orally at a dose of 50–90 mg/m2 every 21 days. A response rate of 47% for measurable cutaneous MCTs treated with single‐agent CCNU (90 mg/m2) is reported (Rassnick et al. 1999). Acute toxicities include neutropenia and thrombocytopenia. CCNU can cause a delayed, cumulative dose‐related, chronic hepatotoxicity that is irreversible and can be fatal (Kristal et al. 2004).
Combination Chemotherapy
Combination chemotherapy protocols using prednisone or prednisolone and vinblastine (Davies et al. 2004; Thamm et al. 1999, 2006), CCNU and vinblastine (Cooper et al. 2009), and CCNU and prednisone (Hosoya et al. 2009) have been reported as adjuvant chemotherapy for macroscopic and microscopic cutaneous MCT disease. The rationale for combination therapy protocols is to increase local recurrence‐free intervals, metastasis‐free intervals, and survival times over single agent protocols. Adjuvant therapy such as prednisone and vinblastine are best employed after the initial tumor resection, rather than at the time of recurrence (Thamm et al. 1999).
Deionized or Hypotonic Water
Conflicting results have been reported on the efficacy of deionized water as an adjunctive therapy after surgical excision of cutaneous mast cell tumors (Brocks et al. 2008; Grier et al. 1995; Jaffe et al. 2000). A prospective, placebo‐controlled, double‐blinded, and randomized clinical trial found that hypotonic water does not decrease the rate of local recurrence in dogs with solitary MCT after marginal surgical excision (Brocks et al. 2008).
Tyrosine Kinase Inhibitors
In dogs, 20–30% of MCTs express a mutated form of KIT, a receptor tyrosine kinase involved in the development or progression of MCT growth and differentiation. Small‐molecule tyrosine kinase inhibitors including imatinib mesylate (Gleevec), masitinib, and toceranib have shown efficacy against canine MCTs (London et al. 2009; Isotani et al. 2008; Hahn et al. 2008).
Toceranib phosphate (Palladia) has recently been licensed for use in veterinary medicine for treatment of mast cell disease. A multicenter, placebo‐controlled, randomized study demonstrated a 42% response rate to Palladia in dogs with grade II or III cutaneous MCTs (London et al. 2009). Ulcers of the stomach and intestine have been a common side effect of this medication (London et al. 2009). The status of the c‐KIT mutation of the mast cell tumor does not predict response to masitinib or toceranib (Weishaar et al. 2018; Horta et al. 2018).
Feline Cutaneous MCT
Cutaneous MCT is the second most common feline skin tumor, after basal cell tumor (Litster and Sorenmo 2006; Melville et al. 2015). Feline cutaneous MCTs are most commonly located on the head and neck, followed by the trunk and extremities (Litster and Sorenmo 2006). Feline MCTs located on the head are less biologically active than in dogs. An increased breed incidence in Siamese cats for cutaneous MCT is reported compared to other breeds (Litster and Sorenmo 2006; Melville et al. 2015). Feline cutaneous MCTs have a benign biological behavior compared to canine cutaneous MCTs. The Patnaik histopathological grading scheme used for canine cutaneous MCTs is not prognostic in cats (Molander‐McCrary et al. 1998; Lepri et al. 2003).
There are two forms of feline cutaneous mast cell disease, mastocytic and the less common histiocytic. The histiocytic form occurs in cats younger than four years old and is usually characterized by multiple nonpruritic, firm, hairless, pink subcutaneous nodules. Histiocytic MCTs generally regress spontaneously.
Histologic classifications of feline cutaneous MCTs are well‐differentiated, poorly differentiated, or histiocytic. High mitotic activity (>4 mitoses/high‐powered field) is reported as a negative prognostic indicator for feline cutaneous MCT (Lepri et al. 2003; Johnson et al. 2002). A recently proposed grading system for feline cutaneous MCTs classified MCTs as high grade if there were >5 mitotic figures in 10 hpfs and at least 2 of the following criteria: tumor diameter >1.5 cm, irregular nuclear shape, and nucleolar prominence/chromatin clusters (Sabattini and Bettini 2019). Further prospective validation of this grading scheme is required.
Cats with cutaneous MCTs should be staged with an abdominal ultrasound to evaluate the spleen for evidence of MCTs that may be metastasizing to the cutaneous location.
The prognosis for feline cutaneous MCT with surgical resection is good, with a 16–36% local recurrence rate. Incomplete surgical excision is not associated with a higher rate of tumor recurrence in cats with cutaneous MCTs (Molander‐McCrary et al. 1998; Litster and Sorenmo 2006). Radiation therapy using strontium‐90 has recently been reported as an effective treatment for feline cutaneous MCT (Turrel et al. 2006).
A distinct visceral form of MCT, which affects the spleen without cutaneous involvement, exists in cats and carries a poor prognosis (Litster and Sorenmo 2006). Systemic signs of chronic vomiting, anorexia, and weight loss can be associated with this form of MCT disease. Splenectomy is the recommended treatment for splenic visceral MCT (Kraus et al. 2015) and is associated with improved survival time compared to no splenectomy (Evans et al. 2018). The role of adjuvant chemotherapy for feline splenic MCT is still to be determined. A form of intestinal mast cell tumor also exists in cats (Sabattini et al. 2016; Barrett 2018).
Mesenchymal Tumors and Melanoma
Introduction
This section will first evaluate the management of soft tissue sarcomas (STS) and describe general adjunctive therapies. Specific types of STS will then be discussed with tumor‐specific treatment options.
Soft Tissue Sarcomas
STS are a heterogenous group of tumors that originate from connective tissues surrounding, supporting, and bridging anatomical structures or tissues. STS have similar biological behaviors, often displaying both benign and malignant characteristics. Although skin and subcutaneous tumors are the most commonly observed STS, these sarcomas can, in principle, arise from any part of the body (Ehrhart 2005; Ettinger 2003; Kuntz et al. 1997). In general, STS are slow‐growing and locally invasive tumors, composed mainly of spindle‐shaped cells, with a low tendency for metastatic spread. STS are grouped together because of their comparable biological behavior and clinical characteristics while further histologic classification and differentiation are often complicated. The nomenclature follows classification of human STS, based on patterns of cellular proliferation and individual cell morphology without conclusive identification of the cells of origin and is poorly standardized for animals. Some pathologists, therefore, prefer the term spindle cell tumors of canine soft tissue (Williamson and Middleton 1998). Further differentiation of histologic diagnosis can be achieved using immunohistochemistry (Gaitero et al. 2008; Ettinger et al. 2006; Liptak and Forrest 2013). Canine STS display histological and immunohistochemical features similar to their human equivalents (Milovancev et al. 2015).
Tumors typically included in the STS group are FSA, perivascular wall tumors (previously called hemangiopericytoma), liposarcoma, malignant fibrous histiocytoma, mesenchymoma, myxosarcoma, nonplexus derived PNSTs (previously called neurofibrosarcoma or schwannoma), and undifferentiated sarcoma.
There are several mesenchymal tumors that are not considered “soft tissue sarcomas” because their individual biological behavior has a more defined character and they can usually be identified on light microscopy, including hemangiosarcoma, synovial cell sarcoma, gastrointestinal stromal tumors (GISTs), oral FSA, and PNSTs. Rhabdomyosarcoma, lymphangiosarcoma, and leiomyosarcoma are included in this exclusion list by some pathologists, whereas others would group them with STS (Ehrhart 2005; Dennis et al. 2011; Liptak and Forrest 2013). Histiocytic sarcoma is also considered not a typical STS
