www.karger.com E-Mail [email protected] Fax +41613061234 true prevalence of testicular microlithiasis in otherwise in microlithiasis testicular of prevalence true The malignancies. testicular with association possible scribed as well. The condition is important because of its de- been have testis) one in focal or (unilateral patterns of distributionisusuallydiffuseinbothtestes,butother echogenic lesions distributed over the testis. The pattern pearance on ultrasound is typical with scattered multiple Garret and Priebe by radiologically out the testicular parenchyma (fi by multiplecalcifi population hasnotbeendefi seminiferous tubules.Thetrueprevalenceinanormal mon conditioncharacterizedbycalcifi ogy oftesticularmicrolithiasisremaintobedone. up regularly.Furtherinvestigationsconcerningtheetiol- tients withtesticularmicrolithiasisshouldbefollowed gies isnotsupportedbytheliterature. between testicularmicrolithiasisandpatholo- ticular cancer.However,adirectcausativeconnection ated withdifferenttesticularpathologies,includingtes- carried out. testicular microlithiasisandmalignancywas the literaturewithemphasisonconnectionbetween University Hospital DepartmentofUrology, Manfred P.Wirth Oliver W.Hakenberg StefanZastrow Dresden, Germany Technical Universityof Testicular microlithiasis is a condition characterized condition a is microlithiasis Testicular Introduction Introduction: Abstract Results: Testicularmicrolithiasisisanuncom- ‘ Carl GustavCarus cations distributedrandomlythrough- www.karger.com/uin Accessibleonlineat: 0042–1138/04/0751–0003$21.00/0 ©2005S.KargerAG, Basel Dresden Testicularmicrolithiasisisassoci- , ned. Copyright ©2005S.KargerAG,Basel g.1). It was fi ’ , Methods: [1] cations withinthe Conclusions: DOI:10.1159/ UrolInt2005;75:3–7 Microlithiasis Signifi in 1970. The ap- The 1970. in rst described

A reviewof 000085918 Pa- cance ofTesticularcance is surrounded by a series of concentric layers. The outer The layers. concentric of series a by surrounded is calcifi a form which cells intratubular E-Mail [email protected] Tel. +493514582447, Fax+493514584333 Fetscherstrasse 74,DE–01307 Dresden(Germany) Department ofUrology, UniversityHospital‘CarlGustavCarus’, TechnicalUniversity Dr.StefanZastrow knowledge aboutthisentity. symptoms. The aim of this article is to review the current ies have been done in patients who presented with scrotal stud- most because unclear, remains individuals healthy with scrotalpain. Fig. 1.

Morphologically, the microliths consist of degenerated Morphology Testicularmicrolithiasisina23yearoldmalepresenting

ed core. This core This core. ed

Review layer consists of cystoplasmic debris with vesicles, degen- 14–22] have been published describing the development erated mitochondria, and collagen fi bers. The intermedi- of testicular cancers in patients after the diagnosis of tes- ate layer contains bundles of collagen fi bers. The inner- ticular microlithiasis (see table 1). So it remains unclear

