Managing mast cell tumors in the age of tyrosine kinase inhibitors (Proceedings)

Background and biologic behavior

Mast cell tumors (MCT) are the most frequently encountered dermal/subcutaneous neoplasm in dogs representing 7% to 21% of all skin tumors in this species. Most MCT develop in older dogs and no sex predilection has been reported. Most dogs with dermal/subcutaneous MCT have a solitary mass; however, multiple masses may be detected in 3% to 38% of patients and represent a unique treatment dilemma. Tumors may be located on the trunk and perineum or to a lesser extent, the extremities. The metastatic rate of MCT may be as high as 96% for high grade tumors and <10% for well-differentiated tumors. Metastasis most commonly involves the regional lymph nodes, the spleen, the liver, bone marrow and the kidneys. Other forms of MCT are much less common but other primary sites of involvement include the oral cavity and tongue, nasopharynx, upper airway, mediastinum, and intestine. Mast cell granules contain a variety of biologically active compounds including histamine, heparin, chondroitin sulfate, prostaglandins and leukotrienes, and cytokines. Disorders caused by the release of mast cell granule contents include gastric ulceration, peritumoral inflammation, cardiopulmonary abnormalities, prolonged local bleeding, and delayed wound healing. Clinical signs reflect the extent of systemic disease and may consist of localized pruritis and erythema (Darrier's sign), anorexia, vomiting (hematemesis), diarrhea and melena, and even hypotensive shock associated with mast cell degranulation. This discussion will review and update the current standards of care regarding diagnosis, staging, treatment, and prognosis for MCT in dogs and cats.

Diagnosis and staging

Cytologic examination of a fine needle aspirate is usually sufficient to make a diagnosis and should be performed before surgical excision of all cutaneous masses. Mast cell tumors are typically distinguished from other round cell tumors (histiocytoma, transmissible venereal tumor, plasma cell tumor, and lymphoma) by the presence of blue to purple cytoplasmic granules. Occasionally, these granules may stain poorly with either Diff-Quik or Wright-Giemsa stains. Poorly granulated cells may require special staining with toluidine blue. Incisional or excisional biopsy is necessary to confirm the diagnosis and for histologic grading of the tumor, although this is not necessary in most clinical situations.

Clinical staging of patients with MCT is strongly recommended because it guides all treatment pathways and there is a correlation between stage of the disease and prognosis. Most importantly, the staging process should involve fine needle aspiration of the regional lymph node(s). Size of lymph node does not correlate to metastasis so all nodes should be aspirated regardless of size. If cytologic examination of the lymph node aspirate is equivocal, then the lymph node should be biopsied and /or removed prior to or at surgery. The first site of metastasis is most often the draining regional lymph node. Because MCT can spread to the liver, spleen, bone marrow, blood, and other sites, a more comprehensive staging workup including abdominal ultrasonography, ultrasound-guided aspiration of spleen, liver, and intra-abdominal lymph nodes, buffy coat smear, and bone marrow aspiration cytology may be performed, although these tests must be considered to be low yield. Because of the low prevalence of pulmonary involvement, thoracic radiography is not usually indicated, but may be performed as part of the overall evaluation of the geriatric patient. Computed tomography (CT) evaluation may be valuable for determining tumor margins for surgery and is necessary for radiation treatment planning. A commonly used histologic grading system developed by Patnaik et al assigns tumors to Grade 1(well-differentiated), Grade 2 (intermediately differentiated), and Grade 3 (poorly differentiated) categories. In most studies, the grade of the tumor is the single most important factor predicting outcome, although other prognostic factors have been shown to be of value including growth rate, oncogene expression( c-kit) and tumor proliferation assays ( AgNor, PCNA, Ki-67 etc), which is the current thinking, although not of definitive benefit. Recent attempts have been made to have 2 rather than 3 grades

Treatment options

Role of surgery

Whenever possible, surgery is the treatment of choice. Pre-surgical treatment with an antihistamine such as diphenhydramine is recommended before surgical manipulation which can result in MCT degranulation and systemic hypotension, H-2 receptor antagonists may also be administered for the same reason in addition to preventing gastric ulceration secondary. It is also advisable to avoid pre-medication with morphine as this drug has the potential to cause MCT degranulation. Other narcotics do not appear to have this effect. The general recommendation is for wide surgical excision maintaining a minimum of 3 cm margins around the tumor and at least one fascial plane deep to the tumor. However, a recent study concluded that excision of MCT with 2 cm lateral margins and a deep margin of one fascial plane may result in satisfactory excision in the vast majority of Grades 1 and 2 MCT in dogs.

