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Testicular Tumors in Patients with Exstrophy-Epispadias Complex
Pediatric Urology
Testicular Tumors in Patients with Exstrophy-Epispadias Complex Anne K. Ebert,*,† Sabine Kliesch, Claudia Neissner, Heiko Reutter† and Wolfgang H. Rösch† From the Department of Pediatric Urology, University Medical Center Regensburg, Regensburg (AKE, CN, WHR), Department of Andrology, Center of Reproductive Medicine and Andrology, University Medical Center Muenster, Muenster (SK), and Institute of Human Genetics and Department of Neonatology, University of Bonn, Bonn (HR), Germany
Abbreviations and Acronyms EEC ⫽ exstrophy-epispadias complex FSH ⫽ follicle-stimulating hormone TM ⫽ testicular microlithiasis Submitted for publication January 18, 2012. Study received local ethics committee approval. * Correspondence: Department of Pediatric Urology, University Medical Center Regensburg, Klinik St. Hedwig, Steinmetzstr. 1-3, 93049 Regensburg, Germany (telephone: 0049-941-3695451; FAX: 0049-941-3695455; e-mail: anne-karoline.ebert@ barmherzige-regensburg.de). † Supported by Grant 01GM08107 from the German Federal Ministry of Education and Research (Deutsches Bundesministerium für Bildung und Forschung, BMBF).
Purpose: Due to separated pubic bone and patent processus vaginalis, males with exstrophy-epispadias complex often present with inguinal hernia during infancy. Since most of these testicles are operatively repositioned, testicular development is assumed to be normal. However, there is a paucity of knowledge about long-term testicular development in males with exstrophy-epispadias complex. We identified males with sonographic intratesticular abnormalities or testicular tumor in exstrophy-epispadias complex. Materials and Methods: Since 2003, a Germany wide cross-sectional followup study has been permanently offered to men with exstrophy-epispadias complex, focusing on andrological issues. A total of 22 men with exstrophy-epispadias complex presented to our clinical service for andrological evaluation, including testicular ultrasound. Results: Sonography showed testicular and epididymal pathology in more than 50% of patients, with intratesticular abnormality in 23%, most commonly testicular microlithiasis (9%). Three patients underwent testicular biopsy. Histopathological evaluation revealed 1 case of testicular intraepithelial neoplasia and 2 benign testicular stromal tumors (1 Sertoli cell tumor and 1 Leydig cell tumor). Followup visits at 10, 28 and 68 months were uneventful. Conclusions: The observation of comorbid testicular tumor in males with exstrophy-epispadias complex should prompt a preventive health examination after puberty, which gives these patients the opportunity for further appropriate diagnostics and treatment if necessary. Biopsy is recommended for sonographically detected intratesticular lesions. Organ sparing procedures are worth considering, especially when stromal tumors with favorable outcome are discovered. However, current oncologic principles must be strictly followed. Although the etiology and true incidence of testicular tumors in exstrophy-epispadias complex are still unclear, our findings highlight the importance of long-term followup in patients with exstrophy-epispadias complex. Key Words: bladder exstrophy; epispadias; follow-up studies; hernia, inguinal; testicular neoplasms
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TESTICULAR cancer is the most common malignancy in adolescents and young adults in Europe, with a recent estimated nationwide incidence in Germany of 10.6 per 100,000 person-
years.1 The established risk factors for testis cancer, such as cryptorchidism, history or family history of testis cancer and infertility, may be modulated by developmental factors or
0022-5347/12/1884-1300/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.06.040 Vol. 188, 1300-1305, October 2012 RESEARCH, INC. Printed in U.S.A.
