JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M11

SLIDE A:  Signalment (JPC #2316310):  Cat

 

HISTORY:  This cat had a well-circumscribed, linear, ulcerated lesion along the lip margin.

 

HISTOPATHOLOGIC DESCRIPTION:  Mucocutaneous junction, lip: Multifocally expanding the subepidermal and submucosal connective tissue, separating hyalinized, fragmented collagen bundles, and extending into the underlying skeletal muscle are numerous viable and degenerate eosinophils admixed with fewer plasma cells, macrophages, lymphocytes, and neutrophils. The overlying mucosal epithelium has a focal extensive ulceration that is replaced by brightly eosinophilic necrotic cellular and karyorrhectic debris, abundant degenerate neutrophils, and aggregates of 1µm cocci (serocellular crust).  Adjacent mucosal epithelium is mildly hyperplastic with acanthosis, short rete pegs and spongiosis. Blood vessels in the subepithelial connective tissue are often lined by hypertrophied endothelial cells and there is mild fibrosis.  Lymphatics are multifocally dilated (edema) and apocrine glands are often ectatic.  Inflammatory cells separate, surround, and occasionally replace skeletal muscle fibers which are often swollen with vacuolated sarcoplasm (degeneration), or shrunken with hypereosinophilic sarcoplasm and loss of cross striations (necrosis).

 

MORPHOLOGIC DIAGNOSIS:  Mucocutaneous junction, lip:  Cheilitis, eosinophilic and ulcerative, focally extensive, chronic, severe, with lymphoplasmacytic dermatitis, and skeletal muscle degeneration and necrosis, breed unspecified, feline.

 

ETIOLOGIC DIAGNOSIS:  Idiopathic eosinophilic granuloma

 

CONDITION:  Eosinophilic granuloma complex

 

SLIDE B: Signalment (JPC #1953607):  Horse

 

HISTORY:  Tissue from a cutaneous nodule.

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin: Expanding the deep dermis up to five times normal thickness; separating and surrounding collagen bundles, muscle fibers, and adnexa, and extending into the panniculus carnosus are multiple individual to coalescing nodules centered on variably mineralized eosinophilic cellular debris (necrosis) and hypereosinophilic collagen fibril fragments.  Foci of necrotic debris are surrounded by numerous degenerate and viable eosinophils and epithelioid macrophages, lymphocytes and plasma cells, and few Langhans and foreign body type multinucleate giant cells, and are encircled by abundant fibrous connective tissue (eosinophilic granuloma). Viable and degenerate eosinophils and epithelioid macrophages often palisade around fragments of hypereosinophilic or hyalinized collagen (“flame figures”). Within the dermis there are few prominent lymphoid aggregates, and endothelial cells are often hypertrophied (reactive). Lymphocytes, plasma cells, and fewer eosinophils infiltrate the superficial panniculus carnosus and surround myofibers.  

 

MORPHOLOGIC DIAGNOSIS:  Haired skin:  Dermatitis and panniculitis, nodular, eosinophilic and granulomatous, focally extensive, severe, with flame figures and mineralization, breed unspecified, equine.

 

ETIOLOGIC DIAGNOSIS:  Idiopathic collagenolytic granuloma

 

CONDITION:  Equine eosinophilic nodular disease

 

GENERAL DISCUSSION:

• Eosinophilic dermatoses should be thought of as a “cutaneous reaction pattern” rather than a specific “disease”
• Characteristic flame figures consist of large irregular foci of collagen fibers surrounded by degranulated and degenerate eosinophils; thought to be associated with eosinophil release of major basic protein (MBP), a protein present in large amounts in the secondary granules of eosinophils  
• Feline eosinophilic granuloma complex (EGC): Encompasses the following three clinically distinct entities with overlapping histopathologic findings (these three entities can occur separately or in combination; there is no breed or sex predilection; considered a mucocutaneous reaction pattern):
  • Eosinophilic granuloma (linear granuloma) – common, young cats, can be cutaneous, mucocutaneous, or oral
  • Indolent ulcer (rodent ulcer) - may be preneoplastic with progression to squamous cell carcinoma
  • Eosinophilic plaque – pruritic; traumatized from constant licking skin
• Canine eosinophilic granuloma (D-M01): Rare; young male Siberian huskies and Cavalier King Charles spaniels
• Equine eosinophilic nodular disease: Eosinophilic inflammation is a common reaction pattern in the horse and there are three nodular conditions
  • Eosinophilic granuloma – most common inflammatory nodular skin disease in the horse
  • Axillary nodular necrosis (girth galls): Rare
  • Unilateral papular necrosis: Uncommon; usually spring and summer; quarter horses may be overrepresented

 

PATHOGENESIS:

