Demystifying mast cell tumors (Proceedings)

Mast cell tumor (MCT) represents the most common malignant cutaneous tumor in the dog, and is commonly encountered in small animals. There is a large degree of variation in the histologic appearance and biologic behavior of canine MCT, ranging from histologically and behaviorally benign to histologically and behaviorally malignant. However, 65 to 80% of MCT will remain local diseases. Knowledge of the signs associated with worrisome prognosis, and the steps to take to address the potential for recurrence and/or metastasis, can help to simplify the approach to this sometimes frustrating neoplasm. Likewise, newer information regarding local and systemic treatment of MCT has increased the management options available for veterinarians and owners to consider.

Diagnosis

Canine MCT have been referred to as "the great pretender", because they can look and feel like anything. This can include soft, subcutaneous masses that can feel exactly like lipomas. Thus, needle aspiration cytology should be offered for any lump or bump encountered. Cytology is sufficient to achieve a diagnosis of MCT in approximately 90% of dogs. The classic appearance is a population of large round cells with central nuclei and abundant cytoplasm, with characteristic blue-purple cytoplasmic granules. Granules will not be visible in approximately 10% of MCT, which may confound the diagnosis in a small number of cases. It is common to see other inflammatory cells, such as eosinophils and neutrophils, admixed with the MCT cells.

When a presumptive diagnosis of MCT is made, it is useful to perform needle aspiration cytology of the regional lymph node at the same time, whether or not it feels enlarged, to rule out early metastasis.

To stage or not to stage

The majority of canine MCT, while locally aggressive, are unlikely to metastasize. Having an idea of which are likely to behave aggressively prior to surgery may help to identify those patients in which additional staging, to rule out disease elsewhere, should be undertaken preoperatively.

Prior studies have identified several prognostic factors associated with MCT: (1) Histologic grade is one of the strongest -- dogs with high-grade (grade III) tumors may die of their disease rapidly despite appropriate local therapy; (2) Clinical stage - Dogs with metastasis to regional lymph nodes or other structures at presentation have a less favorable long-term prognosis; (3) Location - Tumors in the preputial, perianal, oral, subungual (nail bed) and other mucocutaneous sites classically have worse prognoses; (4) Recurrence following initial surgical excision is a negative prognostic indicator; (5) The presence of systemic signs (anorexia, vomiting, hematemesis, melena) is a strong negative prognostic indicator, as it often indicates systemic dissemination; (6) Recent rapid growth or tumor ulceration are also worrying signs.

Animals with tumors displaying these criteria may have a higher likelihood of metastasis, and thus a thorough search for disease elsewhere is reasonable prior to undertaking definitive therapy. This may also be reasonable in lower-risk patients if very expensive or aggressive treatment is likely to be necessary, or if the tumor is in a location not amenable to wide surgical excision. In the absence of these factors, it is reasonable to proceed immediately to appropriately aggressive surgical excision (See below).

Complete staging for canine MCT should include cytologic evaluation of the regional lymph node, abdominal ultrasound, and thoracic radiographs. Of these tests, abdominal imaging and lymph node cytology are the most likely to yield important results. Cytology of abnormal lymph nodes or organs in the abdomen is indicated, however aspirates of structurally normal liver and spleen are rarely useful. If radical, expensive or potentially disfiguring surgery is being contemplated, an incisional biopsy may also be considered for histologic grading. The utility of other tests such as bone marrow aspiration cytology and buffy coat smear is questionable at best, and they are not routinely performed in the author's practice.

If no evidence of disease elsewhere is found, appropriate local therapy can be pursued. Identification of disease in the regional lymph node means that this should be removed as well at the time of surgery, and that additional systemic therapy should be considered irrespective of histologic grade. Identification of disease beyond the regional lymph node usually means that surgery will be of little or no benefit, unless that disease can also be resected surgically.

