Practical answers to testicular microlithiasis mysteries

Dr. Athanasios Zachariou ESUO Board Member Dept. of Urology University of Ioannina Ioannina (GR)

zahariou@otenet.gr

Testicular microlithiasis (TM) was reported for the first time in autopsy specimens by Oliye in 1928 and by Blumensaat in 1929. Doherty et al. [1] described the sonographic appearance of TM as “innumerable tiny bright echoes diffusely and uniformly scattered throughout in the substance of testes”. Since then, numerous publications have addressed the unmet need of office and outpatient urologists for an agreed TM surveillance protocol.

What is testicular microlithiasis? TM is defined as multiple similar small-sized echogenic non-shadowing with > 5 foci per testis. Clustering of the microliths is an essential aspect because five microliths per field may be more problematic than ten disseminated throughout the testis. The European Society of Urogenital Radiology showed a preference for a more detailed definition, describing TM as five or more microliths per field of view. [2]

“There is evidence that TM is a feature of the testicular dysgenesis syndrome (TDS).”

What is the prevalence of TM? Several studies are dealing with the prevalence of TM in both asymptomatic and symptomatic men. In a US army study, Peterson et al. (3) detected TM in 5.6% of asymptomatic males, while in another study of a similar population, the prevalence was 2.4%. [4] TM varies in asymptomatic males from 0.6 to 9.0%. In symptomatic males, the prevalence generally is higher, reaching from 8.7 to 18.1%. [5]

Clinical scenarios 1. TM as incidental finding at scrotal ultrasound The current recommendations are that incidental TM is not an indication for a regular scrotal ultrasound (US) follow-up in the absence of other risk factors. Furthermore, TM is not an indication for biopsy or further US screening. Patients should be monitored with a scrotal self-examination every month. In a patient with TM, office urologists should ascertain that there are no risk factors for developing Germ Cell Tumour (GCT).

Table 1: Risk factors in TM requiring follow-up or referral

Risk Factor > 5 TM per field of view Diffuse TM

Annual ultrasound Annual ultrasound

History of orchidopexy Annual ultrasound Annual ultrasound

GCT history Annual ultrasound Annual ultrasound Genetic diseases Annual or 6-month ultrasound Referral

Family history of GCT Discussion for open access

Discussion for open access Atrophic testis Annual ultrasound Annual ultrasound

2. Family history of GCT TM is significantly more common among men who have family members with GCT than in the general population. [6] Also according to Corde et al., TM was more prevalent among males in families with GCT than in the general population and was more common among familial GCT cases versus unaffected blood relatives. These findings suggest that TM may appear to cluster in certain families. Furthermore, variants of specific genes essential for testicular GCT are more common in TM patients than in fertile men. [7]

3. Association of TM with testicular cancer In recent years, several studies have described a relationship between TM and the risk of testicular cancer. According to Wang et al., the meta-analysis results describe a possible harmful outcome of TM for developing testicular cancer. [8] The authors found that compared with non-TM individuals or the general population, TM men may have more than a 12-fold higher incidence of testicular cancer. On the other hand, data published as part of follow-up programmes showed controversial results. Studies describing observation of men presenting TM for up to 14 years reported a 1.6% higher chance of developing testicular cancer. [9,10]

When the relationship between TM and the histologic subtypes of GCT is evaluated, there is evidence of a positive association between seminomas and a negative association between embryonal cell carcinomas. [11] Furthermore, there are reports that a higher TM count corresponds to a lower initial cancer stage at diagnosis, suggesting that TM may be associated with less aggressive tumours.

Nearly 20% of males with a history of GCT have TM in their contralateral testes. Those patients have an increased risk ratio of 8.9 for concurrent CIS compared with patients who do not have TM. [12]

The preceding studies have produced ambiguous results and did not establish elevated tumour markers in males with incidental TM; hence monitoring serum tumour markers in follow-up is inappropriate.

4. Association of TM with infertility In infertility, the TM prevalence varied between 0.9 to 20.1%, although the association of TM with male infertility is still under discussion. [13] There is evidence that TM is a feature of the testicular dysgenesis syndrome (TDS). TDS is assumed to reinforce disorders of male reproduction such as subfertility, testicular atrophy or cryptorchidism. [14]

TM-related obstruction of seminiferous tubules is a potential etiological factor for reducing sperm count and sperm motility in 30 to 60% of TM patients. The obstruction of seminiferous tubules, possibly formed by sloughing degenerative tubular epithelium, may create secondary inflammation, increased intraseminiferous pressure and alterations in the blood supply of testicles. Inflammation and calcification in the seminiferous tubules produce deterioration in sperm quality and cause subfertility. [15] Fertility potential may be further decreased by atrophy of uninvolved tubules with spermatogenic arrest or a combination of previously reported factors. It was advocated that microliths and infertility may have a mutual undisclosed etiological factor.

