Is ex vivo microdissection testicularsperm extraction indicated forinfertile men undergoing radicalorchiectomy for testicular cancer?Case report and literature review
Nicholas Haddad, M.Sc.,a Khalid Al-Rabeeah, M.D.,a Ronald Onerheim, M.D.,b and Armand Zini, M.D.a
a Division of Urology, Department of Surgery, McGill University Health Center, McGill University, and b Division ofPathology, St. Mary’s Hospital Center, Montreal, Quebec, Canada
Objective: To report a case of an infertile man with nonobstructive azoospermia who underwent simultaneous radical orchiectomy fortesticular cancer and testicular sperm extraction (TESE) for preservation of fertility.Design: Case report and literature review.Setting: University teaching hospital.Patient(s): A couple being treated for infertility.Intervention(s): Radical orchiectomy with simultaneous TESE.Main Outcome Measure(s): Sperm retrieval, histologic evaluation of archived testicular pathology slides.Result(s): We retrieved 20 spermatozoa from the multiple random TESE samples obtained at radical orchiectomy. Histologic evalua-tion of the archived testicular pathology slides revealed that the testis contained several foci of active spermatogenesis, suggesting that asignificantly greater number of spermatozoa would likely have been retrieved had amicrodissection TESE been performed instead of themultiple TESEs.
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Conclusion(s): We propose that microdissection TESE should be considered the preferred spermretrieval technique at the time of radical orchiectomy in men with coexistent nonobstructiveazoospermia and testicular cancer. (Fertil Steril� 2014;101:956–9.�2014 by American Societyfor Reproductive Medicine.)KeyWords: Cryopreservation, microTESE, nonobstructive azoospermia, TESE, testicular cancer
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Infertile men with abnormal semen ana-lyses are believed to be at increased riskof testicular cancer, with some estimates
reaching incidence rates 20-fold greaterthan the general population (1, 2). Inaddition, it is believed that up to 45% ofmen who present with testicular cancer
Received November 2, 2013; revised December 14,online February 12, 2014.
N.H. has nothing to disclose. K.A-R. has nothing tonothing to disclose.
Reprint requests: Armand Zini, M.D., Professor, McGiSurgery, St. Mary’s Hospital Center, 3830 Lacom(E-mail: [email protected]).
have abnormal sperm parameters,typically poor sperm concentration andmotility (3).
The majority of testicular cancerspresent as a palpable mass and radicalorchiectomy is the standard treatmentof choice. For patients interested in
2013; accepted December 29, 2013; published
disclose. R.O. has nothing to disclose. A.Z. has
ll University, Division of Urology, Department ofbe Avenue, Montreal, Quebec, Canada, H3T 1M5
15-0282/$36.00ehalf of the American Society for Reproductive
fertility, surgical treatment and theresultant monorchid status maydecrease the likelihood of reproductivesuccess. In addition, cytotoxic chemo-therapy may cause long-term infertility,further highlighting the importance ofcryopreservation in those patients inter-ested in conserving their reproductivepotential. In a study performed to assessipsilateral spermatogenesis in men withtesticular cancer, mature sperm wasidentified in nearly 80% of normaltesticular and 50% of epididymal histo-logic sections (4). Moreover, testicularsperm was identified in 64% of patientswho did not have detectable sperm in
Histologic cross-section of testicular parenchyma surrounding theseminoma. Background tissue was composed predominantly ofatrophic tubules (arrowhead), but a small number of tubules withcomplete spermatogenesis and mature spermatids were observed(arrow). Sections were stained with hematoxylin and eosin(magnification: �100).Haddad. MicroTESE at radical orchiectomy. Fertil Steril 2014.
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the epididymis, suggesting that some patients diagnosed withnonobstructive azoospermia (NOA) and testicular cancer maybe good candidates for direct testicular sperm extraction(TESE) (4).
