ISVD Case of the month October 2021 A 1.5-year-old, female spayed, golden retriever with a history of gastrointestinal issues for a week. Patient was put on gabapentin, metronidazole, Pro-Pectalin, and metoclopramide. The next day, multiple, ulcerated, raised, erythematous dermal nodules started to arise over the body. Was started on prednisone.

Picture 1.

Picture 2: H&E, 20x magnification.

Picture 3. H&E, 100 x magnification

Picture 4: H&E, 200x magnification

Picture 5. H&E, 400 x magnification

Picture 6. H&E, 400 x magnification

Picture 7. H&E, 400 x magnification

Picture 8. H&E, 400 x magnification

What is the most likely diagnosis?

1. Canine eosinophilic granuloma 2. Canine sterile neutrophilic dermatosis (Sweet’s syndrome) 3. Arthropod bite reaction 4. Canine eosinophilic dermatitis (Wells-like syndrome) 5. Sterile pustular erythroderma of miniature schnauzers

ANSWER:

Clinical history: A 1.5-year-old, female spayed, golden retriever with a history of gastrointestinal issues for a week. Patient was put on gabapentin, metronidazole, Pro-Pectalin, and metoclopramide. The next day, multiple, ulcerated, raised, erythematous dermal nodules started to arise over the body. Was started on prednisone. What is the most likely diagnosis?

1. Canine eosinophilic granuloma 2. Canine sterile neutrophilic dermatosis (Sweet’s syndrome) 3. Arthropod bite reaction 4. Canine eosinophilic dermatitis (Wells-like syndrome) 5. Sterile pustular erythroderma of miniature schnauzers

Histopathologic description:

From the superficial dermis extending to the deep dermis, there is an interstitial infiltration of many eosinophils, lesser neutrophils, and few histiocytes. There is severe edema separating collagen fibers (Figure 2-5). Eosinophils are multifocally degranulated and occasionally surround hypereosinophilic collagen fibers with a mildly frayed appearance (early collagen flame figures)(Figure 6). Occasionally, there are thrombi within small-sized blood vessels (Figure 7). Hair follicles are multifocally ruptured (furunculosis), and free hair shafts are surrounded by neutrophils and eosinophils (Figure 3). The epidermis is diffusely, mildly to moderately hyperplastic. Some sections have extensive ulceration covered by extensive serocellular crusts characterized by proteinaceous material, cellular debris, eosinophils and erythrocytes. Intact epidermis has severe spongiosis and exocytosis of many eosinophils (Figure 8).

Morphologic diagnosis:

Diffuse, severe, interstitial eosinophilic dermatitis with edema, flame figures, furunculosis and epidermal ulceration

Outcome:

The dog was treated for Wells-like syndrome with prednisone, tapering over three weeks. After two weeks, 80% of the lesions were resolved and after three weeks all the lesions had disappeared completely.

Comments:

Canine eosinophilic dermatitis with edema (CAEDE) is a rare syndromic disorder that resembles eosinophilic cellulitis of humans (Wells’ syndrome). Affected dogs have arciform and serpiginous wheals, macules, plaques, or generalized erythema mostly on the glabrous skin of the abdomen, the thorax and the pinnae. Lymphadenopathy is common. Many, but not all, of the affected dogs have associated gastrointestinal tract disease. Causes of the GI disorder include adverse food reaction, inflammatory bowel disease or pancreatitis, but a specific cause cannot be found in a considerable number of cases (Cain et al. JAVMA 2017). In a study (Mauldin et al. Vet Pathol 2006), 75% of the dogs developed skin lesions in association with GI signs. The affected dogs were grouped in three categories: Category 1 included dogs with GI signs prior to the skin lesions, category 2 had dogs with GI disease associated with skin lesions at the time of presentation and category 3 included dogs that had skin lesions without gastrointestinal signs. The etiology is still not known, but an adverse drug reaction or unknown systemic hypersensitivity may play a role. A variety of triggering factors have been reported, such as adverse food reaction, insect bites, vaccination, endoparasitism, vaccination and myeloproliferative disorders. Not all affected dogs have a proven association to drugs. One of the more commonly administered drugs in Wells-like disease cases is metronidazole, however, cause and effect were not proven. GI disease generally resolves before the skin lesions. Skin lesions typically do not recur.

