Sinonasal tumor in 3 dogs after successful topical treatment for frontal sinus aspergillosis

Abstract

Three dogs diagnosed with aspergillosis developed sinonasal tumors several months after successful treatment with topical clotrimazole solution. Chronic rhinosinusitis was also detected in all cases prior to diagnosis of sinonasal tumors. The inflammatory response to Aspergillus, clotrimazole treatment, and chronic inflammation after treatment are discussed as possible neoplastic promoting factors.

Tree dogs referred with chronic nasal discharge and nasal planum alterations were diagnosed with sinonasal aspergillosis on the basis of radiological assessment and endoscopic detection of fungal plaques. All 3 dogs were successfully treated with 1 h of infusion of a 1% solution of clotrimazole and underwent clinical and endoscopic examination within 3 mo after treatment. Clinical and endoscopic signs of chronic rhinosinusitis were observed in the 3 dogs prior to diagnosis of sinonasal tumors at 13, 22, and 30 mo after treatment for aspergillosis.

Case descriptions

Case 1

A 7-year-old female German shepherd was referred because of a purulent-hemorrhagic discharge from the left nasal passage of 3 mo duration and a serous discharge from the right nasal passage of 15 d duration. Additional clinical signs were reverse sneezing, snoring, discomfort opening the mouth and chewing, decreased appetite, hyperkeratosis with crusts of the rhinarium, and discoloration of the left nostril extending to the left upper lip. Radiology on the open mouth ventro-dorsal view (OM-VD) showed rostrally an increased radiolucency and caudally a patchy pattern in the left nasal cavity. The rostrocaudal view of the frontal sinuses (skyline) revealed a nonhomogeneous opacification of the left frontal sinus. The right sinonasal cavities were unremarkable.

Flexible anterograde rhinoscopy (FAR) showed that the right nasal cavity had a mucous exudate, whereas the left nasal cavity had an abundant muco-purulent blood-tinged exudate, turbinate coarctation, a small perforation of the nasal septum and easy access to the frontal sinus which was filled with fungal plaques.

Left sinus aspergillosis was diagnosed and the dog was treated with topical clotrimazole (Fluka polyethylene glycol 200; Sigma-Aldrich Chemie GmbH, Riedstr.2, Steinheim, Germany). The dog was placed in sternal recumbency, the rhinopharynx packed with gauze, and meticulous debridement of the fungal plaques was performed. Subsequently, the dog was placed in dorsal recumbency and a catheter (8 French) was endoscopically placed in the unaffected cavity, whilst a flexible endoscope was placed in the infected sinus. After packing the nostrils with gauze, 40 mL of the clotrimazole solution was administered through the endoscopically placed catheter and 60 mL through the working channel of the flexible endoscope. The dog was kept in dorsal recumbency for 30 min and afterwards the head was tilted 30° to the left and to the right for 15 min in each direction. After 1 h, the head of the dog was pulled towards the floor, the gauze was removed, the solution was allowed to drain and the rhinopharynx was flushed with saline solution.

At the subsequent examination 54 d later, the owner reported persistence of occasional sneezing and left nasal muco-purulent discharge; incomplete resolution of the discoloration of the nasal planum was detected on physical examination. Flexible anterograde rhinoscopy under general anesthesia revealed mild mucous exudate, nasal septum perforation, severe remodeling of the turbinates, and persistence of fungal plaques in the left frontal sinus. A 2nd lavage with clotrimazole was performed. The dog was discharged without any medication and endoscopic examination was planned within 2 mo. Seventy days after the 2nd treatment, the left nasal mucous discharge was still present and the dog underwent a 3rd FAR which revealed the presence of a mild mucous exudate, perforation of the nasal septum, extensive remodeling of the turbinates, but this time, an absence of fungal plaques. Severe chronic rhinosinusitis was diagnosed based on the endoscopic findings.

