Mast cell tumors in the dog

Vet Clin Small Anim 33 (2003) 473–489

Mast cell tumors in the dog Cheryl A. London, DVM, PhD*, Bernard Seguin, DVM, MS Department of Surgical and Radiological Sciences, 2112 Tupper Hall, One Shields Avenue, University of California at Davis, Davis, CA 95616, USA

In most species, neoplastic processes involving mast cells are relatively uncommon. In contrast, mast cell tumors (MCTs) occur frequently in the pet population, representing up to 20% of all cutaneous canine tumors [1–3]. As such, a detailed comprehension of the diagnosis and treatment of mast cell neoplasia in the dog is extremely important. Before discussing the specifics of MCTs, however, it is first necessary to understand normal mast cell biology. Mast cell biology Morphologic characteristics of mast cells Mast cells are discrete round cells roughly one to three times the size of a neutrophil. They possess a round to oval nucleus and distinct cytoplasmic granules that stain with dyes, such as toluidine blue, Giemsa, and methylene blue. Such staining is a result of the affinity of these basic dyes for the acidic proteoglycans contained in the mast cell granules [4–7]. Some of these dyes assume a different color when bound by the granules than they do when staining nuclear DNA, so that the granules are often called metachromatic. Although mast cells may be visualized on hematoxylin and eosin–stained sections, the dyes described previously are used to characterize mast cells definitively. Moreover, mast cell granules may not be visualized with stains like Diff-Quick (Dade Behring, Deerfield, IL), precluding identification on some cytologic specimens [8]. Development of mast cells Mast cells are derived from bone marrow precursor cells. They leave the bone marrow in a presumed immature state and migrate to many * Correspondence. E-mail address: [email protected] (C.A. London). 0195-5616/03/$ - see front matter Ó 2003, Elsevier Inc. All rights reserved. doi:10.1016/S0195-5616(03)00003-2

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tissues, particularly those having primary contact with foreign antigens (eg, skin, respiratory and gastrointestinal tracts), where they then mature into tissue mast cells [5]. Cytokines important in the development and maturation of mast cells include interleukin (IL)-3, IL-6, IL-4, and stem cell factor (SCF) among others [5]. The local tissue microenvironment in which mast cells mature determines the subsequent functional capacities of these cells. For example, mast cells in the mucosa of the gastrointestinal tract (labeled mucosal mast cells) have chondroitin sulfate as their major granule proteoglycan and contain little histamine. In contrast, mast cells in the lung and serosa of body cavities (labeled tissue mast cells) contain heparin as their major granule proteoglycan and produce large amounts of histamine [4]. Experiments in mice suggest that the functional characteristics of mast cells are not fixed, because granule content can change if mast cells are moved from one environment to another. In summary, the precise nature of the mast cell and the mediators it can produce varies with its anatomic location and is probably regulated by the local cytokine environment. Function of mast cells Mature mast cells bind IgE on their cell surface through expression of the high-affinity IgE receptor (FceRI). Mast cells also express receptors for complement components (particularly C5a). The primary manner in which mast cells are activated is by cross-linking of the FceRI-bound IgE on their cell surface, leading to the release and production of various mediators including the following [4,5]: a. Contents of granules, such as histamine, heparin, chondroitin sulfate, mast cell proteases, and others b. Lipid mediators, such as prostaglandins, leukotrienes, and plateletactivating factor c. Cytokines, such as tumor necrosis factor-a, IL-3, IL-4, IL-5, and IL-6 The mediators described here lead to several reactions, including increased vascular permeability, vasodilation, smooth muscle spasm, pruritus, anticoagulation, and activation of eosinophils and neutrophils. Collectively, these effects can lead to local hypersensitivity reactions, or more seriously, to systemic hypersensitivity (anaphylactic shock) [4]. As such, mast cells have primarily been associated with allergic reactions/disorders. It is now evident that mast cells seem to play an important role in the initiation of innate immune responses. Experiments in mice demonstrated that mast cells were important in initiating and sustaining neutrophil migration and activation in response to bacteria [6]. Indeed, mast cells are often seen at sites of inflammation as well as in reactive lymph nodes. Therefore, in addition to playing a role in the induction of pathologic allergic responses, mast cells are critical players in protective immune responses.

