Microdissection testicular sperm extraction for men with nonobstructive azoospermia who have a testicular tumor in situ at the time of sperm retrieval

Abstract

Oncological microdissection testicular sperm extraction (onco-micro-TESE) represents a significant breakthrough for patients with nonobstructive azoospermia (NOA) and a concomitant in situ testicular tumor, to be managed at the time of sperm retrieval. Onco-micro-TESE addresses the dual objectives of treating both infertility and the testicular tumor simultaneously. The technique is intricate, necessitating a comprehensive understanding of testicular anatomy, physiology, tumor biology, and advanced microsurgical methods. It aims to carefully extract viable spermatozoa while minimizing the risk of tumor dissemination. This review encapsulates the procedural intricacies, evaluates success determinants, including tumor pathology and spermatogenic tissue health, and discusses the implementation of imaging techniques for enhanced surgical precision. Ethical considerations are paramount, as the procedure implicates complex decision-making that weighs the potential oncological risks against the profound desire for fatherhood using the male gametes. The review aims to provide a holistic overview of onco-micro-TESE, detailing methodological advances, clinical outcomes, and the ethical landscape, thus offering an indispensable resource for clinicians navigating this multifaceted clinical scenario.

INTRODUCTION

Nonobstructive azoospermia (NOA),1 characterized by the absence of sperm in the ejaculate due to impaired spermatogenesis, poses significant challenges in reproductive medicine. Previous studies on seminal parameters in patients with testicular cancer have reported that 10%–15% of such patients exhibit azoospermia.2,3 The complex interplay between fertility and oncology is further complicated by the concurrent presence of a testicular tumor in patients with NOA. Microdissection testicular sperm extraction (micro-TESE) combined with intracytoplasmic sperm injection (ICSI) can provide an opportunity for reproduction in men with NOA. Moreover, the development of oncological microdissection testicular sperm extraction (onco-micro-TESE) has emerged as a pivotal technique in this context, offering a dual approach to managing both infertility and oncological concerns.

The intricate balance between oncologic safety and the pursuit of biological paternity necessitates a nuanced understanding of testicular anatomy, physiology, tumor biology, and microsurgical techniques. Testicular tumors in NOA patients, varying from benign lesions to malignant neoplasms, significantly impact the decision-making process in sperm retrieval.4,5 The oncological risks associated with testicular tumors, including the potential for seeding and spread of tumor cells during surgical intervention, require careful consideration and expertise.

Onco-micro-TESE, a specialized form of microsurgical sperm extraction, is tailored for men with NOA who have a testicular tumor in situ at the time of sperm retrieval.6 This procedure not only aims at maximizing the yield of viable spermatozoa from the remaining healthy testicular tissue but also involves the strategic management of the tumor. The technique demands meticulous dissection and careful navigation of the testicular parenchyma to avoid disrupting the tumor and to identify viable seminiferous tubules for sperm extraction.

However, since the application of onco-micro-TESE might not necessarily be feasible in all testicular cancer cases, it is important to identify the hallmarks of the cases in which onco-micro-TESE has been associated with successful outcomes.7 The success of onco-micro-TESE hinges on several factors, including the size, location, and histopathologic type of the tumor; the extent of testicular damage or atrophy; and the overall health of the patient’s spermatogenic tissue. The procedure is typically guided by preoperative imaging and intraoperative real-time ultrasound, enhancing precision and safety.

Furthermore, the ethical considerations in onco-micro-TESE are profound.8 The decision to proceed with sperm retrieval in the presence of a testicular tumor must weigh the risks of potential oncological progression against the benefits of achieving biological parenthood. This decision-making process is further complicated by the variable prognosis of different testicular tumors and the patient’s personal and familial aspirations.

CORRELATION OF NOA WITH TESTICULAR TUMORS

Testicular cancer is the most common malignancy among young men of reproductive age.9 The association between testicular cancer and abnormalities in spermatogenesis is well established.10,11 A recent study found that the rising incidence of testicular cancer is correlated with an increase in the number of men experiencing infertility and abnormal semen analysis results.12 Moreover, men diagnosed with infertility are three times more likely to develop testicular cancer compared to healthy normozoospermic men.13 Agarwal and Allamaneni9 reported that the impairment of spermatogenesis is most likely attributed to two factors: (1) local and regional tumor toxicity (as spermatogenesis is more severely affected near the tumor due to paracrine factors, mass effects, and hyperthermia), and (2) systemic toxic effects of the tumor on the normal testis. Furthermore, seminomas were found to impact spermatozoa production more significantly than nonseminomatous tumors, most likely by affecting the tumor-bearing testicle.10

COMBINED NOA FEATURES OF SEVERAL TESTICULAR TUMORS

Approximately 55%–60% of the germ cell tumors (GCTs) consist of pure seminomas, and 40%–45% are non-seminomas.14 The diverse effects of histological types on sperm production are believed to stem from the different origins of each tumor type.