Histologically, the main features of canine Wells-like syndrome is an interstitial eosinophilic dermatitis with edema. However, the histologic presentation may vary depending on the length of time. In the acute stage of the disease, the dermis is edematous with eosinophilic infiltration. Later stages may have collagen flame figures (ranging from early to well-developed flame figures), characterized by degranulated eosinophils surrounding hypereosinophilic collagen fibers with a frayed appearance. With progression of the disease, numbers of macrophages may increase and sometimes there are multinucleated giant cells. The severity of acute inflammation was categorized in three groups by Cain et al. (JAVMA 2017). Pattern 1 has a very mild eosinophilic inflammation with or without intermixed neutrophils in the superficial dermis with vascular ectasia; pattern 2 had a more extensive inflammation that extended into the deeper dermis with few flame figures; pattern 3 had a severe and diffuse inflammation. Vascular lesions may be present (thrombi, intramural eosinophils, erythrocyte diapedesis or perivascular fibrin deposition), but these are considered to be secondary changes rather than a primary vasculitis.

CAEDE and neutrophilic sterile dermatosis (Sweet’s syndrome) have overlapping clinical and histological features in many cases. Generally, CAEDE is associated with an eosinophilic infiltration, whereas Sweet’s syndrome has a neutrophilic predominance. However, differentiation between the two diseases may be difficult. Clinically, CAEDE is more associated with GI signs, concurrent atopic dermatitis and pruritus and Sweet’s syndrome with immune-mediated polyarthropathy/lameness. It remains unclear if these two disease entities are separate diseases or if they represent various manifestations of the same disease (Bradley et al. Vet Dermatol. 2019)

A Luna stain (to highlight the granules of eosinophils) may be helpful if there is a difficulty to differentiate between eosinophils and neutrophils.

Histologically, canine eosinophilic granuloma may be difficult to distinguish from eosinophilic dermatitis and clinical differentiation may be necessary. Miniature schnauzers seem to be predisposed to Wells-like syndrome. A possible differential diagnosis in this breed is sterile pustular erythroderma of miniature schnauzers, which may have identical histologic features to both Wells-like syndrome and Sweet’s syndrome, depending on the percentage of eosinophils and neutrophils, respectively.

References:

1. Gross TL, et al. Canine eosinophilic dermatitis. In: Gross TL, Ihrke PJ, Walder EJ and Affolter VK. eds. Skin Diseases of the Dog and Cat, Clinical and Histopathologic diagnosis. 2nd ed. Blackwell Science, 2005:360-362.

2. Holm KS, et al. Eosinophilic dermatitis in nine dogs compared with eosinophilic cellulitis in humans. J Am Vet Med Assoc. 1999; 215: 649-653.

3. Mauldin EA et al. Comparison of clinical history and dermatologic findings in 29 dogs with severe eosinophilic dermatitis: a retrospective analysis. Vet Dermatol. 2006; 17: 338-347.

4. Mauldin EA et al. Canine acute eosinophilic dermatitis with edema (Wells-like syndrome). Vet Clin North Am Small Anim Pract. 2019; 49: 47-51.

5. Bradley CW et al. Discriminatory features of acute eosinophilic dermatitis with oedema (Wells-like syndrome) and sterile neutrophilic dermatosis (Sweet’slike syndrome) in dogs. Vet Dermatol. 2019; 30: 517-e157.

6. Cain et al. Clinical and histologic feature of acute-onset erythroderma in dogs with gastrointestinal disease: 18 cases (2005-2015). J Am Vet Med Assoc. 2017; 251: 1439-1449.

Acknowledgements

Many thanks to Dr. Alldredge, Babcock Hills Veterinary Hospital, San Antonio, Texas for the clinical pictures.

Contributor

Dominique Wiener, Clinical Assistant Professor, Department of Veterinary Pathobiology, Texas A&M University, Texas, USA