Haitham Dagash, Department of Paediatric Surgery, Sheffield Children’s Hospital, Western Bank, Sheffield S10 2TH, UK. e-mail: email@example.com
To review our current practice of follow-up for boys with testicular microlithiasis (TM), an uncommon condition characterized by calcification within the seminiferous tubules, detected by ultrasonography (US); TM has been associated with both benign and malignant conditions of the testes but the natural history of TM in children remains unclear.
PATIENTS AND METHODS
All boys diagnosed with TM over a 14-year period were included in this study. A search of the radiology database was carried out using the keywords ‘testicular microlithiasis’ and ‘testicular calcification’. A retrospective case-note review was then used to determine age at diagnosis, presenting symptoms, indication for testicular US, outcome and follow-up. We also searched Medline/PubMed, using the same keywords for published data on TM from 1970 to 2006.
Over the study period 711 testicular scans were taken in 623 patients; seven cases (1.1%) of TM were identified. The mean (range) age at presentation was 12 (7–15) years. The presenting symptoms were testicular pain (three), undescended testes (two), hydrocele (one) and asymptomatic scrotal swelling (one). In five cases the TM was bilateral and in two a solitary kidney was identified. Only one patient had tumour markers measured (β-human chorionic gonadotrophin and α-fetoprotein) and these were within normal limits. On yearly US follow-up, the TM was less prominent in one patient, unchanged in four and two were lost to follow-up. Three patients are currently on yearly US follow-up while two are under the care of adult general surgeons. The analysis of reports published to date indicated that malignancy only develops when TM is associated with other predisposing factors.
There is no convincing evidence that TM alone is premalignant. However, when it accompanies other potentially premalignant features we recommend annual US follow-up.
Testicular microlithiasis (TM) is a rare condition in children that can be a radiological or histological diagnosis. The appearances on ultrasonography (US) are of multiple 1–3 mm echogenic foci within the parenchyma of the testis (Fig. 1) . The condition is characterized by calcification within the seminiferous tubules. The microliths are composed of a central calcified core surrounded by fibres of collagen. The pathophysiology is thought to be degeneration of the seminiferous tubules . Priebe and Garret  reported the radiological appearance of TM in a 4-year-old boy, who was being investigated for pharyngitis and right thigh tenderness, as early as 1970. TM has been reported in association with several benign conditions, including cryptorchidism , infertility , varicocele  and torsion of the testis . However, the alleged association between TM and testicular malignancy prompted us to review our current practice.
PATIENTS AND METHODS
A search of the radiology database at Sheffield Children’s Hospital was carried out using the key words ‘testicular microlithiasis’ and ‘testicular calcification’ using various combinations. The study period was from January 1990 to April 2004 and included all patients referred for scrotal US. A retrospective case-note review was then used to determine age at diagnosis, presenting symptoms, indication for testicular US, outcome and follow-up. We also reviewed data on tumour markers and histological data if available. Any children with coexistent testicular tumours were excluded. The scientific database Medline/PubMed was searched from 1970 to 2006, using the keywords ‘testicular microlithiasis’ and ‘testicular calcification’, and relevant reports reviewed.
Over the study period, 711 testicular US scans were taken in 623 patients, and seven cases (1.1%) of TM were identified. The mean (range) age at presentation was 12 (7–15) years. The presenting symptoms were testicular pain (three), undescended testes (two), hydrocele (one) and asymptomatic scrotal swelling (one). In five cases the TM was bilateral and in two cases a solitary kidney was identified. Only one patient had tumour markers measured (β-hCG and α-fetoprotein) and these were within normal limits. None of the patients had a testicular biopsy. On yearly US follow-up, the TM was less prominent in one patient, unchanged in four, and two patients were lost to follow-up. Three patients, with a median age of 13 years, are currently on yearly US follow-up (one had previous bilateral orchidopexy), while two are under the care of adult general surgeons. To our knowledge, none of these patients has developed testicular cancer at a mean (range) follow-up of 35 (8–67) months. One additional case was seen outside the present study group, who presented with testicular asymmetry in early puberty at the age of 12 years. US showed normal testicular architecture and vascular pattern on both sides, but the long axis of the left testis was 7.0 cm, vs 2.6 cm on the right side; annual US follow-up is planned.