• The clinical and histopathologic features of the disease in cats, horses, and dogs suggest that the disease is secondary to hypersensitivity (e.g. flea/arthropod bite, atopy, food allergy); other proposed causes include eosinophil dysfunction, embedded insect parts or other foreign bodies, and elaboration of major basic protein
• Feline eosinophilic granuloma complex
  • Pathogenesis of feline flame figures thought to be primarily due to degranulating eosinophils and release of major basic protein/granule components surrounding edematous but morphologically normal collagen
  • Felis domesticus allergen I (Feld I) could be an autoallergen responsible for chronic inflammatory reactions in cats with EGC
• Canine eosinophilic granuloma
  • Etiology unknown, but genetic basis is suspected in Siberian husky and Cavalier King Charles spaniel, which are predisposed to oral eosinophilic granulomas
• Equine eosinophilic nodular disease
  • Etiology unknown, probably multifactorial
  • Eosinophilic granuloma: Proposed causes include insect bite hypersensitivity, atopic dermatitis, food allergy, injections from silicone-coated needles, close-clipping, trauma
  • Axillary nodular necrosis: Unknown pathogenesis
  • Unilateral papular necrosis: Ectoparasite hypersensitivity suspected

 

TYPICAL CLINICAL FINDINGS:

• Feline eosinophilic granuloma complex - may have peripheral lymphadenopathy
  • Eosinophilic granuloma - variably pruritic; young cats; regression possible
  • Indolent ulcer - non-pruritic, non-painful; ulceration of upper lip (unilateral or bilateral), peripheral eosinophilia is rare
  • Eosinophilic plaque - severe pruritus; peripheral eosinophilia present; can occur with miliary dermatitis
• Canine eosinophilic granuloma - oral cavity (sublingual) is the most common site; cutaneous lesions are non-pruritic; circulating eosinophilia possible
• Equine eosinophilic nodular disease
  • Eosinophilic granuloma - nodules on the withers or dorsum; not pruritic or painful
  • Axillary nodular necrosis - nodules on the trunk behind the axilla; not pruritic or painful
  • Unilateral papular dermatosis – multiple, unilateral, cutaneous nodules and papules 2-10mm on the trunk; not pruritic or painful

 

TYPICAL GROSS FINDINGS:

• Feline eosinophilic granuloma complex

• Eosinophilic granuloma – Cutaneous or oral lesion

• Cutaneous - linear, raised plaques or nodules on caudal or medial thighs; less commonly - single nodular lesions anywhere on body, including footpads, pinnae, lower lip
• Oral - nodule on the tongue, frenulum, or soft palate, more severe, aggressive

• Indolent ulcer - solitary, unilateral or bilateral, ulcerated (non-bleeding), firm lesion on upper lip adjacent to philtrum; +/- regional lymphadenopathy
• Eosinophilic plaque – well demarcated, singular to multiple, raised, round erythematous, alopecic, eroded to ulcerated oozing plaque lesion; abdomen, medial thighs, perineal; regional lymphadenopathy usually present

• Canine eosinophilic granuloma – Nodules or plaques most commonly in the mouth and on the tongue; palatine plaques, lingual masses, cutaneous nodules on pinnae, muzzle, axilla, flank, prepuce, abdomen, digits, eyelid
• Equine eosinophilic nodular disease
  • Eosinophilic granuloma – single or multiple, firm, raised, well circumscribed, round papules on the withers, neck, and back
  • Axillary nodular necrosis – often linear pattern of nodules in axillary region or trunk
  • Unilateral papular dermatosis – multiple, unilateral, cutaneous nodules on the trunk

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Feline eosinophilic granuloma complex
  • All three forms: Dermal infiltrate consisting of predominantly eosinophils in a variable pattern (superficial, deep perivascular, interstitial, or diffuse); +/- flame figures (small foci of collagen fibers expanded by edema surrounded by degranulated eosinophils); +/- granulomatous reaction surrounding flame figures (the result of proteins released from degranulated eosinophils)
  • Eosinophilic plaque: Epidermal hyperplasia with acanthosis, moderate to marked spongiosis, and eosinophilic exocytosis; epidermal and follicular mucinosis is common; eosinophils may extend to panniculus; ulceration is often present
  • Eosinophilic granuloma (linear granuloma): Diffuse dermal inflammation composed primarily of eosinophils, "flame figures"; eosinophilic folliculitis or furunculosis (in cutaneous lesions), giant cells; overlying epithelium is often hyperplastic and often ulcerated
  • Indolent ulcer: Acute lesions include neutrophils, variable numbers of eosinophils, mast cells, and macrophages; chronic lesions contain lymphocytes, plasma cells, macrophages, and neutrophils and fibrosis
• Canine eosinophilic granuloma
  • Diffuse dermal eosinophilic inflammation with foci of brightly eosinophilic collagen surrounded by degranulating eosinophils further surrounded by epithelioid macrophages (flame figures)
  • Cavalier King Charles spaniels: Degranulating eosinophils may be absent and there may be only mild "flame figure" formation
  • Siberian huskies: Flame figures are prominent
• Equine eosinophilic nodular disease
  • Eosinophilic granuloma: Nodular to diffuse infiltrates of eosinophils and granulomatous inflammation within the dermis and panniculus; foci of collagen that are often mineralized (flame figures) surrounded by  palisading granulomas
  • Axillary nodular necrosis: Interstitial to nodular-to-diffuse panniculitis and eosinophilic granulomatous dermatitis; foci of coagulative necrosis with possible eosinophilic vasculitis or eosinophilic arteritis with intimal mucinosis and karyorrhectic nuclear debris within the tunica media
  • Unilateral papular dermatosis: Similar with characteristic eosinophilic folliculitis and furunculosis