Review most layer consists of multiple lamellae [2]. A meticulous whether testicular microlithiasis has to be considered a morphological description of the development of testicu- premalignant condition or represents a precursor state to lar microliths, however, has not been done, thus leaving testicular malignancy. unexplained the origin and the exact mechanism by which A prognostic value of testicular microlithiasis concern- these calcifi cations develop. ing the development of cannot be de- In a histopathological classifi cation two different forms rived from the published data, with one exception, how- of testicular microlithiasis have been described by Ren- ever: if testicular microlithiasis occurs in the remaining shaw [3]. The most frequent type is represented by lami- testis after orchiectomy for testicular malignancies, it nated calcifi cations. They were found in 38 (29%) of 131 seems to be connected with a higher risk of developing a pathological specimens. Laminated calcifi cations oc- secondary malignancy in this testis [23]. Furthermore, if curred in association with testicular malignancies (pure testicular microlithiasis can be found in the contralateral , embryonal carcinomas, and mixed germ cell testis after orchiectomy because of malignancies, the risk tumors), in cryptorchid testes, and also in normal testes. of carcinoma in situ is increased which has been demon- The second type consists of hematoxylin bodies. These strated by Holm et al. [24] in a retrospective study of 64 hematoxylin bodies are exceptionally encountered in patients. connection with testicular malignancies like pure embry- Derogee et al. [14] provided evidence for testicular onal carcinomas and mixed tumors (embryonal carcino- microlithiasis as a premalignant condition. These authors ma with yolk sac tumor and embryonal carcinoma with retrospectively reviewed 1,535 patients who underwent , respectively, in 2 cases). Of 131 pathological ultrasound examination of the external genitalia during specimens, only 6 (5%) contained hematoxylin bodies. a period of 6 years. The indications for ultrasound in- cluded , , , or suspect- ed malignoma. They found microliths in 63 (4.1%) of Testicular Microlithiasis and Associated these 1,535 patients. A preferred side could not be de- Conditions tected (28 left, 25 right, 10 bilateral). 46% of the patients with testicular microlithiasis had a concomitant tumor in Testicular microlithiasis can occur in connection with the same testis. A strong correlation between testicular numerous testicular pathologies but also in otherwise nor- microlithiasis and testicular tumor was calculated in this mal testes. Pathological conditions include malignancies, series. A preferred tumor type could not be found. Histo- cryptorchism [4], [5–7], [8], logical examinations were performed in 28 cases. Tes- [6, 7, 9, 10], epididymo- [5], Klinefelter ticular microlithiasis was seen exclusively inside the tes- syndrome [11] , male pseudohermaphroditism [8], neuro- ticular tumor in only 4 cases. In most cases testicular fi bromatosis, and HIV [12] . microlithiasis showed a preference for a location outside the testicular tumor. Patients with testicular microlithia- sis but no tumor were followed up. During the follow-up Testicular Malignancies period (median 61.8 months) 1 of 31 patients developed a combined teratoma and seminoma 35 months after the The connection between testicular microlithiasis and diagnosis of testicular microlithiasis. According to the au- testicular malignancies (seminoma, teratoma, mixed tu- thors [14] , regular follow-up of patients with testicular mors, and carcinoma in situ) has been frequently de- microlithiasis is warranted. Testicular biopsy should be scribed. In a radiographic study performed on testicular considered an option in these patients. cancer orchiectomy specimens, Ikinger at al. [13] identi- According to the fi ndings of another retrospective fi ed microcalcifi cations in 74% of their cases. In benign study [25], the clinical signifi cance of testicular microli- conditions, microcalcifi cations could be found in only thiasis remains unclear. In this study 1,710 ultrasound 16% of the cases. Thus in testicular cancer specimens a examinations of adults were reviewed. Testicular micro- higher incidence of testicular microlithiasis is present. lithiasis was found in 11 cases (0.6%). In all cases it was Although testicular microlithiasis often can be seen bilateral. In 5 cases it was associated with a testicular tu- together with testicular tumors, only a few case reports [5, mor (3 seminomas, 1 teratoma, and 1 combined semi-

4 Urol Int 775 Zastrow/Hakenberg/Wirth

Table 1. Selected case histories

Case Age History Tumor type Time to tumor Reference No. years appearance after No.

diagnosis of TM Review 132 infertility, TM on the right side embryonal carcinoma 10 months 16 2 17 asymptomatic TM yolk sac tumor 4 years 17 3 21initially pain, hemospermia, unilateral TM mixed germ cell tumor 3 years 18 4 25 asymptomatic unilateral TM metastatic mixed germ cell 16 months 19 tumor 5 40 seminoma 11 years before, TM bilaterally seminoma 11 years 15 6 47 , bilateral TM seminoma, carcinoma in situ 6 months 20 7 n.i. left embryonal carcinoma treated with combined teratoma/seminoma 35 months 14 orchiectomy and chemotherapy 10 years ago, cryptorchid testes in childhood on both sides 8 29 left atrophic testis, bilateral TM left seminoma 2 years 5 9 34 bilateral TM and metastatic embryonal right seminoma with small 4 years 5 carcinoma, disease free following embryonal component chemotherapy, then new tumor on the right side 10 n.i. infertility, bilateral TM seminoma 5 years 21 11 n.i. control group, volunteer, right TM right seminoma 3 years 21 12 n.i. retractile left testis, left TM left seminoma 12 months 22

