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Testicular Microlithiasis

Prevalence and Tumor Risk in a Population Referred for Scrotal Sonography

¹ Department of Radiology, Hull and East Yorkshire NHS Trust, Hull Royal Infirmary, Anlaby Rd., Hull HU3 2JZ, United Kingdom.
² Department of Urology, Hull and East Yorkshire NHS Trust, Hull Royal Infirmary, Hull HU3 2JZ, United Kingdom.
³ Department of Radiology, York Health NHS Trust, York District Hospital, Wigginton Rd., York YO31 8HE, United Kingdom.

Received February 21, 2000; accepted after revision May 15, 2000.

 
Address correspondence to D. J. Breen.

Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
OBJECTIVE. Considerable accrued evidence points to an association between testicular microlithiasis, intratubular germ cell neoplasia, and testicular tumor. This study assesses both the prevalence of testicular microlithiasis revealed on sonography in a referred population and the concurrent tumor risk.

MATERIALS AND METHODS. Over a 32-month period (April 1996 through November 1998), 4892 scrotal sonographic examinations were performed in 4819 patients at four referral centers. All patients underwent high-resolution (7- to 10-MHz) imaging. Using a computerized word search (n = 4102; testicular microlithiasis, calcification, microliths, calcific foci, tumor, neoplasm, cancer, hyperecho, hypoecho, heterogen, and carcinoma) and manual retrieval (n = 790), cases of tumor, testicular microlithiasis (>5 microliths per sonogram), and testicular microlithiasis plus tumor were pulled and retrospectively reviewed. The presence and type of tumor were confirmed at histology after orchidectomy.

RESULTS. Fifty-four tumors were found among 4892 scrotal sonograms (28 seminomas, 14 teratomas, 8 mixed germ cell tumors, 2 Leydig cell tumors, and 2 non-Hodgkin's lymphomas). Testicular microlithiasis was present in 33 patients, giving a prevalence of 0.68%. Concurrent tumor and testicular microlithiasis were detected in seven patients, a relative risk of tumor in testicular microlithiasis was 21.6-fold (95% confidence limits: 10.6-fold, 44.2-fold). In one patient with testicular microlithiasis, a previous orchidectomy for mixed germ cell tumor had been performed (not included in the relative risk calculation).

CONCLUSION. In a referred population of 4819 patients the prevalence of testicular microlithiasis was 0.68% and the relative risk of concurrent tumor was 21.6-fold. Sonographic surveillance of testicular microlithiasis cases for tumor is mandatory.

Introduction

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Testicular microlithiasis is an uncommon condition with a reported prevalence of 0.6% in patients referred for scrotal sonography [1]. There is both accrued and largely anecdotal evidence of an association between testicular microlithiasis, intratubular germ cell neoplasia, and testicular tumor [2,3,4,5,6,7,8,9,10,11].

To our knowledge, this study analyzes the largest cohort of patients referred for scrotal sonography thus far; we assessed the prevalence of sonographic testicular microlithiasis and the relative risk of concurrent tumor.

Materials and Methods

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Over a 32-month period from April 1996 through November 1998, 4892 scrotal sonographic examinations were performed in 4819 patients at four referral centers. All patients scanned were included regardless of indication for referral. Using a standard computerized word search program (Microsoft Word; Microsoft, Seattle, WA) (n = 4102) and a manual search (n = 790), we identified all reports containing "testicular microlithiasis," "calcification," "microliths," "calculi," "calcific foci," "tumor," "neoplasm," "cancer," "hyperecho," "hypoecho," "heterogen," and "carcinoma." The sonograms and case notes of these patients were retrospectively reviewed. The computerized word search relies on testicular microlithiasis being diagnosed or described by the original reporting radiologist, who must pay attention to good sonographic technique with correct positioning of focal zones and use of the appropriate time gain compensation curve. It is therefore possible that some cases were missed.

The presence of testicular microlithiasis was based on the consensus opinion of two consultant abdominal radiologists using the accepted typical sonographic appearance as described by Backus et al. [2] of multiple small nonshadowing echogenic foci up to 3 mm in size, with five or more evident on a single sonogram (Figs. 1 and 2). Solitary calculi or multiple coarse shadowing calcifications were not included.

View larger version (118K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1. —Testicular sonogram of 41-year-old man, who presented with scrotal lump, shows typical appearance of testicular microlithiasis with at least five microliths per sonogram. No other abnormality was seen.

View larger version (134K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2. —Testicular sonogram of 33-year-old man, who presented with scrotal swelling, shows slightly coarser calcifications of up to 3 mm. Number of microliths is, however, in keeping with diagnosis of testicular microlithiasis. Swelling was epididymal cyst (not shown).