 

ULTRASTRUCTURAL FINDINGS:

• Flame figures: Structurally normal collagen fibers composed of fibrils separated by edema and surrounded by numerous degranulating eosinophils and abundant cellular debris; no ultrastructural abnormalities of fibrils themselves are detected

 

DIFFERENTIAL DIAGNOSIS:

• Feline eosinophilic granuloma complex
  • Indolent ulcer: SCC, infectious ulcers (herpes, calicivirus, FELV, Cryptococcus), mosquito bite hypersensitivity
  • Eosinophilic plaque and eosinophilic granuloma: Cutaneous epitheliotropic T-cell lymphoma, infectious granulomas (demodicosis, bacterial [Mycobacterium] or fungal), mast cell tumor, or SCC
• Canine eosinophilic granuloma: Infectious/foreign body granuloma, neoplasms, eosinophilic furunculosis, palisading granulomatous dermatitis
• Equine eosinophilic nodular disease
  • Cutaneous habronemiasis, mast cell tumor, Hypoderma, Pythium spp.
  • Multisystemic eosinophilic epitheliotropic disease (MEED, D-M02): A rare eosinophilic disease characterized by an eosinophilic infiltration with occasional eosinophilic granuloma formation in many organs including the skin and intestine; it is thought to be caused by either a severe hypersensitivity reaction or a clonal proliferation of T lymphocytes resulting in proliferation of eosinophils due to secretion of IL-5

 

ADDITIONAL DIAGNOSTIC TESTS:

• Diagnosis is based on clinical signs and characteristic gross and microscopic features
• Histochemical stains:

• B&B, B&H, GMS, PAS, Ziehl-Neelson, Fite-Faraco to rule out bacterial or fungal disease
• Masson’s trichrome:  Determines the presence of collagen degradation - normal collagen is blue and degraded collagen has a red core
• Toluidine blue, Giemsa:  Highlight mast cells; may be useful to distinguish from MCT, especially in horses

• Immunohistochemical stains: CD117 (C-Kit) highlights mast cells; may be useful to distinguish from MCT, especially in horses
• Clinical: Allergic disease testing to determine underlying hypersensitivity

 

COMPARATIVE PATHOLOGY:

• Reported in the black rhinoceros (oral and nasal cavities and skin caudal to the upper lip) forming proliferative, exophytic masses that easily ulcerate and can recur. Histologically different from other species due to associated neovascularization and acanthocytes.

 

References:

1. Abbott DEE, Allen AL. Canine eosinophilic pulmonary granulomatosis: case report and literature review. J Vet Diagn Invest. 2020;32(2):329-335.
2. Ackermann, MR. Inflammation and healing. In: Zachary JF. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby Elsevier; 2022:146.
3. Gross TL, Ihrke PJ, Walder EJ, et. al. Nodular and diffuse diseases of the dermis with prominent eosinophils, neutrophils, or plasma cells. In: Gross, TL, et. al. Skin Diseases of the Dog and Cat. 2nd ed. Oxford, UK: Blackwell Science; 2005:355-360.
4. Lund M, Mauldin EA, Radaelli E, Bradley CW. Palisading granulomatous dermatitis and panniculitis (palisading granuloma) of dogs. Vet Pathol. 2021;58(6):1091-1099.
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 Saunders; 2015:693-694.
6. Miller WH, Griffin CE, Campbell KL. Muller and Kirk's Small Animal Dermatology. 7th ed. Philadelphia, PA: W.B. Saunders; 2013:714-718.
7. Scott, DW, Miller WH. Equine Dermatology. Louis, MO: Elsevier Science; 2011:436-439.
8. Terio KA, McAloose D, Leger JS, Duncan M. Perissodactyls. In: Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:441.
9. Welle MM, Linder KE. The Integument. In: Zachary JF. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby Elsevier; 2022:1188-1189, 1259.

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