Diagnosis of Erythema Multiforme Associated with Thymoma in a Dog and Treated with Thymectomy
A 7 yr old Labrador retriever initially presented for severe halitosis, mild ptylism, and depigmentation of the nasal planum. Erythema multiforme was diagnosed based on clinical signs and dermatopathology. Treatment was initiated but the condition did not resolve. Six months later, the dog was diagnosed with a mediastinal mass. Trucut biopsy was performed and histopathologic diagnosis was consistent with a thymoma. A median sternotomy was performed, the thymoma was excised, and the dog recovered well. Four months postoperatively, there were no longer any obvious erythema multiforme lesions and the skin condition was controlled without medication. Erythema multiforme may be a paraneoplastic disorder associated with thymoma in the dog, similar to thymoma-associated exfoliative dermatitis in the cat. Clinical signs of erythema multiforme may warrant performing thoracic radiographs or thoracic CT to rule out thymoma as an underlying cause.
Introduction
A 7 yr old neutered male Labrador retriever presented for severe halitosis and mild ptylism. On physical examination, he had hyperemic buccal mucosa and gingiva. Depigmentation of the nasal planum was also noted. The dog was prescribed cephalexina (22 mg/kg per os [PO] q 12 hr) for 7 days. The dog was re-examined 1 wk later and the halitosis was only mildly improved. A CBC and serum chemistry were within normal limits. A dental examination revealed only mild tartar. A dental prophylaxis was performed. There was no cause found to explain the degree of odor and erythema of the gingiva. While under general anesthesia, a biopsy of the patient's nasal planum was also preformed. Histopathologic evaluation revealed individual keratinocyte necrosis and hydropic degeneration of the basal layer of the epidermis and interface. These findings were consistent with erythema multiforme.
Cephalexina (22 mg/kg PO q 12 hr) was prescribed for an additional 7 days and prednisoneb was initiated (0.5 mg/kg PO q 24 hr for 2 wk, 0.25 mg/kg PO q 24 hr for 2 wk, then 0.125 mg/kg PO q 24 hr for 2 wk). The patient was re-evaluated 2 mo later. The halitosis and nasal planum were improved; however, new skin lesions had developed. The patient's preputial and peripreputial region had multifocal hyperpigmented macules and papules with erythema and dry silvery scales ranging from 0.5 cm to 2 cm in diameter and areas of depigmentation in a serpiginous pattern with areas of erythema and ulcerative dermatitis (Figure 1). In addition, there were erythematous erosive and ulcerated lesions present on the pinnae. The prednisone was increased to 0.5 mg/kg PO q 24 hr for an additional 7 days and pentoxifyllinec administration was initiated (10 mg/kg PO q 8 hr).
Citation: Journal of the American Animal Hospital Association 47, 2; 10.5326/JAAHA-MS-5561
One week later, a physical exam revealed an erythematous muzzle, moist erythematous raised papules at the dorsal right side of the neck, and multiple erythematous, raised, pigmented lesions on the ventral abdomen measuring 0.5 cm to 1 cm in diameter. The preputial and peripreputial regions were unchanged from the previous exam. Tachyphylaxis to the prednisolone was suspected and methylprednisoloned was initiated (0.5 mg/kg PO q 24 hr) for 10 days. Ciprofloxacine was also initiated (15 mg/kg PO q 24 hr) for 14 days and pentoxifylline was continued at 10 mg/kg PO q 8 hr.
Ten days later, there was marked dry scaling along the dorsum and sides (seborrhea sicca). Some of the lesions in the peripreputial and preputial areas were resolving with occasional new lesions of erythematous papular dermatitis with crusting, mild scaling, macules, and macular-papular lesions with hyperkeratosis and crusting on the abdomen and peripreputial region (Figure 2). The methylprednisolone was again prescribed (0.3 mg/kg PO q 12 hr for 30 days). In addition, an egg and rice dietf and a commercial preparation of eicosapentaenoic acidg (EPA, 23 mg/kg PO q 12 hr) and docosahexaenoic acid (DHA, 16 mg/kg PO q 12 hr) were prescribed. A topical 0.015% triamcinolone acetonide sprayh was also prescribed to be applied to the abdomen q 12 hr for 1 mo.
