Page 405 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 21 Mast Cell Tumors 383

suggest horizontal transmission. Chromosomal fragile site expres- tumor grade increased, and tumors with c-kit mutations showed
sion, a phenomenon thought to genetically predispose humans to genome-wide aberrant CNVs often involving genes in the p53
and rB pathways, whereas CNVs were very limited in tumors with
develop certain tumors, was shown to be increased in boxer dogs
VetBooks.ir with MCT ; however, the control population for this study was wild-type c-kit. Gene expression profiling comparing MCTs
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from dogs cured with surgery versus those that died of disease
young, non–tumor-bearing boxers, and the increased expression of
chromosomal fragile sites may be due to this age difference. revealed differential expression of genes associated with drug
The genetic changes that predispose to canine MCTs are metabolism and cell cycle pathways including members of solute
incompletely understood. Alterations in the p53 tumor suppressor carrier transporter and UDP glucuronosyltransferase gene fami-
pathway have been identified in some canine MCTs, 26–28 but p53 lies. In contrast, another study found that expression of 13 spe-
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sequencing in a limited number of cases has revealed no muta- cific transcripts divided samples into two categories (differentiated
tions. Perturbations in expression of the proteins p21 and p27, and undifferentiated), harboring a different prognosis. Among
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cyclin-dependent kinase inhibitors that contribute to regulation these, a significant association was found between expression of
of the cell cycle, have been identified in many canine MCTs. FOXM1, GSN, FEN1, and KPNA2 and MCT-related mortal-
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Cytosolic receptors for estrogen and progesterone have also been ity. Using proteomic profiling, four stress response proteins
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detected in canine MCTs, but their role in the etiopathogen- (HSPA9, PDIA3, TCP1A, and TCP1E) were found to be signifi-
esis of MCTs is poorly understood. One European study reported cantly upregulated in high-grade tumors, whereas proteins mainly
that female dogs with MCTs had a more favorable prognosis with associated with cell motility and metastasis had either increased
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chemotherapy. Although the majority of studies performed in (WDR1, ACTR3, ANXA6) or decreased (ANXA2, ACTB)
North America have failed to detect such an association, the rela- expression levels. Lastly, overexpression of micro-RNA-9 was
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tively higher frequency of intact females present in the European associated with MCT metastasis, potentially through the induc-
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population may have allowed the effect of sex hormones to have tion of an invasive phenotype. It is likely that future work to
a greater statistical effect on biologic behavior. Expression of the more definitely characterize the canine MCT genome will help
angiogenic growth factor VEGF and its receptor VEGFR2 has clarify how the abnormalities described earlier influence tumor
been demonstrated in many canine MCTs, and preliminary evi- biologic behavior.
dence suggests that VEGFR2 activation may be associated with
inferior postsurgical outcomes. 33,34 History and Clinical Signs
Perhaps the best-described molecular abnormality in canine
MCTs involves the receptor tyrosine kinase (RTK) KIT. KIT is The vast majority of MCTs in dogs occur in the dermis and sub-
expressed normally on a variety of cells including hematopoietic cutaneous tissue, 5,57 and most are solitary in nature, although
stem cells, melanocytes, and MCs, among others. 35–37 The ligand 11% to 14% of dogs present with multiple lesions. 58,59 Approxi-
for KIT, SCF, induces KIT dimerization, subsequent phosphory- mately 50% of cutaneous MCTs occur on the trunk and perineal
lation, and generation of intracellular signaling that promotes the region, 40% on the limbs, and 10% on the head and neck. 20,60
proliferation, differentiation, and maturation of normal MCs. 35–37 MCTs have also been reported to occur in other sites including
SCF is essential for the differentiation of mature MC from CD34+ the conjunctiva, salivary gland, nasopharynx, larynx, oral cavity,
hematopoietic stem cells in vitro, and inhibition of KIT signaling ureter, and spine. 61–65 A visceral form of MCT, often referred to as
induces apoptosis of cBMMCs. 10,36,37 KIT expression has been disseminated or systemic mastocytosis, has also been documented,
demonstrated on canine MCTs, and aberrant cytoplasmic local- although it is usually preceded by an aggressive primary lesion. 66–70
ization and/or increased phosphorylation of KIT in MCTs may Infiltration of abdominal lymph nodes (LNs), spleen, liver, and
be associated with dysregulated KIT function. 38–42 A significant bone marrow is commonly observed in dogs with visceral disease,
minority of canine MCTs possess somatic mutations in the c-kit and pleural/peritoneal effusions containing neoplastic MCs have
gene involving either the juxtamembrane domain (exons 11–12) been documented. A case series of dogs with primary GI MCT
or extracellular domain (exons 8–9). 43–47 These mutations result in was reported in which most dogs presented for vomiting, diarrhea,
SCF-independent activation of KIT and subsequent unregulated and melena. Only 40% dogs were alive at 30 days after first admis-
KIT signal transduction. 45,46 In dogs, the c-kit mutations appear sion and fewer than 10% were alive at 6 months. 28
to be associated with 25% to 30% of intermediate- and high-grade It is important to note that cutaneous MCTs have an extremely
MCTs, and evidence suggests that they are linked to increased risk varied range of clinical appearances and they are sometimes inad-
of local recurrence, metastasis, and a worse prognosis. 43,46,48–50 vertently mistaken for nonneoplastic lesions. Well-differentiated
More recently, studies have been undertaken to better charac- MCTs tend to be solitary, small, slow-growing tumors that may
terize copy number variation (CNV), gene expression profile, and have been present for several months. They are not typically ulcer-
proteomic profile of canine MCTs to identify those pathways that ated, but overlying hair may be lost. Undifferentiated MCT tend
contribute to aggressive biologic behavior. In one study of CNVs to be rapidly growing, ulcerated lesions that cause considerable
found in MCTs from dogs that survived <6 and >12 months, irritation and attain a large size. Surrounding tissues may become
regions of loss in phosphatase and tensin homolog (PTEN), inflamed and edematous. Small satellite nodules may develop in
FAS*, and regions of gains in MAPK3, WNT5B, FGF, FOXM1, surrounding tissues. Tumors of intermediate differentiation fill the
and RAD51 were detected in those tumors with shorter survival spectrum between these two extremes. A subcutaneous form of
times (STs). In another study, CNVs were found to increase as MCT that is soft and fleshy on palpation is often misdiagnosed
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clinically as a lipoma (Fig. 21.1).
The history and clinical signs of dogs with MCTs may be
*Fas or FasR, also known as apoptosis antigen 1 (APO-1 or APT), cluster complicated by signs attributable to release of histamine, hepa-
of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily rin, and other vasoactive amines from MC granules. Occasionally,
member 6 (TNFRSF6) is a protein that is encoded by the FAS gene. Fas was
first identified using a monoclonal antibody generated by immunizing mice mechanical manipulation during examination of the tumor results
with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated in degranulation and subsequent erythema and wheal formation
surface antigen. in surrounding tissues. This phenomenon has been referred to as