testicular microlithiasis ( tm ) is an uncommon pathologic condition that is commonly diagnosed by scrotal ultrasonography .
the characteristic ultrasound ( us ) appearance of tm involves multiple bright foci , 1 to 2 mm in diameter , that are limited to the testicles .
there is little or no acoustic shadowing , and microliths are either randomly distributed throughout the testicle or limited to only part of the testicle .
tm has been seen in patients with testicular malignancy or various nonmalignant entities such as cryptorchidism , varicoceles , testicular torsion , klinefelter 's syndrome , pulmonary alveolar microlithiasis , neurofibromatosis , aids , intratubular germ cell neoplasia , and most frequently , infertility .
the clinical importance of tm arises from its possible association with testicular cancer and infertility [ 3,5 - 8 ] .
priebe and garret first reported the phenomenon in 1970 , after seeing bilateral , diffuse testicular calcification on a pelvic x - ray of a 4-year - old boy . since then
, other authors have tried to link pathological findings of testicular calcification in testicular tumors and infertility to the us diagnosis of tm . despite these reports , however , the relationship between tm and testicular cancer and infertility has been largely anecdotal and without predictive value .
the lack of current proven follow - up strategies for patients with tm basically stems from ignorance of the exact prevalence of symptomatic and asymptomatic populations and ambiguity in the cause - effect relationship of tm with other potentially associated conditions .
the objectives of the present study were as follows : ( 1 ) to report the prevalence of tm in a symptomatic population from the republic of korea who were undergoing testicular ultrasonography ; ( 2 ) to identify associated pathologic entities , especially testicular cancer and infertility ; ( 3 ) to evaluate the role of further tm grading in the prevalence of associated testicular cancer ; and ( 4 ) to study the seminal profile of tm patients .
scrotal ultrasonography was done in longitudinal and transverse sections by using a scanning device with a high - frequency linear array transducer and a center frequency of 14 mhz ( siemens acuson sequoia 512 system , germany ) . in patients without infertility , the indications for us were scrotal signs and symptoms such as palpable mass , pain , and swelling .
all pathologic entities of patients who had undergone us were recorded . to identify possible associations with tm , analysis was performed by retrospective review of the medical records and us images .
we defined tm as multiple ( more than 2 ) calcifications smaller than 2 mm ( no acoustic shadowing ) inside the testicular parenchyma on us .
the presence of tm , the number of lesions , the involvement of both testicles in relation to symptoms , and the coexistence of other lesions were studied .
patients with tm were divided as follows : 3 or 4 microliths = limited ( fig .
we also recorded laterality of tm in addition to grade . in cases of testicular cancer accompanying tm ,
this analysis included sperm count , motility , morphology , and white blood cell ( wbc ) count .
categorical variables were compared by chi - square test and a student 's t - test was used for comparison of seminal profile .
of the 1,439 patients ( mean age , 19.120.2 years ; range , 0 - 87 years ) who underwent scrotal us during the study period , various pathologic findings were found such as testicular cancer ( n=57 , 4.0% ) , hydrocele ( n=547 , 38.0% ) , cryptorchidism ( n=310 , 21.5% ) , epididymitis ( n=199 , 13.8% ) , varicocele ( n=143 , 9.9% ) , testicular atrophy ( n=46 , 3.2% ) including epididymal cysts or dilation , testicular fibrosis , and normal manifestation ( table 1 ) .
the mean age of these patients was 26.217.9 years ( range , 0 - 74 years ) . among them , testicular cancer ( n=15 , 17.2% ) , hydrocele ( n=31 , 35.6% ) , varicocele ( n=14 , 16.1% ) , cryptorchidism ( n=7 , 8.0% ) , epididymal cysts ( n=6 , 6.9% ) , epididymitis ( n=6 , 6.9% ) , fibrosis , atrophy , inguinal hernia , and epididymal dilation were found .
of the 87 patients with tm , 18 ( 20.7% ) were found to have limited tm , 16 were grade 1 ( 18.4% ) , 26 were grade 2 ( 29.9% ) , 27 were grade 3 ( 31.0% ) , and unilateral and bilateral tms were detected in 28 ( 32.1% ) and 59 ( 67.8% ) patients , respectively .
