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Mast Cell Tumors (MCTs) are the most common cutaneous mass in dogs. Wide excision is the gold standard therapy with surgical guidelines that have been well established. Most commonly, wide excision is defined as 2–3 cm gross lateral margins and one unaffected fascial plane deep, but taking margins proportional to the tumor size, with a maximum of 2 cm margins, has also been described more recently and deemed a comparable technique.1
Two grading schemes that help predict the behavior of the disease (the Patnaik three‐tier system and the Kiupel low‐ or high‐grade system) have also been well established for cutaneous MCTs. Median survival time (MST) for grade I tumors have been reported as >1300 days, grade II as 791–1426 days, and grade III as 278–386, as well as for low‐grade tumors as 690–1452 days and high‐grade tumors as 110–208 days.2, 3, 4 Ki67 index and staining for c‐KIT are also used to prognosticate, with a high Ki67 index and positive staining for c‐KIT being associated with a poorer prognosis. These grading schemes are also used to guide potential adjunct therapies, such as traditional chemotherapy and/or toceranib therapy, especially when microscopic disease remains (and re‐cut is not elected or not possible), metastatic disease is present, or the tumor was identified as high‐grade. Risk of spread to lymph nodes, which is itself prognostic, has also been described for cutaneous MCTs, with 6% for grade I, 16% for grade II, and 46% for grade III, as well as 15% for low-grade and 30% for high-grade reported.5 Local recurrence rates have been reported from 10% to 50%,6 with one paper finding a local recurrence rate of only 30% with known incomplete margins.7 Distant metastasis is also encountered, most commonly in the spleen and liver.
MCTs can also arise in the subcutis. Grading schemes have not been established for entirely subcutaneous MCTs, and the literature is inconsistent with regard to biological behavior of these subcutaneous MCTs. Though surgery remains the recommended therapy for these tumors, this makes it difficult both to prognosticate and to know when to recommend adjunct therapy, as well as what that therapy should be. Furthermore, surgery for these tumors is not as straightforward as with cutaneous masses, as it is more difficult to establish gross margins when resecting subcutaneous masses, given that they can move relative to their adjacent layers, and it is not known if wide excision as defined for cutaneous tumors is appropriate for subcutaneous tumors.
Earlier papers suggested that overall, subcutaneous MCTs more often behaved more benignly than their cutaneous counterparts, with low local recurrence rates and metastatic rates, giving them a good prognosis. In one study, the “[o]verall median survival time was not reached at >1968 days” and “[i]n univariate analysis, argyrophilic nucleolar organizer regions (AgNORs), proliferating cell nuclear antigen, and mitotic index were negatively prognostic for PFS whereas Ki‐67, proliferating cell nuclear antigen, and microvessel density were negatively prognostic for DFI,” with AgNORs being especially promising in predicting negative outcome.8 “The vast majority of subcutaneous MCTs appear[ed] to be low or intermediate grade with excellent outcomes from good local tumor control.”8 Another study also found a favorable prognosis for subcutaneous MCTs, with median survival time not reached after a median follow up of 891 days, as well as a 4% metastatic rate and 8% local recurrence rate.9 This study showed that decreased survival correlated with mitotic index, infiltrative growth paper, and presence of multinucleation, with mitotic index being “strongly predictive of survival, local reoccurrence, and metastasis.”9
More recent studies, however, have identified subcutaneous MCTs with the potential to behave more aggressively. In one such study, subcutaneous MCTs were more often found to be higher grade than cutaneous MCTs, though this was using traditional cutaneous MCT grading schemes, so it is unknown how that translates to subcutaneous tumors.10 In another study, the MST was not reached (range 83–1357 days) and local recurrence rate was 15%, but metastasis to lymph nodes in 63% of evaluated lymph nodes.11 This spread to lymph nodes was much higher than in previous studies, indicating the potential for an aggressive nature of subcutaneous MCTs. Another study found that 34.9% of local lymph nodes displayed signs of metastasis on routine regional lymphadenectomy, but did not perform sentinel lymphadenectomy, which may have increased this percentage.12 Given this literature, evaluation of regional lymph nodes should be considered as a part of staging. Sentinel lymph node mapping and extirpation can also be considered. Overall, the Treggiari study found a greater proportion of dogs (37.8%) with local recurrence, new distant lesion formation, or lymph node metastasis. However, this study also concluded that survival time can be prolonged with surgery alone in the absence of negative prognostic factors. Use of chemotherapy was found to be predictive of shorter overall survival time, but this was not significant using multivariate analysis, suggesting that chemotherapy was used in cases with more aggressive tumors and thus shorter associated survival times. The Marconato study found that while some patients had tumor-related deaths, some patients who received vinblastine as a response to positive lymph nodes had prolonged survival times. However, the role of chemotherapy in subcutaneous MCTs requires further study.
While there is no grading scheme established exclusively for subcutaneous MCTs, one study found that dogs with tumors having a mitotic count >4, multinucleation, or infiltrative architecture may have shorter survival times and a decreased disease‐free interval than dogs without these parameters.9 It follows that using these criteria, in addition to the criteria classically applied to grading cutaneous tumors, should help guide recommendations for staging (such as abdominal ultrasound with aspirates of the spleen and/or liver) if it was not done preoperatively, as well as for further therapy (such as re‐cutting when margins were not clear or adjunct medical therapy).13 One study found that two‐tier histologic grading identified biologically aggressive subcutaneous MCTs (with 10% having a poor prognosis), as it does for cutaneous tumors, though further study of schemes validated for cutaneous tumors is still warranted.14 This study also highlighted concern for cutaneous tumors with subcutaneous invasion, as they “included the largest percentage of high‐grade tumors (33%), had the highest occurrence of overt nodal metastases (33%), and had the lowest one‐year survival rate (86%).”14 Ki‐67 index may also be useful to prognosticate and guide further work-up and therapy, as one study found subcutaneous MCTs with Ki‐67 >21.8 were more likely to relapse and metastasize.9 While further study is needed in solely subcutaneous tumors, staining for c‐KIT may be helpful to prognosticate (as only the high‐grade subcutaneous MCT had diffuse KIT pattern expression in a second study by Thompson)15 and may help guide use of toceranib as adjunct therapy. The author has seen a patient with a completely excised subcutaneous MCT progress to mastocytosis of the spleen and mastocytemia by five months postoperatively, and death at seven months postoperatively. This tumor displayed a mitotic index of 10, moderate differentiation, and anisocytosis and anisokaryosis, but no multinucleated cells, bizarre nuclei, or infiltrative architecture. Thus, though not common in earlier studies, subcutaneous MCTs can progress to fatal disease, even if they display only some of the criteria of malignancy specifically highlighted for subcutaneous tumors.
In conclusion, while no grading scheme exists to prognosticate specifically for subcutaneous MCTs, it is important to recognize that they do not always carry a good prognosis, as initially thought, and thus, owners should be made aware of their malignant potential, and surgery should be recommended. Indicators of malignancy should be evaluated, patients carefully monitored for local recurrence and/or metastasis, and follow-up with a medical oncologist, with the potential for adjunct therapy, considered as more criteria of malignancy (particularly elevated mitotic index, multinucleated cells, patterns of infiltration, and high Ki‐67 and/or AgNORs) are present.
