Diffusion-Weighted MRI of the Testes in Patients With Varicocele: A Preliminary Study

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1 Genitourinary Imaging Original Research Karakas et al. DWI of the Testes in Patients With Varicocele Genitourinary Imaging Original Research Ekrem Karakas 1 Omer Karakas 1 Nesat Cullu 2 Omer Faruk Badem 3 Fatıma Nurefsan Boyacı 1 Mehmet Gulum 4 Hasan Cece 1 Karakas E, Karakas O, Cullu N, et al. Keywords: diffusion-weighted MRI, testis, varicocele DOI: /AJR Received January 17, 2013; accepted after revision May 28, Department of Radiology, Harran University, Faculty of Medicine, Yenisehir Campus, Sanlıurfa 63300, Turkey. Address correspondence to E. Karakas (karakasekrem@yahoo.com). 2 Department of Radiology, Muğla Sitki Kocman University, Faculty of Medicine, Muğla, Turkey. 3 Department of Urology, OSM Middle East Hospital, Sanlıurfa, Turkey. 4 Department of Urology, Harran University, Faculty of Medicine, Sanlıurfa, Turkey. This article is available for credit. AJR 2014; 202: X/14/ American Roentgen Ray Society Diffusion-Weighted MRI of the Testes in Patients With Varicocele: A Preliminary Study OBJECTIVE. This preliminary study aimed to evaluate changes in apparent diffusion coefficient (ADC) values of the testes in patients presenting with varicocele. SUBJECTS AND METHODS. This cross-sectional study included 25 consecutively recruited patients with varicocele and 25 healthy control volunteers. The ADC values were measured in all participants. Kolmogorov-Smirnov tests were used to test the normality of the data distributions, and the data were expressed as arithmetic means and SDs. A one-way analysis of variance with a post hoc Bonferroni test was used to analyze normally distributed continuous data. Independent sample Student t tests were used to compare continuous variables between two groups. Furthermore, a Pearson correlation coefficient analysis was used to examine the association of venous diameters with mean ADC values in patients with varicocele. A two-sided p value < 0.05 was considered statistically significant. Sensitivities, specificities, and areas under the curve were calculated for the ADC values. RESULTS. The ADC values associated with the ipsilateral testicular parenchyma of patients with varicocele were found to be lower than those of healthy volunteers. Moreover, the ADC values of the contralateral testicular parenchyma in patients with varicocele were also lower than those of healthy volunteers. The sensitivity and specificity of ADC values were 90% and 96%, respectively, for patients with varicocele and 89.5% and 96% for healthy volunteers. The mean ADC values were significantly negatively correlated with venous diameter. CONCLUSION. The measurement of testicular ADC values may be used as a diagnostic indicator in the detection of testicular fibrosis. V aricoceles are abnormal dilatations of the pampiniform plexus [1]. Varicocele has been reported in approximately 15% of adolescents and in 10 15% of adult men [2]. The association between male subfertility and clinical varicoceles is well recognized. Varicoceles are found in 20 40% of infertile men, and their negative impact on semen and testicular volume is well known [3, 4]. The testicular histopathology of patients with varicocele has been examined, and findings of a thickened tubular basement membrane, thickened interstitial blood vessel walls, luminal narrowing, and increased interstitial fibrous tissue have been reported [5 7]. Varicocele, which is a cause of male infertility, can be treated by surgery and a percutaneous approach. Varicocelectomy is the traditionally performed surgery. However, percutaneous treatment is a rapid and minimally traumatic approach that has recently been promoted for adolescents [8 11]. Diffusion-weighted imaging (DWI) is a functional imaging technique based on the measurement of increased or restricted microscopic diffusion movements of water molecules in tissue. It does not require an injection of a contrast agent, and the imaging time is quite short [12]. A limited number of researchers have performed studies related to the application of DWI on the testes [13 15]. The degree of water proton restriction can be quantitatively measured using the apparent diffusion coefficient (ADC) [16]. Decreased ADC values occur as a result of inflammation, trauma, ischemia, tumor, and fibrosis [15, 17, 18]. This preliminary study aimed to evaluate changes in the ADC values of the testes in patients with varicocele. In this study, the effects of increased venous diameter on testis diffusion were investigated. 324 AJR:202, February 2014

