Читать книгу Veterinary Surgical Oncology - Группа авторов - Страница 161

Benign melanocytic tumors comprise 3–4% of all skin tumors in dogs and 0.6–1.3% in cats. Malignant melanocytic tumors generally termed melanoma or malignant melanoma (MM), account for 0.8–2% of all cutaneous tumors in dogs and 0.4–2.8% in cats (Gross et al. 2005; Vail and Withrow 2007). MMs are more common in dogs with heavily pigmented skin, whereas cats with black or gray hair coats may be predisposed (Gross et al. 2005). Cutaneous and ocular melanomas in dogs usually behave in a benign manner, whereas amelanotic melanoma arising from mucocutaneous junctions, oral cavity, digits, and the nail bed tends to be malignant, with the tendency to rapidly invade surrounding tissue and to metastasize. Benign melanomas are usually small, pigmented, firm, dome‐shaped tumors of the skin that are freely moveable over deeper tissue structures. MMs tend to grow more rapidly with an invasive growth pattern; more commonly ulcerate, and appear brown, gray, or black, depending on the amount of melanin production (Goldschmidt and Hendrick 2002; Gross et al. 2005). Non‐pigmented or amelanotic melanomas can occur in the skin, but they are more commonly seen in the oral cavity (Vail and Withrow 2007).

In a study of 87 cases, canine cutaneous MM, postsurgery median progression‐free survival time, and median overall survival time have been reported to be 1282 days and 1363 days, respectively. With a post‐surgery metastatic rate of 21.8% and a local recurrence rate of 8%. Increasing mitotic index was predictive of a significantly decreased survival time on multivariable analysis (Laver et al. 2018).

In cats, 42–68% of cutaneous melanocytic tumors show malignant behavior (Gross et al. 2005). They more often involve the head (pinna, nose, and eyelids) or the digits and the eye.

Melanomas can be diagnosed easily by FNA cytology, but histologic evaluation is important to evaluate the malignancy and prognosis. Transformation from benign to malignant melanoma often occurs in humans, and the influence of ultraviolet radiation in the pathogenesis is well documented (Leiter and Garbe 2008). Such transformation has sporadically been reported in dogs. The treatment of choice for local cutaneous melanoma in both the cat and dog is surgical excision.

In cats, prognosis after surgical resection of non‐ocular cutaneous MMs is reasonable, with reported metastatic rates of 5–25% (Luna et al. 2000).

The prognosis for malignant‐behaving melanomas, especially located on the lip or oral cavity, is guarded to poor. In a study of Bostock (1979) 38 of 42 (90%) dogs with a histologically malignant melanoma of the lip or oral cavity died because of the tumor, compared to only 15 of 33 (45%) of malignant skin melanomas. A total of 6 of 59 (10%) dogs with a tumor of mitotic index of 2 or less died from tumor‐associated disease 2 years after surgery compared to 19 of 26 (73%) of dogs having a tumor with a mitotic index of 3 or more (Bostock 1979). WHO’s staging scheme for dogs with oral melanoma is based on diameter size: less than 2 cm tumor (stage I), 2 cm to less than 4 cm tumor (stage II), 4 cm or larger tumor and/or lymph node metastasis (stage III), and distant metastasis (stage IV).

Indoleamine 2,3‐dioxygenase (IDO) per high‐power field was identified as an independent marker for increased risk of death in dogs with primary melanocytic tumors (Porcellato et al. 2019).

As with human MM, response rates to chemotherapy, including mitoxantrone, intravenous melphalan, cisplatin, doxorubicin, carboplatin, and dacarbazine, are low and short‐lived in dogs (Bergman 2007; Vail and Withrow 2007). Carboplatin is reported to have activity against MM according to Rassnick et al. (2001). Smaller dogs were more likely to develop gastrointestinal toxicosis after treatment, and prophylactic gastrointestinal protectants should be considered when small dogs are treated (Rassnick et al. 2001).

There is no evidence that immunotherapy with liposome‐encapsulated muramyl tripeptide phosphatidylethanolamine (L‐MTP‐PE) administered after surgery alone or combined with recombinant canine granulocyte macrophage colony‐stimulating factor (rcGM‐CSF) has antitumor activity in treating advanced stage canine (oral) melanoma, but L‐MTP‐PE administration in early stage (I) may prolong survival time (MacEwen et al. 1999).

Bergman et al. (2003, 2006; Bergman 2007) reported the promising results of a canine melanoma vaccine. Thirty‐three stage II to III dogs with surgical locoregionally controlled melanoma had a median survival time of 569 days. This vaccine evoked a specific anti‐tyrosinase humoral immune response (Bergman et al. 2006). Since then several studies have been conducted on this vaccine, retrospectively, but have not delivered an unequivocal outcome of its effectiveness. Ottnod et al. (2013) reported the vaccine did not achieve a greater progression‐free survival, disease‐free interval, or median survival time for vaccinated compared to non‐vaccinated dogs. Verganti et al. (2017) reported that the vaccine could be considered as palliative treatment in dogs with stage IV disease.

As an adjuvant to surgery, the co‐injection of lipoplexes bearing herpes simplex virus thymidine kinase and canine interferon‐β genes at the time of surgery have been performed combined with the periodic administration of a subcutaneous genetic vaccine. This vaccine is composed of tumor extracts and lipoplexes carrying the genes of human interleukin‐2 and human granulocyte‐macrophage colony‐stimulating factor. This treatment significantly increased the rate of local disease‐free from 11 to 83% and distant metastases‐free from 44 to 89% in the dogs, as compared with surgery‐only‐treated controls. Compared to surgery alone, the treatment provided a significant 7‐fold increase in overall survival and >17‐fold increase in metastasis‐free survival. This approach seems to be able to significantly delay or prevent postsurgical recurrence and distant metastasis, increasing disease‐free and overall survival, and maintaining the quality of life (Finocchiaro and Glikin 2012; Finocchiaro et al. 2015).

Shin et al. tested four canine melanoma cell lines with high‐dose ascorbate in vitro. All cell lines exhibited reduced viability in a dose‐dependent manner. The authors suggested that in vitro high‐dose ascorbate has an anticancer effect on canine melanoma cell lines and advise further in vivo investigation (Shin et al. 2018).

In an in vitro canine melanoma cell line, plasmids encoding canine IL‐12 under constitutive and fibroblast‐specific promoters without the gene for antibiotic resistance were able to provide feasible tools for controlled gene delivery. In vivo studies showed a statistically significant prolonged tumor growth delay of CMeC‐1 tumors compared to control vehicle‐treated mice after intratumoral gene electrotransfer. The authors mention that this could be used for the treatment of client‐owned dogs (Lampreht et al. 2015, 2018).

Safety and immunogenicity of a potential checkpoint blockade vaccine for canine melanoma have been tested, with a mixture of three replication‐defective chimpanzee‐derived adenoviral vectors, one expressing mouse fibroblast‐associated protein (mFAP) and the others expressing canine melanoma‐associated antigens Trp‐1 or Trp‐2 fused into Herpes Simplex‐1 glycoprotein D, a checkpoint inhibitor of herpesvirus entry mediator (HVEM) pathways. All dogs responded with increased frequencies of mFAP‐specific activated CD8+ and CD4+ T cells. Further testing of this checkpoint blockade vaccine combination in dogs with melanoma is necessary (Kurupati et al. 2018). The rapidly expanding field of cancer immunology and immunotherapeutics means that rational targeting of MM in both humans and dogs should enhance treatment outcomes in veterinary and human patients.