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Canine and feline cutaneous mast cell tumour: a comprehensive

review of treatments and outcomes

M.T. Oliveira , M. Campos , L. Lamego , D. Magalhães ,

R. Menezes , R. Oliveira , F. Patanita , D.A. Ferreira

PII: S1938-9736(20)30070-2
DOI: https://doi.org/10.1016/j.tcam.2020.100472
Reference: TCAM 100472

To appear in: Topics in Companion Animal Medicine

Please cite this article as: M.T. Oliveira , M. Campos , L. Lamego , D. Magalhães , R. Menezes ,
R. Oliveira , F. Patanita , D.A. Ferreira , Canine and feline cutaneous mast cell tumour: a com-
prehensive review of treatments and outcomes, Topics in Companion Animal Medicine (2020), doi:
https://doi.org/10.1016/j.tcam.2020.100472

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Highlights

1. Mast cell tumour is one of the most frequent malignant cutaneous tumour
in dogs and second in cats
2. There are several histological and clinical classifications available, and still
no consensus in their use
3. Several other factors as, for example, tumour location, mitotic index, and
the detection of active mutations in the c-Kit gene, influence prognosis
4. The recommended treatment depends on the clinical staging, histological
grade and location of the tumour
5. This review intents to address existent information about the relationship
between the MCTs treatments and subsequent prognosis and survival
times
Review article

Canine and feline cutaneous mast cell tumour: a comprehensive review of treatments
and outcomes

M.T. Oliveira ab*, M. Campos c, L. Lamego c, D. Magalhães c, R. Menezes c, R. Oliveira c, F.

Patanita c, D.A. Ferreira ab
a
MED – Mediterranean Institute for Agriculture, Environment and Development, Instituto de
Investigação e Formação Avançada, Universidade de Évora, Pólo da Mitra, Ap. 94, 7006-
554 Évora, Portugal.
b
Departamento de Medicina Veterinária, Escola de Ciências e Tecnologia, Universidade de
Évora, Pólo da Mitra, Núcleo da Mitra, 7000 Évora, Portugal
c
Universidade de Évora, Pólo da Mitra, Núcleo da Mitra, 7000 Évora, Portugal

* Corresponding author. Tel.: +351 266 760 859.

E-mail address: teresoliveira@uevora.pt (M.T. Oliveira).
Abstract

Mast cell tumour (MCT) or mastocytoma is one of the most frequent malignant

cutaneous tumours in the dog and the second most frequent in the cat. In dogs, some factors,

like age and breed, are known to be related to the occurrence of this tumour, while no gender

tendency was identified. In cats, the Siamese has demonstrated differential predisposition to

the disease. An increased MCT frequency is also suggested in other breeds in England, like

Burmese, Russian blue and Ragdoll. No gender predilection has yet been established.

Several mast cell tumour therapeutic approaches have been proposed in the past years

for dogs and cats, resulting in very distinct outcomes. This review intends to address existent

information about the relationship between the MCTs treatments and the subsequent

prognosis and survival times in dogs and in cats diagnosed with MCTs.

Keywords: mast cell tumours, canine, feline, prognosis factors, treatment, outcomes
Introduction

Mast cell tumour (MCT) or mastocytoma is one of the most frequent malignant

cutaneous tumour in dogs [1–3]. Studies show that mast cell tumours in dogs represent around

17.8% of cutaneous neoplasia [3,4].

A large-scale retrospective study including 25,996 dogs diagnosed with cutaneous

neoplasia reported MCT as the third most frequent cutaneous neoplasia (10.98%) [5]. MCT in

dogs are usually diagnosed between seven months and 18 years of age, with an average age of

8.2 years [4,6].

In cats, MCT is the second most frequent cutaneous neoplasia, following the basal cell

carcinoma [5,7,8]. The incidence of feline MCT varies but overall represents 2-15% of all

tumours in the cat, and usually are diagnosed at an average age of nine years [9]. The MCT in

cats have two different histological subtypes: the most prevalent mastocytic form, similar to

MCTs in dogs, and the rather infrequent atypical form (previously known as histiocytic) of

MCT [7].

This comprehensive review addresses published data related with various approaches

to MCT treatment in dogs and in cats, and related prognosis and survival times.

Tumour location and prevalence

The trunk and the perineum are the most affected regions by cutaneous MCTs (≈40-

50%) in dogs, followed by the limbs (≈30-40%), and less frequently the head and neck (≈10-

15%) [4,10]. Cutaneous mast cell tumours (cMCTs) are usually single masses, but multiple

masses may also represent 11-14% of the cases [11]. In addition to the most common

cutaneous form, MCT presents also visceral forms that, despite being much less common, are

more aggressive. In dogs 10 out of 118 dogs (8.5%) present primary visceral MCT in the
gastrointestinal tract, the liver and the spleen [12]. Primary pulmonary MCT [13] and

intramuscular MCTs [14] were also reported.

Age and breed are reported to be related with the occurrence of MCTs in dogs [15].

Although some studies did not identify a gender tendency [16,17], other report the existence

of a higher risk of MCTs in male dogs, and in intact dogs [18], or even higher risks in female

dogs [4].

In a population of 802 cases of MCTs in dogs, crossbred are considered to be the most

likely to manifest the tumour (n=125), followed by Labrador Retriever (n=107), Boxers

(n=92), Golden Retriever (n=61), Cocker Spaniel (n=41), the Pit Bull (n= 41), Boston Terrier

(n=33), and Shar-Pei (n=18) [10]. Similar data was reported by Shoop and colleagues [17],

and by Śmiech and colleagues [4]. On the other hand, Boxers tend to express a cutaneous

MCT incidence 10 times higher than crossbred dogs (2,35% vs 0,23%, respectively) [19]. As

mutations in the c-Kit may increase the predisposition to the occurrence of MCT in dogs [20],

the existence of genetic factors that predisposes to the emergence of MCTs in certain breeds

is being considered.

Amongst the different breeds of cats one stands out, the Siamese, which has

demonstrated predisposition to develop both the atypical form, and the mastocytic form [21].

An increased MCT frequency is suggested in other breeds in England, like Burmese, Russian

blue and Ragdoll [22]. The skin of the region of the head and the trunk, the spleen, the

intestine and the lymph nodes are the most common locations of the MCT in cats[8]. A study

with 25 cats with cMCT reported that 24% showed multiple masses, which were associated

with a shorter survival time when compared to solitary cutaneous masses [5].

Over 50% of the MCT in cats have visceral locations [7], being the spleen the most

common location [5,23]. The MCTs splenic presentation is also reported as the most common

cause of spleen disease in cats [24]. Other common MCT visceral locations in cats include the
liver and the intestines [7], being the intestinal MCT the third most common primary

intestinal tumour in cats, most often affecting the small intestine [25,26].

Diagnosis and Staging

The most important single prognostic factor both in dogs and cats with MCT is the

histological classification [21]. Biopsy is considered the “gold standard” method of sample

collection [27], despite the high consistency that is observed between the cytology and the

histopathology results [28,29]. Patnaik’s MCT classification (Table 1) [16] was the most used

amongst the veterinary community, but Patnaik’s grading system has not proven to be

predictive of outcome in cats [30,31]. A retrospective study conducted using the Patnaik’s

grading system in cats with MCT revealed that this grading system had no prognostic

significance in this specie [9].

Sabattini and colleagues recently conducted a large retrospective study using the two

MCT main grading systems – Patnaik [16] and Kiupel [32] – suggesting a superior prognostic

value of the two-tier histologic grading system for canine cMCTs, while the three-tier grading

system provided some additional information about survival prognosis [33]. A recent study

also suggested that a two-tier grading system for cMCTs in cats, could provide a more precise

predictive survival time than the Patnaik grading system, although needing further validation

[34].