2 DWI of the Testes in Patients With Varicocele Subjects and Methods Patient Selection After obtaining approval from the institutional review board for this cross-sectional study, we recruited 25 consecutive patients with varicocele and 25 healthy control volunteers who presented to the Department of Urology of the Harran University from 2010 to The clinical diagnosis of varicocele was made following a physical examination in patients presenting with infertility, testicular pain, or both. Patients with varicocele were also examined by color Doppler ultrasound to clarify the diagnosis. Nineteen patients exhibited unilateral varicocele, and six patients had bilateral varicocele. Healthy volunteers were selected from among the patients who were admitted to the urology department with various complaints. The presence of genitourinary disease was not detected by urinalysis or urine culture in these patients. Furthermore, seven patients with clinically suspected varicocele were added to the volunteer group after the possibility of a varicocele diagnosis was excluded on the basis of color Doppler ultrasound results. The following groups were formed: group 1, testicles ipsilateral to varicocele or varicoceles; group 2, testicles contralateral to varicocele or varicoceles; and group 3, healthy volunteer control subjects. The six patients (12 testes) with bilateral varicoceles were placed in group 1. The study excluded patients with the following characteristics: previous varicocele repair, scrotal surgery, or hernia repair; a history of urogenital infection (e.g., orchitis, epididymoorchitis); a single testis; and testicular torsion, trauma, or tumor. Infertile men using medications (e.g., pentoxifylline) were also excluded given the possibility of interactions with testicular ADC values. Diagnostic Criteria In the patients who presented with a history of testicular pain, infertility, or both, the existence of a clinical varicocele was identified by the urologist by palpation and inspection while the patient was standing before and during the Valsalva maneuver. The classification of clinical varicocele was consistent with the guidelines of the World Health Organization: grade 0, no varicocele; grade I, palpable during the Valsalva maneuver; grade II, palpable without the Valsalva maneuver; and grade III, visible through the scrotal skin [19]. Clinically, 17 patients presented with grade I varicoceles, nine patients had grade II varicoceles, and seven patients had grade III varicoceles. Doppler ultrasound of all participants was then performed by an experienced radiologist. Varicoceles were detected in 25 patients via Doppler ultrasound. High-frequency ultrasound with color Doppler imaging was performed using a 5-12 MHz transducer (MyLab Twice, Esaote Biomedica). In all patients, the diameters in the short axis and refluxes of the largest veins of the pampiniform plexuses were measured bilaterally as the patient was in a resting supine position and during the Valsalva maneuver. In patients with varicocele, these measurements were performed separately for both testes. In healthy volunteers, all measurements were performed, and mean diameters were calculated by averaging the bilateral venous diameters. Varicocele was diagnosed if a tubular or oval structure with a diameter of 2 mm or more was detected, if there was venous flow in and around the testis, and if there was a positive response to the Valsalva maneuver. A marked increase in venous flow within A Fig. 1 Diffusion-weighted imaging (DWI) of testes. = region of interest, Min = minimum, Max = maximum, Alan = Area. A, Testicular DW image of 28-year-old man with varicocele. Apparent diffusion coefficient (ADC) map shows that ADC values of ipsilateral and contralateral testicular parenchyma are 858 and s/mm 2, respectively. B, Testicular DW image of healthy 35-year-old man. ADC map shows that ADC values of left and right testicular parenchyma are 1105 and s/mm 2, respectively. the tubular structure and retrograde venous flow (reflux) supported the diagnosis of varicocele [20]. MRI Examination A 1.5-T unit (Magnetom Symphony A Tim System, Siemens Healthcare) was used for imaging with the patient lying in a supine position with a 16-channel body coil placed over the pelvic region. DW images directed at the lower abdomen were collected for all participants. Single-shot spin-echo echo-planar DW images with b values of 0, 500, and s/mm 2 were obtained using the following imaging parameters: TR/TE, 6000/88; FOV, 180 mm; matrix, ; slice thickness, 4 mm; interslice gap, 25%; slice number, 20; and number of TABLE 1: Age Distributions and Testicular Apparent Diffusion Coefficient (ADC) Values of Groups 1, 2, and 3 Group 1 (n = 31 Testes) Group 2 (n = 19 Testes) Group 3 (n = 25 Patients) p a Characteristic Age (y) Mean ± SD ± ± ± 6.36 Testicular ADC value ( 10 3 s/mm 2 ) Mean ± SD ± ± ± Comparison Group 1 vs 2 Group 1 vs 3 Group 2 vs 3 < a b < b < b Note Group 1 = testicles ipsilateral to varicocele or varicoceles, group 2 = testicles contralateral to varicocele or varicoceles, and group 3 = healthy volunteer control subjects. a p < 0.05 was considered statistically significant (one-way analysis of variance). b p < 0.05 was considered statistically significant (one-way analysis of variance with a post hoc Bonferroni test). B AJR:202, February

