JPC SYSTEMIC PATHOLOGY
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 clustered apoptotic keratinocytes that are shrunken with brightly eosinophilic cytoplasm and pyknotic nuclei, admixed with many viable and degenerate neutrophils and fewer lymphocytes (intraepidermal pustules) that are often clustered around apoptotic keratinocytes (satellitosis). Remaining keratinocytes often exhibit hydropic degeneration. There is rare vacuolation of the basement membrane zone (subepidermal vacuolar alteration) and multifocally the epidermis is separated from the dermis immediately subadjacent to the basal cell layer, forming subbasilar clefts that contain erythrocytes, small amounts of fibrin, and few viable and degenerate neutrophils. 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), rete ridge formation, intercellular edema (spongiosis) and mild orthrokeratotic hyperkeratosis.
MORPHOLOGIC DIAGNOSIS: Haired skin: Keratinocyte apoptosis, transepidermal and follicular, multifocal, with hydropic degeneration, subepidermal clefting, satellitosis, and neutrophilic and lymphohistiocytic interface dermatitis, breed not specified, canine.
ETIOLOGIC DIAGNOSIS: Drug-induced dermatosis (historically)
CONDITION: Erythema multiforme (EM)
- Currently, erythema multiforme (EM) is considered a separate disease process from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which are proposed to variants of the same disease spectrum; however, they are very difficult to differentiate histologically
- SJS/TEN in dogs is likely to be triggered by drugs, whereas EM is less likely (infectious triggers may dominate)
- Due to histopathological overlap, dermatopathologists now recommend an umbrella diagnosis of EM-TEN epidermal necrotizing disease unless there is additional clinical evidence favoring EM or SJS/TEN
- Further sub classification must include patient history, clinical signs etc…
- It is very important to note that in EM-TEN epidermal necrotizing disease the dermis is not necrotic; this feature enables distinction of EM/TEN from a thermal burn or cutaneous infarct
- In a recent study, nearly 25%of skin biopsies lacked epithelium and were not diagnostic; recommend the collection of multiple skin biopsies
- Characteristic cytotoxic (interface) dermatitis with epidermal cell injury
- EM: Uncommon; multifactorial etiology; reported in the dog, cat, horse, cow, ferret and wildlife
- German shepherd dogs and Pembroke Welsh corgis predisposed
- Poorly understood in animals > misdirected immune response target keratinocytes
- Proposed: Host-specific T cell-mediated hypersensitivity reaction > cellular immune response directed against various keratinocyte-associated antigens, including those associated with drugs, infections (viral, fungal, bacterial), neoplasia, various chemicals, foods and connective tissue disease > CD8+ T lymphocytes and natural killer cells antigenically altered keratinocytes (ICAM-1, MHC II, CD1a, and CD44 expression upregulated) > apoptosis results from direct cytotoxicity or through soluble mediators (Fas ligand, granzymes, perforin and granulysin) > erosion, ulceration or hyperkeratosis
- Proposed that the extensive epidermal necrosis of TEN is driven by ‘programmed necrosis or necroptosis’
- Studies support a combined type III and type IV immune reaction
- In dogs, parvoviral inclusions have been associated, indicating active virus replication and likely represent systemic viral infection
- Idiopathic form exists without a history of known triggers
- Small animal cases are often 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; self-limiting, resolves with elimination of inciting cause, or may become chronic or recurrent
- SJS/TEN: Widespread painful lesions and systemic signs (fever, lethargy, inappetence) +/- positive pseudo-Nikolsky sign
TYPICAL GROSS FINDINGS:
- Maculopapular to vesiculobullous with ulcerative hyperkeratosis
- Mucocutaneous junctions, ventral trunk, proximal limbs may occur
- Partially symmetric, urticarial, with predominately truncal lesions
- Glabrous skin of the groin and axillae; oral mucosa; pinnae; foot pads
- Annular, serpiginous to arciform, and polycyclic patterns; classic target lesions (circular lesions with cyanotic to vesicular or ulcerated center ringed by an edematous, pale zone, and an erythematous peripheral ring)
- Murticarial plaques and vesiculobullous lesions involving mucocutaneous junctions, ventral trunk, proximal limbs may occur
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Histologically similar findings with EM / SJS / TEN
- Goals for histopathological evaluation: determine the presence of cytotoxic (interface) dermatitis and to rule out clinical differential diagnoses
- Apoptotic epidermal cells at all levels of the epidermis
- May progress to confluent or full thickness coagulation necrosis of epidermis and hair follicles
- Few lymphocytes surround apoptotic keratinocytes (lymphocytic satellitosis)
- Lymphohistiocytic infiltrate that obscures the dermoepidermal junction (interface dermatitis) and around superficial blood vessels; may be cell-poor; 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 (hydropic degeneration)
- Ortho- and parakeratotic hyperkeratosis
- Uncommonly, dermal edema, vertical orientation of collagen (gossamer collagen)
- Chemical/thermal burns: Coagulative necrosis that extends into deep dermis depending on the severity
- Toxic shock syndrome: Early lesions resemble EM; apoptotic keratinocytes surrounded by neutrophils rather than lymphocytes; apoptotic cells tend to cluster rather than being more diffusely distributed
- Cutaneous lupus erythematosus: Very similar histologically; necrosis principally confined to the basal cell layer (Civatte bodies)
- Pemphigus vulgaris: Suprabasilar acantholysis, no apoptosis, usually affects mucous membranes; mucous membrane involvement is a rare occurrence with erythema multiforme
- Bullous pemphigoid: Similar subepidermal clefts and vesicles; little keratinocyte apoptosis and initial hydropic degeneration of the basal cells does not occur
- Ulcerative dermatosis (Shetland sheepdog and collie): Similar histopathology, except necrosis is primarily confined to the basal layer
- Fixed drug eruptions: Uniformly well-circumscribed erythematous edemtaous lesions, forming bullae and ulcerate; uniform reappearance in same site on each occasion the patient is challenged with the offending drug; less inflammation
- Urticaria: Hydropic interface dermatitis with severe edema; transient
- Graft-versus-host disease: Histologically indistinguishable from EM; source of anti-epithelial T cells is exogenous versus pre-existing; history of bone marrow transplant
- Epitheliotropic T-cell lymphoma (CTCL) with apoptosis: Intraepithelial aggregates of Langerhans cells (pseudo-Pautrier's abscesses); lymphocytic infiltration of apocrine sweat glands highly diagnostic
Depth of Necrosis
Mucosa and cutaneous; extensive
full epidermal with +/- subepidermal bullae, does not affect dermis
none or minimal except when ulcerated
Glabrous skin of groin and axillae, mucocutaneous, oral mucosa, pinnae, foot pad
full epidermal with numerous apoptotic keratinocytes and +/- subepidermal bullae
lymphohistiocytic, perivascular and interface
coagulative necrosis extends into dermis depending on degree
peripheral neutrophils and macrophages
- Cat: EM is associated with drug therapy and (anecdotally) triggered by herpesvirus infection
- Feline thymoma-associated exfoliative dermatitis may represent a variant of EM and is similar to EM with milder transepidermal and superficial follicular apoptosis, mild - severe hyperkeratosis, and lymphocytic satellitosis of apoptotic keratinocytes; diagnosis is centered on diagnosis of a thymic mass; however, two cases have been observed without an underlying thymoma
- Horse: EM has been most commonly associated with drug administration (especially potentiated sulfonamides, penicillin, ivermectin), infections (especially herpesvirus), vaccinations, neoplasia (especially lymphoma), topical agents, reactions to food
- 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 in the ferret
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