Citation: Journal of the American Animal Hospital Association 47, 2; 10.5326/JAAHA-MS-5561
One month later, the skin of the abdomen and nasal planum was mildly improved. There were occasional dry crusts with partial hair regrowth. The methylprednisolone was decreased to 0.2 mg/kg PO q 24 hr for 21 days. Cyclosporinei was added at 5 mg/kg PO q 24 hr for 28 days. The pentoxifylline, 0.015% triamcinolone acetonide spray, egg and rice diet, and EPA/DHA were also continued as previously prescribed.
Three weeks later, a moderate amount of erythema was noted at the thoracic inlet, and some newly formed circular raised erythematous target-like lesions with occasional pustular lesions were noted on the abdomen and preputial region. The patient was bright, alert, and responsive and had only minimal halitosis. Both pinnae were violaceous and the skin appeared to be peeling. The remainder of the physical exam was within normal limits. Topical 0.1% tacrolimusj was prescribed and applied by the owner to lesions of the abdomen, prepuce, and peripreputial region q 12 hr for 14 days. In addition, tetracyclinek (1,000 mg PO q 8 hr) and niacinamidel (500 mg PO q 8 hr) were prescribed. The cyclosporine, egg and rice diet, and EPA/DHA were continued. The triamcinolone acetonide spray, the pentoxifylline, and methylprednisolone were discontinued. Dexamethasonem was initiated (0.1 mg/kg PO q 24 hr for 5days, 0.05 mg/kg PO q 24 hr for 5 days, then 0.05 mg/kg PO q 48 hr for 5 doses).
Approximately 3 wk later, the owner reported that the patient had been anorexic for 3 days. On physical exam, the patient was quiet, alert, and responsive with a mildly increased respiratory effort. The skin lesions remained largely unchanged since the time of the last examination, but three additional small, dark erythematous lesions on the lateral thorax and abdomen were noted. Muffled heart sounds were evident bilaterally on auscultation. A CBC was within normal limits. Serum biochemical abnormalities included hypercalcemia (14 mg/dL; reference range, 9.6–11.6 mg/dL) and elevated ALP (1,652 U/L; reference range, 3–60 U/L) and ALT (169 U/L; reference range, 4–91 U/L) levels. Ionized calcium was also elevated (1.64 mmol /L; reference range, 1.25–1.50 mmol /L).
Survey thoracic radiographs (Figures 3 and 4) revealed a soft tissue opaque thoracic mass extending from the cranial mediastinal region caudoventrally to the level of the diaphragm. The ventral lung margins had a scalloped appearance and the trachea and cardiac silhouette were dorsally displaced. The mediastinal mass silhouetted with the cardiac shadow on the ventrodorsal view. No evidence of megaesophagus was noted.
Citation: Journal of the American Animal Hospital Association 47, 2; 10.5326/JAAHA-MS-5561
Citation: Journal of the American Animal Hospital Association 47, 2; 10.5326/JAAHA-MS-5561
The next day, the dog was referred to a cardiologist and an echocardiogram was performed. Systolic function was normal but a large mass cranial to the heart measuring greater than 8 cm × 5 cm was noted. An ultrasound-guided fine-needle aspirate of the mass was performed. Cytology of the fine-needle aspirate revealed 80% small lymphocytes, some average lymphocytes, and occasional epithelioid cells. The sample was consistent with, but not diagnostic for, thymoma. The following day, the cardiologist performed an ultrasound-guided Trucut biopsy of the thoracic mass. Two samples were obtained and submitted for histopathological analysis. Histologic findings were consistent with a mixed lymphocytic-epithelial thymoma.