TM = Testicular microlithiasis; n.i. = not indicated. noma/teratoma). Other concomitant pathologies were testicular microlithiasis included 6 seminomas, 4 terato- /, varicocele, and of mas, 5 mixed tumors, and 1 embryonal carcinoma. Oth- spermatic cord or . During a mean follow-up er testicular pathologies occurring with testicular micro- period of 15.9 (range 2–49) months, no testicular tumor lithiasis were /epididymal cysts (n = 14), developed in testes with microlithiasis. The authors un- (n = 7), epididymitis (n = 2), and small testes derlined the importance of a complete diagnostic workup (n = 8). It is worth mentioning that also 14 testes with to rule out testicular malignancies in patients who have testicular microlithiasis showed otherwise normal fi nd- been diagnosed as having testicular microlithiasis. Unfor- ings. Only 2 patients developed testicular cancer during tunately, the authors do not indicate the reasons for tes- the follow-up period (1 seminoma after 2 years and 1 ticular ultrasound examination in their cohort, thus leav- seminoma with a small embryonal component 4 years ing unanswered the question if their fi gures can be after curative therapy of a metastatic embryonal carci- interpreted as representing the incidence of testicular mi- noma). crolithiasis in an otherwise asymptomatic cohort. Ganem et al. [12] reported their experience with 22 According to Otite et al. [5] there is no suffi cient evi- patients found to have testicular microlithiasis over a 4- dence for classifying testicular microlithiasis as a prema- year period. They also could not fi nd suffi cient evidence lignant condition. They retrospectively analyzed 3,026 for classifying testicular microlithiasis as either a prema- patients who underwent testicular ultrasound examina- lignant condition or a causative agent for testicular neo- tion because of testicular symptoms (pain, swelling, infer- plasia. Their patients were drawn from approximately tility) over a period of 5 years. They found testicular mi- 1,100 testicular ultrasound investigations. 16 of the 22 crolithiasis in 54 patients (1.77%). It was bilateral in 39 patients had bilateral testicular microlithiasis. A coinci- of 54 patients. Eighty-two of all patients had testicular dence with malignancies occurred in 8 patients (36%). tumors, but only 16 (19.5%) of these tumor patients had The types of malignancies included 6 stage 1 seminomas, testicular microlithiasis. Malignancies connected with 1 mixed nonseminomatous germ cell tumor, and 1 meta-

Testicular Microlithiasis Urol Int 775 5 static yolk sac tumor. During the follow-up period (mean tients referred for scrotal ultrasound. The overall 32, range 1–96 months), no patient with testicular micro- prevalence of testicular microlithiasis in this group was lithiasis who did not have testicular cancer at the time of 18.1%. The authors divided testicular microlithiasis into

