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Vet Clin Small Anim

33 (2003) 473–489

Mast cell tumors in the dog


Cheryl A. London, DVM, PhD*,
Bernard Seguin, DVM, MS
Department of Surgical and Radiological Sciences, 2112 Tupper Hall, One Shields Avenue,
University of California at Davis, Davis, CA 95616, USA

In most species, neoplastic processes involving mast cells are relatively


uncommon. In contrast, mast cell tumors (MCTs) occur frequently in the pet
population, representing up to 20% of all cutaneous canine tumors [1–3]. As
such, a detailed comprehension of the diagnosis and treatment of mast cell
neoplasia in the dog is extremely important. Before discussing the specifics of
MCTs, however, it is first necessary to understand normal mast cell biology.

Mast cell biology


Morphologic characteristics of mast cells
Mast cells are discrete round cells roughly one to three times the size of
a neutrophil. They possess a round to oval nucleus and distinct cytoplasmic
granules that stain with dyes, such as toluidine blue, Giemsa, and methylene
blue. Such staining is a result of the affinity of these basic dyes for the acidic
proteoglycans contained in the mast cell granules [4–7]. Some of these dyes
assume a different color when bound by the granules than they do when
staining nuclear DNA, so that the granules are often called metachromatic.
Although mast cells may be visualized on hematoxylin and eosin–stained
sections, the dyes described previously are used to characterize mast cells
definitively. Moreover, mast cell granules may not be visualized with stains
like Diff-Quick (Dade Behring, Deerfield, IL), precluding identification on
some cytologic specimens [8].

Development of mast cells


Mast cells are derived from bone marrow precursor cells. They leave
the bone marrow in a presumed immature state and migrate to many

* Correspondence.
E-mail address: calondon@ucdavis.edu (C.A. London).

0195-5616/03/$ - see front matter Ó 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0195-5616(03)00003-2
474 C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489

tissues, particularly those having primary contact with foreign antigens


(eg, skin, respiratory and gastrointestinal tracts), where they then mature
into tissue mast cells [5]. Cytokines important in the development and
maturation of mast cells include interleukin (IL)-3, IL-6, IL-4, and stem
cell factor (SCF) among others [5]. The local tissue microenvironment
in which mast cells mature determines the subsequent functional ca-
pacities of these cells. For example, mast cells in the mucosa of the
gastrointestinal tract (labeled mucosal mast cells) have chondroitin sul-
fate as their major granule proteoglycan and contain little histamine. In
contrast, mast cells in the lung and serosa of body cavities (labeled tissue
mast cells) contain heparin as their major granule proteoglycan and pro-
duce large amounts of histamine [4]. Experiments in mice suggest that the
functional characteristics of mast cells are not fixed, because granule
content can change if mast cells are moved from one environment to
another. In summary, the precise nature of the mast cell and the mediators
it can produce varies with its anatomic location and is probably regulated
by the local cytokine environment.

Function of mast cells


Mature mast cells bind IgE on their cell surface through expression of the
high-affinity IgE receptor (FceRI). Mast cells also express receptors for
complement components (particularly C5a). The primary manner in which
mast cells are activated is by cross-linking of the FceRI-bound IgE on their
cell surface, leading to the release and production of various mediators
including the following [4,5]:
a. Contents of granules, such as histamine, heparin, chondroitin sulfate,
mast cell proteases, and others
b. Lipid mediators, such as prostaglandins, leukotrienes, and platelet-
activating factor
c. Cytokines, such as tumor necrosis factor-a, IL-3, IL-4, IL-5, and IL-6
The mediators described here lead to several reactions, including in-
creased vascular permeability, vasodilation, smooth muscle spasm, pruritus,
anticoagulation, and activation of eosinophils and neutrophils. Collectively,
these effects can lead to local hypersensitivity reactions, or more seriously,
to systemic hypersensitivity (anaphylactic shock) [4]. As such, mast cells
have primarily been associated with allergic reactions/disorders. It is now
evident that mast cells seem to play an important role in the initiation of
innate immune responses. Experiments in mice demonstrated that mast cells
were important in initiating and sustaining neutrophil migration and ac-
tivation in response to bacteria [6]. Indeed, mast cells are often seen at sites
of inflammation as well as in reactive lymph nodes. Therefore, in addi-
tion to playing a role in the induction of pathologic allergic responses, mast
cells are critical players in protective immune responses.
C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489 475