The Medline/PubMed search detected 142 abstracts in English. All the abstracts deemed pertinent to the study were scrutinized by one of the authors (H.D.) and the relevant full-text papers, which were in English, were acquired and reviewed by both authors. In all we reviewed 65 full papers, including all the case reports of testicular malignancy developing in patients with previously documented TM.
The association between TM and malignancy was first highlighted in 1982 by Ikinger et al. ; testicular specimens from 92 postoperative patients (43 with malignant and 49 with non-malignant disease) were examined by a mammographic technique. Microcalcifications were found in 32 (74%) of tumour specimens, but in only eight (16%) of benign specimens. Backus et al.  reviewed 42 cases of TM; 40% had associated tumours, but the location and extent of TM did not correlate with the presence or absence of tumour. Because the natural history of this condition was ill-defined, and with various published case reports proclaiming that TM is premalignant, most urologists and radiologists at the time opted to follow patients with TM. Hobarth et al.  diagnosed TM by US in 16 patients, six of whom had a testicular tumour also present. They recommended that, in the presence of a definitive US diagnosis of TM, exclusion of malignancy and US follow-up are indicated. Similarly Patel et al.  identified four patients with TM over a 7-year period, of which three had a coexistent testicular carcinoma. Again their recommendation was follow-up with US.
TM is usually an incidental finding on scrotal US during patient evaluation. The true incidence of TM in the general population has not been determined. There are various reports claiming incidence rates, but these are actually prevalence rates because they are from a selected group of patients undergoing scrotal US; the reported prevalence is 0.6–9%[11–13]. In an elegant study by Peterson et al.  the incidence of TM in an asymptomatic group of 1504 army reservists aged 18–35 years was 5.6%. The incidence varied with race, being 4.2% in White subjects, 14.1% in Afro-Caribbeans and 8.5% in Hispanics. This racial distribution, coupled with the lower incidence of testicular cancer in Afro-Caribbeans, questions the association between TM and testicular malignancy. Another point raised by that report is the negative correlation between the geographical prevalence of testicular cancer (lowest in south-eastern USA) with the incidence of TM, which was higher in subjects from that area.
There were nine reports of testicular malignancy developing in patients with previously documented TM (Table 1) [4,15–21]. Salisz and Goldman  reported on a 32 year-old man with a history of left cryptorchidism who developed a mass in the right testis while under surveillance for subfertility; this mass was subsequently found to be an embryonal cell carcinoma. Otite et al.  reviewed 3026 scrotal US, and found TM in 54 patients (1.7%). Two patients (5.2%) developed interval testicular cancers; a 29-year-old who had initially presented with an atrophic left testicle and bilateral TM and who was diagnosed with a seminoma of his left testicle 2 years later, and a 34-year-old who presented with weakness and back pain, and was found to have a metastatic embryonal cell carcinoma and bilateral TM at presentation. At 4 years after chemotherapy, he was found to have a right testicular seminoma with a small embryonal component . Golash et al.  reported on a 47-year-old man who presented with an atrophic left testis and bilateral TM, and 6 months later developed a mass in the atrophic testis, which histology confirmed to be a seminoma. Gooding  reported on a 29-year-old with an atrophic left testis who developed a seminoma on the same side 11 years later. The patient reported by Winter et al.  initially presented with haematospermia and testicular pain and left TM, which developed into a seminoma 3 years later. The youngest case of tumour developing in association with TM was reported by McEniff et al. in a 21-year-old who was being followed-up for 4 years for his right TM; notably, the reason for his referral was that the right testis was larger than the left, and the histology in that case was a yolk sac tumour. Emberton and Moody  reported on a 39-year-old man who presented with an abdominal swelling and diffuse bilateral TM; biopsy of this mass confirmed seminoma. By carefully analysing these cases, it is evident that most of these cases had another predisposing factor for the development of testicular tumours (atrophic testis, cryptorchidism, infertility and previous testicular tumour).
