With increasing evidence on the impact of variety of viral infections on cancer development and limited data on relation between viral infections and RCC, we have conducted a prospective study aimed at assessment of the incidence of selected viral infections within renal tumors. We have found that EBV and ADV tumor infections are common and are associated with different histological cancer features.
While there are some data regarding the link between EBV infection and renal malignancy, to the best of our knowledge the association of ADV with renal tumors is raised for the first time. ADV usually causes acute self-limiting infections with mild clinical symptoms within eyes, respiratory or gastrointestinal tract. However, in some cases ADV can establish a latency within T lymphocytes [10]. For this reason, it is advised to differentiate ADV infection from disease [11].
The ADV infections and reinfections are more common and have more severe clinical course in immunocompromised patients, i.e. after organ transplantation [12–13]. Cancer related alterations within immune system can explain high rate of ADV presence in renal tumors, that we have noted in our study. The role of ADV infection in cancers is poorly understood and our study highlights the need of future research.
Much more is known in the field of EBV and cancer. After primary infection, EBV causes a lifelong asymptomatic latent infection within memory B lymphocytes [14]. It is assumed that 95% of healthy adult population is infected [15]. This can be associated with latent gene heterogeneity and deletions. A special interest was paid to the loos of function of LMP1, EBNA3B, EBNA2 and B95-8 suppressor genes [16–19]. In some cases, especially in the context of immunodeficiency, such infection can promote carcinogenesis, i.e. Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin’s disease and others [20]. Latent EBV infection also increases the risk of gastric cancer, so called EBV-associated gastric carcinoma, which nowadays accounts for 2–20% of gastric cancer cases and is associated with relatively good prognosis [21–23]. Simultaneously, EBV was detected in numerous tumors, including lymphoid, epithelial and mesenchymal tumors [20]. The first report on the causative role of EBV infection in kidney carcinogenesis in transgenic mice was published in 1997 by Tornell et al [24].
The relation between EBV infection and renal cancer was previously reported [6–8, 25–26]. What we did find is that EBV infection within renal tumors is frequent and associated with high-grade tumors. Shimakage et al. noted EBV infection within 100% of renal tumors [7]. On contrary, Salehipoor et al. did not find any case of EBV infection among 49 renal cancer patients [8]. Kim et al. found that EBV virus could be a marker of sarcomatoid RCC, as it is present in tumor-infiltrating B cells due to local modulation of immune response [6]. On the other hand, Karaarslan et al. observed EBV infection in 48% of RCCs, including infected tumor cells in 22% of cases [25]. Also Kang et al. noticed EBV presence in both tumor cells and tumor-infiltrating lymphocytes in 34% of RCC patients and the later phenomenon was found to be independent prognostic factor of poor patients survival [26]. Finally, Becker et al. showed that EBV infection of renal proximal tubular cells may participate in evoking a cellular immunue response that results in a damaged renal interstitium in patients with chronic interstitial nephritis [27]. Taking all these data together, it remains unclear whether EBV infection is a cause or a result of RCC development and whether the infection is specific for tumor cells, B lymphocytes, renal parenchyma or all of them.
Apart from the finding that RCCs are infected with EBV and ADV, we did show that these infections lead to higher rate of high-grade cancers. Therefore, one can expect shorter survival in these patients as cancer grade is one the most important prognostic factors in postoperative follow-up [28–29]. This was already proven by Kang et al., who noticed significantly shorter overall survival in RCC patients and EBV infected tumor-infiltrating lymphocytes [26].
We have also noted that patients with viral infections have higher rate of chronic renal disease. However, this fact can be at least partially attributed not to virus, but to other differences in patient characteristics, including older age, higher rate of diabetes and overweight. All these facts are well known risk factors for renal disease. This explanation is supported by study from Blazquez-Navarro et al., which showed that EBV has no significant impact on the risk of renal failure in patients after renal transplantation [30].
This study is not free from limitations. First, study population is limited. However, for a pilot study with seven viruses tested, this limitation is justified to some extent. For future studies, one should plan to focus on EBV and ADV and enroll more patients. Second, as study methods clearly diagnosed or excluded viral infections in tissue homogenates, no information was gathered whether viral genetic material comes from cancer cells, infiltrative lymphocytes or other cells. This doubt does not change substantially clinical meaning of our findings. However, it needs to be addressed in the future. Third, selection of tested viruses was subjective and does not rule out the importance of other viral infections in renal malignancies.