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Thymoma-associated exfoliative dermatitis was suspected in a cat with a cranial mediastinal mass. The dermatopathy resolved with surgical removal of a thymoma. The cat manifested neurologic signs consistent with myasthenia gravis 7 wk after surgery. Exfoliative dermatitis and post-thymectomy myasthenia gravis in the same cat has not been reported previously.
Dermatite exfoliative associée au thymome avec myasthénie post-thymectomie chez un chat. La dermatite exfoliative associée au thymome a été suspectée chez un chat avec une masse médiastinale crânienne. La dermatophathie s’est résorbée avec l’enlèvement chirurgical d’un thymome. Le chat a manifesté des signes neurologiques conformes à une myasthénie grave 7 semaines après la chirurgie. La dermatite exfoliative et une myasthénie grave suite à une thymectomie chez un même chat n’avait pas été signalée antérieurement.
(Traduit par Isabelle Vallières)
An 8-year-old, female spayed, domestic longhair cat was evaluated at the Ontario Veterinary College Teaching Hospital (OVCTH) for a cranial mediastinal mass suspected to be a thymoma. The cat was initially evaluated for generalized seborrhea. Multiple skin scrapings taken at that time did not reveal any abnormalities. Re-evaluation 14 d later revealed multifocal areas of epidermal erythema and exfoliation. Skin biopsies and histopathologic examination revealed marked parakeratotic hyperkeratosis with lymphocytic interface dermatitis. These findings were consistent with an autoimmune skin disease, most likely the result of an underlying thymoma (thymoma-associated feline exfoliative dermatitis). Thoracic radiographs demonstrated a mass in the cranial mediastinum causing caudal displacement of the cardiac silhouette and cranial lung lobes. There was no evidence of metastatic disease. The cat was tested for evidence of infection with feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV); the tests for both viruses were negative.
Upon initial evaluation at the OVCTH, vital parameters were normal. The cranial thorax was non-compressible. The skin lesions were unchanged from prior evaluation (Figures 1a and 1b). Thoracic auscultation revealed a grade III/VI rate dependant systolic heart murmur with point of maximal intensity along the left and right parasternal borders. Echocardiography did not reveal any structural abnormalities of the heart. The murmur was physiologic in origin and suspected to be a result of displacement by the mediastinal mass. Thoracic radiography was repeated (Figure 2) and the cranial mediastinal mass appeared to have grown. There was no evidence of megaesophagus or metastatic disease. Surgical exploration of the thoracic cavity with resection of the cranial mediastinal mass was recommended to the owners. In order to further characterize the origin of the mass, an ultrasound-guided fine-needle aspirate was performed. Cytological evaluation of the aspirate revealed abundant small lymphocytes and frequent clusters of epithelial cells consistent with sampling of the thymus. Based on the signalment, history, and clinical signs the cytological diagnosis was thymoma. A complete blood (cell) count (CBC) and serum biochemical profile in preparation for general anesthesia, were within reference limits. Results of coagulation tests (prothrombin time and partial thromboplastin time) were normal.
The following day, a median sternotomy was performed to allow for exploration of the thoracic cavity. An 8 cm × 6 cm mass was present in the cranial thorax that was well encapsulated (Figure 3). The mass was completely removed and hemostasis was achieved using a combination of electrocautery and vascular hemoclips. Prior to closure of the sternotomy, a thoracostomy tube was placed and exited through a separate incision on the lateral aspect of the thorax. A pain diffusion catheter (Mila diffusion/wound catheter, Mila International, Erlanger, Kentucky, USA) was applied over the closed sternotomy site to provide analgesia in the post-operative period. Remaining closure of the surgical site was routine. Post-operative radiographs revealed adequate apposition of the sternotomy site and complete removal of the mass. Histopathological evaluation confirmed that the mass was a thymoma.
The cat recovered without complication in the intensive care unit (ICU). Analgesia was provided via bupivicaine (Bupivicaine hydrochloride injectable USP; Hospira Healthcare Corporation, Montreal, Quebec), 1 to 2 mg/kg, q6h, through the pain diffusion catheter, systemic administration of meloxicam [Boehringer Ingelheim (Canada), Burlington, Ontario], 0.1 mg/kg, q24h, and a constant rate infusion of fentanyl (Fentanyl citrate injectable USP, Sabex, Boucherville, Quebec), 2 to 6 μg/kg/h. Minimal fluid and air were removed from the thoracostomy tube post-operatively. The thoracostomy tube and pain diffusion catheter were removed 36 h after surgery. The cat was discharged from hospital 48 h after surgery and deemed clinically normal.
