Testis cancer therapy and fertility

Three challenging cases in the outpatient and office urology setting

brenneis-dr@gmx.de helabio@yahoo.gr

In the case of a newly diagnosed malignant tumour, the initial focus is on the therapy strategies and chances of cure. Most patients with urological cancers have already concluded their family plans. However patients with malignant testicular tumours have a low age of predilection (15-35 years) and thus they are just prior to or during their reproductive age. Therefore, in addition to inquiries of further diagnostics, therapy, and prognosis, the question of further life planning with regard to the desire for children and fertility preservation should also be addressed during the diagnosis.

Since the cure rate of testicular tumour is almost 100% in predominantly young patients, the question of fertility preservation after completion of therapy is becoming increasingly important. Studies in gynaecology show that 76% of men and women wish to have a child after completion of therapy, however, only 12% felt adequately informed by the treating physician prior to therapy [1,2]. Since the primary diagnosis is usually made in the office or at the outpatient urology clinic, this specialist group has a high responsibility in terms of counselling this group of patients.

This fact is also taken into account by the EAU Guidelines on Testicular Cancer [3], which points out that the patient should be informed about fertilitypreserving measures during the diagnostic process. In particular, a pre-therapeutic ejaculate analysis should be performed if necessary. Furthermore, a hormone status (testosterone, FSH, LH) should be determined. Pretherapeutic sperm quality is often reduced in affected patients. Leydig cell insufficiency is also frequently present. Treatment of testicular carcinoma can further damage the reproductive function. However, sperm quality often recovers within 1-4 years after surgery, radiation, or chemotherapy depending on the doses of radiation and the type of the administered chemotherapy.

Case 1 - L.S. *1990 and the remaining genitals were inconspicuous. The ultrasonographic examination showed two 5 and 10 mm inhomogeneous masses centrally in the left testis (Figure 2) and dilated venous vessels confirmed the presence of varicocele. Tumour markers (ßHCG, AFP) were within the normal range. Peripheral testosterone level was normal at 6.73ng/ ml (3-9ng/ml). Semen analysis revealed normal findings with normal sperm count. After discussion with the patient, a cryo-depot was created from 2 sperm donations. In July 2022, a radical orchiectomy on the left testis with contralateral testicular biopsy on the right testis was subsequently performed. Histologically, a seminoma with GCNIS in the surrounding testicular tissue was found. Right testicular biopsy showed no GCNIS. In seminoma stage 1 Lugano (pT2cN0cM0L0V1S0R0), a good prognosis, a surveillance strategy was proposed. This proposal was confirmed in the presentation at the German Second Opinion Centre Testicular Tumour (eKonsil). The follow-up was scheduled for January 2023 without any finding.

On September 2022, patient L.S. (born in 1990) presented to the urology office with painless right testicular enlargement. In his medical history he reported a bilateral orchidopexy during his childhood. He was suffering from the sequelae of a COVID-19 infection in the sense of long-COVID syndrome. The clinical examination showed a hardened and enlarged right testis of about 8cm. The left testis was normal. Ultrasonographically the entire right testis was consumed by an inhomogeneous tumour. Only a narrow fringe of normal testicular parenchyma was found marginally (Figure 1). Testicular tumour markers were negative (ßHCG <0.1 IU/l; AFP 2.5ng/ml). His hormonal profile revealed decreased testosterone with normal pituitary hormones (testosterone 1.82ng/ml (3-9), FSH, LH, estradiol normal). The CT examination of the thorax and abdomen showed inconspicuous organs, with no enlarged lymph nodes. As the couple wished to have a child, a semen analysis was performed. The semen analysis showed only a few motile spermatozoa (on average 1 sperm WHO-A motile, 1-2 dead spermatozoa per field of view) in the context of OAT syndrome (oligoasthenoteratozoospermia).

Cryopreservation was not possible. The patient underwent right radical orchiectomy and the histological examination revealed an embryonal cell carcinoma of the right testis pT1cN0cM0R0. A surveillance strategy was recommended. The case was presented to the German Second Opinion Centre Testicular Carcinoma (eConsil) and the recommendation was confirmed. In January 2023, an inconspicuous follow-up examination was performed and a re-evaluation of the fertility status is planned after 1 year. The question of testosterone substitution has not yet been conclusively resolved, as it will also have a negative impact on sperm quality which may also be negatively affected by testicular carcinoma per se. In addition, it is unclear to what extent the long-COVID syndrome could influence his fertility potential.

