Canine melanoma is relatively common in dogs and comprises 5–7% of all skin tumors. The incidence is highest in highly pigmented older dogs. The disease is generally less malignant in Dobermans and miniature Schnauzers but maybe more aggressive in Poodles. In contrast to humans, cutaneous melanoma in dogs is not sun induced. However, genetic mutations in tumors suppressor genes have been identified in canine melanoma. Mutation in these genes can be passed to later generation via germinal cells.¹ In the dog, melanoma occurs commonly although not exclusively at the following sites; cutaneous, oral, ocular and nail bed (subungual). Diagnosis is typically made either by fine needle aspirate or by biopsy. Generally the diagnosis is not difficult because of the presence of melanin granules, but in the case of amelanotic melanomas they fall in the nebulous category of round cell tumors. These include agranular mast cell tumors, lymphoma, and others. To aid in the diagnosis biopsy should be done and specific markers such as S100, vimentin and Melan A or, lately, microphthalmia-associated transcription factor (MiTF), PNL2 can be used.^2,3 Amelanotic melanomas are usually vimentin (+), cytokeratin (-), positive for S100 (marker of neural tissue), PNL2 and MiTF. Staging of the disease is important to gauge the extent of the disease as well predicting survival. Staging includes radiographs of the offending area, especially oral tumors. FNA or biopsy of the regional (sentinel) lymph node/s and radiographs of the lung. While brain metastasis in malignant melanoma is more common in humans it is not unheard of in dogs and so veterinarians should be on the lookout for neurological signs. Diagnosis of metastasis to the regional lymph nodes can be problematic as not all glands are enlarged and FNA is not 100% sensitive.

Biopsy would generally be regard as the more advanced method in practice. Newer methods include PCR of the lymph node. Criteria for staging of oral melanoma are listed below:

Oral Melanoma: Staging

 Stage I - <2 cm Ø, node negative

 Stage II - tumors 2–4 cm diameter, negative node

 Stage III - tumor >4 cm and/or positive nodes

 Stage IV - distant metastatic disease

A good review of prognostic criteria for canine malignant melanoma can be found in reference 3.

Prognostic Factors for Canine Melanoma

 Location

 Skin (haired areas) - 85% benign

 Mucocutaneous (except eyelid) - malignant

 Histopathology

 Mitotic index correlates to malignancy

 Breed

 Benign - Doberman's & miniature Schnauzers

 Malignant - Poodles

Ocular

 Canine

 Limbal - benign

 Anterior uveal - benign

 Choroidal - can remain asymptomatic for years

Treatment of oral melanoma includes surgery and in some cases radiation therapy. Combination radiation and carboplatin are thought to improve local control.⁴ When chemotherapy was used to control metastatic disease the results showed moderate efficacy,⁵ but in our experience results have been mostly disappointing. The relatively poor efficacy of chemotherapy in preventing metastasis has largely been the impetus in the search for alternative therapies.

Biological response modifiers or immunotherapy are considered a viable approach as the immune response to melanoma is well known. People with melanoma have been known to show areas of depigmentation (vitiligo like signs) concurrent with cessation in tumor growth for a period of time. This has led to research in nonspecific and specific immunotherapy, see below:

Immunotherapy

A. Nonspecific Immunotherapy

 BCG vaccine

 Interleukin - 2

 NSAID

 Liposomal encapsulated muramyl tripeptide (LMTP)

 Acemannan

B. Immunotherapy

 Cancer vaccines - Oncept

Gene therapy. Currently a number of centers offer melanoma vaccines. Oncept⁶ vaccine uses xenogeneic tumor antigens introduced into the dog via naked DNA. The vaccine has been reported to show increased survival in dogs with Stage 2 & 3 oral melanoma.⁷

