Intranasal Malignant Melanoma in a Dog
A 10-year-old, female Newfoundland-cross dog was presented for evaluation of chronic intermittent unilateral epistaxis, nasal stertor, and sneezing. Nasal magnetic resonance imaging revealed a 3 × 5-cm mass in the left nasal cavity. Histopathological evaluation of nasal biopsies determined that the mass was a malignant melanoma. The mass was surgically resected and treated with bilateral opposed photon-beam radiation. This is the first report to describe the presentation, diagnosis, and treatment of an intranasal malignant melanoma in a dog.
Introduction
Intranasal malignant melanoma is a rare tumor in any species and has not been described in dogs in the veterinary literature.1–3 LaDue et al. referred to a case of canine intranasal malignant melanoma; however, a description was not included.3 In people, intranasal malignant melanoma accounts for approximately 3% of tumors in the nasal cavity and/or paranasal sinuses.1 With respect to tumor type alone, intranasal malignant melanoma represents 0.5% to 2.0% of all melanomas in people, according to one study.1 Historically, it was thought that melanocytes were not a component of the nasal mucosa, and in order for a melanoma to grow, it would have to be preceded by squamous metaplasia.4 However, Zak and Lawson concluded in their study that melanocytes are a natural component of human nasal mucosa and that tumor genesis from these cells does not require cellular metaplasia.4 Although a similar study has not been reported in dogs, the same premise may be true. The purpose of this report is to describe the presentation, diagnostic plan, tumor behavior, treatment, and response to treatment of an intranasal malignant melanoma in a dog.
Case Report
A 10-year-old, 59-kg, spayed female, Newfoundland-cross dog was referred to the Washington State University Veterinary Teaching Hospital for further evaluation and treatment of a presumptive nasal cavity squamous cell carcinoma, based on nasal swab cytology performed at the referring veterinary clinic. Initially, the dog was presented to the referring veterinarian for intermittent left epistaxis and sneezing of 6 to 8 months’ duration. The episodes of epistaxis were mild to moderate and stopped spontaneously without treatment. Nasal stertor had developed insidiously over the same time period. Treatment with erythromycin, cephalexin, and prednisone did not change the clinical signs.
On physical examination at referral, the dog was bright, alert, responsive, and obese (body condition score=5/5). She panted excessively throughout the examination. Mucous membranes were pink and moist. Capillary refill time, heart rate, and temperature were all within normal limits. Mild bilateral mucoid ocular discharge was noted, but epistaxis was not observed. Nasal stertor was heard when the dog was not panting. A complete blood count revealed a mild leukocytosis (16.2 × 103 cells/μL; reference range 5.8 to 11.7 × 103 cells/μL), mild neutrophilia (13.1 × 103 cells/μL; reference range 3.0 to 7.1 × 103 cells/μL), and mild monocytosis (1.8 × 103 cells/μL; reference range <8.0 × 102 cells/μL). Serum biochemical abnormalities included increased alanine aminotransferase (72 U/L; reference range 21 to 67 U/L) and alkaline phosphatase (ALP, 216 U/L; reference range 14 to 72 U/L).
Right and left lateral and ventrodorsal thoracic radiographs revealed no evidence of pulmonary metastasis. Additionally, submandibular lymph node aspiration and subsequent cytology were normal. Magnetic resonance imaging (MRI) of the dog’s nasal passages was performed to localize the mass and to plan for radiation therapy. Magnetic resonance imaging delineated a mass in the middle portion of the left nasal cavity; it was locally destructive but did not invade the right side of the nasal cavity. As measured on MRI, the mass was 5.5 cm long in the rostro-caudal direction and 3 cm long in the mediolateral direction. On T2-weighted and proton density-weighted images, the mass was hyperintense relative to adjacent tissues [Figure 1].a
A transnasal pinch biopsy of the mass was submitted for histopathology and aerobic, anaerobic, and fungal cultures. Cultures and gram stains were negative for organisms. Histopathological evaluation revealed densely packed, polygonal to spindle-shaped cells that were arranged in sheets within the mass. The proliferative cells had abundant eosinophilic cytoplasm and occasional large, clear, intracytoplasmic vacuoles. Small numbers of cells contained dark-brown, finely granular melanin pigment. Nuclear heterogeneity was noted within the proliferative cells. The intracytoplasmic granules were argyrophilic and stained positively with periodic acid-Schiff. Presumptive histological diagnosis was balloon cell melanoma of the nasal cavity.
