Gerry Polton, MA, VetMB, MSc(Clinical Oncology), DECVIM-CA(Oncology), MRCVS, European Veterinary Specialist in Oncology, RCVS Recognised Specialist in Veterinary Oncology (Small Animals)
Cutaneous mast cell tumours are common in domestic dogs. Many publications cite a prevalence of over 7–21%. They are heterogeneous in appearance and behaviour. The physical appearance of a mast cell tumour does not reliably provide an accurate assessment of tumour severity.
Diagnosis is straightforward in most cases using fine needle aspirate biopsy. However, a diagnosis alone does not provide sufficient information to make informed decisions about therapy. Further prognostic information is provided by the histological grade. Definition of histological grade allows us to predict biological behaviour of the tumour, including risk of metastasis. This is integral to rational mast cell tumour management. However, it should always be remembered that the purpose of histological grade is to aid the clinician to predict future behaviour. If the tumour already exhibits clinically severe behaviour, histological grade has limited purpose.
In canine mast cell tumours the presence or absence of lymph node and distant metastases is of enormous prognostic significance. The most common sites of distant metastasis are the spleen and liver.
Most grade I mast cell tumours have zero or only limited capacity for local infiltration and no capacity for metastasis. Approximately 15% of intermediate-grade mast cell tumours exhibit metastasis. Some metastatic cases are identified at diagnosis, for instance by recognition of an enlarged regional lymph node. High-grade tumours metastasise in 80–95% of cases. In the absence of medical therapy, most high-grade mast cell tumours cause the death of the patient within six months of diagnosis.
Frequently, routine diagnostic evaluations prove inadequate for decision-making, largely due to the relative frequency of intermediate-grade tumours. A number of ancillary evaluations have been reported.
Two-Tier Grading Scheme
Since 1973 mast cell tumours have been graded according to a three-tier scheme. An alternative two-tier histological grading scheme for canine mast cell tumours was published in 2011. In practice, this does not appear to have aided decision-making. In a recently reported study using metastasis as an index of whether a tumour has the capacity to be harmful, 15% of the Kiupel low-grade tumours were misgraded. Only 3/44 misgraded tumours would have been similarly misgraded by the Patnaik system.
Mitotic index has long been noted to be of prognostic importance. Mast cell tumours with mitotic indices of zero or one have a low risk of progression; cases with mitotic indices of two to four have an 'intermediate' prognosis, and those with a mitotic index of five or more are expected to die from mast cell neoplasia in almost 95% of cases.
Ki-67 is a marker of cell proliferation rate. High Ki-67 expression correlates with a higher risk of tumour-related death. Ninety-five percent of dogs with an intermediate-grade mast cell tumour exhibiting a Ki-67 index of less than 1.8% were alive 3 years after diagnosis. By comparison, the 1-year, 2-year and 3-year survival proportions for dogs with intermediate-grade mast cell tumours with Ki-67 indices of greater than 1.8% were 54%, 45% and 33%, respectively.
c-Kit Immunohistochemistry and DNA Sequence Analysis
c-kit is a cell-surface growth factor receptor. It is relevant in the context of the newer mast cell tumour therapies. Immunohistochemical analyses of patterns of c-kit expression have been linked to prognosis. However, no association has been demonstrated between c-kit immunohistochemistry and drug response. Tyrosine kinase inhibitors exert their effects through inhibition of an altered c-kit molecule and to definitively recognise this, DNA sequence must be analysed. Modern techniques allow this to be performed on fine needle aspirate samples and results can be generated in as little as two weeks. However, these techniques only screen for known highly prevalent mutations. For complete analysis, full reverse transcriptase DNA sequencing would be required; this would be expected to take a whole month. These delays have obvious adverse implications for therapy.
Commonly used treatment options include surgery, chemotherapy, radiotherapy, corticosteroids, and tyrosine kinase inhibitor therapy. These treatments are frequently combined in appropriate circumstances.
For low-grade tumours surgery is appropriate in all cases where it is anatomically possible. Most low-grade tumours should be cured by resection with 2-cm margins and one fascial plane beneath the tumour.