Seminoma

Testicular seminoma is the most common malignant tumor of the testis, comprising about 55%–60% of all GCTs.15,16 Testicular GCTs originate from primordial germ cells, with seminoma cells closely resembling normal multipotent germ cells, while nonseminomas and mixed tumors exhibit gene expression profiles similar to pluripotent embryonic cells.17 Seminomas are more frequently diagnosed in men over the age of 35 years.15,18 Typically, seminomas are diagnosed at clinical stage I (CSI), where the disease is confined to the testis, with no evidence of regional or distant metastasis on imaging. Due to their slower progression, about 80% of seminomas are detected at CSI, whereas only 60% of nonseminomatous germ cell tumors (NSGCTs) are diagnosed at this stage.14

Seminoma is highly sensitive to both radiation and chemotherapy, with cure rates reaching an impressive 99%–100% for stage I cases.16 However, long-term treatment is associated with significant risks, including cardiovascular toxicity and a heightened likelihood of secondary malignancies (SMN). As a result, onco-micro-TESE offers a viable alternative to reduce these long-term adverse effects. According to the study by Giulioni et al.,19 the SRR for seminomas was 47.1% (8 out of 17 cases).

Nonseminomatous cell tumor

A recent review of five retrospective studies found that onco-micro-TESE had a relatively low success rate for NSGCTs, with only 25.0% of cases showing success.19

Embryonal carcinoma is a highly malignant type of testicular germ cell tumor that predominantly affects young adult males. It is one of the components of NSGCTs,20 often found in combination with other cell types such as teratomas, yolk sac tumors, and choriocarcinomas. Pure embryonal carcinoma is rare, constituting about 2%–3% of all testicular cancers.21 In a case report by Hamano et al.,22 a 25-year-old male underwent onco-TESE on his remaining testicle affected by a NSGCT. The pathological diagnosis was GCTs of more than one histological type (embryonal carcinoma, immature teratoma, yolk sac tumor, seminoma, and choriocarcinoma; pT1N0M0). Onco-micro-TESE is essential in such cases for optimizing sperm retrieval.

Testicular Leydig cell tumors (LCTs) are the rare neoplasms originating in the interstitial tissue of the testes, accounting for approximately 1%–3% of all testicular tumors.23 LCTs are most frequently diagnosed in prepubertal boys between the ages of 5 years and 10 years, as well as in adult men aged 20–60 years.24,25,26 While LCTs are typically benign, malignant variants are reported in around 10% of adult cases.27 In adults, these tumors carry a small risk of malignancy, though no significant evidence of such risk has been documented in children.28 For this reason, they are considered suitable for testis-sparing surgery.

Carmignani et al.29 reported a case of a benign LCT in which the patient underwent micro-TESE. Cytological analysis of the micro-TESE sample revealed rare spermatozoa and a few mature spermatids. The sample was subsequently cryopreserved. In a review by Giulioni et al.,19 the sperm retrieval rate for malignant LCTs was reported as 75.0% (3 out of 4 cases).

Choriocarcinoma is an aggressive form of testicular cancer with a significantly poorer prognosis, marked by a 5-year survival rate of less than 80%.30 Although rare, it accounts for approximately 0.3% of all testicular germ cell tumors, making it one of the least common subtypes.31 Although onco-TESE has been more commonly practiced, the evidence supporting onco-TESE performed in patients with testicular cancer is insufficient due to the tumor’s aggressive nature, which often necessitates immediate treatment that can compromise spermatogenesis.22 In cases of choriocarcinoma, onco-micro-TESE must be performed with extreme caution due to the aggressive nature of the tumor. The procedure involves meticulous dissection under high magnification to avoid tumor spread and identify any potentially viable areas of spermatogenesis. This procedure is often challenging due to the extensive damage to the testicular tissue.

