What is a mast cell tumor with Dr. Laura Brown

Introduction Mast cell tumors (MCTs) arise from malignantly transformed mast cells. In dogs, most of these tumors arise as primary tumors in the skin. They are the most common skin tumor in dogs, accounting for roughly 20% of all reported skin tumors.1 Any breed may be affected with MCTs, but certain breeds are predisposed, including golden retrievers, Labrador retrievers, Boston terriers, boxers, and pugs. Pugs are more likely to have multiple MCTs at diagnosis (56% of pugs with MCT in one study), but these tumors demonstrate more benign behavior and rarely lead to death.2 MCTs can affect dogs of any age but typically affect middle-aged to older dogs. An underlying etiology for most tumors cannot be identified. Breed predilections support some component of underlying genetic causes. Mutations in the c-kit tyrosine kinase receptor, which can lead to malignant transformation of mast cells, are found in 25%–30% of intermediate to high-grade tumors.3,4 KIT mutations will be further discussed in regards to both prognosis and treatment options for MCTs. MCTs can be located anywhere on the body and may lie within the dermis and/or subcutis. They have a wide range of gross appearance, from raised and superficial to very deep and fixed; they may feel soft and fluctuant or firm. Most MCTs are easily diagnosed with fine needle aspiration (FNA). Infrequently, MCT granules will not stain with Diff-Quik (Jorgensen Laboratories Inc., Loveland, CO, USA) and need to be stained with a Wright’s stain. On Diff-Quik cytology, if eosinophils are seen along with large round cells that lack granules, suspicion should be raised for an MCT and the slide submitted to a clinical pathology laboratory for a non-Diff-Quik stain.5 The majority of MCTs will be cured with surgical excision.1 Prognostic factors for predicting MCTs that will exhibit a more aggressive biologic behavior – ie, tumors that will not be cured despite local excision and that will ultimately lead to the patient’s death – are varied as well as controversial. When to pursue staging tests in dogs with MCTs, which tests to perform, and treatment recommendations beyond surgery are based on the predicted biologic behavior of the tumor, with staging diagnostics and systemic therapy the recommendation for dogs with biologically aggressive MCTs. Prognostic factors relating to history and physical examination Some factors that can be obtained from a history and physical examination that are generally accepted to carry a more guarded prognosis in dogs with MCTs include recent, rapid tumor growth and fixed, ulcerated tumors.6–8 Although publications regarding these features are limited, one early study reported doubling of the survival percentage at 30 weeks post-MCT excision for dogs with slow-growing tumors versus (vs) those with more rapidly growing masses.8 Biologically, both the ability to grow quickly and to become fixed to deeper tissues are physical manifestations of more aggressive behavior. Tumor location on the body can also be associated with biologic behavior; this topic is more controversial and the pertinent locations and published papers are highlighted as follows. Mucocutaneous location In limited published cases, eyelid margin MCTs appeared to have relatively benign behavior and were effectively treated with local therapy, although one dog was reported to have regional lymph node (LN) metastasis.9–11 MCT of the conjunctiva may be of concern only locally, without reported metastasis in three dogs.12,13 In a paper evaluating chemotherapy for high-risk MCT patients, eleven dogs with mucous membrane MCTs (vulva, prepuce, conjunctiva, oral cavity) had significantly shorter median survival times (MST) than 50 dogs with MCTs of haired skin.14 However, a recent paper of 32 dogs with 33 conjunctival MCTs treated with surgery alone showed prolonged survival times, with only two dogs having local recurrence despite incomplete margins in 25 cases, and no dogs dying of mast cell-related disease.15 Muzzle/perioral/oral location Early case reports described aggressive behavior and local metastatic disease at diagnosis in two dogs with MCT of the lip; survival times were 6 months or less.16,17 Of five dogs with MCT of the tongue, two presented with LN and/or systemic metastasis, and two of the remaining three had postoperative local recurrence leading to euthanasia.18 Larger, more recent studies confirmed that MCTs on the muzzle, perioral mucocutaneous junction, or oral mucosa have a more aggressive biologic behavior, with increased risk of locoregional LN metastasis.19–21 The rate of documented metastasis to local (mandibular) LNs was 55%–59%, compared with a 2 years) for low grade (85 dogs). A retrospective study with 47 dogs attempted to validate the two-tier scheme; although some of