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Oncology

Diagnosis and Treatment of Canine Oral Melanoma

In asymptomatic cases of OMM, an oral mass is often discovered by the owner or during a routine dental examination.

Brian T. MeyerDVM

Dr. Meyer is a medical oncology intern at the University of Tennessee College of Veterinary Medicine. He received his veterinary degree at Kansas State University and completed an internship at the University of Missouri. His special interests include canine osteosarcoma and immunotherapy.

Olya MartinDVC, DACVIM (Oncology)

Dr. Martin is a clinical associate professor in oncology at the University of Tennessee College of Veterinary Medicine. She received her DVM at the University of Tennessee and completed a rotating internship at the University of Illinois and a residency in oncology at the University of Tennessee. Dr. Martin’s special interests include canine and feline lymphoma, tyrosine kinase inhibitors, and metronomic chemotherapy.

Diagnosis and Treatment of Canine Oral Melanoma
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Malignant melanoma is the most common oral tumor in dogs. Overrepresented breeds include miniature poodle, dachshund, Scottish terrier, cocker spaniel, chow chow, and golden retriever.1-3 Most dogs that develop oral malignant melanoma (OMM) are older; there is no gender predilection.4 OMM must be differentiated from other malignant tumors of the oral cavity (e.g., squamous cell carcinoma, fibrosarcoma) as well as benign oral tumors and inflammatory and hyperplastic lesions, which are more prevalent than oral malignancies.5,6

PRESENTATION AND CLINICAL SIGNS OF OMM

Affected dogs may be asymptomatic. In these cases, an oral mass is often discovered by the owner or during a routine physical examination or dental prophylactic procedure. Clinical signs of OMM include halitosis, excessive drooling, bleeding from the oral cavity, dysphagia, facial swelling, and pain on mouth manipulation.4,7,8 OMMs are often pigmented (Figure 1), but up to 38% can be amelanotic.9 The most common locations are the gingiva, lips, tongue, and hard palate.3,4,10

DIAGNOSIS OF OMM

In some cases, especially if a tumor is pigmented, the diagnosis of OMM may be confirmed with cytology of a fine-needle aspirate. An incisional punch or a wedge biopsy, often in conjunction with immunohistochemistry (IHC), is needed for most nonpigmented oral tumors, as amelanotic melanoma can histologically mimic a poorly differentiated sarcoma or epithelial tumor. Application of IHC antibodies such as Melan-A, S-100, PNL2, TRP-1, and TRP-2 may be recommended by a pathologist to help reach a definitive diagnosis.11-13

Excisional biopsies result in incomplete margins and should be avoided when possible. If a tumor is small and an excisional biopsy is unavoidable, accurate documentation of tumor size and location, including photographs, is important for planning further treatment. Biopsy should always be performed from within the oral cavity. Special care should be taken to avoid contaminating normal tissue.

STAGING FOR OMM

Staging for OMM (Table 1) should include blood work (complete blood count and serum biochemistry profile), urinalysis, assessment of regional lymph nodes, and imaging of the thoracic cavity. Submandibular lymph nodes are the only palpable regional lymph nodes. Both ipsilateral and contralateral nodes should be aspirated regardless of size. Up to 40% of normal-sized lymph nodes may contain metastatic disease.15

Three-view thoracic radiography or thoracic computed tomography (CT) should be used to screen for pulmonary metastasis. Abdominal ultrasonography, although not routinely performed, should be considered to rule out metastasis to the liver and other intra-abdominal organs as well as comorbidities unrelated to melanoma.

Preoperative cross-sectional imaging of the head and neck is imperative for surgical planning, especially for tumors arising from the hard palate, caudal maxilla, or caudal mandible (Figure 2). Both CT and magnetic resonance imaging (MRI) are more sensitive than radiography for assessing the extent of invasion into the surrounding tissues, including bone. CT scans provide better bone detail than MRI. Cross-sectional imaging also allows assessment of the nonpalpable parotid and medial retropharyngeal lymph nodes.

TREATMENT OF OMM

Surgery for OMM

Surgery is the best means of achieving locoregional tumor control.16 When OMMs are excised, margins of at least 2 cm of normal tissue should be taken in all directions if possible.7 Margins must include bone when the tumor is located on the maxilla or mandible, necessitating a partial or full maxillectomy or mandibulectomy (Figure 3).

