A clinical oncology case report

History and clinical signs

A 10-year-old, neutered male miniature schnauzer was referred to the Western Veterinary Cancer Centre for further evaluation and treatment of a soft tissue mass involving the rostral lower lip. The owners had noticed the mass 2 wk prior to presentation and it had been biopsied by the referring veterinarian. Histopathology revealed that the lesion was a grade II mast cell tumor (MCT).

On presentation the dog was bright and alert with normal vital parameters. There was a poorly defined 1-cm diameter soft tissue mass involving the rostral lower lip that extended into the underlying tissues; the referring veterinarian’s biopsy incision was located centrally within the mass. The mandibular lymph nodes were firm and slightly enlarged bilaterally.

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The dog was admitted to the hospital for MCT staging, which included a complete blood cell count (CBC), serum biochemistry, urinalysis, 3-view thoracic radiographs, abdominal ultrasonography, mandibular lymph node aspirates, and a bone marrow aspirate. Blood work revealed an increased total white blood cell count [22.4 × 10⁹/L; reference range (RR): 4.8 to 13.9 × 10⁹/L] with atypical lymphocytosis (15.7 × 10⁹/L; RR: 1.2 to 5.0 × 10⁹/L). Thoracic radiographs were normal, and abdominal ultrasonography showed no overt evidence of neoplasia. Lymph node aspiration cytology showed mast cells scattered within a homogenous population of round cells with scant, basophilic cytoplasm. Bone marrow aspiration cytology revealed that approximately 25% of all nucleated cells present were small- to intermediate-sized lymphocytes, which were morphologically identical to the round cells seen in the mandibular lymph node aspirate as well as the lymphocytes present on the CBC. These results were interpreted to be consistent with locally metastatic MCT and concurrent lymphoid neoplasia.

Surgical biopsy of the mandibular lymph nodes and review of the original lip mass biopsy was performed, and definitive histo-pathologic diagnoses of grade II MCT of the lip and concurrent stage V lymphoma were confirmed. Mast cells were noted in the sinuses of the biopsied lymph node, but they were not felt to be numerous enough to represent true metastasis.

Concurrent treatment for lymphoma and MCT was recommended. The dog was started on a modified CHOP protocol for the treatment of its lymphoma, consisting of 16 chemotherapy treatments over a 30-week period using cyclophosphamide, doxorubicin, vincristine, L-asparaginase, and prednisone. A median survival time of 12 to 14 mo is typically expected with this regimen (1). The dog was in complete clinical remission for its lymphoma after the second chemotherapy treatment based on palpation of peripheral lymph nodes and evaluation of the CBC, and stayed in remission throughout the remainder of therapy.

Since staging tests did not demonstrate unequivocal systemic metastasis of MCT, this tumor was treated locally with coarsely fractionated radiotherapy. A total dose of 32 Gy divided into 4 weekly 8 Gy fractions was delivered to the rostral lip and mandibular lymph nodes by a linear accelerator using 6 MeV photons. Also, the dog was started on famotidine (Merck Frosst Canada, Kirkland, Quebec), 0.5 mg/kg body weight (BW), PO, BID and diphenhydramine (Laboratoire Riva, Blainville, Quebec), (2.5 mg/kg PO BID) to alleviate potential side effects of MCT degranulation as the tumor responded to therapy. There was no clinical evidence of MCT 3 wk after completion of radiotherapy, although there was still concern regarding the dog’s long-term prognosis: high grade MCTs treated with surgery alone have a reported median survival of 6 mo (2).

Sixteen weeks after starting treatment 3 new dermal masses were found along the dog’s right ventral mandible, outside the radiation field. Fine-needle aspiration cytology revealed that all 3 were MCTs. Based on progression of disease, the dog was started on toceranib (Palladia; Pfizer, New York, New York, USA), 2.5 mg/kg BW, PO, EOD). Partial regression of the new MCT lesions was noted within a week, but vomiting and decreased appetite were also observed. Omeprazole (AstraZeneca Canada, Mississauga, Ontario), 1.0 mg/kg, BW, PO, SID, sucralfate (Novopharm, Toronto, Ontario), 0.5 g, PO, TID and maropitant citrate (Cerenia; Pfizer), 16 mg, PO, SID were added to the previous oral medications. The dog’s quality of life stabilized after starting these drugs, although he continued to have an intermittently inconsistent appetite and weight loss.

Eight weeks after starting toceranib, several new dermal masses were found scattered over the dog’s head and trunk. The left mandibular lymph node was also slightly enlarged. Fine-needle aspiration cytology of the skin masses again revealed mast cells; neoplastic mast cells were also present in the lymph nodes, although there was no evidence of lymphoma. Because of further MCT progression, toceranib was discontinued and the dog was switched to masitinib (Masivet; AB Science, Paris, France), 100 mg, PO, SID. The dermal lesions stabilized for a short period and the dog’s appetite improved, but within 2 wk of starting masitinib the skin lesions began to slowly enlarge again. Masitinib was continued, but anorexia, lethargy, and a progressive, nonregenerative anemia developed over a 4-week period. Abdominal ultrasonography was performed and showed multiple heterogenous masses within the spleen, with the largest measuring 4 cm in diameter.

Cytopathology obtained from a fine-needle aspirate of the spleen revealed large numbers of markedly pleomorphic round cells characterized by a variable nuclear to cytoplasmic ratio (see Figures 1 and 2). Clear vacuoles were present within the cytoplasm of most cells. Although granularity appeared sparse overall, the Diff-Quik preparation used to stain the slides does not always highlight mast cell granules adequately. Marked anisocytosis and anisokaryosis were present, and binucleate and multinucleate forms were also seen. On average, 1 to 3 mitotic figures were present in each ×50 objective oil immersion field. A cytologic diagnosis of malignant MCT was made. The owners elected to have the dog euthanized because of his progressive tumor and clinical signs. The overall survival from the time of initiation of therapy to euthanasia was 8 mo.

Figure 1.

Fine-needle aspirate of spleen. Neoplastic mast cells are characterized by poor granularity and marked anisocytosis and anisokaryosis. Cytoplasm is basophilic and finely granular to mildly vacuolated. A large bilobed nucleus is present in one cell (arrow). Diff Quik stain, ×100 oil immersion objective.

Figure 2.

Fine-needle aspirate of spleen. Again, marked anisocytosis and anisokaryosis are evident in the poorly granulated neoplastic mast cell population and several mitotic figures (arrows) are present, including asymmetric mitotic figures. Diff Quik stain, ×100 oil immersion objective.

Discussion

Although the outcome in this case was disappointing, the case illustrates several valuable points regarding the management of small animals with cancer. First, a careful work-up is important to determine the definitive diagnosis, as well as the stage or extent of disease. The work-up also assesses the animal’s general condition and identifies concurrent medical problems that may or may not be tumor-related. The miniature schnauzer in this report was presented initially for further evaluation and treatment of its MCT, but workup revealed a significant and unexpected peripheral lymphocytosis. The atypical morphology of the circulating lymphocytes was initially missed in this case, because the dog’s first CBC was performed using an in-house machine and was not reviewed by a clinical pathologist. However, together with the results of the lymph node and bone marrow aspirates, the CBC raised suspicion for concurrent lymphoma, changing the treatment plan and prognosis significantly. This emphasizes the importance of a thorough workup in every case, as well as critical evaluation of the results.

This case is also an example of one of the basic principles of cancer therapy, which is to match treatment with the biologic behavior of the disease. Cancers can be divided into 2 categories based on biologic behavior: local and systemic. Localized cancers are best treated with local therapies such as surgery or radiotherapy, while systemic cancers should be treated with chemotherapy. The “local therapy for local disease, systemic therapy for systemic disease” principle was used to decide what treatments were most appropriate for this dog. Chemotherapy was clearly indicated for the dog’s multicentric lymphoma. However, since the initial workup indicated that the dog’s MCT was localized, radiotherapy was chosen to treat it. Unfortunately, systemic MCT developed within 4 mo, necessitating additional systemic therapy. Tyrosine kinase inhibitors were chosen because of concern that adding traditional chemotherapy agents for MCT to the dog’s ongoing treatment for lymphoma would result in unacceptable myelosuppression.

Finally, veterinarians offering therapy for small animals with cancer need to stay informed regarding new treatment advances, including specific indications and complications. Two new tyrosine kinase inhibitors (TKIs) were used to treat this dog, toceranib (Palladia), and masitinib (Masivet). Tyrosine kinases play a key role in signal transduction and regulate a variety of cellular processes. Abnormalities in such processes are often involved in the development and progression of cancer. Tyrosine kinase inhibitors are small molecule inhibitors that target specific tyrosine kinases, and many of these have shown significant clinical activity in human cancers. Recently, the TKIs toceranib and masitinib have become available for dogs. Both have been used successfully to treat canine MCTs (3,4) and they are indicated for some other malignant tumors as well.

In the dog described in this report, toceranib was used initially, but masitinib was substituted because of progressive disease and side effects. The most common side effects of toceranib are diarrhea, vomiting, decreased appetite, weight loss, and gastrointestinal bleeding. Like the dog in this report, animals receiving toceranib often require dose adjustments and concurrent medications such as famotidine, omeprazole, metoclopramide, maropitant, and sucralfate. Also, dogs that are sick before therapy are more likely to develop side effects. Minimizing tumor volume with traditional chemotherapy or radiotherapy prior to initiating TKIs may help to preserve quality of life and achieve better results. In most cases, side effects can be managed with good quality of life. Initial discussion with owners about potential side effects and the need for concurrent medications, close monitoring, and immediate intervention for complications are critical in dogs receiving TKIs.