the data reported were inconsistent (including no description of the MI of the cases), the high-grade cases did have significantly worse progression-free and overall survivals than the low-grade ones.31 Further studies validating this proposed system are warranted; currently, the author’s university pathology department provides the standard grade, an MI, and the two-tier grade for every sample. Clinically, heavy reliance is placed on the MI for behavior prediction. Other assessments on biopsies – highlighting mitotic index As grade is so variable and subjective, many other prognostic factors, including DNA aneuploidy, c-kit-staining pattern, presence of c-kit mutations, microvessel density, Ki67, proliferating cell nuclear antigen, and MI, have been evaluated in an attempt to better predict the behavior of canine MCTs and to pick out the “bad” grade II tumors. Two groups have evaluated the MI (total number of mitotic figures counted in ten high-power fields; fields with the highest mitoses counted) and found that it is predictive of survival time, even within the grade II tumor category. The groups did identify different values for the index, with the first paper showing an MST of >70 months for an index score ≤5 and survival 5.32 The second group wrote a letter to the editor in response to the first paper and confirmed that high scores have very short survival times, with index scores broken down into three groups: MI =0, MST not reached; MI =1–7, MST =18 months; and MI >7, MST =3 months.33 The cutoff of MI ≥7 was subsequently adopted for the two-tier system. Although MCT histologic “prognostic panels” are offered by some laboratories, no publications have shown how these panels may provide additional benefit over the MI and grade for prediction of tumor behavior. Staging information In general, staging tests for asymptomatic dogs with cutaneous MCTs are extremely low yield. The test most often positive is regional LN aspiration. Cytologic assessment of the locoregional LN is important, even if the node is not enlarged. In a study of dogs with muzzle MCT, four of eleven LNs with metastases were of normal size.19 Another study with 55 dogs with confirmed LN metastasis and 35 dogs without metastasis showed a sensitivity of 71% and specificity of 54% for palpation as a predictor of metastasis.34 Sixteen of 35 dogs (46%) with normal size LNs on physical examination had metastasis, whereas in another study eight out of 21 (38%) normal size LNs showed metastasis.35 FNA of the LN is ideally performed prior to excision of the primary MCT, as surgical treatment of the tumor can produce confusing LN results due to local postoperative inflammation. As mast cells can be a normal feature in LNs, some MCT cases will not have a definitive answer on LN cytology. Criteria for LN involvement have been proposed and used in several subsequent reports.34–37 Prognostically, the implication of a metastatic LN is also a controversial topic. LN involvement has been associated with a worse prognosis in a number of studies.20,36–39 However, several papers also report long-term survival in dogs with LN involvement where the primary tumor and the LN are treated to achieve local control using surgery with or without radiation therapy.14,34,35,40,41 Chemotherapy was used in many of the reported cases as well, although the protocols varied, and the added benefit of chemotherapy after local control was achieved cannot be proven via the retrospective noncontrolled studies that currently exist. To summarize the information in the literature, LN involvement may carry a worse prognosis, yet dogs can still have prolonged survival with adequate treatment of the primary tumor and the metastatic node, with chemotherapy potentially having a benefit as well. Assessment of any locoregional LNs, whether normal sized or enlarged, with cytology or histopathology is critical to determine the stage of the tumor and appropriate therapy for the patient. Other staging tests are rarely positive and may have false positive results as well. In general, staging tests other than LN aspiration are recommended in patients who have negative prognostic factors associated with their MCT. Thoracic radiographs are indicated to evaluate the sternal LN if the mass is on the ventral abdomen, or to rule out other non-MCT diseases. MCTs metastasize so rarely to the lungs that radiographs are not indicated to evaluate for pulmonary spread. Buffy coat preparation to look for circulating mast cells is a quick and easy test, but it is both insensitive and nonspecific. The bone marrow may still be infiltrated in spite of a normal buffy coat, and dogs with skin disease, parvo virus, and nonmast cell illnesses often have positive buffy coats despite not having an MCT.42–44 Bone marrow evaluation for mast cell infiltration is positive in