Sonographic Quantitative Evaluation of Scrotal Veins in Healthy Subjects: Normative Values and Implications for the Diagnosis of Varicocele

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1 european urology 50 (2006) available at journal homepage: Andrology Sonographic Quantitative Evaluation of Scrotal Veins in Healthy Subjects: Normative Values and Implications for the Diagnosis of Varicocele Alessandro Cina a, *, Marco Minnetti b, Tommaso Pirronti a, Maria Vittoria Spampinato a, Adolfo Canadè a, Giulio Oliva c, Domenico Ribatti c, Lorenzo Bonomo a a Department of Radiology, Agostino Gemelli Hospital, Catholic University, Rome, Italy b Department of Radiology, San Giovanni-Addolorata Hospital, Rome, Italy c Health Service, Carabinieri Army, Italy Article info Article history: Accepted February 21, 2006 Published online ahead of print on March Keywords: Color-Doppler ultrasonography Normative study Scrotal varicocele Sonography Abstract Objectives: To define the normative values of scrotal vein diameters, investigate the eventual presence and characteristics of scrotal reflux in healthy subjects, and describe its implication for the diagnosis of scrotal varicocele. Methods: Color-Doppler ultrasonography was performed on a population of 145 healthy, symptomless subjects, with clinical examinations and semen analyses within normal limits. Results: The upper limit of the scrotal veins diameter ( mm) exceeds values presently employed for a diagnosis of varicocele. Furthermore, a high percentage of healthy subjects (53%) were found to have reflux in the scrotal veins, currently considered one of the criteria for diagnosing varicocele, especially in its subclinical form. Conclusions: To reduce the risk of misinterpretations between the various specialists involved in Color-Doppler ultrasonography and urologists, quantitative data of the scrotal veins (i.e., maximum diameter and the presence, velocity, and duration of reflux) should be described in reports of sonographic examinations performed for scrotal varicocele. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Radiology, Università Cattolica del Sacro Cuore, Policlinico Agostino Gemelli, 1 L.go A gemelli 1, Rome, Italy. Tel ; Fax: address: alescina@tin.it (A. Cina). 1. Introduction Idiopathic scrotal varicocele (SV), not related to the presence of a mass or to mechanic venous obstruction, is a physical abnormality affecting 15% of the general population [1] and is especially common among teenagers and young adults. The clinical relevance of SV is based on its symptoms being /$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 346 european urology 50 (2006) related to scrotal venous stasis and the potential association with male infertility. Incidence of SV is higher (25 40%) in men of infertile partnership with abnormal semen analysis. According to the EAU Working Group on Male Infertility, The exact association between reduced male fertility and varicocele is unknown, but analysis of WHO data [2] clearly indicates that varicocele is related to semen abnormalities, decreased testicular volume and decline in Leydig cell function. Treatment of varicocele to achieve pregnancy in infertile partnerships remains controversial and all investigations to date have been subject to criticism. Current information supports the hypothesis that in some men the presence of varicocele is associated with progressive testicular damage from adolescence onwards and consequent reduction in fertility. While treatment of varicocele in adolescents may be effective, there is a significant risk of overtreatment [3]. Although phlebography is still the gold standard, color-doppler ultrasonography (CDUS) plays a crucial role in the diagnostic workup of SV because of its low costs, widespread availability, and noninvasiveness. Moreover CDUS is well suited and widely employed for the study of various other pathologic conditions of the scrotum in children and adults [4]. The classic sonographic appearance of SV consists of dilated veins in the pampiniform plexus and around the testis, with evidence of a retrograde venous flow during respiratory cycles or Valsalva s maneuver at the pulsed-wave and CDUS sampling. Several authors have examined groups of patients with a diagnosis of SV to establish qualitative and quantitative CDUS criteria (Table 1) [5 12]. However, the present diagnostic criteria are surprisingly heterogeneous and poorly defined from a quantitative point of view. Current