all detected tms were ipsilateral to the associated abnormalities . in 15 patients with testicular cancer and tm ,
the histopathologic diagnosis was classic seminoma in 6 patients , 6 mixed germ cell tumors , 2 teratomas , and 1 yolk sac tumor .
all 15 patients with testicular cancer and tm had classic tm , which meant more than five microliths per transducer field . applying this to the grading system
, it was found that there was no limited tm in testicular cancer with tm .
of the 15 patients with testicular cancer and tm , grades 1 , 2 , and 3 consisted of 3 ( 20% ) , 7 ( 46.7% ) , and 5 ( 33.3% ) patients , respectively ( fig .
there was no significant difference in the prevalence of testicular cancer between grades ( p=0.72 ) . among the us examinations performed in 60 patients ,
all established pathologic entities , only testicular cancer was meaningfully associated with tm ( table 2 ) .
the prevalence of tm in testicular cancer was 26.3% ( 15/57 ) compared with 5.2% ( 72/1,382 ) in patients without testicular cancer ( p<0.001 ) . in 60 cases of infertility ( mean age , 33.74.6 years ; range , 27 - 45 cases ) , 33 had varicocele ( 55% ) and the rest had testicular atrophy , epididymal cysts , testicular fibrosis , and other afflictions .
all patients showed abnormal semen quality in semen analysis according to world health organization criteria . among them , 10 cases were accompanied by tm , a prevalence rate of 16.7% ( 10/60 ) compared to 5.6% ( 77/1,439 ) in others ( p=0.002 ) ( table 2 ) .
of the 10 , 5 were found to be limited tm , 1 was grade 1 , 2 were grade 2 , and 2 were grade 3 tm .
there was no significant difference in the presence of other pathologies in those with or without tm ( p=0.68 ) .
furthermore , seminal profiles ( sperm count , motility , morphology , and wbc count ) were not statistically different between infertile men with and without tm ( table 3 ) .
testicular microlithiasis is a rare , asymptomatic finding suggested to be associated with various benign and malignant urological pathologies and genetic anomalies that are usually found incidentally during unrelated us examinations .
doherty et al reported the first use of real - time us to diagnose tm . in the current study ,
the reported prevalence of tm has varied widely and has been generally presented as 0.5% to 9% . in their retrospective review of 1710
scrotal us scans , hbarth et al documented 11 cases of tm ( 0.6% ) in a population undergoing examination for varicocele , hypogonadism , and epididymal cysts .
in their retrospective review of 1,100 us scans performed for infertility , pain , or masses , ganem et al found tm in 2% .
middleton et al reviewed us data from 1,079 patients at their institution and found a prevalence of 0.68% .
this wide range partially comes from the recent introduction of high - frequency probes and the sensitization of radiologists and urologists to the problem .
but much more importantly , the vast majority of studies have investigated patients examined for testicular pathology . virtually no true screening test for tm in an asymptomatic population has ever been performed except in two published reports .
peterson et al performed screening us scans on 1,504 healthy nonsymptomatic males and reported a prevalence of 5.6% .
more recently , serter et al found the prevalence of tm in an asymptomatic population to be 2.4% after screening 2,179 us scans . despite these findings ,
although the true incidence of tm is not yet known , tm has become a concern for the practicing urologist because of its possible correlation with testicular cancer .
the coexistence of many benign and malignant pathologies with tm has been reported , and some authors have recognized that tm may be associated with a variety of nonneoplastic conditions , such as cryptorchidism , chromosomal anomaly , and atrophy . however , the most commonly held views in the literature are those that support a correlation between tm and testicular cancer .
we retrospectively reviewed all us cases and evaluated whether there was any possible significant association between tm and pathologic entities .
of all detected testicular pathologies , only testicular cancer showed a significant difference in prevalence .
previous ultrasonography studies showed a prevalence of tm ranging from 16.9% to 48.3% . in our study
, we found 15 cases with tm out of 57 ( 26.3% ) testicular cancers versus 72 cases with tm out of 1,382 ( 5.2% ) patients without testicular cancer ( p<0.001 ) .