A CT scan of the thorax performed 9 days after the radiographic series were obtained (approximately 6 mo after initial presentation) demonstrated a nonuniformly contrast enhancing soft tissue density 10 cm × 12 cm × 20 cm with numerous internal low density cyst-like lesions measuring 2 mm to 16 mm (Figures 5 and 6). The mass was located in the mediastinum to the left of midline and extended from the thoracic inlet on the left side of the diaphragm caudally to the eighth rib, displacing, but not surrounding, the lung and vital mediastinal structures dorsally or to the right. There was no evidence of pulmonary metastatic disease. Mildly enlarged lymph nodes were visible in the cranial ventral mediastinum at the cranial edge of the mass. Surgery to remove the thymoma was recommended as the treatment of choice and the owners agreed.
Citation: Journal of the American Animal Hospital Association 47, 2; 10.5326/JAAHA-MS-5561
Citation: Journal of the American Animal Hospital Association 47, 2; 10.5326/JAAHA-MS-5561
The dog was premedicated with intramuscular (IM) hydromorphonen (0.1 mg/kg) and glycopyrrolateo (0.01 mg/kg IM). Anesthesia was induced with a slow IV infusion of lidocaine (2 mg/kg) and hydromorphone (0.1 mg/kg) followed by diazepamp (0.02 mg/kg IV). An endotracheal tube was placed and anesthesia was maintained with isofluraneq and 100% oxygen. Positive-pressure ventilation was provided for the duration of the anesthesia. Via a median sternotomy, a 20 cm multilobulated mass was located in the mediastinum and excised (Figure 7). Associated vasculature was ligated with 2–0 polydioxanone suture (PDS)r. A local lymph node was also resected and the thorax was flushed with sterile saline. A thoracostomy tubes was placed and secured with a Chinese finger trap pattern using 2–0 PDS. The sternabrae were reapposed with 20 gauge cerclage wiret. The deep musculature was closed with 0 PDS in a simple continuous pattern, the deep fascia was closed with 0 PDS in a simple continuous pattern, and the skin was closed with 2–0 monocrylu in a subcuticular pattern. The excised mass and associated lymph node were submitted for histopathology. Microscopic findings revealed a lymphocytic thymoma and a moderate chronic proliferative lymphadenomegaly. There was no evidence of metastatic neoplasia.
Citation: Journal of the American Animal Hospital Association 47, 2; 10.5326/JAAHA-MS-5561
The patient recovered uneventfully from surgery. Tetracyclinej (1,000 mg PO q 8 hr) and niacinamidek (500 mg PO q 8 hr) for 3 mo were the only medications continued for management of the erythema multiforme. Three months postoperatively, thoracic radiographs were normal and serum calcium was within normal limits. The tetracycline and niacinamide were discontinued and the patient was examined weekly. The skin improved considerably and by 4 mo postoperatively, the patient was doing well with no obvious erythema multiforme lesions, and the fur was growing back. (Figure 8).
