Primary intranasal melanoma with brain invasion in a dog

Abstract

A 6-year-old castrated male boxer dog with right-sided dark purulent nasal discharge and acute bilateral blindness was diagnosed on magnetic resonance imaging (MRI) and then on necropsy with primary nasal malignant melanoma that extended into the brain, as well as concurrent ocular melanosis. There was no evidence of metastasis in other organs.

In human and veterinary medicine, melanoma is one of the few neoplasms for which location is an important prognostic indicator. While oral melanoma, the most common form of melanoma in dogs, and melanoma of the digit, foot pad, and mucocutaneous junction are usually aggressive malignant tumors with high potential for local invasiveness and metastasis, 95% of the haired-skin melanomas and most intraocular melanocytic tumors are benign (1).

In humans, sinonasal melanoma is invariably malignant and aggressive (2–7). Contrary to its human counterpart for which sinonasal melanoma is more common than oral melanoma, primary malignant intranasal melanoma has been rarely reported in dogs, and only 2 cases are fully described (8,9). The tumor was limited to the nasal vestibule in 1 case based only on surgical findings and to 1 nasal cavity in a second case based on magnetic resonance imaging (MRI) of the head. There was no metastasis based on repeated thoracic radiographs for both cases and lymph node aspirations for the second case (8,9).

Ocular melanosis, on the other hand, is a benign lesion of the melanocytic system that is known to occur mainly in cairn terriers, although similar lesions have been described in boxers and Labrador retrievers (10).

To the authors’ knowledge, this is the first case of primary nasal melanoma with brain invasion and concurrent ocular melanosis in a dog. Clinical presentation was interesting as the dog presented for both signs of nasal and neurological diseases.

Case description

A 6-year-old castrated male boxer dog was referred to the Western College of Veterinary Medicine, Saskatoon, Saskatchewan because of a 3-week history of unilateral nasal discharge from the right nostril, progressive lethargy, and blindness over 2 d. The nasal discharge was dark brown/purple and purulent but became hemorrhagic on the day of presentation. No pain was detected on palpation of the nose or retropulsion of the eyes, and submandibular lymph nodes were normal in texture and size. A neurological examination showed bilateral absence of menace response and marked bilateral mydriasis with poor direct and consensual pupillary light reflexes. The remainder of the neurological and physical examinations was normal. An ophthalmological examination showed very myelinated and prominent optic nerves that were interpreted as possible individual variation. The marked mydriasis prevented a good evaluation of the irises. An electroretinogram was found to be normal. The origin of the blindness was therefore suspected to involve the proximal portion of the visual pathway, from the optic nerves to the lateral geniculate nuclei, and more likely the optic chiasma.

Complete blood cell count, serum biochemistry, and urinalysis were unremarkable. Thoracic radiographs and abdominal ultrasound were performed to look for metastasis since a nasal tumor was the most likely diagnosis. Findings were mild and non-specific. A mild bronchial pattern and possible mild sternal lymphadenomegaly were seen on the thoracic radiographs and splenomegaly was seen on abdominal ultrasound examination. A magnetic resonance image of the brain showed a large (8 × 4 × 2.5 cm) contrast-enhanced mass of mixed intensity that filled the entire right nasal passage and extended into the left nasal passage and caudally through the cribiform plate into the olfactory and likely the frontal lobes of the rostral right brain (Figures 1A, B). The nasal mass was isointense to hyperintense on T2 sequences, isointense and moderately hyperintense on T1 sequences, and enhanced on the post-contrast T1 sequences. There was also a focal lesion in the left frontal lobe, immediately rostral to and displacing the left lateral ventricle, as well as bilateral symmetrical lateral ventriculomegaly. This lesion was hyperintense on T2 sequences, hypointense on T1 sequences, did not contrast enhance and was considered to be a fluid-filled lesion. The right frontal sinus was fluid-filled, likely secondary to the obstruction from the mass. Differential diagnoses for the mass included primary neoplasia and less likely fungal infection. Due to the poor prognosis, the dog was euthanized and a postmortem examination was conducted.

Figure 1.