Canine mast cell tumors


Incidence and signalment
As previously mentioned, the MCT is the most common skin tumor of the
dog and one of the most common malignant tumors noted in the canine
population. Whereas MCTs are usually found in older dogs (mean age of
approximately 8–9 years), they have also been reported in younger dogs [9–
12]. Several breeds seem to be at increased risk for the development of MCTs,
including dogs of bulldog descent (Boxer, Boston Terrier, and English
Bulldog), Labrador and Golden Retrievers, Cocker Spaniels, Schnauzers, and
Chinese Sharpeis [9,12–14]. No sex predilection has been reported.

Etiology
The etiopathogenesis of MCTs in the dog is unknown, as is the reason for
the extremely high incidence in this species. Although some studies have
suggested the possibility of a viral cause and MCTs have been transmitted
from dogs with solid tumors to susceptible laboratory dogs using tumor
tissue or extracts, there is no epidemiologic evidence to indicate horizontal
transmission of tumors [15]. Because most of the tumors arise in the skin, it
has been suggested that topical carcinogens may play a role in this disease.
No reports exist to imply such a cause, however, and there seems to be no
particular regional distribution of these tumors. The increased incidence of
MCTs in certain breeds suggests the possibility of an underlying genetic
cause [13]. Interestingly, although dogs of bulldog ancestry are at higher risk
for MCT development, it is generally accepted that MCTs in these dogs are
more likely to be benign [12].
As previously mentioned, SCF is an important growth factor for mast cells
[7]. The receptor for SCF is Kit, encoded by the proto-oncogene c-kit; SCF-Kit
interactions are required for the differentiation, survival, and function of mast
cells [7,16–21]. Mutations in c-kit leading to activation of Kit in the absence of
SCF binding have been demonstrated to occur in systemic mastocytosis in
people [22–28]. Additionally, Kit dysfunction has now been recognized in
a variety of other human cancers, including gastrointestinal stromal tumors,
small cell lung cancer, ovarian carcinoma, and gliomas [29–36]. Several
authors have recently identified the presence of activating mutations in the
proto-oncogene c-kit in canine MCTs. These mutations consist of internal
tandem duplications in the negative regulatory juxtamembrane domain of Kit
[37–40]. The high frequency of mutations in a gene known to play a role in
tumorigenesis suggests that aberrations in c-kit may be involved in the
development or progression of MCTs in dogs.

History and clinical signs


Although normal mast cells are found in abundance in the lungs and
gastrointestinal tract, the overwhelming majority of MCTs in the dog occur
476 C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489

in the dermis and subcutaneous tissue [9,41]. Rarely, primary MCTs may
present in other sites, such as the oral cavity, nasopharynx, larynx, and
gastrointestinal tract [42,43]. Visceral MCT involving the spleen, liver, or
bone marrow (often referred to as disseminated mastocytosis) is usually
the result of systemic spread of an aggressive primary cutaneous MCT,
although it can occur as an independent syndrome [44,45]. Primary mast cell
leukemia in the dog is extremely rare.
Cutaneous MCTs usually occur as solitary nodules, although roughly
10% to 15% of dogs present with multiple tumors [46]. Approximately
50% of cutaneous MCTs occur on the trunk and perineal region, 40%
on the limbs, and 10% on the head and neck [2,46,47]. Perhaps most
importantly, the clinical appearance of MCTs can vary widely. Dermal
MCT may be well circumscribed, raised, and firm, or the surface maybe
erythematous and ulcerated; invasion into the subcutaneous tissue may be
present. MCTs arising in the subcutaneous tissue are often poorly cir-
cumscribed and may resemble lipomas. It is therefore not possible to
identify a cutaneous lesion as an MCT simply by its appearance.
Cutaneous MCTs may also be present for various lengths of time. In
general, MCTs that are slow growing and present for at least 6 months are
more likely to behave in a benign manner, whereas those that are rapidly
growing large tumors are more likely to behave in a malignant manner
[41]. The duration of the lesion does not always predict the subsequent
biologic behavior, however.
Clinical signs of MCTs are caused by the release of histamine, heparin,
and other vasoactive amines. Mechanical manipulation of the tumor during
physical examination can induce degranulation leading to erythema and
wheal formation (termed Darrier’s sign), and an owner occasionally reports
that the tumor seems to change in size over short periods [47]. Gastro-
intestinal ulceration is also a potential complication of MCTs; between 35%
and 83% of dogs with MCTs that underwent necropsy had evidence of
gastric ulcers, and plasma histamine concentrations were found to be ele-
vated in dogs with MCT [48,49]. Elevated histamine levels presumably lead
to stimulation of H2 receptors on parietal cells, excessive gastric acid pro-
duction, and the development of ulcers. Consequently, signs like vomiting,
anorexia, melena, and abdominal pain may be present. In one study, the
levels of histamine in dogs with MCTs were not related to clinical stage, his-
tologic grade, or tumor size [48].