Testicular yolk sac tumor (TYST) is the most common malignant GCT in children, accounting for approximately 70%–80% of testicular malignancies, although their incidence is <1%.32,33 The clinical progression of SYST, similar to that of certain “somatic-type” malignancies arising in TGCTs, is marked by multiple recurrences that show limited or no response to chemotherapy.34 Currently, there are no reported cases of micro-TESE performed specifically for pure yolk sac tumors, indicating a significant gap in this field of research. Future studies should focus on investigating the feasibility and effectiveness of onco-micro-TESE in treating pure yolk sac tumors, aiming to improve fertility outcomes for these patients. Additionally, further research into the molecular characteristics and biomarkers of pure yolk sac tumors may help develop more effective targeted therapies, ultimately enhancing clinical management outcomes.

IMPACT OF TESTICULAR TUMORS ON NOA MICRODISSECTION SPERM RETRIEVAL

Choy et al.7 analyzed 83 specimens, finding spermatogenesis in 48 of 77 (62%) cancerous samples. These included 54% in pure seminomas and 72% in nonseminomatous and mixed germ cell tumors, with no significant difference between these subtypes (P = 0.11). Additionally, a significant inverse correlation was observed between tumor size and spermatogenesis (P = 0.004). However, they also mentioned that although small tumor size served as a positive predictor for spermatogenesis, a large tumor size did not absolutely preclude the possibility of spermatogenesis, as 2 of 4 specimens that were 8 cm in size still exhibited detectable spermatogenesis. However, Delouya et al.35 noted a moderate, yet not statistically significant, inverse relationship between estimated tumor volume and the likelihood of detecting spermatozoa in histological sections. Both studies confirmed no link between tumor histologic subtype and spermatogenesis.7,35 Furthermore, Choy et al.7 reported a significant negative impact of maximum tumor diameter on spermatogenesis in their study involving 77 patients. Notably, Suzuki et al.11 explored the relationship between the distance from tumor margins and spermatogenesis, finding an increase in spermatogenesis with greater distances from the tumor margins. Therefore, the size, histological type, and staging of the tumor, as well as the proximity of the micro-TESE to the tumor, may all influence the outcomes of onco-micro-TESE. However, specific conclusions require further investigation.

When performing testicular sperm retrieval concurrently with orchiectomy for a testicular mass, several pertinent issues must be addressed. Since the tunica albuginea needs to be opened to access the seminiferous tubules, it is crucial to properly inform the pathologist to ensure lesion staging. In cases of uncertainty, the presence of a pathologist might be required during the opening of the tunica. Concerns may arise regarding the potential risks of transferring malignancy through the use of sperm retrieved for assisted reproduction if the lesion is malignant. However, we believe such risks are minimal.36 It is important to highlight that microdissection techniques allow for the retrieval of only individual seminiferous tubules, unlike traditional TESE which involves removing larger pieces of testicular parenchyma. Consequently, the risk of transferring malignant tissue is significantly minimized with micro-TESE.

MICRO-TESE

Anatomic considerations

The human testis is divided into 200–400 wedge-shaped lobes, each containing three to ten seminiferous tubules. Its primary blood supply is from the testicular artery, supported by the cremasteric and vas deferens arteries.37,38 Vascular-rich areas are found in the upper pole, mediastinum, and posterolateral segments. Two main arterial branches supply the testis: the superficial arteries, which travel along the tunica albuginea and enter the parenchyma from the anterior border, and the less common transmediastinal arteries, which pass through the mediastinum the anterior border. These anatomical considerations are essential, as micro-TESE is an invasive procedure that carries risks of vascular injury and tissue damage.

Inguinal approach and oncological considerations

The procedure involves delivering the testis through an inguinal incision, following oncological principles to prevent tumor cell spread.36 While inguinal orchiectomy remains the standard approach for suspected testicular malignancy due to its straightforward and definitive nature, it may significantly impact fertility and endocrine function. For patients with bilateral tumors or a single testis, the role of organ-sparing surgery may be a viable alternative to preserve testicular tissue.39 Although some studies question organ-sparing surgery’s role when a healthy contralateral testis is present, partial orchiectomy has been shown to be a safe option for potentially benign intratesticular lesions.40,41 Evidence supports the use of organ-sparing surgery for certain testicular germ cell tumors, with low recurrence rates and preserved endocrine function in most cases, allowing approximately 50% of patients to achieve paternity posttreatment.42,43

Microsurgical technique and tumor excision

An incision was made in the tunica albuginea at an avascular site under an operating microscope (8×–10× magnification). Following this, meticulous dissection preserved the integrity of testicular lobules and arteries.36 The seminiferous tubules were gently separated using blunt dissection until the tumor was fully excised. It is crucial to utilize microinstruments for tumor removal while leaving 2–3 mm of normal tissue around the nodule to ensure complete resection. The excised tissue was sent for frozen section analysis, and additional biopsies from the tumor bed were preserved in Bouin’s solution for histological examination.

