Treatment options for canine cutaneous mast cell tumors

Canine mast cell tumors are the most frequently diagnosed malignant skin neoplasms in dogs.1 Although they often appear as raised, erythematous, alopecic masses, mast cell tumors can adopt various benign or aggressive clinical presentations, as well as involve different anatomical sites (Figures 1-4). While dogs of any breed can develop mast cell tumors, overrepresented breeds include boxers, bulldogs, Boston terriers, Weimaraners, golden and Labrador retrievers, and Shar-Peis.2,3 Because you will likely encounter canine cutaneous mast cell tumors in your practice, this review article focuses on summarizing the therapeutic options available for treating canine mast cell tumors. With a better understanding of available treatment regimens, you will be able to educate and guide pet owners regarding the treatment options that may best suit their dogs.

FIGURE 1. A large pedunculated cutaneous mast cell tumor on a mixed-breed female dog. This mass was assumed to be benign until cytologic and histopathologic diagnosis of mast cell disease was confirmed three years after being first noticed. FIGURE 2. Shar-Peis are reported to have more aggressive and invasive mast cell tumors. This female Shar-Pei had diffuse infiltrative mast cell disease originating from the medial aspect of the left hindlimb, with rapid involvement of the mammary tissues. FIGURE 3. A hyperpigmented raised lesion involving the left lateral thigh region. Given the anatomical location, complete surgical excision with wide margins was obtained, providing a local cure for this dogs grade II mast cell tumor. FIGURE 4. A raised erythematous mucocutaneous lesion involving the preputial orifice on a castrated male pug. The mass was surgically excised and confirmed to be a grade II mast cell tumor.

BIOLOGIC BEHAVIOR AND CLINICAL STAGE

Before instituting the most appropriate therapy, it is important to understand that treatment options are based on the predicted biologic behavior, as well as the extent of disease associated with canine mast cell tumors. Histologic grade has been shown to be the most important prognostic factor for predicting biologic behavior and survival times in dogs with mast cell tumors.2 Currently in dogs, mast cell tumors are histologically categorized into grades I, II, and III (Table 1). With surgical resection only, the percentages of dogs surviving 1,500 days after diagnosis have been reported to be 83%, 44%, and 6% for grades I, II, and III tumors, respectively.2 Grade I mast cell tumors tend to be locally confined to the skin and nonmetastatic. Grade II mast cell tumors are generally local, but some can be aggressive with regional node and distant organ metastasis. Grade III mast cell tumors tend to be biologically aggressive, possessing a high propensity for regional and distant metastasis. Although histologic grade remains the gold standard for predicting the biologic behavior of cutaneous mast cell tumors, other prognostic factors include tumor location, proliferative indices, breed, recurrence, c-kit mutations, c-kit staining pattern, and microvessel density.4-11

TABLE 1. Accepted Histologic Grading System for Cutaneous Canine Mast Cell Tumors

In addition to biologic behavior, the appropriate treatment for canine mast cell tumors will also be dictated by the extent of disease, referred to as the clinical stage (Table 2). To determine the clinical stage in dogs with mast cell tumors, a complete blood count, a serum chemistry profile, urinalysis, a thoracic radiographic examination, and an abdominal ultrasonographic examination should be performed before therapy is begun. Additionally, because mast cell tumors may spread to regional or distant sites, bone marrow aspirates and the cytologic evaluation of regional lymph node, liver, and spleen samples may also be recommended as part of the routine staging procedure. For dogs with locally confined tumors (stage 0 to 1), the treatment of grade I or II mast cell tumors should include surgery alone or surgery in combination with curative-intent radiation therapy. For stage 0-1 grade III mast cell tumors, local treatment options should also be implemented, but systemic chemotherapy should be recommended given the high metastatic rate associated with grade III mast cell tumors. In dogs with stage 2-4 tumors, combining local therapies with systemic chemotherapy should be offered in attempts to provide improved quality of life and prolonged survival times.