Diagnosis
Cytologic evaluation of fine-needle aspirates is probably the easiest
method to diagnose the presence of an MCT. The mast cells appear as
discrete round cells with a round to oval centrally placed nucleus that may
be difficult to visualize because of the presence of granules. As mentioned
previously, mast cell granules may not stain with Diff-Quik, leading to
C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489 477

difficulty in making a definitive diagnosis by cytology. Additionally, poorly


differentiated malignant mast cells may contain few, if any, granules; in this
case, special stains (eg, toluidine blue, Giemsa) may be required. Other
round cell tumors that should be included in the differential diagnosis in-
clude lymphoma, plasmacytoma, histiocytoma, amelanotic melanoma, and
transmissible venereal tumor. Whereas the diagnosis of MCT can almost
always be made by fine-needle aspiration cytology, excisional biopsy is
required for histologic grading of the tumor. It is important to note that
because wide surgical excision is the treatment most likely to cure most
MCTs, every effort should be made to obtain a definitive diagnosis via
cytology before surgical intervention. Moreover, because any cutaneous
tumor may potentially be an MCT, fine-needle aspiration should be
performed on all masses before removal. If cytologic diagnosis proves
difficult, a needle or punch biopsy of the tumor can be obtained before
surgery. This may be preferable to a larger incisional biopsy, because local
release of mast cell mediators will significantly inhibit healing and may result
in excessive bleeding.

Staging
Because any MCT is capable of metastasis, all dogs with MCTs should be
staged to determine the extent of their disease and overall health. This is
particularly important for dogs in which radiation therapy may be used in
the course of treatment. Some of or all the following procedures may be
indicated.

Complete blood cell count, biochemistry profile, urinalysis


These tests are part of a minimum database and should be included in the
workup of any animal suspected to have cancer. Dogs with MCTs may have
eosinophilia because of chemotactic factors and IL-5 produced by the mast
cells [4]. Anemia may be present secondary to hypersplenism or gastroin-
testinal bleeding. Occasionally, mast cells may be seen on a routine complete
blood cell count.

Buffy coat smear


A buffy coat smear is made by spinning peripheral blood in a micro-
hematocrit tube, breaking the tube at the buffy coat layer, and smearing the
concentrated leukocytes on a slide. The buffy coat is then carefully examined
for the presence of mast cells. For many years, examination of the buffy
coat for circulating mast cells has been used to screen dogs with MCTs for
the presence of systemic/metastatic disease. It was originally believed that al-
though the buffy coat smear was not an extremely sensitive test, it was fairly
specific for mast cell neoplasia. It is now clear that this may not be the case,
478 C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489

however, because several studies have demonstrated that dogs with many
different kinds of disease, including pneumonia, parvovirus, pancreatitis,
skin disease, and gastrointestinal diseases, may have mast cells circulating
in the periphery [50–52]. In summary, the buffy coat smear is a relatively
easy test to perform; the finding of circulating mast cells in a patient
with cutaneous MCT warrants further investigation.

Bone marrow aspiration


In the normal bone marrow, mast cells are found infrequently. In one
study, of 51 bone marrow samples examined, only 2 contained a single mast
cell [52]. It should be pointed out that these marrow samples were obtained
from normal dogs, and it is possible that dogs with inflammatory disorders
may exhibit higher numbers of mast cells in the bone marrow [50,51]. In gen-
eral, bone marrow aspiration is considered to be a more sensitive indica-
tor of systemic involvement than the buffy coat smear [45].