AND
TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
exposures during early in utero organogenesis. In addition, a systematic review of perinatal variables in testicular cancer epidemiology provided several lines of evidence that additional factors, including inguinal hernia, twinning, birth weight and gestational age, might be causally related.2 Although these epidemiological risk factors are common among males with exstrophy-epispadias complex, to our knowledge the specific incidence of testicular tumors and testicular pathology in this complex has not yet been defined. Conversely it is common knowledge that despite normal cord length, the unique anatomy of the anterior pelvic ring and the inguinal canal in males with classic bladder exstrophy predispose to congenital inguinal hernia and possibly malpositioned testes not requiring orchiopexy.3–5 Additionally there is sparse information in the medical literature on the long-term testicular outcome after hernia, exstrophy and epispadias repair among males with EEC. Furthermore, in adulthood infertility is common in patients with EEC, although this finding is mainly understood as a consequence of obstruction caused by bladder neck or urethral surgery, or epididymitis during childhood and adolescence. In the existing sparse literature patients with congenital abnormal external genitalia, including epispadias and coexisting cryptorchidism, are reported to have an increased risk of testis cancer.6 Furthermore, several hereditary disorders and constitutional chromosomal abnormalities are known to be associated with testis cancer.7 In this study we evaluated men with EEC for intratesticular pathologies or testicular tumors in a Germany wide crosssectional cohort, to assess whether there is a specific risk of testis cancer and testicular anomalies in patients with EEC.
METHODS Patient Recruitment We issued a Germany wide study call via German SelfHelp Group, in their official newsletter and permanently on their Web site. We addressed all males with EEC 16 years or older who had undergone any kind of operative repair during childhood, offering noninvasive andrological followup at our clinical service.
Study Design The study design was cross-sectional, enrolling all males who followed our study call between August 2004 and December 2009. The study was approved by the local ethics committee, and informed consent was obtained from all participants. The study was part of a research project on the long-term outcome of patients with EEC.8
Assessment A total of 22 males older than 16 years with EEC had completed a semistructured interview about their medical
1301
history, andrological risk factors, and genital and sexual function. In addition, hormone and semen analysis was carried out. Testicular ultrasound was performed with the patient in the relaxed supine position using a 5 MHz ultrasound probe during clinical examination. The ultrasound examination included testicular volume measurements, documentation of testicular parenchymal echogenicity and epididymal morphology, according to the literature.9 Particularly with regard to methodology we referred to previous published genital long-term outcome data of the same EEC cohort,8 which were updated regarding current histological testis biopsy and testicular ultrasound results. Due to the limited numbers, mainly descriptive methods, including counts, means and ranges, were used.
RESULTS A total of 22 males with a mean age of 24.8 years (range 18.3 to 39.9) with EEC were evaluated. Of the patients 19 had classic bladder exstrophy and 3 had epispadias, and all had undergone surgical reconstruction at a mean age of 1.8 years. Due to the retrospective nature of the investigation, it was impossible to accurately define the initial testes location and the consecutive necessity of herniotomy with or without prophylactic scrotal orchiopexy in early childhood for the underlying EEC cohort. However, there was no history of patient or familial testis cancer in the cohort. A total of 44 testes were clinically and sonographically examined. Of the patients 41% did not demonstrate pathological findings, whereas 59% had single or multiple pathological findings, including unilateral or bilateral small testicles (27.3%), hydrocele (18.2%), varicocele (9.1%) and spermatocele (4.5%). Of the patients 22.7% had intratesticular disturbance of homogenicity, such as cyst, hypoechoic or hyperechoic lesions, or microlithiasis (9.1%). In 3 individuals (ages 17, 21 and 23 years) sonography showed suspicious intratesticular findings warranting testicular biopsy. History regarding phenotype, testis management, tumor marker and semen analysis of these 3 patients is outlined in the table. Medical history for these 3 patients revealed bilateral inguinal hernia repair with prophylactic scrotal orchiopexy at a mean age of 12 months. In 1 patient secondary bilateral testes ascended to the groin, both testes were small and firm on palpation, and the parenchyma demonstrated microlithiasis. The other 2 patients had normal testicular palpation regarding structure, although ultrasound showed unilateral hypoechoic or hyperechoic lesions (figs. 1 and 2). In 1 of these cases the hyperechoic lesion was located in a small testis (9 ml, case 2). No patient exhibited hormone related symptoms such as gynecomastia or isosexual precocious puberty.