The cat required post-operative re-evaluation after 7 wk for a 1-week history of progressive lethargy and anorexia. Upon presentation, the cat was non-ambulatory and quiet but alert. Vital parameters were normal. A CBC, serum biochemical profile, and total thyroxine evaluation did not reveal any abnormalities. Serum was submitted to the Comparative Neuromuscular Laboratory at the University of California, San Diego (UCSD) for measurement of anti-acetylcholine receptor (AchR) antibody titer. Thoracic radiographs were recommended but declined by the owner due to financial concerns. Neurological examination revealed bilateral, weak palpebral reflexes, generalized weakness, and hypotonia of both pelvic and thoracic limbs. Withdrawal reflexes were decreased in all limbs. The remainder of the neurological examination, including postural reactions, pain perception, and other spinal reflexes, was normal. These findings were consistent with a lesion located in the peripheral nervous system, likely involving the neuromuscular junction. Based on the cat’s prior history of thymoma, acquired myasthenia gravis (MG) was highly suspected. Empirical therapy with immunosuppressive doses of corticosteroids (prednisone 10 mg, q12h) was initiated. The cat’s clinical signs improved rapidly and within 48 h it was ambulating again. Confirmation of the diagnosis of acquired myasthenia gravis was provided 1 wk after initiating corticosteroid therapy. The cat’s anti-AchR antibody titer was 9.02 nmol/L; reference range: 0.0 to 0.3 nmol/L. The cat was re-evaluated at the OVCTH 9 wk after surgery. The physical examination was normal, and the prior dermatopathy had resolved (Figures 4a and 4b). According to the owner, the cat was still unable to jump to high surfaces. The only abnormality discovered during neurological examination was bilateral weak palpebral reflexes. Thoracic radiographs, however, did not reveal any abnormalities. Re-evaluation and repeat anti-AchR antibody titer were recommended in 4 wk with the potential of tapering the dose of corticosteroids. Unfortunately, due to financial concerns this could not be performed; however, 10 mo post-operative the cat was clinically normal according to her owners and is currently not receiving any medications.
Despite previous reports of thymoma-associated exfoliative dermatitis (1–6) and myasthenia gravis (7–10) in cats, this is, to the authors’ knowledge, the first report of confirmed exfoliative dermatitis and post-thymectomy myasthenia gravis (MG) in the same cat. Forster-Van Hijfte (5) suspected both paraneoplastic syndromes in the same cat; however, MG could not be confirmed.
Thymoma is a rare diagnosis in the dog and cat. The tumor arises from the epithelium of the thymus but is usually permeated with small, mature lymphocytes (11). This tumor is deemed benign or malignant based on its ability to be resected at the time of surgery and not from histopathologic evaluation (11). In general, metastatic disease is not a common sequela of feline or canine thymoma; however, it has been reported (11–13). Affected animals commonly present with clinical signs related to respiratory compromise as a result of the mediastinal mass. Thymoma has also been associated with a number of paraneoplastic syndromes including MG (8,13–16), autoimmune diseases such as granulocytopenia (17) and polymyositis (2,7), and feline exfoliative dermatitis(1,3–5,7). As many as 30% to 50% of human thymoma patients will experience a paraneoplastic syndrome, with the most common being MG (18). The cat of this report initially presented for a dermatopathy that was a result of a thymoma-associated paraneoplastic syndrome. Feline exfoliative dermatitis is a rare paraneoplastic syndrome that is characterized by diffuse, non-pruritic erythema and exfoliation. These lesions can progress and become widespread throughout the dermis (4). The exfoliation can lead to alopecia and eventual ulceration (4). Histological characteristics include a marked orthokeratotic hyperkeratosis with an interface dermatitis comprised of predominantly CD3+ lymphocytes (1). Exfoliative dermatitis has been described in humans as a paraneoplastic syndrome of lymphoma and leukemia, but not as a thymoma-associated paraneoplastic syndrome (19).
