Testicular Microlithiasis

Transcription

1 Article Testicular Microlithiasis Our Experience of 10 Years Diana L. Lam, BS, Eugenio O. Gerscovich, MD, Michael C. Kuo, MD, John P. McGahan, MD Objective. Testicular microlithiasis (TM) is characterized on sonography by multiple microprecipitates in the testes. The correlation between TM and testicular malignancies is variable. The purpose of this study was to review our 10-year experience regarding the prevalence of TM and its association with testicular malignancies. Methods. This was a retrospective study in which 3254 testicular sonographic examinations over a 10-year period identified 137 patients with TM. Testicular microlithiasis was divided into 2 groups: classic TM (CTM; 5 calcifications per image) and limited TM (<5 calcifications/image). A control population without TM was also randomly selected during the same period. Associations with testicular cancers and other findings were then noted and compared between the TM and control groups. Results. One hundred thirty-seven (4.6%) of the 2957 individual patients with scrotal sonographic examinations had TM; 8 (5.8%) of the 137 patients with TM had testicular cancer, whereas 1 (0.73%) of the 137 patients without TM had primary testicular cancer (P =.04). There were 9 testicular neoplasms in 8 patients, all of whom had CTM. Thirty patients with TM and no malignancy were followed for an average of 19 months (range, 1 90 months; SD, 19.7 months); none had tumor development. Conclusions. We found a strong association between TM and testicular malignancy. We think that the most prudent use of resources for early detection of malignancy would be to have all patients with CTM perform testicular self-examinations, and follow-up sonography should be limited to a subgroup of patients with CTM and other associated risk factors. Key words: cancer; microlithiasis; sonography; testis. Abbreviations CTM, classic testicular microlithiasis; LTM, limited testicular microlithiasis; TM, testicular microlithiasis Received February 12, 2007, from the University of California, Davis School of Medicine, Sacramento, California USA (D.L.L.); and Department of Radiology, University of California, Davis Medical Center, Sacramento, California USA (E.O.G., M.C.K., J.P.M.). Revision requested February 27, Revised manuscript accepted for publication March 26, We thank Saul Schaefer, MD, and the Predoctoral Research Fellowship Program for project funding, Judy Li for helping with statistics, John Brock for coordinating Institutional Review Board approval, Scott Foster for helping gather data, and Angela Michelier for help in manuscript preparation. Address correspondence and reprint requests to Eugenio O. Gerscovich, MD, Department of Radiology, University of California, Davis Medical Center, 4860 Y St, Suite 3100, Sacramento, CA USA. eugenio.gerscovich@ucdmc.ucdavis.edu Testicular microlithiasis (TM) is an uncommon condition characterized on sonography by multiple microprecipitates, with prevalence reported in the range of 0.6% to 9%. It is usually an incidental finding with no clinical symptoms of its own. 1 3 The criteria for diagnosing TM vary among different authors. Currently, the most commonly used criterion is having 5 or more echogenic foci on at least 1 sonographic image of a testicle (classic microlithiasis), although this definition may be somewhat arbitrary. 4 The recognition of TM has increased over the past few years, probably in part because of advances in technology such as the use of higher-frequency (7 14 MHz) ultrasound transducers and an increased awareness of the condition. 5 The prevalence of TM within the general population also varies because of the above-described technical factors and a diverse study population. Testicular microcalcifications are idiopathic; most of the time, however, they may be associated with cryptorchidism, Klinefelter syndrome, Down syndrome, varicocele, testicular torsion, and male pseudohermaphroditism by the American Institute of Ultrasound in Medicine J Ultrasound Med 2007; 26: /07/$3.50

2 Testicular Microlithiasis Currently, there are different opinions as to the clinical importance of TM in association with testicular malignancy. A prospective study by Peterson et al 6 concluded that the prevalence of TM was about 5% in asymptomatic young men, and it had no relationship with testicular cancer. A study by Ringdahl et al 7 indicated that the prevalence of testicular cancer in men with scrotal symptoms and TM was 8% versus 2% in patients without symptoms. Whether the presence of TM increases the risk for development of testicular malignancies is still inconclusive; however, there is a general consensus that there is an increased prevalence of testicular tumors in patients with TM. 8 The aim of our study was to review our own data regarding the prevalence of TM and its association with testicular malignancies in our patient population. Materials and Methods This was an Institutional Review Board approved retrospective study partially funded by the Predoctoral Research Fellowship Program at University of California, Davis Medical Center. Patients with the