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TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
Patient Characteristics Pt 1 Phenotype Semen analysis Clinical testicular findings: Rt/lt testis vol (ml) Extratesticular pathology Testicular sonography Laboratory tests: alpha-Fetoprotein (less than 25 ng/ml) Human chorionic gonadotropin (less than 5 mU/ml) Testis management: Bilat hernia repair ⫹ scrotal orchiopexy (age) Secondary ascent to groin Tumor diagnosis (age) Operative strategy regarding testis tumor Tumor histology
Pt 2
Classic exstrophy Azoospermia* 8/10 None Microlithiasis
Pt 3
Classic exstrophy Oligoasthenospermia
Grade III epispadias Normospermia
15.6/9 None Hyperechoic lesion
18.8/21 Hydrocele Hypoechoic lesion
Less than 2
2.9 Less than 2
1.5
2 Less than 2
12 Mos Yes 17 Yrs Biopsy at redo orchiopexy Testicular intraepithelial neoplasia
11 Mos No 23 Yrs Excision biopsy, secondary orchiectomy Leydig cell
12 Mos No 21 Yrs Testis sparing surgery Sertoli cell
No patient had epidemiological risk factors for testis cancer. * After radiation and testosterone substitution intramuscularly every 4 weeks.
All 3 patients with intratesticular findings underwent inguinal exploration with strict adherence to oncologic principles. Intraoperative ultrasound helped to identify the lesions, and excision biopsy was taken for frozen section examination. Operative strategy was based on intraoperative histopathological results. The patient with classic bladder exstrophy and secondary bilateral ascent underwent testicular biopsy during redo orchiopexy at age 17 years. Histological evaluation revealed Leydig cell hyperplasia and placental alkaline phosphatase positive cells, indicating testicular intraepithelial neoplasia (case 1). The patient did not want a surveillance strategy, so he was consecutively treated with testicular radiation in 2005. The other patient with classic bladder exstrophy and a 1 cm hyperechoic lesion underwent excision biopsy. Although histological assessment demonstrated a Leydig cell tumor with benign features, the individual asked for secondary orchiectomy because excision biopsy did not guarantee complete tumor
resection (case 2). The third individual with previous grade III epispadias underwent a macroscopically complete tumor resection of a well circumscribed Sertoli cell tumor with tubular differentiation and a low proliferation rate (case 3). All patients had uneventful followup at 10, 28 and 68 months. Followup investigations included testicular ultrasound and initial computerized tomography of the abdomen and chest in the patients with Leydig and Sertoli cell tumors.
DISCUSSION EEC is understood as a spectrum of genitourinary malformations ranging in severity and involving various organ systems. However, the impacts of this congenital anomaly (especially the influence of early developmental factors in utero) and subsequent surgical interventions on long-term outcome, especially the genital system, are not fully understood. Most
Figure 1. Sertoli cell tumor
TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
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Figure 2. Leydig cell tumor
probably EEC results from mechanical alteration of the cloacal membrane during early organogenesis with genetic and environmental factors having an important role. Today as a consequence of sophisticated reconstruction concepts, long-term genital issues have gained significance for adults with EEC. However, data on testicular development in patients with EEC are sparse. Due to the open processus, abnormal scrotal morphology and lack of intra-abdominal pressure with decreased local intramuscular forces, inguinal hernia is a frequent complication of EEC in male newborns.3,4 In current pediatric urology textbooks the testes in bladder exstrophy are reportedly “frequently undescended but without the need for orchiopexy.”5 In the literature the overall incidence of inguinal hernia in males with exstrophy is about 82% and the condition most often is bilateral, either synchronically or metachronically.3 In exstrophy a remarkably wide defect of the internal ring and a lack of obliquity of the inguinal canal have been described as relevant confounding factors. Furthermore, the timing of observation seems relevant, as only 25% of inguinal hernias are found before bladder closure, emphasizing the importance of