Review presentation subsequently developed a testicular malig- classic testicular microlithiasis with 65 microliths in one nancy. Of the patients who underwent ultrasound inves- ultrasound picture and limited testicular microlithiasis tigation because of infertility, 5 out of the 22 patients with !5 microliths. The prevalences were 3.7 and 14.4% (23%) had testicular microlithiasis as well. 3 of the 22 pa- for classic and limited testicular microlithiasis, respec- tients (14%) with spermatic cord torsion had testicular tively. Tumors occurred in 8% of the patients with classic microlithiasis. The authors also reported for the fi rst time and in 5.8% of those with limited testicular microlithiasis the fi nding of testicular microlithiasis in patients with (difference not signifi cant). In this study, 190% of the pa- neurofi bromatosis (n = 1) and AIDS (n = 1). However, as tients with testicular microlithiasis had no tumor. there is no obvious relationship between AIDS, neurofi - After reviewing the data presented, it must be con- bromatosis, and testicular microlithiasis; these fi ndings luded that a classifi cation of testicular microlithiasis as a were probably coincidental. Concerning the connection premalignant condition cannot be clearly supported. between testicular neoplasia and testicular microlithiasis, However, to some degree it occurs with testicular malig- the attractive hypothesis is presented that testicular mi- nancies. The coincidence of testicular cancer and testicu- crolithiasis could be the manifestation of another unde- lar microlithiasis suggests that both conditions might fi ned pathology which predisposes to malignant (and pos- share a common etiology. sibly benign, e.g., infertility) disease. The authors recommend regular follow-up with testicular ultrasound examinations. Testicular Microlithiasis and Infertility However, strong evidence against a connection be- tween testicular microlithiasis and testicular cancer has In a retrospective analysis performed by Thomas et al. been presented by Peterson at al. [26] . These authors per- [6], a coincidence of testicular microlithiasis ( 15 echo- formed a prospective screening study in 1,504 healthy genic foci/ picture) and infertility was found in 5 out of young men between 18 and 35 years of age. In this popu- 159 infertile men (3.1%) having undergone testicular ul- lation, 84 subjects (5.6%) had testicular microlithiasis. It trasound examination. All of these 5 men also had other occurred bilaterally in 66.7% of all cases. The incidence testicular pathologies (3 had varicoceles, 1 had a history of testicular microlithiasis in this study was far higher of testicular torsion, and 1 had a missing contralateral than the incidence of testicular cancer which according testis). Concerning varicoceles, it is important to note that to the authors is a strong argument against the epidemio- 59 of the 159 patients in this study had this condition. logical association of malignancy and testicular microli- Thus, only 8.5% of all patients with a varicocele had tes- thiasis. They also found a higher proportion of testicular ticular microlithiasis. There were also 5 additional men microlithiasis in black men (14.4%) who, on the other with minimal microlithiasis ( !5 echogenic foci/picture). hand, have a very low incidence of testicular cancer. In When these patients were compared with men with gen- addition, the incidence of testicular microlithiasis was eralized testicular microlithiasis ( 15 echogenic foci/pic- higher in men from the southeast of the USA, a region ture), they showed a signifi cantly better migration which has the lowest incidence of testicular cancer. These test and . There were no signifi cant differ- observations do not support a connection between tes- ences between the groups with respect to sperm count or ticular cancer and microlithiasis. The authors, therefore, number of white cells. But the data suggested a relation- question the necessity of a regular and cost-intensive fol- ship between degree of calcifi cations and sperm func- low-up of testicular microlithiasis patients and suggest tion. regular self-examinations. It must be underlined that Aizenstein et al. [9] reviewed 180 infertile men and these results were found in a clearly asymptomatic and found 5 patients (2.8%) with testicular microlithiasis. Sa- otherwise healthy population. This increases the value of sagawa et al. [10] found 1 case among 125 testicular bi- this study, because selection of patients with testicular opsies performed because of infertility. Kessaris and Mel- symptoms has been omitted. linger [7] detected 2 patients (1.3%) out of 150 infertile Similarly, Middleton et al. [27] were not able to pro- men. The 1st patient had a left-side grade I varicocele. vide clear evidence for testicular microlithiasis as a pre- The 2nd patient had bilateral varicoceles (right grade I, malignant condition. They recorded data of 1,079 pa- left grade II) and a history of herniorrhaphy as a child.

6 Urol Int 775 Zastrow/Hakenberg/Wirth

Four months after bilateral microsurgical correction of cases of contralateral tumor or infertility with cryptor- the varicoceles and right scrotal exploration, this patient’s chism or atrophic testes [28, 29]. wife became pregnant. Review Conclusions Management of Patients with Testicular Microlithiasis Testicular microlithiasis is not a rare condition. How- ever, it is an incidental fi nding on scrotal ultrasound Presently, regular self-examinations are recommend- examination because of other testicular conditions. ed in patients with testicular microlithiasis. The roles of Although it can occur synchronously with testicular ma- ultrasound controls every 6–12 months and regular inves- lignancies in a more than random fashion, a causality tigation of tumor markers recommended in some studies between testicular microlithiasis and testicular cancer is remain unclear. There is no scientifi c basis for a biopsy not supported by the literature. However, once diagnosed, in isolated testicular microlithiasis without further ac- it requires regular follow-up, at least by self-examination. companying pathologies. A biopsy may be warranted in Further studies to elucidate the etiological basis and sig- case of additional pathological ultrasound or clinical fi nd- nifi cance of this condition remain to be done. ings, in focal or unilateral testicular microlithiasis, or in

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