Surgery for mast cell tumors

Even well-differentiated MCT are associated with aggressive local tissue infiltration. Thus, it is necessary to include a generous margin of normal-appearing tissue on all sides of the tumor (including deep) to insure that any microscopic nests of tumor are removed. The standard recommendation is to remove a minimum of 3 cm of normal-appearing tissue 360 degrees around the tumor, and at least one uninvolved fascial plane deep. The entire specimen should be submitted in one piece, preferably with the margins inked, so that the pathologist can assess all margins for adequacy of excision. There is accumulating information, however, that surgical margins less than 3 cm may be sufficient in "tight spots". This seems especially true for low/intermediate grade tumors, and those that are fairly small in diameter.

When necessary, very aggressive or radical surgical procedures, such as amputation or body wall resection, are reasonable to consider. Prior to contemplating procedures such as these, complete staging is recommended, and incisional biopsy for determination of histologic grade may be helpful. When dealing with a low or intermediate-grade tumor, very aggressive surgery is reasonable because the likelihood of metastasis is low.

The question of whether or not to administer perioperative histamine blockers is a matter of personal choice. The risk of a serious degranulation reaction is very small unless the tumor is extensively handled (which should not happen if 3 cm of normal tissue is removed!).

Interpreting the pathology report

Two important pieces of information need to be gleaned from the pathology report: (1) Histologic grade; and (2) Adequacy of surgical margins. If only a representative piece of the tumor is submitted, margins cannot be evaluated and the utility of the report is cut in half. Pathologists often utilize a numeric grading scheme, where "Grade I" is well-differentiated and "Grade III" is poorly differentiated, however some pathologists will now utilize words such as "low, intermediate or high-grade" or "well, poorly or intermediately differentiated". If information regarding grade or margins is not provided, it should be requested from the pathologist.

Low or intermediate grade MCT with complete surgical margins usually require no further therapy, as the risk of recurrence or metastasis is only approximately 10%. However, regular rechecks for recurrence, metastasis, or new cutaneous masses is indicated. Low or intermediate grade tumors with incomplete surgical margins have a high chance of recurrence, but a low chance for metastasis. Thus, further aggressive local therapy is reasonable. When possible, immediate re-excision of the surgical scar (and an additional 3 cm tissue in all directions and another fascial plane deep) is the most useful treatment. The entire excised tissue should be inked and re-submitted for histopathology. When this is not possible, the next best option would be the use of radiation therapy. Chemotherapy may be useful to delay or prevent recurrence in cases where additional surgery or radiotherapy is not possible or has been declined.

High grade MCT with complete surgical margins have a low chance for recurrence, but a high chance for eventual metastasis. Systemic therapy (e.g. chemotherapy) can be offered in an attempt to delay or prevent this. High grade MCT with incomplete margins have a high likelihood of both recurrence and metastasis: Therapy designed to address both of these possibilities (e.g. additional surgery or radiotherapy, with chemotherapy) is indicated.

There is new information that assessment of mitotic index (a measure of the rate of proliferation, which can be assessed on any histology slide), may be a strong predictor of outcome, identifying intermediate grade tumors at high risk of spread and, potentially, high-grade tumors at lower risk of spread.

Caution owners against a "wait and see" approach

The importance of addressing the potential for local recurrence the very first time the tumor appears cannot be overstated. Owners should be strongly cautioned against adopting a "wait and see" attitude, with the intent of becoming more aggressive if/when the tumor grows back. Recurrent tumors are likely to grow more quickly, invade more deeply, and are more likely to ulcerate or become painful. In a recent study, dogs with MCT that were locally recurrent at the time systemic therapy was started were more than 4 times more likely to die as a result of MCT than dogs that started therapy at the first occurrence.

Radiation therapy

In addition to aggressive local surgery, several other local therapeutic modalities have been investigated for the adjuvant treatment of canine MCT. Radiation therapy (RT) has proven to be a very effective local treatment modality when combined with "marginal" surgical excision. 2-year control rates of 85 to 90% can be expected when incompletely excised low- or intermediate-grade MCT are treated with RT. Radiation therapy to bulky tumors is consistently less effective than RT to microscopic disease, with a one-year control rate of approximately 50%.