increased intra-abdominal pressure after abdomen closure to show the underlying pathology.3 In our series all 3 males with EEC and testicular tumors underwent bilateral inguinal hernia repair with prophylactic scrotal orchiopexy around the first year of life. In contrast to mechanical concepts, today testicular descent is recognized as a complex endocrine mediated process, whereas mechanical factors may have a more or less supportive role. Possible anomalies of the gubernaculum or epididymis interfering with normal testis descent have not yet been described for EEC. Contrary to the general assumption of normal testicular development,5 we recently found FSH to be increased in 19% of adults with EEC, predominantly patients with azoosper-
mia, indicating a multifactorial etiology of the wellknown infertility problem, mainly related to postoperative obstruction.8 Of the entire cohort infertility was common with azoospermia in 26.3% and oligoasthenospermia in 57.9%.8 However, no patient with EEC and testicular tumor had increased FSH before tumor treatment, and 1 patient with previous grade III epispadias who had undergone only 1 bladder neck procedure had normospermia on semen analysis. Furthermore, in the present EEC cohort testicular and epididymal pathology was quite frequent, with only 41% of patients with EEC having no pathological findings during scrotal sonography. Compared to a large cohort of patients presenting to a German center for reproductive medicine,9 testicular pathology, especially hydrocele, low testicular volume and nonhomogeneity, seem to be more common in patients with EEC. Testicular microlithiasis was discovered in 9% of patients with EEC, which seems to be greater than the prevalence reported for the general population (1.5% to 5.6%).10 Although TM is not necessarily considered a premalignant condition, all male patients with TM, including those with EEC, should be examined for other criteria of testicular dysgenesis syndrome, such as testicular atrophy, testicular maldescent, or low or zero sperm count, indicating additional evidence for the presence of malignancy and, therefore, the need for testicular biopsy.10,11 Based on this algorithm, the patient with EEC and bilateral testicular volume less than 12 ml underwent biopsy during redo orchiopexy and a testicular intraepithelial neoplasia was found. The other patient with exstrophy, TM, normal testicular volume (18 ml) and normal testis position is monitored with regular self-examination and yearly testicular sonography. In the literature several hereditary disorders and constitutional chromosomal abnormalities are reportedly associated with testis cancer.7 However,
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TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
the coincidence of rare gonadal stromal tumors, such as Sertoli cell and Leydig cell tumors, or testicular germ cell tumors with EEC, has yet not been reported. Hence, Cortes et al provided evidence that mostly patients with bilateral cryptorchidism, not only with intra-abdominal testis location or abnormal karyotype, but also with abnormal congenital genitalia, may have an increased risk of testicular tumors in the range of 5%.6 Interestingly 4 of the 35 patients with cryptorchidism, congenital external genital anomalies and bilateral cryptorchidism reported by Cortes et al presented with epispadias, suggesting that testicular dysgenesis syndrome might be part of the EEC spectrum.6 Due to the rare occurrence of stromal tumors, the literature provides limited experience not only on associated anomalies, but also on treatment and followup recommendations.12–17 The mostly benign Leydig cell tumors may occasionally occur in association with genetic disorders such as Klinefelter syndrome. Malignancy is reported in 10% of cases, with metastasis, as true evidence, possibly being present after a long latency period, with a limited median survival of 2 years.12,13 Testis sparing surgery in adults is still a matter of debate and is usually only recommended for a small group of selected patients, mostly with impalpable tumors or imperative indications of a solitary tumor bearing testis.18 However, for Leydig cell tumors smaller than 2.5 cm testis sparing surgery can be discussed when histological malignant features are excluded, as evidenced by favorable long-term followup results.16,17 