Subfertility is reported to be a risk factor for a testicular tumour. Data analysis revealed that GCT prevalence was 22.6% in infertile members of the TM group versus 1.7% in the infertile TM-free group. [16] Bilateral testicular microlithiasis is indicative of CIS (carcinoma in situ) in subfertile men. Therefore, the prevalence of CIS in subfertile men with bilateral testicular microlithiasis is significantly higher than in patients without testicular microlithiasis (0.5%) and with unilateral testicular microlithiasis (0%). [17] Thus, men with CIS are at particular risk of developing invasive GCT.

Fig. 1a and b: TM in the right testis of an infertile 37-year-old adult with a history of left orchidopexy

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“Men with risk factors and TM should be counselled about the potential increased risk of GCT, perform periodic self-examination and be followed by a medical professional.”

Conclusions Men with incidentally detected microlithiasis should not undergo further evaluation or screening. TM in the absence of solid mass and risk factors for developing a GCT does not represent an increased risk of malignant neoplasm and does not require further evaluation. Men with risk factors and TM should be counselled about the potential increased risk of GCT, perform periodic self-examination and be followed by a medical professional.

References

1. Doherty FJ, Mullins TL, Sant GR, et al. Testicular microlithiasis: a unique sonographic appearance. J

Ultrasound Med 1987; 6:389–392 2. Richenberg J, Belfield J, Ramchandani P et al. Testicular microlithiasis imaging and follow-up: guidelines of the

ESUR scrotal imaging subcommittee. European

Radiology 2015;25(2):323-30 3. Peterson AC, Bauman JM, Light DE et al. The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2001;166:2061–2064 4. Serter S, Gümüs¸ B, Unlü M et al. Prevalence of testicular microlithiasis in an asymptomatic population. Scand J

Urol Nephrol 2006;40:212–214 5. Deganello A, Svasti-Salee D, Allen P et al. Scrotal calcification in a symptomatic paediatric population: prevalence, location, and appearance in a cohort of 516 patients. Clin Radiol 2012;67:862–867 6. Tan, MH., Eng, C. Testicular microlithiasis: recent advances in understanding and management. Nat Rev

Urol 2011;8:153–163 7. Korde LA, Premkumar A, Mueller C, et al. Increased prevalence of testicular microlithiasis in men with familial testicular cancer and their relatives. Br J Cancer 2008;99(10):1748–1753 8. Wang T, Liu LH, Luo JT, et al. A meta-analysis of the relationship between testicular microlithiasis and incidence of testicular cancer. Urol J. 2015;12:2057–2064 9. DeCastro BJ, Peterson AC, Costabile RA. A 5-Year

Followup Study of Asymptomatic Men With Testicular

Microlithiasis. J Urol. 2008;179:1420–1423 10. Patel K V, Navaratne S, Bartlett E, et al. Testicular

Microlithiasis: Is Sonographic Surveillance Necessary?

Single Centre 14 Year Experience in 442 Patients with

Testicular Microlithiasis. Ultraschall der Medizin. 2016;37:68–73 11. Sharmeen F, Rosenthal MH, Wood MJ, Tirumani SH,

Sweeney C, Howard SA. Relationship between the pathologic subtype/initial stage and microliths in testicular germ cell tumors. J Ultrasound Med. 2015;34:1977–1982 12. Tan IB, Ang KK, Ching BC, et al. Testicular microlithiasis predicts concurrent testicular germ cell tumors and intratubular germ cell neoplasia of unclassified type in adults:A meta-analysis and systematic review. Cancer 2010;116:4520-32 13. Thomas K, Wood SJ, Thompson AJM, Pilling D,

Lewis-Jones DI. The incidence and significance of testicular microlithiasis in a subfertile population. Br J

Radiol. 2000;73:494–497. 14. Rassam Y, Grommol J, Kliesch S et al. Testicular microlithiasis is associated with impaired spermatogenesis in patients with unexplained infertility.