Closure of surgical wounds associated with MCT excision can be challenging at times due to either the location of the tumor or due to the size of the defect associated with wide surgical excision or both. Attention to pre-operative planning is critical—anticipating the size of the defect and the options for wound closure before an incision is even made is very important and can substantially minimize intraoperative anxiety. It is strongly recommend to painti all surgical margins with India ink and tagging margins for orientation of the tissues in the patient—this facilitates microscopic examination of the surgical margins for residual tumor.

Complete surgical excision is typically curative for Grade 1 tumors and Grade 2 tumors with localized disease but other factors such as lymph node status and other host and tumor factors should be included in the overall assessment to properly manage individual patients. De-ionized water has been shown to be toxic to neoplastic mast cells, the hypotonicity causing mast cells to swell and rupture but intralesional deionized water is not effective at controlling disease locally

If a tumor cannot be surgically resected, then neo-adjuvant therapy (chemotherapy and radiation therapy) may effectively reduce the size of the tumor so that surgical excision becomes feasible. Incompletely excised MCT should receive additional treatment and may include re-excision of the tumor, radiation therapy, and/or chemotherapy.

It is not uncommon (10-15%) for dogs to develop multiple cutaneous MCT either concurrently or over time. Results of a recent retrospective study indicate that survival times in dogs with multiple simultaneous cutaneous MCT treated with wide surgical excision may be comparable to those in dogs with solitary Grade 2 MCT. It is important to inform clients that dogs with MCT may develop new tumors—these should be accessed via fine needle aspiration and surgical excision whenever possible. Some dogs, especially brachycephalic breeds may develop multiple, but indolent tumors with little progression over time. Even when many tumors develop, they remain quiescent for long periods of time. Differentiating the indolent from the fulminated can be problematic

Role of radiation therapy

Radiation therapy has been used for decades to control mast cell tumor disease in dogs. Even as surgery has become more aggressive and surgical cures more common, radiation therapy is still routinely employed for highly invasive tumors and preservation of function, limbs and cosmesis. Treatment of microscopic disease with curative doses (16-19 treatments and doses of 50-60 Gy) results in > 90% local control. Dog with gross disease can also be treated with good results although surgery should always be performed is possible.

Lymph node disease can also be effectively managed with radiation therapy and control times of regionally metastatic MCT, approaching those with no nodal disease. Chemotherapy is still indicated, as there is likely disease outside the radiation field.

Radiation therapy can also be given in a palliative setting for advanced disease or high-risk patients. This lower dose radiation is less aggressive, but can provide significant improvement in quality of life. There is a slight risk of tumor degranulation when treating gross tumor so patients should be on H1 and H2 blockers and even supported with IV fluids for the first 24-48 hours, especially in patients with significant tumor burden.

Role of chemotherapy

Chemotherapy has long played a role in managing advanced mast cell tumor both locally and systemically and there can be dramatic responses in patients when they respond to therapy, making surgery possible and providing improvements in quality of life and better pain control, even if long term control is not achieved. Predicting individual response is highly variable but overall response rates range from 40-50%, a fairly high number when treating gross disease.

The value of chemotherapy in the adjuvant setting either following surgery, radiation therapy or both, is less clear. Despite what is considered to be routine use of chemotherapy such as Lomustine (CCNU), Vinblastine, prednisone and other agents, there are no controlled studies proving survival benefit in metastatic or Grade III tumors or use adjunctively. More recently some studies have reported use of chemotherapy with intent to control local recurrence of incompletely resected disease. Results are encouraging, but comparison to radiation therapy will need to be done before recommending chemotherapy over radiation. Use of chemotherapy will continue to be based on somewhat subjective criteria although in Grade III and widely metastatic tumors it is considered standard of care.