This approach was initially applied to patient 2 in our present report, with the patient later wanting orchiectomy. The even more rare Sertoli cell tumor may present with an early onset, as in our patient 3, or late onset, usually unilateral and multifocal in 30% of patients, and associated with endocrine disorders such as gynecomastia and accelerated bone growth in 40%.14,15 Early onset Sertoli cell tumors occur with dysplastic syndromes such as Peutz-Jeghers syndrome, Bourneville syndrome and the Carney complex. Because of the more favorable prognosis, excision of the tumor appears to be the treatment of choice, whereas late onset tumors in older patients require orchiectomy
due to a 23% malignancy risk, most commonly with consecutive retroperitoneal nerve sparing lymphadenectomy.15 Taken together, the occurrence of testicular tumors in EEC is a clinically interesting incidental finding that has not been described before. However, the clinical relevance is still under debate. Selection bias cannot be excluded, because this underlying cohort includes only a small percentage of men with EEC living in Germany. Birth prevalences for epispadias and classic bladder exstrophy in males have been estimated to be 1.2 and 2.2, respectively, per 100,000 live births in a mainly white population.19,20 Taking these figures into account, approximately 350 males with classic bladder exstrophy and 140 with epispadias were born during the relevant birthyears of the overall cohort. Therefore, it would be highly desirable to implement a Germany wide survey to evaluate the true prevalence of testis cancer in the male EEC population. Although our present knowledge does not warrant a population based screening program, we would highly recommend an appropriate preventive health examination at the end of puberty, including testis sonography and FSH measurement, to be aware of the potential risk for testis tumor in patients with EEC.
CONCLUSIONS Due to the occurrence of testicular tumors and the high incidence of abnormal testicular findings, the concept of normal testicular development in EEC needs to be discussed. A preventive health examination after puberty might afford males with EEC the opportunity for further appropriate diagnostics and treatment, if necessary. However, sonographically detected intratesticular lesions require histological clarification with strict attention to oncologic principles. In cases of impalpable tumor or negative tumor markers even in adulthood organ sparing procedures are worth considering, especially when gonadal stromal tumors with mostly benign behavior and, therefore, favorable outcome are discovered. Although the etiology and true incidence of testicular tumors in EEC are still unclear, the current findings highlight the importance of dedicated longterm followup in patients with EEC.
REFERENCES 1. Stang A, Katalinic A, Dieckmann KP et al: A novel approach to estimate the German-wide incidence of testicular cancer. Cancer Epidemiol 2010; 34: 13. 2. Cook MB, Akre O, Forman D et al: A systematic review and meta-analysis of perinatal variables in
relation to the risk of testicular cancer— experiences of the son. Int J Epidemiol 2010; 39: 1605.
4. Quinlan DM, Gearhart JP and Jeffs RD: Abdominal wall defects and cryptorchidism an animal model. J Urol 1988; 140: 1141.
3. Connolly JA, Peppas DS, Jeffs RD et al: Prevalence and repair of inguinal hernias in children with bladder exstrophy. J Urol 1995; 154: 1900.
5. Gearhart JP: The bladder exstrophy-epispadiascloacal exstrophy complex. In: Pediatric Urology. Edited by JP Gearhart, RC Rink and PDE Mori-
TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
quand. Philadelphia: WB Saunders Co 2010; chapt 30, pp 386 – 415. 6. Cortes D, Thorup JM and Visfeldt J: Cryptorchidism: aspects of fertility and neoplasms. A study including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism. Horm Res 2001; 55: 21. 7. Lutke Holzik MF, Sijmons RH, Sleijfer DT et al: Syndromic aspects of testicular carcinoma. Cancer 2003; 97: 984. 8. Ebert AK, Bals-Pratsch M, Seifert B et al: Genital and reproductive function in males after functional reconstruction of the exstrophy-epispadias complex—long-term results. Urology 2008; 72: 566. 9. Behre HM, Kliesch S, Schädel F et al: Clinical relevance and transrectal ultrasonography in andrological patients. Int J Androl 1995; 18: 27.