Urologia Internationalis 2020;104:610-6. 15. Xu C, Liu M, Zhang FF, et al. The association between testicular microlithiasis and semen parameters in

Chinese adult men with fertility intention: Experience of 226 cases. Urology 2014;84:815–820 16. Leblanc L, Lagrange F, Lecoanet P et al. Testicular microlithiasisand testicular tumor: a review in the literature. Basic and Clinical Andrology, 2018;28:8 17. De Gouveia Brazao CA, Pierik FH, Oosterhuis JW, et al.

Bilateral testicular microlithiasis predicts the presence of the precursor of testicular germ cell tumors in subfertile men. J Urol. 2004;171:158–160

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Updates from the EAU Adjunct Secretary General – Education

As of EAU21, Prof. James N'Dow (GB) is succeeding Prof. Van Poppel (BE) as Adjunct Secretary General - Education. In this exclusive interview, the former Chair of the EAU Guidelines Office Prof. N’Dow talked about his current role and his vision, updates on his PIONEER programme, and the people who inspired him.

What does your position entail and what are your aspirations in this role? It is an incredible honour to be entrusted with the EAU Adjunct Secretary General – Education position. The core mission of the EAU is to improve the quality of urological care. To provide our 19,000 EAU members with exceptional resources that help them in their daily clinical practice, education is a fundamental aspect in achieving this goal.

My team and I aim to truly understand the individual and collective endeavours of the many talented people involved in education within and beyond the EAU. Together, we will evaluate and see how our aspirations align with the expectations of the EAU members and the patients we all serve.

My role involves ensuring connectivity and collaborations across the EAU and its different Offices in terms of activities relating to education to harness diverse, complementary expertise across within and beyond the organisation; to limit unnecessary duplication of effort; and most importantly, to ensure that we are able to demonstrate the impact of educational activities on patient outcomes and healthcare efficiency over time.

Achieving these objectives will help fulfil the hopes of patients and meet their needs, as well as, help realise the aspirations of urologists wherever they may be in the world. You initiated the PIONEER programme, which is a project aimed to harness the potential of big data analytics as a means to ensure optimal care for European prostate cancer patients. Please tell us more about it. A key ambition of the Guidelines Office has always been to use the best evidence available to underpin guideline recommendations. It soon became clear that the quality of the majority of published evidence is unsatisfactory as the basis for recommendations. We needed to look for innovative ways to fill the gap. The use of big data was one such option. However, to do so would require significant funding. With the EAU’s support in partnership with its Research Foundation, the Guidelines Office put together a strong consortium to secure €12M-funding from the European Commission’s Innovative Medicines Initiative to collate the best and largest PCa datasets from within and beyond Europe. We feel fortunate to have had the privilege of working with patients, PCa specialists, scientists, epidemiologists, big-data analytics experts, ethicists, and Health Technology Assessment (HTA) experts.

In June 2021, we received confirmation of a €21.3M-funding from the European Commission’s Innovative Medicines for another Big Data project called OPTIMA, this time focussing on prostate, breast and lung cancers whereby Clinical Practice Guidelines are interfaced with Electronic Health Records and real-world data powered by Artificial Intelligence, if necessary. The OPTIMA consortium is also coordinated by the EAU.

Your other notable initiative is Horizons, which was created to increase the capacity and standard of healthcare through provision of education and training in your home country. What are Horizons’ latest developments?

Horizons now supports six childbirth facilities in The Gambia and has trained hundreds of mothers and midwives on maintaining clean, safe and infectionfree childbirth environments. The Horizons Charitable Trust installed solar-power facilities, renovated rundown infrastructure, guaranteed clean safe water supplies and safe disposal of clinical waste.

When did you know that you wanted to be a urologist? I always wanted to be a doctor but I didn’t know which speciality. My first surgical job was an attachment with the urology ward in Aberdeen. I was incredibly fortunate to work for an exceptional surgeon, John Steyn, who encouraged me to always do better.

Even though I was the most junior doctor in the department at that time, John Steyn didn’t treat me differently. Along with other senior hospital specialists, he welcomed me to his home. I admired John. He had amazing qualities as a surgeon and as a human being. He was an inspiration that cultivated my interest in the field of urology.

Who are your biggest inspirations and why? Aside from John Steyn, I was blessed with the guidance of other exemplary mentors, two of them no longer with us sadly. Prof. Adrian Grant, who was co-Chair of the Cochrane Collaboration, trained me in a breadth of research methods which helped secure numerous research grants. Prof. Robert Pickard, an academic urologist who trained me in Newcastle. He was an outstanding academic surgeon and a kind-hearted person.

