Page 804 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

782 PART IV Specific Malignancies in the Small Animal Patient

tissue, skin, eyes, oral mucosa, liver, spleen, peritoneum, hypoph- the host’s histocompatibility barrier, particularly T-cell cytotoxic-
ysis, brain, and bone marrow. 186,195,207,208,209 Because TVT is also ity. 234 Some cell-surface MHC class I expression remains, likely to
prevent recognition and killing by natural killer (NK) cells. This
transmitted by licking, sniffing, and biting, many cases of reported
VetBooks.ir metastases may instead actually be spread by mechanical exten- immunoevasion is partly due to the high concentration of tumor-
secreted transforming growth factor-beta (TGF-β ), which inhib-
sion, autotransplantation, or heterotransplantation.
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TVT is commonly described as a round (or discrete) cell tumor its tumor MHC antigen expression and NK cell activity. 230 TVT
and suggested to be of histiocytic origin. 187–189 This is supported by also targets and damages dendritic cells (DCs). 234 It has been sug-
immunohistochemical (IHC) expression of vimentin, lysozyme, gested that TVT has evolved under survival pressures to escape
alpha-1-antitrypsin (AAT), and macrophage-specific ACM1, as host immunosurveillance. 235
well as negative IHC staining specific for other cell types. 187– Tumor-infiltrating lymphocytes (TILs) produce interferon-
189,192,210–212 TVT also expresses p53, proliferating cell nuclear gamma (IFN-γ) but fail to promote tumor MHC expression due
antigen (PCNA), Ki67, MYC, retinoblastoma (Rb), cyclin D1, to inhibition of IFN-γ effects by tumor-derived TGF-β , which
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matrix metalloproteases (MMPs) -2 and -9, and variably expresses also suppresses the cytotoxicity of the NK cells that migrate to
S-100. 212–214 IHC has been helpful in confirming metastatic TVT the tumor site because of low tumor-antigen expression. 227,229,230
in various anatomic locations. 207,208,209 Furthermore, there have However, late in the P phase, a marked increase in immune cell
been reports describing TVT cells with intracellular Leishmania infiltration occurs and TILs produce high concentrations of the
organisms, also suggesting a histiocytic origin. 200,215 proinflammatory cytokine interleukin-6 (IL-6), which acts syn-
Cytogenetic and genetic analyses have provided robust evidence ergistically with host-derived IFN-γ to antagonize the immuno-
of clonality. Whereas normal canine chromosomes consist of 76 inhibitory activity of TGF-β and results in MHC expression in
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acrocentric autosomes plus submetacentric X and Y sex chromosomes, up to 40% of tumor cells and restores NK cytotoxicity. 228,236,237 A
TVT cells have a vastly rearranged karyotype consisting of 57 to 59 critical threshold level of IL-6 secreted by TILs has to be reached to
chromosomes, including 15 to 17 submetacentric chromosomes as trigger TVT into R phase. 230,236 Therefore after progressive growth
a result of multiple centric fusions. 187,188,192 ,207 However, the total for 3 to 4 months, the tumor spontaneously regresses with upregu-
number of chromosome arms in TVT is grossly comparable to that lation of MHC antigen expression, possibly under epigenetic con-
in the normal dog, so it appears that the karyotypic rearrangement trol. 235 Regression has been correlated with upregulation of genes
is not associated with significant change in DNA content. 201,206 involved with inflammation and chemotactic cytokines. 238,239
Although TVT cells are aneuploid, they exhibit remarkably stable In addition to cell-mediated immunity, TVT also elicits a
and similar karyotypes in samples obtained from widely separate humoral immune response demonstrable by antibodies against
geographic regions (i.e., different continents). 201 Likewise, TVT antigens. 226,240,241 Dogs recovered from TVT have serum-
molecular genetic studies of globally distributed TVT tumors transferable immunity to reinfection and puppies born to bitches
provide evidence of a monophyletic origin, which has diverged into exposed to TVT are less susceptible to the disease. 242 In addition
subclades. 201,216,217 to the host immune response, during TVT regression stromal
In addition, TVT cells all share an insertion of a long inter- cells and extracellular matrix (ECM) react comparably to wound
spersed nuclear element (LINE-1) upstream of the c-myc oncogene repair with collapse of the tumor parenchyma and replacement by
that is not found in normal dog genomes. 218–220 This insertion has fibrous stroma. 233
the potential to disrupt transcriptional regulation of downstream
genes, possibly initiating oncogenic activity, and may have been History and Clinical Signs
causally involved in the origin of the tumor. 221 This unique rear-
ranged LINE-c-myc gene sequence has been used with polymerase The archetypical TVT patient is a sexually intact young adult dog
chain reaction (PCR) as a diagnostic marker of TVT to confirm either living in or having traveled to an area endemic for TVT, with
diagnosis. 222,223 TVT cells have also demonstrated point muta- a history of contact (coitus, sniffing, licking, or biting) with dogs
tions in the tumor suppressor gene p53, which is responsible for of similar signalment. 186,189,190 The primary lesions are usually on
protecting the integrity of the DNA. 219,224,225 Mutations of such the external genitalia. In the male, the tumor is usually located
a key regulator of the cell cycle, apoptosis, and senescence may be on the caudal part of the penis, requiring caudal retraction of the
another factor in the oncogenesis of TVT. penile sheath for visualization (Fig. 34.6). 186–189 Occasionally, it is
TVT is an immunogenic tumor and the immunologic response on the prepuce. In the bitch, the tumor is usually in the posterior
of the host appears to play a critical role in determining the natu- vagina or vestibule. 186–189 Tumors appear initially as small 1 to
ral behavior of the disease. The course of disease is divided into 3 mm hyperemic papules that progress by fusing together into
three distinct phases of growth: a progressive phase (P) in which nodular, papillary, multilobulated cauliflowerlike or pedunculated
the tumor grows for 3 to 6 months, then a stationary phase (S) proliferations up to 10 to 15 cm in diameter. The mass is firm but
that can last for months to years, which is followed by a regres- friable, with an ulcerated inflamed surface. The tumor often oozes
sive phase (R) unless the dog is elderly, in poor general condition, a serosanguineous or hemorrhagic fluid. Examples of extragenital
or immunologically compromised, in which case metastasis may sites are illustrated in Fig. 34.7.
occur. 189,226–233 Spontaneous regressions have been associated Clinical signs vary according to the location of the lesions.
with immune responses against the tumor; therefore immunosup- Genital lesions often manifest with chronic signs of discomfort or
pression from any cause may be a risk factor for the development hemorrhagic discharge from the penile sheath or vulva for weeks
and maintenance of TVT and may predispose to widespread dis- to months before diagnosis, which can result in anemia. 186,189
semination. When spontaneous regression occurs, it usually starts Lesions can predispose to ascending bacterial urinary tract infec-
within 3 months after implantation but rarely if the tumor is pres- tions but rarely interfere with micturition. 243 Extragenital lesions
ent for more than 9 months. 186 cause a variety of signs, depending on anatomic location, such as
Initially, in the P phase, the tumor downregulates MHC class I sneezing, epistaxis, epiphora, halitosis, tooth loss, exophthalmos,
β -microglobulin and class II expression, which allows it to evade skin masses, facial deformation, and regional LN enlargement.
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