Post-contrast sagittal (A) and dorsal (B) T1-weighted post contrast magnetic resonance images of a 6-year-old boxer dog with an intranasal melanoma with brain invasion. The large hyperintense area (star) indicates the tumor originating in the right nasal passage with extension into the cranial cavity and into the region of the olfactory and frontal lobes. The arrows designate the caudal borders of the main part of the tumor. Tendrils of invasion into the brain tissue are delineated by the arrowheads. (Post contrast T1* sequences (A) TR = 413, TE = 12, 3.5 mm slice thickness, 200 × 200 (B) TR = 516, TE = 12, slice thickness 3.5 mm).

Grossly, a black firm mass measuring 8 × 4 × 2.5 cm filled the right nasal cavity, destroyed the cribiform plate and extended into the cranium. The ventral and rostral aspect of the right frontal lobe of the brain contained a solitary, round, dark grey, soft mass which replaced the olfactory bulb area (Figures 2A, B). A focal round area was found on the spleen. Microscopically, expanding and infiltrating the submucosa, destroying the nasal bone and multifocally elevating or ulcerating the nasal mucosa, there was an unencapsulated, poorly demarcated, highly infiltrative, and densely cellular neoplastic mass that was composed of cells arranged in interlacing bundles, whorls and dense clusters and that was supported by a fine fibrovascular stroma. Neoplastic cells were pleomorphic, ranging from round to polygonal to spindloid, with variably distinct cell borders and a variable amount of eosinophilic cytoplasm, often obscured by dark brown melanin pigment. Nuclei were round to oval to spindloid with moderately stippled chromatin, and had 1 to 3 distinct nucleoli. There was marked anisocytosis and anisokaryosis, and mitotic figures ranged from 3 to 10 per high power field (40×). Areas of nasal bone invasion and necrosis were also seen. Similar neoplastic cells were seen infiltrating and effacing the brain (Figures 2C, D, E). These tumor cells infiltrated the olfactory nerve fibers and the olfactory bulb of the brain but did not infiltrate the optic chiasm. There was no evidence of metastasis in any of the other organs examined including draining lymph nodes and the spleen. Based on gross and histological findings a diagnosis of malignant melanoma was made and was confirmed by immunohistochemistry. Tumor cells were positive for Melan A (Figure 2F) and S100, two melanoma associated antigens.

Figure 2.

A — Cross section of the head. A dark black nasal mass was found occupying most of the nasal cavity and extending into the cranium. B — Brain, ventral view. Solitary, round, dark black, soft mass replaced the olfactory bulb area. Inset: Dorsal view: the mass extended dorsally. C — Nose: A large neoplastic mass replaced the nasal epithelium and underlying bone. Hematoxylin and eosin stain (H&E), 100×. D — Closely packed neoplastic cells invaded the brain. (H&E), 400×. E — Round to polygonal neoplastic cells, some of them containing intracytoplasmic dark brown pigment. (H&E), 400×. F — Positive immunohistochemistry for melan A. Brown pigment is present within the cytoplasm of tumor cells. ABC diaminobenzidine method, hematoxylin counterstain; 200×. Inset: Omission control. G — A bleached histology section of the eye displaying melanocytes occupying the iris and ciliary body. 20×. Inset: The iris is expanded by many round to polygonal cells with variably distinct cell borders and moderate to abundant amount of cytoplasm. Nuclei were mostly polygonal, rarely had prominent nucleoli with no mitotic figures. H — A large population of melanocytes expanding the iris and ciliary body. (H&E), 20×. Inset: Pigmented melanocytes with expanding iris stroma. H&E.

In both eyes, the iris was diffusely infiltrated by a dense population of highly pigmented round cells which obscured the iris architecture and extended into the filtration angle, ciliary body, choroid and around the optic disc. A bleached section revealed the cells to be round to polygonal with indistinct cell borders. Nuclei were polygonal to spindle and no mitotic figures were seen (Figures 2G, H).

Discussion

We describe a case of primary nasal melanoma with brain infiltration, along with ocular melanosis, in a boxer dog. To the authors’ knowledge, this is the first description of these 2 lesions combined in a dog and the first description of brain invasion by a primary nasal melanoma. Nasal melanoma in dogs has only been described twice previously (8,9).

Extensive local invasiveness and infiltration of surrounding tissues is a characteristic common to all types of malignant melanoma and is attributed to submucosal lymphatic spread of the disease (2). The case of primary nasal malignant melanoma presented herein had a very aggressive local behavior, as seen by the extensive bone and brain invasion.

