Table_1_Role of Viral Infections in Testicular Cancer Etiology: Evidence From a Systematic Review and Meta-Analysis.docx

The most represented histotype of testicular cancer is the testicular germ-cell tumor (TGCT), both seminoma and non-seminoma. The pathogenesis of this cancer is poorly known. A possible causal relationship between viral infections and TGCTs was firstly evoked almost 40 years ago and is still a subject of debate. In the recent past, different authors have argued about a possible role of specific viruses in the development of TGCTs including human papillomavirus (HPV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), Parvovirus B-19, and human immunodeficiency virus (HIV). The aim of this present review was to summarize, for each virus considered, the available evidence on the impact of viral infections on the risk of developing TGCTs. The review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included all observational studies reported in English evaluating the correlations between viral infections (HPV, CMV, EBV, Parvovirus B19, and HIV) and TGCTs. The methodological quality of studies included in the meta-analysis was evaluated using a modified version of the “Newcastle–Ottawa Scale.” Meta-analyses were conducted using the “Generic inverse variance” method, where a pooled odds ratio (OR) was determined from the natural logarithm (LN) of the studies' individual OR [LN (OR)] and the 95% CI. A total of 20 studies (on 265,057 patients) were included in the review. Meta-analysis showed an association with TGCTs only for some of the explored viruses. In particular, no association was found for HPV, CMV, and Parvovirus B-19 infection (p = ns). Conversely, EBV and HIV infections were significantly associated with higher risk of developing TGCTs (OR 7.38, 95% CI 1.89–28.75, p = 0.004; OR 1.71, 95% CI 1.51–1.93, p < 0.00001). In conclusion, we found adequate evidence supporting an oncogenic effect of HIV and EBV on the human testis. Conversely, available data on HPV and TGCTs risk are conflicting and further studies are needed to draw firm conclusions. Finally, current evidence does not support an effect of CMV and Parvovirus B-19 on testicular carcinogenesis.

睾丸癌最常见的组织学类型为睾丸生殖细胞肿瘤（testicular germ-cell tumor, TGCT），涵盖精原细胞瘤与非精原细胞瘤亚型。该肿瘤的发病机制迄今尚未完全阐明。约40年前，研究者首次提出病毒感染与TGCT之间可能存在因果关联，这一假说至今仍处于争议之中。近年来，诸多学者围绕人乳头瘤病毒（human papillomavirus, HPV）、EB病毒（Epstein–Barr virus, EBV）、巨细胞病毒（cytomegalovirus, CMV）、细小病毒B19及人类免疫缺陷病毒（human immunodeficiency virus, HIV）等特定病毒在TGCT发生发展中的潜在作用展开了广泛讨论。本综述旨在针对上述各类病毒，系统总结现有关于病毒感染与TGCT发病风险相关性的研究证据。本研究严格遵循《系统评价与Meta分析首选报告条目》（Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA）规范完成撰写。本研究纳入所有以英文发表的、评估病毒感染（HPV、CMV、EBV、细小病毒B19及HIV）与TGCT相关性的观察性研究。采用改良版纽卡斯尔-渥太华量表（Newcastle–Ottawa Scale）对纳入Meta分析的研究进行方法学质量评价。Meta分析采用通用逆方差法（Generic inverse variance），通过对各项研究的个体比值比（odds ratio, OR）取自然对数（natural logarithm, LN）及95%置信区间（95% CI），合并得到汇总OR值。本综述最终纳入20项研究，共计265057名患者。Meta分析结果显示，仅部分被探索的病毒与TGCT存在相关性。具体而言，未发现HPV、CMV及细小病毒B19感染与TGCT存在统计学关联（p=无显著性差异）。与之相反，EBV及HIV感染与TGCT发病风险升高存在显著相关性（OR=7.38，95%CI：1.89~28.75，p=0.004；OR=1.71，95%CI：1.51~1.93，p<0.00001）。综上，本研究发现充分证据支持HIV与EBV对人类睾丸具有致癌作用。就HPV与TGCT发病风险的相关性而言，现有研究结论存在分歧，尚需开展更多高质量研究以得出确定性结论。此外，当前证据不支持CMV与细小病毒B19对睾丸癌变存在影响。