TABLE 2. Clinical Staging of Mast Cell Tumors

DEFINITIVE TREATMENTS FOR LOCALIZED DISEASE

Definitive surgery can be performed in most practice settings, requiring neither additional instrumentation nor specialized equipment. Definitive surgery is most appropriate in dogs with localized mast cell tumors of low or intermediate histologic grade (grade I or II, respectively). Surgery is also best suited for tumors involving anatomical sites amenable to wide resection.

Two recent reports describe the effectiveness of surgery alone for treating grade II, localized cutaneous mast cell tumors.12,13 The studies found that surgical resection was an effective treatment option, with recurrence in only 5% to 11% of dogs after complete excision. These studies emphasize that complete excision is often a curative treatment option, when anatomically feasible, for localized cutaneous mast cell tumors in dogs.

Because definitive surgery of localized mast cell tumors may be curative, defining the extent of surgical margins required for complete excision is important. A recent study assessed the surgical margins necessary for completely excising grades I and II cutaneous mast cell tumors greater than 1 cm in diameter. The results suggest that complete excision of cutaneous mast cell tumors should be achievable with lateral surgical margins of 2 cm and deep surgical margins including one fascial plane.14

Although obtaining complete margins should be the goal of any definitive surgical procedure, one recent study did not find any difference between local tumor recurrences in dogs with histologically tumor-free vs. nontumor-free margins. This unexpected finding may be due to the small sample population analyzed, so strong conclusions should not be drawn from this study.15 In addition, when looking at surgical margins for mast cells, normal mast cells often cannot be differentiated from neoplastic ones, complicating the interpretation of clean vs. dirty surgical margins.

ADJUVANT TREATMENTS FOR LOCALIZED OR REGIONAL LYMPH NODE METASTATIC DISEASE

Not all dogs with localized mast cell tumors are candidates for curative surgery. In some situations, surgery may only be cytoreductive, thereby leaving behind either residual microscopic or even macroscopic disease (Figure 5). For these patients, instituting adjuvant therapies should be recommended to decrease the likelihood of local tumor regrowth. Best suited for the management of small tumor burdens, adjuvant therapies should be instituted shortly after cytoreductive surgeries before measurable tumor regrowth. Although the most effective adjuvant therapy for treating canine cutaneous mast cell tumors is external beam megavoltage radiation therapy, other treatment options such as systemic chemotherapy, intraregional deionized water, and interstitial brachytherapy have been investigated.

FIGURE 5. A large and invasive mast cell tumor involving the left tarsus in a female Labrador retriever. The size and location of the tumor precluded complete surgical excision. The dog was treated with cytoreductive surgery, and the residual microscopic disease was cured with curative-intent megavoltage radiation therapy.

External beam megavoltage radiation therapy

External beam megavoltage radiation therapy is the most effective and best described adjuvant treatment currently used for managing incompletely resected cutaneous mast cell tumors (Figure 6). To adequately treat localized, microscopic disease, individual doses of radiation, or fractions, are repeatedly delivered to the tumor site and margins. The therapeutic goal of radiation therapy can be categorized as either curative-intent or palliative; these two treatment intents differ in the total number of fractions delivered and the amount of radiation energy administered per treatment fraction.

FIGURE 6. This German shepherd was treated with surgical excision followed by curative-intent radiation therapy for a mast cell tumor involving the metatarsal area. The alopecic area and abnormal looking skin represent early self-limiting side effects of radiation therapy.

Curative-intent radiation involves delivering multiple sequential fractions, usually every day or every other day, for three to six weeks. As implied, the purpose of curative-intent radiation is to provide durable and definitive local tumor control. Patients receiving radiation therapy are sedated or anesthetized during each treatment session. Adequate patient immobilization ensures the accurate delivery of radiation therapy to the target site, allowing for maximal tumor kill and minimal adverse effects to normal surrounding tissues. However, radiation side effects are common in dogs receiving curative-intent treatment and may include moist desquamation, hair loss, pain, inflammation, and localized erythema.

