lupus erythematosus
  • German shorthaired pointer; UNC93B1 gene mutation
  • Severe heritable CLE variant; autosomal recessive inheritance on chromosome 18
  • Lesions develop as early as 6 weeks and all affected dogs demonstrate lesions by 6 months; initial adherent scale on dorsal muzzle that progresses to erythema, alopecia, loss of pigment, erosion and ulceration; shifting leg lameness; infertility (both sexes)
  • Negative ANA titer 
• Vesicular cutaneous lupus erythematosus (idiopathic ulcerative dermatosis)
  • Rough-coated collies, Shetland sheepdogs, border collies
  • Middle-aged to older dogs
  • Vesicular and bullous lesions that progress to erosions and ulcers; most commonly affects axillary and inguinal regions in addition to mucocutaneous junctions
• Lupus panniculitis (lupus profundus)
  • Rarely reported in dogs
  • Discrete subcutaneous nodules distributed along trunk and proximal limbs; identical to rabies vaccine associated panniculitis
  • Overlying dermis and epidermis demonstrate typical histologic features of lupus
• Mucocutaneous lupus erythematosus
  • Multiple breeds affected; German shepherd dogs overrepresented
  • Females overrepresented (1.8:1); onset between 4-8 years of age
  • Symmetrical, well-demarcated erosions and ulcerations typically arising at mucocutaneous junctions of the genital, anal, oral, and nasal regions and extend into haired skin

 

PATHOGENESIS: 

• Failure of mechanisms that maintain B- and T-cell self-tolerance results in production of autoantibodies against a range of nuclear and cytoplasmic components of the cell (e.g. histones, double-stranded DNA, nonhistone proteins bound to RNA, and nucleolar antigens)
• Regulatory T-cell response is reduced or absent, essentially allowing a positive feedback loop of immunoreactivity to autoantibody-antigen complexes
• Autoantigen-antibody complexes deposit throughout the body, inciting a type III hypersensitivity reaction, resulting in inflammation of joints, skin, and kidney (i.e. arthritis [nonerosive], dermatitis, glomerulonephritis)
• To a lesser extent, tissue damage is induced by antibodies directed toward self-antigen on erythrocytes, leukocytes, and thrombocytes initiating a type II hypersensitivity reaction, or cell-mediated immunity (type IV hypersensitivity)
• Genetic, environmental, and transmissible factors have been implicated; the definitive cause of SLE remains unknown; proposed triggers include:

• Endogenous (genetic, hormonal, metabolic)
• Exogenous (UV light, drugs, infectious agents) 

• Ultraviolet-exacerbated cutaneous lesion (humans):  Induces the translocation of antigens normally expressed only intracellularly to the keratinocyte cell membrane; damaged cells then release IL-1, IL-2, IL-6, and TNF-alpha that increase damage; UV light also induces ICAM-1 expression, which is the major ligand for LFA-1, an adhesion molecule found on all leukocytes
• Abnormality in cellular immunity includes a lymphopenia that is characterized by a high CD4+:CD8+ ratio (as high as 6 in dogs with SLE versus <2 in normal dogs)

 

TYPICAL CLINICAL FINDINGS: 

• Variable; may mimic numerous diseases
• Chronic illness characterized by periods of progression and remission
• Associated syndromes:  Dermatitis, shifting leg lameness with swollen and painful joints (nonerosive polyarthritis), glomerulonephritis, stomatitis, mucocutaneous lesions, pericarditis, myocarditis, generalized muscle wasting (polymyositis), pneumonitis, pleuritis, meningitis, myelitis, polyneuropathy, and lymphedema

• Lethargy, anorexia, fever of unknown origin
• Dermatitis reported in approximately 1/3 of the cases of SLE; reports rarely indicate “lupus specific” vs. “lupus non-specific”; true cutaneous manifestations of SLE are probably rare

• Clinical pathology: suggestive of systemic disease, including proteinuria, hemolytic anemia, thrombocytopenia, bone marrow necrosis 

 

TYPICAL GROSS FINDINGS: 

• Gross skin lesions are extremely variable; more classic lesions consist of non-specific distribution of erythematous, alopecic, crusting, oozing, ulcerative skin lesions affecting sparsely haired areas of the face (especially the nose, lips, pinnae), limbs (especially the cranial aspect of the thoracic limbs), axilla, groin, and ventral abdomen
• Smoothing and loss of epidermal features (e.g. loss of canine nasal planum’s “cobblestone” appearance) with localized DLE

