Individual and seminal characteristics of patients with testicular germ cell tumors

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1 MALE FACTOR Individual and seminal characteristics of patients with testicular germ cell tumors Renato Fraietta, M.D., Ph.D., Deborah Montagnini Spaine, Ph.D., Ricardo Pimenta Bertolla, D.V.M., Ph.D., Valdemar Ortiz, M.D., Ph.D., and Agnaldo Pereira Cedenho, M.D., Ph.D. Department of Surgery, Division of Urology, Sao Paulo Federal University, Sao Paulo, Brazil Objective: To analyze the characteristics of patients with testicular germ cell cancer and compare patients sperm quality according to histologic type (seminomatous and nonseminomatous tumors). Design: Prospective study. Setting: Sperm bank at a university. Patient(s): One hundred consecutive patients with testicular tumor who had been referred to our infertility center for cryopreservation, between 2004 and Intervention(s): A questionnaire, through personal interview, was given to all patients and collection of seminal data before cryopreservation was performed. Main Outcome Measure(s): Patient characteristics, including age, time between diagnosis and orchiectomy, history of cryptorchidism, histologic type, and seminal analysis were taken into consideration. Result(s): The mean age of the patients at the time of diagnosis was 26.9 years. The mean time between cancer suspicion and the diagnosis of neoplasm was 58.9 days, and 19.4 more days were necessary until orchiectomy was performed. Eleven patients had a history of cryptorchidism. Thirty-seven patients had seminomatous tumors. Men with a seminoma present a higher number of motile and morphologically normal sperm in the ejaculate than men with a nonseminoma, although individual semen variables are not different. Conclusion(s): The majority of the patients with testicular cancer, referred to our infertility center, are very young, single, do not have children, and are unaware of their fertility potential status by the time diagnosis is made. Men with a nonseminoma present semen of lower quality. (Fertil Steril Ò 2010;94: Ó2010 by American Society for Reproductive Medicine.) Key Words: Testicular neoplasms, infertility, semen, orchiectomy Testicular germ cell tumors, or simply testicular tumors, are the solid tumors with the highest prevalence among young men (aged years) (1 3). Although malignant, the development of new technical resources used in diagnosis and staging, and the establishment of both chemotherapeutic (4) and radiotherapeutic treatment plans, associated with complete removal of the affected testis, have increased survival rates, and up to 95% of patients are considered cured in a 5-year period (2, 3, 5 7). On the other hand, both the chemotherapeutic agents and radiotherapy are known to be gonadotoxic (4, 7) and may determine a decrease in sperm production. Treated patients may therefore present with severe oligozoospermia or even azoospermia, and therefore, infertility (3, 5, 8). Because epidemiologic data reveal that, in 2010, 1 in every 250 adults will be a survivor of childhood or adolescent cancer (9), it was rapidly noted that a change in focus from survival at any cost Received August 13, 2009; revised November 26, 2009; accepted December 10, 2009; published online February 19, R.F. has nothing to disclose. D.M.S. has nothing to disclose. R.P.B. has nothing to disclose. V.O. has nothing to disclose. A.P.C. has nothing to disclose. Reprint requests: Renato Fraietta, M.D., Ph.D., Sao Paulo Federal University, R. Borges Lagoa, 1065, apt. 87, , Sao Paulo, SP, Brazil (FAX: þ ; renatofraietta@yahoo.com.br). to maintenance of quality of life was necessary. Most patients with testicular cancer are affected during their reproductive age, many are still single, whereas others are recently married. However, the majority of them wish to become fathers in the future (5). Current literature has not yet established whether testicular cancer histology may determine different alterations to semen quality. Some investigators show that a nonseminoma usually impacts more negatively on semen quality than a seminoma, whereas others fail to demonstrate this difference (6, 10). In any case, the American Society of Clinical Oncology currently recommends a few guidelines for fertility preservation in men with cancer who will be submitted to potentially sterilizing treatments. In summary, sperm cryopreservation is considered standard practice for these men, whether sperm is collected by masturbation or by other techniques, such as testicular sperm extraction (TESE), assisted ejaculation techniques (i.e., electroejaculation), or even collection of urine sperm in patients with retrograde ejaculation. On the other hand, other fertility preservation methods, such as testicular tissue cryopreservation, testis xenografting, spermatogonial isolation, and testicular suppression with GnRH analogues, should be considered investigational (11). Although much has been developed in treatment and diagnosis, information regarding these patients is still necessary to better comprehend their current lifestyles and what they project for their future /$36.00 Fertility and Sterility â Vol. 94, No. 6, November doi: /j.fertnstert Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 TABLE 1 Questionnaire applied to patients referring to the Sao Paulo Federal University Sperm Bank following diagnosis of testicular tumor. Name: Age when diagnosed: How was the diagnosis performed? ( ) auto-exam ( ) routine examination for other reason ( ) increase in volume ( ) other: Time between suspicion and diagnosis: Time between diagnosis and orchiectomy: Previous paternity before diagnosis? ( ) yes. How many? ( ) no How was the patient informed about the sperm bank? When? By whom? Laterality of the tumor ( ) right ( ) left ( ) bilateral History of cryptorchidism? ()no ( ) yes: ( ) right ( ) left ( ) bilateral Treatment: ( ) clinical ( ) surgical Was the patient aware of possible sterility due to the tumor or its treatment, when diagnosed? ()no ( ) yes. Informed by whom? Sperm banking was considered more important by whom? ( ) patient ( ) patient s parents ( ) patient s spouse How knowledgeable in semen cryopreservation was the Urologist who treated the patient for the tumor, in the patient s opinion? ( ) little ( ) somewhat ( ) very During patient follow-up, was the Urologist concerned with the result from the sperm bank? ( ) yes ( ) no When, in relation to the orchiectomy, was semen cryopreservation performed? ( ) before ( ) after. Time between orchiectomy and cryopreservation: Histological type of tumor: Did the patient receive adjuvant therapy? ( ) yes ()no ( ) chemotherapy ( ) radiotherapy ( ) retroperitoneal lymphadenectomy Fraietta. Individual and seminal characteristics in patients with testicular tumor. Fertil Steril Therefore, this study set out to verify individual traits and semen quality in patients with testicular cancer, and to compare semen quality in patients with seminoma and nonseminoma. MATERIALS AND METHODS Study Design A prospective study was carried out involving 100 consecutive patients with testicular tumor referred to the Human Reproduction Section Sperm Bank at the Sao Paulo Federal University. Both clinical information and laboratory examinations were performed, and patients were divided into two groups: having seminoma and nonseminoma. Patients with multiple types were considered as patients with nonseminoma, due to its more aggressive nature and treatment schemes. Institutional Review Board (IRB) approval was obtained from the Sao Paulo Federal University Research Ethics Committee. A questionnaire was given to all the patients in an office adjacent to the sperm bank, through personal interview. The physician filled out a form with all the questions during the interview (Table 1). It is important to emphasize that, as an interview, there was no interference in the management of the patient referral; therefore, cancer staging was not available, serum markers were not obtained, and testicular volumes were not measured as physical examination was not performed. Semen Analysis Semen was collected by masturbation, and the abstinence period was not fixed, as urgency for cryopreservation due to initiation of adjuvant therapy may not allow for a definite abstinence period. After semen liquefaction, seminal analysis was performed according to World Health Organization criteria (12), and sperm morphology was evaluated by Kruger s strict criteria (13). Normal values were: sperm motility R50% (aþb), sperm concentration R /ml, and normal sperm forms >14%. Statistical Analysis Patients were grouped according to: [1] type of tumor and [2] whether semen was collected for cryopreservation before or after orchiectomy. Within these groups, numerical variables were initially analyzed to verify whether variances were homogenous. The total number of motile and morphologically normal sperm in the ejaculate was calculated by multiplying sperm 2108 Fraietta et al. Individual and seminal characteristics in patients with testicular tumor Vol. 94, No. 6, November 2010