And last but definitely not least, my parents. My father was an inspirational physician and philanthropist who taught me all I know about medicine as a vocation. He taught me that curing disease was not enough; that we must commit to supporting our patients and their families to regain their quality of life.

My mother, whom I loved dearly and think of every day, was a brilliant educator. She was an empowered, strong woman who taught my siblings and I that with hard work, determination, integrity and humility, we could reach and touch the stars. She always told us that the only limits were the limits of our imagination.

Converse with and follow Prof. N’Dow on Twitter via his handle @NDowJames.

Profiles Prof. Sønksen succeeds Prof. Wirth as EAU treasurer

“I have learned a lot from him, and I’ll do my best to bring that experience with me”

Prof. Jens Sønksen (DK) has a long history at the EAU. A member since 1996, he was part of the Scientific Congress Office from 2012 to 2017 and has served as Adjunct Secretary General - Clinical Practice since 2017. When the executive board, in the absence of Prof. Sønksen, discussed whom to suggest for the upcoming vacancy for treasurer, they decided to recommend a reliable force. Bring in Prof. Sønksen. “I was very honoured and proud, and I felt deep respect,” the newly appointed treasurer shared. “I hope to do it as well as my predecessor Prof. Manfred Wirth (DE) did. I will do whatever I can to be a treasurer that the EAU members are pleased with.”

Having been the president of the Danish Association of Urology and the chairman of the EU-financed collaboration between Denmark and Sweden named ReproUnion, which aims to manage and prevent fertility problems, Prof. Sønksen has gained relevant experience which prepared him for his new role. “Although I have never held the title of treasurer before, I have a lot of experience, both nationally and internationally. And as professor of urology at the University of Copenhagen, I also have to manage finances,” he stated.

“In my view, being a treasurer of an organisation such as the EAU is slightly different from, let’s say, a private company. The EAU is an organisation where a considerable part of the funds comes from paying members living all around the world. You should have a deep respect for that, and consequently employ a much more cautious investment strategy.”

What can you say about the position of the EAU at present? Prof. Sønksen: “We are still in a strong position despite the challenges we are facing due to the COVID-19 pandemic. Once again, things changed almost overnight just like they did back in 2008. The EAU proved that it was able to handle the financial crisis back then and I believe we shall be able to handle the current challenges, too.”

“However, COVID is changing the world, so including the medical world and not least its financial aspects. Before COVID, we already noticed a trend of decreasing sponsorships for the national societies and also for the EAU itself. It has not become easier to obtain sponsorships and other types of funding during the pandemic. And yet we are still in good financial shape. In respect of that, I have to mention Prof. Wirth, who has held this position for seventeen years. His time as a treasurer has been hugely successful. Sitting with him in the executive board for five years now, I have learned a lot from him, and I’ll do my best to bring that experience with me.”

“The EAU is an organisation where a considerable part of our funds comes from paying members living all around the world. You should have a deep respect for that.”

“I see a lot of opportunities for the EAU to expand. One of them is to strengthen our political profile in a European context and I feel we have taken a great step towards that with the establishment of the EAU Policy Office. Another development concerns patient-directed information. We want to extend our guidelines with evidence-based materials suitable for patients. EAU Patient Information is going to be a huge factor within the EAU and an EAU Patient Office has already been established.” Roots The roots of Prof. Sønksen’s involvement in the EAU go back to the urologist’s eagerness to educate himself and others. “I first learned about the EAU because of educational development,” he recalled. I took some courses and was involved in symposia.

After I had become an associate professor at the University of Copenhagen in 2003, I created a platform in my department for the development of more clinical science. I had many young colleagues who were very active in the EAU. They suggested that I should apply for a position at the scientific office. That’s how this was set in motion.”

Prof. Sønksen’s roots as urologist are in his home country Denmark, where he learned the importance of international collaboration. “Countries such as Denmark, Sweden, the Netherlands, and Belgium are relatively small countries in comparison with Germany, France, and Italy. You see that those smaller countries work together in terms of patient mobility. Take the Øresund Bridge between Denmark and Sweden, which brought Southern Sweden and the greater Copenhagen area much closer in terms of traveling time. We should utilise the expertise of, for example, a Swedish hospital highly specialised in a certain area as opposed to specialising in that same area at a Danish hospital nearby. And vice versa.”

These Danish influences contribute to who Prof. Sønksen is as an executive board member of the EAU. “I want to help build up international collaborations. When we facilitate collaboration between different countries, we will gain much more knowledge, knowledge which will be useful for patients in all countries under the umbrella of the EAU.”