3 Karakas et al. signals acquired, 4. The high b value (b = s/ mm 2 ) was preferred to avoid the perfusion effects of the low b values [21]. The DWI data were transferred to a workstation (Leonardo Console, Siemens Healthcare), and ADC maps of the images were automatically generated. Circular regions of interest (ROIs) were used for quantitative analysis of the ADC values of the testicular parenchyma (Fig. 1). Images were taken distal from the parenchymal areas at least 5 mm away from the capsule to avoid artifacts. The measured ROI area was set at approximately 0.5 cm 2. According to these criteria, three measurements were made from the same level. The mean of the three ADC values was used for the evaluations. In patients with varicocele, ADC measurements of the ipsilateral and contralateral testicular parenchyma were performed separately. In healthy volunteers, bilateral testicular parenchymal measurements were performed, and the mean ADC values were calculated by averaging the bilateral testicular parenchymal ADC values. The readers were blinded to all clinical information. All DWI assessments were performed by two experienced radiologists to minimize intraobserver and interobserver variability for DWI measurements, resulting in less than 5% variability. Statistical Analysis All statistical analyses were performed using statistics software (SPSS, version 20.0, SPSS) for Microsoft Windows. Kolmogorov-Smirnov tests were used to test the normality of the data distributions. The data were normally distributed, and therefore, parametric tests were performed. The data were expressed as arithmetic means and SDs. A one-way analysis of variance with a post hoc Bonferroni test was used for normally distributed continuous data. Independent sample Student t tests were used to compare continuous variables between two groups. A Pearson correlation coefficient analysis was used to examine the association of venous diameters with mean ADC values in patients with varicocele. A two-sided p value < 0.05 was considered statistically significant. A receiver operating characteristic curve analysis was performed to investigate the efficacy of ADC values in the diagnosis of varicocele. The sensitivity, specificity, and area under the curve (AUC) were calculated for the ADC values. Cutoff values were determined to predict the diagnosis of the varicocele. Results The age distributions and ADC values for all groups are given in Table 1. There was no statistically significant group difference in terms of age (p = 0.165). A statistically significant difference was observed among groups in terms of ADC values (p < 0.001). The ADC values of group 1 were lower than those of Fig. 2 Box plots depict testicular apparent diffusion coefficient (ADC) values for each group. Boxes stretch from 25th to 75th percentiles. Horizontal line across each box signifies median. Vertical lines with whiskers extending below and above boxes indicate minimal and maximal values, respectively. Group 1 = testicles ipsilateral to varicocele or varicoceles, group 2 = testicles contralateral to varicocele or varicoceles, and group 3 = healthy volunteer control subjects. group 3 (p < 0.001). Moreover, the ADC values of group 2 were also reduced compared with group 3 (p < 0.001). No statistically significant differences were identified between groups 1 and 2 (p = 0.857) (Fig. 2). The venous diameters (mean ± SD) during rest for groups 1, 2, and 3 were 2.91 ± 0.59 mm, 1.22 ± 0.29 mm, and 0.90 ± 0.36 mm, respectively. The venous diameters during the Valsalva maneuver for groups 1, 2, and 3 were 3.30 ± 0.65 mm, 1.35 ± 0.29 mm, and 1.00 ± 0.35 mm, respectively. The venous diameters of group 1 during rest and the Valsalva maneuver were higher than those of groups 2 and 3 (all p < 0.001). Although the venous diameters of group 2 were elevated compared with those of group 3, there were no statistically significant differences (p = and p = 0.077, respectively). The AUCs, cutoff ADC values, sensitivities, and specificities for the mean testicular ADC values are given in Table 2. In patients with varicocele, the mean ADC values were significantly negatively correlated with larger venous diameters during rest p = p < Group 1 Group 2 Group 3 (Pearson correlation coefficient = 0.541, p < 0.001) (Fig. 3A) and during the Valsalva maneuver (Pearson correlation coefficient = 0.550, p < 0.001) (Fig. 3B). Linear regression analysis revealed that venous diameters during rest and the Valsalva maneuver were independent predictors of the mean ADC values (rest: R 2 = 0.292, β coefficient = 0.541, p < 0.001; Valsalva maneuver: R 2 = 0.303, β coefficient = 0.550, p < 0.001). Discussion To our knowledge, this article is the first report to evaluate the ADC values of the testicles in patients with varicocele. The main findings of this study were as follows: First, the mean ADC values significantly differed between patients with varicocele and healthy volunteers; second, the mean ADC values of the contralateral testicular parenchyma of patients with varicocele were significantly lower than those of healthy volunteers; and, third, as venous diameters increased, the mean ADC values decreased. TABLE 2: Area Under the Curve (AUC), Cutoff Value, Sensitivity, and Specificity of the Testicular Apparent Diffusion Coefficient (ADC) Values Performance Value Group 1 (n = 31 Testes) Group 2 (n = 19 Testes) AUC Cutoff ADC value ( 10 3 s/mm 2 ) Sensitivity (%) Specificity (%) Note Group 1 = testicles ipsilateral to varicocele or varicoceles, group 2 = testicles contralateral to varicocele or varicoceles. 326 AJR:202, February 2014