3 TABLE 2 Age and semen analysis results in men with seminoma (n [ 37) and nonseminoma (n [ 63). Seminoma Nonseminoma P value Age (y) Mean SD a 95% CI Min Max Volume (ml) Mean SD % CI Min Max Progressive motility (% aþb) Mean SD % CI Min Max Concentration (million/ml) Mean SD % CI Min Max Morphology (% normal) Mean SD % CI Min Max Total motile morphologically normal sperm (millions) Mean SD a 95% CI Min Max Round cells (millions/ml) Mean SD % CI Min Max Neutrophils (millions/ml) Mean SD % CI Min Max Note: 95% CI ¼ 95% confidence interval of the mean; Min Max ¼ minimum and maximum values observed. a Statistically significant difference (P<.05). Fraietta. Individual and seminal characteristics in patients with testicular tumor. Fertil Steril concentration (in million per milliliter) by volume (in milliliter) by progressive motility (in percentage), and by sperm morphology (in percentage). Heteroscedastic variables were transformed into their logarithmic or square root values for statistical analysis (data presented are untransformed). An unpaired samples Student s t-test was used to compare numerical variables within these groups. Data are presented as mean and SD. A P value less than 5% was considered significant. RESULTS All the data are presented in Tables 2 through 4. Mean age of all the individuals studied was 26.9 years, and varied from years. Of the 100 patients studied, 37 presented a seminoma and 63 a nonseminoma, and in 95 patients tumor was unilateral, in 3 bilateral, and in 2 extragonadal. Eleven patients had a history of cryptorchidism (10 unilateral and 1 bilateral). The most common diagnostic suspicion in patients with seminoma and nonseminoma was an increase in scrotal volume (78% of the cases), and, in the 100 patients studied, the mean period of time between suspicion and ultrasound diagnosis was 58.9 days, with another 19.4 days until orchiectomy. In addition, 74% of these men collected semen for cryopreservation after orchiectomy, with an average period of time between the surgery and collection of 72.5 days. Most patients with a testicular cancer were single (72%) and had not achieved paternity (84%). Although these patients were almost always referred to the sperm bank by their physician (96%), most were only referred after removal of the affected testis (74%), and 55% of them did not have any knowledge of the adverse effects of testicular cancer and its therapy on semen quality or fertility potential. Patients with nonseminoma were mostly treated with chemotherapy and patients with seminoma, with radiotherapy. Patients with a seminoma were older than patients with a nonseminoma ( and years, respectively, P¼.00002), but also presented a higher number of total motile and morphologically normal sperm in the ejaculate ( and millions, respectively, P¼.022) (Table 2). The time intervals between suspicion and diagnostic confirmation, between diagnostic confirmation and orchiectomy, and between orchiectomy and semen collection were not different between the men with seminoma and with nonseminoma (Table 3). No differences were observed in age or semen analysis results between men who collected semen before or after orchiectomy (Table 4). Because two men presented with extragonadal tumors, they were not included in this comparison. DISCUSSION Testicular cancer is responsible for 1% 2% of all tumors in men (1). In infertile couples, the risk for testicular cancer in the male partner after a clinical investigation is at 0.35% (14), which means a 20-fold greater incidence of testicular cancer compared with the general population (15). On the other hand, in couples with a diagnosed male infertility factor, prevalence of testicular cancer may reach up to 6% (16), which demonstrates that sometimes infertility may precede diagnosis of testicular cancer (17). There are few reports on pretreatment semen quality in patients with testicular cancer (5). Howell and Shalet (4), when analyzing 170 patients with testicular cancer, reported that 24% were azoospermic and 24% oligozoospermic before any therapy. Lass et al. (7) reported a prevalence of azoospermia at 15% during diagnosis of the testicular tumor. It is generally accepted that most patients with testicular cancer present with oligozoospermia (1, 3, 5, 6, 8, 10, 17 20), of which 50% present with less than 10 million sperm/ml of semen (5). In our study, 6% of the patients referred to the sperm bank were azoospermic, two of which were referred to the bank after orchiectomy. The remaining four patients did not present sperm at the time of the procedure. It has not yet been elucidated whether the etiology for infertility in patients with testicular cancer arises from testicular alterations, presence of the tumor, or from treatment (20), but it is generally accepted that this occurs due to: [1] altered development of the genitourinary system or primary endocrine dysfunction associated to an altered contralateral testis (atrophy, testicular intratubular neoplasia) (5, 8); [2] tumor-associated factors (b-hcg, a-fetoprotein, E 2, Fertility and Sterility â 2109

4 TABLE 3 Time intervals between suspicion of the testicular tumor and semen collection in men with seminoma (n [ 37) and nonseminoma (n [ 63). Seminoma Nonseminoma P value Time between suspicion and diagnostic confirmation (d) Mean SD % CI Min Max Time between diagnostic confirmation and orchiectomy (d) Mean SD % CI Min Max Time between orchiectomy and semen collection (d) Mean SD % CI Min Max Note: 95% CI ¼ 95% confidence interval of the mean; Min Max ¼ minimum and maximum values observed. Statistically significant difference (P<.05). Fraietta. Individual and seminal characteristics in patients with testicular tumor. Fertil Steril LH, decreased T levels, production of tumor-mediated cytokines, antisperm antibodies); and [3] emotional stress leading to alteration in catecholamine levels, and increased PRL, corticotropin-releasing factor [CRF], and endogenous opioid levels (3, 6, 10, 17 20). In addition, cryptorchidism is a well-established cause for both a decrease in semen quality and an increase in occurrence of testicular cancer (3, 17, 21). Patients with a history of cryptorchidism present a 25- to 40-fold increase in the chance of developing a testicular tumor. Also, approximately 10% of men with testicular cancer have a history of cryptorchidism (5, 17). In our study, 11% of men with testicular cancer had a history of cryptorchidism, which is within the expected range. Testicular cancer is usually a unilateral disease only 2% of men present with bilateral tumors (8). In our study three men (3%) presented with bilateral testicular cancer one presented with a synchronous bilateral seminoma, the other presented with a seminoma 3 years after unilateral orchiectomy and radiotherapy for a seminoma, and the other presented with a seminoma 10 years after orchiectomy and retroperitoneal lymphadenectomy for a nonseminoma. According to literature data, the chance of reappearance of tumor after complete remission for testicular cancer is 2.7% in 5 years and 4.6% in 10 years (8). Two patients presented with an extragonadal germ cell cancer (one with a seminoma in the cervical lymph nodes, and the other, with a nonseminoma with a complaint of lumbar pain), and both were treated with retroperitoneal lymphadenectomy and chemotherapy. Semen analysis in these patients showed a decrease in sperm concentration, which agrees with current information (18). Classically, seminomas represent 40% of testicular tumors and 60% nonseminomas (2). In our study, 37% of the patients presented with a seminoma and 63% with a nonseminoma, which shows that the group we drew our data from is indeed a subset of the population of men with testicular cancer. It has not yet been established whether testicular cancer histology may determine different alterations to semen quality. Although some investigators show that, when compared with a seminoma, a nonseminoma determines a more important decrease in the total number of sperm with progressive motility, other investigators do not find that difference (6, 10). In our study, men with a seminoma presented with a higher number of motile and morphologically normal sperm in the ejaculate than men with a nonseminoma (P¼.022), although individual semen variables were not different. It is interesting that, although this analysis does not allow us to understand which variable is causative for decreased fertility potential, men with a nonseminoma present semen of lower quality (Table 2). If comparing with World Health Organization guidelines and Kruger s strict criteria (at least 2.8 million motile and morphologically normal sperm in the ejaculate), patients with seminoma are within a normal range, and patients with nonseminoma, below this cutoff point (12, 13). On the other hand, it has been extensively demonstrated that patients with testicular cancer present with lower semen quality, even before therapy is initiated (1, 3, 5 8, 10, 17 20). Because adjuvant therapy may lead to azoospermia, and because most patients are cured, it is extremely important to consider maintenance of quality of life in these men. Also, testicular tumors affect mostly young men. In our study, age varied from years, 72% of these were not yet married, and 84% had not yet fathered