In a conventional TESE, random samples of testicular tis-sue are extracted in an attempt to recover spermatozoa forsubsequent in vitro fertilization (IVF) and intracytoplasmicsperm injection (ICSI) (5). Testicular sperm extraction withICSI has resulted in successful pregnancy in azoospermic pa-tients with testicular cancer (6, 7). However, because spermproduction is not uniform throughout the testis in men withNOA, sperm extraction using random incisions may not beoptimal (8). To more efficiently target seminiferous tubulescontaining spermatozoa, an operating microscope can beemployed in a procedure known as microdissection TESE ormicroTESE (9). This case report demonstrates thatsignificant areas of spermatogenesis may be missed withconventional sperm extraction techniques such as TESE inpatients with testicular cancer and concomitant NOA.Therefore, we propose that microTESE be considered as analternative to TESE to maximize sperm retrieval in this veryselect patient population.
MATERIALS AND METHODSThe patient consented to right radical orchiectomy withsimultaneous conventional TESE. He received spinal anes-thesia before being prepared and draped in a sterile fashion.A right inguinal incision was done, and the radical orchiec-tomy was performed in the usual fashion.
The excised cancerous testicle was taken to a new sterilefield, and a transverse incision of the tunica albuginea wasperformed. A total of eight random biopsy samples (each bi-opsy approximately 5 mm in diameter) were harvested fromdifferent areas of the noncancerous testicular tissue. Thetunica albuginea was then closed with a single silk suture,and the cancerous testicle was sent to surgical pathologyfor histologic analysis. The random samples were placed insterile buffer (Global Fertilization Medium; IVFonline). Tissueexamination and cryopreservation are not available on site atSt. Mary’s Hospital, so the TESE samples were transferred tothe IVF laboratory for subsequent sperm isolation and cryo-preservation. Institutional review board approval was waived.
RESULTSA 30-year-old male with no prior surgical or medical historypresented to our fertility clinic for evaluation of primaryinfertility of 18 months’ duration. His partner was a28-year-old woman with no known gynecologic abnormal-ities. He had a history of infrequent recreational marijuanause. Physical examination revealed a small right testicle (10mL) with a small induration on the lower pole. The left testiclewas smaller and softer (with an estimated volume of 5 mL),and there was an associated left varicocele (clinical grade 2).
He had two semen analyses: the first revealed a normalvolume (4.3 mL) azoospermia, and the second analysis re-vealed a normal volume (4.0 mL) severe oligozoospermiawith rare motile and non-motile sperm. Scrotal ultrasonog-raphy revealed a centrally located, hypervascular, and
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isoechoic right testicular mass measuring 2.8 � 1.3 cm.His basic laboratory evaluation, which included completeblood count, creatinine, and electrolytes, was unremark-able. His serum tumor markers were also normal (lactatedehydrogenase at 394 IU/L, b-human chorionic gonado-tropin at 2.4 mIU/mL, and alfa-fetoprotein at 0.3 ng/mL).
The patient was counseled to submit several semen sam-ples for sperm cryopreservation before his planned radical or-chiectomy. He submitted seven semen samples, but all werefound to be inadequate for cryopreservation: five sampleswere azoospermic, and two samples showed rare non-motilesperm. Therefore, none of the preoperative semen sampleswere cryopreserved.
A right radical orchiectomy with simultaneous conven-tional TESE was performed as described above. An experi-enced embryologist evaluated all eight TESE samples andidentified a total of 20 non-motile spermatozoa in the entiresample set. The final pathology report revealed a pure semi-noma (2.8 � 2.2 cm) localized to the testis. The remainingtesticular tissue consisted of atrophic seminiferous tubulesand Leydig hyperplasia. Interestingly, focal intact spermato-genesis was also observed (Fig. 1).
