Learning Objectives

Understand the peri-operative management, staging, and surgical oncology principles for cutaneous MCT in dogs and cats, and the indications for adjunctive radiation therapy or chemotherapy in conjunction with surgery. Understand treatment options for non-resectable MCTs.

Canine Cutaneous MCTs

Diagnosis

• Cytology is usually diagnostic, and finding of suspected high grade MCT on cytology is highly predictive for histologic high grade.
• In my practice, complete staging involves evaluation of local/draining lymph nodes, abdominal ultrasound with liver and spleen cytology, and bone marrow evaluation. Bone marrow is typically reserved for cases with CBC abnormalities because it is uncommon (<5%).
• Lymph node (LN) evaluation is always recommended because low-grade MCT may metastasise. MCTs affecting the muzzle and perioral tissues may be more likely to metastasise. LN mapping is ideal to identify the ‘sentinel’ node. Diagnosis of metastasis from both cytology and histology can be challenging, but criteria have been recently published that may assist.^1,2 Good outcomes can be achieved with aggressive treatment in low grade, stage 2 MCT so identifying metastatic LN prior to surgery is important. Abdominal ultrasound and liver and spleen cytology is recommended in cases of known or suspected high grade tumours or when grade is unknown and local therapy is likely to be radical.
• Histology: The 2-tier histologic grading scheme (low/high grade) has better inter-pathologist agreement than the 3-tier scheme, however, combining the two may give additional information. Mitotic index (per 10 high power fields) is i prognostic, though the most useful value is not fully determined. The significance of additional prognostic factors (Ki67, AgNORs, c-kit staining pattern, and mutation) is, in my opinion, not fully determined in terms of effect on prognosis.

Treatment

• Surgery: For MCT with distant (beyond LN) metastasis, removal of the primary tumour is not likely to impact prognosis, though it may improve quality of life in painful/ulcerated tumours. General oncologic principles of local en bloc resection with a margin of normal tissue around the tumour apply for cutaneous MCT. MCT should be minimally manipulated during preparation and surgery to decrease degranulation. Many MCT will have definitive excisional surgery on the basis of a cytology result. As a general rule, 1 cm lateral margins are adequate for Grade 1 MCT, 2 cm lateral margins for Grade 2 MCT, and 3 cm lateral margins for Grade 3 MCT. These have not been re- evaluated for the 2-tier grading scheme. If the grade is not known, then a minimum of 2 cm lateral margins is recommended. For cytologically diagnosed MCT where definitive surgery is feasible based on size and location, biopsy for pre-operative grading is not usually required. Deep margins are more qualitative than quantitative. The deep margin should comprise fascia or muscle. Careful pre-operative palpation and imaging (ultrasound, CT, or MRI) are useful to determine degree of fixation to deeper structures in planning the deep margin. The excised tumour specimen should have the surgical margins inked to facilitate histological margin assessment. If the MCT is greater than 1 cm in diameter, then the skin surface should be cut at 1 cm intervals to allow appropriate formalin fixation of the tissues.
• Adjuvant local therapy: In cases of incomplete or narrow histological margins (i.e., risk of local recurrence), additional local therapy with revision surgery or radiation therapy is recommended. Electrochemotherapy is a newer modality which may also be an option. It is important to remember that the ‘safe’ histological margin (i.e., sufficient to prevent local recurrence) has not been determined for MCT and is influenced by grade. Many incompletely or narrowly excised low-grade MCT do not recur, however, additional local therapy with re-excision or radiation therapy has been shown to improve survival and so should be considered in all cases.³
• Adjuvant systemic therapy: Chemotherapy is recommended following surgery in high grade MCT, even without visible metastasis, as adjuvant chemotherapy appears to improve survival over surgery alone. The ideal protocol for adjuvant chemotherapy in high grade/high risk MCT is not fully determined. Vinblastine and prednisolone appears to be most commonly used, but protocols including CCNU alone or alternating with vinblastine are also reported. The adjuvant use of TKIs such as toceranib (Palladia) or masitinib (Kinavet/Masivet) is not well studied, though one retrospective study reported improved outcome in dogs with high risk MCT receiving adjuvant vinblastine and prednisolone compared to those receiving masitinib.⁴ The other major challenge with adjuvant use of TKIs is determining appropriate duration of treatment. The use of adjuvant corticosteroids or anti-histamines has not been studied and is not generally recommended.
• Non-resectable primary tumours.
• Radiation therapy (RT): Palliative or definitive RT may be considered. There are no large prospective studies, but it appears that the addition of prednisolone +/- toceranib may improve response (approximately 80% versus approximately 50%) and control duration over palliative RT alone.
• Chemotherapy: Many different chemotherapy drugs alone and in combination (+/- corticosteroids) have been studied, including vinblastine, CCNU, TKIs, paclitaxel, cyclophosphamide, and hydroxyurea, and metronomic chlorambucil. Response rates range from approximately 20% to 80% and response durations from weeks to many months. In general, combination therapies seem more effective. I usually offer three options for chemotherapy for non-resectable MCT: 1) ‘traditional’ chemotherapy with vinblastine and/or CCNU along with prednisolone, 2) toceranib with prednisolone, or 3) metronomic chlorambucil and prednisolone.
• Alternative local therapies: Electrochemotherapy results in response rates of 60–80% in the small studies published to date, and is generally well-tolerated. Intra-lesional triamcinolone may be an effective option in some cases, though responses are generally relatively short-lived.
• Treatment of metastatic MCT: In cases of MCTs with LN but no distant metastasis (stage 2), aggressive local therapy, often along with adjuvant chemotherapy is generally recommended. For low-grade stage 2 MCT aggressive local therapy (surgery +/- radiation therapy) may be sufficient for long-term control. In distant metastasis, systemic treatment options as for non-resectable MCT are typically attempted, with some retrospective data suggesting that using vinblastine and CCNU is more effective than toceranib.
• Supportive care: Anti-histamines +/- antacids are recommended in all dogs with gross MCT disease.