In several reports, curative-intent radiation therapy has been demonstrated to be effective in treating incompletely resected cutaneous mast cell tumors in dogs.16-19 In these clinical studies, curative-intent radiation therapy for microscopic residual disease prevented local tumor recurrence in most (about 90% to 95%) of the dogs treated.

In addition to its effectiveness in treating localized microscopic disease, curative-intent radiation therapy is useful for treating regionally metastatic cutaneous mast cell tumors. In one report, grade III cutaneous mast cell tumors with or without regional lymph node metastasis, were treated with curative-intent radiation. Both incompletely resected microscopic disease and macroscopic tumor burden within the affected lymph nodes received curative-intent radiation therapy. In this study, dogs receiving radiation therapy achieved a median survival time of 28 months. However, most tumor-related deaths were attributed to regional disease progression, emphasizing the limitation of curative-intent radiation therapy for treating metastatic, high-grade mast cell tumors.20

In a second study, dogs with incompletely excised cutaneous mast cell tumors with regional lymph node metastasis were treated with a combination of oral prednisone and curative-intent radiation therapy. In that study, dogs receiving radiation to both the primary tumor site and metastatic lymph nodes, in conjunction with oral prednisone therapy, achieved an impressive median survival time of 1,240 days.21 These results may suggest that incompletely excised, high-grade mast cell tumors and their associated regional metastasis are best treated with a combination of adjuvant therapies.

Systemic chemotherapy

Although curative-intent radiation therapy is effective for treating residual microscopic cutaneous mast cell tumors, the need for special facilities and associated high treatment costs have limited its use to pet owners with adequate financial means and a willingness to seek treatment from veterinary specialists. Because of these limitations, other adjuvant treatment options have been evaluated for treating residual cutaneous mast cell tumors, including the use of systemic chemotherapy.

The efficacy of systemic chemotherapy for treating measurable canine mast cell tumors has been recently reported.22-26 Intuitively, if chemotherapeutic agents possess efficacy against measurable cutaneous mast cell tumors, it would be expected that these same antineoplastic drugs would also be effective in managing residual microscopic disease. Unfortunately, prospective clinical trials evaluating the efficacy of systemic chemotherapy or oral prednisone for treating residual microscopic disease are few. In one study, seven dogs with residual microscopic disease were treated with prednisone and vinblastine in lieu of curative-intent radiation therapy.22 The median survival time of these seven dogs was more than 1,013 days, thereby suggesting the therapeutic efficacy of prednisone and vinblastine used in an adjuvant setting for the treatment of residual mast cell tumor disease. To better support the adjuvant use of systemic chemotherapy, a recent report evaluated the therapeutic effectiveness of prednisone and vinblastine in 27 dogs with inadequately excised cutaneous mast cell tumors (24 grade II, three grade III). In that study, 20 dogs available for follow-up were evaluated for local and distant tumor growth after a median of 537 days. Two dogs (10%) experienced local tumor regrowth, but four additional dogs developed new mast cell tumors involving distant cutaneous sites.27

Collectively, it may be concluded from clinical studies evaluating the effectiveness of systemic chemotherapy for treating mast cell tumors that adjuvant systemic chemotherapy for treating residual microscopic disease is an alternative to curative-intent radiation therapy. However, additional studies are required to better define the true effect of different systemic chemotherapy protocols for treating residual neoplastic mast cell disease. Systemic chemotherapy administration is not restricted to referral centers, so it is a more widely available therapeutic option for both pet owners and veterinary practitioners. If you choose to treat an animal with adjuvant systemic chemotherapy, you must know the basic precautions required for the safe handling and administration of chemotherapy.

Intraregional deionized water

Mast cells are sensitive to changes in osmolality and when exposed to hypotonic solutions, will undergo cellular swelling and ultimately membrane lysis. Based on this cellular response, several studies have evaluated the safety and efficacy of intraregional deionized water injections as an adjuvant treatment for incompletely resected cutaneous mast cell tumors. Although all studies suggest that intraregional deionized water injections are well-tolerated, a marked disparity exists among studies regarding the efficacy of the injections in preventing local tumor recurrence.28-30

In one study, the survival times and tumor recurrence rates were compared between two treatment groups: dogs receiving only surgical resection (n = 28) and dogs receiving surgical resection and adjuvant intraregional deionized water injections (n = 27). Disconcertingly, dogs treated with surgery and intraregional deionized water injections experienced greater local tumor recurrences and shorter overall survival times than did dogs treated with surgery alone.29 These results suggested that intraregional deionized water injections may negatively influence the outcome of dogs with mast cell tumors.

