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Keywords:

  • testicular microlithiasis;
  • germ cell neoplasms;
  • testicular carcinoma in situ;
  • meta-analysis

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

There is an increasing body of literature associating testicular microlithiasis (TM), a common finding on testicular ultrasound, with testicular germ cell tumor (TGCT) and intratubular germ cell neoplasia of unclassified type (ITGCNU). Determining these associations is pertinent both clinically and biologically. To the authors' knowledge, no previous systematic review or meta-analysis has been performed.

METHODS:

A comprehensive systematic literature review was performed without language restrictions through July 2009 and included an exhaustive search of electronic databases and article references. Two reviewers extracted data independently. Studies were categorized according to the clinical context in which sonography was performed. The primary study outcomes were concurrent diagnoses of TGCT or ITGCNU, with TM. In addition, studies with prospective follow-up of patients with TM were reviewed.

RESULTS:

Thirty-three studies met inclusion criteria. TM was not associated with an increased risk of TGCT in asymptomatic men. However, in referral populations, TM was associated overall with a risk ratio of 8.5 (95% confidence interval [CI], 4.5-16.1; P < .001) for a concurrent diagnosis of TGCT and 10.5 (95% CI, 5.3-20.8; P < .0001) for ITGCNU. Seventeen observational studies were identified in which the interval development of TGCT in patients with TM was reported; however, the majority of those studies did not report the follow-up of a control arm and could not be summarized.

CONCLUSIONS:

In the presence of risk factors, TM was associated with a substantially elevated risk of a concurrent diagnosis of TGCT and ITGCNU. The authors suggest modifications to recently proposed guidelines for the management of TM. Cancer 2010. © 2010 American Cancer Society.

Testicular microlithiasis (TM) characteristically is recognized by a sonographic pattern of multiple, 1-mm to 3-mm foci of increased echogenicity distributed randomly throughout the testicular parenchyma. TM can be an incidental finding in approximately 5% of asymptomatic young men.1-4 Studies report TM in association with conditions that increase the risk for developing testicular germ cell cancer (TGCT), such as cryptorchidism5-7 and subfertility1, 8 and its precursor condition, intratubular germ cell neoplasia of unclassified type (ITGCNU).9 TM commonly is found synchronous with TGCT.10 There also are several case reports of the interval development of testicular tumors in patients who had a previous sonographic diagnosis of TM.11, 12

These associations relating the sonographic diagnosis of TM to the pathologic diagnosis of TGCT are pertinent both clinically and biologically. Establishing the magnitude of risk of concurrent TGCT or ITGCNU and the subsequent development of TGCT when TM is identified in asymptomatic men and in men who are at risk of TGCT may address uncertainties regarding the need for tissue biopsy and the frequency of clinical and radiologic follow-up. It may also offer biologic insights into these conditions.

Despite the body of publications on multiple case-control and cohort studies, to our knowledge, there has been no meta-analysis to integrate the existing data. To clarify the literature and to provide a synthesis, we performed a systematic review and meta-analysis of the published literature to provide a more objective estimate of the risk of 1) concurrent TGCT, 2) concurrent ITGCNU, and 3) the interval development of TGCT.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Literature Search and Inclusion and Exclusion Criteria

A systematic literature review of original articles analyzing the relation between TM and germ cell tumors was performed by searching the MEDLINE and EMBASE databases and the Cochrane Library through to July 2009. The search strategy included the following keywords: “germ cell tumors,” “germ cell neoplasms,” “testicular neoplasms,” “testicular cancer,” “nonseminoma,” “seminoma,” “testicular carcinoma-in situ,” “intratubular germ cell neoplasm,” “intratubular germ cell tumor,” “microlithiasis,” “testicular calcification,” and “testicular microcalcification.” Studies were eligible if the exposure risk factor for TM was accessed by ultrasound and was correlated with a diagnosis of either of the 2 outcomes under study, namely, TGCT and ITGCNU. There was no restriction criterion on language of publication or the number of patients enrolled in each study, although inclusion criteria for individual studies were reviewed. Studies were excluded if sampling or selection of the TM cohort and the non-TM cohort was not drawn from populations with similar risk exposure. When overlapping or duplicate datasets were detected, only the most recent study was included in the analysis. Searches were supplemented by scanning the bibliographies from included articles.