Prednisone and other corticosteroids have been used as single agents and part of combination protocols. Its effectiveness is real, but how much it adds to the overall control is difficult to know. Corticosteroids should not be offered as a single agent front line therapy for any MCT, unless owners decline other recommendations.

Tyrosine kinase inhibitors are a new class of chemotherapy drugs which specifically target both transduction pathways and angiogenic pathways in tumors. These recently FDA approved drugs have shown great promise in both naïve and recurrent tumors and represent a new way to approach MCT

Palladia (SU11654, Pfizer), exhibits activity against members of the split-kinase RTK family (VEGFR, PDGFR and Kit) In 57 dogs with a variety of cancers (carcinomas, sarcomas, MCTs, melanomas, and lymphomas) objective responses occurred in 16 dogs (RR=28%) with stable disease in an additional 15 dogs for an overall biological activity of 54%, including sarcomas, carcinomas, melanomas, myeloma, and MCTs. The highest RR was in MCTs, with 10/11 dogs with Kit mutations exhibiting responses (n=9) or stable disease (n=1). A placebo controlled randomized study of Palladia was then performed in dogs with non-resectable Grade II and III MCTs During the blinded phase, the RR in Palladia treated (n=86) dogs was 37.2% (7 CR, 25 PR) versus 7.9% (5 PR) in placebo-treated (n=63) dogs. Of 58 dogs that received Palladia following placebo-escape, 41.4% (8 CR, 16 PR) experienced an objective response. The overall RR for all 145 dogs receiving Palladia was 42.8% (21 CR, 41 PR). Dogs with Kit mutations were much more likely to respond (SD>10 weeks, CR, or PR) to Palladia than those without (82% vs. 55%) and dogs without lymph node metastasis had a higher response rate than those with involvement (67% vs. 46%).

Kina vet (AB Science) is another TKI that primarily targets Kit. In a phase II study of a Kinavet in 13 dogs with grade II and III MCTs there were 2 CRs, 2 PRs, and stable disease in an additional 2 dogs (Axiak et al, VCS 2006). A randomized double blind placebo controlled phase III clinical trial of Kinavet was then performed in over 200 dogs with non-metastatic Grade II or III MCTs(38). While the overall RR was not significantly different between placebo and Kinavet treated dogs (15% vs. 16%), there was a significant difference in time to progression between the two groups (75 vs. 118 days), suggesting that Kinavet has biologic activity in MCTs. Although dogs with MCTs possessing Kit mutations did not experience a significantly greater response to therapy when treated with Kinavet (20%) compared to placebo (10%), they did experience a significantly longer time to progression in dogs with Kit mutations.

Both Palladia and Kinavet also have the capacity to cause unique side effects. Palladia can induce a mild, non-life threatening neutropenia in a subset of treated patients. This does not seem to predispose dogs to bacterial infection, and often resolves with dose reduction. Also a poorly understood lameness can be seen as well Kinavet can induce a protein losing nephropathy and a syndrome of hemolytic anemia in a small subset of patients, the origins of which are not clear.

Prognosis

Based on the recent literature, the prognosis for mast cell tumors is dependent on many factors including grade, completeness of excision, location, lymph node status ( controversial), systemic involvement and a host of proliferation markers such as mitotic index, PCNA, mitotic index, Ki-67 and others. Expression of c-kit has also been shown to have prognostic significance although any of the above factors taken alone will not be a good indicator of outcome. Many dogs with advanced disease or even metastatic disease can have extended survival especially if radiation therapy and chemotherapy are employed. About 10% of dog will develop additional cutaneous lesions, which do not predict a poor outcome and can be managed effectively with another surgery. Only a small subset of dogs will develop aggressive multiple aggressive tumors and these are managed with chemotherapy.

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