The MCTs histological classification may provide us with information about the MCT

metastatic potential, but it does not allow, by itself, the prediction of the MCT biological

behaviour. Thus, for a more complete MCT characterization, molecular screening methods

are essential, such as the evaluation of proliferation markers (Ki67, AgNORs, PCNA and

KIT) and the detection of the active mutation of the c-KIT gene through rt-PCR [29].
 Regarding the clinical staging, MCTs are graded in a five-tier system originally

developed by the World Health Organization in 1980 (table 2) [35]. Horta and colleagues

recently suggested an additional stage by dividing stage III in two different stages, whether

there was lymph nodes involvement or not [36].

All animals with MCT should undergo clinical staging, from a minimum dataset with

a complete blood count (CBC), a serum chemistry panel, and fine needle aspiration of the

regional lymph nodes, to a more complete appraisal that also includes abdominal

ultrasonography and fine-needle aspiration of the liver and the spleen, bone marrow

evaluation and pulmonary imaging. MCT prognosis should always take in consideration the

clinical staging, regardless of the histologic grading system used [37].

Therapeutic approaches

Surgical excision of less severe MCT tumours can promote a complete cure in less

severe grade I and some grade II MCT tumours [38–41], combined with radiotherapy, and/ or

chemotherapy, and also with complementary therapies [11,21,36,42–58].

Surgical treatment consists of the excision of the neoplastic mass with appropriate

safety margins to prevent the postsurgical tumour recurrence, but the surgical excision of

MCTs granting safety margins in all sides of the tumoural mass is not always easy or possible

to achieve. The peritumoural inflammation and/or oedema and tumour location often presents

a challenge when planning MCT surgical excision, especially in large tumoural masses. Limb

amputation and, consequently, complete resection of the tumoural mass, respecting the safety

margins, represents an aggressive option that potentially compromises the patient’s quality of

life and welfare, and should therefore be carefully thought out [59,60]. According to Fulcher

and colleagues, the excision of MCT tumours with a two centimetres lateral margin and a

fascial plane on the deep margin in dogs with grade I to II MCTs, leads to similar recurrences
rates to those reported for three centimetres safety margins [61]. Recent studies reiterate that

the conservative-margin approach (2 cm) appeared to be noninferior to the wide-margin

approach (3 cm) for achieving tumour-free histologic margins in the dogs, potentially

reducing the risk of postoperative complications [62,63]. Marconato and colleagues studied

the benefits of surgical excision of the primary tumour and lymphadenectomy in 73 dogs

with grade I and II cMCT and with early metastasis in the regional lymph node, followed or

not by adjuvant medical treatment (chemotherapy and/or kinase inhibitors). [64].

Radiotherapy can be used as treatment for MCTs after surgery

[11,42,48,50,53,65,66], combined with prednisolone [52,67] or with chemotherapy

[11,44,48,53,54,57,66]. Radiotherapy has also been suggested to be beneficial in a

prophylactic approach in the regional lymph nodes in MCTs with high risk of metastases,

even in cytologically negative lymph nodes [54,57]. Nonetheless, according to Poirier and

colleagues’ study, there were no differences in the mean survival rates of dogs with

incomplete surgical excision of grade II MCT and stage 0 submitted to prophylactic

irradiation of the regional lymph nodes, when compared to dogs in the same clinical situation

but not submitted to radiotherapy [50]. However, a recent study involving 42 dogs with high

grade MCT confirms that prophylactic and therapeutic lymph node irradiation is beneficial

and improves outcome [57]. The difficult access to radiotherapy equipment, the associated

financial costs and the frequent acute adverse skin reactions associated to radiotherapy

protocols, mainly on the face and the perineum [68], should be taken into consideration before

deciding to perform irradiation treatments.

Chemotherapy is conventionally recommended for control of metastatic MCTs with a

high risk of metastization, and in cases where complete surgical excision is not achieved [69].

Contrariwise, a recent study by Marconato and colleagues observed that the use of adjuvant

medical treatment in dogs with cMCT grade I and II, submitted to surgical removal of the
primary tumour and metastatic lymph node does not seem to yield any benefit in terms of

progression and survival [70].

Several chemotherapeutic agents have been described for addressing MCTs in dogs.

Vinblastine (VBL) has been frequently used in combination with prednisolone, and its

cytotoxic effects result from hindering the microtubules binding during the mitotic cycle,

which leads to cell death.[71]. A study by Rassnick and colleagues showed that VBL, when

used alone, has activity against MCTs in dogs though the response rate is lower than those

reported for multimodal protocols [72]. Prednisolone binds to the cytoplasmic receptors,

entering in the nucleus and altering DNA transcription, changing the cellular metabolism [73].

Lomustine (CCNU) is widely used and well tolerated as a chemotherapeutic agent in adjuvant

treatment for MCTs in dogs, as interferes with the synthesis and function of DNA, RNA and

proteins [52,74,75]. Burton and colleagues hypothesised that intermittent administration of

toceranib (TOC) (orally on days 1, 3, and 5 of a 21‐day cycle) combined with CCNU (on day

3 of the 21‐day cycle) could chemosensitize canine MCT in dogs with non-resectable or

metastatic MCT. The results report a maximum tolerated dose of CCNU of 50 mg/m 2, and a

median progression‐free survival of 53 days (1 to >752 days). This pulse-administered TOC

and CCNU treatment protocol was well tolerated by the dogs enrolled in the study [76].

Bavcar and colleagues also studied the combination of TOC and CCNU in the treatment of

non-resectable or recurrent MCT in dogs reporting high grade toxicities associated with this

therapeutic protocol. [77]. This observation is probably associated with the higher CCNU

dose used (60 mg/m2) and the higher frequency of TOC administration (orally every other

day) by Bavcar and colleagues [77] when compared to the pulse-administered protocol

reported by Burton and colleagues [76]. The receptor tyrosine kinase (KIT) inhibitors, TOC,

masitinib, and imatinib, have been used with safety and efficacy in the treatment of non‐

resectable or metastasized high‐grade MCT in dogs [78,79], and also effective in other MCT
patients [78–80]. Masitinib is more effective in tumours with active mutations in the C-kit

gene and is recommended for these cases [78]. Another recent tyrosine kinase (Bruton's

tyrosine kinase-BTK) inhibitor, ibrutinib, is being studied as a possible future alternative drug

to address MTC in dogs. Ibrutinib inhibits the tumoural growth and suppresses IgE-dependent

histamine release in neoplastic canine MCs by targeting BTK [81].

According to the “European consensus document on mast cell tumours in dogs and

cats”, the most commonly used chemotherapy protocols for the treatment of canine MCT are:

1) the combination of intravenous VBL (2 mg/m2 weekly for four weeks, then fortnightly for

four further treatments) and oral prednisolone (2 mg/kg daily for one week, then 1 mg kg−1

daily for two weeks, then 1 mg kg−1 every other day); 2) oral CCNU (70 mg/m2 every 21

days, four cycles); 3) the combination of alternate intravenous VBL (2 mg/m2 week one, and

then every fourth week) and oral CCNU (60 mg/m2 week three, an then every fourth week);

and 4) the combination of alternate intravenous VBL (3.5 mg/m2 week three, and then every

fourth week), oral CCNU (70 mg/m2 PO week one, and then every fourth week), and oral

prednisolone (2 mg/kg daily for first two weeks, and then 1 mg/kg daily until week 24 then

tapered over four weeks) [21].

Several other less established approaches for MCT in dogs have been described,

including intralesional injections, hyperthermia (in combination with radiotherapy)[82],

photodynamic therapy [83], and cryosurgery[84]. However, there is still lack of evidence

regarding their use [21].