4 DWI of the Testes in Patients With Varicocele Pearson correlation coefficient = 0.541, p < Pearson correlation coefficient = 0.550, p < Venous Diameter During Rest DWI is one of the latest technologies to provide unique quantitative information about tissue integrity [22]. When diffusion is restricted, ADC values decrease. As a result, inflammation, trauma, ischemia, tumor, and fibrosis decrease ADC values [15, 17, 18]. In patients with varicocele, dysfunction of the valves of the internal spermatic vein increases the pressure up to eightfold higher than physiologic levels, inducing hypoxia and oxidative stress in the testicles [23]. Consequently, depressed spermatogenesis, thickening of the tubular basement membrane and interstitial blood vessel wall, and increased interstitial fibrosis develop in the testicles [5 7]. Kangasniemi et al. [13] reported that ADC values are 18% and 20% lower in ischemic testes than in control testes at the first and second hours of observation, respectively. Maki et al. [14] reported that diagnostic-quality DW images can be obtained in 82% of patients with testicular torsion. In testicular torsion, the mean ADC value of affected testes is significantly lower than that of unaffected testes. In a study by Gulum et al. [15], the ADC values of the testes with hydrocele were changed significantly before surgery and 3 months after hydrocelectomy and there was a significant negative correlation between the testicular ADC values and the amount of liquid used. Gulum et al. also reported decreased testicular ADC values in patients with hydrocele. Ischemic and fibrotic processes can be related to increased pressure and liquid, and testicular fibrosis has been shown through a histopathologic assessment of the testicles in patients with varicocele [5 7] Venous Diameter During Valsalva Maneuver Fig. 3 Relationship between changes in testicular apparent diffusion coefficient (ADC) values and venous diameters in patients with varicocele. A and B, Scatterplots depict relationship between changes in testicular ADC values and venous diameters during rest (A) and during Valsalva maneuver (B). A In the current study, the ADC values of the ipsilateral testicular parenchyma of the patients with varicocele (group 1) were lower than those of healthy volunteers. Moreover, the ADC values of the contralateral testicular parenchyma of patients with varicocele (group 2) were also reduced compared with those of healthy volunteers. The sensitivity and specificity of ADC values for groups 1 and 2 were high, and the mean ADC values were significantly negatively correlated with venous diameter. According to these findings, the decreased ADC values of the ipsilateral testicles may have been related to hypoxic and fibrotic changes, similar to the findings of previous studies. Decreased ADC values in the contralateral testicles may also be explained by hormonal and autoimmune factors and heat stress [24 28]. Some experimental studies regarding the effect of temperature on the testes have found that a left varicocele bilaterally increases testicular temperature, which reasonably explains how the unilateral lesion causes bilateral testicular damage [26 28]. The most important limitation of this study was the absence of the reference standard histopathologic diagnosis. The other limitation is that the specificity was relatively high in this study because other causes of testicular fibrosis were excluded in the patient selection process. In conclusion, ADC values are a promising parameter in the detection of testicular fibrosis in patients with varicocele. Testicular ADC values may be an indicator of testicular fibrosis. Based on the results of our study, DWI may be used increasingly in the future for the early detection of testicular damage due to varicocele and for the determination of the degree of testicular damage. Moreover, the effectiveness of treatments can be evaluated by ADC measurements during the postoperative period. References 1. Nöske HD, Weidner W. Varicocele: a historical perspective. World J Urol 1999; 17: Meacham RB, Townsend RR, Rademacher D, Drose JA. The incidence of varicoceles in the general population when evaluated by physical examination, gray scale sonography and color Doppler sonography. 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