historically , frequently reported testicular cancer subtypes have been seminoma , teratoma , and mixed germ cell tumors in decreasing order . however , we found six patients with seminoma and another six with mixed germ cell tumors .
the association between tm and malignancy was first highlighted in 1982 by ikinger et al , who examined testicular specimens from 92 postoperative patients ( 43 with malignant and 49 with nonmalignant disease ) .
microcalcifications were found in 32 ( 74% ) tumor specimens but only 8 ( 16% ) benign specimens .
hbarth et al found tumors coexisting with tm in 44% of the 42 cases of tm .
backus et al , in a cross - sectional retrospective study , reviewed 42 cases of tm and their association with identified intratesticular abnormalities .
they noted that 40% of patients with tm on us had associated tumors . in a larger series , otite et al reviewed the records of 3,026 patients who had undergone scrotal us
thirty percent of their patients with tm were diagnosed with testicular tumors . on the other hand ,
song et al reviewed 1,088 patients who underwent ultrasonography . in that study , tm was found in 6% and 5.8% of the testicular cancer patients and the noncancer controls , respectively , in the children 's group ( p=0.152 ) . in the adult group , 11.6% and 3.3% of the patients in the respective groups were found to have tm ( p=0.001 ) .
to overcome the limitations of the majority of published reports , which have been retrospective in nature , several authors have performed prospective follow - up studies of patients with tm .
although many published reports found subsequent testicular cancer development in men who had been previously diagnosed with tm , the relationship between tm and testicular cancer remains unresolved due to several drawbacks of those studies .
the majority of the prospective studies that have reported subsequent tumor occurrences were performed in a relatively small group ( mostly less than 40 ) and involved short follow - up periods ( mostly less than 4 years ) .
more importantly , by carefully analyzing the reports that found subsequent tumor occurrence in patients with tm , most cases had other predisposing factors for the development of testicular tumors , such as cryptorchidism , testicular atrophy , or previous contralateral testicular tumors .
another important aim of our study was to evaluate the impact of grading on the prevalence of tm . because there has been no accurate prevalence and a lack of agreed upon clinical importance of tm , further classifying was suggested to help to understand the nature of tm .
generally , tm has been accepted as classic tm when at least one image shows five or more microliths .
patients who have at least one microliths and do not meet the criteria for classic tm have been considered to have limited tm .
further classification of tm as done in our study was also suggested by backus et al . presently , the number of microliths required to obtain a diagnosis of tm has been agreed upon at five and above for each sonographic plane .
however , in cases with smaller numbers of microliths that were associated with malignancy , we documented all microliths except 1 or 2 that could be an incidental finding without pathological significance .
as we investigated the further grading of tm according to the number of microliths per us image , we found no difference in the prevalence between grades 1 , 2 , and 3 in accordance with the reports by sanli et al . in that study , they reviewed 4,310 cases with classic tm and further graded tm as in the present study ; however , there was no significant difference between grades .
bennett et al compared the rates of testicular cancer in patients with 5 to 10 microliths per image ( grade 1 ) with those having more than 10 microliths per image ( grade 2 and 3 ) and reported no significant difference between the two groups .
therefore , we concluded that further grading of tm is not essential in patients with tm .
but this should be carefully interpreted because the relatively small number of cases of testicular cancer with tm may limit the power of this result .
because there were only five bilateral tm cases in 15 tumor cases with tm , we could n't determine the clinical significance of laterality with respect to tm .
several other studies have shown that bilateral tm is associated with the pre - invasive stage of germ cell testicular cancer more so than unilateral .
testicular microlithiasis , which is frequently seen with testicular cancer , may be associated with infertility [ 5 - 8 ] .
theoretically , decreased fertility could be expected because 30% to 60% of seminiferous tubules can be obstructed by intratubular concretions , which is considered to be a pathogenesis of tm .
infertile patients with tm may have significant reductions in sperm migrations and motility compared with those with minimal microcalcification .
however , although some authors have reported abnormal semen parameters in infertile men with tm , others have found no significant difference among infertile men with or without tm . in the present study
, we found a prevalence rate of tm of 16.6% ( 10/60 ) in the infertile group , which fits into the currently reported prevalence ( 0.8 to 20% ) and confirms a significant co - occurrence ( p=0.002 ) .
