JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

September 2024

D-M01

 

SLIDE A: SIGNALMENT (JPC #1619733): Adult cat

 

HISTORY: Long-standing ulcerated lesion was removed surgically from the mouth 

 

HISTOPATHOLOGIC DESCRIPTION: Oral mucosa (per contributor): Approximately 60% of the submucosa is infiltrated by numerous eosinophils, fewer neutrophils, macrophages, lymphocytes, plasma cells, mast cells, and reactive fibroblasts that surround and separate bundles of collagen. Within the areas of dense eosinophilic infiltrate, intensely hypereosinophilic material is fragmented, granular, and surrounded by amphophilic to basophilic debris creating a highly eosinophilic center (“flame” appearance), surrounded by macrophages and multinucleate giant cells, both Langhans and foreign body type (flame figures). The submucosa is mildly expanded by increased clear space (edema), lymphatic vessels are mildly dilated, and blood vessels are often lined by plump, reactive endothelial cells. The overlying mucosal epithelium is mildly hyperplastic.

 

MORPHOLOGIC DIAGNOSIS: Oral mucosa (per contributor): Stomatitis, eosinophilic and granulomatous, focally extensive, moderate, with flame figures, breed unspecified, feline.

 

CONDITION: Feline oral eosinophilic granuloma

 

SLIDE B: SIGNALMENT (JPC #2648048): 1-year-old female Siberian husky

 

HISTORY: Mass on the frenulum of the tongue

 

HISTOPATHOLOGIC DESCRIPTION: Oral mucosa (per contributor): Expanding the submucosa and elevating the overlying multifocally eroded and extensively ulcerated mucosa is a sessile mass composed of multifocal to coalescing eosinophilic granulomas characterized by abundant viable and necrotic eosinophils centered on intensely eosinophilic, fragmented, granular material (flame figures) admixed with amphophilic to basophilic debris surrounded by multinucleated giant cells, epithelioid macrophages, and fewer neutrophils, foreign body type multinucleated giant cells, reactive fibroblasts, and fibrosis.  Predominantly in areas of ulceration, there are many small caliber blood vessels lined by reactive endothelium and oriented perpendicularly to plump, reactive fibroblasts (granulation tissue). There are multifocal ectatic lymphatics. Neutrophils and eosinophils transmigrate the mucosal epithelium.

 

MORPHOLOGIC DIAGNOSIS: Oral mucosa (per contributor): Eosinophilic granulomas, multifocal to coalescing, severe, with flame figures, multifocal ulceration, and granulation tissue, Siberian husky, canine.

 

CONDITION: Canine oral eosinophilic granuloma

 

GENERAL DISCUSSION:

• Considered a cutaneous to mucocutaneous reaction pattern rather than specific disease
• Dermatological lesions characterized by focal or multifocal infiltrates of eosinophils that have a consistent clinical presentation; the 3 presentations may occur together or separately:
  1. Eosinophilic granuloma (linear granuloma)
  2. Eosinophilic plaque
  3. Indolent ulcer (rodent ulcer)/ oral eosinophilic granuloma 
• Common in cats and horses (nodular necrobiosis)
• Pathogenesis not well understood; most likely cause is a hypersensitivity reaction 
• Eosinophils have protein granules (cytokines, chemokines, proteases, and oxidative radicals) that, when released, result in degradation of collagen as seen in these conditions 
• Feline eosinophilic granuloma complex includes lesions affecting the skin (I-M11), mucocutaneous junctions, and oral cavity of cats, no breed predilection; highest incidence in young adult cats  
• Canine eosinophilic granulomas are rare, occur the oral cavity or rarely the skin, and primarily affect Siberian huskies and sporadically Cavalier King Charles spaniels 

 

PATHOGENESIS:

Eosinophils:

• Responsible for inflammation and tissue destruction with profound vasoactive and neurogenic properties
  • Four major granules with many different proteins and enzymes:
    • Primary granules (Charcot-Leyden crystals)
    • Secondary granules (major basic protein/MBP, eosinophil-derived neurotoxin, eosinophilic cationic protein, eosinophil-specific peroxidase)
    • Small granules (arylsulfatase and acid phosphatase)
    • Lipid bodies – result in eicosanoid formation
  • Produce transforming growth factor-beta, associated with chronic inflammation and fibrosis 
• Eosinophilic recruitment > degranulation resulting in release of a wide range of toxic granule proteins (i.e. MBP), enzymes (i.e. peroxidase, collagenase), cytokines (i.e. IL-3, IL-5, GM-CSF), chemokines (i.e. IL-8), and lipid mediators > damage to lipid membranes, collagenolysis, edema, granulomatous reaction
  • Over time, intensely eosinophilic material (“flame figures”) may accumulate (largely composed of MBP) adjacent to collagen fibers