indications for scrotal CDUS are clinical suspicion of VS and investigation of subclinical forms of SV in cases of male infertility. Subclinical varicocele was defined in the late 1970s as a scrotal venous reflux without any palpable distension of the pampiniform plexus [13]. A few studies have shown that the outcome (measured as number of pregnancies) of subfertile men treated for varicocele has no relation to the degree of this condition [14], and the results between patients with clinical and subclinical varicocele are not different [15]; therefore, some authors suggested that infertile men with subclinical varicocele should be treated. At present, attitudes toward the treatment of subclinical varicocele are more conservative, but the matter is still open to debate and welldesigned studies are needed. Because objective diagnostic tests to detect varicocele must be used in future studies, the assessment of normative values for scrotal sonography and quantitative criteria for a diagnosis of varicocele are needed. In addition, until now there have been few studies [16] on the presence of reflux in normal fertile subjects, and quantitative criteria to define scrotal reflux as pathological have not been defined in the literature. The purpose of this paper was to define the normative values of scrotal vein diameters, investigate the eventual presence and characteristics of scrotal reflux in healthy subjects, and describe its implication for the diagnosis of SV. Table 1 Summary of proposed values for scrotal vein diameter at sonography in normal subjects and patient with clinical or subclinical varicocele Assessment Diameter (mm) No. of subjects Characteristics of population Reference Scrotal vein diameter in clinical varicocele Clinical varicocele [5] Normal value of scrotal vein diameter 2 10 Scrotal pathology not suspected [5] Normal value of scrotal vein diameter 2 21 Clinical varicocele [6] Scrotal vein diameter in subclinical varicocele >2 19 Abnormal semen analysis [7] Scrotal vein diameter in clinical varicocele Clinical varicocele [8] Normal value of scrotal vein diameter Minor surgical problems [8] unrelated to genital area Mean value of scrotal vein diameter Patients with suspected infertility [9] Scrotal vein diameter in subclinical and >3 56 Infertile patients [10] clinical varicocele Cutoff for diagnosis of clinical (1) and 3.6 (1) 168 Patients with suspected infertility [11] subclinical (2) varicocele 2.7 (2) Mean value of normal scrotal vein diameter Patients with suspected infertility [11] Cutoff for palpable internal spermatic vein 3 78 Infertile patients [12] Cutoff for internal spermatic vein reflux 3.5 Infertile patients [12]

3 european urology 50 (2006) Materials and methods After approval of the institutional review board, we recruited 210 healthy volunteer soldiers (mean age 23 yr, range 19 29). All subjects gave their written informed consent and underwent clinical interviews, clinical examinations, and semen analyses. Semen analyses (n = 210) were performed in the same laboratory, up to 2 weeks before CDUS, after a sexual abstinence of at least 3 d. Samples were considered normal if the volume ranged between 2 and 6 cc, sperm count was between 20 and 110 million/cc, percentage of normal cells was >30%, and percentage of motile cells after 2 h was 45 75% and after 6 h 18 30%. Sixty-five subjects were excluded due to previous scrotal surgical procedures (n = 4), history or clinical examination that suggested SV (n = 11), previous genital-urinary infections (n = 15), family history of symptomatic SV (n =20),orabnormal semen analysis (n = 15 ). A total of 145 subjects were admitted to the study and underwent CDUS. All the tests were performed by the same physician (A.C.) using the same equipment (7.5 Mhz electronic linear probe, SSH 140, Toshiba, Tokyo, Japan) and a standard technique, both in clinostatism and in orthostatism. We evaluated bilaterally the maximal diameter of the venous vessels in the scrotal sac and spermatic cord and the presence of a retrograde venous flow during Valsalva s maneuver. We recorded the duration and maximal velocity of the retrograde venous flow. The maximal diameter of peri- and supratesticular veins was recorded in the orthostatic position during inspiratory apnea by measuring the distance between the internal walls of the vessels on an axial projection. For each patient, the maximal diameter of the three largest peri- and supratesticular veins visible in each