Lymph node aspiration


All regional lymph nodes should be carefully examined for signs of en-
largement, and any suspicious nodes should be aspirated for cytologic exam-
ination. Additionally, because metastatic nodes may palpate within normal
size, it is recommended by some that all accessible regional lymph nodes be
examined by aspiration cytology. Mast cells may be present in normal
lymph nodes and are often found in reactive lymph nodes; thus, it may be
difficult to determine if mast cells found on cytologic examination are neo-
plastic or part of the normal immunologic cellular repertoire. Indeed, 24% of
lymph node aspirates from normal Beagles contained mast cells [52]. There-
fore, lymph node biopsy with histopathology may be a better tech-
nique for diagnosis of lymph node metastasis.

Evaluation of the abdominal and thoracic cavities


Thoracic radiographs are always indicated as part of any staging pro-
cedure, although pulmonary involvement is uncommon in dogs with MCTs.
Abnormalities reported include lymphadenopathy (sternal and hilar), pleural
effusion, and anterior mediastinal masses [45]. Evaluation of the abdomi-
nal cavity is important in dogs with MCTs, because spread to the liver and
spleen as well as other abdominal structures may be noted. Ultrasound is a
more sensitive diagnostic technique for evaluation of abdominal organs. Any
suspicious organ should be aspirated and examined by cytology. Some have
recommended that splenic and hepatic aspiration be performed as part of the
routine staging procedure, regardless of the presence of splenomegaly or
hepatomegaly. Because mast cells may be found normally in these organs,
however, the utility of this procedure is not clear. Evidence suggests that fine-
needle aspiration of the liver and spleen should be performed if abnormalities
are detected in these organs during ultrasound examination or if the dog is
known to have a grade III MCT [53–55].
C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489 479

Clinical staging system for canine mast cell tumors


The following is the current clinical staging system for canine mast cell
tumors:
0: single tumor, incompletely excised from dermis
I: single tumor confined to dermis without regional lymph node
involvement
II: single tumor confined to the dermis with regional lymph node
involvement
III: multiple dermal tumors or large infiltrating tumors, with or without
regional lymph node involvement
IV: any tumor with distant metastases or recurrence with metastases
(including blood or bone marrow involvement
substage a: no signs of systemic disease
substage b: signs of systemic disease

Prognostic factors
Canine MCTs possess a wide range of biologic behaviors ranging from
benign to extremely aggressive leading to metastasis and eventual death from
disease. Several prognostic factors have been identified that help to predict
the biologic behavior of an MCT as well as to direct the course of therapy.

Histologic grade
The histologic grade of an MCT is determined after incisional or
excisional biopsy of the tumor and cannot be assessed simply by cytologic
evaluation of fine-needle aspirates. The grade of an MCT is determined by
the characteristics of the neoplastic cells (eg, degree of granulation, cytologic
and nuclear pleomorphism), number of mitotic figures, and extent of tumor
invasion into the underlying tissues (Table 1). Histologic grade is the most
consistent prognostic factor and correlates significantly with survival, but it
does not predict the behavior of every tumor. The most commonly used
grading system is the one described by Patnaik et al [14]:
i. Well-differentiated tumors (grade I) are considered to behave in benign
manner, and complete surgical excision is usually curative. These
represent between 30% and 55% of all MCTs reported [14,41,46,56].
Several retrospective studies have demonstrated that 75% to 90% of
dogs do not die of their disease after definitive therapy [14,41,56,57].
ii. Intermediately differentiated tumors (grade II) represent between
25% and 45% of all MCTs reported, and their biologic behavior is
more difficult to predict [14,41,46,56]. On histopathology, these
tumors exhibit invasion into the underlying subcutaneous tissue. As
a result, they may be more challenging to remove by surgical excision.
Historically, dogs with grade II MCT have a reported mean survival
time of 28 weeks after surgical removal, although the completeness of
480 C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489

Table 1
Patnaik scheme for grading of canine mast cell tumors
Grade Patnaik grade Microscopic
Well differentiated I Well-differentiated mast cells with
clearly defined cytoplasmic borders
with regular spherical, or ovoid
nuclei; mitotic figures are rare or
absent; granules are large, deep
staining, and plentiful; cells confined
to the dermis and interfollicular
spaces
Intermediately differentiated II Cells closely packed with indistinct
cytoplasmic boundaries; nuclear/
cytoplasmic ratio lower than
anaplastic; mitotic figures
infrequent; more granules than
anaplastic; neoplastic cells infiltrate
or replace the lower dermal and
subcutaneous tissue
Anaplastic undifferentiated III Highly cellular, undifferentiated
cytoplasmic boundaries, with
irregular size and shape of the
nuclei; frequent mitotic figures; low
number of cytoplasmic granules;
neoplastic tissue replaces the
subcutaneous and deep tissues
Data from Patnaik AK, Ehler WJ, MacEwen EG. Canine cutaneous mast cell tumors:
morphologic grading and survival time in 83 dogs. Vet Pathol 1984;21:469–74.