On follow-up by telephone, the owner reported persistence of sneezing and occasional mucous discharge. Thirteen months after the first topical treatment, the dog was referred again because of bilateral mucopurulent-hemorrhagic discharge that was more severe on the right side, occasional frank epistaxis, reverse sneezing and sneezing. Radiography of the sinonasal cavities under general anesthesia showed on the skyline view complete opacification of the left frontal cavity and a “moth-eaten” pattern of the left frontal bone. On the contralateral side, lysis of the frontal bone with mild periostial reaction and nonhomogeneous radiodensity of the frontal cavity was seen.

Flexible anterograde rhinoscopy detected abundant mucous exudate and multiple mucosal blebs in the left nasal cavity and easy access to both frontal sinuses, where a cerebroid-like tissue was found in the left frontal sinus extending to the contralateral frontal cavity. Cytology of brush samples was highly suggestive of epithelial neoplasia. Upon surgical biopsy of the sinusal lesion, a histopathological diagnosis of squamous cell carcinoma (SCC) was made. The tumor was classified as T2, N0, M0 [stage 2 of the modified classification of Théon et al (1)] because of the presence of a bilateral frontal sinus tumor with frontal bone erosion. There was no evidence of regional lymph node involvement or distant metastasis. The owner declined any further therapy and the dog was euthanized 3 mo later because of progression of the neoplastic disease.

Case 2

A 3-year-old male Rottweiler was referred because of right muco-hemorrhagic nasal discharge of 3 mo duration. Other clinical signs were occasional sneezing, reverse sneezing, hyper-keratosis, and crust on the right side of the rhinarium. After radiological (OM-VD and skyline views) and rhinoscopic examination, right sinus aspergillosis was diagnosed and the dog was treated with topical clotrimazole as described in Case 1.

Fungal plaques were not observed on endoscopic examination 30 d after treatment and the dog was treated with empirical antibiotic therapy consisting of amoxicillin and clavulanic acid (Synulox; Pfizer, Via del Commercio-Zona Industriale, Marino del Tronto, Marche, Italy) 20 mg/kg PO, BID for 10 d because of recurrence of right mucous discharge and occasional sneezing followed by moderate epistaxis. The signs of rhinitis detected on FAR were confirmed by brush cytology which was negative for hyphae and consistent with nonspecific rhinitis.

On follow-up by telephone, the owner reported persistence of moderate right sero-mucous discharge and occasional sneezing after the antibiotic therapy. The dog underwent a 2nd FAR examination 113 d after the initial diagnosis because of sudden onset of paroxysmal sneezing and hemorrhagic discharge. Severe chronic rhinosinusitis was diagnosed based on the endoscopic findings. Culture of a nasal swab yielded Klebsiella pneumoniae that was susceptible only to amikacin. Amikacin (Amikavet; Merial, Chignolo Po, Lombardia, Italy) 8 mg/kg SC, TID was prescribed for 7 d and, after kidney function assessment, for 7 additional days. At follow-up, the owner reported partial remission of the clinical signs.

Twenty-two months after the clotrimazole infusion, the dog was presented with right epistaxis of 1 mo duration and snoring. Right frontal tumor was suspected from the results of computed tomography (CT) and FAR. Computed tomography of the sinonasal cavities showed complete hyperdensity with signs of mineralization in the right frontal cavity. Brush samples and multiple pinch biopsies were obtained and were both suggestive of spindle cell neoplasia probably originating from bone tissue. Based on CT features of the nasal cavity and radiologic findings of 3 chest projections, the tumor was classified as T2, M0, N0 because of the presence of sinusal tumor with bone erosion. There was no evidence of regional lymph node involvement or distant metastasis.

The owner accepted only palliative surgical debulking and the 2nd histopathology after surgical debulking diagnosed a nonproductive osteosarcoma. The dog was euthanized 20 mo after surgery because of recurrence of the sinus tumor.

Case 3

A 6-year-old male German shepherd was referred because of left sero-mucous nasal discharge of 30 d duration, stertorous breathing of 40 d duration, paroxysmal sneezing and pawing at the nose. Physical examination revealed discoloration of the right nostril, profuse nasal discharge, and nasal pain.

