It seems the more we learn about mast cell tumors (MCTs), the more complex they become; however, the increase in complexity is also giving us more tools to sort out the good from the bad and leading us to more novel, effective treatment options. The gross presentation of these tumors varies widely (figures 1-3) and diagnosis prior to definitive treatment is the key to early, first-time effective treatment. The first step in treating MCTs is diagnosis. It is important to keep in mind that while diagnosis can almost always be made by fine-needle aspiration cytology (figure 4), excisional biopsy is required for histologic grading of the tumor. This is especially noteworthy as wide surgical excision is the treatment that is most likely to cure the majority of MCTs. Therefore, a definitive diagnosis via cytology allows a curative surgical approach the first time.
The second step in treating MCTs is staging. Any MCT has the capability to metastasize therefore staging prior to surgery is essential. However, the recommended staging for MCTs has evolved markedly in the last decade. Every patient should have a minimum data base of a complete blood count, serum biochemistry profile, and urinalysis. Historically the evaluation of a buffy coat for circulating mast cells was a routine part of staging. Recently, several studies have shown that many other inflammatory diseases including pneumonia, parvovirus, and pancreatitis, as well as patients with neoplasia other than MCTs and post-trauma patients demonstrate mast cells circulating in the peripheral blood.1 These patients also exhibited a higher mean number of mast cells/buffy coat smear than patients with MCTs. Another study confirmed the presence of mast cells in the buffy coat smears of patients with inflammatory skin diseases.2
Bone marrow aspirates used to also be a central part of the staging process. This invasive procedure has also fallen out of routine practice. In one study, the incidence of MCT infiltration in MCT patients was as low as 2.8%.3 While the presence of mast cells in the bone marrow is indicative of systemic disease, it is usually easier to find evidence of systemic involvement in other organs such as the liver and spleen.
MCTs commonly metastasize to lymph nodes and therefore all regional lymph nodes should be assessed. Although a lymph node may palpate normal, it is suggested that all regional lymph nodes be examined with aspiration cytology. Recall that normal lymph nodes can contain mast cells, for that reason, unless cytology contains clusters or clumps of mast cells that are indicative of metastasis, often lymph node biopsy is necessary for confirmation. Presence of lymph node metastasis generally carries a poorer prognosis than for those without metastasis.4
Abdominal ultrasound is the most sensitive technique for evaluation of the liver and spleen. Generalized infiltration with or without organomegaly is more common than discrete nodules. Aspiration cytology of structurally normal liver and spleen is generally unrewarding. Further, interpretation of cytology from structurally normal liver and spleen may be complicated by the presence of non-malignant mast cells. Therefore, fine-needle aspiration is indicated only if abnormalities are noted in the liver or spleen. Abnormal lymph nodes found with in the abdominal cavity should be assessed by needle cytology as well. Finally, thoracic radiographs rarely exhibit pulmonary involvement but it is important to evaluate the thorax for lymphadenopathy and pleural effusion.
Several studies have elucidated numerous prognostic factors for MCTs. Most importantly, histologic grade correlates significantly with survival and has been a valuable predictor of the biologic behavior of MCTs.5 As mentioned previously, grade cannot be determined by cytology, as histologic grade is determined by characteristics of the neoplastic mast cells, number of mitotic figures/10 high power fields, and the extent of tumor invasion into the underlying tissues.
The grading system used by most pathologists for mast cell tumors was developed by Dr Patnaik. This system incorporates cytoplasmic boundaries, nuclear shape and size, anaplasia, mitotic index, granules, and invasiveness. These characteristics differentiate mast cell tumors into three grades - I, II, and III. There has recently been proposed a two-tier histologic grading system. This was driven by a study that evaluated the consistency of microscopic grading among veterinary pathologists. The study found that concordance amongst pathologists was 75% for grade III MCTs and was less than 64% for grade I and II MCTs.6
It appears that more and more MCTs are being classified as grade 2 creating wide variation in the biologic behavior with in this group. Fortunately, several proliferative indices are aiding in sorting this group so that we can better predict MCT behavior. These include Ki-67 value, argyrophilic nucleolar organizing regions (AgNOR value), proliferating cell nuclear antigen (PCNA count), and KIT expression pattern. AgNOR value and Ki-67 have been predictive of survival.7,8 AgNOR value, PCNA count, and pattern of KIT expression have all been associated with rate of metastasis.9,10 A comprehensive immunohistochemical panel containing different combinations of these markers and PCR testing for C-kit is currently available through most commercial and veterinary diagnostic laboratories.
Traditionally, treatment of MCTs has consisted of surgical excision. Incompletely excised MCTs are adequately treated with follow up radiation therapy providing >90% 3-year control rate for grade 1 and 2 tumors.11, 12, 13 Adjunctive therapies such as corticosteroids and chemotherapy (vinblastine and lomustine) have demonstrated effectiveness against high grade, metastatic, and incompletely excised MCTs.14, 15, 16
C-kit is a tyrosine kinase receptor on mast cells. Mutations in C-kit lead to signal transduction that results in loss of normal cellular growth control (figure 5) and constituitive activation of C-kit.17 C-kit is also known as Stem Cell Factor Receptor or CD117. In the last few years, novel small molecular drugs that target C-kit have proven activity in clinical studies. These small molecule inhibitors of C-kit are administered orally and block C-kit phosphorylation and signal transduction that leads to cellular differentiation, survival and function (figure 6). Response rates as high as 55% were seen in one such study.17
Palladia® (toceranibphosphate) is a new oral targeted therapy developed specifically for dogs by Pfizer Animal Health. Palladia® is a small molecule inhibitor which blocks several receptor tyrosine kinases (RTK). By blocking these RTKs, Palladia® has proven to have antiproliferative and antiangiogenic effects.18 The overall response rate (partial and complete responses) in the preliminary multi-institutional MCT study was 37.2%. However, the biological response rate which includes those patients that had clinically stable disease, partial response, or complete response in this study was 59.5%. Further, the biological response rate for those patients whose tumors had Kit mutations was 82.1% versus 54.5% for those dogs without Kit mutation.18
Recently available, Kinavet-CA1® (masitinib), a novel tyrosine kinase inhibitor (TKI) is currently being marketed by a European based pharmaceutical company called AB Science. Masitinib blocks the signal transduction through C-kit causing cell cycle arrest and apoptosis of mast cells. Patients receiving masitinib demonstrated a significantly longer time to tumor progression than patients receiving placebo.19
Finally, ancillary therapy to protect the patient from the systemic side effects of mast cell degranulation is recommended in all patients with macroscopic disease. Histamine release can be blocked by oral administration of a combination of the H1 blocker diphenhydramine and one of the H2 blockers cimetidine or ranitidine.
MCTs have certainly undergone a dramatic evolution in veterinary medicine. This is one of the reasons why researchers, pathologists, and veterinary oncologists continue to examine MCTs in their complexity. Much like many of the different tumors that plague our patients, their complexity makes them more confusing, but we seem to be gaining some encouraging ground in our understanding and treatment of this multifaceted tumor. I for one remain encouraged in our battle to win.
If you have any questions regarding mast cell disease in one of your patients or would like to discuss a case with any of our specialists, please call us at 713-693-1155.
