JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M29

Signalment (JPC 2017927):  4-year-old dog   

 

HISTORY:  The dog was treated for vomiting and diarrhea with trimethoprim-sulfa and prednisolone, and developed sudden onset erythema and sloughing of the epidermis 48 hours after treatment began.

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin:  Multifocally within all layers of the epidermis and follicular epithelium are many individualized and occasionally clusters of apoptotic keratinocytes that are shrunken with brightly eosinophilic cytoplasm and pyknotic nuclei.  Apoptotic keratinocytes are often surrounded by lymphocytes (lymphocytic satellitosis); lymphocytes occasionally aggregate and are often admixed with many viable and degenerate neutrophils (intraepidermal pustules).  Remaining keratinocytes often exhibit hydropic degeneration. There is rare vacuolation of the basement membrane zone (subepidermal vacuolation), and there are multifocal to confluent clefts immediately subjacent to the basal cell layer (sub-basilar clefts) that contain erythrocytes, small amounts of fibrin, and few viable and degenerate neutrophils.  Occasionally the overlying epithelium is lost (ulceration).  Multifocally infiltrating the superficial dermis, obscuring the dermoepidermal interface, and surrounding superficial dermal blood vessels and adnexa are numerous neutrophils, macrophages, and fewer lymphocytes (interface dermatitis). Dermal fibroblasts are often hypertrophied (reactive), and vessels in affected areas are lined by hypertrophied endothelial cells. Multifocally there is mild epidermal and follicular hyperplasia with thickening of the stratum spinosum (acanthosis), intercellular edema (spongiosis), and mild orthrokeratotic hyperkeratosis. 

 

MORPHOLOGIC DIAGNOSIS:  Haired skin:  Keratinocyte apoptosis, transepidermal and follicular, multifocal to coalescing, with hydropic degeneration, subepidermal clefting, lymphocytic satellitosis, and neutrophilic and lymphohistiocytic interface dermatitis, breed not specified, canine.

 

ETIOLOGIC DIAGNOSIS:  Drug-induced dermatosis (historically)

 

CONDITION:  Erythema multiforme (EM) / Stevens-Johnson syndrome (SJS) / Toxic Epidermal Necrolysis (TEN)

 

GENERAL DISCUSSION: 

• There is current controversy without consensus in the classification of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) in animals
• Until recently it was thought that these conditions represented a spectrum of the same disease process with EM being the mildest (also known as erythema multiforme minor) and TEN the most severe (and SJS is also known as erythema multiforme major)
• A recent study reclassified cases of EM using the human classification system and found SJS/TEN to be triggered by drugs and EM was not
• Historically considered to be caused by adverse drug reactions, however this has been challenged recently (two different case series reported 19% and 59% of EM cases caused by adverse drug reactions
• Diagnosis of EM/SJS/TEN requires histopathology, but diseases are separated based on clinical features, not microscopic findings (cannot differentiate between EM/SJS/TEN lesions histologically)
• SJS involves >50% of the skin with <10% epidermal detachment and involves more than 1 mucosal surface
• TEN has similar criteria but has >30% epidermal detachment
• Reported in dogs, cats, horses, cattle, swine, a ferret, and anecdotally in a goat

 

PATHOGENESIS: 

• Poorly understood in animals; suspected misdirected cell-mediated (type IV) immune response targeting keratinocytes because microscopic lesions, cellular infiltrates, and types of lymphocytes present (CD4 and CD8+) are similar to GVHD
• In dogs, parvoviral inclusions have been associated with cutaneous lesions, indicating active virus replication and likely represent systemic viral infection
• Idiopathic form exists without a history of known triggers
• Small animal cases are historically associated with drug hypersensitivity
• Commonly: D-limonene–based dips, levamisole, cephalexin, trimethoprim-sulfa, gentamicin, penicillin

TYPICAL CLINICAL FINDINGS:

• Diagnosis of EM and SJS/TEN is based on a combination of gross, microscopic, and clinicopathological findings
• Acute onset; may be mild; syndrome may be self-limiting with resolution upon elimination of inciting cause, or more commonly may become chronic or recurrent
• SJS/TEN: Widespread painful lesions and systemic signs (fever, lethargy, inappetence) +/- positive pseudo-Nikolsky sign; clinical emergency; requires intensive care; high mortality

 

TYPICAL GROSS FINDINGS:

• Wide variety of clinical lesions reported in animals, including maculopapular to vesiculobullous and ulcerative and hyperkeratotic lesions
  • EM:
    • Erythematous macules, papules, and plaques with central clearing (target-like lesions), often symmetrical/partially symmetric, may be urticarial (often predominately truncal urticarial lesions)
    • Erythematous areas progress to serpiginous vesicles, erosions, ulcers
  • Dogs may have thick hyperkeratotic crusted plaques that ulcerate
  • Lesions typically affect mucocutaneous junctions, ventral trunk, proximal limbs, glabrous skin of the groin and axillae, oral mucosa, pinnae, foot pads
  • SJS/TEN
    • Widespread lesions of epidermal detachment and urticarial plaques with resulting ulcers; Pseudo-Nikolsky sign: separation of inflamed skin with digital pressure (see pemphigus vulgaris I-M25)
    • In dogs and cats can involve mucocutaneous junctions and footpads