Following radiological (OM-VD and skyline views) and endoscopic examination, left sinus aspergillosis was diagnosed and the dog was treated with topical clotrimazole as described in Case 1. After 60 d clinical signs ceased and the dog was considered cured based on endoscopic examination. After 20 mo, the dog was presented because of recurrence of clinical signs characterized by left serous discharge over the last 2 mo, pawing at the nose and paroxysmal sneezing. Radiographs of the skull were similar to those seen on initial radiographs. Absence of fungal plaques and signs of moderate chronic rhinosinusitis were detected on FAR (Figure 1). Punch biopsies were collected and the histopathologic diagnosis was severe chronic active rhinitis, characterized by irregular epithelial hyperplasia, focal mucosal erosions, and infiltration of inflammatory cells, mainly lymphocytes. The dog was treated with carprofen (Rimadyl; Pfizer) 2 mg/kg PO, BID for 7 d and empirical antibiotic therapy consisting of enrofloxacin (Baytril; Bayer, Via Delle Industrie, Filago, Italy) 5 mg/kg PO, SID for 10 d. On follow-up, the owner reported almost complete resolution of the clinical signs. Thirty months after clotrimazole treatment, the dog was presented because of left sero-hemorrhagic nasal discharge, epistaxis, left ocular discharge, pawing at the nose, sneezing and snoring of 1 mo duration.

Figure 1.

Presence of blood, edema of the mucosa and mucosal blebs at the opening of the left frontal sinus.

A left nasal tumor was suspected based on CT and endoscopic findings (Figure 2). From the CT features of the nasal cavity and thorax, the tumor was classified as T2, N0, M0 because of the presence of a nasal tumor with bone erosion. There was no evidence of regional lymph node involvement or distant metastasis. The owner agreed to a polychemotherapy protocol with doxorubicin, carboplatin, and piroxicam as suggested by Langova (2). The dog was euthanized 180 d after initiation of chemotherapy because of progression of the tumor characterized by orbital swelling, third eyelid prolapse, anteropulsion movements, depression, and severe epistaxis.

Figure 2.

Endoscopic findings at 30 months post treatment (case 3): presence of a whitish vascularized new growth of tissue occluding the left nasal cavity. cavity.

Discussion

This report describes 2 cases of sinus neoplasia and 1 case of nasal tumor which occurred in 3 dogs previously treated for sinus aspergillosis with infusion of a clotrimazole solution. A possible link between clotrimazole treatment, Aspergillus fumigatus toxins, chronic inflammation, and tumor development is also discussed.

Aspergillosis infection and nasal neoplasia are the 2 most common diagnoses in dogs referred with signs of chronic rhino-sinusitis (3–6). Dolichocephalic and mesocephalic large breeds dogs are most commonly affected (3–5,7,8). Sinonasal tumors are diagnosed in 33% of middle- to old-aged dogs (5,7,9), while aspergillosis is diagnosed in 12% to 34% of young to middle-aged dogs (3,4,8–10). Several systemic and topical antimycotic agents have been evaluated for treatment of canine sinonasal aspergillosis (3,4,6,10). Different techniques for the administration of clotrimazole solution or enilconazole emulsion have been successfully used for the treatment of sinonasal aspergillosis (3,4,6,8,10,11).

Diagnosis of nasal aspergillosis and nasal tumor should be based on history and physical examination, imaging, endoscopy, and histopathological examination (3–6,7,9,10). Most frequent clinical signs in dogs affected by sinonasal aspergillosis and sinonasal tumor are nasal discharge, epistaxis, reverse sneezing, and sneezing (5,7,9,10). However, profuse purulent-hemorrhagic discharge, nasal planum alterations such as discoloration of the nostrils, crusts, erosion, ulcers and hyperkeratosis, and nasal pain are considered landmarks of nasal aspergillosis (3,4,6,10). Conversely, these clinical signs in the presence of decreased air passage through the nostril and snoring but absence of nasal planum alteration are more suggestive of nasal tumor (5,7,9).