In contrast to this case, the 2 previously described cases of malignant nasal melanoma had a longer duration of clinical disease and did not progress to brain invasion. In the first report, malignant melanoma was diagnosed within the ventral left nasal vestibule of a 14-year-old intact male miniature schnauzer 1 mo after the mass was treated with topical hydrocortisone. The tumor extended to the upper lip caudally and ventrally. Three months after complete surgical excision, there were no clinical signs of tumor recurrence and no evidence of metastasis in repeated thoracic radiographs (8). The second case occurred in a 10-year-old, spayed female, Newfoundland-cross dog which was presented to the referring veterinarian for intermittent left epistaxis and sneezing of 6 to 8 months’ duration (9). Magnetic resonance imaging of the head revealed a mass in the middle portion of the left nasal cavity which was locally destructive and histologically diagnosed as epithelioid melanoma. The tumor was cytoreduced surgically via a rhinotomy followed by radiation. Complete resection was not possible because of the tumor location. Clinical signs improved after surgery; however, the dog was presented for a gingival mass on the right side of the oral cavity, which was contralateral to the location of the original mass. A second MRI showed no evidence of a nasal mass. The gingival mass was diagnosed as malignant melanoma and was treated with radiation 3 mo later. No evidence of metastasis was found on repeated radiographs and submandibular lymph node aspirations, and the dog was still alive after 12 mo (9).

Sinonasal melanoma occurs rarely in humans, representing approximately 4% to 8% of malignant tumors of the nasal cavity and paranasal sinuses (5). Comparable to other forms of malignant melanoma, sinonasal melanoma in humans is characterized by extensive local invasion. Humans with primary nasal melanoma usually present with one-sided nasal obstruction and/or epistaxis (4,11). Due to the non-specific nature of the symptoms experienced by humans with sinonasal melanoma, delay in diagnosis is frequent, patients having symptoms for months to years before diagnosis (5,11). Therefore the tumor is often advanced at the time of diagnosis. However, brain invasion is very rarely reported (4,7).

Studies in humans have reported high rates of local recurrence of primary nasal melanoma after surgical removal (31% to 85%); low rates of invasion of regional lymph nodes (10% to 30%); high rates of distant metastasis (25% to 50%), which occurs late in the disease process; and often poor 3- and 5-year survival rates (19% to 62.5%) (2,3,6). Since these tumors are invariably aggressive in humans, the classification of mucosal melanoma of the head and neck (70% of which are sinonasal melanoma) by the American Joint Committee on Cancer does not include stages T1 and T2 (5). The tumor is classified stage T3 when it only invades the mucosa and stage T4 for deeper invasion, with 2 sub-stages a and b for moderately advanced disease and very advanced disease, such as brain invasion, respectively. The absence of distant metastasis in this case based on necropsy and in the 2 previously described reports based on repeated thoracic radiographs, and submandibular lymph node aspirations in 1 of the 2 cases, could suggest that nasal malignant melanoma in dogs, unlike humans, is a locally invasive tumor with lower metastatic potential, but a higher number of cases would be necessary to investigate this hypothesis.

The tumor is suspected to originate from melanocytes within the nasal mucosa and less likely within meninges or brain. It has been previously thought that melanocytes were not present within the nasal mucosa, thus, malignant nasal melanomas in humans were suspected to arise after squamous metaplasia of nasal epithelium (12). Later studies in humans have confirmed the presence of nasal melanocytes within the nasal mucosa. The clinical course of this tumor with epistaxis preceding the development of neurological signs as well as the presence of a larger mass within the nasal cavity are consistent with a nasal origin (12). Although studies confirming the presence of melanocytes within the nasal mucosa in dogs are lacking, the clinical presentation in this case and the absence of squamous metaplasia within the nasal mucosa suggests their existence within the canine nasal mucosa.

The origin of the blindness in this dog was suspected to be due to swelling and compression around the optic chiasm, as opposed to an infiltration by the tumor as the tumor was not seen microscopically.