Based on the unexpected diagnosis of melanoma, the decision was made to surgically cytoreduce the tumor via a rhinotomy prior to treating with coarse fraction radiation. A rhinotomy revealed a gray, irregularly shaped, poorly encapsulated, 5 × 4-cm mass in the middle meatus of the left nasal cavity. Most of the mass was removed; however, complete resection was not possible because of its location. Postoperative recovery was uneventful.
The mass was submitted for histopathology. Hematoxylin and eosin-stained sections revealed large, neoplastic cells packed within the propria mucosa. The proliferative cells had distinct borders, were predominately polygonal, and contained small to moderate amounts of eosinophilic, coarsely granular cytoplasm [Figure 2A]. The nuclei were centrally located, varied in size, and ranged in shape from round to oval to irregular. The nuclei contained finely stippled chromatin with multiple, prominent nucleoli. Zero to three mitotic figures were seen per high-power field. Neoplastic cells extended deep into the surgical margins. No vascular invasion was seen. Immunohistochemistry using the monoclonal antibody Melan A demonstrated the presence of melanin within the cytoplasm [Figure 2B]. Intracytoplasmic granules also stained black with Fontana-Masson stain. Histopathological findings confirmed the diagnosis of intranasal malignant epithelioid melanoma.
After adequate surgical recovery (2 weeks), the tumor was treated with coarse fraction radiation. Radiation was delivered with a linear accelerator using bilaterally opposed, 6-millivolt (MV) photon beams with a field size of approximately 11 × 4 cm.b The total dose of radiation was 30 Gy delivered in five fractions of 6 Gy each, over a 10-day period. Radiation was delivered on Monday, Wednesday, and Friday during the first week and on Monday and Wednesday during the second week. Lymph nodes were not treated. The clients declined further treatment with carboplatin or immunotherapy.
During the 6-month period after treatment, the dog was clinically stable and had no evidence of tumor recurrence. Epistaxis did not recur, and sneezing was reduced considerably. A brief episode of rhinitis (i.e., mucoid to mucopurulent nasal discharge and sneezing) developed 5 months after treatment. Administration of antimicrobials resolved the problem. No further diagnostics were performed to elucidate the cause of the rhinitis. The dog was presented for a 6-month re-evaluation and nasal MRI. Nasal stertor, epistaxis, and sneezing were not noted, but a mild, bilateral, mucoid nasal discharge was present. A gingival mass (12 × 15 mm) surrounding the upper incisors and extending toward the right canine tooth was also discovered. Most of the mass was on the right side of the oral cavity, which was contralateral to the original mass.
A complete blood count revealed thrombocytosis (4.17 × 105 cells/μL; reference range 1.57 to 3.94 × 105 cells/μL), eosinophilia (3.75 × 102 cells/μL; reference range <1.0 × 102 cells/μL), and lymphopenia (1.05 × 103 cells/μL; reference range 1.1 to 5.1 × 103 cells/μL). Serum biochemical profile revealed increased ALP (74 U/L; reference range 14 to 72 U/L) and hypercholesterolemia (376 U/L; reference range 123 to 363 U/L). Thoracic radiographs (three views) showed no evidence of pulmonary metastasis. Aspiration of left and right prescapular and submandibular lymph nodes showed no evidence of metastasis. None of the peripheral lymph nodes were enlarged.
Magnetic resonance imaging of the head revealed no evidence of a nasal mass but identified an oral mass in the rostral incisive bone. Extension of the mass into the nasal cavity was not observed. The oral mass shared MRI characteristics of the previous intranasal mass; namely, it was the same intensity on differently weighted MR images. The mass was biopsied using a 6-mm dermal punch, and a histological diagnosis of oral malignant melanoma was made. The dog was administered a genetically modified anti-melanoma vaccine,c but additional chemotherapy and radiation therapy were declined by the owner.