Data Extraction and Study Outcomes

Two investigators (I.B.T. and I.K.A.) independently extracted data on study design, patient characteristics, study outcomes, and measures of study quality. The study outcomes were a concurrent diagnosis of TGCT, a concurrent diagnosis of ITGCNU, and an interval diagnosis of TGCT. For the exposure factor (TM), the indication for ultrasound investigation, efforts to ensure the quality of radiologic assessments, and diagnostic criteria for TM were extracted. For outcome endpoints (germ cell tumors or ITGCNU), we noted the modalities that were used to search for overt and occult malignancy. For studies in which patients with TM were followed for the development of testicular tumors, the duration of follow-up, surveillance strategy, the number of tumors, and the time to develop tumors were recorded. We assessed study quality using the Newcastle-Ottawa scale13, 14 with modifications to match the needs of the current meta-analysis. This instrument uses 3 aspects of study design to assess quality: namely, patient selection, comparability of study groups, and assessment of outcome. Studies that achieved ≥5 stars on the modified Newcastle-Ottawa scale were considered high quality. After independent extraction, discrepancies were resolved through consensus agreement. Articles were classified according to the population under study (asymptomatic or high-risk population, including populations with a personal or family history of testicular cancer, scrotal symptoms, or subfertility) and according to the outcome under study (concurrent diagnosis of TGCT or ITGCNU or interval development of TGCT).

Meta-Analysis and Statistical Testing

Meta-analyses of risk ratios were performed using a random effects model, which assigned a weight to each study based on both within-study variance and between-study heterogeneity.15 Significance was based on 2-tailed testing. Heterogeneity was measured with the inconsistency index (I2).16 The presence of potential publication or selection bias was evaluated qualitatively using funnel plots that displayed the logarithm of the risk ratio versus the inverse standard error of the logarithm of the treatment effect.17 All analyses were conducted using Review Manager version 5 (Cochrane Collaboration, Oxford, United Kingdom). We tabulated the reported incidence of interval development of TGCT in patients with TM and the relevant follow-up duration.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Literature Search and Study Characteristics

One hundred fifty-two articles were identified from our electronic database search. Sixty-two articles were case reports or case series. Full text articles of the remaining 90 articles were retrieved. Further review excluded letters, reviews, pediatric and preclinical studies, studies with nonuniform sampling, studies evaluating pathologic but not radiologic TM, and studies in which the endpoints of TGCT or ITGCNU were not evaluated. Thirty-one articles met inclusion criteria. Another 14 articles were retrieved after a bibliographic search, and 2 of those articles met our inclusion criteria. Thus, we included a total of 33 studies, all of which achieved ≥5 stars on the Newcastle-Ottawa scale. A Consolidated Standards of Reporting Trials (CONSORT) diagram and characteristics of the included studies are provided in Figure 1 and in Table 1, respectively.

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Figure 1. This is a Consolidated Standards of Reporting Trials (CONSORT) diagram of 34 articles that were identified from the current systematic literature search. TM indicates testicular microlithiasis; TGCT, testicular germ cell tumor; ITGCNU, intratubular germ cell neoplasia of unclassified type.

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Table 1. Summary of Included Articles
StudyNo. of PatientsStudy DesignIndication for UltrasoundDefinition of MicrolithiasisRadiologic Quality ControlSearch for Overt Tumor PerformedEndpoints Studieda
  • CC indicates case-control; FTGCT, familial testicular germ cell tumor; Co, cohort; TM, testicular microlithiasis; TGCT, testicular germ cell tumor; plAP, placental alkaline phosphatase.

  • a

    For endpoints, 1 indicates TGCT; 2, intratubular germ cell neoplasia of unclassified type; 3, interval TGCT.