Feline MCTs

• Cutaneous: The majority are benign, but a subset are more aggressive and identifying those is challenging. The 3-tier grading system for canine MCT is not useful, the 2-tier system has not been evaluated. Features that have been assessed for impact on prognosis include:
• Histologic subtype.
• Mastocytic - most common, further divided into compact and diffuse (pleomorphic/anaplastic) forms. Diffuse MCT tend to have a higher mitotic index and may be associated with more aggressive behaviour, however, prediction of behaviour based on histologic subtype alone is difficult. A more recent study described a subset of well-differentiated tumours with prominent multinucleated cells which appeared to have aggressive behaviour.
• Histiocytic - more likely to affect young cats, with Siamese being most affected in some studies. Generally benign, may spontaneously resolve.
• Proliferation indices: Higher mitotic index (per 10 hpf) is associated with outcome, though the appropriate cutoff value is not known. Ki67 staining is also associated with prognosis.
• KIT labelling pattern appears to be associated with prognosis as for dogs.
• Multiple lesions: Unlike in dogs, multiple cutaneous tumours are associated with splenic involvement and worse outcomes than solitary tumours in cats in some studies, though other studies found no effect on prognosis.
• Histologic margins may not predict recurrence, though evaluation of this factor in a group of ‘high-risk’ MCT may be of more clinical significance.
• Recurrent tumours may be associated with a worse prognosis.

I currently recommend evaluation of local lymph nodes in every cat and abdominal ultrasound and buffy coat assessment in cats with multiple or high mitotic index MCT. For tumours with aggressive growth, more aggressive surgery is warranted, but given the benign behaviour of the majority of feline cutaneous MCT surgical margins of 1–2 cm seem reasonable.

• Splenic MCT may be solitary or associated with cutaneous tumours. Involvement of the liver and bone marrow/peripheral blood is common. Splenectomy is the treatment of choice, even if liver involvement or mastocytemia is documented, as it is associated with the longest survival times (>1-year median). The addition of chemotherapy should be considered for cats with evidence of more distant disease (liver involvement, persistent mastocytemia), though the best protocol, and whether or not it impacts outcome, is not known.
• Intestinal: Prognosis was previously thought to be poor because of extensive disease at diagnosis but a recent study suggests that the behaviour of these tumours is extremely variable. Based on this, my current recommendation is for surgical excision if possible. Chemotherapy could be considered for metastatic or unresectable tumours.

Systemic Treatment in Feline MCT

Response rates of approximately 50–80% to CCNU and to toceranib are reported, and there are anecdotal/case reports of responses to other such as vinblastine, chlorambucil, and imatinib. For cats with gross disease, it would seem reasonable to start with CCNU or toceranib and consider the other drugs as alternatives if a good response was not seen.

References

1.  Krick EL, Billings AP, Shofer FS, Watanabe S, Sorenmo KU. Cytological lymph node evaluation in dogs with mast cell tumours: association with grade and survival. Vet Comp Oncol. 2009;7:130–138.

2.  Weishaar KM, Thamm DH, Worley DR, Kamstock DA. Correlation of nodal mast cells with clinical outcome in dogs with mast cell tumour and a proposed classification system for the evaluation of node metastasis. J Comp Pathol. 2014;151:329–338.

3.  Kry KL, Boston SE. Additional local therapy with primary re-excision or radiation therapy improves survival and local control after incomplete or close surgical excision of MCTs in dogs. Vet Surg. 2014;43:182–189.

4.  Miller RL, van Lelyveld S, Warland J, Dobson JM, Foale RD. A retrospective review of treatment and response of high-risk MCTs in dogs. Vet Comp Oncol. 2016;14:361–370.