Cats

• Eosinophilic inflammation is a common tissue reaction in cats; chemotactic stimuli that attracts neutrophils in most species attracts both eosinophils and neutrophils in cats (and horses)
• Underlying allergic etiology suspected in cats (environmental allergens, food, and insect bites [fleas and mosquitoes]); however:
  • Reported in related cats (possible heritable eosinophil dysregulation)
  • Felis domesticus allergen I (Feld I) is a possible autoallergen responsible for chronic inflammatory reaction in cats
  • Some lesions spontaneously resolve; allergy unlikely in those cases 
  • Some lesions resolve with antibiotics alone; bacterial involvement may be a significant factor, especially for indolent ulcers eosinophilic plaques

Dogs

• Cause unknown; possible hypersensitivity reaction à lesions are eosinophilic, corticosteroid responsive, and often there is circulating eosinophilia
• Lesions occur in the oral cavity, less frequently there are skin lesions on the ventral abdomen, prepuce, digits, flanks, muzzle, nasal planum, and external ear canal 

 

TYPICAL CLINICAL FINDINGS:

Feline eosinophilic granuloma complex:

• Feline eosinophilic granuloma
  • Common cutaneous, mucocutaneous, or oral lesion; variable presentation
    • If in mouth, may be malodorous or dysphagic; if on paws, may be lame 
  • Often nonpruritic, possible genetic predisposition 
  • Primarily affects young cats, especially <1 year of age; may spontaneously regress 
• Feline eosinophilic plaque
  • Common pruritic, well demarcated, cutaneous lesion; cats lick constantly
• Indolent ulcer
  • Common mucocutaneous lesion; not pruritic or painful
  • Some lesions respond with antibiotics alone (bacterial infection) 

Canine oral eosinophilic granuloma:

• Variable presentation on mouth and tongue: 
  • Oral lingual lesions markedly painful and, if necrotic, malodorous à dysphagia, coughing while eating, decreased appetite, reluctance to eat/chew
  • Palatal lesions typically not painful
  • Cutaneous lesions usually nonpruritic and painless
• Eosinophilia variable
• More common in male, young (<3 years old) Siberian Huskies
• Responsive to corticosteroids 

 

TYPICAL GROSS FINDINGS:

Feline eosinophilic granuloma complex:

• Feline eosinophilic granuloma 
  • Lesions can be linear, nodular, or papular and occur on skin, paw pads, mucocutaneous junction, and in oral cavity. +/- ulceration. 
    • Linear lesions (most common): Caudal or medial thigh
    • Nodular lesions: Lips, chin, ears, oral cavity, face, and feet
  • Cutaneous: Raised, pink to orange-yellow, and frequently alopecic 
  • Oral: Commonly ulcerated with multifocal pinpoint, yellow to white foci over the surface; uncommonly nodules may affect the tongue, tonsillar region, frenulum, or palate
• Feline eosinophilic plaque 
  • Well-demarcated, singular to multiple, raised, erythematous, alopecic, eroded to ulcerated to oozing plaque +/- peripheral lymphadenopathy
  • Most commonly on ventral abdomen, perineum, and medial thighs
  • Secondary bacterial infection common 
  • +/- peripheral lymphadenopathy
• Indolent ulcer (rodent ulcer) 
  • Ulcerated lesion on the upper lip adjacent to the philtrum, adjacent to upper canine tooth or hard palate; unilateral or bilateral
    • Can be seen anywhere in the mouth
  • +/- peripheral lymphadenopathy

Canine oral eosinophilic granuloma

• Occurs sporadically, not as common as in cats 
• Nodules or plaques, occur most often on the palate and ventral and lateral tongue Skin lesions less frequent; single to multiple papules, nodules, or plaques on ventral abdomen, prepuce, digits, flank, muzzle, external ear canal, nasal planum, or eyelid
• Ulceration common

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Feline eosinophilic granuloma complex:

• Feline eosinophilic granuloma 
  • Perivascular to interstitial to diffuse dermal inflammation composed primarily of eosinophils, fewer mast cells, macrophages, lymphocytes, and plasma cells; and large irregular foci of collagen fibers and degranulated and degenerating eosinophils (flame figures) 
  • +/- surrounded by epitheloid macrophages and multinucleated histiocytic giant cells; often granulomas palisade around flame figures in older lesions 
  • +/- epidermal/follicular epithelial mucinous (pale basophilic or gray mucin between keratinocytes), focal infiltrative to necrotizing mural eosinophilic folliculitis or furunculosis, focal eosinophilic panniculitis, acanthotic or ulcerated epidermis, or dermal mucin and/or edema
• Feline eosinophilic plaque 
  • Epidermal hyperplasia and moderate to marked spongiosis with exocytosis of eosinophils
  • +/- epidermal/follicular epithelial mucinosis 
  • Perivascular to interstitial to sometimes diffuse dermal inflammation, containing numerous eosinophils with mast cell hyperplasia; may extend to subcutis.
  • Typically no flame features
  • Raised, variably sized, erythematous, pruritic, and eroded to ulcerated plaques. 
• Mast cells, lymphocytes, and macrophages are present in smaller numbers 
• Indolent ulcer
  • Acute lesions: Diffuse infiltrates of neutrophils with variable numbers of neutrophils, eosinophils, mast cells, and macrophages
    • Chronic phase (often biopsied at this stage): Lymphocytes, plasma cells, macrophages, neutrophils (depending on degree of ulceration/lesion age), fibrosis
  • Concurrent bacterial infection is common
  • Collagenolysis is characteristically central in the lesion