Citation: Journal of the American Animal Hospital Association 47, 2; 10.5326/JAAHA-MS-5561
Discussion
Erythema multiforme is an uncommon dermatological disease of dogs and cats presumed to be a host specific cell-mediated hypersensitivity against antigens associated with keratinocytes.1–3 Keratinocytes are altered via antigens, and T-cell lymphocytes bind to the altered keratinocytes triggering apoptosis.1,3,4 Erythema multiforme commonly manifests itself as an acute dermatitis with erythematous skin of different forms including: a maculopapular form consisting of papules and macules; a vesiculobullous form consisting of vesicles/bulla that lead to ulcers; an urticarial form consisting of nonpitting urticara; or a combination of these forms (hence the name multiforme). Crusting occurs later in the course of the disease.3 Lesions commonly spread peripherally and clear centrally, creating a target-like appearance. Alternatively, the lesions may merge together to create arciform or serpiginous patterns.1–3,5 In dogs, lesions may be seen anywhere on the skin; however, the most commonly affected areas include the axillae, inguinal area, mucocutaneous junctions, oral cavity, pinnae, and footpads.1,3,6
Differential diagnoses for exfoliative dermatitis include dermatophytosis, feline thymoma-associated dermatitis, graft-versus-host disease, Malassezia dermatitis, ectoparasitosis, epitheliotropic T-cell lymphoma, exfoliative Staphylococcus dermatitis, sebaceous adenitis, pemphigus foliaceus, erythema multiforme, systemic lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis.3 Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis represent different severities of the same condition. Erythema multiforme affects <50% of the body surface with epidermal separation involving <10% of the body surface area. In contrast, Stevens-Johnson syndrome affects >50% of the skin surface with epidermal separation involving <10% of body surface, and toxic epidermal necrolysis affects >50% of the body surface with epidermal detachment involving >30% of body surface area.7
Diagnosis of erythema multiforme is made by clinical manifestation along with histopathological conformation via biopsy.1 Most cases of erythema multiforme are believed to have an underlying etiology, and treatment involves the elimination of the associated triggering cause along with supportive care.1 Trigger factors include medications (i.e., penicillins, cephalosporins, sulfonamides, phenobarbital, L-thyroxine), adverse food reaction, infection (i.e., Staphylococcus dermatitis, otitis externa due to Pseudomonas spp., necrotizing parvoviral enteritis), or internal disease (i.e., splenic sarcoma).1–3,6,8,9
If the underlying cause is not identified, treatment consists of immunosuppressive therapy including glucocorticoids and either cyclosporine or azathioprine.1,2 Pentoxifylline increases erythrocyte flexibility and is used in immune-mediated skin diseases because it is believed to improve microcirculation and decrease the negative effects of endotoxemia.2,10 Pentoxifylline also has immunomodulatory effects such as inhibiting phosphodiester, increasing cyclic adenosine monophosphate, decreasing the production of interleukins, and inhibiting adherence of T cells to keratinocytes.11 Tetracycline suppresses lymphocyte blastogenesis, suppresses antibody production, inhibits WBC chemotaxis, inhibits prostaglandin synthesis, and inhibits lipases and collagenases. Niacinamide, a vitamin B derivative, inhibits mast cell degradation, blocks antigen immunoglobulin E-induced histamine release, inhibits phosphodiesterase, and decreases protease release. Tetracycline and niacinamide used in combination have been shown useful in the treatment of autoimmune skin diseases.12
Neoplasia causing paraneoplastic erythema multiforme in humans is rare.3 Erythema multiforme has previously been described in conjunction with a neoplasm in one dog.8 The patient, diagnosed with splenic sarcoma, had evidence of both pemphigus vulgaris and erythema multiforme. The skin lesions were identified in association with the splenic neoplasia.8 The authors of the present case report are unaware of a confirmed erythema multiforme case in conjunction with thymoma in the dog as reported herein.