In accordance with the EAU Guidelines, all patients should be offered sperm cryopreservation (3). This should ideally be done before surgery, or at the latest, before chemotherapy. Since cryopreservation causes a 50% deterioration of sperm quality, a pretherapeutic ejaculate analysis is necessary to assess the existing fertility and to exclude higher grade fertility disorders. The goal is to preserve sufficient sperm for approximately 10 ICSI cycles. However, after recovery of spermiogenesis, the dissolution of the cryo-depot should be considered, also for cost reasons. This is also one of the tasks of outpatient follow-up urologists.

Case 2 - M.L. *1999

In July 2022, patient M.L. (born in 1999) presented with a slight pain in the left testicle. In addition, there was a fear of a testicular tumour following the press reporting 3 testicular tumour cases in players of the German "Bundesliga" (national soccer league). These reports led to many presentations in urological offices in Germany in 2022 to emphasise the need of the clinical and ultrasonographic examination of young men.

Clinical examination showed two hard lumps in the left testis and a varicocele grade I-II. The right testis

Approaches to cryopreservation of spermatogenetic stem cells in prepubertal patients with testicular tumours are currently still considered experimental [4, 5]. In particular, fertility preservation in the case of germ cell neoplasia in situ (GCNIS) of the contralateral testis should also be considered. Recommended radiotherapy of the residual testis can lead to irreversible damage to the germinal epithelium and subsequent infertility. In this case, a detailed explanation to the patient is necessary. In this rare situation, individual therapy planning is necessary, also in the sense of a risk-adapted watchful waiting strategy in case of an existing desire for parenthood. Bilateral synchronous and metachronous testicular tumours represent a further challenge. In this case, attention to the fertility situation is also urgently required.

Case 3 - M.H. *1992

In November 2011, patient M.H. (born in 1992) underwent radical orchiectomy for a mixed testicular tumour (70% seminoma, 30% teratoma). Clinically it was a stage 1, therefore a surveillance strategy was followed. In the regular follow-up, last 9-monthly, control examinations presented normal findings without change of tumour marker levels. On July 2022 an echo-reduced finding in the left residual testis near the vascular bundle was noticed (see figure 3). This finding was confirmed by the MRI. In the laboratory, ßHCG increased to 5.0ng/ml

(to 3.0ng/ml) with normal AFP and LDH. Peripheral testosterone levels were within normal range. There was an urgent suspicion of metachronous testicular carcinoma in the remaining testis on the left side after orchiectomy for testicular carcinoma right sided 10 years ago. The findings were discussed in detail with the patient, who had no children of his own yet. A normal semen analysis was performed and 2 cyrosperm deposits were created. The left testis was surgically exposed. Cryosection confirmed the finding of testicular carcinoma. Because of the anatomically very unfavourable position at the vascular pedicle, it was not possible to perform an organ-sparing resection and radical left orchiectomy was performed. The histological examination showed a classic seminoma without angio- and neural sheath infiltration with extensive GCNIS and reduction of spermiogenesis, Stage 1, pT1cNx M0 V0Pn0. The MRI revealed suspicious retroperitoneal lymph nodes but these had completely regressed on follow-up 3 months later. This was also followed by presentation to eConsil. Surveillance strategy was initiated. Follow up was unremarkable. Shortly after surgery, testosterone substitution with testosterone undecanoate depot (TUD) was initiated.

Thus, in addition to the diagnosis and treatment modalities of testicular carcinoma, the issue of fertility forms an important pretherapeutic aspect in young patients with a high chance of cure and long-term survival. These aspects should not be lost sight of, especially in office and outpatient urology when the diagnosis is mostly shocking for the patient, since mistakes in primary management can be hardly corrected later.

References

1. Liebenthron J, Baston-Büst DM, Bielfeld AP, Fehm TN, Kreuzer VK, Krüssel J-S. S2k guideline: fertility preserving measures in oncological diseases. Gynaecologist 2018; 51(11):926-36.

2. Schover LR, Rybicki LA, Martin BA, Bringelsen KA. Having children after cancer. Cancer 1999; 86(4):697-709.

3. M.P.Lagana et al: EAU Guidelines on testicular cancer 2015.

4. Picton HM, Wyns C, Anderson RA, Goossens E, Jahnukainen K, Kliesch S et al. A European perspective on testicular tissue cryopreservation for fertility preservation in prepubertal and adolescent boys. Hum Reprod 2015; 30(11):2463-75.

5. Kliesch S. Androprotect and perspectives on fertility therapy. Urologe 2016; 55(7):898-903.