of diphenhydramine did not provide any clear benefit in preventing hypotension in dogs undergoing MCT removal (Sanchez et al. 2017).
The use of neoadjuvant corticosteroid (prednisone) treatment may facilitate resection of MCT when adequate surgical margins cannot be confidently expected because of location, size, or both (Stanclift and Gilson 2008; Dobson et al. 2004). Mean reduction in MCT volume was 80.6% in 70% of cases treated with neoadjuvant prednisolone. Reduction in tumor size may be related to the anti‐inflammatory effect of prednisolone, reducing tumor‐related inflammation and edema secondary to tumor cytokine release. There was no difference in response rate between a high dose (2.2 mg/kg) and a low dose (1.0 mg/kg) prednisone protocol. Using neoadjuvant prednisone did not increase the risk of incomplete margins or local recurrence in one study (Saunders 2020).
Margins
Surgical Margins
Wide surgical excision with adequate lateral and deep margins has historically been the primary treatment of choice for most MCTs. The deep surgical margin is a qualitative margin rather than a quantitative margin. Fascia and collagen‐dense tissues are good barriers to tumor infiltration. The deep margin should include at least one fascial plane deep to the tumor that has not been invaded by the tumor. This margin should be removed en bloc with the tumor so that tumor contamination is not encountered during the surgery. The appropriate lateral surgical margin is grade and tumor size dependent. Historically, many MCTs have been treated with ‘surgical dose’ that is greater than required for local control. Simpson et al. (2004) reported that a 2 cm lateral margin and a deep margin of one fascial plane were adequate for complete excision of grade I and II MCTs in dogs. In fact, a 1 cm lateral margin was able to obtain tumor‐free margins in 75% of grade II and 100% of grade I cutaneous MCTs. In another study, a 2 cm lateral margin and one deep facial plane excision were successful in completely excising 100% of grade I and 89% of grade II MCTs (Fulcher et al. 2006). A similar local recurrence rate and de novo development rate were observed compared to previous reports with a 3 cm margin. Investigators concluded that excision of grade I and II MCTs with 2 cm margins might minimize complications associated with larger local tumor resection (Fulcher et al. 2006).
Wide surgical margins do not appear to be a prerequisite for a successful long‐term outcome in dogs with well‐differentiated cutaneous MCTs (Murphy et al. 2004). A proportional size model for surgical margins has been proposed where the lateral margins are equivalent to the widest diameter of the MCT, with an upper limit of 2–4 cm (Pratschke et al. 2013; Chu et al. 2020; Saunders et al. 2020). Using the proportional margins approach, 85–95% of tumors had complete excisional margins and local recurrence of 0–3%.
Complete removal of grade I or II cutaneous MCTs, even with narrow histologic margins, is associated with successful outcome without adjuvant therapy. Narrow (≤3 mm) histologic margins are likely adequate to prevent local recurrence of low‐grade MCTs (Schultheiss et al. 2011). In one study, the width of the tumor‐free margins on histology was not prognostic for local recurrence for completely excised tumors (Donnelly et al. 2015). High‐grade tumors have significant risk of local recurrence (36%) regardless of histologic margins width (Donnelly et al. 2015). Adequate margins for grade III MCTs have not yet been determined; thus 3 cm lateral and at least one fascial plane deep margins are recommended.
Intraoperative real‐time assessment of surgical margins has the strong advantage of allowing the surgeon to know where incomplete margins are and to take appropriate measures to rectify this at the surgery table without necessitating an additional surgery at a later time. Two methods that provide assessment of surgical margins intraoperatively described in veterinary surgery are fluorescence‐based imaging and optical coherence tomography (see Novel diagnostic imaging techniques in soft tissue sarcomas section). Using a fluorescent‐based imaging technique, sensitivity and specificity of the imaging system for identification of cancer (soft tissue sarcomas and mast cell tumors) in biopsies have been reported to be 92% for both. Although responsive to antihistamines, hypersensitivity to the fluorescent agent was seen in 53% of dogs and the risk needs to be considered in light of the potential benefits of this imaging system in dogs (Bartholf DeWitt et al. 2016). Optical coherence tomography‐guided pathology sections of canine mast cell tumors were able to detect incompletely excised MCT near the surgical margin with a sensitivity of 90% and specificity of 56.2% in one study (Dornbusch et al. 2020).
The excised specimen should be submitted in toto and not in sections. The anatomical relationship between the deep fascial plane and lateral margins should be preserved with sutures to help orient the pathologist, and the deep and lateral margins should be inked (ideally with separate colors). There is a significant amount of shrinkage artifact that occurs with each step of sample processing (Milovancev et al. 2018). Tissue shrinkage occurs mainly in the skin tissues (24%) compared to the tumor tissue (4%) (Upchurch et al. 2018). Mean histologic margins have been reported to be 35–42% smaller than the surgical margins (Risselada et al. 2015). Clinicians should take these factors into account when interpreting histologically reported margins relative to surgical margins.
Regional Lymph Node Treatment
Locoregional control incorporates treatment of the regional lymph node as well as the primary MCT. Approximately, 20% of dogs with cutaneous mast cell tumors will have nodal metastasis at the time of diagnosis.
Surgical removal or prophylactic and therapeutic irradiation of the regional lymph nodes is indicated as part of locoregional disease control and is associated with increased survival time (Mendez et al. 2019).
Anatomical Site Considerations
Appropriate therapy for cutaneous MCTs located on an extremity is dictated by tumor grade. For low‐ and intermediate‐grade MCTs, a combination of a marginal surgical resection with planned external beam radiation therapy (if incomplete margins are achieved) is a rational treatment option. Amputation may be indicated for grade III MCTs to achieve wide surgical margins.
Palliative radiation therapy (4 × 8 Gy weekly) in combination with prednisolone has been reported to be useful in the management of measurable MCTs located on a distal extremity (Dobson et al. 2004). Another favorable protocol for measurable MCTs is the combination of prednisone, toceranib, and hypofractionated radiation therapy (Carlsten 2012).
Prognostic Factors
Histologic Parameters
Grade
There are two grading systems in common use for canine cutaneous MCTs; the Patnaik and Kiupel systems (Patnaik et al. 1984; Kiupel et al. 2011).
The grading system developed by Patnaik and colleagues is based on histomorphologic features, including cellularity, cell morphology, invasiveness, mitotic activity, and stromal reaction and is prognostic for survival. Well‐differentiated (grade I) MCTs account for 26–55% of all MCTs, intermediate differentiated (grade II) MCTs account for 25–59% of MCTs, and poorly differentiated (grade III) MCTs account for 16–40% of MCTs (Murphy et al. 2006). Tumor grade is the most consistent prognostic indicator for biological behavior and survival time in cutaneous MCTs across multiple studies (Turrel et al. 1988; Patnaik et al. 1984; Thamm et al. 1999). Higher tumor grade is associated with higher risk of metastasis, lower local control rates, and shorter survival times. Grade II MCTs are the most common grade identified and have the widest range of biological behavior compared to the other two grades. Most dogs diagnosed with grade II MCT will have a good prognosis; however, there is a subset of these patients that will develop metastases and have decreased survival time. Grade III MCTs have an aggressive clinical behavior and poor survival time compared to grade I or II MCTs, with a reported median survival time for dogs with grade III MCTs of 224–257 days and a metastatic rate of 55–96% (Bostock 1986; Hume et al. 2011).
There is significant variation in grading of MCTs between pathologists using the Patnaik grading scheme. In one study, 10 veterinary pathologists independently graded the same 60 cutaneous MCTs using the Patnaik grading system (Northrup et al. 2005). Agreement was 62.1%