In these 3 cases, sinonasal aspergillosis was suspected on the basis of history and clinical signs and radiological findings (3,12,13) and was confirmed by endoscopic detection of fungal masses. Afterwards, the presence of nasal discharge, epistaxis, respiratory noises without nasal planum alterations at 13 to 30 mo after aspergillosis had been diagnosed were highly suggestive of neoplasia (5,7,9).

Sinonasal tumors are considered a rare oncologic condition in the dog (1,5,7), and the authors are unaware of previous cases of sinus or nasal tumors in dogs after sinonasal aspergillosis treatment. We have, therefore, used human and veterinary literature to explore whether inflammation induced by Aspergillus, treatment with clotrimazole, or the chronic inflammation after treatment could have caused tumor development in these 3 cases. Clotrimazole is a thiazole derivate which inhibits fungal cytochrome P-450 synthesis of ergosterol and decreases fungal cell wall integrity (14). Clotrimazole is reported by the Food and Drug Administration to have no carcinogenic or mutagenic properties (15); furthermore, it has been recently investigated for its anti-tumor activity and has been reported as one of the most promising antitumor agents (16,17). Polyethylene glycol, a polyether used as vehicle, is reported to have low toxicity but no carcinogenic or mutagenic properties (18), and has been experimentally used for cancer treatment (19).

Aspergillus spp. are able to produce toxins that are potentially mutagenic and carcinogenic (20); however, these toxins are generally found in food storage and are not produced by Aspergillus fumigatus (20). Only a few of the toxins produced by Aspergillus fumigatus and their mechanisms of action are known, but these are not recognized to be carcinogenic or mutagenic (21–23). An association between chronic inflammation and tumor development has been well-established and recognized in human medicine (24–28). Moreover, epidemiological and genetic studies have demonstrated that chronic inflammation can lead to tumor growth, and more recent studies have shown that liberation of the endogenous factors of inflammation can stimulate tumor development, but the factors that promote neoplasia have not been identified (24).

Many veterinary publications have reported delayed development of neoplasia, such as osteosarcoma, at the site of previous orthopedic surgery; in these cases, the abnormal cellular activity due to chronic local inflammation, the repair and regenerative processes have been considered the likely possible causes (29–31). Moreover, late occurrence of bone sarcoma has been reported in 2 dogs treated with radiotherapy for cutaneous mastocytoma, at the site of previous irradiation. The local chronic inflammation of the irradiated site was considered the underlying cause of tumor growth (32).

In veterinary medicine, the main long-term complications reported after medical or surgical treatment of aspergillosis are chronic rhinosinusitis, characterized by occasional sneezing with or without persistence of mild to severe nasal discharge and, less frequently, recurrence of the disease (4,8,10,11). To our knowledge, an association between chronic rhinosinusitis and sinonasal cancer has not been described in veterinary medicine; however, a retrospective study in humans has recently shown that nasal and paranasal cancers are linked to chronic sinonasal inflammation (33).

The 3 dogs described herein showed both clinical and endoscopic signs of chronic rhinosinusitis after successful treatment of aspergillosis (4,8,11). However it was only in Case 3 that chronic inflammation was confirmed by histology. In Case 2, the presence of chronic inflammation was detected using brush cytology and the bacterial rhinitis, secondary to the destruction of the nasal anatomy by the fungal infection, was confirmed by microbiology sampling. In Case 1, neither histologic nor microbiologic investigations were performed to confirm chronic rhinosinusitis. The presence of chronic rhinosinusitis in dogs successfully treated for aspergillosis has been diagnosed by relying on the persistence of clinical signs (4) and/or endoscopic findings consistent with inflammation (8,11).

Although the correlation between chronic sinonasal inflammation and subsequent sinonasal tumor development has been reported in humans (25), a similar correlation could only be speculated in these 3 cases. It was not possible to establish exactly what the most likely inciting factor for tumor development was. After reviewing human and veterinary literature; however, there is a good possibility that chronic inflammation, whether as an inflammatory response to Aspergillus or to clotrimazole treatment, or as chronic inflammation after treatment, could represent a likely inducing factor. In conclusion, this report notes that delayed sinonasal neoplasia can be a long-term complication in dogs treated for sinonasal aspergillosis. CVJ