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10. van Casteren NJ, Looijenga LH and Dohle GR: Testicular microlithiasis and carcinoma in situ overview and proposed clinical guideline. Int J Androl 2009; 32: 279.
16. Giannarini G, Mogorovich A, Fabris FM et al: Long-term followup after elective testis sparing surgery for Leydig cell tumors: a single center experience. J Urol 2007; 178: 872.
11. Costabile RA: How worrisome is testicular microlithiasis? Curr Opin Urol 2007; 17: 419.
17. Loeser A, Vergho DC, Katzenberger T et al: Testissparing surgery versus radical orchiectomy in patients with Leydig cell tumors. Urology 2009; 74: 370.
12. Carmignani L, Colombo R, Gadda F et al: Conservative surgical therapy for Leydig cell tumor. J Urol 2007; 178: 507. 13. Kim I, Young RH and Scully RE: Leydig cell tumors of the testis. A clinicopathological analysis of 40 cases and review of the literature. Am J Surg Pathol 1985; 9: 177. 14. Young RH: Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol 2005; 18: 81. 15. Giglio M, Medica M, De Rose AF et al: Testicular Sertoli cell tumors and relative subtypes. Urol Int 2003; 70: 205.
18. Giannarini G, Dieckmann KP, Albers P et al: Organ-sparing surgery for adult testicular tumours: a systematic review of the literature. Eur Urol 2010; 57: 780. 19. Gearhart JP and Jeffs RD: Exstrophy-epispadias complex and bladder anomalies. In: Campbell’s Urology, 7th ed. Edited by PC Walsh, AB Retik, ED Vaughan Jr et al. Philadelphia: WB Saunders Co 1998; pp 1939 –1990. 20. Epidemiology of bladder exstrophy and epispadias: a communication from the International Clearinghouse for Birth Defects Monitoring Systems. Teratology 1987; 36: 221.
Testicular Tumors in Patients with Exstrophy-Epispadias Complex Anne K. Ebert,*,† Sabine Kliesch, Claudia Neissner, Heiko Reutter† and Wolfgang H. Rösch† From the Department of Pediatric Urology, University Medical Center Regensburg, Regensburg (AKE, CN, WHR), Department of Andrology, Center of Reproductive Medicine and Andrology, University Medical Center Muenster, Muenster (SK), and Institute of Human Genetics and Department of Neonatology, University of Bonn, Bonn (HR), Germany
Abbreviations and Acronyms EEC ⫽ exstrophy-epispadias complex FSH ⫽ follicle-stimulating hormone TM ⫽ testicular microlithiasis Submitted for publication January 18, 2012. Study received local ethics committee approval. * Correspondence: Department of Pediatric Urology, University Medical Center Regensburg, Klinik St. Hedwig, Steinmetzstr. 1-3, 93049 Regensburg, Germany (telephone: 0049-941-3695451; FAX: 0049-941-3695455; e-mail: anne-karoline.ebert@ barmherzige-regensburg.de). † Supported by Grant 01GM08107 from the German Federal Ministry of Education and Research (Deutsches Bundesministerium für Bildung und Forschung, BMBF).
Purpose: Due to separated pubic bone and patent processus vaginalis, males with exstrophy-epispadias complex often present with inguinal hernia during infancy. Since most of these testicles are operatively repositioned, testicular development is assumed to be normal. However, there is a paucity of knowledge about long-term testicular development in males with exstrophy-epispadias complex. We identified males with sonographic intratesticular abnormalities or testicular tumor in exstrophy-epispadias complex. Materials and Methods: Since 2003, a Germany wide cross-sectional followup study has been permanently offered to men with exstrophy-epispadias complex, focusing on andrological issues. A total of 22 men with exstrophy-epispadias complex presented to our clinical service for andrological evaluation, including testicular ultrasound. Results: Sonography showed testicular and epididymal pathology in more than 50% of patients, with intratesticular abnormality in 23%, most commonly testicular microlithiasis (9%). Three patients underwent testicular biopsy. Histopathological evaluation revealed 1 case of testicular intraepithelial neoplasia and 2 benign testicular stromal tumors (1 Sertoli cell tumor and 1 Leydig cell tumor). Followup visits at 10, 28 and 68 months were uneventful. Conclusions: The observation of comorbid testicular tumor in males with exstrophy-epispadias complex should prompt a preventive health examination after puberty, which gives these patients the opportunity for further appropriate diagnostics and treatment if necessary. Biopsy is recommended for sonographically detected intratesticular lesions. Organ sparing procedures are worth considering, especially when stromal tumors with favorable outcome are discovered. However, current oncologic principles must be strictly followed. Although the etiology and true incidence of testicular tumors in exstrophy-epispadias complex are still unclear, our findings highlight the importance of long-term followup in patients with exstrophy-epispadias complex. Key Words: bladder exstrophy; epispadias; follow-up studies; hernia, inguinal; testicular neoplasms
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TESTICULAR cancer is the most common malignancy in adolescents and young adults in Europe, with a recent estimated nationwide incidence in Germany of 10.6 per 100,000 person-
years.1 The established risk factors for testis cancer, such as cryptorchidism, history or family history of testis cancer and infertility, may be modulated by developmental factors or
0022-5347/12/1884-1300/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.06.040 Vol. 188, 1300-1305, October 2012 RESEARCH, INC. Printed in U.S.A.
AND
TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
exposures during early in utero organogenesis. In addition, a systematic review of perinatal variables in testicular cancer epidemiology provided several lines of evidence that additional factors, including inguinal hernia, twinning, birth weight and gestational age, might be causally related.2 Although these epidemiological risk factors are common among males with exstrophy-epispadias complex, to our knowledge the specific incidence of testicular tumors and testicular pathology in this complex has not yet been defined. Conversely it is common knowledge that despite normal cord length, the unique anatomy of the anterior pelvic ring and the inguinal canal in males with classic bladder exstrophy predispose to congenital inguinal hernia and possibly malpositioned testes not requiring orchiopexy.3–5 Additionally there is sparse information in the medical literature on the long-term testicular outcome after hernia, exstrophy and epispadias repair among males with EEC. Furthermore, in adulthood infertility is common in patients with EEC, although this finding is mainly understood as a consequence of obstruction caused by bladder neck or urethral surgery, or epididymitis during childhood and adolescence. In the existing sparse literature patients with congenital abnormal external genitalia, including epispadias and coexisting cryptorchidism, are reported to have an increased risk of testis cancer.6 Furthermore, several hereditary disorders and constitutional chromosomal abnormalities are known to be associated with testis cancer.7 In this study we evaluated men with EEC for intratesticular pathologies or testicular tumors in a Germany wide crosssectional cohort, to assess whether there is a specific risk of testis cancer and testicular anomalies in patients with EEC.
METHODS Patient Recruitment We issued a Germany wide study call via German SelfHelp Group, in their official newsletter and permanently on their Web site. We addressed all males with EEC 16 years or older who had undergone any kind of operative repair during childhood, offering noninvasive andrological followup at our clinical service.
Study Design The study design was cross-sectional, enrolling all males who followed our study call between August 2004 and December 2009. The study was approved by the local ethics committee, and informed consent was obtained from all participants. The study was part of a research project on the long-term outcome of patients with EEC.8
Assessment A total of 22 males older than 16 years with EEC had completed a semistructured interview about their medical
1301
history, andrological risk factors, and genital and sexual function. In addition, hormone and semen analysis was carried out. Testicular ultrasound was performed with the patient in the relaxed supine position using a 5 MHz ultrasound probe during clinical examination. The ultrasound examination included testicular volume measurements, documentation of testicular parenchymal echogenicity and epididymal morphology, according to the literature.9 Particularly with regard to methodology we referred to previous published genital long-term outcome data of the same EEC cohort,8 which were updated regarding current histological testis biopsy and testicular ultrasound results. Due to the limited numbers, mainly descriptive methods, including counts, means and ranges, were used.