excision could not be assessed in this study [41]. More recently, it has
been shown that radiation therapy after incomplete excision of
solitary grade II MCTs can cure greater than 80% of affected
patients, indicating that adjuvant radiation therapy clearly improves
the survival times of dogs with these tumors [57,58]. It is important to
note that grade II MCTs have the ability to spread to local lymph
nodes as well as distant sites and that a proportion of dogs undergoing
definitive therapy (surgery and radiation) may go on to develop
metastatic disease. Furthermore, some dogs that present with grade II
MCTs already have evidence of metastatic disease, making appropri-
ate staging imperative for these dogs.
iii. Poorly differentiated tumors (grade III) represent between 20% and
40% of all MCTs reported [14,41,46,56]. They often behave in a
biologically aggressive manner, exhibiting metastasis early on in the
course of disease. The mean survival time of dogs with grade III MCT
has been reported as 18 weeks when treated with surgery alone [41]. In
one study, the percentage of dogs with grade III MCTs surviving at
1500 days was reported as 6%, and in another study, the percentage
of dogs surviving at 24 months was 7%, indicating that these tumors
are particularly malignant [14,59].
C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489 481

Clinical stage
Although the clinical staging scheme has been developed for prognostic
purposes, each increase in stage (0–IV) has not necessarily been proven to
worsen the prognosis. It has been demonstrated that when dogs are treated
with radiation therapy, those with stage 0 MCTs survived significantly
longer than did dogs with stage I through III MCTs. In that study, no dog
had stage IV MCT; therefore, stage IV MCT could not be compared for
prognostic purposes [57]. In two other studies, the presence of mast cells in
the regional lymph node was a negative prognostic factor for survival and
disease-free interval on univariate analysis, suggesting that stage II has
a worse prognosis than stage I [60,61]. Dogs with stage III MCT with the
presence of multiple dermal masses may not necessarily have a worse prog-
nosis than dogs with stage I or II MCT. Indeed, in one study, dogs with mul-
tiple MCTs (stage III) did not have a worse prognosis than dogs with a
single MCT when treated with chemotherapy [60].

Anatomic location
MCTs that develop in the oral cavity, nail bed, or inguinal, preputial, and
perineal regions have been reported to behave in a more malignant fashion
regardless of histologic grade [57]. Definitive evidence for this in the liter-
ature is lacking, however. MCTs that originate in the viscera (eg, gastro-
intestinal tract, liver, spleen), bone marrow, or peripheral blood carry a grave
prognosis [45,62].

Growth rate
Tumors present for long periods (months to years) may be more likely to
behave in a benign manner. In one study, 83% of dogs with tumors present
for longer than 28 weeks before surgery survived for at least 30 weeks com-
pared with only 25% of dogs with tumors present for less than 28 weeks [41].
The same study demonstrated that most dogs surviving for longer than 30
weeks after surgery appeared to be cured.

Breed
Boxers have a high incidence of MCTs, but these tend to be more well
differentiated and carry a better prognosis [12,41]. Nevertheless, every MCT
should be treated as potentially malignant, regardless of breed.

Argyrophilic nucleolar straining organizing regions


Argyrophilic nucleolar staining organizing regions (AgNORs) are areas
present in the nucleus that take up silver stain and provide an indirect
measure of cell proliferation. This stain can be performed on formalin-fixed
specimens or on cytologic samples. It has been demonstrated that the rel-
ative frequency of AgNORs correlates with histologic grade and is pre-
dictive of postsurgical outcome. The higher the AgNOR count, the poorer
is the prognosis [56,63,64].
482 C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489

DNA ploidy
MCTs possessing an abnormal DNA content (aneuploid) exhibited
a trend toward shorter survival times; however, a significant difference was
found between aneuploid and diploid tumors when comparing stage I and
non-stage I disease [65].