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Goals for histopathological evaluation: determine the presence of characteristic cytotoxic (interface) dermatitis, rule out clinical differential diagnoses
• Apoptotic epidermal cells at all levels of the epidermis and follicular epithelium with few lymphocytes surrounding apoptotic keratinocytes (lymphocytic satellitosis)
• May progress to confluent or full thickness coagulation necrosis of epidermis and follicular epithelium
• Interface dermatitis: damage to basal keratinocytes that obscures the dermoepidermal junction, sparse (cell-poor) lymphohistiocytic infiltrate at dermoepidermal junction and around superficial blood vessels; neutrophils, eosinophils, and plasma cells may be present especially with ulceration
• Subepidermal cleft and vesicle formation at basement membrane zone, vacuolation of the basement membrane zone
• Basal cell hydropic degeneration
• Ortho- and parakeratotic hyperkeratosis

 

DIFFERENTIAL DIAGNOSIS

Clinical:

• Thermal or caustic burns (I-M04)
• Cutaneous lupus erythematosus (I-M28)
• Pemphigus vulgaris (I-M25)
• Bullous pemphigoid (I-M27)
• Urticarial lesions
• Vasculitis
• Epitheliotropic lymphoma (I-N26)
• Superficial necrolytic dermatitis (I-M16)
• Necrotic arachnidism

Microscopic:

• Epitheliotropic T-cell lymphoma (CTCL, I-N26): Atypical epitheliotropic lymphocytes; lack of apoptosis with lymphocytic satellitosis in all levels of the epidermis (as for EM)
• Graft-versus-host disease: Histologically indistinguishable from EM; source of anti-epithelial T cells is exogenous versus pre-existing; history of bone marrow transplant
• Lupus erythematosus (cutaneous lupus erythematosus and systemic lupus erythematosus, I-M28): Similar histopathology except necrosis is primarily confined to the basal layer

 

COMPARATIVE PATHOLOGY:

• Cat:
• EM is associated with drug therapy and (anecdotally) triggered by feline herpesvirus infection
• Feline thymoma-associated exfoliative dermatitis may represent a variant of EM and is similar to EM; diagnosis is centered on diagnosis of a thymic mass (H-N01); however, two cases have been observed without an underlying thymoma
• Horse: equine herpesvirus-5 associated dermatitis described in one horse resembling herpesvirus-associated EM in humans (Mauldin 2016)
• Equine herpesvirus-5 is more classically associated with equine multinodular pulmonary fibrosis (P-V27)
• Cattle: TEN has been associated with Mycoplasma bovis infection in calves
• Ferret: Adrenal disease should be considered as a primary underlying cause of erythema multiforme
• NHPs: rarely reported in NHPs. Characterized by full thickness necrosis of the epidermis; often occurs as adverse drug reaction
• Humans: EM is considered a separate entity from SJS/TEN; clinical lesions are critical to diagnosis in humans: EM lesions are raised and palpable, SJS/TEN lesions are flat
• EM: 90% of EM cases in humans are associated with herpes simplex infection (herpesvirus-associated EM (HAEM)); rarely EM is caused by adverse drug reactions (drug-associated EM)
• HAEM pathogenesis:
• viral proteins on surface of keratinocytes incite a Th1 CD4+ αβ response à activated T cells secrete IFN-γ à cytokine cascade
• CD8+ T cells and NK cells target keratinocytes expressing herpesvirus protein à perforin induces transient pores in keratinocyte cell membrane à granzyme enters cell and mediates apoptosis
• SJS/TEN: Likely triggered by adverse drug reactions in humans but may be associated with infections, especially Mycoplasma pneumoniae
• SJS/TEN pathogenesis: unclear as to what causes sensitization and why rare individuals are affected
• Proposed Hapten model: drug moieties bind to host proteins and are recognized as immunogenic à incite a CD8+ T cell and NK cell response à apoptosis
• 2 requirements for drug sensitization to occur:
• Particular HLA subtype along with a particular T cell receptor clonotype
• Soluble mediators may play a role (TNF-α, FAS-ligand, and granulysin)

 

REFERENCES:

1. Banovic F, Dunston S, Linder KE, Rakich P, Olivry T. Apoptosis as a mechanism for keratinocyte death in canine toxic epidermal necrolysis. Vet Pathol.2017; 54(2):249-253..
2. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin Diseases of the Dog and Cat, 2nd ed. Ames, IA: Blackwell Publishing Professional; 2005: 61-63, 65-68, 75-86, 94-98.

3. Kramer JA, Bielitzki. 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: 579-580.

1. 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: 609-610.  

5. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed., St. Louis, MO: Elsevier; 2022: 1242.
6. Williams BH, Burek Huntingon KA, Miller M Ch.11 Mustelids In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:293.

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