The histologic slides were reevaluated by an infertilityfellowship-trained urologist (A.Z.) for quantitative assess-ment of spermatogenesis. A full cross-section of the testiswas examined, and a total of 900 seminiferous tubules wereidentified in the noncancerous areas of the testis. The majorityof the tubules demonstrated a Sertoli cell-only pattern (60%or 540 of 900 tubules) or tubular hyalinization (34% or 306of 900 tubules), with a few tubules demonstrating maturationarrest: 36 (4%) of 900 tubules. However, 18 (2%) of the 900tubules were found to have active spermatogenesis withroughly 10 to 20 spermatozoa per tubule. Tubules with activespermatogenesis were observed in several areas of the
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noncancerous tissue; in some instances, the areas of activespermatogenesis were located only two tubules away fromthe cancer.
DISCUSSIONIn the case described, conventional (non-microsurgical)testicular sperm extraction was used as a sperm retrieval tech-nique at the time of radical orchiectomy for testicular cancer.Although sperm retrieval was successful, a relatively lownumber of spermatozoa (20 spermatozoa) were recovered. Ahistologic evaluation of the archived testicular pathologyslides (a full cross-section of the testis was examined) revealedthat 2% of the noncancerous testicular tissue contained focalareas of active spermatogenesis: 18 of the 900 seminiferoustubules showed active spermatogenesis, with 10 to 20 sper-matozoa per seminiferous tubule for a total of approximately180 to 360 spermatozoa in the entire cross-section. Althoughit is difficult to determine the total testicular sperm countaccurately, we would estimate the count to be close to 1million spermatozoa, assuming that other areas of the testisare comparable to the one that was evaluated histologicallyand given that the width of the testis is 2 cm and a thin sectionis approximately 5 mm. As such, we believe that a microTESEwould likely have allowed for a greater sperm recovery thanthe multiple random TESEs used in this case.
Based on our histologic evaluation of several slides, wedid not observe a relationship between the noncancerous tis-sue histology and the proximity to the testicular tumor. In aretrospective study of 28 patients, Ho et al. (10) found thattesticular cancer impaired spermatogenesis in the vicinity ofthe tumor. Any effect on spermatogenesis can in theory beattributed to local tumor toxicity, such as mass effects, hyper-thermia, and paracrine effects (e.g., interleukin-1, interferon-g, leukemia-inhibiting factor). However, very few data havebeen published to support these theories. Furthermore, tumortype may also affect sperm production in the noncanceroustissue. In a retrospective study of 1,158 men with testicularcancer, Rives et al. (11) observed that the total sperm numberand the concentration were significantly lower in men withseminomas when compared with those with nonseminomas.It was postulated that because seminomas are similar tonormal, multipotent germ cells, they could directly influencesurrounding normal germ or Sertoli cells. To date, there is nounequivocal evidence to support this theory, with earlierstudies demonstrating that patients with seminomas havehigher sperm counts compared with those with nonsemino-mas (12). Our results do not favor one theory over the otherwith regards to seminomas, though larger studies are neededto accurately address this interesting question.
MicroTESE enables the surgeon to visualize those semi-niferous tubules that are most likely to contain spermatozoawhile preserving adjacent testicular tissue. With regards tosperm retrieval rates (SRRs), microTESE has consistently out-performed other sperm extraction techniques such as fine-needle aspiration, open or percutaneous biopsy, yieldingsignificantly higher SRRs (13, 14). A prospective studyinvolving 116 patients found an SRR of 47% usingmicroTESE versus 30% in conventional TESE (9). In a
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retrospective study of 46 patients, Okada et al. (13) foundSRRs of 44.6% and 16.7% in patients receiving microTESEand conventional TESE, respectively. Furthermore, it hasbeen shown to be successful in 35% of men who had failedconventional TESE, with more recent studies generatingSRRs of 55% in cases of severe testicular atrophy (9, 15).Although these data are based on studies of noncanceroustesticles, the benefits of microTESE may be transferable toan oncologic setting to provide the highest possible spermyields in patients with NOA and testicular cancer.
