Testicular microlithiasis: is it significant?

Men with scrotal symptoms, such as pain and swelling, not infrequently present to genitourinary medicine (GU) (sexual health) clinics. Scrotal ultrasonography is now considered a routine investigation in men presenting with such symptoms. ¹ In patients with chronic scrotal pain when physical examination and infection screening are negative, scrotal ultrasonography has been shown to be of little diagnostic value. ² In the presence of a palpable testicular mass ultrasound scanning has a clear diagnostic role. ³ Confirmation of an intratesticular mass on ultrasound scanning is diagnostic for a testicular neoplasm and would result in urgent urological referral. However, a more common finding than testicular cancer on scrotal ultrasonography is testicular microlithiasis (TM); the management of such men whose ultrasound is reported as showing TM remains unclear.

A BENIGN CONDITION?

Prior to the mid-1990s TM was considered to be a benign condition of little consequence until it was recognized that there was an association with testicular cancer. It was subsequently recommended that such a finding on scrotal ultrasonography should heighten the radiologist's suspicion of coexistent testicular malignancy. ⁴ Increasingly, case reports at this time showed compelling evidence for an association between TM and both seminoma and non-seminoma germ cell testicular cancers ^5–8 resulting in a recommendation that men with TM should be placed on surveillance ⁶ and that there should be regular ultrasonographic follow-up examinations. ⁵

PREVALENCE OF TM

Testicular microliths manifest themselves in a characteristic pattern on ultrasonography using high frequency transducers, showing themselves as multiple echogenic specks in an otherwise normal testicular parenchyma. ⁹ Modern ultrasound machines with transducer frequencies of 7–13 MHz are able to identify structures smaller than 1 mm leading to more accurate views of the testicular parenchyma and a higher detection rate of intrascrotal abnormalities, including TM. ¹⁰ The prevalence of TM on scrotal ultrasonography in symptomatic adult men (being investigated primarily for scrotal pain, scrotal swelling or infertility) has varied among published reports from a minimum reported 0.6% ⁹ to a maximum reported 18.1%. ¹¹ A prevalence of TM has been reported to be between 2.4% ¹² and 5.6% ¹³ among asymptomatic male adult volunteers. Pooled data from 15 published reports with a combined 33,549 scrotal ultrasound examinations give an overall prevalence of TM in adult men of 2.7%, with no significant difference between those with scrotal symptoms and those without. ^9–25 TM is not confined only to the adult men population but has been shown to have a prevalence of 4.2 percent in asymptomatic men aged 0–19 years old. ²⁶ The association of TM with testicular cancer is not confined to adult men but has also been described in association with germ cell tumours in boys aged two-, nine- and 16-years-old. ^27–29

CLINICAL ASSOCIATIONS

TM is almost universal in men with pseudoxanthoma elasticum (92–100%) ^30,31 and has been reported to be as high as 29% in men with Down's syndrome, ³² and to lie between 2.8% and 6.2% in subfertile men. ^33,34 TM is also associated with McCune–Albright syndrome ³⁵ as well as GALNT3 gene mutations. ³⁶ Although microliths in the testis are located in the seminiferous tubules and are composed of the inert substance hydroxyapatite ³⁷ their most important association is with germ cell testicular cancer.

TM AND TESTICULAR NEOPLASIA

Studies of symptomatic adult men (most common symptoms being scrotal pain, scrotal swelling or infertility) who had scrotal ultrasonography and were found to have TM have shown that between 5.8% ²⁴ and 53.8% ³⁸ were also found to have a germ cell testicular cancer. Pooled data from 15 studies in which 752 symptomatic adult men were found to have TM on scrotal ultrasonography revealed that 129 (17.2%) had a co-existent germ cell testicular cancer. ^{11,14–21,23–25,38–40} The relative risk of a testicular germ cell tumour in the presence of TM has been recorded in three studies and has been reported to be 21.6 (95% confidence interval [CI] 10.6–44.2), ¹⁶ 13.2 (CI 8.3–21.5) ¹⁸ and 36.5 (CI 4.2–429.6). ⁴⁰ In one study of infertile men who were referred for scrotal ultrasonography an association was observed between TM and testicular carcinoma in situ in men with bilateral microliths but not in those men with unilateral microliths. ⁴¹

The interval development of testicular neoplasia in men with pre-existent TM diagnosed by scrotal ultrasonography has been difficult to interpret due in part to the small numbers of men with TM involved and the relatively short follow-up in all published studies. Pooled data from 10 studies of 586 men with pre-existent TM who underwent surveillance revealed six new cases of testicular cancer with a median follow-up in the studies of between three and five years. ^{14,15,17,18,20,23,24,39,42,43} This has led some authors to question whether there is a significant association between TM and testicular cancer, ^12,13 However, isolated case reports have continued to report testicular germ cell tumour in the setting of TM detected by previous ultrasonography; ²⁹ in one case report after three years ²⁸ and another two cases after five and nine years, respectively. ⁴⁴

MANAGEMENT OF TM

Varied approaches have been advocated for the management of men diagnosed with TM on scrotal ultrasonography. Some authors have suggested that men with TM should be followed up by regular surveillance; ^{6,17,40,45–47} the most common form of follow-up being advocated seeming to be periodic testicular ultrasound, ^{4,5,14–16,20,28,29,31,48–50} with most reports suggesting annual scrotal ultrasonography. A few studies have recommended testicular self-examination alone as an acceptable method of surveillance. ^23,43,51,52 While some authors believe TM to be benign condition and question the need for any follow-up. ^{12,13,18,39,53} Some authors have advocated testicular self-examination alone with regular scrotal ultrasonography only for those men with additional risk factors for testicular cancer, ^24,42 such as an undescended testis, previous testicular cancer or a family history of testicular cancer. ^54,55

A national questionnaire survey of practicing urologists in the UK and Ireland (members of the British Association of Urological Surgeons) was conducted in 2006 to provide a snapshot of attitudes towards the investigation and surveillance of men diagnosed with TM. ⁵⁶ A total of 251 completed questionnaires were returned of which 173 (69%) did and 78 (31%) did not follow-up men with TM. Of the 173 who did follow-up men with TM, 119 (69%) followed up all men while 54 (31%) followed up only a selected group of men. Of those urologists who did follow-up men with TM, 6% arranged ultrasonography every six months, 88% annually and 6% at longer intervals. Lifelong follow-up was employed by 38%, until 55 years of age by 47% and 15% follow-up men for a minimum of five years. However, of those urologists who did follow-up men with TM, 38% reported that they did not think that such follow-up conferred any survival benefit.

More recently urologists in the Netherlands proposed a management algorithm for the follow-up of TM, which they define as ‘all hyperechogenic foci smaller than 3 mm without shadowing and irrespective of number’. ¹⁰ They suggest taking a testicular biopsy in men under 50 years of age with TM and at least one additional risk factor for testicular germ cell tumours. The risk factors include infertility, bilateral TM, cryptorchidism, atrophic testicles and contralateral tumour. For all other patients long-term follow-up with examination and ultrasound is not recommended but testicular self examination is advised.

CONCLUSION

In the last decade it has become generally accepted that TM is not the benign condition that it was initially considered to be but is associated with the development of testicular germ cell cancer. However, the management of those men who are found to have TM on scrotal ultrasonography remains unclear. We therefore recommend that in the setting of a GU (sexual health) clinic that men found to have TM on scrotal ultrasonography should have their general practitioner informed with a recommendation that they be referred to a urological unit.