In direct contrast, two other reports discuss intraregional deionized water injections as being effective when used in an adjuvant setting. In one study, 74 dogs with 118 mast cell tumors were treated with surgery alone or surgery combined with intraregional deionized water injections.28 The local tumor recurrence rate in dogs receiving only surgery was 52.6% (10/19), while dogs treated with surgery and the injections had a recurrence rate of 26.2% (26/99). Furthermore, in a recent pilot investigation, only one dog out of 17 with incompletely resected cutaneous mast cell tumors treated with adjuvant intraregional deionized water injections developed local tumor regrowth.30 Although intraregional deionized water injections may be reasonable for the adjuvant treatment of small, low- to moderate-grade mast cell tumors, their use is unlikely to be beneficial in treating diffuse, infiltrative tumors or aggressive grade III mast cell tumors.

The cost-effectiveness and ease of administering intraregional deionized water injections makes this investigational adjuvant therapy attractive. However, the direct contradictory results from clinical trials assessing their efficacy for treating resected cutaneous mast cell tumors remain problematic and a reason for concern. Until further studies are conducted to better clarify the role of deionized water injections, it remains difficult to wholeheartedly support this adjuvant treatment option. Additionally, despite being reported as well-tolerated, it is the experience of many clinicians that deionized water injections can cause moderate pain and discomfort.

Interstitial brachytherapy

Brachytherapy is a radiation treatment modality in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near a tumor. Treatment with brachytherapy may be intracavitary, intraluminal, or interstitial. For interstitial brachytherapy, radioactive materials are placed directly through the body tissue encompassing the tumor. Iridium-192 is a radioisotope capable of releasing both gamma and beta particles and can be used as a radioactive source for brachytherapy.

Recently, interstitial brachytherapy with iridium-192 has been evaluated as an adjuvant treatment for cutaneous mast cell tumors in dogs.31 In this study, nine dogs with microscopic residual disease and two dogs with macroscopic disease were treated with interstitial brachytherapy. Five of the 11 treated dogs ultimately had local tumor regrowth at a median of 1,391 days. Although a high percentage of dogs experienced tumor recurrence, the long median latency period before tumor regrowth was impressive. Given the extended period between initial brachytherapy and local regrowth, it remains a possibility that some of the dogs identified as treatment failures may actually have been affected with de novo tumor formation.

Interstitial brachytherapy offers some advantages over conventional external beam megavoltage radiation therapy, including more localized energy deposition, greater normal tissue sparing effect, and decreased total treatment duration. Unfortunately, the number of facilities offering brachytherapy is limited, and in conjunction with the observed high incidence for local tumor regrowth (5/11), it is difficult to recommend interstitial brachytherapy as a realistic or practical adjuvant treatment option for incompletely resected mast cell tumors.

TREATMENTS FOR MACROSCOPIC AND METASTATIC DISEASE

Contrary to the success in treating localized disease with surgery alone or with adjuvant therapies, the effective management of surgically nonresectable macroscopic disease or advanced distant metastatic mast cell disease remains problematic. In these patients with extensive disease, the intent of therapy is no longer curative. Rather, therapy should be focused on reducing tumor burden, improving quality of life, and prolonging survival times. Therapies with these defined goals are categorized as palliative. Several palliative treatment options exist for managing noncurable mast cell tumors in dogs, including systemic chemotherapy, palliative radiation, and intralesional triamcinolone.