Proliferating cell nuclear antigen


Proliferating cell nuclear antigen (PCNA) is a protein required for DNA
synthesis; expression is associated with cell proliferation. In one study,
PCNA was significantly higher in recurrent versus nonrecurrent tumors and
in metastatic versus nonmetastatic tumors, and it was a good predictor for
tumor recurrence at 6 months [56].

Ki-67
Ki-67 is composed of two protein subunits that are present in cells during
the active phases of the cell cycle but absent during rest. Levels of Ki-67 in
the nucleus seem to correlate with cell proliferation. In one study, the mean
number of Ki-67-positive nuclei per 1000 tumor nuclei was significantly
higher for dogs that died of MCTs than for those that survived. For dogs
with grade II tumors, the number of Ki-67-positive nuclei per 1000 tumor
nuclei (<93 versus 93) was significantly associated with outcome [59].

Other factors
Several other factors are currently under investigation to determine if
they may play a role in the aggressiveness of canine MCTs, including the
levels of active matrix metalloproteinase 2 and 9, tryptase, and chymase
[66,67]. Two recent studies evaluated the potential role of p53 in canine
MCTs; both found that although p53 overexpression was noted in some
MCTs, there was no obvious association with tumor behavior [68,69].

Treatment
The choice of treatment modalities used for a particular canine MCT
depends heavily on the prognostic indicators discussed previously, especially
the histologic grade and clinical stage.

Surgery
Wide surgical excision is indicated for all canine MCTs; although they
may feel like discrete masses, microscopically, most extend well beyond the
palpable borders. It is generally accepted that the lateral margins of excision
need to be at least 3 cm in each direction. Deep margins are as important as
the lateral margins and follow the concept of a quality margin as opposed to
a quantity margin. Collagen-dense and vascular-poor tissues tend to behave
as biologic barriers against cancer [70]. Therefore, the deep margin should
include a fascial plane that has not been invaded by the tumor and is
removed en bloc with the tumor. All the excised tissue should be submitted;
C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489 483

the lateral and deep margins should be accurately labeled so that the
pathologist is able to identify specifically any areas of incomplete excision.
Careful examination of the histologic margins is imperative; however, even
histologically clean margins do not guarantee that a tumor will not recur.
This is particularly relevant for grade II and III tumors in which the
underlying tissues may be involved. Part of the difficulty in evaluating tumor
margins is that normal mast cells are present in all tissues, and it may be
difficult for the pathologist to determine if a mast cell present at the tissue
margin represents a malignant cell or a normal cell. In one study, 83% of
dogs with grade I MCT, 44% of dogs with grade II MCT, and 6% of dogs
with grade III MCT were alive 1500 days after surgical excision [14]. In
another study, 100% of dogs with grade I MCT, 44% of dogs with grade II
MCT, and 7% of dogs with grade III MCT were alive 2 years after surgical
excision [59].
Complete surgical excision is likely to be curative for dogs with grade I
MCT. The need to perform adjuvant therapy for local control of the tumor
in dogs with completely excised grade II MCT seems to be unnecessary. Two
studies have reported a rate of local recurrence of 5% and 11% after
complete excision of grade II MCT [71,72]. Postsurgical treatment rec-
ommendations are as follows:
Grade I complete excision: no further therapy
Grade I incomplete excision: wider excision or radiation therapy if
surgery is not possible
Grade II complete excision: consider radiation therapy only if margins
are close
Grade II incomplete excision: wider excision or radiation therapy if
surgery is not possible
Grade III complete excision: chemotherapy
Grade III incomplete excision: chemotherapy with or without radiation
therapy
It has been advocated that the injection of deionized water in the surgical
site can decrease the likelihood of local recurrence after incomplete MCT
removal [73]. A more recent study found no benefit in this procedure; as
such, the use of deionized water is currently not recommended [74].