Thymoma is an uncommon neoplasm of thymic epithelial cells. When it does occur, thymomas are most commonly diagnosed in older animals.13–16 Thymomas, found in the anterior mediastinum, may be either noninvasive or invasive and rarely metastasize.15,17–20 Clinical signs may include dyspnea, coughing, decreased lung sounds over the anterior mediastinum, decreased compressibility of the chest, and/or signs of precaval syndrome (i.e., pitting edema of the head, neck, or front legs, enlarged jugular veins).13,15 Paraneoplastic syndromes associated with thymomas include myasthenia gravis, polymyositis, nonthymic cancer, hypercalcemia, and/or thymoma-associated exfoliative dermatitis.14,21–23
Diagnosis of an anterior mediastinal mass may be achieved with thoracic radiographs, ultrasound, and/or advanced imaging such as CT or MRI.13,18,24 Differential diagnoses of an anterior mediastinal mass include neoplasia (i.e., mediastinal lymphoma, thymoma, chemodectoma, ectopic thyroid carcinoma, primary lung tumor, metastatic neoplasia), a granulomatous mass secondary to infection, inflammation arising from the cranial mediastinum or pleural space, hematoma, cyst, or abscess. Cytology via needle aspirate of a mediastinal mass is sometimes inconclusive. The two most common mediastinal masses are mediastinal lymphoma and thymoma. Cytology of both masses can yield small lymphocytes.25 Distinguishing between the two neoplasms is achieved by either biopsy or flow cytometry.21,25 Ultrasound-guided needle biopsy is helpful in obtaining a tissue sample for biopsy. Histopathologic examination of the biopsy sample determines the tumor type.24 Contrast-enhanced CT scan is helpful in determining the invasiveness of the tumor.24 Further, if myasthenia gravis is present, megaesophagus may be observed.13
Treatment of thymoma involves surgery, radiation, or both. If the mass is resectable, the treatment of choice is a thoracotomy with surgical excision of the mass.13,14,18,24 If the mass is invasive and nonresectable, radiation therapy is indicated with or without surgical debulking.19 Dogs that have thymoma without megaesophagus have 1 yr survival rate of 83%.21 Prognosis becomes less favorable if the tumor cannot be removed completely or if megaesophagus is present.14,19,21,23
Thymoma-associated exfoliative dermatitis is a well-described paraneoplastic syndrome in cats and has also been described in one rabbit.3,26–29 The association of thymoma with exfoliative dermatitis was identified when the clinical resolution of the skin disease occurred after the surgical removal of the thymoma in the cats.29,30 The pathogenesis of thymoma exfoliative dermatitis remains unknown; however, one hypothesis is that the skin becomes affected through an immune-mediated mechanism associated with neoplastic thymic epithelial cells creating abnormal antigen presentation in the skin.3,29 This is similar to the pathogenic mechanism of both graft-versus-host disease and erythema multiforme involving the attack of cytotoxic T-cells on keratinocytes.4
Thymoma-associated exfoliative dermatitis is, for the most part, histologically identical to erythema multiforme. Both diseases are characterized histologically as cell-poor interface dermatites with lymphocyte satellitosis and apoptotic keratinocytes.1,3,29 Differentiating between the two diseases is based on the presence or absence of a thymoma.3
Conclusion
This case involves erythema multiforme as a paraneoplastic disorder associated with thymoma in the dog. The case is similar to thymoma-associated exfoliative dermatitis in the cat. Following surgical removal of the thymoma, all signs of the erythema multiforme resolved. The presence of erythema multiforme warrants taking a thorough history and performing a complete physical examination and minimum database. Any possible triggering factors should be eliminated and, if none are identified, imaging of the thorax is indicated to rule out thymoma as an underlying etiology.
Erythematous plaque-like region with areas of erosion and multifocal hyperpigmented macules and papules with dry silvery scales were noted on the patient's preputial and peripreputial region. There were areas of depigmentation in a serpiginous pattern and several similar satellite regions. M, macules; P, papules; S, scaling; U, ulceration.
Multiple circular lesions with hyperkeratosis and crusting were noted on the patient's abdomen. C, crusting; M-P, macules-papules.
Lateral radiograph of the patient's thorax identified a soft tissue opaque thoracic mass extending from the cranial mediastinal region caudoventrally to the level of the diaphragm.
Ventrodorsal radiograph of the patient's thorax showing the mediastinal mass silhouetted with the cardiac shadow.
A reformatted CT image in the dorsal plane demonstrating the mediastinal mass extending throughout the ventral mediastinum displacing the heart to the left.
Axial postcontrast CT image demonstrating the mass within the cranial mediastinum ventral to the great vessels and vital structures of the mediastinum, displacing, but not surrounding, these structures. CV, cranial vena cava; T, trachea.
A large multilobulated mass from the mediastinum was surgically excised via a median sternotomy with the dog in dorsal recumbency.
The patient's preputial and peripreputial region 4 mo postoperatively. The skin had improved dramatically, there was no longer any obvious evidence of erythema multiforme, and the fur appeared to be growing back.
Contributor Notes