field of view was averaged. Retrograde venous flow was first investigated by CDUS during Valsalva s maneuver, then by sampling the veins where flow inversion was identified by PW Doppler, with the angle of incidence of the ultrasound beam set to <608. When no retrograde venous flow was found by CDUS, the PW Doppler sampling was performed on the largest veins found. Quantitative ultrasound measures were correlated to height, weight, and body mass index (BMI). BMI was calculated as BMI = weight (kg)/height 2 (m). A follow-up control at mo confirmed that the history and clinical examinations were negative in 143 subjects; the remaining two subjects were lost at follow-up. Because our data showed a distribution assimilable to a normal distribution, results are reported as mean and standard deviation. Pearson s correlation coefficient was used to examine correlations between variables of interest. Unpaired Student s t-tests were employed to assess differences between population variables. Fig. 1 Box plot of diameters of peritesticular and spermatic cord veins in a population of healthy subjects (n = 145), the currently proposed normative values (dotted lines), and values employed for sonographic diagnosis of varicocele (dashed lines). Box-plot error bars represent 97th percentiles. (+) median; ( ) inner fence; ( * ) outliers; (*) far outlier. (n = 35) of which in both supra- and peritesticular veins, 23.4% (n = 34) in supratesticular veins only, and 5.5% (n = 8) in peritesticular veins only. The mean duration of the retrograde venous flow in spermatic cord veins was s and the peak velocity was m/s, whereas the mean duration of the venous reflux in peritesticular vessels was s and the peak velocity was m/s. In our population we did not find spontaneous blood flow directed to the testicles and augmenting with an intra-abdominal pressure increase [17]. No significant correlation was found between weight, height, or BMI and spermatic cord venous diameters (R = 0.11, R = 0.16, R = 0.1, respectively; P > 0.05) or peritesticular diameter (R = 0.42, R = 0.01, R = 0.04, respectively; P > 0.05). No statistically significant differences in the diameters of supra- and peritesticular veins were observed between subjects with and without reflux (P = 0.42 and 0.26, respectively). In the subjects selected for the study, we analyzed possible correlations between the variables of semen analysis (concentration, motility, and morphology; Table 2) and CDUS examination (venous 3. Results The mean diameter of the spermatic cord veins was mm, the mean diameter of the peritesticular veins was mm, and the 97th percentiles were 3.8 and 3.7 mm, respectively (Fig. 1). A retrograde venous flow during Valsalva s maneuver was observed in 53% (n = 77) of subjects: 24.1% Table 2 Results of semen analyses in 145 healthy men Characteristic Mean standard deviation (range) Normal value by WHO criteria [22] Concentration (21 150) >20 (million/ml) Motility (%) (51 90) >50 Normal morphology (%) (64 97) >50

4 348 european urology 50 (2006) diameter, velocity and duration of reflux); no statistically significant correlations were found ( 0.52 < R < 0.57; 0.09 < P < 0.52). 4. Discussion Although there is general agreement on qualitative diagnostic criteria for SV (i.e., the dilation of the peritesticular and spermatic cord veins, which increases during Valsalva s maneuver, and evidence of retrograde venous flow at CDUS), no definitive quantitative criteria exist. Reviewing the literature, it is evident that some essential points need to be clarified, namely a definition of the limit of normality for the diameter of scrotal veins and whether the finding of scrotal retrograde venous flow should always be considered pathological. To establish quantitative diagnostic criteria, sufficiently large normative studies need to be done on carefully selected subjects. Quantitative criteria suggested by different authors (Table 1) are heterogeneous and were obtained from populations of subjects with a clinical diagnosis of SV, small samples of healthy individuals, or subjects without clinical or sonographic evidence of SV but suffering from some other scrotal disorder or infertility. Ultrasound technology has improved considerably in recent years. At present it allows the identification of minimal ectasies of the scrotal veins and minimal retrograde venous flow. The upper normal limit of scrotal vein diameter in our population, defined as the 97th percentile ( mm), is higher than most of the reported upper values for healthy subjects ( mm; Fig. 1), with the exception of the measure reported by Eskew et al. (4 mm) [11]. In this last series, however, the value of normal scrotal vein diameter was obtained from a population of patients with suspected infertility. Caskurlu et al. [18] used CDUS to analyze the diameter of the veins in the pampiniform plexus in patients with clinical or subclinical varicocele and in controls. The authors suggested that venous diameter should not be used as a diagnostic criterion in patients without clinical signs of varicocele, but rather to document and quantify pathology in patients with clinical varicocele. Reflux is an important criterion for the diagnosis of varicocele. Consistent with previous studies [17], our findings showed that a scrotal retrograde venous flow can be found in a significant percentage of healthy subjects, without any evidence of SV. Our findings are similar to those of the study by Kocakoc et al. [19], who reported a 62.3% incidence of reflux in the testicular veins with a diameter <3 mm. However, the quantitative values found by the same author in another study on healthy men [16] (diameter of testicular veins mm; duration of reflux s, velocity of reflux m/s) differed from our results. In this case, the authors considered veins >2 mm in diameter to be a varicocele and excluded subjects in this group from the analysis; moreover, unlike our study, their measures were obtained only in the supine position. A new scoring system to improve CDUS criteria to diagnose SV was proposed by Chiou et al. [20], by incorporating the maximal venous diameter, the presence of a venous plexus, the sum of diameters of veins in the plexus, and the change of flow on Valsalva s maneuver. However, the clinical impact and reproducibility of this score must still be demonstrated. An attempt to identify new criteria for the CDUS diagnosis of subclinical varicocele was performed by Mihmanli et al. [21], although these criteria have not provided new information on the diagnosis of subclinical varicocele in infertile patients. Quantitative measures of scrotal vein diameters and scrotal reflux obtained in our population of healthy subjects showed a wide overlap with the values reported in the literature and currently in use for a CDUS diagnosis of varicocele (Table 1). A scrotal diameter of up to 3.7 mm and a reflux lasting up to 3 s with a velocity of 0.1 m/s also may be observed in healthy subjects and should not be interpreted as a certain sign of SV. Physical examination alone is not a highly reliable tool in the diagnosis of varicocele, and the use of venography is inappropriate for routine screening. Moreover, a gold standard for detecting subclinical varicocele does not exist. The impact of a false-positive diagnosis at CDUS is not negligible. Because CDUS often is the only imaging technique performed before treatment, false-positive results in subjects with ambiguous histories or borderline semen analyses may be responsible for overtreatment, particularly if a careful clinical evaluation is not performed. In the case of asymptomatic subjects with normal semen analyses, in which dilated veins may be a collateral finding of a scrotal sonography performed for another purpose, false-positive CDUS may cause additional costs due to further examinations as well as needless worry. Based on previous observations and our personal experience, the clinical significance of moderately dilated veins or reflux detected by CDUS should be carefully considered. The quantitative criteria presently in use for the CDUS diagnosis of clinical and subclinical varicocele may lead to a high number of false-positive findings. Data of our study, gathered from an adult population, cannot provide conclusions or indications on the pediatric-adolescent

5 european urology 50 (2006) population. Similar studies performed in childhood and adolescence are needed to define limits of normality for this age group. To reduce the risk of misinterpretations between the various specialists involved in CDUS and urologists, quantitative data of the scrotal veins (i.e., maximum diameter and the presence, velocity, and duration of reflux) should be described in reports of sonographic examinations performed for SV. References [1] Greenberg SH. Varicocele and male fertility. Fertil Steril 1977;28: [2] World Health Organization. WHO manual for the standardised investigation and diagnosis of the infertile couple. Cambridge, UK: Cambridge University Press; [3] Dohle GR, Colpi GM, Hargreave TB, Papp GK, Jungwirth A, Weidner W, EAU Working Group on Male Infertility. EAU guidelines on male infertility. Eur Urol 2005;48: [4] Aso C, Enriquez G, Fite M, et al. Gray-scale and color Doppler sonography of scrotal disorders in children: an update. Radiographics 2005;25: [5] Wolverson MK, Houttuin E, Heiberg E, Sundaram M, Gregory J. High-resolution real-time sonography of scrotal varicocele. Am J Roentgenol 1983;141: [6] Rifkin MD, Foy PM, Kurtz AB, Pasto ME, Goldberg BB. The role of diagnostic ultrasonography in varicocele evaluation. J Ultrasound Med 1983;2: [7] Gonda Jr RL, Karo JJ, Forte RA, O Donnell KT. Diagnosis of subclinical varicocele in infertility. Am J Roentgenol 1987;148:71 5. [8] Orda R, Sayfan J, Manor H, Witz E, Sofer Y. Related Articles, Diagnosis of varicocele and postoperative evaluation using inguinal ultrasonography. Ann Surg 1987;206: [9] Nashan D, Behre HM, Grunert JH, Nieschlag E. Diagnostic value of scrotal sonography in infertile men: report on 658 cases. Andrologia 1990;22: [10] McClure RD, Khoo D, Jarvi K, Hricak H. Subclinical varicocele: the effectiveness of varicocelectomy. J Urol 1991; 145: [11] Eskew LA, Watson NE, Wolfman N, Bechtold R, Scharling E, Jarow JP. Ultrasonographic diagnosis of varicoceles. Fertil Steril 1993;60: [12] Hoekstra T, Witt MA. The correlation of internal spermatic vein palpability with ultrasonographic diameter and reversal of venous flow. J Urol 1995;153:82 4. [13] Comhaire F, Monteyne R, Kunne M. The value of scrotal thermography as compared with selective retrograde venography of the internal spermatic vein for the diagnosis of subclinical varicocele. Fertil Steril 1976;27: [14] Dubin L, Amelar RD. Varicocele size and results of varicocelectomy in selected subfertile man with varicocele. Fertil Steril 1970;21: [15] Dhabulwala CB, Hamid S, Moghissi K. Clinical versus subclinical varicocele: improvement in fertility after varicocelecomy. Fertil Steril 1992;57: [16] Kocakoc E, Kiris A, Orhan I, Bozgeyik Z, Kanbay M, Ogur E. Incidence and importance of reflux in testicular veins of healthy men evaluated with color duplex sonography. J Clin Ultrasound 2002;30: [17] Tasci AI, Resim S, Caskurlu T, Dincel C, Bayraktar Z, Gurbuz G. Color Doppler ultrasonography and spectral analysis of venous flow in diagnosis of varicocele. Eur Urol 2001;39: [18] Caskurlu T, Tasci AI, Resim S, Sahinkanat T, Ekerbicer H. Reliability of venous diameter in the diagnosis of subclinical varicocele. Urol Int 2003;71:83 6. [19] Kocakoc E, Serhatlioglu S, Kiris A, Bozgeyik Z, Ozdemir H, Bodakci MN. Color Doppler sonographic evaluation of inter-relations between diameter, reflux and flow volume of testicular veins in varicocele. Eur J Radiol 2003;47: [20] Chiou RK, Anderson JC, Wobig RK, et al. Color Doppler ultrasound criteria to diagnose varicoceles: correlation of a new scoring system with physical examination. Urology 1997;50: [21] Mihmanli I, Kurugoglu S, Cantasdemir M, Zulfikar Z, Halit Yilmaz M, Numan F. Color Doppler ultrasound in subclinical varicocele: an attempt to determine new criteria. Eur J Ultrasound 2000;12:43 8. [22] World Health Organization. Laboratory manual for the examination of human semen and semen-cervical mucus interactions. Ann Ist Super Sanita 2001;37: Editorial Comment G.R. Dohle, Department of Urology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands Varicocele is a common abnormality found in 11% of the general male population. It can be associated with impaired male infertility, scrotal pain and discomfort, testicular growth retardation and hypogonadism. However, a substantial number of men with a clinical varicocele are asymptomatic and have no fertility problems [1]. The diagnosis of varicocele largely depends on physical examination. Men with impaired fertility are often screened for the presence of a varicocele by scrotal ultrasound. However, no strict criteria for the ultrasonographic diagnosis of a varicocele are yet available and current criteria were largely determined in men with reduced fertility. In the present study the authors have investigated 145 healthy men without evidence of clinical varicocele and normal semen analysis. They conclude that the range of the scrotal diameter largely overlaps the currently employed criteria of a varicocele. Also, a reversal of blood flow in the scrotal veins was found in 53% of the men. This could mean that either the presence of a varicocele