As is the case in humans, the pathophysiology of thymoma-associated exfoliative dermatitis in cats has yet to be completely determined. A number of theories have been hypothesized and are focused on the role of the normal thymus in the development of the immune system (1). Based on the interface dermatitis with permeation of CD3+ lymphocytes, an immune-mediated process directed by the tumor has been suspected. Interestingly, Rottenberg et al (1) performed immunofluorescence evaluation of skin biopsies in 5 cats with thymoma- associated exfoliative dermatitis and found that cross-reacting IgG antibodies were not present in the skin. This finding, along with the presence of CD3+ lymphocytes within the affected dermis, is suggestive of a T-cell-mediated response that may be initiated from the thymoma (1). In cats with thymoma-associated exfoliative dermatitis that survive surgery, as was the case with the cat described in this report, removal of the tumor resulted in improvement and eventual normalization of the dermatopathy. This suggests that the thymoma has a key role in causing the exfoliative dermatitis.
Myasthenia gravis is a rare disorder of the neuromuscular junction and results in progressive loss of muscle strength with activity (20). This condition is most commonly a result of an aberrant immune-mediated response; however, in rare circumstances can also be congenital (20). Antibodies are produced to the post-synaptic nicotinic AchR at the neuromuscular junction leading to the destruction of the receptor (20). This decreases the number of receptors available to bind acetylcholine, lowering the chances of muscle activation (20). A definitive diagnosis of MG can be made by measuring anti-AchR antibody titers. Clinical signs of cats affected by acquired MG include generalized weakness, lack of palpebral reflexes, cervical weakness, and rarely regurgitation as a result of megaesophagus (10). In approximately 25% of cases of feline acquired MG a cranial mediastinal mass is present (10). Thymoma-associated MG in a cat was first reported in 1989 (14). One year later, Scott-Moncrieff et al (8) reported another case of a cat with thymoma-associated MG. In this report, the cat’s clinical signs related to MG resolved after thymectomy (8). There are several other reports describing thymoma-associated MG in cats; however, there are only 2 previously reported cases where MG was first diagnosed post-thymectomy as occurred with the cat herein (7).
A paraneoplastic syndrome of the nervous system can occur when an immune response is mounted against a particular epitope that is shared by tumor cells and elements of the nervous system (18). In thymoma-associated myasthenia gravis, epitopes expressed on tumor cells are similar to portions of AchR and other muscle proteins (18). In normal thymic physiology, lymphocyte precursors develop into immature T-cells that are able to recognize a number of different antigens. During the maturation of T-cells, any potential for autoreactivity leads to their destruction. In thymoma, the maturing T-cells are exposed to neoplastic epithelial cells that express antigens that cross-react with AchR and other muscle proteins such as titin and ryanodine receptor (RyR) (18,21–23). Due to a faulty selection process these self-reactive T-cells are not destroyed and are allowed to propagate an immune-mediated response leading to MG (18,23). In humans, paraneoplastic MG is most commonly diagnosed prior to thymectomy; however, like the cat in this report, it has been reported post-thymectomy without pre-operative MG (24). Namba et al (24) reported the development of MG in a subset of human thymoma patients anywhere from 2 wk to 6 y post-thymectomy. It was speculated that self-reactive T-cells created within the thymoma have the potential to circulate for several years allowing for paraneoplastic MG to occur even after thymectomy (24).
There is a correlation between fluctuations in anti-AchR antibody titers and the clinical course of disease (22). Human MG patients with thymoma have antibodies that react with muscle proteins titin and RyR in addition to AchR. Titin is involved in muscle gene activation after mechanical strain, whereas RyR is the calcium channel allowing for Ca2+ release and eventual muscle contraction (18). In humans, thymoma-associated MG is considered a more serious disease with a worse prognosis in comparison to non-thymoma MG (18,21,23). A recent study in humans has shown that patients with antibodies against titin and RyR have a more aggressive form of MG (25). This correlation has also been shown in canine MG patients that exhibited a more severe form of the disease (22). Furthermore, by examining the immunological profile of an MG patient, the clinical course of disease may be predicted. Currently, there is no literature examining the association between RyR and titin antibodies in feline MG patients and severity of disease. However, a hallmark clinical sign of human MG patients that have RyR antibodies is cervical weakness, which is also a common finding in cats with MG (8,18).
The cat herein suffered from 2 separate paraneoplastic diseases that have been reported to occur with thymoma; however, not in the same animal. Paraneoplastic syndromes can alert the clinician about underlying neoplasia or demonstrate recurrence. Thymoma-associated exfoliative dermatitis in the cat described in this report resolved approximately 7 wk post-thymectomy. The development of post-thymectomy MG may have been predicted by performing anti-AchR antibody titers in the pre-operative period.
The authors wish to acknowledge the late Dr. David L. Holmberg for his contribution to their surgical training. CVJ
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