Table 1. Reported cases of TM and testicular malignancy
In a study of 263 subfertile men, 53 (20%) had TM. Six of 30 men with bilateral TM were diagnosed with carcinoma in situ (CIS). The prevalence of CIS in subfertile men with bilateral TM was significantly higher than in men with unilateral TM (6/30 vs 0/23, P < 0.001) . It was also found that US at 2 years after orchidopexy for cryptorchidism revealed a 10% incidence of TM in the fixed testis. Nineteen patients were followed-up for a median (range) of 8 (2–15) years and two developed malignancy. This represents a two- to three-fold greater risk of malignant transformation in the cryptorchid testis with TM than in the cryptorchid testis with no TM .
There are few data about TM in children, as most published reports deal with adults. The natural history of the condition has not been defined, and the need for and method of follow-up are controversial among paediatric urologists. Kocaoglu et al. followed-up nine boys with TM (mean age 9.2 years, range 3–16) for 0.5–6 years, and who did not develop any tumours. However, they concluded that a larger population and longer control period were necessary before any firm conclusions could be drawn. Furness et al.  solicited 15 institutions for cases of incidentally discovered TM. Data were collected from only seven, for a total of 26 patients with a mean (range) age of 12.3 (0.5–21) years. The follow-up was 1 month to 7 years (mean 27.6 months), and again no testicular tumours developed during this time. Coley  reported on an 8-year-old boy who presented with left scrotal pain and was found to have bilateral TM; he was followed-up by US and 4 years later the TM had resolved.
The pathogenesis of the microcalcospherites in TM is unknown. As early as 1979, Nistal et al.  reported TM in two boys with bilateral cryptorchidism. In biopsy samples the seminiferous tubules contained calcified microliths. They hypothesized that microlithiasis might be a systemic disease, as a similar concentration of microliths was present in the lungs and nervous system. Cortes et al.  found that multinucleated spermatogonia occurred in 13/163 (8%) of 163 cryptorchid boys. In two of the 13 cases, TM was present. The finding of multinucleated spermatogonia in cryptorchid boys might be regarded as a feature of possible testicular degeneration. In another study, 112 males had their fertility evaluated; they had all had orchidopexy and bilateral testicular biopsy (mean age 8.6 years) for unilateral or bilateral undescended testes. At a mean age of 19.6 years, they all had a physical examination and scrotal US to evaluate testis size, echo texture and abnormalities, and eight (7%) were found to have TM . These reports suggest that TM might be due to degenerative histological changes. However, Drut and Drut  suggested that microliths might result from multifocal Sertoli cell dysfunction. In a detailed study of 11 children aged 3–15 years, using histological and immunohistochemical techniques, the microliths were located outside the tubules and thus could have been present since the early stages of testicular development.
The method of follow-up for patients with TM is debatable. Miller et al.  recommend CT surveillance. Most authors would agree on US follow-up, but for how long? Rosenfield  recommended US every year for those aged 20–50 years. Ganem et al.  went further and suggested extensive evaluation, including chest X-ray, abdominal CT and testicular biopsy, but this was for men with TM and a history of testicular cancer.
In conclusion, we think that routine follow-up of TM is unnecessary, a waste of resources and, much more importantly, generates unnecessary anxiety for patients and their families. The view that TM is premalignant is based on a few case reports rather than firm scientific data. Our approach is not to follow-up cases of incidentally discovered TM unless there are other risk factors for developing malignancy. The patients will be advised to carry out monthly self-examinations. However, if TM is found in a patient with a known risk factor for testicular cancer, e.g. cryptorchidism, infertility, testicular atrophy, testicular asymmetry or previous history of testicular cancer, then they warrant annual scrotal US and regular examination by the urologists.