More recent independent publication seems to confirm the increased survival albeit in a smaller population of dogs.⁸ Nevertheless a retrospective paper by Ottnod et al.⁹ did not confirm increased survival once again albeit in a smaller population of dogs. The University of Wisconsin at Madison¹⁰ had an allogeneic whole-cell vaccines transfected to express gp100 to enhance immunity. Another vaccine from Ontario Canada¹¹ uses a dendritic cell vaccines induced to express tumor antigen. At Florida our approach has been to develop a vaccine along traditional lines using a tumor surface antigen, disialoganglioside GD3.¹² Like a vaccine in the conventional sense it also contains adjuvants which enhance the immune response to overcome the body's tolerance to the autoantigen (GD3). We have conducted a trial in normal and dogs with melanoma where we were able to show that the vaccine stimulated antibodies to GD3 and induced melanoma specific cytotoxicity in vitro. Results from this study have allowed us to start a clinical trial in dogs with melanoma. The study is currently accruing phase 3 cases. In the future immunomodulation is likely to form part of the standard treatment of canine malignant melanoma and other cancers.¹³

References

1.  Modiano JF, Ritt MG, Wojcieszyn J. The molecular basis of canine melanoma: pathogenesis and trends in diagnosis and therapy. J Vet Intern Med. 1999;13(3):163–174.

2.  Smedley RC, Lamoureux J, Sledge DG, Kiupel M. Immunohistochemical diagnosis of canine oral amelanotic melanocytic neoplasms. Vet Pathol. 2011;48(1):32–40.

3.  Smedley RC, Spangler WL, Esplin DG, et al. Prognostic markers for canine melanocytic neoplasms: a comparative review of the literature and goals for future investigation. Vet Pathol. 2011;48(1):54–72.

4.  Freeman KP, Hahn KA, Harris FD, King GK. Treatment of dogs with oral melanoma by hypofractionated radiation therapy and platinum-based chemotherapy (1987–1997). J Vet Intern Med. 2003;17(1):96–101.

5.  Rassnick KM, Ruslander DM, Cotter SM, et al. Use of carboplatin for treatment of dogs with malignant melanoma: 27 cases (1989–2000). J Am Vet Med Assoc. 2001;218(9):1444–1448.

6.  Bergman PJ, McKnight J, Novosad A, et al. Long-term survival of dogs with advanced malignant melanoma after DNA vaccination with xenogeneic human tyrosinase: a phase I trial. Clin Cancer Res. 2003;9(4):1284–1290.

7.  Grosenbaugh DA, Leard AT, Bergman PJ, et al. Safety and efficacy of a xenogeneic DNA vaccine encoding for human tyrosinase as adjunctive treatment for oral malignant melanoma in dogs following surgical excision of the primary tumor. Am J Vet Res. 2011;72(12):1631–1638.

8.  McLean JL, Lobetti RG. Use of the melanoma vaccine in 38 dogs: the South African experience. J S Afr Vet Assoc. 2015;86(1):1246.

9.  Ottnod JM, Smedley RC, Walshaw R, Hauptman JG, Kiupel M, Obradovich JE. A retrospective analysis of the efficacy of Oncept vaccine for the adjunct treatment of canine oral malignant melanoma. Vet Comp Oncol. 2013;11(3):219–229.

10. Alexander AN, Huelsmeyer MK, Mitzey A, et al. Development of an allogeneic whole-cell tumor vaccine expressing xenogeneic gp100 and its implementation in a phase II clinical trial in canine patients with malignant melanoma. Cancer Immunol Immunother. 2006;55(4):433–442.

11. Gyorffy S, Rodriguez-Lecompte JC, Woods JP, et al. Bone marrow-derived dendritic cell vaccination of dogs with naturally occurring melanoma by using human gp100 antigen. J Vet Intern Med. 2005;19(1):56–63.

12. Milner RJ, Salute M, Crawford C, Abbot JR, Farese J. The immune response to disialoganglioside GD3 vaccination in normal dogs: a melanoma surface antigen vaccine. Vet Immunol Immunopathol. 2006;114(3–4):273–284.

13. Milner RJ, Chimura N, Bowles KD, Salute M. Abstract A29: Differential expression of the gangliosides GD3 and GD2 in canine and human osteosarcoma cell lines: An immunotherapy target. Cancer Immunol Res. 2015;3(10 Supplement):A29–A29.