6 350 european urology 50 (2006) is likely to be overestimated by ultrasound or that varicocele is indeed a common abnormality in both fertile and subfertile men. In the past venography of the internal spermatic vein used to be the gold standard to confirm the diagnosis, but this investigation has been abandoned because of its invasiveness. Trum et al. compared colour Doppler ultrasound of the scrotum to venography and found ultrasound to have a sensitivity of 97% and a specificity of 94% [2]. In contrast, physical examination had a specificity of only 69%. Ultrasound seems the most reliable noninvasive tool in detecting varicoceles, but we need to sharpen our current ultrasound criteria based on population studies, such as the present study. References [1] World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril 1992;57: [2] Trum JW, Gubler FM, Laan R, van der Veen F. The value of palpation, varicoscreen contact thermography and colour Doppler ultrasound in the diagnosis of varicocele. Hum Reprod 1996;11: Editorial Comment Kok Bin Lim, Gerald Brock, St Joseph Health Center, University of Western Ontario, London, Ontario limkokbin@yahoo.com.sg, gebrock@sympatico.ca Despite being generally accepted as the most common reversible cause of male factor infertility, varicoceles remain a controversial area of urology. Currently, the coexistence of an abnormal semen analysis coupled with physical findings of a varicocele is taken to be presumptive evidence of a pathological condition. A significant body of literature exists that addresses the importance of the size of the varicocele and its impact on fertility [1]. Dubin and Amelar s landmark study promoted the belief that small varicoceles had an equally adverse effect on spermatogenesis as did larger varicoceles [2]. This had led to a variety of investigations into the relationship between subclinical varicoceles and infertility. Subsequent studies demonstrated that not all subclinical varicocele repairs were associated with improved spermatogenesis [3]. Although color Doppler ultrasound can measure the size of the pampiniform plexus and spermatic vein blood flow, the reliability and predictive value remains controversial as the diagnostic criteria are poorly defined [4]. The authors of this report are to be congratulated for attempting to refine our understanding of what is normal by evaluating 145 men with normal semen analyses. While most previous reports describe an upper limit of mm, this study reports a larger upper normal limit of 3.7 mm. They have also reported that venous reflux is common even in this group of normal men, a finding supported by earlier reports [5]. Before adopting these new normative values however one must evaluate the study population and determine if it is truly a normal one. The impact of varicoceles is a progressive one and these men have unreported fertility. Additionally, have the authors selected the appropriate cut-off point that provides ideal sensitivity and compromised specificity or vice versa? Is the flow velocity used to define reflux of physiologic significance? While I understand the authors interest in informing the readership about their findings, compelling evidence adequate to refine normative values will require much larger numbers of subjects, followed longitudinally with multiple semen analyses and fertility rates. Ideally, integration of the impact of varicocelectomy or embolization on bulk sperm parameters and fertility would also be used to define normal. Until I see those data, I will continue to use my clinical examination coupled to adjunctive imaging with the older standards of normal. References [1] Hoekstra T, Witt MA. The correlation of internal spermatic vein palpability with ultrasonographic diameter and reversal of venous flow. J Urol 1995;153:82 4. [2] Dubin L, Amellar RD. Varicocele size and results in varicocelectomy in selected subfertile men with varicocele. Fertil Steril 1970;21: [3] Jarow JP, Ogle SR, Eskew LA. Seminal improvement following repair of ultrasound detected subclinical varicocele. J Urol 1996;155: [4] Kocakoc E, Kiris A, Orhan I, et al. Incidence and importance of reflux in testicular veins of healthy men evaluated with color duplex sonography. J Clin Ultrasound 2002;30: [5] Chiou RK, Anderson JC, Wobig RK, et al. Color Doppler ultrasound criteria to diagnose varicoceles: correlation of a new scoring system with physical examination. Urol 1997;50:953 6.