Oral Malignant Melanoma in Dogs and Cats
Melanoma is a tumor of melanocytes, which arise from neural crest cells and function to synthesize melanin. Melanocytes are commonly located in the oral cavity, haired skin and eye, making these the most common locations where melanomas arise. Biologic behavior of melanoma depends in part on tumor location. The majority of melanomas that arise in the oral cavity are classified both histologically and biologically as malignant. Histologic features that support a diagnosis of oral malignant melanoma include a mitotic index greater than 2 mitoses per 10 high-powered fields, nuclear atypia, vascular or lymphatic invasion and ulceration. Malignant tumors may be variably pigmented or amelanotic (one third of cases). Since melanocytes are derived from neural crest cells, which ultimately give rise to both glandular tissues and connective tissues, melanomas can resemble both carcinomas and sarcomas morphologically. Given these challenges to diagnosing a malignant melanoma, several immunohistochemical stains have been developed to aid in the diagnosis. Melanomas typically stain positive for vimentin, melan A, S100, and neuron-specific enolase (NSE); these stains can be helpful in diagnosis.
Oral melanoma is the most common oral malignancy in dogs, accounting for up to one-third of oral tumors in the species. In comparison to other malignant oral tumors, melanoma tends to occur in smaller body weight dogs. Predisposed breeds include the cocker spaniel, miniature poodle, Scottish terrier, chow chow and golden retriever. The median age at presentation for dogs with oral melanoma is 11-12 years. Malignant melanoma occurs in cats, but is much less common, accounting for less than one percent of oral tumors in the feline species.
Melanoma can affect any part of the oral cavity but most commonly arises in the gingiva with the cheek, lips and soft or hard palate less commonly affected. The tumor also occasionally arises on the tongue or within the tonsil or pharynx. Typically, melanomas are extremely locally invasive with more than half of gingival tumors exhibiting bony lysis. Melanomas are also highly metastatic. The metastatic rate is site, size and stage dependent but has been reported to occur in up to 80%. Melanoma most commonly metastasizes to the regional lymph nodes and lungs but metastases to the central nervous system, abdominal organs and muscle have also been reported. A normal-sized lymph node on palpation does not rule out metastatic disease, as up to 40% of dogs with normal-sized nodes had metastasis in one study. Recommended staging tests for a patient with oral malignant melanoma include complete blood count, chemistry profile, urinalysis, three-view thoracic radiographs, abdominal ultrasound and regional lymph node aspiration.
Median survival time in both dogs and cats with untreated melanoma is short—approximately two months. Wide surgical excision, when possible, is the recommended treatment for oral melanomas without clinical evidence of metastatic disease. Median survival time for dogs with oral melanoma of the mandible or maxilla treated with aggressive surgical excision ranges from 7 to 10 months with local recurrence rates on the order of 20-50%. Potential positive prognostic factors for melanomas treated with surgery include small size (<2 cm diameter), low mitotic index (≤3 mitoses/10 HPF), aggressive surgery (mandibulectomy or maxillectomy), and rostral or lip locations.
Radiation therapy is highly effective in the local treatment of oral melanoma. Several radiation protocols have been evaluated in the veterinary literature, ranging from hypofractionated protocols (8 to 9 Gy per fraction given weekly for 3 to 4 fractions) to definitive protocols (2 to 4 Gy per fraction given daily for 12 to 19 fractions). No statistically significant difference in response rate, duration of local control, or survival has been found between the various protocols. Dogs with oral melanoma irradiated for gross disease have response rates ranging from 82-94%, local recurrence rates between 20-60% and median survival times of 5 to 8 months. Dogs with incompletely resected oral melanomas irradiated for residual microscopic disease have lower local recurrence rates(15-25%) and median survival times (12 to 15 months). Potential positive prognostic factors for melanomas treated with radiation include small size (microscopic or <2 cm diameter), complete response to therapy, lack of bony lysis and rostral location within the oral cavity (cranial to the 4th premolar). Potential side effects of radiation therapy to the oral cavity include oral mucositis, moist desquamation of the skin and ocular or nasal effects if the eye or nasal cavity is within the radiation field. These acute side effects are more commonly seen with definitive protocols than with hypofractionated protocols. Late side effects of radiation therapy are rare but may be seen in dogs surviving several years after therapy and include bone necrosis and secondary tumor induction (typically <3-5% incidence). The addition of low-dose chemotherapy as a radiosensitizer has also been studied and may modestly improve survival in dogs. A single study evaluating hypofractionated radiation therapy for oral melanoma in cats found a lower response rate than in dogs – 60% – and a similar median survival time of 5 months in the face of gross disease.
Systemic chemotherapy is not very effective in the treatment of measurable disease. Carboplatin has been reported to produce a response rate of 28% with a median duration of 5.5 months. Cisplatin and melphalan have similarly low response rates of 18% and 27%, respectively.
Given the lack of efficacy of conventional chemotherapy for melanoma and the fact that melanoma is an immunogenic tumor, immunomodulatory therapy is an active area of research. One study evaluating liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE), which can activate the tumoricidal activity of the monocyte-macrophage system following intravenous injection, showed a survival benefit for dogs with stage-I disease (primary tumor <2 cm and no metastatic disease). Cancer vaccines have also been developed to treat oral malignant melanoma. The goal of cancer vaccine therapy is to elicit an antitumor immune response that results in clinical regression of a tumor or its metastasis. The clinical response to vaccine therapy can take several months or more to appear. Merial released the canine melanoma vaccine in 2007, which subsequently received full FDA-approval for the treatment of dogs with stage II or III oral melanoma (tumors ≥2 cm in diameter ± regional lymph node metastasis) in which adequate locoregional disease control has been achieved with surgery and/or radiation therapy. ONCEPT™ is a xenogeneic DNA vaccine that that delivers a foreign gene for tyrosinase inserted in a small ring of DNA. Tyrosinase, a protein present on canine melanoma cells, is not usually targeted by the dog’s immune system because it is also present in normal canine melanocytes. The foreign tyrosinase in the vaccine is different enough from canine tyrosinase to induce an immune response to the tumor. Median survival for dogs treated with this vaccine has been reported to be between 12 to 18 months. ONCEPT™ is only available from veterinary oncologists.