diagnosis of TM by sonography were reviewed for a 10-year period. The number of patients who underwent scrotal sonography between January 1, 1996, and December 31, 2005, was identified. From these patients, we searched for the complete key words testicular microlithiasis, microcalcifications of the testes, and calcifications to identify patients who may have had TM. The records of each patient were reviewed to determine the presence of TM, and, if present, we looked at relevant clinical notes such as cryptorchidism or infertility, indication for examination, age, pathologic reports (of testicular malignancies), and follow-up. Patients with TM were divided into 2 groups: classic TM (CTM; Figure 1) and limited TM (LTM; Figure 2) depending on the number of echogenic foci per image. Testes with 5 or more echogenic foci on a single image were placed in the CTM category, whereas testes with fewer than 5 echogenic foci were placed in the LTM category. The echogenic foci must have been within the testicles and less than 1 mm to be considered. The sonographic images were only reviewed for patients who had indeterminate reports as to the presence or absence of TM and for patients in whom a testicular tumor was reported. Some patients had more than 1 sonographic examination. We analyzed individual testes in each patient for the presence of microlithiasis. Therefore, a patient with positive findings may have had microlithiasis in 1 testis or both testes. The mean follow-up was determined for these patients by rounding up to the nearest month. A separate control group (patients without TM) of 137 patients was also randomly selected from patients who underwent scrotal sonography during the same time period as the study (January 1, 1996, to December 31, 2005). No other selection criteria were used. The Fisher exact test was applied to test for statistical significance between the number of patients with a primary testicular neoplasm with TM and those without TM. P <.05 was considered to indicate a statistically significant difference. A review of the studies with positive findings for TM regarding reviewer experience and dates of interpretation was also performed. Results There were a total of 3254 scrotal sonographic examinations performed at our institution over the 10-year period. Among the 2957 individual patients who underwent scrotal sonography, TM was diagnosed in 219 of the 274 testes in 137 (4.6%) patients. Of the 219 testes, 139 (63.5%) were characterized as CTM, and 80 (36.5%) were characterized as LTM (Table 1). Three patients had CTM in 1 testis and LTM in the other. These were counted as separate testes. The mean age at presentation was 32 years (range, 14 days 75 years; SD, 14 years). Although there were a variety of indications for testicular sonography (Table 2), the most common indications were pain and a mass, consistent with 2 of the most common indications for scrotal sonography. Note that some patients had more than 1 indication. One hundred thirty-seven patients who had scrotal sonography and no microlithiasis served as a control group. The mean age of this group was 40 years (range, 1 day 89 years; SD, 19 years). The 3 top indications for scrotal sonography in this group were pain (n = 42), swelling (n = 27), and a mass (n = 25). The Fisher exact test was 868 J Ultrasound Med 2007; 26:

3 Lam et al used to compare the CTM group with the control group, and CTM was found to have a significant correlation with malignancy (P =.04). However, there was no statistical difference between the LTM group and the control group (P =.50). Testicular Malignancies Without TM Of the 137 patients in the control group without TM, only 2 (1.46%) had testicular neoplasms, but only 1 (0.73%) had a primary testicular neoplasm: anaplastic seminoma. The other patient had testicular invasion from acute leukemia. Testicular Malignancies With TM Eight (5.8%) of the 137 patients with TM were identified at the time of testicular sonography as having an associated primary testicular malignancy (Table 1 and Figure 3). The mean age of these patients at presentation was 28 years (range, years; SD, 5 years). All 8 patients with testicular malignancies had CTM (Table 3). There were 9 testicular tumors in 8 patients. This included 3 with bilateral CTM, 3 with unilateral CTM and ipsilateral malignancy, and 2 with unilateral CTM and malignancy in the contralateral testis. In the latter 2 patients, their testicular tumors were large (12 and 17 cm, respectively) and replaced the entire testicle. One patient with bilateral CTM had bilateral malignancies. The most common tumor was seminoma (n = 4), followed by mixed germ cell tumors (n = 3), and choriocarcinoma (n = 1). One patient had a seminoma within his right testicle, and his left testicle was later removed for intratubular germ cell neoplasia. This finding was already seen on the original sonographic examination. Five of the 8 patients had risk factors for development of testicular cancer. Two patients had atrophy of the testis containing the tumor. One patient had a history of contralateral testicular cancer. One patient had a history of cryptorchidism. One