Radiation therapy
Evidence suggests that radiation therapy is extremely effective at elim-
inating remaining microscopic disease after incomplete excision of grade I
and II MCT ([90% 3-year control rate) [58,75]. Protocols that deliver the
total dose of radiation in a shorter period by administering more fractions
per week seem to provide better control of the MCTs [61]. Unfortu-
nately, dogs with grade III tumors do not fare as well; whereas the
radiation may be effective at preventing local recurrence of tumor, most dogs
eventually develop metastasis.
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Radiation therapy has been used to treat solid MCTs (macroscopic


disease) when surgery was not an option. Varying degrees of success have
been found; in one study, a 50% 1-year control rate was obtained using total
doses of 45 to 57 Gy [61]. Radiation therapy should not be used as the
primary therapeutic modality if surgical intervention is an option, however.
Palliative radiation has also been used to treat dogs with nonresectable high-
grade MCT. This may result in an improvement in quality of life but is
unlikely to significantly increase survival time. Moreover, systemic effects of
mast cell degranulation after radiation may lead to vomiting, hypotension,
and gastrointestinal ulceration.

Chemotherapy
The use of adjuvant chemotherapy is indicated after excision of grade III
MCTs and metastatic MCTs as well as for nonresectable high-grade tumors.
It is important to note that radiation therapy (not chemotherapy) is the
treatment of choice for incompletely excised grade I and II MCTs. In
general, chemotherapy for macroscopic MCT has been unrewarding, and
long-term responses have not been demonstrated in well-controlled clinical
trials.
i. Corticosteroids: the exact mechanism of how corticosteroids kill
malignant mast cells is not known. The reported response rate of
canine MCT to prednisone is 20%, with reported remission times of
10 to 20 weeks [76]. Partial remissions are more common than
complete remissions, and at least some of the observed response may
be a result of a decrease in tumor-associated edema. Intralesional
corticosteroids have also been shown to be of some benefit.
ii. CCNU (lomustine): a nitrosourea alkylating agent that has been used
to treat lymphoma and brain tumors in dogs, CCNU, was recently
found to have activity against canine MCT. A response rate of ap-
proximately 42% was noted when dogs with grade II and III MCTs
that had failed all other therapies were treated with CCNU [77].
As with prednisone, most of these were partial responses, and the
duration of response was only 79 days. Nevertheless, it does appear
that this drug has some efficacy in treating MCT, and clinical trials
are currently underway to evaluate its efficacy.
iii. Vinblastine: vinblastine has been reported to have efficacy against
canine MCT in two separate studies. In the first study, dogs with
grade II or III MCT with metastasis to the regional lymph node
underwent surgical removal of the primary tumor and involved lymph
node. They were then treated with a combination of vinblastine,
prednisone, and cyclophosphamide, resulting in a median survival
time of 18 months [78]. Interestingly, dogs with grade II or III MCT
and metastasis to the regional lymph node that did not undergo
surgery but were treated with the combination chemotherapy protocol
C.A. London, B. Seguin / Vet Clin Small Anim 33 (2003) 473–489 485

lived for a median of 5 months. This would seem to indicate that


vinblastine is more useful in the face of microscopic rather than bulky
MCT. The second study was a retrospective analysis of dogs with
various forms of MCT treated with a combination of vinblastine and
prednisone [60]. This study revealed a 47% response rate, although
the retrospective nature of the analysis makes the data difficult to
interpret. Interestingly, vincristine, a close relative of vinblastine,
appears to have little efficacy in the treatment of canine MCT [79].
Studies are currently underway to further evaluate the utility of
vinblastine in the treatment of canine MCT.
iv. Miscellaneous drugs: in limited clinical reports, both L-asparaginase
and chlorambucil have been found to have activity against MCT.

Supportive care
Animals with large primary MCT, evidence of metastatic disease, or
systemic signs should be treated with medications to block some of or all the
effects of histamine release.
a. H2 antagonists: because histamine stimulates gastric acid production
by parietal cells, MCT may cause gastrointestinal ulceration. To pre-
vent this, any of the standard H2 antagonists may be used, including
cimetidine, ranitidine, or famotidine. Alternatively, omeprazole may
be used; this is not a direct H2 antagonist but works by inhibiting
the proton pump on parietal cells necessary for the generation of gas-
tric acid.
b. H1 antagonists: massive mast cell degranulation can lead to hypo-
tensive shock and death. Therefore, patients with bulky mast cell dis-
ease should be placed on an H1 antagonist like diphenhydramine.
c. Miscellaneous: treatment with sucralfate is indicated for dogs with
evidence of gastrointestinal ulceration. Cyproheptadine and antihis-
taminic drugs with antiserotonin activity stabilize mast cells and may be
useful in the treatment of dogs with bulky mast cell disease.

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