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Canine Transmissible Venereal Tumor: Is Its Biological Behavior Changing?

Canine transmissible venereal tumor (CTVT) is a sexually transmitted tumor clone that has proliferated continuously for thousands of years in canine populations (Strakova and Murchison, 2014); over the years, CTVT has been the subject of numerous investigations. However, many questions regarding its biological behavior remain unresolved. It is known that some CTVTs present with varying degrees of aggressiveness (Amaral et al., 2011) and resistance to chemotherapy (Florez et al., 2016). Usually, the more severe cases result in metastasis and dissemination of the tumor. This demonstrates the need for specific treatments for different tumor types, thereby minimizing cost and side effects by avoiding excessive use of chemotherapy (Gaspar et al., 2010; Florez et al., 2016). This tumoral behavior has led a group of veterinarian pathologist researchers from the S~ ao Paulo State University, Brazil (UNESP-Botucatu) to conduct several studies, which evidenced the following common fact: as CTVT becomes more aggressive, the tumor begins to exhibit changes in its biological profile. Initially, a cytopathological analysis of the tumors revealed that CTVT presents different cytomorphological types, which are currently classified as plasmacytoid and lymphocytoid; we hypothesized that there is a correlation between these cytomorphological types and the degree of tumor aggressiveness (Amaral et al., 2007; Montoya et al., 2012). Subsequently, it was established and supported by several studies that CTVT cases with a higher level of aggressiveness had tumors consisting of predominantly plasmacytoid cells (Bassani-Silva et al., 2007; Gaspar et al., 2010; Amaral et al., 2011). Moreover, single-cell gel electrophoresis, a visual technique to analyze and measure DNA breaks in mammalian cells that is also known as the “comet test”, demonstrated that CTVT cases with a plasmacytoid morphology exhibited fewer DNA breaks, which is probably an evasive mechanism for the elimination of tumor cells (Amaral et al., 2011). Likewise, immunohistochemical studies (IHC) performed in CTVT cases revealed that the plasmacytoid morphology is associated with both high Ki-67 reactivity (Bassani-Silva et al., 2015) and an increased expression of PGlycoprotein, indicating a higher mitotic potential and resistance to chemotherapy, respectively (Gaspar et al., 2010; Montoya et al., 2012). In our in vivo studies, we assessed the expression of P-glycoprotein in 102 CTVT cases; of these samples, 50% presented plasmacytoid morphology, 18.63% presented lymphocytoid morphology and 31.37% presented mixed morphology. Furthermore, 46 (45%) expressed Pglycoprotein and 56 (55%) were negative. In addition, the plasmacytoid group displayed a significantly greater level of immunoreactivity to the anti-Pglycoprotein antibody (P< 0.05) compared to the lymphocytoid group (Gaspar et al., 2010). In the current investigations, CTVT cells subjected to vincristine displayed a high expression level of the (Pgp) MDR-1 gene (Florez et al., 2016), with these tumors requiring more chemotherapeutic applications for regression or even a modified therapy in some cases (Gaspar et al., 2010; Florez et al., 2016). In other in vitro studies, the plasmacytoid pattern of CTVT showed a higher resistance against propolis action (Bassani-Silva et al., 2007). Furthermore, these studies have established that a large percentage of metastatic CTVTs exhibits a predominantly plasmacytoid morphology (Gaspar et al., 2010). Therefore, our study suggests that the plasmacytoid form is a progressive stage of the lymphocytoid pattern, which indicates the possibility of progressive modifications in the biological profile of tumoral cells. Therefore, the adaptive and continuing evolution of CTVT cells from a less aggressive lymphocytoid form to a more aggressive plasmacytoid one is very likely. Despite this, the question of whether resistance to vincristine is related to the plasmacytoid cytological phenotype in CTVT is controversial because research conducted by other groups found no such association (Lima et al., 2013; Paranzini et al., 2015). This controversy may be a function of the need for a better understanding of and a detailed utilization of the classification system, which does not occur in all cases; however, both factors, the resistance and aggressiveness of CTVT, still require a greater clarification from a multi-causal perspective, taking into account the cytological, histopathological, and molecular aspects, with the aim of determining the degree of association between the cytological pattern of the THE ANATOMICAL RECORD 300:1009–1010 (2017)