  • b

    Overlap with a previous study for Endpoint 1.

Korde 20083281CCFamilies with FTGCT: cases, 48; relatives, 33Includes limitedSingle radiologist reviewed all filmsNo1
Coffey 20074227CCCases, 169; relatives, 58 (100 healthy volunteers; separate analysis)Includes limitedSingle radiologist reviewed all filmsNo1
Sanli 2008404310CoReferred for radiology, no breakdown providedClassicNoneNo1
Ou 2007411978CoReferred for radiology: no breakdown providedIncludes limitedNoneNo1, 3
Kosan 200719197CoInfertility, 95; scrotal mass, 51; infertility and pain, 40; other scrotal symptoms, 3Not detailedNoneNo1, 3
Ahmad 2007424259CoReferred for radiology, scrotal symptoms and infertilityClassicNoneNo1, 3
Lam 200743274CCReferred for radiology, no breakdown provided (from 3254; selected 137 with TM and 137 random controls without TM)Includes limitedNoneNo1, 3
Sakamoto 200644969CoInfertility, 550; scrotal symptoms, 419ClassicRadiologic review by blinded radiologistNo1, 3
Miller 2007453477CoReferred for radiology: no breakdown providedIncludes limitedIndependent radiologic reviewNo1
Middleton 2002361079CoReferred for radiology: scrotal symptoms or infertility: scrotal swelling, 489; history of testicular cancer, 31Includes limited18 Different radiologistsNo1
Otite 2001463026CoReferred for radiology: No breakdown providedClassicNoneNo1, 3
von Eckardstein11701CCReferred to andrology clinic: Subfertile, 1399, preservation of sperm for other nontesticular pathologies, 219; 83 with prior history of TGCT, 83Includes limitedRadiologists (4) performed all examinationsYes, but biopsy only available in 76 infertile patients1, 2, 3
Bach 200147528CoScrotal symptoms or infertility; 90 patients had scrotal massClassicIndependent radiologic reviewNo1
Cast 2000484819CoReferred for radiology: no breakdownClassicIndependent radiologic review of TM casesNo1
Derogee 2001491535CoScrotal symptoms and infertilityMore than 3 microcalcificationsIndependent radiologic review of TM casesNo1, 3
Skyrme 2000392215CoScrotal symptoms and infertilityClassic onlyIndependent radiologic review of TM casesNo1, 3
Negri 2008182172CoSubfertilityIncludes limitedFilm reviewed by 2 radiologists with consensus diagnosisNo1, 3
Schrey 2001501314CoSubfertilityNot detailed No1
Konstantinos 200651391CoScrotal symptomsClassicRadiologists (2) performed all examinationsNo1
Ringdahl 200452242CoScrotal symptomsClassicNoneNo1
Bach 200353156CoRadiology of contralateral testes of TGCT patientsClassicIndependent radiologic reviewNo1
Holm 20035464CoTGCT patients referred for cryopreservation and elective testicular biopsy of contralateral testesNot detailedNoneYes, contralateral testicular biopsy in all patients2
Shichijo 20075541CoPersonal history of TGCTClassicNoneYes, archival tissue of contralateral testes stained for plAP2
Leinmuller 200456       
 216CoPersonal history of TGCTNot detailedNoneYes, contralateral testicular biopsy in all patients2
de Gouveia Brazao 20049263CoSubfertilityClassicNoneYes, all patients had bilateral testicular biopsy for investigation of subfertility2
Serter 200622179CoAsymptomatic soldiersClassicNoneNo1, 3
Peterson 200131504CoAsymptomatic soldiersClassicNoneNo, but determination of tumor markers only in TM group1
DeCastro 20085763CoAsymptomatic soldiers with TM (follow up of Peterson 2001)ClassicNoneNo3
Sakamoto 200658969CoSubfertile, 545bClassicRadiologic review by blinded radiologistNo1,b 3
Janzen 19925911CoTM identified in 11 patients on ultrasound for scrotal symptomsNot detailedNoneNo3
Bennett 20013572CoTM identified in 72 patients on ultrasound for scrotal symptomsIncludes limitedNoneNo3
Pourbagher 20056036CoBilateral TM identified on ultrasound for scrotal symptomsIncludes limitedRadiologists (2) performed all examinationsNo3
Hobarth 19926111CoTM identified in 11 patients on ultrasound for scrotal symptomsNot detailedNoneNo, but tumor markers assayed3

