Background

Mast cell tumors (MCT) are among the most common tumors treated in dogs and are periodically seen in cats. Tumors are typically located in the dermis or subcutis and patients are presented for evaluation of a mass. Diagnosis is easily made in most cases by fine needle aspiration and cytology, with heavily granular round cells distinguished on in-house cytology. Tumors that recur or are high grade present a challenge and may benefit from referral to a specialist. This talk will include a review of previously known factors in MCT diagnosis and treatment with newer information about grading, staging, and treatment options, as well as insights into novel tests and therapeutics.

Staging

Because canine mast cell tumors spread primarily by lymphatics, staging for this disease parallels that for lymphoma (regional lymph node evaluation, liver, spleen, and bone marrow aspiration). However, liver and splenic aspirates, regardless of ultrasonographic appearance, appear to be most useful in the setting of high risk/grade disease, and the value of bone marrow aspiration in the setting of otherwise negative staging tests is likely very small. While some practitioners still use buffy coat smears as a monitoring tool with the rationale that if it is positive at diagnosis and clear for mast cells during remission, that buffy coat smears may correlate with relapse. However, this has not been shown and buffy coat smears still are often influenced by non-neoplastic diseases. Aspiration of regional lymph nodes remains the most critical staging test. It can be difficult to identify which mast cells are neoplastic and which are innocent bystanders in lymph node aspirates and on histologic assessment of margins.

Prognostic Factors

The single most important prognostic factor for canine mast cell tumor is the grade of the tumor. Whereas low-grade tumors (grade I) have greater than 80% survival in several studies, and approximately 40–50% of grade II tumors survive the first year with surgery alone, grade III tumors treated with surgery alone have poor long-term survival rates of less than 10%. In addition, a new grading scheme is currently in use for which tumors are considered to be either high or low grade. Mitotic index is arguably the most important aspect of grading. Dogs with tumors that had a mitotic index (MI; number of mitoses per ten high power fields at 400x) greater than 5 had a median survival time of 3 months, versus 80 months for those with MI less than or equal to 5. Similar findings were reported when a cut-off of 7 was used. The new grading scheme uses a mitotic index of 7, presence of multinucleated cells, and presence of bizarre nuclei.

While dogs with multiple tumors (approximately 20–25% of dogs with MCT) are categorized as stage III disease, it has been noted that affected dogs may not have a worse prognosis than lower stages, so long as the disease remains cutaneous. Advanced stage, however, is often associated with a worse prognosis and warrants chemotherapy as part of treatment.

Despite earlier studies to the contrary, some studies show that inguinal or perineal location is not necessarily a negative prognostic factor. The tumor grade and behavior (grade 3 and/or recurrent) is more important for these locations. Other mucocutaneous sites, including oral and subungual locations as well as visceral MCT, continue to be viewed as locations with aggressive tumors.

Evaluation of MCTs includes the use of proliferation indices. Although grade is considered the most important prognostic factor, markers of cellular proliferation may offer subtle differentiation among similarly graded tumors. These markers include proliferation indices such as AgNOR and Ki-67, and the often mutated receptor tyrosine kinase c-kit. Results have correlated well with grade, subgrade, local recurrence, and metastasis. In multivariate analysis, only AgNOR score and local recurrence were prognostic for survival in a series of nearly 300 dogs. Of the other proliferation indices, Ki-67 has also correlated well with tumor grade and behavior. In one study, Ki-67 helped identify which dogs with grade 2 tumors were more likely to survive. The soluble proliferation marker thymidine kinase type 1 (TK1) has been assessed and may correlate with tumor grade as well, providing another tool to monitor response to therapy.

Some studies report older age as a negative prognostic indicator (> 8 years in one study). Additional prognostic factors include growth rate (rapid = bad), and systemic signs (presence = bad). MCTs typically recur or metastasize within the first 6 months after treatment if at all, as indicated by similar short- and long-term survival times in some studies.

Molecular Advances

Targeted therapies typically exploit some molecular aspect of the cancer cell that is either not found in normal cells or is found with much greater frequency in cancer cells. Stem cell factor receptor, also known as the kit tyrosine kinase receptor (encoded by the protooncogene c-kit) is important in mast cell tumor growth, proliferation, and differentiation. An activating mutation can lead to constitutive activity in which the cellular signaling is constantly "on" leading to uncontrolled proliferation of mast cells. Activating mutations in the juxtamembrane region encoded by exons 11 and 12 have been found in approximately 30% of canine mast cell tumors and are thought to be spontaneous rather than heritable mutations as they do not appear to occur in the germ line cells. However, breeds of bulldog descent are overrepresented in studies of canine MCT and these dogs tend to develop tumors that are behaviorally benign or low grade. Therefore there may be other genetic influences on the development of this tumor in certain breeds.