a child. Thus, assurance of future fertility is not only desirable, it is absolutely necessary when considering patients with testicular cancer. Currently, the only option that will guarantee the future ability to achieve fatherhood is semen cryopreservation, especially, because other options, such as down-regulation of the hypothalamic-pituitary-testicular axis during chemotherapy or radiotherapy, have all failed to guarantee fertility (4). Thus, referral to a sperm bank has been adopted as part of testicular cancer therapy. In a large retrospective study, Lass et al. (7) demonstrated that the average period of time between diagnosis of testicular cancer and collection of the first semen sample was 3 weeks (from 1 day 16 weeks). In our study, the period of time between diagnostic suspicion and ultrasound confirmation was 58.9 days, with another 19.4 day period until orchiectomy. Also, 74% of the patients only collected semen after orchiectomy (but before adjuvant therapy), with an average period of time between surgery and semen collection of 72.5 days (about 10 weeks), which agrees with other reports (10, 18, 22) Fraietta et al. Individual and seminal characteristics in patients with testicular tumor Vol. 94, No. 6, November 2010

5 TABLE 4 Age and semen analysis results in men with seminoma and nonseminoma before (n [ 31) and after (n [ 67) orchiectomy. Before After P value Age (y) Mean SD % CI Min Max Volume (ml) Mean SD % CI Min Max Progressive motility (% aþb) Mean SD % CI Min Max Concentration (million/ml) Mean SD % CI Min Max Morphology (% normal) Mean SD % CI Min Max Total motile morphologically normal sperm (millions) Mean SD % CI Min Max Round cells (millions/ml) Mean SD % CI Min Max Neutrophils (millions/ml) Mean SD % CI Min Max Note: 95% CI ¼ 95% confidence interval of the mean; Min Max ¼ minimum and maximum values observed. Statistically significant difference (P<.05). Fraietta. Individual and seminal characteristics in patients with testicular tumor. Fertil Steril It is interesting to note that, although it is usually recommended that patients with testicular cancer initiate therapy as soon as possible, there is still a sufficient period of time in which semen cryopreservation may be performed. Because maintenance of the ability to father a child is important for most of these men, there is no excuse for not offering this aid to these patients, especially as only 6% will present with azoospermia before any treatment (1, 5, 7, 18) and therefore will not be able to cryopreserve semen. For the group of men presenting with azoospermia, one important therapeutic option is TESE of the contralateral testis at the time of orchiectomy (onco- TESE) followed by sperm cryopreservation (23). In this case, it is suggested that men with a testicular tumor should be referred to a sperm bank before orchiectomy, so that there is enough time to perform TESE in this group of patients. Our study demonstrated that the period of time between suspicion of a testicular tumor and diagnosis, and then to orchiectomy, was not different according to tumor type (Table 3). Thus, treatment periods were homogenous between the groups. It should be noted that information regarding the period of time between suspicion and diagnosis is based on patient referral only, which may subject these specific results to recall bias. When verifying, if semen quality was higher if semen was collected after or before orchiectomy, no differences could be observed (Table 4). Sibert et al. (1) demonstrated that semen may be collected for cryopreservation after orchiectomy in men with testicular cancer, because spermatogenesis in the contralateral testis would be enough to support spermatogenesis. However, to understand whether orchiectomy does potentially improve semen quality a paired study is necessary, comparing semen quality before and after orchiectomy in the same patients. Finally, it is especially important to note that although 96% of the patients were referred to the bank by their physician, most (55%) were not aware that adjuvant therapy may lead to persistent azoospermia, and this brings up two important factors. First, the medical doctor is the most important source of referral to a sperm bank. Second, this necessity to cryopreserve semen samples is not always being emphatically passed on to the patient. Thus, and in accordance to Lass et al. (7), it is imperative that physicians treating patients with testicular cancer be aware of this necessity and passes it on to the patients. Fertility and Sterility â 2111

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