Concurrent Diagnosis of TGCT in Asymptomatic Men

TM is a relatively common finding in asymptomatic men. Serter et al identified TM in 53 of 2179 asymptomatic men (2.4%), but none had TGCT.2 Petersen et al reported TM in 84 of 1504 asymptomatic men (5.6%) and 1 man without TM who had TGCT.3 von Eckardstein et al1 identified TM in 3 of 198 asymptomatic men (1.5%). Among those asymptomatic men, 1 volunteer with TM had coexisting TGCT. Six of 101 healthy volunteers (5.9%) had classic TM in the case-control study by Coffey et al, none of whom had TGCT.4 Thus, TGCTs are rare in asymptomatic, healthy men with TM. Only 2 cases from separate studies were reported in these 4 series.

Concurrent Diagnosis of TGCT in Men With Risk Factors for TGCT

In patients at risk for TGCT, the pooled risk ratio for concurrent TGCT in the presence of TM was 8.5 (95% confidence interval, 4.5-16.1; P < .0001). The funnel plot did not reveal asymmetry to suggest a substantial publication bias (Figs. 2, 3).

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Figure 2. This forest plot demonstrates the risk ratio (RR) of a concurrent diagnosis of testicular germ cell tumor (TGCT) in the presence of testicular microlithiasis (TM). M-H indicates Mantel-Haenszel odds ratio; CI, confidence interval; GCT, germ cell tumor; df, degrees of freedom; I2, inconsistency index.

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Figure 3. This of a funnel plot of studies that explored the relation between concurrent testicular germ cell tumor and testicular microlithiasis. SE indicates standard error; RR, relative risk; GCT, germ cell tumor.

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Concurrent Diagnosis of ITGCNU in Men With Risk Factors for TGCT

Five studies evaluated the relation between TM and ITGCNU, a precursor lesion of testicular cancer, by performing elective testicular biopsies. In patients who underwent previous orchiectomy for testicular cancer, 3 studies indicated that TM conferred an increased risk of ITGCNU (pooled risk ratio, 8.9). In subfertile patients, TM was related to a similarly elevated risk of identifying ITGCNU on testicular biopsy (pooled risk ratio, 25). The funnel plot did not suggest substantial publication bias (Fig. 4, 5).

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Figure 4. This forest plot demonstrates the risk ratio of a concurrent diagnosis of intratubular germ cell neoplasia of unclassified type in the presence of testicular microlithiasis (TM). M-H indicates Mantel-Haenszel odds ratio; CI, confidence interval; GCT, germ cell tumor; df, degrees of freedom; I2, inconsistence index.

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Figure 5. This is a funnel plot of studies that explored the relation between concurrent intratubular germ cell neoplasia of unclassified type and testicular microlithiasis. SE indicates standard error; OR, odds ratio; GCT, germ cell tumor.

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Interval Development of TGCT

The duration and strategy of follow-up was heterogeneous. Only 2 studies reviewed the follow-up of patients with and without TM. After a median follow-up of 24 months in subfertile patients, Negri et al18 reported a risk ratio of 24.3 for the development of germ cell tumors in patients with TM (3 of 25 men vs 4 of 810 men). In the study by Kosan et al,19 none of the 194 patients who were followed for a mean of 19.5 months developed germ cell tumors and 18 of those patients had TM. Other studies reported follow-up only in patients with TM. In Table 2, we present the estimated crude incidence rate for studies that reported the follow-up of patients with TM.