Systemic chemotherapy

Although potentially useful as an adjuvant to surgery, systemic chemotherapy has been traditionally indicated to treat metastatic and nonresectable mast cell tumors. Several studies have identified chemotherapeutic regimens possessing marginal to moderate therapeutic efficacy for treating advanced mast cell tumors in dogs (Table 3). The response rates, duration of remission, disease-free intervals, and survival times of dogs with metastatic or nonresectable mast cell tumors can be quite variable, with a subset of patients maintaining a high quality of life for an extended period. For this reason, treatment options for patients with advanced disease should not be limited solely to euthanasia.

TABLE 3. Systemic Chemotherapy for Macroscopic Mast Cell Tumor Burden

Most chemotherapeutic regimens are easy to administer, but specialized equipment is recommended (a biologic safety cabinet) to minimize unnecessary and hazardous exposure to chemotherapeutic agents. In addition, familiarity with the handling, safety, side effects, and administration of each anticancer agent should be considered a necessity before instituting chemotherapy.

Radiation of macroscopic tumors: Curative and palliative fractionation schemes

When cytoreductive surgeries are not an option for cutaneous mast cell tumors, using radiation therapy alone or in conjunction with other adjuvant therapies may be considered (Figure 7). In one study, 21 dogs with macroscopic tumor burden were treated with curative-intent radiation therapy.19 As would be expected, the initial tumor volume affected the duration of response to radiation therapy. Dogs with tumor volumes 9 cm3 or less had a significantly longer disease-free interval (about 20 months) than dogs with tumor volumes 10 cm3 or greater (about four months) had. While dogs with larger tumors had a shorter duration of response, the results from this study support the role of curative-intent radiation therapy for managing dogs with macroscopic tumor burden.

FIGURE 7. This male Labrador retriever is suffering from aggressive multicentric cutaneous mast cell disease. Therapeutic options, including palliative radiation therapy and systemic chemotherapy, provided a partial clinical response and quality-of-life improvement. FIGURE 8. Intralesional therapy with triamcinolone may be useful in reducing the size of mast cell tumors before surgical resection or for shrinking macroscopic tumors for palliative purposes.

Although curative-intent radiation may have a role in treating macroscopic disease, a large time and financial commitment is required of pet owners. In some situations, palliative radiation therapy may be considered a more appropriate treatment option. In comparison to curative-intent treatment regimens, palliative radiation involves administering larger doses of radiation at less frequent intervals. A typical palliative protocol would be administering one large dose of radiation every week for four consecutive weeks.

With the intent of increasing therapeutic effectiveness, palliative radiation therapy can be combined with other adjuvant treatments such as oral prednisone or systemic cytotoxic chemotherapy. In one recent study, 35 dogs with nonresectable cutaneous mast cell tumors were treated with oral prednisone and palliative radiation therapy.32 This palliative treatment protocol provided an impressive overall response rate of 88.5%, with 12 complete responses and 19 partial responses. In addition to the high response rate, the median progression-free survival time of treated dogs was 1,031 days.

Radiation therapy, either curative-intent or palliative, to treat nonresectable cutaneous mast cell tumors should be considered a viable treatment option in dogs. Although most dogs will ultimately experience local tumor recurrence or distant metastasis, reasonably long median survival times appear to be achievable. Combining radiation therapy with other systemic adjuvant treatments such as oral prednisone or chemotherapy may provide beneficial additive effects, further improving quality-of-life scores and survival times in dogs with macroscopic tumor burdens.

Intralesional triamcinolone

Corticosteroids are often used to treat cutaneous mast cell tumors, either as single agents or preferably in combination with other adjuvant therapies. The direct injection of the long-acting corticosteroid triamcinolone into cutaneous mast cell tumors has been anecdotally reported to be an effective treatment option (Figure 8). Biologically, the reduction in mast cell tumor size subsequent to intralesional corticosteroid administration may be attributed to reduced peritumoral inflammation and swelling, as well as a direct cytolytic effect on neoplastic mast cells.