Removal of locoregional lymph nodes with suspected or confirmed metastatic disease may be beneficial.17 Removal of normal locoregional lymph nodes is not routinely performed.18 Sentinel lymph node mapping is being investigated in veterinary medicine and may prove to be useful in identifying target nodes for lymphadenectomy.19,20

Dogs that undergo oral surgery, including maxillectomy and mandibulectomy, have good cosmetic and functional outcomes (Figure 3). They enjoy a great quality of life, and many dogs adapt to their new jaw conformation and learn how to eat as early as 3 days after surgery.16 Ptyalism that reduces over time is the most commonly noted long-term side effect, especially after mandibulectomy.7

Radiation for OMM

Radiation therapy is another option for treatment of locoregional disease. Melanomas are considered to be relatively radioresistant tumors that may respond better to higher doses of radiation per fraction.21 A variety of radiation protocols have been described in veterinary literature.16 They typically consist of 3 to 6 treatments delivered either daily or weekly.22-24 Total doses of more than 30 Gy are associated with better tumor response.22-24 In the authors’ institution, a protocol of 4 weekly fractions of 8 Gy is preferred for both microscopic and gross OMM.

Chemotherapy and Immunotherapy for OMM

Chemotherapy has a limited role in management of canine OMM. The overall response rates in dogs with gross disease have been low, with the most promising rates being 18% for cisplatin and piroxicam25 and 28% for carboplatin.26 Moreover, multiple studies have failed to identify a survival benefit with addition of chemotherapy to surgery and radiation.24-26

Systemic immunotherapy for adjuvant treatment of canine melanoma may be more promising than chemotherapy. A xenogeneic DNA vaccine, Oncept (Boehringer Ingelheim, petcancervaccine.com), has made headway as the first conditionally approved immunotherapy for the treatment of canine OMM. Initial literature described promising activity against OMM: dogs with stage II and III OMM treated with Oncept after surgical resection (with or without radiation therapy) had longer median survival times (MSTs) than dogs in the control group.27 Subsequent studies failed to show similar significant differences in survival.28-30 However, these studies were retrospective, with small numbers of patients in vaccinated and nonvaccinated groups, among other weaknesses inherent to retrospective studies, and should be interpreted with caution. Other retrospective studies have shown evidence of complete responses to Oncept alone in dogs with gross disease.28,29

Based on the current body of research, Oncept melanoma vaccine is safe and easy to administer and may be an effective adjuvant systemic therapy for dogs with OMM.27,30 The authors believe that Oncept’s pitfalls and potential benefits should be discussed with owners on a case-by-case basis.

PROGNOSIS FOR OMM

The overall prognosis for OMM remains guarded. Most dogs die of metastatic disease. Dogs that undergo radical surgery that includes 2- to 3-cm bone and 1-cm soft tissue margins, or surgery and radiation therapy, have longer MSTs than dogs that receive no treatment.23,31 Overall, MSTs after complete excision are 1 to 2 years for stage I disease, 6 months to 2 years for stage II, and 5 to 8 months for stage III.31

Dogs with nonresectable tumors have shorter progression-free survival and MSTs. In a report looking at radiation as a sole treatment for dogs with macroscopic OMM, MSTs were highly variable.22 Dogs showing no negative prognostic indicators had an MST of up to 21 months; MST for dogs with 1, 2, or 3 negative prognostic indicators was 11, 5, and 3 months, respectively. Table 2 lists prognostic factors for canine OMM.

References

1. Dobson JM. Breed-predispositions to cancer in pedigree dogs. Vet Sci 2013:941275. doi: 10.1155/2013/941275

2. Boerkamp KM, Teske E, Boon LR, et al. Estimated incidence rate and distribution of tumours in 4,653 cases of archival submissions derived from the Dutch golden retriever population. BMC Vet Res 2014;10:34.

3. Ramos-Vara JA, Beissenherz ME, Miller MA, et al. Retrospective study of 338 canine oral melanomas with clinical, histologic, and immunohistochemical review of 129 cases. Vet Pathol 2000;37(6):597-608. doi: 10.1354/vp.37-6-597

4. Liptak JM. Cancer of the gastrointestinal tract. In: Vail DM, ed. Withrow & McEwen’s Small Animal Clinical Oncology. 6th ed. St. Louis, MO: Elsevier, Inc; 2020:432-490.

5. Mikiewicz M, Pazdzior-Czapula K, Gesek M, et al. Canine and feline oral cavity tumours and tumour-like lesions: a retrospective study of 486 cases (2015-2017). J Comp Pathol 2019;172:80-87.

6. Wingo K. Histopathologic diagnoses from biopsies of the oral cavity in 403 dogs and 73 cats. J Vet Dent 2018;35(1):7-17.

7. Sarowitz BN, Davis GJ, Kim S. Outcome and prognostic factors following curative-intent surgery for oral tumours in dogs: 234 cases (2004 to 2014). J Small Anim Pract 2017;58(3):146-153.

8. Bronden LB, Eriksen T, Kristensen AT. Oral malignant melanomas and other head and neck neoplasms in Danish dogs: data from the Danish veterinary cancer registry. Acta Vet Scand 2009;51(1):54.

