Abstract

Canine mast cell tumors (MCT) vary greatly, and no prediction can be made for their behavior on clinical appearance alone. Important prognostic information can be gained from histologic grading and assessment of surgical margins. Surgical excision is indicated if the tumour is solitary and is the treatment of choice for grade 1 and 2 MCT. Excision should include a minimum 2cm margin around the borders of the tumor and one fascial plane below. Incomplete excision should be followed by further surgery, or by radiation therapy; both provide excellent long-term local control. Grade 3 or metastatic MCT are best treated by chemotherapy and/or palliative therapy. Active chemotherapy agents include vinblastine and lomustine (CCNU). Recent identification of mutations in tyrosine kinase receptors on MCT cells implies an exciting new therapeutic role for drugs that target these receptors.

In dogs, mast cell tumors (MCTs) are most commonly found in the cutaneous tissue. In most dogs, tumors are solitary, but in about 6%, the tumors are multiple. Tumors usually occur in older dogs (mean age = 9 years) with no sex predilection. Boxers, Rhodesian ridgebacks, pugs, Boston terriers, pit-bull terriers and Weimaraners are at high risk (4 to 8 times more than the population) for developing MCTs. Shar-Peis, particularly young dogs, are predisposed to developing MCT, and these tumors are often poorly differentiated and aggressive biologically.

It is uncommon to diagnose MCTs without skin involvement in dogs. Mast cell tumors vary greatly in appearance, and no estimate of their malignancy or prediction of their behavior can be made on clinical appearance alone. Some MCTs may be present for months to years before rapidly disseminating; others act aggressively from the beginning. Approximately 6% of dogs will develop multiple cutaneous MCT.

Occasionally, mechanical manipulation during examination of this tumor causes degranulation of mast cells, producing erythema and wheal formations. This phenomenon has been observed in both dogs and cats (the "Darier's sign") and is considered of diagnostic significance. Owners may report that the tumor enlarges rapidly and then diminishes in size over a period of about 24 hours. Such a history should increase the clinician's suspicion of mast cell tumor.

The clinical appearance of MCTs in dogs may vary widely but diagnosis is relatively easy using aspiration cytology. Presurgical aspiration of these tumors provides a cytology specimen characterized by round cells that may have well-stained and large cytoplasmic granules (well-differentiated) or that may be more anaplastic with small, poorly staining cytoplasmic granules. Eosinophils are often seen in aspirates of MCTs because of eosinophil chemotaxis to histamine release.

Diagnosis of MCT often can be made by fine-needle aspiration cytology; but excisional biopsy is required for accurate histologic grading of the tumor. Histopathologic grading of the tumor has been correlated with both recurrence and survival.

All dogs with MCTs should be staged to determine the extent of their disease. This is especially important for dogs being considered for aggressive surgery such as amputation, or radiation therapy.

To establish the stage of a dog with a cutaneous MCT, the following information is needed:

1.  Complete Blood Count (CBC), Serum Chemistry Profile and Urinalysis

2.  Lymph Node Aspirates
The clinician should perform fine-needle aspiration of the regional lymph node if the node is enlarged. The presence of clusters of mast cells (and eosinophils) is an indication that the MCT may no longer be confined to the primary site. Mast cells may infiltrate a regional lymph node in a dog with a MCT as an inflammatory response to the tumor, therefore a suspicious cytology result should be confirmed by biopsy.

3.  Radiographs and Ultrasonography
Splenomegaly or hepatomegaly may indicate spread of MCTs systemically. Pulmonary metastasis of MCTs is rare. Ultrasonography is most useful for staging a dog with MCT if used in conjunction with histopathology or cytology.

4.  Bone Marrow Aspirates
The presence of >1% mast cells indicates systemic spread of the neoplasm. In a recent report 4.5% of dogs with cutaneous MCT had either >1% or abnormal mast cells in a bone marrow aspirate.

5.  Miscellaneous Tests
Fecal occult blood tests may be useful in evaluating patients with mast cell disease. In many cases, feces may contain small amounts of blood that are insufficient to produce melena. Evidence of gastrointestinal bleeding in a patient with a MCT should prompt the clinician to treat with medications that block the effects of mast cell hyperhistaminemia (i.e., H₂ blockers, such as cimetidine, ranitidine, famotidine).

6.  Buffy Coat Smears
Care must be exercised in interpreting buffy coat smears, because mastocythemia has been reported in a variety of canine acute inflammatory diseases (see below). For this reason, some oncologists now feel that this test has limited applicability to staging of dogs with MCT. We no longer recommend it as part of staging for MCT.

PROGNOSTIC FACTORS

Recent clinical research has led to the identification of prognostic factors for dogs undergoing therapy with surgery and radiation therapy, and this same research has led to changes in thinking about other previously well-accepted prognostic factors.

Gender: male dogs had a worse prognosis after chemotherapy treatment for MCT.

Age: dogs older than 8 years were nearly 3 times more likely to die of their disease after treatment for MCT.