The presence and type of sonographically suspected tumor were confirmed at histology after orchidectomy and in one case by paraaortic nodal biopsy. Any relevant previous medical history was recorded from the case notes.

All patients underwent high-resolution sonography on a range of commercially available scanners (Elegra Advanced Platform, Siemens, Bracknell, UK; SSD2000, Aloka, Tokyo, Japan; Eccocee, Toshiba, Crawley, UK; Diasonics VSP Masters and Gateway, IGE, Slough, UK; ATL Ultramark 9 and HDI5000, Philips Medical Group, London, UK; and 128, Acuson, Uxbridge, UK) with 7.5- to 10-MHz linear array probes or a 7-MHz sector probe (Acuson 128).

The prevalence of testicular microlithiasis in the referred population and a relative risk analysis for concurrent tumor and testicular microlithiasis were calculated.

All patients in whom testicular microlithiasis was detected were scheduled for 6-month or annual sonographic follow-up.

Results

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A total of 4892 scrotal sonograms were obtained in 4819 patients (age range, 18-74 years; mean, 37 years). These yielded 54 testicular tumors, of which 28 (51.9%) were seminomas, 14 (25.9%) were teratomas, and eight (14.8%) were mixed germ cell tumors. Two (3.7%) were Leydig cell tumors, and two (3.7%) were non-Hodgkin's lymphomas. The prevalence of testicular tumors in this population is therefore 1.1%.

Testicular microlithiasis was present in 33 patients (age range, 13-61 years; mean, 37.2 years) resulting in a prevalence of 0.68%. Concurrent tumor and testicular microlithiasis were detected in seven patients (age range, 24-43 years; mean, 31 years) (Fig. 3). The calculated relative risk of concurrent tumor in the setting of testicular microlithiasis is 21.6-fold (95% confidence limits: 10.6-fold, 44.2-fold).

View larger version (136K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3. —Testicular sonogram of 25-year-old man who presented with mass in left testis. Note testicular tumor showing coarse calcification with microlithiasis in surrounding testis.

A 46-year-old man, not included in the relative risk calculation as a concurrent tumor, had undergone previous orchidectomy for a mixed germ cell tumor in 1990. The original sonogram from 1990 was not available for review and only testicular microlithiasis was seen on subsequent sonographic examinations of the remaining testis performed during the study period. Review of the histologic specimen from 1990 did, however, show intratubular germ cell neoplasia and intratubular calcifications (pathologic testicular microlithiasis) in the background testis. By implication, sonographic testicular microlithiasis in 1990 may have been subtle, unrecognized, or missed. If this patient was included in the calculations as having concurrent tumor and testicular microlithiasis, the resulting relative risk would increase to 24.7-fold (95% confidence limits: 12.7-fold, 48.1-fold).

A 43-year-old man with testicular microlithiasis and tumor had also undergone previous orchidectomy. This was performed in 1988 for seminoma without preoperative sonographic examination. Histologic review showed intratubular germ cell neoplasia in the adjacent background testis but no pathologic testicular microlithiasis. This patient is included in the relative risk calculation because he presented later in the study period with seminoma in the contralateral testis in the setting of sonographic testicular microlithiasis.

Discussion

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Testicular microlithiasis was first reported by Priebe and Garret [12] in 1970 in a healthy 4-year-old boy. With increasing pathologic awareness came the first description of its sonographic appearance by Doherty et al. [13] in 1987. Sonographic testicular microlithiasis appears as small nonshadowing hyperechoic foci ranging in diameter from 1 to 3 mm [2, 3] (Figs. 1 and 2). These occur within the testicular parenchyma but may be distributed peripherally or segmentally. Testicular microlithiasis usually occurs bilaterally, but it has been reported in a single testis [6, 8, 10]. The number of microliths required to define testicular microlithiasis has been arbitrary, but the consensus now is to accept five on a single sonogram as a reasonable cutoff [2, 8]. Small localized areas of calcification have long been recognized in benign processes such as inflammatory scars, granulomata, and infarction with hemorrhage [2]. Similarly, variable testicular calcifications are often seen sonographically within testicular tumors, but they do not tend to show the characteristic configuration of testicular microlithiasis as previously described (Fig. 3).

Several associations have been reported with testicular microlithiasis including Klinefelter's syndrome, cryptorchidism, Down's syndrome, male pseudohermaphroditism, pulmonary alveolar microlithiasis, previous radiotherapy, and subfertility states [3, 13,14,15,16]. The most important association is with testicular neoplasms [2,3,4,5,6,7,8,9]; a strong association is again confirmed by this study. These are, however, only associations, and no cause-and-effect relationship has been established. Indeed, testicular microlithiasis may simply act as a marker of an abnormal testis affected by a range of abnormal processes, all of which may in their own right be associated with testicular malignancy.