Table 2. Cumulative Incidence of Testicular Germ Cell Tumor After Follow-Up of Patients With Testicular Microlithiasis
Study Category and Reference(s)Median Follow-Up [Range], moFollow-Up StrategyNo. of Tumors Developed/Total Tumors (%)Incidencea
  • TGCT indicates testicular germ cell tumor; ND, not described; NR, not reported.

  • a

    Cases per 1000 person-years of follow-up.

  • b

    Mean (rather than median) value.

Subfertility    
 Negri 20081824 [12-119]Either yearly ultrasound or self-palpation3/25 At 19 mo, 22 mo, and 49 mo60
 Sakamoto 20065811.3b [2-29]ND0/31 (0)0
Personal history of TGCT    
 Sakamoto 20064451.5b [4-96]ND0/8 (0)0
Referred to radiology for scrotal symptoms or subfertility    
 Ou 20074129.3b [3-74]ND0/48 (0)0
 Kosan 20071919.5b [16-23]ND0/18 (0)0
 Lam 20074319b [1-90]≥1 Further ultrasound0/30 (0)0
 Otite 20014636 [12-81]Annual ultrasound2/30 (5.5) At 24 mo and 48 mo22.2
 Derogee 20014961.8 [16-105]Questionnaire and interview1/31 (3.2) At 35 mo6.3
 Skyrme 20003941/29b [19-54]Serial ultrasound and clinical examination0/27 (0)0
 Janzen 199259NR [14-49]ND0/11 (0)0
 von Eckardstein 2001148 [36-60]1 Extra ultrasound2/14 (14.2) At 36 mo and 60 mo35.7
 Bennett 20013545b [12-90]At least 1 serial ultrasound0/72 (0)0
 Pouhrbagher 20056034 [1-96]6-Mo ultrasound0/36 (0)0
 Hobarth 19926115.9b [2-49]ND0/11 (0)0
 Ahmad 20074240/33.9b [3-72]Yearly follow-up, serial ultrasounds2/29 (6.9); Details not provided24.4
Asymptomatic    
 Serter 2006212Ultrasound at 6 mo and 12 mo0/53 (0)0
 DeCastro 20085760Self-palpation and interview1/63 (1.6) At 64 mo3.2

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

To our knowledge, this study represents the first systematic review and meta-analysis evaluating the association of TM with TGCT and ITGCNU. TM is detected increasingly because of the widespread use of scrotal ultrasounds, higher image resolution, and greater awareness and recognition by radiologists. Clinical recommendations pertaining to the need for testicular biopsies and follow-up have ranged from observation with or without testicular self-examination to testicular biopsy followed by regular biannual follow-up, including ultrasonography.20, 21

On the basis of our summary, management should depend on the clinical context. In otherwise healthy, asymptomatic individuals, the absolute risk of concurrent or interval TGCT or ITGCNU is very low. Further investigations or follow-up is unwarranted. Among patients who are referred for scrotal ultrasound because of complaints like subfertility, cryptorchidism, or a personal history of germ cell tumor, who already are at an elevated risk of testicular cancer, the presence of TM further increases the risk of a concurrent diagnosis of germ cell tumors. In our pooled analysis, the estimated summary risk ratio was 8.5. The interval development of TGCT also has been reported after the follow-up of patients who have TM discovered in the context of such risk factors; however, in the absence of follow-up of patients without TM and according to the various incidence rates reported, it cannot be concluded definitively that this risk is higher than baseline.

Although identifying occult TGCT on testicular biopsy in the absence of a testicular mass is unlikely, we report a high summary risk ratio for concurrent ITGCNU with TM when elective testicular biopsy was performed in the contralateral testes of patients with previous testicular cancers and in subfertile patients. ITGCNU is the noninvasive precursor of invasive seminoma.22, 23 Approximately 50% of ITGCNU progresses to malignancy within 5 years.24, 25 Nearly 20% of patients with a previous TGCT have TM in their contralateral testes; these patients have an elevated risk ratio of 8.9 for concurrent ITGCNU compared with patients who do not have TM. Overall, the prevalence of contralateral ITGCNU in patients with previous TGCT is approximately 5%26 which corresponds to the cumulative incidence of bilateral testicular tumors.

Guidelines from Europe have been proposed for the management of TM20 that advocate the consideration of a testicular biopsy for young patients with TM and for those who have at least 1 risk factor for germ cell tumor, and self-examination is recommended for all other patients. Although we do report significantly elevated risks for TGCT and ITGCNU in the presence of TM (the basis for the European group's views), our conclusions differ substantially from the proposed European guidelines with regard to blanket recommendations for biopsy.

The main clinical dilemma is in patients with previous TGCTs. Practice patterns in Europe favor biopsy, whereas urologists in the United States generally avoid biopsies in the absence of a testicular mass. At the heart of this divide is the lack of definitive evidence of an overall survival benefit with early treatment of ITGCNU compared with deferred treatment in the subgroup of patients who develop TGCT, for whom cure rates are very high.

Even before considering a testicular biopsy of the contralateral testes, a major consideration that was omitted by the European guidelines is the patient's postoperative treatment, specifically, adjuvant chemotherapy, radiation, or surveillance alone. In the major UK trial of early stage seminoma,27 adjuvant chemotherapy definitively reduced the incidence of second primary testicular tumors. It also is established that chemotherapy also is effective for ITGCNU.24 The overall benefits of finding ITGCNU on a contralateral testicular biopsy and receiving testicular irradiation are likely to be attenuated significantly in patients with TGCT who have already elected to receive adjuvant chemotherapy, rendering further discussion about testicular biopsy irrelevant. Whether TM should influence the discussion about adjuvant chemotherapy itself may require a closer study of the outcomes of patients with TM in prospective trials.27, 28 However, such data are not publicly available.

In patients who do not elect to receive adjuvant chemotherapy, the options are testicular biopsy of the contralateral testes and scrotal radiation if ITGCNU is identified or surveillance with deferred treatment in patients who develop TGCT. Given the lack of a proven overall survival benefit, the morbidities of both options must be considered, especially hypogonadism. In our summary results, there was an estimated 20% prevalence of ITGCNU in patients who had TGCT with TM compared with <1% in patients without TM. Biopsies should be limited to patients with TM, and patients should be advised of an estimated chance ≥10% that they will develop a contralateral primary tumor over 5 years (based on a 50% risk of developing TGCT over 5 years, possibly higher with prolonged follow-up), mandating orchiectomy of the remaining testis, testosterone replacement, and the possible need for adjuvant treatment. Conversely, choosing an aggressive approach toward biopsy carries a 3% risk of developing edema, superficial hematoma, or infection. In the 20% of patients who have ITGCNU identified, approximately half would require androgen replacement after scrotal radiotherapy.29 Furthermore, based on the most extreme assumption that all ITGCNU will progress inevitably to TGCT (ie, contralateral ITGCNU in 20% of patients with TGCT, leading inevitably to contralateral TGCT, reports of burnt-out ITGCNU notwithstanding), a testicular biopsy remains unnecessary in 80% of patients with TM and TGCT, Because there are no current data supporting superior survival with either approach, either may be appropriate for individual patients. With this information, which is summarized in Figure 6, patients on both sides of the Atlantic will be able to make more informed decisions regarding whether a testicular biopsy would be in their best interests rather than being faced with an absolute recommendation 1 way or the other.

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Figure 6. This is a flow chart of recommendations for patients with testicular microlithiasis (TM). TGCT indicates testicular germ cell tumor; ITGCNU, intratubular germ cell neoplasia of unclassified type; chemo, chemotherapy.

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Patients with TM and subfertility have a lower potential risk for bilateral orchiectomy and may benefit less from radiation in terms of testes preservation. We believe that, in the absence of data supporting an overall survival benefit for early treatment of ITGCNU versus deferred treatment of a potential TGCT, minimizing potential toxicities of treatment is likely to be most sensible. Thus, on the basis of the assumptions detailed above, we favor a surveillance strategy.

Our meta-analysis highlights interesting biologic issues surrounding a condition for which the etiology, pathogenesis, and implications remain unclear. The interval development of TGCT does suggest that TM predates TGCT in some patients, fulfilling 1 criterion of causality. However, TM is an incidental finding in approximately 5% of asymptomatic men,1-4 the vast majority of whom do not develop TGCT, and their risk of TGCT is not increased. However, when risk factors for TGCT are present, TM defines a subset of men with an even higher risk of TGCT and ITGCNU. Even then, TM is neither necessary nor sufficient to identify TGCT nor ITGCNU. It seems likely, therefore, that TM is a marker of a condition that leads to TGCT rather than being causal. TM is associated with cryptorchidism,5-7 Klinefelter syndrome,30 subfertility,1, 8 poor sperm function,31 and clusters in certain families with familial germ cell tumors.32 One proposal has TM as a marker of testicular dysgenesis syndrome,22, 33 a poorly defined condition believed to be acquired in utero and associated with impaired testicular development manifested as testicular maldescent, testicular atrophy, low or absent sperm count, ITGCNU, and TGCT.

Limitations

The correlation of radiologic and pathologic TM may be incomplete, as noted by Renshaw.34 Two types of microcalcifications may be identified pathologically: hematoxylin bodies and multiple laminated calcifications within seminiferous tubules. It should be noted that these 2 types may be indistinguishable radiologically. Our pooled estimates are derived predominantly from retrospective studies, which may suffer from inherent biases. Several studies addressed inter-radiologist variability with independent radiologic review or by limiting the reading of scans to a few experienced radiologists. There is no consensus on criteria for diagnosing TM. The major subclassifications, classic TM or limited TM, are defined as >5 microliths per view or <5 microliths per view, respectively. Although several studies32, 35 suggest that classic TM may have a stronger association with germ cell tumors than limited TM, other studies suggest that this distinction is arbitrary and that there is no difference in the magnitude of risk.36 Most studies do not analyze these groups separately, precluding a separate analysis. It is noteworthy that bilateral microlithiasis may have a stronger association with preinvasive ITGCNU9 or TGCT, but this effect is difficult to study systematically, because TM usually is bilateral,1, 2, 37-39 and most studies do not consider them separately. We excluded pediatric studies, because concurrent TGCT is rare, and the duration of follow-up was too short to determine the development of interval TGCT. We conducted a comprehensive search of several databases and the bibliographies of included studies, and, although heterogeneity is high, the generated funnel plots do not suggest major publication bias.

Regarding the risk of interval development of TGCT in men with TM, only 2 studies reported the follow-up of men with and without TM. No TGCT was diagnosed in the study by Kosan et al,19 and Negri et al reported a risk ratio of 24 in subfertile patients. In this analysis, a summary risk ratio would not be meaningful. Crude incidence rates of individual studies were estimated using the median values if the mean values were not provided, which may have led to an underestimation of follow-up and an overestimation of risk. We did not attempt to summarize the overall crude incidence rates given the heterogeneity of follow-up and incidence rates.

In conclusion, TM is a common radiologic finding. It represents a heterogeneous condition that is observed in various benign and malignant processes. The vast majority of men with TM will not have and will not develop a germ cell malignancy. Asymptomatic, healthy men with TM probably do not need further surveillance or close follow-up. In the presence of risk factors for TGCT, TM is associated with coexisting TGCT and ITGCNU. The interval development of TGCT in patients with TM has been reported. Given the uncertainty of survival benefits resulting from early detection of TGCT and ITGCNU, the optimal management strategy is unclear. Patients with TM who have subfertility or who had a previous TGCT also have a considerable risk of premalignant ITGCNU, and a biopsy can be considered for these patients, offering them the possibility of avoiding orchiectomy and/or adjuvant treatment.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Dr. Iain B. Tan is supported by the National Research Foundation, Singapore. Dr. Min-Han Tan is supported by the Singapore Millennium Foundation.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES