## 4 Discussion  
Based on contemporary literature, CEUS appears to be a useful tool for characterization of testicular masses. To assess the real value of this imaging technique and its possible applications in everyday clinical practice, we performed a systematic review and meta-analysis of the literature. Our analyses resulted in several noteworthy observations.  
First, we identified 419 patients for a total of 428 testicular masses. All studies were conducted in Europe between 2011 and 2020. Of those, three were retrospective and three were prospective. These results show a growing interest for CEUS especially in Europe,  
Figure 3: Pooled sensitivity, specificity, and SROC curve of CEUS in detecting malignant lesions.  
where public healthcare systems are in search of cost-effective strategy to support clinician in differential diagnosis [21].  
Second, pooled sensitivity, specificity, and accuracy of CEUS in the diagnosis of neoplastic vs. non-neoplastic testicular masses were 0.89, 0.62, and 0.96, respectively. The low value of specificity was mainly attributable to [PERSON] et al., who reported the lowest specificity (0.31), probably due to the high heterogeneity of the histological findings in the non-neoplastic group. Moreover, we observed a high pooled PPV (0.85) in detecting neoplastic lesions.  
Third, pooled sensitivity, specificity, and diagnostic accuracy of CEUS in the diagnosis of malignant vs. benign testicular masses were 0.86, 0.87, and 0.96, respectively. Here, the three eligible studies analyzed for this endpoint reported overlapping diagnostic performance, with sample size of 115, 55, and 45 patients in [PERSON] et al., [PERSON] et al., and [PERSON] et al., respectively. Moreover, we observed a high NPV (0.91) in excluding benign testicular masses.  
Taken together, our findings strongly suggest that CEUS is a high-accuracy and non-invasive tool in differential diagnosis of TM. Specifically, in the daily clinical practice, CEUS may support the clinician in the identification of neoplastic TM, thanks to the high PPV. Moreover, when a neoplastic testicular mass is identified, CEUS may provide a further guidance in excluding a malignant tumor, thanks to the high NPV.  
To the best of our knowledge, we are the first to systematically review and meta-analyze the diagnostic performance of CEUS in TM. Moreover, our analyses addressed two important issues in clinical practice, that are both the differential diagnosis between neoplastic vs. non-neoplastic and malignant vs. benign TM. However, our study is not devoid of limitations. First, CEUS results may be interpreted according to several parameters (wash-out, wash-in, peak intensity, etc.); here, we selected only studies whose authors aimed to report CEUS's results in the easiest fashion (i.e., just positive vs. negative). Second, some of the eligible studies were retrospective (\(n=3\)) and/or limited in sample size. Third, not all lesions relied on histopathological findings, but follow-up, as well as clinical surveillance were applied as reference standard. However, the present study represents the strongest available evidence, since high-quality, well-designed, and adequately powered longitudinal studies are still lacking.