9. Iussich S, Maniscalco L, Di Sciuva A, et al. PDGFRs expression in dogs affected by malignant oral melanomas: correlation with prognosis. Vet Comp Oncol 2017;15(2):462-469. doi: 10.1111/vco.12190

10. Smith SH, Goldschmidt MH, McManus PM. A comparative review of melanocytic neoplasms. Vet Pathol 2002;39(6):651-678.

11. Giudice C, Ceciliani F, Rondena M, et al. Immunohistochemical investigation of PNL2 reactivity of canine melanocytic neoplasms and comparison with Melan A. J Vet Diagn Invest 2010;22(3):389-394.

12. Ramos-Vara JA, Miller MA. Immunohistochemical identification of canine melanocytic neoplasms with antibodies to melanocytic antigen PNL2 and tyrosinase: comparison with Melan A. Vet Pathol 2011;48(2):443-450. doi: 10.1177/0300985810382095

13. Grandi F, Rocha RM, Miot HA, et al. Immunoexpression of S100A4 in canine skin melanomas and correlation with histopathological parameters. Vet Q 2014;34(2):98-104.

14. Owen LN. TNM Classification of tumors in domestic animals. World Health Organization. apps.who.int/iris/bitstream/handle/10665/68618/VPH_CMO_80.20_eng.pdf?sequence=1&isAllowed=y. Accessed November 2020.

15. William LE, Packer RA. Association between lymph node size and metastasis in dogs with oral malignant melanoma: 100 cases (1987- 2001). JAVMA 2003;222(9):1234-1236.

16. Bergman PJ, Selmic LE, Kent MS. Melanoma. In: Vail DM, ed. Withrow & McEwen’s Small Animal Clinical Oncology. 6th ed. St. Louis, MO: Elsevier, Inc; 2020:367-381.

17. Skinner OT, Boston SE, Souza CHdM. Patterns of lymph node metastasis identified following bilateral mandibular and medial retropharyngeal lymphadenectomy in 31 dogs with malignancies of the head. Vet Comp Oncol 2016;15(3):881-889. doi: 10.1111/vco.12229

18. Smith MM. Surgical approach for lymph node staging of oral and maxillofacial neoplasms in dogs. J Vet Dent 2002;19:170-174.

19. Brissot HN, Edery EG. Use of indirect lymphography to identify sentinel lymph node in dogs: a pilot study in 30 tumours. Vet Comp Oncol 2016;15(3):740-753. doi: 10.1111/vco.12214

20. Leong SPL, Accortt NA, Essner R, et al. Impact of sentinel node status and other risk factors on the clinical outcome of head and neck melanoma patients. Arch Otolaryngol Head Neck Surg
2006;132(4):370-373. doi: 10.1001/archotol.132.4.370

21. Khan BA, Khan MK, Almasan A, et al. The evolving role of radiation therapy in the management of malignant melanoma. Int J Radiat Oncol Biol Phys 2011;80(3):645-654. doi: 10.1016/j.ijrobp.2010

22. Proulx DR, Ruslander DM, Dodge RK, et al. A retrospective analysis of 140 dogs with oral melanoma treated with external beam radiation. Vet Radiol Ultrasound 2003;44(3):352-359.

23. Kawabe M, Mori T, Ito Y, et al. Outcomes of dogs undergoing radiotherapy for treatment of oral malignant melanoma: 111 cases (2006-2012). JAVMA 2015;247(10):1146-1153.

24. Dank G, Rassnick KM, Sokolovsky Y, et al. Use of adjuvant carboplatin for treatment of dogs with oral malignant melanoma following surgical excision. Vet Comp Oncol 2014;12:78-84.

25. Boria PA, Murry DJ, Bennett PF, et al. Evaluation of cisplatin combined with piroxicam for the treatment of oral malignant melanoma and oral squamous cell carcinoma. JAVMA 2015;246:1230-1237.

26. Brockley LK, Cooper MA, Bennett PF. Malignant melanoma in 63 dogs (2001-2011): the effect of carboplatin chemotherapy on survival. NZ Vet J 2013;61:25-31. doi: 10.1080/00480169.2012.699433

27. 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.

28. Turek M, LaDue T, Looper J, et al. Multimodality treatment including ONCEPT for canine oral melanoma: a retrospective analysis of 131 dogs. Vet Radiol Ultrasound 2020;61(4):471-480. doi: 10.1111/vru.12860

29. Ottnod JM, Smedley RC, Walshaw R, et al. 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.

30. Verganti S, Berlato D, Blackwood L, et al. Use of Oncept melanoma vaccine in 69 canine oral malignant melanomas in the UK. J Small Anim Pract 2017;58:10-16. doi: 10.1111/jsap.12613

31. Tuohy JL, Selmic LE, Worley DR, et al. Outcome following curative-intent surgery for oral melanoma in dogs: 70 cases (1998-2011). JAVMA 2014;245(11):1266-1273. doi: 10.2460/javma.245.11.1266

32. 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;48:54-72.

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