The dog was returned 3 months later (9 months following the initial presentation) for additional palliative radiation therapy of the oral malignant melanoma, because the tumor had progressed (7 × 3 cm). Thoracic radiographs (three views) did not show any evidence of metastasis. Radiation was delivered via a linear accelerator using bilaterally opposed, 6-MV photon beams with a field size of approximately 6 × 4 cm.b Only part of the old radiation field was incorporated in the new field. A total dose of 15 Gy was delivered in a single fraction. The single palliative dose was chosen for a couple of reasons: the owners desired to have the dog hospitalized only once, and the late effects of this single dose were not expected to develop, based on the dog’s predicted life expectancy. Lymph nodes were not treated.
The oral mass decreased in size after the radiation therapy, and the dog appeared to eat more comfortably and had an increased activity level. At the time of manuscript submission 12 months after initial presentation, the dog was alive and had an acceptable quality of life according to the client. Bilateral mucoid nasal discharge was still present, and the oral tumor had again increased in size.
Discussion
Benign melanomas are observed in dogs with relative frequency. They represent 9% to 20% of all skin tumors in dogs.5 Typically, benign melanomas are cured by complete excision with wide margins.5 Malignant melanomas are also commonly diagnosed in dogs.6 Melanomas of the oral cavity, nail bed, and oral mucocutaneous junction are typically malignant and are characterized by aggressive behavior.6–10 Oral malignant melanomas are the most common malignant forms diagnosed in dogs.6,11,12 To the authors’ knowledge, a primary intranasal malignant melanoma has not been reported previously in a dog.
The clinical signs of the dog reported here were similar to previous reports of nasal disease in dogs and nasal melanomas in people.1,7,13 Other intranasal diseases such as inflammatory granuloma, infectious or allergic rhinitis, or other types of tumors were considered as differential diagnoses in this case, but they were ruled out based on a complete diagnostic workup with tissue biopsy and histopathological evaluation.
Routine light microscopic evaluation using hematoxylin and eosin stain, while helpful in identifying neoplastic cells, is often insufficient for the diagnosis of hypo-or amelanotic melanomas.14 Therefore, special stains and immunohistochemical studies are important in the diagnosis of such tumors.14 Fontana-Masson staining was used to detect melanin pigment in the neoplastic cells of the tumor of this report. Additionally, intracytoplasmic granules stained positively with periodic acid-Schiff stain, which was also consistent with melanoma. Immunohistochemistry was also performed with Melan A (a monoclonal antibody that is a sensitive marker for the detection of melanin) as the primary antibody, and horseradish peroxidase as the secondary antibody.15 The tumor of this report bound Melan A, supporting the diagnosis of melanoma. Currently, other monoclonal antibodies are being evaluated to aid in the diagnosis of occult melanomas; however, none were used in the diagnosis of this tumor.
Criteria established by Greene et al. for diagnosing primary melanoma of mucous membranes in humans include the 1) presence of gross and microscopic characteristics of malignant melanoma; 2) presence of junctional activity (i.e., intraepithelial activity) in the area of origin of the tumor; and 3) inability to demonstrate another primary site.16 Histopathology of the current tumor was consistent with malignant melanoma, and a thorough search at the time of initial presentation did not reveal another primary tumor site, so the mass was considered to originate within the nasal cavity.
In humans, intranasal malignant melanoma is characterized by extensive local invasion, frequent metastasis to distant sites, and rare metastasis to local lymph nodes.5,8 Similarly, oral malignant melanomas of dogs often invade the surrounding tissue and frequently metastasize to distant locations.7 Metastatic sites of melanomas reported in both species include the diaphragm, liver, lymph nodes, heart, lungs, kidneys, eyes, brain, and skin.7,9,13 A thorough search for metastases was conducted prior to initiating therapy in the case reported here. Thoracic computed tomography would have been more sensitive for identifying pulmonary metastases.