Chemotherapy

Animals with undifferentiated MCT, MCT that have metastasized, or tumors in a historically unfavorable location (see above) may benefit from the addition of some form of systemic therapy to appropriate local therapy. In addition, aggressive surgery or RT may be cosmetically unappealing or financially impossible for some owners. Recently, several studies have been published investigating various systemic therapies for measurable canine MCT, the results of which are summarized in Table 1.

Table 1: Response to chemotherapy in dogs with mast cell tumors

Two studies have been published evaluating the efficacy of chemotherapy in the prevention of recurrence or metastasis in the post-surgical setting. These utilized oral prednisone and injectable vinblastine.

Prednisone and vinblastine administration - Prednisone is administered orally at an initial dose of 2 mg/kg SID, for the first week, and this dose is tapered and discontinued over approximately 3 months. VBL is given as a rapid intravenous bolus at 2 mg/m2 every 1-2 weeks. The standard postoperative protocol consists of weekly injections for 4 weeks, followed by 4 biweekly injections.

Side Effects - Adverse effects are noted in approximately 20% of patients, usually after the first dose of VBL. These are mild in most. Mild side effects include self-limiting vomiting, neutropenia without evidence of sepsis (7-day neutrophil count less than 1,000/µL), or lethargy/soft stool. Severe side effects occur in only approximately 5% of patients.

Efficacy - As an adjuvant therapy to incomplete surgical resection ("microscopic disease"), VBL and prednisone treatment conferred a 57% one and two-year disease free rate in one report. In another report, postsurgical VBL and prednisone were able to prevent local recurrence in the large majority of incompletely excised, grade-II MCT treated. Although probably not as efficacious as "appropriately aggressive" surgery or cytoreduction and RT, many feel that this represents a significant improvement over incomplete resection alone.

As adjuvant therapy to prevent metastasis in patients with "high-risk" disease (i.e. high grade tumor, lymph node metastasis, unfavorable location), prednisone and vinblastine results in 2-year disease-free intervals of 60%. Interestingly, there seems to be a profound difference between the outcome of a high-grade tumor and an intermediate-grade tumor with lymph node metastasis. Despite the presence of lymph node metastasis, 90% of patients with grade II tumors with positive lymph nodes are disease-free at one year. Patients with grade III tumors treated in the adjuvant setting have 2-year survival rates of 60%. This appears to be a significant improvement over historical data employing surgery alone, which report a median survival of 8 months and a 2-year survival percentage of less than 15%.

Other clinicians recommend postoperative treatment with lomustine (CCNU), an oral alkylating agent, or alternating lomustine and vinblastine. At this time, there is no information regarding the efficacy of these treatments in the postsurgical setting in the peer-reviewed literature.

New directions

Perhaps the most important recent finding with potential to translate into new and exciting forms of therapy is the discovery that the majority of canine (and human) mast cell neoplasms express the tyrosine kinase growth factor receptor KIT, and a large minority of canine MCT possess a mutation in the gene coding for the KIT protein. This gene codes for a transmembrane protein that serves as the receptor for the growth factor stem cell factor, important in the maturation of normal mast cells and other hematopoietic cells. Mutations can render KIT active even in the absence of bound stem cell factor. In other words, these mutations mean that the cells are receiving signals to proliferate and survive when they normally would not, leading to unchecked growth. New molecules have been developed that inhibit signaling through the KIT tyrosine kinase, and there is now information that some of these compounds are able to interfere with the proliferation of canine MCT in vitro. Furthermore, evidence of antitumor activity has been documented in dogs with MCT treated with these compounds. The 2 molecules that are in late-stage clinical development for the veterinary market are toceranib (Palladia, Pfizer Animal Health) and masitinib (Kinavet, AB Science). It is hoped that an orally available inhibitor of KIT may be approved for the treatment of canine MCT in the near future.

Summary

While recent advances in the medical treatment of MCT are very exciting, it is important to remember that, aggressive surgery remains the mainstay of treatment for canine MCT, and is sufficient to successfully treat the majority of MCT encountered in practice.

References

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