In recent years, oral anticancer drugs have been developed for veterinary use to inhibit c-kit and other tyrosine kinases. Palladia^TM (toceranib phosphate) is the first drug that is FDA approved for the treatment of cancer in dogs. The label indication is for recurrent grade 2 or 3 MCT with or without nodal metastasis. Of note, the label dose is 3.25 mg/kg every other day, but lower doses (2.5–3 mg/kg) are associated with adequate blood concentrations and decreased side effects, especially gastrointestinal toxicity. Palladia^TM also inhibits other key split kinases in the same family including vascular endothelial growth factor receptor and platelet-derived growth factor receptor. For this reason, anecdotal and published results support its use in metastatic cancer (mammary carcinoma and osteosarcoma, for example) as well as other primary tumors such as neuroendocrine tumors and apocrine gland anal sac adenocarcinoma.

Kinavet® (masitinib, Masivet, dosed at 12.5 mg/kg/day) also inhibits c-kit; because this drug is more specific for c-kit, side effects are fewer. In the US, this drug has conditional FDA approval and has been used for both cancer and non-cancer (atopy) applications. These drugs are delivered orally, which is attractive to many owners. In addition, for dogs that have a mutated c-kit gene, the response rate for MCT is very high.

Future treatment options may include heat-shock protein 90 inhibitors (HSP90). HSP90 is a chaperone for kit and inhibition has shown efficacy in vitro and in vivo.

Other Standard Treatment Options

Routine cancer therapy consists of surgery, radiation, and chemotherapy. When possible, surgery is the first line of treatment for mast cell tumors. It is now known that most tumors (grade 1 and 2) are completely excised with 2-cm margins. The deep margin should include an intact fascial plane and is most predictive of recurrence. Additionally, in one study only 22% (8/34) of dogs with incompletely excised low-grade mast cell tumor had recurrence, and in another less than 4% recurred with complete excision, even if margins were narrow. High-grade tumors are reported to have a 35% recurrence rate even if completely excised. If the first surgery leaves histologically incomplete margins, some anatomic locations will permit a second surgery with wider and deeper margins which can help avoid the need for radiation therapy.

For high-grade tumors, chemotherapy is often recommended and vinblastine-containing protocols have performed favorably. Vinblastine and prednisone therapy yielded a 45% one-year survival rate for grade 3 tumors and a 90% survival rate for grade 2 tumors. All dogs that lived to one year went on to live two years. The 90% survival rate with grade 2 tumors is comparable to the control rate with radiation alone, making chemotherapy an attractive alternative to adjuvant radiation therapy.

Radiation therapy improves local control for incompletely excised mast cell tumors. Daily fractionation performed better than dogs receiving three times weekly dosing. In one study of grade III tumors treated with surgery and radiation without chemotherapy, the one-year survival rate was 71% and only one of 31 dogs died of systemic disease. Therefore locoregional treatment with radiation may be adequate for some dogs with grade III tumors.

Dogs with mast cell tumor can do very well and each tumor must be evaluated based on clinical and pathologic characteristics.

References

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5.  Hahn KA, King GK, Carreras JK. Efficacy of radiation therapy for incompletely resected grade-III mast cell tumors in dogs: 31 cases (1987–1998). J Am Vet Med Assoc. 2004;224:79–82.

6.  Simpson AM, Ludwig LL, Newman SJ, et al. Evaluation of surgical margins required for complete excision of cutaneous mast cell tumors in dogs. J Am Vet Med Assoc. 2004;224:236–240.

7.  Sfiligoi G, Rassnick KM, Scarlett JM, et al. Outcome of dogs with mast cell tumors in the inguinal or perineal region versus other cutaneous locations: 124 cases (1990–2001). J Am Vet Med Assoc. 2005;226:1368–1374.

8.  London CA, Malpas P, Wood-Follis S, et al. Multicenter, placebo-controlled, double-blind randomized study of oral toceranib phosphate (SU11654) , a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clin Cancer Res. 2009;15(11):3856–3865.

9.  Kiupel M, Webster JD, Bailey KL, et al. Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior. Vet Pathol. 2011;48(1):147–155.