Growth Rate: Dogs with tumors that grow at a rate greater than 1 cm per week appear to have a worse prognosis, in an early study of dogs treated with surgery alone.

Tumor Grade: Recent studies using aggressive surgical technique, and histology to examine margins (rather than the surgeon's clinical impression), has shown that dogs with grade 2 MCT have a much lower rate of local recurrence and longer survival rates than was previously believed. Nonetheless grading is still an important prognostic factor. Grade 3 tumors are more likely to be incompletely excised, more likely to metastasize and nearly 4 times more likely to result in death than tumors of lower grades.

Surgical Margins: The completeness of excision (i.e., whether the surgical margins are "dirty") is an important prognostic factor and also important in determining if further surgery or adjunctive radiation therapy is needed. There is often disparity between the surgeon's assessment of margins and those assessed by histopathology. In one study 22 of 59 tumors thought to have been excised widely had either questionable (10) or incomplete (12) excision based on histological examination.

Dogs with incomplete excisions are more likely to develop metastatic disease. Because of this finding, and because tumor recurrence is still more common following incomplete excision, the clinician is counseled to obtain clear surgical margins wherever possible, and not to rely on a marginal excision.

Tumor Location: Although it was often reported that MCT in the inguinal and perineal regions had a poor prognosis regardless of histologic grade, this has recently been shown to not always be true. Although MCTs in this location have long been thought to be more likely to recur than MCTs in other subcutaneous locations, aggressive local therapy often results in long-term control and there is no difference in recurrence rate, time to recurrence and survival compared to dogs with MCT at other locations. MCT of the muzzle were found to often be grade 3 tumors, and to have a higher rate of regional lymph node metastasis (nearly 60% of dogs evaluated).

Multiple Tumors: Although the staging scheme detailed above includes multiple tumors as being a higher clinical stage, the occurrence of multiple tumors has not been shown to be a worse prognostic factor. In a study that compared dogs with single MCT and dogs with multiple MCT, there was no significant difference in survival times between these two groups. It appears that the staging scheme should be amended to exclude multiple tumors in the category of stage 3.

Tumor Stage: Dogs with lymph node metastases are nearly 8 times as likely to die of MCT. A potential problem with staging is that small numbers of mast cells may be found in the circulation, spleen, liver and bone marrow, so the significance of such a finding is unclear. In one study the presence of small numbers of mast cells in theses locations did not seem to influence survival in dogs with grade 2 MCTs. Mast cells may infiltrate a regional lymph node in a dog with a MCT as an inflammatory response to the tumor, therefore a suspicious cytology result should be confirmed by biopsy.

TREATMENT

Control of canine MCTs involves the use of surgery, chemotherapy, or radiation therapy, either individually or in combination.

Surgery

Surgical excision is indicated if the tumor is solitary and evidence of lymph node involvement or systemic spread is lacking. Excision should be wide and deep to a minimum margin of 2-3 cm around the perceived borders of the tumor and one fascial plane below. With this aggressive surgical approach, recurrence of grade 1 and grade 2 MCTs is very low. A recent study examined the completeness of surgical excision at margins 1cm, 2cm and 3cm from the edges of grade 1 and 2 MCT. All grade 1 tumors were excised 1 centimeter from the tumor borders, while only 75% of grade 2 tumors were completely excised at the same distance. All grade 2 tumors were excised 2cm from the tumor borders, leading the authors to speculate that it may be possible to completely excise MCT with these narrower than usually prescribed margins.

As previously stated, surgical excision should be aggressive. All excised tissue should be examined histologically for completeness of tumor excision as described above under Prognostic Factors. If the tumor is grade 1 or grade 2 and excision is complete, no further treatment is necessary. Extension of the tumor beyond the surgical borders or a report of "close" margins (as defined above) should prompt wider excision if this is possible. A second excision should include the previous excision site plus lateralmargins of 2-3 cm and additional deep tissue. If the tumor cannot be completely excised due to tumor location or other factors, or if it is a grade 3 MCT, further therapy is indicated. The animal should be evaluated for radiation therapy, if available. Chemotherapy may be considered if staging disclosed metastases, or if the MCT is grade 3.

Radiation Therapy

Mast cell tumors are quite sensitive to the effects of radiation therapy, even at moderate doses.

Dogs that have no measurable evidence of disease after surgical removal of MCTs but which had incomplete excision on histologic examination of excised tissues (Stage 0), has significantly longer tumor control and survival following radiation therapy than other dogs. Thus, post-surgical radiation therapy for incompletely excised tumors seems beneficial. Mast cell tumors of the extremities often present the greatest challenge for complete surgical excision. For well- or moderately differentiated tumors in these locations, combined modalities of less aggressive surgical "debulking" followed by radiation therapy may be a more acceptable treatment--both functionally and cosmetically.

Grade 3 MCT: Radiation therapy was used to treat dogs with grade 3 MCT that had only residual microscopic disease after surgery. In all case the regional lymph node was irradiated as well. Local control of the MCT was excellent, with a median remission time of 28 months. More than half of the dogs eventually developed lymph node metastases underscoring the need for systemic therapy in this disease.