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Canine mast cell tumors Incidence and signalment As previously mentioned, the MCT is the most common skin tumor of the dog and one of the most common malignant tumors noted in the canine population. Whereas MCTs are usually found in older dogs (mean age of approximately 8–9 years), they have also been reported in younger dogs [9– 12]. Several breeds seem to be at increased risk for the development of MCTs, including dogs of bulldog descent (Boxer, Boston Terrier, and English Bulldog), Labrador and Golden Retrievers, Cocker Spaniels, Schnauzers, and Chinese Sharpeis [9,12–14]. No sex predilection has been reported. Etiology The etiopathogenesis of MCTs in the dog is unknown, as is the reason for the extremely high incidence in this species. Although some studies have suggested the possibility of a viral cause and MCTs have been transmitted from dogs with solid tumors to susceptible laboratory dogs using tumor tissue or extracts, there is no epidemiologic evidence to indicate horizontal transmission of tumors [15]. Because most of the tumors arise in the skin, it has been suggested that topical carcinogens may play a role in this disease. No reports exist to imply such a cause, however, and there seems to be no particular regional distribution of these tumors. The increased incidence of MCTs in certain breeds suggests the possibility of an underlying genetic cause [13]. Interestingly, although dogs of bulldog ancestry are at higher risk for MCT development, it is generally accepted that MCTs in these dogs are more likely to be benign [12]. As previously mentioned, SCF is an important growth factor for mast cells [7]. The receptor for SCF is Kit, encoded by the proto-oncogene c-kit; SCF-Kit interactions are required for the differentiation, survival, and function of mast cells [7,16–21]. Mutations in c-kit leading to activation of Kit in the absence of SCF binding have been demonstrated to occur in systemic mastocytosis in people [22–28]. Additionally, Kit dysfunction has now been recognized in a variety of other human cancers, including gastrointestinal stromal tumors, small cell lung cancer, ovarian carcinoma, and gliomas [29–36]. Several authors have recently identified the presence of activating mutations in the proto-oncogene c-kit in canine MCTs. These mutations consist of internal tandem duplications in the negative regulatory juxtamembrane domain of Kit [37–40]. The high frequency of mutations in a gene known to play a role in tumorigenesis suggests that aberrations in c-kit may be involved in the development or progression of MCTs in dogs. History and clinical signs Although normal mast cells are found in abundance in the lungs and gastrointestinal tract, the overwhelming majority of MCTs in the dog occur

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in the dermis and subcutaneous tissue [9,41]. Rarely, primary MCTs may present in other sites, such as the oral cavity, nasopharynx, larynx, and gastrointestinal tract [42,43]. Visceral MCT involving the spleen, liver, or bone marrow (often referred to as disseminated mastocytosis) is usually the result of systemic spread of an aggressive primary cutaneous MCT, although it can occur as an independent syndrome [44,45]. Primary mast cell leukemia in the dog is extremely rare. Cutaneous MCTs usually occur as solitary nodules, although roughly 10% to 15% of dogs present with multiple tumors [46]. Approximately 50% of cutaneous MCTs occur on the trunk and perineal region, 40% on the limbs, and 10% on the head and neck [2,46,47]. Perhaps most importantly, the clinical appearance of MCTs can vary widely. Dermal MCT may be well circumscribed, raised, and firm, or the surface maybe erythematous and ulcerated; invasion into the subcutaneous tissue may be present. MCTs arising in the subcutaneous tissue are often poorly circumscribed and may resemble lipomas. It is therefore not possible to identify a cutaneous lesion as an MCT simply by its appearance. Cutaneous MCTs may also be present for various lengths of time. In general, MCTs that are slow growing and present for at least 6 months are more likely to behave in a benign manner, whereas those that are rapidly growing large tumors are more likely to behave in a malignant manner [41]. The duration of the lesion does not always predict the subsequent biologic behavior, however. Clinical signs of MCTs are caused by the release of histamine, heparin, and other vasoactive amines. Mechanical manipulation of the tumor during physical examination can induce degranulation leading to erythema and wheal formation (termed Darrier’s sign), and an owner occasionally reports that the tumor seems to change in size over short periods [47]. Gastrointestinal ulceration is also a potential complication of MCTs; between 35% and 83% of dogs with MCTs that underwent necropsy had evidence of gastric ulcers, and plasma histamine concentrations were found to be elevated in dogs with MCT [48,49]. Elevated histamine levels presumably lead to stimulation of H2 receptors on parietal cells, excessive gastric acid production, and the development of ulcers. Consequently, signs like vomiting, anorexia, melena, and abdominal pain may be present. In one study, the levels of histamine in dogs with MCTs were not related to clinical stage, histologic grade, or tumor size [48]. Diagnosis Cytologic evaluation of fine-needle aspirates is probably the easiest method to diagnose the presence of an MCT. The mast cells appear as discrete round cells with a round to oval centrally placed nucleus that may be difficult to visualize because of the presence of granules. As mentioned previously, mast cell granules may not stain with Diff-Quik, leading to

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difficulty in making a definitive diagnosis by cytology. Additionally, poorly differentiated malignant mast cells may contain few, if any, granules; in this case, special stains (eg, toluidine blue, Giemsa) may be required. Other round cell tumors that should be included in the differential diagnosis include lymphoma, plasmacytoma, histiocytoma, amelanotic melanoma, and transmissible venereal tumor. Whereas the diagnosis of MCT can almost always be made by fine-needle aspiration cytology, excisional biopsy is required for histologic grading of the tumor. It is important to note that because wide surgical excision is the treatment most likely to cure most MCTs, every effort should be made to obtain a definitive diagnosis via cytology before surgical intervention. Moreover, because any cutaneous tumor may potentially be an MCT, fine-needle aspiration should be performed on all masses before removal. If cytologic diagnosis proves difficult, a needle or punch biopsy of the tumor can be obtained before surgery. This may be preferable to a larger incisional biopsy, because local release of mast cell mediators will significantly inhibit healing and may result in excessive bleeding. Staging Because any MCT is capable of metastasis, all dogs with MCTs should be staged to determine the extent of their disease and overall health. This is particularly important for dogs in which radiation therapy may be used in the course of treatment. Some of or all the following procedures may be indicated. Complete blood cell count, biochemistry profile, urinalysis These tests are part of a minimum database and should be included in the workup of any animal suspected to have cancer. Dogs with MCTs may have eosinophilia because of chemotactic factors and IL-5 produced by the mast cells [4]. Anemia may be present secondary to hypersplenism or gastrointestinal bleeding. Occasionally, mast cells may be seen on a routine complete blood cell count. Buffy coat smear A buffy coat smear is made by spinning peripheral blood in a microhematocrit tube, breaking the tube at the buffy coat layer, and smearing the concentrated leukocytes on a slide. The buffy coat is then carefully examined for the presence of mast cells. For many years, examination of the buffy coat for circulating mast cells has been used to screen dogs with MCTs for the presence of systemic/metastatic disease. It was originally believed that although the buffy coat smear was not an extremely sensitive test, it was fairly specific for mast cell neoplasia. It is now clear that this may not be the case,

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however, because several studies have demonstrated that dogs with many different kinds of disease, including pneumonia, parvovirus, pancreatitis, skin disease, and gastrointestinal diseases, may have mast cells circulating in the periphery [50–52]. In summary, the buffy coat smear is a relatively easy test to perform; the finding of circulating mast cells in a patient with cutaneous MCT warrants further investigation. Bone marrow aspiration In the normal bone marrow, mast cells are found infrequently. In one study, of 51 bone marrow samples examined, only 2 contained a single mast cell [52]. It should be pointed out that these marrow samples were obtained from normal dogs, and it is possible that dogs with inflammatory disorders may exhibit higher numbers of mast cells in the bone marrow [50,51]. In general, bone marrow aspiration is considered to be a more sensitive indicator of systemic involvement than the buffy coat smear [45]. Lymph node aspiration All regional lymph nodes should be carefully examined for signs of enlargement, and any suspicious nodes should be aspirated for cytologic examination. Additionally, because metastatic nodes may palpate within normal size, it is recommended by some that all accessible regional lymph nodes be examined by aspiration cytology. Mast cells may be present in normal lymph nodes and are often found in reactive lymph nodes; thus, it may be difficult to determine if mast cells found on cytologic examination are neoplastic or part of the normal immunologic cellular repertoire. Indeed, 24% of lymph node aspirates from normal Beagles contained mast cells [52]. Therefore, lymph node biopsy with histopathology may be a better technique for diagnosis of lymph node metastasis. Evaluation of the abdominal and thoracic cavities Thoracic radiographs are always indicated as part of any staging procedure, although pulmonary involvement is uncommon in dogs with MCTs. Abnormalities reported include lymphadenopathy (sternal and hilar), pleural effusion, and anterior mediastinal masses [45]. Evaluation of the abdominal cavity is important in dogs with MCTs, because spread to the liver and spleen as well as other abdominal structures may be noted. Ultrasound is a more sensitive diagnostic technique for evaluation of abdominal organs. Any suspicious organ should be aspirated and examined by cytology. Some have recommended that splenic and hepatic aspiration be performed as part of the routine staging procedure, regardless of the presence of splenomegaly or hepatomegaly. Because mast cells may be found normally in these organs, however, the utility of this procedure is not clear. Evidence suggests that fineneedle aspiration of the liver and spleen should be performed if abnormalities are detected in these organs during ultrasound examination or if the dog is known to have a grade III MCT [53–55].

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Clinical staging system for canine mast cell tumors The following is the current clinical staging system for canine mast cell tumors: 0: single tumor, incompletely excised from dermis I: single tumor confined to dermis without regional lymph node involvement II: single tumor confined to the dermis with regional lymph node involvement III: multiple dermal tumors or large infiltrating tumors, with or without regional lymph node involvement IV: any tumor with distant metastases or recurrence with metastases (including blood or bone marrow involvement substage a: no signs of systemic disease substage b: signs of systemic disease Prognostic factors Canine MCTs possess a wide range of biologic behaviors ranging from benign to extremely aggressive leading to metastasis and eventual death from disease. Several prognostic factors have been identified that help to predict the biologic behavior of an MCT as well as to direct the course of therapy. Histologic grade The histologic grade of an MCT is determined after incisional or excisional biopsy of the tumor and cannot be assessed simply by cytologic evaluation of fine-needle aspirates. The grade of an MCT is determined by the characteristics of the neoplastic cells (eg, degree of granulation, cytologic and nuclear pleomorphism), number of mitotic figures, and extent of tumor invasion into the underlying tissues (Table 1). Histologic grade is the most consistent prognostic factor and correlates significantly with survival, but it does not predict the behavior of every tumor. The most commonly used grading system is the one described by Patnaik et al [14]: i. Well-differentiated tumors (grade I) are considered to behave in benign manner, and complete surgical excision is usually curative. These represent between 30% and 55% of all MCTs reported [14,41,46,56]. Several retrospective studies have demonstrated that 75% to 90% of dogs do not die of their disease after definitive therapy [14,41,56,57]. ii. Intermediately differentiated tumors (grade II) represent between 25% and 45% of all MCTs reported, and their biologic behavior is more difficult to predict [14,41,46,56]. On histopathology, these tumors exhibit invasion into the underlying subcutaneous tissue. As a result, they may be more challenging to remove by surgical excision. Historically, dogs with grade II MCT have a reported mean survival time of 28 weeks after surgical removal, although the completeness of

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Table 1 Patnaik scheme for grading of canine mast cell tumors Grade

Patnaik grade

Microscopic

Well differentiated

I

Intermediately differentiated

II

Anaplastic undifferentiated

III

Well-differentiated mast cells with clearly defined cytoplasmic borders with regular spherical, or ovoid nuclei; mitotic figures are rare or absent; granules are large, deep staining, and plentiful; cells confined to the dermis and interfollicular spaces Cells closely packed with indistinct cytoplasmic boundaries; nuclear/ cytoplasmic ratio lower than anaplastic; mitotic figures infrequent; more granules than anaplastic; neoplastic cells infiltrate or replace the lower dermal and subcutaneous tissue Highly cellular, undifferentiated cytoplasmic boundaries, with irregular size and shape of the nuclei; frequent mitotic figures; low number of cytoplasmic granules; neoplastic tissue replaces the subcutaneous and deep tissues

Data from Patnaik AK, Ehler WJ, MacEwen EG. Canine cutaneous mast cell tumors: morphologic grading and survival time in 83 dogs. Vet Pathol 1984;21:469–74.

excision could not be assessed in this study [41]. More recently, it has been shown that radiation therapy after incomplete excision of solitary grade II MCTs can cure greater than 80% of affected patients, indicating that adjuvant radiation therapy clearly improves the survival times of dogs with these tumors [57,58]. It is important to note that grade II MCTs have the ability to spread to local lymph nodes as well as distant sites and that a proportion of dogs undergoing definitive therapy (surgery and radiation) may go on to develop metastatic disease. Furthermore, some dogs that present with grade II MCTs already have evidence of metastatic disease, making appropriate staging imperative for these dogs. iii. Poorly differentiated tumors (grade III) represent between 20% and 40% of all MCTs reported [14,41,46,56]. They often behave in a biologically aggressive manner, exhibiting metastasis early on in the course of disease. The mean survival time of dogs with grade III MCT has been reported as 18 weeks when treated with surgery alone [41]. In one study, the percentage of dogs with grade III MCTs surviving at 1500 days was reported as 6%, and in another study, the percentage of dogs surviving at 24 months was 7%, indicating that these tumors are particularly malignant [14,59].

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Clinical stage Although the clinical staging scheme has been developed for prognostic purposes, each increase in stage (0–IV) has not necessarily been proven to worsen the prognosis. It has been demonstrated that when dogs are treated with radiation therapy, those with stage 0 MCTs survived significantly longer than did dogs with stage I through III MCTs. In that study, no dog had stage IV MCT; therefore, stage IV MCT could not be compared for prognostic purposes [57]. In two other studies, the presence of mast cells in the regional lymph node was a negative prognostic factor for survival and disease-free interval on univariate analysis, suggesting that stage II has a worse prognosis than stage I [60,61]. Dogs with stage III MCT with the presence of multiple dermal masses may not necessarily have a worse prognosis than dogs with stage I or II MCT. Indeed, in one study, dogs with multiple MCTs (stage III) did not have a worse prognosis than dogs with a single MCT when treated with chemotherapy [60]. Anatomic location MCTs that develop in the oral cavity, nail bed, or inguinal, preputial, and perineal regions have been reported to behave in a more malignant fashion regardless of histologic grade [57]. Definitive evidence for this in the literature is lacking, however. MCTs that originate in the viscera (eg, gastrointestinal tract, liver, spleen), bone marrow, or peripheral blood carry a grave prognosis [45,62]. Growth rate Tumors present for long periods (months to years) may be more likely to behave in a benign manner. In one study, 83% of dogs with tumors present for longer than 28 weeks before surgery survived for at least 30 weeks compared with only 25% of dogs with tumors present for less than 28 weeks [41]. The same study demonstrated that most dogs surviving for longer than 30 weeks after surgery appeared to be cured. Breed Boxers have a high incidence of MCTs, but these tend to be more well differentiated and carry a better prognosis [12,41]. Nevertheless, every MCT should be treated as potentially malignant, regardless of breed. Argyrophilic nucleolar straining organizing regions Argyrophilic nucleolar staining organizing regions (AgNORs) are areas present in the nucleus that take up silver stain and provide an indirect measure of cell proliferation. This stain can be performed on formalin-fixed specimens or on cytologic samples. It has been demonstrated that the relative frequency of AgNORs correlates with histologic grade and is predictive of postsurgical outcome. The higher the AgNOR count, the poorer is the prognosis [56,63,64].

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DNA ploidy MCTs possessing an abnormal DNA content (aneuploid) exhibited a trend toward shorter survival times; however, a significant difference was found between aneuploid and diploid tumors when comparing stage I and non-stage I disease [65]. Proliferating cell nuclear antigen Proliferating cell nuclear antigen (PCNA) is a protein required for DNA synthesis; expression is associated with cell proliferation. In one study, PCNA was significantly higher in recurrent versus nonrecurrent tumors and in metastatic versus nonmetastatic tumors, and it was a good predictor for tumor recurrence at 6 months [56]. Ki-67 Ki-67 is composed of two protein subunits that are present in cells during the active phases of the cell cycle but absent during rest. Levels of Ki-67 in the nucleus seem to correlate with cell proliferation. In one study, the mean number of Ki-67-positive nuclei per 1000 tumor nuclei was significantly higher for dogs that died of MCTs than for those that survived. For dogs with grade II tumors, the number of Ki-67-positive nuclei per 1000 tumor nuclei (<93 versus 93) was significantly associated with outcome [59]. Other factors Several other factors are currently under investigation to determine if they may play a role in the aggressiveness of canine MCTs, including the levels of active matrix metalloproteinase 2 and 9, tryptase, and chymase [66,67]. Two recent studies evaluated the potential role of p53 in canine MCTs; both found that although p53 overexpression was noted in some MCTs, there was no obvious association with tumor behavior [68,69]. Treatment The choice of treatment modalities used for a particular canine MCT depends heavily on the prognostic indicators discussed previously, especially the histologic grade and clinical stage. Surgery Wide surgical excision is indicated for all canine MCTs; although they may feel like discrete masses, microscopically, most extend well beyond the palpable borders. It is generally accepted that the lateral margins of excision need to be at least 3 cm in each direction. Deep margins are as important as the lateral margins and follow the concept of a quality margin as opposed to a quantity margin. Collagen-dense and vascular-poor tissues tend to behave as biologic barriers against cancer [70]. Therefore, the deep margin should include a fascial plane that has not been invaded by the tumor and is removed en bloc with the tumor. All the excised tissue should be submitted;

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the lateral and deep margins should be accurately labeled so that the pathologist is able to identify specifically any areas of incomplete excision. Careful examination of the histologic margins is imperative; however, even histologically clean margins do not guarantee that a tumor will not recur. This is particularly relevant for grade II and III tumors in which the underlying tissues may be involved. Part of the difficulty in evaluating tumor margins is that normal mast cells are present in all tissues, and it may be difficult for the pathologist to determine if a mast cell present at the tissue margin represents a malignant cell or a normal cell. In one study, 83% of dogs with grade I MCT, 44% of dogs with grade II MCT, and 6% of dogs with grade III MCT were alive 1500 days after surgical excision [14]. In another study, 100% of dogs with grade I MCT, 44% of dogs with grade II MCT, and 7% of dogs with grade III MCT were alive 2 years after surgical excision [59]. Complete surgical excision is likely to be curative for dogs with grade I MCT. The need to perform adjuvant therapy for local control of the tumor in dogs with completely excised grade II MCT seems to be unnecessary. Two studies have reported a rate of local recurrence of 5% and 11% after complete excision of grade II MCT [71,72]. Postsurgical treatment recommendations are as follows: Grade I complete excision: no further therapy Grade I incomplete excision: wider excision or radiation therapy if surgery is not possible Grade II complete excision: consider radiation therapy only if margins are close Grade II incomplete excision: wider excision or radiation therapy if surgery is not possible Grade III complete excision: chemotherapy Grade III incomplete excision: chemotherapy with or without radiation therapy It has been advocated that the injection of deionized water in the surgical site can decrease the likelihood of local recurrence after incomplete MCT removal [73]. A more recent study found no benefit in this procedure; as such, the use of deionized water is currently not recommended [74]. Radiation therapy Evidence suggests that radiation therapy is extremely effective at eliminating remaining microscopic disease after incomplete excision of grade I and II MCT ([90% 3-year control rate) [58,75]. Protocols that deliver the total dose of radiation in a shorter period by administering more fractions per week seem to provide better control of the MCTs [61]. Unfortunately, dogs with grade III tumors do not fare as well; whereas the radiation may be effective at preventing local recurrence of tumor, most dogs eventually develop metastasis.

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Radiation therapy has been used to treat solid MCTs (macroscopic disease) when surgery was not an option. Varying degrees of success have been found; in one study, a 50% 1-year control rate was obtained using total doses of 45 to 57 Gy [61]. Radiation therapy should not be used as the primary therapeutic modality if surgical intervention is an option, however. Palliative radiation has also been used to treat dogs with nonresectable highgrade MCT. This may result in an improvement in quality of life but is unlikely to significantly increase survival time. Moreover, systemic effects of mast cell degranulation after radiation may lead to vomiting, hypotension, and gastrointestinal ulceration. Chemotherapy The use of adjuvant chemotherapy is indicated after excision of grade III MCTs and metastatic MCTs as well as for nonresectable high-grade tumors. It is important to note that radiation therapy (not chemotherapy) is the treatment of choice for incompletely excised grade I and II MCTs. In general, chemotherapy for macroscopic MCT has been unrewarding, and long-term responses have not been demonstrated in well-controlled clinical trials. i. Corticosteroids: the exact mechanism of how corticosteroids kill malignant mast cells is not known. The reported response rate of canine MCT to prednisone is 20%, with reported remission times of 10 to 20 weeks [76]. Partial remissions are more common than complete remissions, and at least some of the observed response may be a result of a decrease in tumor-associated edema. Intralesional corticosteroids have also been shown to be of some benefit. ii. CCNU (lomustine): a nitrosourea alkylating agent that has been used to treat lymphoma and brain tumors in dogs, CCNU, was recently found to have activity against canine MCT. A response rate of approximately 42% was noted when dogs with grade II and III MCTs that had failed all other therapies were treated with CCNU [77]. As with prednisone, most of these were partial responses, and the duration of response was only 79 days. Nevertheless, it does appear that this drug has some efficacy in treating MCT, and clinical trials are currently underway to evaluate its efficacy. iii. Vinblastine: vinblastine has been reported to have efficacy against canine MCT in two separate studies. In the first study, dogs with grade II or III MCT with metastasis to the regional lymph node underwent surgical removal of the primary tumor and involved lymph node. They were then treated with a combination of vinblastine, prednisone, and cyclophosphamide, resulting in a median survival time of 18 months [78]. Interestingly, dogs with grade II or III MCT and metastasis to the regional lymph node that did not undergo surgery but were treated with the combination chemotherapy protocol

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lived for a median of 5 months. This would seem to indicate that vinblastine is more useful in the face of microscopic rather than bulky MCT. The second study was a retrospective analysis of dogs with various forms of MCT treated with a combination of vinblastine and prednisone [60]. This study revealed a 47% response rate, although the retrospective nature of the analysis makes the data difficult to interpret. Interestingly, vincristine, a close relative of vinblastine, appears to have little efficacy in the treatment of canine MCT [79]. Studies are currently underway to further evaluate the utility of vinblastine in the treatment of canine MCT. iv. Miscellaneous drugs: in limited clinical reports, both L-asparaginase and chlorambucil have been found to have activity against MCT. Supportive care Animals with large primary MCT, evidence of metastatic disease, or systemic signs should be treated with medications to block some of or all the effects of histamine release. a. H2 antagonists: because histamine stimulates gastric acid production by parietal cells, MCT may cause gastrointestinal ulceration. To prevent this, any of the standard H2 antagonists may be used, including cimetidine, ranitidine, or famotidine. Alternatively, omeprazole may be used; this is not a direct H2 antagonist but works by inhibiting the proton pump on parietal cells necessary for the generation of gastric acid. b. H1 antagonists: massive mast cell degranulation can lead to hypotensive shock and death. Therefore, patients with bulky mast cell disease should be placed on an H1 antagonist like diphenhydramine. c. Miscellaneous: treatment with sucralfate is indicated for dogs with evidence of gastrointestinal ulceration. Cyproheptadine and antihistaminic drugs with antiserotonin activity stabilize mast cells and may be useful in the treatment of dogs with bulky mast cell disease.

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