Malone and colleagues reported that calcitriol (1,25-dihydroxycholecalciferol), when

used in combination with CCNU, VBL, imatinib or toceranib, had a synergistic

antiproliferative effect in in canine mastocytoma C2 cells activity in vitro. In the same study,

the use of high concentrations of calcitriol PO as single therapy in 10 dogs with MCT induced
partial (n=3) or complete (n=1) remission of the MCT. Nevertheless, all dogs experienced

significant toxicity which led to the discontinuation of the study [85].

Tigilanol tiglate, a novel diterpene ester currently under clinical evaluation, is being

studied for intra-tumoural treatments, including MCTs in dogs [86–88]. Intra-tumoural

administration of tigilanol tiglate leads to the destruction of the tumour mass within 2 to 7

days [86,87]. Other intralesional treatments for cMCT in dogs have been reported using

brachytherapy [89], hypotonic solutions [90,91] and deionized water [92], with variable

results. Recently, Case and Burgess showed that intralesional triamcinolone administration in

the treatment of non-resectable MCT in dogs may be well tolerated and effective [93].

The administration of Senday virus with oncolytic properties has also been reported as

possible future alternative therapy for the treatment of canine MCTs [94]. In this study, six

dogs with variable grades and stages of MCT disease were treated with Senday virus as

monotherapy (n=2) or in combination with surgery (n=4), with five dogs showing a complete

response to treatment (MCT local recurrence and/or remaining tumour masses completely

cleared), and just one dog showing a partial response (MCT local recurrence and some

metastases were cleared). During two to three years, duration of the time of observation, five

dogs remained disease free [94].

A resume of the main studies addressing MCTs surgical and/or adjuvant medical

treatments and outcomes in dogs are displayed in table 3 [11,36,41–46,48–51,51,52,52–

58,62–67,70,72,73,75–78,88,95].

Electrochemotherapy (ECT) is a recent technique in veterinary medicine used for

treatment of cutaneous non-neoplastic and neoplastic lesions, including cMCT, and has

shown to be very effective in the treatment of canine cMCT [96–100]. The combination of

chemotherapy drugs with permeabilizing electric pulses (electroporation), the bases of ECT,

increases the uptake of chemotherapy drugs by cancer cells [101–104] with high efficacy and
low toxicity [105]. These combined with the ease of administration and relative

inexpensiveness [101–104] is turning ECT in the first-line therapy in veterinary oncology for

different tumour histotypes [105]. Additionally, ECT can be used alone or in combination

with other tumour therapies and can also be used intraoperatively [99]. Intraoperative ECT is

usually used when ECT alone cannot cover all the tumour, and the best approach would be a

combination of surgical excision and ECT. In this case, MCTs are excised but without

complete safety margins and ECT is applied intraoperatively to all surgical margins before

wound closure [99]. In large tumoural masses, the combination of surgery and intraoperative

ECT should also be carefully considered, because the use of ECT alone in large tumoural

masses may result in toxicosis secondary to the massive destruction of neoplastic tissues,

delayed wound healing, cheloids, and local necrosis [106].

In general, ECT uses sequences of eight permeabilizing pulses, about five minutes

after local or intravenous administration of the chemotherapy drug, every two weeks until

complete regression of the tumour or observation of tumour progression; or just two

treatments if ECT is used postoperatively [106]. Once the drugs cross the cellular membrane,

promote various changes in cellular DNA leading to cell death [101–104,107,108]. The

increase in transmembrane passage enhanced by electroporation also allowed the topical used

of cisplatin in cats, which are very intolerant to this drug [106].

Several chemotherapy drugs can be used during ECT for the treatment of tumours,

such as bleomycin and cisplatin [101–104], doxorubicin [107] and mitoxantrone [108],

although only bleomycin [96,99] and cisplatin [97,98,100] have been studied in the treatment

of MCT in dogs [96–100]. Bleomycin and mitoxantrone can be administered by an

intravenous bolus at doses of 20 to 30 mg/m2 or 5 mg/m2, respectively [101–104,109].

Bleomycin at a dose of 1.5 mg/mm3 can also be administered within the tumour or in tumour

beds [106]. Cisplatin is injected locally at a dose of 0.5 to 1 mg/mm3 [106]. One study used a
combination of ECT (cisplatin in a dose of ~1 mg/cm3) with IL-12 gene electrotransfer in

dogs with MCT, mainly reporting a drastic reduction in the microvessel density of MCT when

compared to the MCT samples prior to the treatment [100].

Supportive therapies are also important adjuvants to minimise the side effects

associated with MCTs and MCTs treatments. These therapies are recommended in cases of

systemic disease, when the tumours are likely to be manipulated (e.g. surgery), or when

radiotherapy/chemotherapy will lead to degranulation of the mast cells. Drugs H1-blockers

(eg. diphenhydramine or chlorpheniramine) and H2-blockers (eg. cimetidine, famotidine or

ranitidine) can minimise the increase production and secretion of hydrochloric acid (HCl) into

the gastric lumen associated with the abnormal release of histamine by tumour mast cells. The

proton-pump inhibitors such as omeprazole is also quite effective in bulky MCTs. The oral

administration of sucralfate is also recommended in the presence of gastrointestinal

ulceration, due to its properties of reacting with gastric HCl acting as an acid buffer, and by

binding to proteins on the surface of ulcers forming stable and insoluble complexes that

protects the gastric mucosa [110]. In addition to histamine, mastocytes degranulation also

leads to heparin release, which increases the risk of surgical haemorrhages, an important fact

to consider when planning MCT surgical excision in order to avoid excessive manipulation of

the tumours by the surgeon [111].

In cats, the ideal treatment for cMCTs is surgery and incomplete excision of the

tumour does not seem to be associated to tumour recurrence, nor to decreased survival time

[9]. Thus, the surgical safety margins in cats are not as crucial as in dogs, because feline

cMCTs tend to behave benignly. However, multiple cMCTs, recurrent tumours and splenic

MCTs or infiltrated lymph nodes are associated with a more guarded prognosis [5]. The

atypical MCT form (previously known as histiocytic form) occurs in young cats with less than
four years of age and, in most cases, regresses spontaneously [112]. However, if regression

does not occur, the MCT should be surgically removed [21].

Radiotherapy may be a good alternative to surgery for the treatment of cMCT in cats

[113]. Its use should also be considered in incompletely surgical removal of cMCTs in cats,

although its efficacy is questionable [9] because, as abovementioned, feline cMCTs tend to

behave benignly, and the surgical safety margins in cats are not as crucial as in dogs.

The use of chemotherapy protocols in cats is questionable, and less advocated in feline

cMCTs [5,114]. However, chemotherapy can be used in histologically pleomorphic,

infiltrative and metastatic tumours [7]. The most commonly used chemotherapeutic agents in

cats are VBL, CCNU and TOC. Oral CCNU (48-65 mg/m2 every four weeks) is well tolerated

by cats and has confirmed activity against feline MCTs [74]. Oral TOC is also well tolerated

and seems to have evident MCT antitumoural activity in cats [24,115,116]. Up-to-date, to the

authors’ knowledge, only three studies were published addressing the clinical benefits and the

adverse events of TOC administration in cats with MCT [24,115,116]. These studies report

that TOC administration was well tolerated [24,115,116], although 60% of the cats

experienced mild adverse events (grade 1 or 2) and 10% experienced severe adverse events

(grade 4 or 5) [24]. Also, one study reports toxicity in 71% of the cats with MCT and

squamous cell carcinoma during the treatment with toceranib, with two cats developing

severe hepatotoxicity [115]. Nevertheless, the profile of the adverse events reported by Berger

et al, was similar to those described in dogs when using common TOC dosages [24]. Clinical

benefit was observed in 80% [24] and in 57,1% [115] of the cats that received toceranib, with

a median response duration of 32 weeks (range 5–199 weeks) [24], 90 days (range 14-570

days) [115], and 100 days (range 1-924 days) [116]

The advocated approach for splenic MCT treatment in cats is total splenectomy.