Intermediate-grade tumours have the capacity to undergo significant infiltrative growth and to undergo metastasis. Mast cell tumours that undergo metastasis do so preferentially to the regional lymph node. All enlarged lymph nodes should undergo fine needle aspirate biopsy. Identification of isolated individual mast cells is of no consequence, but the presence of small clusters or atypical mast cells indicates regional lymph node metastasis. Systemic therapy would be indicated.
High-grade mast cell tumours are rapidly progressive, significantly infiltrative, and frequently metastatic. In general, surgery is contraindicated, as it is likely to fail to achieve the desired outcome and it carries a significant risk of inducing troublesome complications. Systemic therapy is indicated in most cases.
There are multiple chemotherapy protocols reported for the management of canine cutaneous mast cell tumours. Most protocols incorporate one or both of vinblastine and lomustine.
The dose of vinblastine in common use is 2 mg/m2 weekly or biweekly. Vinblastine is typically administered in conjunction with prednisolone at reducing doses over a twelve-week period. Side effects are relatively predictable.
The dose of lomustine used in the management of cutaneous mast cell tumours is 70–90 mg/m2 once every 3–6 weeks. The interdose interval is defined by the duration of myelosuppression and by the perceived risk of cumulative toxic effects. The primary toxicities are myelosuppression and gastrointestinal signs. Additional side effects include fatal cumulative hepatotoxicity, thrombocytopenia, nephrotoxicity, and interstitial lung fibrosis. Serial monitoring to evaluate haematological, hepatic, and renal parameters should be considered mandatory prior to every treatment administration.
Chlorambucil and prednisolone have been used for the management of unresectable mast cell tumours. A 38% response rate was reported with a median remission duration of 533 days. The results compare favourably with expectation but may reflect rarefied case selection.
Radiation therapy is used for adjuvant therapy of incompletely excised primary tumours or regional lymph nodes and in the management of tumours that are considered unresectable.
It is hard to measure the value of radiotherapy following incomplete tumour removal; without radiotherapy only 10–28% of cases recur. Cases are selected on the basis of risk/benefit analysis. Risks include moist desquamative dermatitis, chronic ulcer formation, pathological fracture, tendon rupture, and radiation-induced neoplasia.
There is more evidence for the efficacy of radiotherapy in the management of macroscopic tumours. In one study, 88.5% of patients demonstrated a complete or partial remission after treatment. The median progression-free interval was 1031 days. Most of the cases treated were unresectable intermediate-grade tumours.
Tyrosine Kinase Inhibitors
There are two tyrosine kinase inhibitors licensed for veterinary use: masitinib (Masivet®, AB Science) and toceranib (Palladia®, Zoetis). The most significant difference between the products is the breadth of activity. Masitinib is a highly focussed targeted therapy, with very few off-target molecular interactions. This results in a superior safety profile. Toceranib's broader profile of activity is an advantage in some contexts and not in others.
In the largest reported study of masitinib use, 8% of cases exhibited grade 3 or 4 side effects. One percent died due to anaemia; the mechanism remains unknown. Two percent developed a protein-losing syndrome; this is reversible. In a report of field use of Palladia®, 19% of cases developed severe adverse events with 14% of all cases dying or being euthanized due to adverse drug events or the combination of adverse drug events and disease progression. Palladia®-induced adverse events are mostly gastrointestinal. The explanation for the higher incidence of severe side effects is damage to the vascular supply resulting in necrosis of neoplastic mast cells and degranulation effects.
Recent work has reported what might be best described as a clinical caseload. One hundred and forty-seven cases of 'suitable' tumours were treated with Masivet®. The unifying factor was that these mast cell tumours were extremely aggressive. Fifty-one percent of cases were presented with metastases (including regional lymph node metastases). Forty-five percent of evaluable cases were known to be histological grade 3 (55% grade 2). In response to masitinib, 79% achieved complete or partial remission. Ninety percent demonstrated a biological response. Progression-free survival was best for cases treated with masitinib alone or masitinib in combination with prednisolone. However, prior treatment with prednisolone had a detrimental effect on progression-free survival.
Feline Mast Cell Tumours
Over 90% of feline cutaneous mast cell tumours are benign and will be cured by marginal excision. Multifocal disease, high mitotic activity, and cellular atypia indicate malignancy. At present, advice is to treat feline cases with lomustine (60 mg/m2 q 3–6 wks). Despite scientific interest in the role of tyrosine kinase inhibitors, clinical results have been disappointing.