Hallak et al.39 presented a technique for microsurgical organ-sparing resection of testicular tumors combined with sperm extraction, suitable for selected azoospermic patients diagnosed with incidental masses via ultrasound. This conservative approach is especially recommended for patients with solitary testis or bilateral tumors. By integrating organ-sparing surgery, microdissection for micro-TESE, cryopreservation, and assisted reproductive technologies, a robust strategy for preserving fertility in these patients has been established.

Ischemia management and postoperative evaluation

Concerning the surgical procedure, an increased risk of hematoma, as well as additional difficulties in organizing micro-TESE in an emergency context, are to be weighed against a possible higher extraction rate.31 Cold ischemia was sustained until the frozen section analysis confirmed the benign nature of the tumor. In one case involving a seminoma, hypothermia was maintained throughout the sperm retrieval process. Postexcision, the tunica albuginea was meticulously sutured using nonabsorbable 4-0 sutures. Upon unclamping the spermatic cord, Doppler ultrasonography was employed to assess the immediate postoperative state of the testicular parenchyma. It seems impossible to formally conclude that micro-TESE is superior to conventional TESE (c-TESE) due to the surgical procedure, an increased risk of hematoma, and additional difficulties in an emergency context.

This advanced microsurgical approach to tumor resection and sperm retrieval in cases of NOA with concurrent testicular tumors ensures the maximal preservation of testicular function while adhering to the highest standards of oncological safety.39 However, to date, no reliable predictive factors exist to determine the success of sperm retrieval through onco-micro-TESE. Further studies are warranted to expand our knowledge in this field, as to date, few high-level evidence is available. Moreover, the challenge to pathologic tumor size measurement posed by diffuse and poorly circumscribed tumors could conceivably have introduced a source of measurement bias to the present onco-micro-TESE. Future studies could use alternative methods of tumor sizing, such as more intricate ultrasound of the testes or magnetic resonance imaging, which may become an effective preoperative step for predicting the results of sperm retrieval during onco-micro-TESE.11 Moreover, future research should focus on determining the optimal timing for sperm extraction, assessing and managing changes in hormone levels postoperation, and improving the success rate.

DISCUSSION

In conclusion, micro-TESE is increasingly recognized as a valuable method for sperm retrieval in men with NOA, even in testicular tumor men. Researches show that micro-TESE generally offers higher sperm retrieval rates compared to c-TESE, particularly for patients with specific histopathological diagnoses such as Sertoli cell-only syndrome (SCOS) and maturation arrest, which are often present in NOA patients with testicular tumors. Furthermore, micro-TESE tends to be less invasive, preserving testicular tissue and reducing postoperative complications such as pain, hematoma, and the potential for testosterone deficiency. Although both c-TESE and micro-TESE show similar live birth outcomes, the precision and reduced tissue damage of micro-TESE make it especially suitable for challenging cases, such as those involving a testicular tumor, by allowing targeted retrieval from viable sperm-containing regions. Continued research and larger randomized controlled trials are recommended to establish more definitive guidelines for choosing between micro-TESE and c-TESE based on patient-specific factors, including histopathology, age, and hormonal profiles.

However, certain types of testicular tumors, such as pure yolk sac tumors and other rare variants, have not yet been widely studied or reported in conjunction with micro-TESE. This highlights an urgent need for further research into the applicability and efficacy of micro-TESE in these cases. Due to the unique histopathological characteristics of these tumor types, standard sperm retrieval techniques may not be suitable or effective, and micro-TESE could potentially offer a more precise and less invasive approach. Expanding the scope of micro-TESE research to include these rarer tumor types could significantly improve fertility outcomes for a broader range of patients with NOA and concurrent testicular malignancies.

CONCLUSION

Integrating current research findings, onco-micro-TESE has proved to be a safe and effective option for improving fertility preservation in azoospermic males. Future research needs to further explore the effectiveness of onco-micro-TESE in cancer patients of different types and stages and how to optimize the technique and protocols to enhance its safety and efficacy. Additionally, more clinical trials and long-term follow-up data will significantly impact the assessment of onco-micro-TESE’s long-term fertility outcomes and the quality of life of the patients.

AUTHOR CONTRIBUTIONS

KH, WHT, and HCL conceived and reviewed the manuscript. HCL, YC, and YYF contributed to the literature review and writing of the manuscript. KH revised and edited the manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.