Interestingly, this dog presented with another lesion involving the melanocytic system. Ocular melanosis, a non-neoplastic condition in which pigmented cells proliferate in several tissues of the eyes, occurs mainly in cairn terriers, less commonly in other breeds, and is thought to be inherited (13). Diffuse over-pigmentation of the uvea is typically seen histologically resulting from an increase in the number and size of round and heavily pigmented cells. Two cell types are present within the lesion, i.e., melanocytes and melanophages. Melanocytes are thought to predominate in the cairn terrier while melanophages are thought to be predominant in other breeds (13). A few consider ocular melanosis to be a variant of melanocytoma while others make a distinction between the 2 lesions (13). Melanocytomas typically form a regional mass (i.e., are not diffuse), and contain heavily pigmented round and spindle cells. This is unlike most cases of ocular melanosis in which only a single population of round and heavily pigmented cells is present diffusely. In this case, only a single population of round and heavily pigmented cells was seen histologically in both eyes which is consistent with a diagnosis of ocular melanosis. It is possible that the lesions in both eyes represent a site of distant metastasis; however, this possibility is less likely given the organized nature of this lesion, the benign cellular morphology and the lack of local invasion or mitotic figures.

Gross and histological findings were consistent with malignant melanoma in this case, but because malignant melanoma can be amelanotic and highly pleomorphic, the histological diagnosis may need to be confirmed by immunohistochemistry. Tests for Melan-A, an antigen present on the surface of melanocytes; PNL2, an antigen of melanocytes and granulocytes; and tyrosinase-related proteins 1 and 2 were found to be highly sensitive and 100% specific in a study evaluating canine oral amelanotic melanocytic neoplasms (14). S-100, a calcium-binding protein that is widely distributed in the central and peripheral nervous systems, as well as in other cells including melanocytes, is considered a less reliable marker because tests for this protein are less specific but sensitive. Melan A and the S-100 proteins were used in our case, both showing positive staining. The dog in this report had poor short- and long-term prognoses, regardless of the type of tumor diagnosis; therefore, nasal biopsies and treatments were declined by the owners, and the diagnosis of primary nasal malignant melanoma was made on postmortem examination.

Available treatments for malignant melanomas in dogs include wide surgical resection, radiation therapy, and adjunctive systemic therapies such as melanoma vaccine and various chemotherapy protocols (15–19). Wide surgical excision remains the treatment of choice if complete resection is feasible (15,16,19). External beam radiotherapy can also be used for local tumor control, despite older data which suggested that melanoma was radioresistant (2,8,19). However, given the high metastatic rate of malignant melanoma, systemic therapy is often added. No consensus has been established on the optimal systemic management of mucosal malignant melanoma in dogs and humans (15,16).

Studies investigating the chemotherapeutic agents carboplatin, cisplatin, both in association with piroxicam, melphalan, lomustine, dacarbazine, doxorubicin, or temozolomide showed response in a small subset of dogs with malignant oral melanoma; and the combination of adjunctive systemic therapies to surgery and/or radiation does not seem to improve the survival time compared to loco-regional control alone (16,20–25). However, type II errors were possible in these studies due to the small number of dogs studied.

Various immunotherapy strategies have been developed, some of them showing promising results, but the development of these products is expensive, time-consuming, and difficult to reproduce or commercialize (15). The development and commercialization of a vaccine containing xenogeneic plasmid DNA encoding human tyrosinase represents a leap forward, but its efficacy has recently been questioned (17). Despite initial data indicating promising results of the vaccine (26), a more recent study failed to show greater progression-free survival, disease-free interval, or median survival time in dogs receiving the vaccine compared with control dogs (17). Other promising strategies are under development such as the xenogeneic electrovaccination against the human chondroitin sulfate proteoglycan-4 (hCSPG4) DNA for dogs with oral malignant melanoma expressing CSPG4 (27).

Regardless of the treatment strategy chosen, early diagnosis and treatment are important to improve the outcome of patients with primary nasal malignant melanoma and, although very rare, primary malignant nasal melanoma is a possible cause of nasal discharge in dogs.

In conclusion, this report describes a case of primary nasal malignant melanoma with brain invasion and concurrent ocular melanosis in a 6-year-old castrated male boxer dog. Signs of neurological involvement, acute bilateral blindness with marked mydriasis, and poor direct and consensual pupillary light reflexes, were seen 3 wk after the development of unilateral dark purulent nasal discharge. Due to the poor prognosis based on MRI findings, euthanasia was elected and the diagnosis of primary intranasal malignant melanoma with brain invasion was made at necropsy. CVJ