Despite the clear advantages provided by microTESE, it isnot without limitations. First, simultaneous TESE at the timeof orchiectomy in patientswith a testicularmassmay alter can-cer staging due to the inherent disruption of the tunica albugi-nea and manipulation of the presumably normal surroundingtesticular tissue. The pathologist should therefore be duly noti-fied of these changes before reviewing the specimen. Micro-TESE requires an operating room equipped with an operatingmicroscope, located in close proximity to an IVF laboratory.MicroTESE is technically challenging, requiring microsurgicaltraining and expertise and may require considerably longeroperating times. In a retrospective study involving 793 patientswho underwent microTESE, 37% of cases extended beyond 4hours with a mean operative time of 1.8 hours (16). Incomparing microTESE with conventional TESE, Tsujimuraet al. (17) showed that the mean operative time is considerablylonger at 146.8 minutes versus 68.2. These factors drasticallyincrease the cost of microTESE and limit its application to cen-ters that are adequately equipped and staffed.
In patients with testicular cancer, optimal fertility preser-vation is achieved by the cryopreservation of ejaculatedsperm before orchiectomy or subsequent adjuvant chemo-therapy or radiotherapy (11, 18). However, testicular canceris known to reduce sperm quality such that approximately10% to 15% of these patients are azoospermic, makingsurgical testicular sperm retrieval their only means offertility preservation (11, 19, 20). To date, both TESE andmicroTESE have been used successfully in the setting oftesticular cancer and azoospermia, and a clear argument infavor of one approach over the other has not been made (6,7, 21–24). In a recent series involving six patients,conventional TESE was capable of generating an SRR of66.7%, exceeding the rates obtained using microTESE innoncancerous testicles (7). Our case report highlights thepotential limitations of multiple TESE procedures in a manwith azoospermia-cryptozoospermia and testicular cancer,and provides strong support for the use of microTESE inthis setting.
In men with NOA, there is some, albeit minimal, addedvalue in performing a contralateral microTESE when spermretrieval in the initial testis has failed. In men with NOAand testicular cancer, the evidence in favor of performing acontralateral microTESE is lacking. Rives et al. (11) havedemonstrated that sperm counts in men with testicular cancerare highest before orchiectomy, suggesting that the bestchance of sperm retrieval in men with testicular cancer andNOA is at the time of radical orchiectomy, especially in caseswhere adjuvant chemotherapy is likely. However, microTESEis associated with risks, such as hematoma, vascular damage
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(tunica albuginea and intratesticular), intratesticular scarring,and testicular atrophy with further reduction in sperm pro-duction and endocrine function. In addition, contralateral mi-croTESE will substantially increase the operative time and thefinancial costs. In a recent study involving 900menwith NOA(the study did not includemen with testicular cancer), 506 un-derwent bilateral microTESE, and only 40 (8%) of 506 hadsperm found in the contralateral side after exploration ofthe initial testis had failed (25). The majority of the patientswho benefited from contralateral microTESE had Klinefeltersyndrome with small testes. Based on these lines of evidence,we cannot make definitive recommendations regarding thevalue of contralateral microTESE in the context of ipsilateraltestis cancer and NOA. However, we suggest that in men withipsilateral testis cancer and NOA the option of contralateralmicroTESE should be discussed and should include a compre-hensive review of the risks and benefits (i.e., low probabilityof sperm retrieval). A contralateral microTESE should be per-formed via an inguinal approach to preserve scrotal integrityin the event of a contralateral testicular malignancy.
In summary, in the case we have presented conventionalTESE resulted in a relatively low sperm retrieval rate whencompared with the significant foci of spermatogenesis subse-quently identified in archived histologic sections. Therefore,we propose that microTESE be considered the preferred spermretrieval technique at the time of radical orchiectomy in menwith coexistent NOA and testicular cancer to maximize spermretrieval rates. However, we recognize that microTESE is amore complex, more time consuming, and more costly proce-dure than non-microsurgical testicular sperm retrievaltechniques.
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