Canine eosinophilic granuloma: 

• Diffuse dermal eosinophilic inflammation with foci of degranulating eosinophils sometimes surrounded by epithelioid macrophages; overlying epithelium/epidermis may be acanthotic or ulcerated
• Collagenolysis is characteristically central in the lesion 

 

ADDITIONAL DIAGNOSTIC TESTS:

• Cytologic findings: 

• Eosinophilic plaque: Eosinophils and mast cells are predominant inflammatory cells with occasional lymphocytes. 
• Eosinophilic granuloma: Mixed inflammatory cells; eosinophils and mast cells comprise the larger population along with macrophages, lymphocytes, plasma cells, and neutrophils, fibroblasts often seen, rarely, multinucleated giant cells; cells are present on a background of amorphous basophilic material (collagen damage)

 

DIFFERENTIAL DIAGNOSIS:

For gross lesions in the oral cavity of cats:

• Feline eosinophilic plaque: Severe allergic military dermatitis, mosquito bite hypersensitivity, food allergy, eosinophilic feline herpesvirus ulcerative dermatitis (without inclusions), eosinophilic indolent ulcer
• Feline indolent ulcer: Eosinophilic herpes virus ulcerative dermatitis (in which inclusions not found), feline calicivirus infection, FeLV, cryptococcus, mosquito bite hypersensitivity, or severely ulcerated eosinophilic plaque
• Neoplasia (squamous cell carcinoma, cutaneous epitheliotropic T-cell lymphoma, mast cell tumor)
  • Paraneoplastic eosinophilia due to IL-5 production by neoplastic lymphocytes
• Ulceration/granulomatous inflammation (fungal, mycobacteria, demodicosis, viral)
• Feline plasma cell gingivitis-pharyngitis: Typically raised, erythematous, proliferative lesions, mainly in the glossopalatine arches

For gross lesions in the oral cavity of dogs:

For cutaneous lesions, consider:

• Granulomas (fungal, bacterial, demodicosis) and noninfectious granulomatous disease
• Neoplasia (mast cell tumor, cutaneous epitheliotropic T-cell lymphoma, squamous cell carcinoma, melanoma, plasmacytoma)
• Foreign body reactions
• Erythema multiforme (ulcerative stomatitis)

 

COMPARATIVE PATHOLOGY

Horses

• Eosinophilic inflammation is a common tissue reaction in horse, most commonly seen in spring and summer.
• Equine eosinophilic granuloma: Most common of the cutaneous eosinophilic nodular diseases and the most common inflammatory nodular skin disease of the horse; pathogenesis thought to be linked to hypersensitivity and trauma due to pressure points; papules or nodules occur most commonly on withers, neck, or back but can be generalized; has been found on the conjunctiva, neither painful nor pruritic; overlying skin/haircoat typically normal
• Equine multisystemic, eosinophilic, epitheliotropic disease (MEED): Rare; characterized by eosinophilic and lymphoplasmacytic infiltration of multiple organs (skin, pancreas, liver, common bile duct, gastrointestinal tract, lungs); exudative, exfoliative dermatitis, ulcerative stomatitis, wasting
• Oral, nasal, and cutaneous eosinophilic granulomas are reported in the black rhinoceros
• Well’s syndrome is the human counterpart to eosinophilic granuloma in animals

 

REFERENCES:

1. Ackermann, MR. Inflammation and healing. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:118-119.
2. Bernreuter DC. Oropharynx and Tonsils. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2020:133-134. 
3. Duncan M. Perissodactyls. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:441. 
4. Fisher DJ. Cutaneous and Subcutaneous Lesions. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2020:85.
5. Gelberg, HB. Alimentary system and the peritoneum, omentum, mesentery, and peritoneal cavity. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:420-421.
6. 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; 2016:693-695. 
7. Raskin RE, Conrado FO. Integumentary System. In: Raskin RE, Meyer DJ, Boes, KM eds. Canine and Feline Cytology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:38-42. 
8. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1188-1189.

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