Palliative radiation therapy: Radiation therapy may alleviate symptoms of extensive or systemic disease. When the tumor is poorly differentiated or metastasis is already confirmed, the use of high-dose intermittent radiation treatments may improve the quality of life by stopping bleeding or reducing the size of a bulky or irritating tumor. In these cases, a fully fractionated course would be costly and reduce the amount of time spent by owners with the dog. A coarsely fractionated series of three 8-Gy treatments on a schedule of day 0, 7, and 21, however, provides relief from symptoms, although it will not increase life span. Systemic therapy, as outlined later, can also be considered.

Systemic Therapy

Metastatic disease was found to occur more frequently in dogs that had grade 3 MCT, and in dogs that had incomplete surgical excision of their cutaneous tumor. When MCTs have metastasized or spread systemically, localized therapies, such as surgery or radiation, are appropriate only as palliation for discomfort or mechanical obstruction. For these dogs, systemic therapy is required.

Corticosteroids are primarily palliative, but some long-term responses do occur. Oral prednisone (2 mg/kg/day for 2 weeks, then 1 mg/kg/day for 2 weeks, then 1 mg/kg every other day) is given as long as the tumor does not progress. Anecdotally, dogs that are tumor-free after six months have a lower incidence of recurrence; therefore, therapy is usually discontinued at this time.

Vinblastine and prednisone were used to treat MCTs in one study. The overall response rate in dogs with measurable disease was 47%, there were 5 complete responses and 2 partial responses. The median response duration was 5 months (1 to >22 months). Dogs with lower grade tumors seemed to respond better. Vinblastine is myelosuppressive, and a weekly CBC should be performed prior to administering the drug at this inter-treatment interval.

CCNU (Lomustine) at a dose of 90mg/m² every 4 weeks PO was given to 19 dogs. One dog had a complete response for 15 months, and 7 had a partial response for an average of 3 months (1 to 9 months). This drug can be safely combined with prednisone. If using CCNU, monitor CBC (especially platelet count) and liver enzymes prior to each administration, discontinue if thrombocytopenia or increased liver enzymes are seen.

Vincristine was found to be an inactive agent for the treatment of MCT and often causes severe gastrointestinal toxicity. It is not recommended as a first-line chemotherapy agent for the treatment of MCT.

Novel Therapies

Mutations in the proto-oncogene c-kit were shown to lead to constitutive phosphorylation of the gene product, and are believed to be important in the development and progression of canine MCT.⁶⁵ There is no evidence that such mutations are breed associated. Abnormalities in c-kit are more common in grade 2 and grade 3 tumors than in grade 1 MCT implying a role in biologic behavior of MCT in dogs. Mutations in one study were seen in more than one-third of dogs with grade 2 or grade 3 MCT.

The therapeutic implication of such a finding is that kinase inhibitors may be useful, such as imatinib mesylate (Gleevec) which has been reported to cause clinical remissions in human patients with similar c-kit mutations. Gleevec has anecdotally caused serious morbidity and mortality when used in the dog limiting its clinical usefulness for veterinary medicine. However, clinical trials using drugs with a similar mode of action are underway in canine patients with preliminary encouraging results with one such drug (SU11654).

Palliation of Paraneoplastic Symptoms

Ancillary drug therapy is important with canine MCTs. Animals with mastocytosis or bulky mast cell disease should receive H₂ antagonists, as rapid degranulation of neoplastic mast cells may follow surgery or chemotherapy. Elevated systemic histamine levels may also be seen with recurrent disease. The objective of the therapy is to prevent gastrointestinal ulceration associated with elevated levels of histamine and to treat ulcers already present. This is most likely to occur in dogs with larger, bulky disease, with recurrence of cutaneous disease, or with systemic spread of MCT. Cimetidine reduces gastric acid production by competitive inhibition of the action of histamine on H₂ receptors of the gastric parietal cells. Ranitidine or famotidine, H₂ antagonists that require less frequent administration, may be used for a similar effect. Omeprazole, which inhibits gastric acid production by the gastric parietal cells through proton pump inhibition, may also be used. Dogs with evidence of gastrointestinal ulceration and bleeding may benefit from sucralfate therapy at a dose of 0.5 to 1.0 g TID PO. Sucralfate reacts with stomach acid to form a highly condensed, viscous, adherent, paste-like substance that binds to the surface of both gastric and duodenal ulcers. The barrier formed protects the ulcer from potential ulcerogenic properties of pepsin, acid, and bile, allowing the ulcer to heal. Such H₁ antagonists as diphenhydramine should be considered for use along with cimetidine before and after surgical removal of canine MCTs to help prevent the negative effects of local histamine release on fibroplasia and wound healing. A second generation H₁ antagonist, loratadine, has been shown to be very effective at inhibiting histamine release by blocking degranulation from normal canine mast cells, and therefore may be a good choice for palliation of dogs with MCT.

References

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