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• All subtypes share distinct histpathologic changes in the basal layer and basement membrane zone:  Basal cell hydropic degeneration, thickened basement membrane, cell-poor to lichenoid lymphohistiocytic (predominantly lymphocytes)  interface dermatitis, infiltration of the dermoepidermal junction, and edema/mucin deposition within the dermis
• Pigmentary incontinence 
• Civatte bodies (basal cell apoptosis)
• Acute:  Dermal edema, capillary dilation, deep and superficial perivascular lymphohistiocytic infiltrates; variably severe mucinous degeneration
• Chronic:  Basement membrane thickening, perivascular fibrin deposition, leukoclastic vasculitis
• Cleft and bulla formation (bullous SLE) between epidermis and dermis with severe subepidermal vacuolization; rare, one well-documented case in a dog demonstrating IgG autoantibody to type VII collagen  

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Antinuclear antibody (ANA) titer:  Identifies serum antibodies to nuclear material

• Veterinary (and human) SLE definitively diagnosed based on meeting 4 of 11 criteria established by the American College of Rheumatology; positive ANA titer present in nearly all cases  
• High sensitivity for SLE, less specificity (i.e. may also be positive in animals with leishmaniasis, bartonellosis, ehrlichiosis, or malignancies)
• >256 titer in 97-100% of canines with SLE 
• CLE is usually ANA negative

• Histochemical stains:  PAS to demonstrate thickened basement membranes in the kidney or skin
• Cytology: Synovial fluid may contain neutrophils with phagocytized granular, variably degraded, nuclear material (ragocytes); neutrophils may alternatively contain discrete homogenous, pink to purple inclusions (nuclear material) that peripherally displaces the nucleus (also known as lupus erythematosus (LE) cells); new methylene blue stain highlights LE inclusions; not a reliable method of diagnosing immune-mediated disease 

 

DIFFERENTIAL DIAGNOSIS:  

For histologic lesions:

• Mucocutaneous pyoderma: Alar fold junctions and haired skin typically affected rather than entire nasal planum; basal cells typically unaffected and primarily lymphoplasmacytic
• Epidermolysis bullosa acquisita: May be histologically identical and requires identification of criteria compatible with SLE for differentiation;  IHC staining of collagen IV is above subepidermal vesicles, whereas in all other autoimmune blistering diseases the staining is below the vesicle
• Lupoid drug reactions: May be essentially identical; history of treatment
• Erythema multiforme (I-M29): Individual keratinocyte apoptosis in all layers of epidermis in addition to interface dermatitis and basal cell degeneration
• Canine dermatomyositis (Shetland sheepdogs and collies): Autosomal dominant disease linked to chromosome 35; in addition to skin lesions, dogs develop myositis, lymphadenomegaly, and conjunctivitis; histopathologic lesions include follicular atrophy, perifollicular inflammation/fibrosis, and hydropic degeneration of basal keratinocytes leading to dermal-epidermal clefts and vesiculation

 

COMPARATIVE PATHOLOGY: 

• Mice: NZB/NZW strain is well-described model 
• Cats: Rare; lesions similar to those in dogs; primarily fever, glomerulonephritis, and hemolytic anemia; may develop diffuse osteosclerosis; intraepidermal acantholytic pustular dermatitis; true SLE dermatitis is more often present than in dogs or horses
• Horses: Most common presenting sign is a sharply demarcated zone of depigmentation of the skin around the eyes, lips, nostrils, genitalia, and skin of the perianal and perineal regions
• NHPs: Spontaneous or induced by an alfalfa sprout enriched diet
• Humans: Similar presentation to dogs; more common in females; CLE subdivided into 3 major categories:

• Chronic CLE: Localized and generalized discoid lupus; higher likelihood of only skin being affected, however generalized skin involvement (i.e. disseminated discoid LE) associated with increased risk of developing SLE
• Subacute CLE: Associated with history of solar exposure 
• Acute CLE: Associated with a malar “butterfly” facial rash during SLE flare-ups

 

REFERENCES:

1. Barger AM. Musculoskeletal system. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023: 491-492. 
2. Cooper BJ, Valentine BA.  Muscle and tendon. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2016:227.
3. Craig LE, Dittmer KE, Thompson KG.  Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2016:52,158-159.
4. Fernandes PJ. Synovial fluid analysis. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and hematology of the dog and cat. 5th ed. St. Louis, MO: Elsevier; 2020: 200-201.
5. Mauldin EA, Peters-Kennedy J.  Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2016:519, 604-607.
6. Pritzker KPH, Kessler MJ. Arthritis, muscle, adipose tissue, and bone diseases. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research Volume 2: Diseases. 2nd ed. London, UK: Academic Press; 2012:651.
7. Snyder PW. Diseases of immunity. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:320, 329-332.
8. Stockham SL, Scott MA. Leukocytes. In: Stockham SL, Scott MA, eds. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Blackwell Publishing; 2008: 94-95, 240.
9. Welle MM, Linder KE. The integument. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1108, 1238-1241.

Click the slide to view.

---