Previous reports have indicated a prevalence of testicular microlithiasis of 0.6% in a population referred for symptomatic scrotal sonography [1]. In our referred patient cohort we found testicular microlithiasis in 0.68% of patients. The mean age of patients presenting with testicular microlithiasis alone was higher than that previously observed: 37.2 years (age range, 13-61 years) versus 22.3 years [5]. However, the reported age range for this condition has ranged from 10 months to 70 years [2, 5]. In this study, the mean age of patients with concurrent testicular microlithiasis and tumor was 31 years (age range, 24-43 years), similar to that which has been previously observed (29.8 years) [5]. These mean ages and age ranges suggest that testicular microlithiasis becomes less significant in terms of tumor risk when detected in older patients. The overall incidence of testicular microlithiasis in specific age groups remains unclear. Although covering a wide age range, our referred patient cohort tends to reflect the age group deemed at highest risk of testicular tumor.

The exact cause of testicular microlithiasis remains unclear. Pathologically, the microliths are intratubular bodies with a central calcified core and surrounding concentric laminations composed of collagen fibers. The microliths are thought to result from defective phagocytosis of degenerate tubular cells by Sertoli's cells [17]. The question remains as to whether the presence of microliths indicates abnormal tubular epithelium and Sertoli cell dysfunction or their presence incites epithelial change.

A number of reports have highlighted the close association between testicular microlithiasis and intratubular germ cell neoplasia. Based on autopsy data, the prevalence of intratubular germ cell neoplasia in the general population is approximately 0.8% [18], and it has been found in 4.5% (n = 1188) of biopsies of the contralateral testis in patients presenting with testicular tumor [19]. This figure is likely to be an under-estimate; intratubular germ cell neoplasia may be focal or missed by virtue of sampling error. Intratubular germ cell neoplasia can progress to carcinoma in 50% of cases [20]. Of particular note, in one series of 21 patients with testicular tumor and intratubular germ cell neoplasia, 14 (67%) were found to have sonographically identifiable testicular microlithiasis in the ipsilateral parenchyma [11]. This small series suggests that testicular microlithiasis might be used as a marker for underlying intratubular germ cell neoplasia.

Despite a compelling association between tumor, intratubular germ cell neoplasia, and testicular microlithiasis, there are few reports of tumor developing in the setting of testicular microlithiasis. This subject was recently reviewed by Ganem et al. [21] who summarized five reported cases in which a tumor had arisen in testicular microlithiasis between 10 months and 11 years after the original finding of microlithiasis [7, 8, 22,23,24]. To date, we have accrued 234 months of follow-up scanning from our cases of testicular microlithiasis, with the longest follow-up being 38 months. Thus far, no metachronous tumor has been detected. The 43-year-old patient previously described does, however, have testicular microlithiasis and seminoma in the remaining testis where a previous orchidectomy yielded seminoma and intratubular germ cell neoplasia.

Testicular microlithiasis has also been reported in association with intraabdominal [25] and intrathoracic germ cell tumors [3]. We have encountered a similar case: a 37-year-old man underwent excision of a poorly differentiated malignant mediastinal teratoma in 1994. Scrotal sonography at that time revealed low-grade testicular microlithiasis but no focal mass. Onco-logic follow-up revealed no tumor recurrence. The patient presented again in 1999 with lower abdominal discomfort. During his diagnostic workup a scrotal sonogram revealed low-grade testicular microlithiasis and a focal hypoechoic area at the lower pole of the left testis measuring approximately 12 mm (Fig. 4). A left inguinal orchidectomy was performed. Histology revealed atrophic seminiferous tubules lined only by Sertoli's cells with no evidence of intratubular germ cell neoplasia or focal tumor. A small fibrotic focus was seen but could not be directly equated with the sonographic abnormality. The significance of an association between abdominal or thoracic teratomas and testicular microlithiasis remains unclear.

View larger version (98K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4. —Testicular sonogram of 37-year-old man, who presented with mediastinal teratoma in 1994, shows clustered microlithiasis centered around irregular 12-mm hypoechoic area (arrow) toward lower pole. Histology showed tubular atrophy but no evidence of neoplasia.

In summary, this population study of 4819 patients referred for scrotal sonography has yielded a prevalence of 0.68% for testicular microlithiasis and a 21.6-fold relative risk for tumor in the setting of testicular microlithiasis (95% confidence limits: 10.6-fold, 44.2-fold). Although the findings do not prove a cause-and-effect relationship, they do suggest that sonographic testicular microlithiasis may indicate underlying testicular abnormality and may be a strong indirect marker of intratubular germ cell neoplasia with its proven malignant potential. Surveillance of patients with testicular microlithiasis for tumor appears mandatory. We recommend annual sonographic follow-up and patient education about self-examination.

References

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