patient had a history of both cryptorchidism and infertility. One patient with bilateral CTM had bilateral testicular malignancies in the form of seminoma and intratubular germ cell neoplasia. Six of the 8 patients had no evidence of recurrence after an average of 47 months of follow-up (range, months; SD, 20 months). The other 2 were lost to follow-up within 3 months of the original US findings. Figure 1. Testis with CTM in a 36-year-old patient with a history of left scrotal pain. Testicular Microlithiasis and Follow-up A small subset of 30 patients with 49 testes with TM had subsequent sonographic examinations with an average follow-up time of 19 months (range, 1 90 months; SD, 19.7 months). Of the 49 testes followed, 55% were characterized as CTM, and 45% were characterized as LTM. One of these patients was initially discovered to have unilateral testicular cancer, and his other testicle was subsequently followed by sonography. None of our patients with TM who did not have testicular cancer at the time of presentation had development of testicular malignancies during our follow-up. However, we had 1 patient with a history of a right mixed germ cell tumor that presented with a seminoma along with TM on his left testicle. Figure 2. Testis with LTM in a 35-year-old patient with a history of scrotal swelling. Arrows indicate microliths; and calipers, testis. J Ultrasound Med 2007; 26:

4 Testicular Microlithiasis Table 1. Summary of Data Total scrotal sonographic examinations performed 3254 Total patients who had scrotal sonography 2957 Incidence of patients with TM (10 y), % (n) 4.6 (137) Incidence of patients with cancer and TM, % (n) 5.8 (8) Average age of detected TM, y (SD) 32.3 (14.2) Average age of detected TM with tumors, y (SD) 27.8 y (5.1) Total testes with TM 219 Testes with CTM, n (%) 139 (63.5) Testes with LTM, n (%) 80 (36.5) Patients with tumors containing CTM, n (%) 8 (100) Patients with tumors containing LTM, n (%) 0 (0) One patient with bilateral CTM had findings very suggestive of a testicular neoplasm within the right testis that did not appreciably change over 7 months. Despite his urologist s recommendations for orchiectomy, the patient wished to be followed by sonography. Testicular Microlithiasis and Associations Associated histories of cryptorchidism, atrophy, impotence, infertility, and varicocele were noted for all of our patients with TM (Table 4). Both the isolated TM group and synchronous cancer group showed the above associations. Infertility was only seen in testicles with CTM (Table 4). Table 2. Testicular Sonographic Indications in Patients With TM* Patients With Indication Total Patients Cancer Testicular pain 62 2 Testicular mass 40 6 Scrotal swelling 23 0 Suspected torsion 12 0 History of cryptorchidism 11 2 History of testicular cancer 8 1 Suspected epididymitis/orchitis 6 0 Suspected varicocele 6 0 Testicular atrophy 4 2 Testicular enlargement 4 0 Infertility 3 1 History of TM 3 0 Impotence 2 0 Suspected abscess 2 0 Twin brother with testicular cancer 1 0 Preoperative for hernia repair 1 0 *Some patients had more than 1 indication. Testicular Microlithiasis and Reviewer Experience We reviewed 169 studies with positive findings for TM with regard to the interpreter and date of interpretation. These studies were read by multiple radiologists who had postresidency and fellowship experience ranging from 1 year to decades. Some radiologists interpreted only 1 study. Others interpreted multiple studies, up to 42 (25%) of 169, including one of the authors of this report (E.O.G.). One hundred thirty-one (78%) of the 169 studies were interpreted after the year 2000, whereas 38 (22%) of 169 were interpreted before. Discussion To our knowledge, a review of the literature fails to document a conclusive relationship between TM and the risk of testicular malignancy development, although there is an increase in the prevalence of testicular tumors in patients with TM. The prevalence of TM (4.6%) in our study falls within the range of previous studies (0.6%- 9%); however, it is interesting to note that our population consisted of symptomatic men with conditions not related to TM (Table 2), whereas in a study by Peterson et al, 6 patients with TM (5%) who underwent routine military physical examinations were asymptomatic. Eight (5.8%) of our 137 patients with TM had a primary testicular malignancy at the time of the first sonographic examination. Only 1 (0.7%) of the 137 patients without TM had a primary testicular malignancy (P =.04). This suggests a strong association between TM and testicular malignancies. Five of the 8 patients with TM who had testicular malignancies at the time of sonography already had other risk factors for developing testicular cancer, such as a contralateral testicular tumor, testicular atrophy, and cryptorchidism. From our study, we cannot determine whether TM independently increases the risk of development of a testicular malignancy because with our mean follow-up of 19 months (range, 1 90 months), we did not see development of testicular malignancies in our patients with TM. The patient who had a history of a right mixed germ cell tumor and had left testicular TM and a seminoma could have had bilateral TM before the seminoma developed; therefore, he could be seen as having development of a malig- 870 J Ultrasound Med 2007; 26:

5 Lam et al nancy in a testicle with TM. However, he already had a risk factor for development of testicular cancer in the form of a contralateral tumor. All 8 patients with testicular malignancies had CTM as opposed to LTM (Table 3), which indicates that in our population, testicular malignancies were only associated with CTM and not LTM. Two of the patients had the CTM in the contralateral testis, whereas TM was not noted in the testis containing the malignancy. In a review of these 2 cases, the malignancy completely replaced the affected testis. Therefore, it is possible that microlithiasis occurred in the affected testis, but the large tumor replaced visualization of the microlithiasis. As noted in the literature, because the clinical importance of TM is still in debate, the follow-up for patients with TM independent of other testicular findings still needs to be determined. Figure 3. Seminoma in a testis with CTM in patient 7 of Table 3. Arrow indicates the area of microlithiasis; and calipers, seminoma. Table 3. Cases of Synchronous TM and Tumors Follow-up Since First Age, Clinical Risk CTM/ Sonographic Patient y Race Presentation Factors LTM Pathologic Findings Treatment Examination 1 33 White Right scrotal None CTM on Right choriocarcinoma, Right orchiectomy, No recurrence mass known left* 12 cm, 1.07 kg chemotherapy at 44 mo 2 22 White Left testicular None CTM on Left mixed nonsemino- Left radical orchiectomy, No records at mass known right* matous germ cell tumor, chemotherapy our institution 17 cm, 1.16 kg after 3 mo 3 19 Hispanic Left testicular None CTM on Left mixed seminomatous Left radical orchiectomy, No recurrence mass known left, LTM and nonseminomatous chemotherapy at 22 mo on right germ cell tumor 4 30 Un- Right testicular Right testi- CTM Right seminoma Right orchiectomy, radiation No recurrence known pain cular bilaterally therapy at 71 mo atrophy 5 28 White Left testicular Right testi- CTM on Right mixed germ cell Right orchiectomy, chemo- No recurrence pain cular right tumor therapy with autologous at 40 mo atrophy bone marrow transplant 6 28 White Left testicular Prior right CTM on Left seminoma Left testicular mass partial No records at mass orchiec- left, patient orchiectomy with bilateral our institution tomy for with only nerve-sparing surgery, after 2 mo mixed germ 1 testis chemotherapy, radiation cell tumor therapy 7 34 Un- Right testicular Bilateral CTM Right seminoma, left Right radical orchiectomy, No recurrence known mass cryptorchid- bilaterally intratubular germ left orchiectomy, chemo- at 70 mo ism, left cell neoplasia therapy testicular atrophy 8 28 Un- Right testicular Crypto- CTM Right seminoma Right radical orchiectomy, No recurrence known mass rchidism bilaterally radiation therapy at 34 mo (unknown side), infertility *No TM identified on the contralateral side with malignancy. J Ultrasound Med 2007; 26:

6 Testicular Microlithiasis Table 4. Patients With TM and Associated Findings Isolated TM Cancer and TM, Finding CTM LTM Subtotal CTM only Total Testicular atrophy 0.5* 1.5* Cryptorchidism Impotence Infertility Varicocele 19.5* 11.5* *0.5 was used when a patient had CTM in 1 testis and LTM in the other. Current recommendations for patients with TM vary from no follow-up to complete follow-up with almost full-body CT scans, depending on the patient population as well as the provider. 8 Some authors suggest annual clinical examinations with sonographic follow-up, whereas others suggest annual follow-up physical examinations with no sonography. Most encourage periodic self-examinations. 9,10 A review article by Kim et al 11 described a high association between the incidence of TM and testicular germ cell tumors and advocated a long-term study on patients with TM to establish a protocol for follow-up. A recent article by Ravichandran et al 12 concluded that most consulting urologists in the United Kingdom thought that surveillance of patients with TM had no survival benefit. To our knowledge, there are currently no published studies that have followed patients with TM for more than a 45-month mean period. 8 We did not find development of testicular malignancies during our mean of 19 months (range, 1 90 months) on follow-up of patients with TM. The follow-up for patients with TM at our institution was also fairly inconsistent, despite radiologists recommendations, in that most patients who had follow-up sonography did so for reasons unrelated to TM. Only a few patients were specifically followed because of TM only. Because this was a retrospective series, we can only conclude that there is a strong association between TM and testicular neoplasms; we cannot assess whether TM is a cause or risk factor for development of testicular neoplasms or whether TM occurs more frequently in men with testicular tumors. A prospective study must be done with a long-term follow-up period to assess those measures. Given the current literature