there were no significant differences in sperm count , motility , or morphology in terms of sperm function between infertile men with or without tm .
our results suggest that , although there is a significant association between tm and infertility , it seems unwise to expect an adverse effect of tm on seminal profile .
we also assume that the relatively low grade of tm in the infertile group might have affected the seminal profile comparison .
thomas et al reported that cases with minor degrees of calcification generally had better sperm count and sperm migration tests than did those with marked calcification .
there may therefore be a relationship between the degree of calcification and poor sperm function .
on the other hand , in the study by sakamoto et al , which showed a similar seminal profile comparison result as in the present study , the authors mentioned that the degree of subfertility in patients with tm was variable and may reflect underlying testicular dysgenesis or concomitant intrascrotal abnormality .
apart from the adverse effect on seminal profile , tm itself might be a risk factor for testicular cancer in infertile men who are already in a high - risk group . in a study of 263 subfertile men by de gouveia brazao et al
, the authors demonstrated that carcinoma in situ ( cis ) was present in 20% of infertile men with bilateral tm .
skakkebaek et al interpreted this increased risk for developing malignancy as the so - called testicular dysgenesis syndrome .
those authors suggested that in men with tm , or other criteria for testicular dysgenesis such as testicular maldescent , atrophy , low sperm count , or inhomogeneous us appearance , the risk for cis should be examined .
testicular microlithiasis , infertility , and testicular cancer all therefore seem to be interlinked . under these circumstances
, it seems convincing that particular attention should be paid to tm patients who already have significant risk factors for the development of testicular cancer , such as infertility , cryptorchidism , or infertility , especially in diffuse bilateral cases .
first , it was a retrospective review and was based on a preselected population undergoing us for myriad conditions that have the potential for increased incidence of germ cell tumors , which limits the power of the results .
second , we presented the prevalence of tm on the basis of a symptomatic population .
together with the retrospective nature of the present study , this makes it difficult to determine the true incidence and natural course of tm . to the best of our knowledge ,
only two prospective studies are available to determine the incidence and natural history of tm in a healthy asymptomatic population .
the prevalence of tm in the symptomatic population in our study was found to be 6.0% .
our study indicates the significant co - occurrence of tm , testicular cancer , and infertility . even if a true cause - effect relationship between tm and testicular cancer exists , further grading of tm does not seem to be essential with regard to the detection of patients with testicular cancer and tm .
furthermore , tm showed no significant impact on seminal profiles in infertile men in the present study ; however , it should be carefully interpreted with respect to other accompanying pathologies . despite a significant pool of knowledge ,
the natural history and clinical significance of tm are not well understood . to reach a definitive conclusion about tm , further larger prospective and collaborative studies are required .
 purposetesticular microlithiasis ( tm ) is an uncommon pathologic condition that is commonly diagnosed by scrotal ultrasonography . 
 indirect evidence suggests that this syndrome may be associated with an increased risk of testicular malignancy and infertility.materials and methodsa total of 1,439 patients undergoing scrotal ultrasound during a 6-year , 5-month period ( january 2003 to may 2009 ) were retrospectively reviewed . 
 any possible association of tm with pathologic findings was assessed . among patients with tm , further grading of tm with testicular cancer and semen analysis of the infertile group with tm 
 were also performed.resultstm was diagnosed in 87 patients ( 6.0% ) out of a total of 1,439 . 
 of all established pathologic entities , only testicular malignancy and infertility were meaningfully associated with tm . 
 there was no significant difference in the prevalence of testicular cancer between each grade . 
 seminal profiles ( sperm count , motility , morphology , and white blood cell count ) were not found to be statistically different between infertile men with and without tm.conclusionsthe prevalence of tm in symptomatic men was found to be 6.0% with significant co - occurrence of tm , testicular cancer , and infertility . 
 further grading of tm does not seem to be essential with regard to the detection of patients with testicular cancer and tm . 
 tm showed no significant effect on the seminal profiles of infertile men . 
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
CONCLUSIONS