Splenectomy significantly prolonged the survival time of cats with splenic MCT, and
chemotherapy does not seem to positively contribute to the increase of survival time. As a

single treatment, chemotherapy seems to have just contributed to the degradation of the cats’

health conditions, decreasing its survival time when compared to cats that only received only

supportive therapy. Therefore, the role of chemotherapy use in cats for treatment of MCT

remains arguable [114].

Intestinal MCT in cats should also be surgically removed with wide safety margins of

about 10 cm in relation to the tumour location, as this form typically extends histologically

beyond the obvious area of the primary lesion [117]. A recent study by Barrett and

colleagues, compared different therapeutic approaches to gastrointestinal MCTs in cats and

concluded that surgical and medical treatments (including prednisolone alone) were both

associated with prolonged survival times [26]. As the treatment type did not significantly

affect cats survival time, additional cytotoxic treatment, besides glucocorticoids treatment,

may not be of benefit for cats [26].

A resume of the main studies addressing MCTs surgical and/or adjuvant medical

treatments and outcomes in cats are displayed in table 4 [24,26,74,113,114,118].

Prognosis and Survival times

The clinical staging, tumour location, cell proliferation and growth rate, microvascular

density, DNA ploidy, tumour recurrence, the presence of systemic signs, age, race, sex,

tumour size and the detection of active mutations in the c-Kit gene through polymerase chain

reaction are factors known to influence prognosis [48]. Tumour location that prevents

complete excision of the tumour, or the presence of multiple MCTs also leads to worse

prognosis. On the other hand, the depth of the cMCT is not relevant for establishing the

prognosis [119].
 Low grade MCT tumours are less likely to metastasize, while intermediate grade

tumours generally do not metastasize, though some present metastatic behaviour. High grade

MCT frequently metastasize [120,121]. The conventional pattern of metastasis shown by

canine MCTs is less obvious in cats. Metastatic rates for cMCTs in cats vary from 0% to

22%, and prognosis is demanding since it is hard to identify those MCT that have a higher

risk of metastasizing [7].

In dogs, the prognosis related to MCTs is correlated with the histological classification

of the tumour. Grade I MCT is related to a better prognosis, while grade II-III MCTs are

associated with worse prognosis [55,69]. Noteworthy, the MCT malignancy within the same

histological grade is hugely influenced by the mitotic index [122]. The mitotic index (MI) is

an indirect measurement of cell proliferation and it directly correlates with the histological

grade of the tumour. Dogs with MI ≤ 5 have survived significantly longer than those who

presented MI > 5. Dogs with grade II MCTs and MI ≤ 5 had a median survival time of 70

months, much higher when compared to the five months presented by dogs with grade II

MCT but with a MI > 5 [122].

The cell proliferation markers, such as Ki67 and AgNOR (argyrophilic nucleolar

organizer region), may also be good indicators of tumour prognosis. The Ki67 is a protein

present in the cell nucleus that is expressed in all phases of the cell cycle except G0 phase or

quiescence, being recognized by the monoclonal antibody MIB-1. Its levels correlate with cell

proliferation and are increased in the case of tumours [36]. However, the agreement between

MI and Ki67 using previously established cut-offs is poor, and while the MI was less sensitive

but more specific than Ki67, the MI screening should be used as a three-tier or continuous

prognostic marker for MCTs [123].

Regarding DNA ploidy and other chromosome abnormalities, in the past the ploidy

status was not considered a strong prognosis factor in dogs with MCTs, although aneuploid
tumours, with cells containing abnormal DNA quantities due to duplication failure during

mitosis, were associated with shorter survival times within the first year, when compared to

diploid tumours. The ploidy status could provide some guidelines for the staging of the

disease and for treatment planning and some survival information for the first year after

diagnosis [124]. Recently, Vozdova and colleagues studied 14 cancer-related genes to reveal

clonal structural chromosome rearrangements and copy number variants in canine cMCTs and

reported that the heterogenicity of the detected abnormalities indicated increased chromosome

instability in canine MCTs. Nonetheless, further research is mandatory to evaluate the

significance of these abnormalities as prognostic factor for the survival time or recurrence risk

assessments in canine cMCTs [125].

Intratumoural microvascular density may be used as a sensitive prognostic indicator of

postsurgical behaviour of the MCTs and is correlated with the MI and MCTs invasiveness

[126]. Quantification of microvessels through the measurement of angiogenic growth factors

and their receptors, like the vascular endothelial growth factor (VEGF), can also be used to

assess the response to anti-angiogenic chemotherapy [127].

The receptor tyrosine kinase protein (KIT), along with other growth factors, plays an

important role in angiogenesis under normal conditions. However, overexpression of this

protein or mutations in the c-Kit gene can potentially lead to cancer. In fact, there is an

association between the existence of mutations in the c-Kit gene and high-grade MCTs [128].

Immunohistochemical KIT expression in neoplastic mast cells aids in establishing the

prognosis of intermediate-grade tumours. Increased cytoplasmic KIT staining is significantly

associated with a worse prognosis, due to an increased rate of local recurrence and a

decreased survival rate [129]. This method can be used in the prognostic evaluation of cMCTs

in dogs [36,129] although the KIT pattern localization or c-Kit mutation status alone are not
sufficient to make treatment decisions between TOC and VBL, as they did not seem to predict

response to treatment in dogs with macroscopic MCT [55].

The prognosis for dogs with cMCTs in the inguinal and perineal region, regarding the

disease-free interval and survival time, is the same as for dogs with cMCTs in other locations

[53]. If radiotherapy is associated to the frequently incomplete surgical excision of cMCT in

dogs, the prognosis for survival time is better if the cMCT is located in one limb extremity

than in the inguinal and perineal regions [48]. Contrasting, the MCTs originating from

visceral organs such as the gastrointestinal tract, liver, spleen, and bone marrow, present the

worst prognosis, when compared to other forms of MCT in dogs [12].

Dogs with MCTs located in oral and perioral regions present a median survival time of

52 months. However, there is a 59% probability of metastasis in the regional lymph node at

the time of diagnosis, which, in these cases, reduces the median survival time for around 14

months [130]. Recent data indicates that subcutaneous MCTs have more favourable

prognosis, with high survival time and low local recurrence (8% of the cases) and low

metastization rates (4% of the cases) [131].

Local recurrence of the tumour occurs more frequently in high-grade than in low-

grade tumours (36% and 4%, respectively), and is associated with the worst prognosis [132],

with reported expected median survival time of around five months [48].

Breed and age are also factors to be considered when establishing a prognosis for

MTC disease. For example, although MCT are quite frequent in Boxers, they tend to be of

low to intermediate grade, therefore of good prognosis. On the opposite, MCT in Shar-Pei and

Labradors tend to be more aggressive [111]. While in Boxers 96.8% of MCT are usually

classified as low grade, the high grade MCTs form are mostly present in Shar-Pei (92.3%)

and Weimaraners (66.6%) [4].

 In cats, the prognosis is somewhat different when compared to dogs. The

histopathological classification does not provide useful prognostic information for feline

cMCTs [9]. The relationship between several histological features and prognosis in the large

majority of feline cMCTs has not been established, even though cytomorphologic features

such as anisocytosis, anisokaryosis, cytomegaly, nuclear atypia, and multiple nuclei

presenting a benign biologic behaviour are described. Nevertheless, the high mitotic rate

seemed to be the best prognostic indicator for feline cMCT [30,133].

The vast majority of feline cMCTs are well-differentiated and should be considered

benign and of good prognosis, if there is no evidence of systemic or visceral disease [7]. Also,

incomplete excision of the tumour is not associated with decreased survival time or increased

local recurrence rate [9].

In splenic MCT, the therapy that assures a longer survival time in cats is total

splenectomy, with a median survival time of 360-570 days, ranging from 60 to 1140 days

[118]. Evans and colleagues recently compared the various therapeutic approaches to feline

splenic MCT, concluding that splenectomy, with or without adjuvant chemotherapy, is the

option that leads to longer survival times, with a median postoperative survival time of 856

days [134]. Nonetheless, Gordon and colleagues reported a 132 days period of median

postsurgical (splenectomy) survival time in ten cats with MCT [118]. There is the possibility

that undetectable metastases at the time of diagnosis influenced the results obtained in this

study.

Conclusions

The recommended treatment, prognosis and survival times for dogs and cats with

MCTs depends on the clinical staging, histological grade and location of the tumour. In

solitary cMCTs with a location that allows complete surgical excision, surgery is potentially
curative. If the result of the histopathology is favourable, i.e., surgical margins of two

centimetres and absence of metastases, there is no need for further treatment.

Contrariwise, a second, more aggressive surgery may be attempted to achieve

complete MCT excision, combined with radiotherapy or chemotherapy (e.g. VBL and

prednisolone). In cases where the MCT is in a location that prevents complete surgical

excision, previous radiotherapy or chemotherapy will allow the cytoreduction of the tumour

before surgery, increasing the probability of achieving a complete surgical excision with

safety margins.

When metastases are present, cure is not expected and the recommended treatment

should be palliative, consisting of chemotherapy and supportive therapy. The chemotherapy

protocols available use combinations of VBL and prednisolone, VBL alternating with CCNU,

or even only CCNU, among others. In all cases, follow-up visits are crucial to assess the

patient’s response to treatment, its efficacy, and side effects.

Conflict of interest statement

None of the authors of this paper has a financial or personal relationship with other

people or organisations that could inappropriately influence or bias the content of the paper.

Appendix A. Supplementary material

Supplementary data associated with this article can be found, in the online version, at

doi: …

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 Table 1 – Classification of Patnaik (adapted from Patnaik, Ehler, & MacEwen, 1984)
Grade Designation Description
I Well-differentiated Absent mitotic figures, regular and spherical/ovoid
nuclei, large, stained and abundant cytoplasmic granules
II Intermediate Absent or rare mitotic figures (0-2/ high-power field).
Cells together with indistinguishable cytoplasmic
borders, lower nucleus-cytoplasm ratio and more granules
than in undifferentiated.
III Undifferentiated Frequent mitotic figures (3-6/ high-power field).
Indistinguishable cytoplasmic borders, irregular shaped
nuclei and spaced granules.
Table 2 – World Health Organization’s clinical staging of MCTs (adapted from Owen et al., 1980)
Stage Description
A single incompletely excised tumour of the dermis, histologically identified,
without involvement of regional lymph nodes
0
a) no systemic signs
b) with systemic signs
One tumour confined to the dermis without regional lymph node involvement
I a) without systemic signs
b) with systemic signs
One tumour confined to the dermis, with regional lymph node involvement
II a) without systemic signs
b) with systemic signs
Multiple dermal tumours or large infiltrating tumours with or without regional
lymph node involvement
III
a) without systemic signs
b) with systemic signs
Any tumour with distant metastasis or recurrence with metastasis (including
IV
involvement of blood and bone marrow)
 Table 3 – Resume of the main published research about MCTs surgical and/or adjuvant
medical treatments and outcomes in dogs
Study N Diagnosis Treatment Main results
Chu et al, 83 MCTs grades I Surgery alone CMG: 74% grade I
2020 and II MCT
CMG- 2 cm for tumours ≥ 2 cm in
diameter or equal to the tumour WMG: 97% grade II
diameter for tumours < 2 cm MCT
(n=46)
HTFM: 93% in CMG
WMG- lateral margins of 3 cm and 92% in WMG
(n=37)
Gill et al, 43 Subcutaneous Surgery alone Median PFS = 1474d
2020 MCT Median DFI was not
Complete surgical margins (n=29) reached at > 1968d
MCT grade I MST was not reached
(n=42) Incomplete surgical margins at > 1968 d
(n=14)
MCT grade II
(n=1)
Marconato et 73 Grade I or II Surgical excision of primary Group 1:
al, 2020 cMCT tumour and lymphadenectomy of Local recurrence after
early metastatic lymph node. 592 and 321d (n=2)
Nodal relapse after a
Followed by: median 321d (n=3)
Group1-VBL 2-3 mg/m-2 IV every Distant relapse in
14 days for 8 cycles, and lungs (n=2), liver and
prednisone (n=34) spleen (n=2) after a
TOC 2.4-2.8 mg/kg on a Monday- median 230d
Wednesday- Friday schedule for a Tumour related deaths
median of 6 months (n=7) after a median 358 d
Both (n=1) (n=5)
n=42; grade I (1) and grade II (41) Alive at the end of the
study (n=37)
Group 2- No adjuvant medical
treatment (n=31); grade I (4) and Group 2:
grade II (27) Local recurrence
(n=0) at a median
follow-up of 688d
Nodal or distant
relapse (n=0)
Deaths of unrelated
causes after a median
693d (n=12)
Alive at the end of the
study (n=19)

Mendez et 42 High grade Surgical excision (n=42) Definitive irradiation;

al, 2020 MCT, multiple Chemotherapy (n=41): MST = 615 (n=25)
locations (n=42) VBL (+/- cyclophosphamide) PFS= 410d
(n=33)
WHO Stage: Prednisone alone (n=5) Palliative irradiation:
0- n=24 CCNU (n=1) MST = 221d
1- n=4 Tyrosine-kinase inhibitor (TOC or PFS= 72d
2- n=12 masitinib) (n=1)
4- n=2 Concurrent vinblastine and CCNU Stage 0 (n=25)
(n=1) MST = 615d
Single-agent doxorubicin (n=1) PFS = 425d
Rescue chemotherapy (n=25):
CCNU (n=16), vinblastine-based Stage 1-4 (n=17)
 chemotherapy (n=2), tyrosine MST = 314d
kinase inhibitor (n=7) PFS = 125d

Radiation therapy of drainage LN: A) MST = 284d

Definitive intent median total dose PFS = 197d
of 48 Gy (range: 24‐51 Gy), 3 to 4 B) MST = 695d
Gy per fraction (n=28). PFS = >2381
Palliative intent median total dose C) MST = 1908
of 27 Gy (range: 8‐36 Gy), 6 to 8
Gy per fraction (n=14).

Groups:
A) Stage 0 at irradiation with no
LN treatment (n = 14)
B) Stage 0 at irradiation with
prophylactic LN irradiation (n = 6)
C) Stage 0 at irradiation but
previously stage 2 (n = 5)
D) Stage > 0 at irradiation (n = 17)

Moore et al, 49 All cMCT Surgical excision MST = 1046d

2020 Kiupel high- 1-year SR = 79,3%
grade. Chemotherapy (n=33) 2-year SR = 72,9%
VBL IV 3.0 mg/m-2 (2.5 mg/m-2 Tumour related death
Grade II MCT for dogs weighing < 10 kg) every at the end of the study
(n=12) 2 weeks (total of 10 treatments) (n=14)
and prednisolone (n=22) Alive at the end of the
Grade III MCT VBL alternating every 2 weeks study with a median
(n=37) with CCNU PO 50 to 90 mg/m-2 follow-up of 980d
(total of 6 treatments of each drug) (n=23)
and prednisolone (n=4)
TOC PO 2.5-2.75 mg/kg three
times weekly, ongoing while
tolerated, and prednisolone (n=7)
Ridder et al, 123 MCT Tigilanol tiglate (1 mg/mL) Single treatment: 75%
2020 intratumourally with dose based complete response by
WHO stages Ia on tumour volume. day 28
and IIIa
Evaluation of treatment response No recurrence at day
at 28 and 84 days. 84 in 93% of the dogs

8 additional dogs
achieved complete
response after a
second treatment

Saunders et 65 cMCT single Surgery with lateral median Complete excision

al, 2020 solitary mass HTFM of 5 mm (range 0.5 – 15 rate
(n=46) or mm) and deep margin of at least of 95% (95/100)
multiple one fascial plane
cutaneous Of the incompletely
masses (n=19) excised masses, four
were low-grade, and
Stage 1 (n=39) one was high-grade.

Stage 2 (n=9)

Stage 3 (n=17)

Total cMCT
 removed =100

Hay et al, 15 High-grade Complete surgical excision MST = 904d

2019 MCT 1-year SR: n=9
Chemotherapy 2-year SR: n= 6
Grade II MCT CCNU at 70 mg/m-2 every 4 weeks
(n=9) (6 treatments) and prednisone at
0.5 to 1 mg/kg PO daily tapered at
Grade III MCT the time of the final CCNU
(n=6)
Case and 23 24 MCT on oral A median of two (range, 1 to 15) CR (n=4)
Burgess, mucosa or intralesional triamcinolone PR (n=12)
2018 mucocutaneous treatments (median dose of 2.0 SD (n=6)
junction and mg/cm -range, 0.125 to 19 mg/cm) PD (n=2)
cMCT of administered to all 23 dogs (24
various tumours)
locations.
With or without concurrent
Grade I (n=1) administration of corticosteroids,
Grade II (n=8), chemotherapy or radiation therapy
Grade III (n=7)
Single dose (n = 10)
Weekly doses (n=4),
As needed at the discretion of the
treating clinician (n=10)
Marconato et 152 cMCT stage II Surgery of primary cMCT and LNS:
a al, 2018 (refers to dogs cytotoxic chemotherapy, tyrosine Median TLR = 511d
with LN kinase inhibitors or both thereafter. Median TNR = 170 d
metastasis Median TDR = 1045d
regardless of the LNS group (n=71): without LN Median TTP = 170d
dimension of the surgical removal Median TSS = 360d
primary cMCT)
LND (n=81): with LN surgical
removal LND:
Median TLR, TNR,
TDR = NR
Median TTP = 1461d
Median TSS = 2231d

Olsen et al., 40 Grade II and III Group 1: surgery preceded and MST (group 1) not
2018 MCTs: followed by a combined protocol reached (median
Group 1: of VBL 1.6 mg/m2 IV EOW for a follow-up time of
incomplete total of 8 doses, TOC 2.5 mg/kg 287d)
resection PO EOD, prednisolone 1 mg/kg MST (group 2) = 893d
followed PO daily (in a total of 4-16 weeks) MST (group 3) = 218d

Group 2: Group 2: surgery followed by a Toxicity was noted in

complete combined protocol of VBL, TOC 67% (27/40) patients
resection and prednisolone (16 weeks) who
received this
Group 3: Group 3: palliative treatment with chemotherapy
palliative a combined protocol of VBL, TOC protocol.
treatment, dogs
and prednisolone (12 weeks)
with gross
metastatic
disease

Weishaar et 88 Group 1 (n=60), Group 1: ORR (group 1) = 46%

al, 2018 wherein 20% TOC (2.75 mg/kg EOD) ORR (group 2) = 30%
 had c-kit Median PFS (group 1)
mutations Group 2: = 95.5d
VBL (2.5 mg/m2 Median PFS (group 2)
Group 2 (n=28), weekly for 4 weeks, then EOW for = 78d
wherein 30% 4 treatments MST (group 1) = 159d
had c-kit MST (group 2) =
mutations 241.5d

Neither PFS nor MST

was significantly
different between
treatment groups.
Dogs receiving TOC
having an increased
number of
adverse events overall
than those receiving
VBL
Bavcar et al., 10 Grade II/III CCNU 70 mg/m2 PO every 3 CR (n=3)
2017 MCTs: weeks, TOC 2.7 mg/kg PO EOD, PR (n=2)
measurable starting a day after CCNU SD (n=3)
primary or (minimum of 6 cycles) and PD (n=2)
recurrent, non- prednisolone 1 mg/kg PO EOD ORR = 50%
resectable and/or (alternating with TOC). Median PFI = 86d
metastatic (range from 35 to
Total planned treatment time = 6 613d)
months
Horta et al., 89 Clinical stage I- Surgery followed by DFI = 134d
2017 IV: chemotherapy protocol: MST = 258d

Group 1: low Group 1 (n=16): prednisone 40 Group 1 and 2: MST

risk patients (of mg/m2 daily during the first seven not reached
recurrence or days, followed by 25 mg/m2 daily
metastasis of for 30 days and 25 mg/m2 EOD for Group 3:
cMCTs) 60 days i) DFI = 686d;
MST not reached
ii) DFI = 107d
Group 2: Group 2 (n=30): i) VBL 2 mg/m2
MST = 148d
intermediate risk every 7 days (4 treatments) plus
patients every 14 days (4 treatments) iii) DFI = 109d;
followed by an eight-week MST = 213d
Group 3: high protocol with chlorambucil at 4-6
risk patients mg/m2 EOD; ii) eight-week
protocol with chlorambucil at 4-6
mg/m2 EOD; or iii) no additional
treatment (control)

Group 3 (n=34): i) CCNU 60-90

mg/m2 every 3 weeks (3-4
treatments) followed by an eight-
week protocol with chlorambucil
at 4-6 mg/m2 EOD; ii) exclusively
CCNU; or iii) no treatment
(control)
Burton el al, 47 Measurable ORR = 46%
Prior treatment:
2015 MCT CR ≈ 10%
Surgery n=26 PR ≈ 37%
Chemotherapy n=12 (29.3) Median TTMR = 21d
(range 7–175d)
Radiation therapy 1 (2.4) Median PFS = 53d
No prior treatment 2 (4.9) (range 1 to >752d)
 Median MST = 131d
TOC at days 1,3 and 5 of a 21-day (range 4 to >752d).
cycle at a target dosage of 2.75
mg/kg PO and CCNU at a target
dosage of 50 mg/m2 PO once
every 3 weeks
Lejeune et 21 Grade II stage 2 Surgery (n=13) MST for all dogs =
al, 2015 MCT Complete resection of the primary 1359d (range, 188–
MCT 2340)
DFI = 2120d (149–
Surgery and radiotherapy (n=8) 2325d)
Lymph node excision or
incomplete excision of the primary
MCT
Radiotherapy (16 fractions
Monday through Friday of 3 Gy
for a total of 48 Gy)

Chemotherapy (n=21)
Prednisone (40 mg m−2 PO q24h
for 2 weeks, 20 mg m−2 PO q24h
for 2 weeks and then 20 mg m−2
PO q48h
VBL (2 mg m−2 IV bolus)
alternated with CCNU (60–80 mg
m−2 PO delivered to the nearest 5
mg) every 2 weeks
Carlsten et 17 Grade II-III: Chemotherapy: TOC and ORR = 76.4%
al., 2012 non-resectable, prednisone CR = 58.8%
measurable PR = 17.6%
cMCT Radiotherapy PFST = 316d
MST – not reached
Median follow-up
time = 374d
O’Connel et 63 Multiple cMCTs Surgery with or without adjuvant Median PFS (range
al., 2011 treatment: 14-1835d) and MST
VBL, CCNU, combined protocol (range 28-1835d) not
of VBL and CCNU, prednisolone reached for all dogs in
the study.
Radiotherapy (curative or
palliative) Dogs that had surgery
performed to remove
Alternative medical therapy all MCTs, had
(tyrosine-kinase inhibitors, significantly longer
imatinib or toceranib) PFS and MST
on univariable
Multimodal therapies: surgery, analysis than dogs that
chemotherapy, radiation therapy, did not have
and tyrosine-kinase inhibitor surgery.

Patients with clean

margins were not
found
to have longer PFS or
MST.

There was no
significant difference
in PFS or MST in
those dogs that
 received
chemotherapy
compared to those
dogs that did not
Hahn et al., 132 Grade II-III: Chemotherapy: 1-year SR (group 1) =
2010 non-resectable 62.1%
MCTs Group 1 - masitinib 12.5 1-year SR (group 2) =
mg/kg/day 36%
2-year SR (group 1) =
Group 2 - placebo 39.8%
2-year SR (group 2) =
15%
MST (group 1) = 617
days
MST (group 2) = 322
days
2-year CR (group 1) =
9%
Rassnick et 52 Group 1 (n=17): Group 1: combined protocol of Group 1:
al., 2010 non-resectable VBL 3.5 mg/m2 IV, CCNU 70 ORR = 65%
MCTs mg/m2 PO and prednisone 1-2 Median PFS = 489d
mg/kg PO SID (24 weeks) PFS (group 1) = 954d
Group 2 (n=35): PFS (group 2) = 190d
metastatic Group 2: surgery followed by a
MCTs or grade combined protocol of VBL 3.5
III MCTs mg/m2 IV, CCNU 70 mg/m2 PO
and prednisone 1-2 mg/kg PO
SID; radiotherapy (n=7): 3 Gy
daily treatments over 3
consecutive weeks (total dose 48
Gy)
Cooper et 57 Grade II-III: Chemotherapy: CCNU and VBL 1-year ORR (group 2)
al., 2009 Group 1 (n=20) = 57%
– complete or PFST (group 2) = 30
incomplete weeks
resection, MST (group 2) = 35
microscopic weeks
disease PFST (group 1) = 35
weeks
Group 2 (n=37) MST (group 1) = 48
– macroscopic weeks
disease Chemotherapy-related
toxicity = 54%
Hahn et al, 202 Measurable non- Masitinib 12.5 mg/kg/d PO All dogs
2008 resectable or (reduced to 9 mg/kg/d or from 9 to TTP-Mb vs TTP-Plc =
recurrent grade 6 mg/kg/d, if toxicity was 118d vs 75d
II or III MCT observed) for at least 6 months MST-Mb vs MST-Plc
without nodal or (Mb) =491d vs 340d
visceral Mutated KIT (TTP-
metastasis. Placebo (Plc) Mb vs TTP-Plc =
All dogs (n=202): 230d vs 42d; MST-
Mutated KIT Mutated KIT (n=50) Mb vs MST-Plc
and Wild-type Wild‐type KIT (n=139) =417d vs 182d)
KIT Wild‐type KIT (TTP-
Masitinib as first‐line treatment: Mb vs TTP-Plc = 83d
All dogs (n=85) vs 98d; MST-Mb vs
Mutated KIT (n=25) MST-Plc =NR vs NR)
Wild‐type KIT (n=53)
Masitinib as first‐line
Masitinib at second‐line or later treatment:
 treatment:
All dogs (n=117)
Mutated KIT (n=25)
Wild‐type KIT (n=86)
All dogs (TTP-Mb vs
TTP-Plc = 253d vs
75d; MST-Mb vs
MST-Plc =NR vs
340d)
Mutated KIT (TTP-
Mb vs TTP-Plc = NRd
vs 83d; MST-Mb vs
MST-Plc =417d vs
242d)
Wild‐type KIT (TTP-
Mb vs TTP-Plc =
253d vs 66d; MST-
Mb vs MST-Plc =NR
vs NR)

Masitinib at second‐
line or later treatment:
All dogs (TTP-Mb vs
TTP-Plc = 84d vs
140d; MST-Mb vs
MST-Plc =380d vs
361d)
Mutated KIT (TTP-
Mb vs TTP-Plc =
230d vs 28d; MST-
Mb vs MST-Plc
=396d vs 113d)
Wild‐type KIT ((TTP-
Mb vs TTP-Plc = 72d
vs 140d; MST-Mb vs
MST-Plc =434 vs 361

Rassnick et 51 One or more VBL 2.0 Group (n=25): VBL 2.0 Group:
al., 2008 measurable VBL 2.0 mg/m2 IV every week, 4 PR (median duration
cMCTs treatments, followed by EOW, 4 of 77 days; range, 49-
treatments 229d): n=3

VBL 3.5 Group (n=26): VBL 3.5 Group

VBL 3.5 mg/m2 IV EOW, 5 ORR (median duration
treatments of 28d; range, 28-78d)
=27%

Toxicosis were
uncommon in VBL
2.0 Group. Twelve
(46%) dogs in the
VBL 3.5 Group had <
500
neutrophils/microL 7
days after treatment; 2
dogs with neutropenia
developed concurrent
fevers.
Camps- 35 Grade II-III: Chemotherapy: VBL, PFST (group 1) = 74d
Palau et al., Group 1 (n=11) cyclophosphamide and prednisone PFST (group 2) =
2007 – non-resectable, (VCP) 865d
macroscopic MST (group 1) = 145d
disease MST (group 2)
>2092d
 Group 2 (n=24)
– incomplete
resection,
microscopic
disease
Mullins et 54 Multiple cMCTs Surgery with or without adjuvant DFI = not reached at
al., 2006 treatment: 1,917d
Prednisone only MST = not reached at
VBL and CCNU (2-16 cycles) 1,917 days
Radiotherapy: palliative radiation 1-year SR = 87%
therapy (1 to 4 fractions of 6 to 8 2-5 years SR = 85%
Gy), or curative radiation therapy
(14 to 16 fractions of 45 to 48 Gy)
Poirier et al., 45 Grade II: Radiotherapy 1-year disease-free SR
2006 complete = 80.6%
resection Group 1 (n=21): cobalt 60 2- and 3- year disease-
teletherapy unit (15 fractions of free SR = 67.1%
3.2 Gy for a total of 48 Gy) to the 1-, 2- and 3-year
primary tumour site disease-free SR
=97.6%
Group 2 (n=24): identical
treatment of the primary tumour No statistically
significant differences
site, with concomitant regional
in disease-free
lymph node irradiation
survival rate, time to
local recurrence, or
overall survival rate
were observed
between the 2 groups
Thamm et 61 Grade II-III Surgery MST not reached:
al., 2006 65% alive at 3 years
Radiotherapy (15 fractions of 3.2 MST (grade III) =
Gy for a total of 48 Gy or 4 1374d
fractions of 8 Gy for a total dose DFI = 1305d
of 32 Gy)

Chemotherapy (prednisone 2
mg/kg daily, tapered and
discontinued over 12 to 26 weeks,
and VBL, 2 mg/m2 every 1-2
weeks)
Sfiligoi et 124 Group 1 (n=37): Surgery alone (n=85) Group 1:
al., 2005 dogs with MST = 40.6 months
cMCTs in the Surgery and intralesional 6-month SR = 76%
inguinal or corticosteroids (n=3) 1-year SR = 62%
perineal region 2-year SR = 58%
Surgery and radiation therapy 5-year SR = 34%
Group 2 (n=87):
(n=5)
dogs with Group 2:
cMCTs in other MST = 55 months
cutaneous Systemic treatments (n=31): 6-month SR = 88%
locations Oral corticosteroids (n = 9) 1-year SR = 83%
Cytotoxic chemotherapy (20) 2-year SR = 68%
Radiation therapy and 5-year SR = 36%
chemotherapy (n= 2)
DFI and MST for dogs
with MCTs in the
inguinal or perineal
region were not
significantly different
 from values for dogs
with MCTs in other
cutaneous locations
Davies et al., 27 Grade II-III, Chemotherapy: VBL and 1-year SR = 100%
2004 stage 0: prednisolone 1-year ORR = 74%
incomplete 499-days MST = 70%
resection Local recurrence rate
= 10%
Distant cutaneous
recurrence rate = 25%
No confirmed tumour-
related mortality
Chemotherapy-related
mortality = 5%
Dobson et 35 Grade I-III, non- Prednisolone 40 mg/m2 SID 10-14 PR (prednisolone) =
al., 2004 resectable days followed by radiotherapy 4 x 75%
800 cGy fractions every week and CR (6-8 weeks post-
prednisolone continued at 20 radiotherapy) = 34%
mg/m2 during radiotherapy and for PR (6-8 weeks post-
another 2-month period radiotherapy) = 54%
ORR = 88.5%
PFST = 1,031d
Local recurrence rate
= 11%
Distant recurrence rate
(metastasis) = 14%
Both local and distant
recurrence rate = 6%
1-year PFS= 60%
2-year PFS = 52%
Hahn et al., 31 Grade III: Radiotherapy: 52 Gy in an 18- DFI = 27.7 months
2004 incomplete fraction alternating-day protocol MST ≈ 840d
ressection 1-year SR = 71%

Michels et 31 Stage 0 Surgery: DFI (group 1) = 13

al., 2002 months
Group 1 (n=20) – complete DFI (group 2) = 7.5
margins months
MST (group 1) = 53.5
months (6 dogs alive
Group 2 (n=11) – incomplete
at the end of the study)
margins
MST (group 2) = 15
months

Rassnick et 23 Grade I, II and Previous treatments: prednisone PR (median duration

al, 1999 III MCTs (n=22) and radiotherapy (n=6)
CCNU 90 mg/m2 every 3 weeks
(median number of treatments = 2;
range 1-12)
of 77 days; range, 21-
254d) = 37%
SD (median duration
of 78 days; range, 42-
347d) = 32%

One dog died after

440 days, while in
complete remission.
Al-Sarraf et 32 Grade II, stage 0 Surgery 1-year DFI = 94%
al., 1996 2-, 3-, 4-, 5-year DFI
Radiotherapy = 86%
 1-year MST= 100%
2- and 5-year MST =
96%
3% tumour related
mortality (n = 1)
McCaw et 25 One or more Previous surgical excision (n=13) CR (n=1)
al., 1994 measurable PR (n=4)
cutaneous or Oral prednisolone 1 mg/kg PO PD (n=7)
subcutaneous SID 28 days SD (n=2)
MCT (grade II
and III)
CCNU – lomustine; cMCT – cutaneous mast cell tumour; CMG – conservative margin group; CR –
complete response; d – days; EOD – every other day; EOW – every other week; Gy – gray; HTFM –
histologic tumour-free margins; IV – intravenous; KIT – KIT tyrosine kinase receptor; LN – lymph
nodes; MST – median overall survival time; DFI – median disease-free interval; MC – mast cells; NR-
not reached; ORR – overall response rate; PD – progressive disease; PFS – progression-free survival;
PO – per os; PR – partial response; SD – stable disease; SR – survival rate; TDR – time to distance
relapse; TLR – time to local recurrence; TNR – time to nodal relapse; TOC – toceranib; TSS –
tumour-specific survival; TTMR – time to maximal response; TTP – time to tumour progression; VBL
– vinblastine; WHO – World Health Organization; WMG – wide margin group.
 Table 4 – Resume of the main published research about MCTs surgical and/or
adjuvant medical treatments and outcomes in cats.
Study N Diagnosis Treatment Main results

Barrett et al, 31 Gastrointestinal 1. Chemotherapy (n = 15) MST (total) = 531 days

2018 MCT 2. Surgery and MST (group 1) = 541
chemotherapy (n = 7) days
3. Glucocorticoid only (n = MST (group 2) = 396
6) days
4. Surgery and MST (group 3) = 555
glucocorticoid (n = 3) days
5. Oral CCNU (n = 15) MST (group 4) = 340
6. Oral chlorambucil (n = days
12)
Surgical and medical
treatments were
associated with
prolonged survival
times.
Animals treated with
glucocorticoids had
similar survival times
that the animals from the
group that received
chemotherapy.
The treatment type did
not significantly affect
survival time and so the
authors concluded that
given the outcome with
glucocorticoids alone,
additional cytotoxic
treatment may not be
warranted for some cats.
Evans et al., 64 Splenic MCT 7. Splenectomy (n = 20) 1. MST = 856 days
2018 8. Splenectomy and 2. MST = 853 days
chemotherapy (n = 20) 3. MST = 244 days
9. Chemotherapy alone (n = 4. MST = 365 days
15)
10. Supportive therapy (n = Splenectomy (+/-
9) chemotherapy)
significantly prolongs
survival in cats with
mast cell tumours.
Chemotherapy as a
single treatment seems to
have contributed to the
degradation of the health
conditions of cats.
Berger et al., 50 cMCT (n=22) No cytoreductive treatments All cats:
2017 prior to TOC therapy (n=14) CR = 13 cats
Visceral MCT PR = 22 cats
(n=10) Cytoreductive (one or SD ≥ 10 weeks = 5 cats
multiple) prior treatments SD <10 weeks = 7 cats
Gastrointestinal (chemotherapy and/or PD = 3
MCT (n=17) radiation and/or Median CB = 32 weeks
glucocorticoids and/or (5-199 weeks)
Other MCT surgery) (n=26)
 (nasopharyngea cMCT:
l) (n=1) CR = 7 cats
TOC median dose of 2.5 PR = 10 cats
mg/kg (range 1.6–3.5 mg/kg) SD ≥ 10 weeks = 2 cats
PO, three times per week SD <10 weeks = 3 cats
(n=45) or EOD (n=59) PD = 0 cats

35 cats received concurrent Visceral MCT:

glucocorticoid therapy, either CR = 3 cats
daily (n = 12) or every PR = 4 cats
SD ≥ 10 weeks = 1 cat
other day (n = 23) SD <10 weeks = 1 cat
PD = 0 cats

Gastrointestinal MCT
CR = 3 cats
PR = 8 cats
SD ≥ 10 weeks = 2 cats
SD <10 weeks = 2 cats
PD = 2 cats

Nasopharyngeal MCT
SD <10 weeks = 1 cat

Gordon et al., 19 Splenic MCT Surgery: total splenectomy MST = 197 days (range
2010 2-1959 days)

Rassnick et al., 38 Group 1 CCNU dosage was 50 mg/m2 CR = 18.4%

2008 (n=26): cMCTs in 22 cats and 60 mg/m2 in 16 PR = 31.6%
Group 2 (n=7): cats ORR = 50%
MCTs of the
mesenteric Median response
lymph nodes duration = 168 days
Group 3 (n=2):
GI MCTs
Group 4 (n=2):
Hepatic MCTs
Group 5 (n=1):
Multiple organs
affected
Turrel et al., 35 Solitary or Radiotherapy: 135 Gy of MST = 1075 days
2006 multiple strontium 90 β irradiation
cMCTs Strontium 90 β
irradiation resulted in
long-term tumour control
and should be considered
an effective alternative
to surgical resection in
management of cMCTs
in cats
cMCT – cutaneous mast cell tumour; CB – clinical benefit; CCNU – lomustine; CR – complete
response; Gy – gray; MST – median overall survival time; DFI – median disease-free interval; EOD –
every other day; ORR – overall response rate; PD – progressive disease; PFS – progression-free
survival; PO – per os; PR – partial response; SD – stable disease; SR – survival rate; TOC – toceranib;
VBL – vinblastine.