Excision with wide surgical margins is the initial, preferred treatment for intranasal malignant melanoma in people.8 Similarly, resection of canine oral malignant melanoma is routinely performed. Radical excision with clean surgical margins has improved median survival times; however, local recurrence is common after surgery in dogs.7,11,17,18 Some reports in dogs have also indicated that surgery alone results in shorter survival times than multimodality therapy.18,19
Historically, oral malignant melanomas were thought to be radioresistant; however, recent studies have shown that these tumors are responsive to radiation.7–9,18,20 Radiation therapy is currently the most common ancillary treatment administered for both canine oral malignant melanomas and human intranasal malignant melanomas.18 High doses per fraction appear to be the most important factor of radiotherapy when successfully treating melanomas; however, high doses increase the risk of radiation toxicosis, especially necrosis of the surrounding soft tissue and bone.18,21 Numerous coarse fraction radiation protocols have been described for dogs with oral malignant melanomas.7,9 The radiation treatment regimen chosen for this dog was based upon a protocol utilized at the College of Veterinary Medicine, Washington State University.
Malignant melanoma traditionally carries a poor prognosis. Median survival time for dogs with malignant melanoma is 8 to 12 months, even with multimodality therapy.5,18,22 LaDue et al. reported that permanent local control of nasal tumors of all types was difficult using standard treatments, and that lack of local control may lead to the death of affected dogs.3 The same outcome has been reported for dogs with oral malignant melanoma.7,18 The dog of this report achieved the expected median survival time for dogs with oral melanomas, possibly because of multimodality therapy.
Based on the diagnosis of an oral malignant melanoma at the 6-month postoperative evaluation of the dog reported here, it is possible that the nasal mass was an unusual presentation of primary oral malignant melanoma. However, care was taken to rule out oral involvement at the initial presentation. The oral mass was also predominantly on the right side of the oral cavity, while the nasal tumor was on the left side. Additionally, the radiation treatment field came just to the edge of where the oral mass originated, so the radiotherapy may have missed tumor in this area. It was the authors’ impression that the oral melanoma either arose spontaneously or represented local recurrence of the intranasal mass.
Conclusion
A rare diagnosis of canine intranasal malignant melanoma was made in a 10-year-old, Newfoundland-cross dog that had chronic intermittent unilateral epistaxis, sneezing, and nasal stertor. Histopathological findings on biopsies demonstrated the difficulty in differentiating intranasal malignant melanoma from other nasal epithelial tumors. Surgical cytoreduction and coarse fraction radiation were used to treat the tumor. An oral malignant melanoma was diagnosed in the same dog 6 months after radiation therapy and may have represented local recurrence or metastasis. The dog was alive and without proven nodal or pulmonary metastasis 12 months after initial diagnosis of the intranasal malignant melanoma.
Philips Gyroscan Intera, 1.0 Tesla; Philips Medical Systems, 5680 DA Best, Netherlands
Philips SL15 Linear Accelerator; Philips Medical Systems, 5680 DA Best, Netherlands
Canine Melanoma Vaccine Study, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706
Acknowledgments
The authors thank Drs. Jeff Abbott, Dave Barbee, Sean Berens, Travis Saveraid, and Russell Tucker for their assistance.
Citation: Journal of the American Animal Hospital Association 42, 6; 10.5326/0420472
Citation: Journal of the American Animal Hospital Association 42, 6; 10.5326/0420472
Magnetic resonance image of a 10-year-old, Newfoundland-cross dog with an intranasal melanoma. The transverse image was taken at the level of the mid-nasal cavity. The hyperintense area (arrows) delineates the tumor in the left nasal cavity (Proton density, fast spin echo technique at TR=5875.1, TE=13.8; bar=1 cm; L=left).
Histopathology specimens of the intranasal tumor of the dog in Figure 1. (A) Many epithelioid neoplastic cells are seen in the background. Arrows indicate melanin pigment. Further staining was required to definitively diagnose melanoma (Hematoxylin and eosin stain, 400×; bar=100 μm). (B) Immunohistochemistry of the tumor using Melan A-specific antibodies. Note the diffuse, dark-red staining that is consistent with melanin (Horseradish peroxidase detection, 400×; bar=100 μm).
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