and our data, it may be difficult to give an exact recommendation regarding follow-up examinations in patients with TM. Our study and studies by others show that CTM is associated with an increased prevalence of testicular malignancy. However, would sonographic follow-up of patients with CTM in fact reduce morbidity or mortality in this group? This is dependent on several factors, such as the lead time between detection of testicular malignancies in patients with CTM and when it would have been diagnosed because of symptoms such as a palpable mass. In addition, would early detection in fact increase survival in this group? The same debate has occurred with mammographic detection of breast cancer for years. It would seem from one conclusion that woman ages years whose invasive carcinoma is detected by mammography have significantly smaller tumors, more localized diseases, and may have a lower risk of mortality than women whose tumors are detected by other methods. 13 However, the same may not hold true for early detection of testicular cancer by sonography in patients with CTM. This is because, first, the disease, such as seminoma, is most often curable (90% cure rate for all stages combined) even when clinically evident. 14 Second, it is unknown whether sonography will show testicular malignancies earlier than self-examination, so as to limit the extent of disease and decrease mortality. Neither of these questions can be answered with certainty in our study or other studies because of the low prevalence of TM and limited follow-up. Third, is CTM in itself an independent risk factor for disease? For instance, in our study, CTM was almost always associated with an independent risk factor, such as cryptorchidism. It may be that both CTM and malignancy are results of cryptorchidism. However, in 3 of our patients, there were no known associated risk factors. Finally, the true cost of a sonographic screening program, in terms of the number of lives saved, cannot be estimated with the current limited number of patients. We think that the most prudent approach would be to instruct patients with microlithiasis to perform testicular self-examinations. This is a no- or low-cost program that may be effective in earlier detection of testicular malignancy. Next, patients with inde- 872 J Ultrasound Med 2007; 26:

7 Lam et al pendent risk factors such as cryptorchidism and CTM might be considered for follow-up sonographic examinations. Currently, we have no statistical proof that such a program will improve survival and cannot make an exact recommendation on the frequency of these sonographic examinations (eg, 3 months, 6 months, or yearly). This higher risk-group may benefit most by sonographic screening. In summary, we conclude that CTM is associated with testicular malignancy. We think that all patients with CTM should be instructed in testicular self-examination as a potential low-cost procedure for detecting testicular neoplasms. We also think that limiting follow-up sonography to a subgroup of patients with CTM and other risk factors would be the most prudent use of resources for early detection of malignancy. Our data should be added to those of the existing literature. 10. Skyrme RJ, Fenn NJ, Jones AR, Bowsher WG. Testicular microlithiasis in a UK population: its incidence, associations and follow-up. BJU Int 2000; 86: Kim B, Winter TC, Ryu J. Testicular microlithiasis: clinical significance and review of the literature. Eur Radiol 2003; 13: Ravichandran S, Smith R, Cornford PA, Fordham MV. Surveillance of testicular microlithiasis? Results of an UK based national questionnaire survey. BMC Urol 2006; 6: McPherson CP, Swenson KK, Jolitz G, Murray CL. Survival of woman ages years with breast carcinoma according to method of detection. Cancer 1997; 79: Gori S, Porrozzi S, Roila F, Gatta G, De Giorgi U, Marangolo M. Germ cell tumours of the testis. Crit Rev Oncol Hematol 2005; 53: References 1. Miller FN, Sidhu PS. Does testicular microlithiasis matter? A review. Clin Radiol 2002; 57: Hobarth K, Susani M, Szabo N, Kratzik C. Incidence of testicular microlithiasis. Urology 1992; 40: Bach AM, Hann LE, Hadar O, et al. Testicular microlithaisis: what is its association with testicular cancer? Radiology 2001; 220: Bennett HF, Middleton WD, Bullock AD, Teefey SA. Testicular microlithiasis: US follow-up. Radiology 2001; 218: Middleton W, Teefey S, Santillan C. Testicular microlithiasis: prospective analysis of prevalence and associated tumor. Radiology 2002; 224: Peterson AC, Bauman JM, Light DE, McMann LP, Costabile RA. The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2001; 166: Ringdahl E, Claybrook K, Teague L, Northrup M. Testicular microlithiasis and its relation to testicular cancer on ultrasound findings of symptomatic men. J Urol 2004; 172: Rashid HH, Cos LF, Weinberg E, Messing EM. Testicular microlithiasis: a review and its association with testicular cancer. Urol Oncol 2004; 22: Cast JE, Nelson WM, Early AS, et al. Testicular microlithiasis: prevalence and tumor risk in a population referred for scrotal sonography. AJR Am J Roentgenol 2000; 175: J Ultrasound Med 2007; 26: