JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M25

Signalment (JPC #2618546):  Dog

 

HISTORY: This dog had multiple erosive and ulcerative lesions in the mouth and at the mucocutaneous junctions of the anus and the vagina. 

 

HISTOPATHOLOGIC DESCRIPTION:  

Haired skin: There is extensive loss of the suprabasilar epithelium (erosion) with hypertrophy of the retained basilar epithelial cells (“tombstoning”). There are multifocal detached remnants of epithelium admixed with an overlying serocellular crust composed of moderate numbers of viable and degenerate neutrophils, degenerate and keratinized epithelial cells, and scant eosinophilic cellular debris. Diffusely infiltrating the superficial dermis and surrounding adnexa are moderate numbers of plasma cells and fewer neutrophils, lymphocytes, macrophages, and mast cells. Subjacent to areas of erosion there are increased numbers of small caliber blood vessels oriented perpendicular to fibroblasts (granulation tissue). Multifocally, apocrine glands are mildly ectatic and contain homogenous eosinophilic material (secretory product), and there is mild superficial dermal edema, fibrin, and hemorrhage.

 

Mucous membrane: There is a focally extensive suprabasilar cleft with extensive partial loss of the overlying epithelium (erosion) and hypertrophy of the retained basilar epithelial cells (“tombstoning”). The remaining epithelium is mildly hyperplastic with acanthosis. Keratinocytes contain prominent intracytoplasmic vacuoles (mild intracellular edema), there is prominent intracellular bridging (spongiosis), rare intracytoplasmic brown globular pigment (melanin), and neutrophilic and lymphocytic exocytosis. Diffusely, at the mucosal-submucosal junction, there is a thin, moderately cellular band of lymphocytes, plasma cells, degenerate neutrophils, and fewer macrophages (interface mucositis) admixed with increased numbers of small caliber blood vessels arranged perpendicularly to reactive fibroblasts and loose, immature fibrous connective tissue (granulation tissue).

 

MORPHOLOGIC DIAGNOSIS: 

1. Haired skin: Suprabasilar clefting, focally extensive, marked, with loss of suprabasilar epithelium, basal cell hypertrophy, and moderate lymphoplasmacytic and neutrophilic dermatitis, breed unspecified, canine.
2. Mucous membrane: Suprabasilar clefting, multifocal, marked, with multifocal loss of suprabasilar epithelium, basal cell hypertrophy, and mild lymphoplasmacytic interface mucositis.

 

ETIOLOGIC DIAGNOSIS:  Autoimmune dermatitis/mucositis/stomatitis/vaginitis/ proctitis

 

CAUSE:  Autoantibodies against desmoglein 3 (Dsg3) – Type II hypersensitivity

 

CONDITION:  Pemphigus vulgaris

 

GENERAL DISCUSSION:

• Pemphigus vulgaris (PV) is a rare, severe, erosive and ulcerative autoimmune disease that causes intra-epidermal vesicles or bullae; reported in dogs (middle-aged), cats, horses, goats, NHPs, and llamas
• Affects basal layer of keratinocytes of the epidermis and mucosal epithelium, hence lesions occur deeper in the epidermis and in the oral mucosa

 

PATHOGENESIS:

• Desmoglein 3 (Dsg3) is the major pemphigus vulgaris antigen in dogs and humans. Dsg3 is the dominant desmosomal cadherin protein responsible for squamous cell adhesion and is most prominent in basal layer epidermal keratinocytes and deep mucosal epithelium
• Desmoglein 1 (strongly expressed in superficial keratinocytes of haired skin) may also be involved when lesions affect both haired skin and mucous membranes
• Pathogenesis is incompletely known; proposed mechanism:
  • Autoantibodies bind to desmoglein 3 -> keratinocytes release proteases -> adhesion proteins digested -> disrupt intercellular adhesions between keratinocytes (acantholysis) -> form suprabasilar vesicles and bullae
    • May involve secretion of urokinase-type plasminogen activator (uPA), a serine protease that activates plasminogen (a fibrinolytic protein) or may involve antibody binding disrupting structural integrity of the keratinocyte adhesion molecules
    • Overexpression of the proto-oncogene c-Myc may be involved in pathogenesis, (likely a consequence of anti-desmoglein 3 antibody binding to its target on basal keratinocytes)
    • Autoantibodies against keratinocyte acetylcholine receptors are also involved in the initial pathogenesis
  • Drugs or other environmental factor linked or suspected in many cases: Drugs may be involved in as many as 10% of pemphigus cases
  • NOTE: Complement does not appear to be involved

 

TYPICAL CLINICAL FINDINGS:

• Drooling; halitosis and salivation (thick, ropey saliva)
  • 90% of cases have oral lesions (e.g. coalescing ulcers on the tongue, palate, gingiva); in 50% of cases, lesions start in the mouth
• Varying pruritus and/or pain
• Severely affected animals may be anorectic, depressed, or febrile with a leukocytosis
• Positive Nikolsky sign: firm sliding pressure to adjacent unaffected skin may induce fresh vesicle formation or dislodge the skin

 

TYPICAL GROSS FINDINGS: 

• Lesions involve mucous membranes, mucocutaneous junctions and skin in mechanically stressed areas, such as inguinal and axillary regions
  • +/- Involvement of the nailbeds and cornea
  • Cases can largely affect oral mucosa (mucosal-dominant PV), affect the skin and oral mucosa (mucocutaneous PV), or affect mostly skin (cutaneous dominant PV)
• Fragile vesicles or bullae in the epidermis are extremely transient and readily rupture, leaving the common presenting lesion of a roughly circular, shallow, flat-based erosion or ulcer
  • Oral lesions (ulcers of tongue and hard palate) are generally more prominent than, and precede, skin lesions

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Early lesions have spongiosis and vacuolation of suprabasilar epidermis progressing to suprabasilar acantholysis with intraepidermal clefts, vesicles, or bullae between the stratum basale and the stratum spinosum
• Intraepidermal cleft:
  • “Row of tombstones”: The row of rounded, individualized basal keratinocytes within the intraepidermal cleft that are still attached to the basement membrane but separated on lateral and superficial surfaces
  • Acantholytic keratinocytes, singly or in clumps, may be seen above the cleft and in the lumen
  • Lumen contains few to no inflammatory cells
• Lesions frequently extend to superficial and sometimes deep hair follicles
• Superficial perivascular mixed lymphoplasmacytic inflammation (+/- eosinophils) present
  • Lymphoplasmacytic interface dermatitis may be present in mucosal lesions

 

ADDITIONAL DIAGNOSTIC TESTS:

• Direct immunofluorescence (IF) that demonstrates (usually IgG) and complement in the intercellular spaces of stratified squamous epithelium
• Indirect IF that demonstrates demonstrate circulating anti-keratinocyte membrane antibodies

 

DIFFERENTIAL DIAGNOSIS:

• Clinical differentials include mucous membrane pemphigoid, erythema multiforme, bullous pemphigoid, toxic epidermal necrolysis, vesicular lupus erythematosus of Collies and Shetland Sheepdogs, mycosis fungoides, and other diseases resulting in oral ulcers
• Gross - oral and/or skin lesions
  • Bullous pemphigoid (I-M27): Dogs; vesicles do not coalesce or spread, oral lesions are less common, Doberman pinschers and collies at increased risk
  • Mucocutaneous candidiasis: Immunosuppressed animals; ulcers and erosions coated with adherent, foul-smelling exudate
  • Epitheliotropic lymphoma (mycosis fungoides) (I-N26): Uncommon in dogs; rare in cats; oral lesions may resemble those seen with pemphigus vulgaris
  • Toxic epidermal necrolysis (TEN): Dogs and cats
  • Erythema multiforme (EM) (I-M27): Apoptotic keratinocytes in all layers, interface dermatitis; similar lesions to and may be part of continuum with TEN
  • Vesicular lupus erythematosus of Collies and Shetland sheepdogs
  • If lesions limited to oral cavity: Numerous other causes of canine and feline ulcerative stomatitis
• Microscopic - oral and/or skin lesions
  • Bullous pemphigoid (I-M27): Autoantibodies against bullous pemphigoid antigen (produced by keratinocytes; normal component of dermal-epidermal junction); subepidermal clefts and vesicles; no acantholysis
  • Paraneoplastic Pemphigus: Features of PV, PF and EM; suprabasilar clefts with tombstoning; intraepidermal pustules; apoptotic keratinocytes in all layer
  • Epidermolysis bullosa acquisita: Subepidermal bullae filled with blood
  • Mucocutaneous candidiasis: Candida yeast/pseudohyphae in crusts or pustules
  • Epitheliotropic lymphoma (mycosis fungoides) (I-N26): Intraepithelial neoplastic lymphocytes (Pautrier's microabscesses)
  • Toxic epidermal necrolysis: Acute coagulation necrosis of epidermis; bullae; ulcers; no inflammation until epidermis begins to separate from dermis

 

COMPARATIVE PATHOLOGY:

• Most commonly reported in dogs in veterinary literature
• Humans: Pemphigus vulgaris is by far the most common form in humans (80% of cases)
• NHPs: Reported in a baboon and pig-tailed macaque with similar lesions as in dogs (suprabasilar vesiculation, acantholysis, and interepidermal anti-IgG antibody immunofluorescence)

References:

1. Kramer JA, Bielitzkiy J. Integumentary System Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T, ed. Nonhuman Primates in Biomedical Research. Volume 2: Diseases. 2nd ed. Oxford, UK: Elsevier Inc; 2012: 578.
2. Lazar AJ. The Skin. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier Saunders; 2021:1133, 1160-2.
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 Inc; 2016: 600-2.
4. Uzal FA, Plattner BL, Hostetter JM. Alimentary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier Inc; 2016: 14-15.
5. Welle MW, Linder, KE. The Integument. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier Mosby; 2022: 1130, 1132, 1193-4.

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