Because of the lack of controlled clinical trials evaluating the efficacy of specific intralesional protocols, dosing regimens may vary widely among veterinary practitioners. Anecdotally reported protocols include injecting 1 mg triamcinolone for every centimeter of the tumor's diameter every 14 days and injecting a systemic dose of triamcinolone (0.22 mg/kg) uniformly into the tumor every two or three weeks.

Intralesional corticosteroid administration is an easy and cost-effective means to reduce measurable tumor burden. It is best suited for relatively small mast cell tumors and should be considered a treatment option to reduce the size of localized tumors before definitive surgical resection. In addition to serving as a neoadjuvant before curative surgery, intralesional therapy may be useful as a palliative treatment option in small- to moderate-size tumors that are refractory to radiation therapy or chemotherapy.

TARGETED THERAPIES

Mast cells grow and proliferate in response to specific cellular signals transduced by membrane-bound receptors, such as c-kit. Mutations in c-kit signaling can dysregulate cellular physiology, leading to the formation of a neoplastic population of mast cells. It has been confirmed that some malignant mast cell tumors in dogs carry a mutation in the gene coding for the c-kit receptor, resulting in unregulated intracellular signaling, cell proliferation, and subsequent mast cell tumor formation.33,34

In laboratory experiments, indolinone derivatives capable of inhibiting constitutively activated c-kit mutants have shown promise in killing neoplastic mast cells in vitro.35 As a clinical corollary, one recent study evaluated the use of an indolinone derivative (SU11654) for treating spontaneous canine cutaneous mast cell tumors.36 Study results demonstrate SU11654 to be well-tolerated and therapeutically effective. Of the 22 dogs with mast cell tumors treated with SU11654, 50% experienced tumor shrinkage, with six patients achieving a complete remission. Although the findings from this clinical study are extremely promising and could dramatically change the way we treat cancers such as cutaneous mast cell tumors, additional prospective trials need to delineate the exact role of small molecule inhibitors, such as SU11654, for treating cancer-bearing pets.

SUPPORTIVE THERAPIES

In dogs with extensive tumor burden, ancillary therapies to minimize the systemic effects of mast cell degranulation should be implemented. Mast cells are capable of liberating a wide range of preformed and newly synthesized inflammatory mediators, which can cause marked patient morbidity and mortality. Histamine is one predominant inflammatory mediator released by degranulating mast cells, so treatment with histamine-blocking agents may decrease the likelihood of undesirable paraneoplastic complications. Blocking gastric H2 receptors with either cimetidine (5 to 10 mg/kg orally t.i.d. to q.i.d.), ranitidine (1 to 4 mg/kg orally b.i.d. to t.i.d.), or famotidine (0.3 to 0.6 mg/kg orally b.i.d. to t.i.d.) should be implemented to minimize gastroduodenal irritation from excessive parietal cell hydrochloric acid secretion. Occasionally, dogs not responding to H2 blockade may benefit from a proton-pump inhibitor such as omeprazole (0.5 to 1 mg/kg orally once a day). Blocking the H1 receptors with diphenhydramine (1 to 4 mg/kg orally t.i.d.) or hydroxyzine (2.2 mg/kg orally t.i.d.) may be indicated to minimize complications derived from peripheral H1 receptor activation, such as hypotension, bronchospasms, local erythema, swelling, and pain.

CONCLUSION

Although mast cell tumors in dogs were described more than a century ago, our understanding of the etiopathogenesis for malignant mast cell transformation is constantly expanding. Several treatment options exist for canine cutaneous mast cell tumors. Localized mast cell tumors are often cured with surgery, radiation therapy, or a combination of the two. Successful management of nonresectable mast cell tumors may be achieved with combination adjuvant therapies, with many patients experiencing high quality-of-life scores and long survival times. Most important, the recent discovery of small molecule inhibitors such as SU11654, demonstrating therapeutic efficacy against cutaneous mast cell tumors, may revolutionize cancer management in companion animals.

Timothy M. Fan, DVM, DACVIM (internal medicine, oncology)

Louis-Philippe de Lorimier, DVM

Department of Veterinary Clinical Medicine

College of Veterinary Medicine

University of Illinois

Urbana, Il 61802

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