RESULTS A total of 22 males with a mean age of 24.8 years (range 18.3 to 39.9) with EEC were evaluated. Of the patients 19 had classic bladder exstrophy and 3 had epispadias, and all had undergone surgical reconstruction at a mean age of 1.8 years. Due to the retrospective nature of the investigation, it was impossible to accurately define the initial testes location and the consecutive necessity of herniotomy with or without prophylactic scrotal orchiopexy in early childhood for the underlying EEC cohort. However, there was no history of patient or familial testis cancer in the cohort. A total of 44 testes were clinically and sonographically examined. Of the patients 41% did not demonstrate pathological findings, whereas 59% had single or multiple pathological findings, including unilateral or bilateral small testicles (27.3%), hydrocele (18.2%), varicocele (9.1%) and spermatocele (4.5%). Of the patients 22.7% had intratesticular disturbance of homogenicity, such as cyst, hypoechoic or hyperechoic lesions, or microlithiasis (9.1%). In 3 individuals (ages 17, 21 and 23 years) sonography showed suspicious intratesticular findings warranting testicular biopsy. History regarding phenotype, testis management, tumor marker and semen analysis of these 3 patients is outlined in the table. Medical history for these 3 patients revealed bilateral inguinal hernia repair with prophylactic scrotal orchiopexy at a mean age of 12 months. In 1 patient secondary bilateral testes ascended to the groin, both testes were small and firm on palpation, and the parenchyma demonstrated microlithiasis. The other 2 patients had normal testicular palpation regarding structure, although ultrasound showed unilateral hypoechoic or hyperechoic lesions (figs. 1 and 2). In 1 of these cases the hyperechoic lesion was located in a small testis (9 ml, case 2). No patient exhibited hormone related symptoms such as gynecomastia or isosexual precocious puberty.
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TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
Patient Characteristics Pt 1 Phenotype Semen analysis Clinical testicular findings: Rt/lt testis vol (ml) Extratesticular pathology Testicular sonography Laboratory tests: alpha-Fetoprotein (less than 25 ng/ml) Human chorionic gonadotropin (less than 5 mU/ml) Testis management: Bilat hernia repair ⫹ scrotal orchiopexy (age) Secondary ascent to groin Tumor diagnosis (age) Operative strategy regarding testis tumor Tumor histology
Pt 2
Classic exstrophy Azoospermia* 8/10 None Microlithiasis
Pt 3
Classic exstrophy Oligoasthenospermia
Grade III epispadias Normospermia
15.6/9 None Hyperechoic lesion
18.8/21 Hydrocele Hypoechoic lesion
Less than 2
2.9 Less than 2
1.5
2 Less than 2
12 Mos Yes 17 Yrs Biopsy at redo orchiopexy Testicular intraepithelial neoplasia
11 Mos No 23 Yrs Excision biopsy, secondary orchiectomy Leydig cell
12 Mos No 21 Yrs Testis sparing surgery Sertoli cell
No patient had epidemiological risk factors for testis cancer. * After radiation and testosterone substitution intramuscularly every 4 weeks.
All 3 patients with intratesticular findings underwent inguinal exploration with strict adherence to oncologic principles. Intraoperative ultrasound helped to identify the lesions, and excision biopsy was taken for frozen section examination. Operative strategy was based on intraoperative histopathological results. The patient with classic bladder exstrophy and secondary bilateral ascent underwent testicular biopsy during redo orchiopexy at age 17 years. Histological evaluation revealed Leydig cell hyperplasia and placental alkaline phosphatase positive cells, indicating testicular intraepithelial neoplasia (case 1). The patient did not want a surveillance strategy, so he was consecutively treated with testicular radiation in 2005. The other patient with classic bladder exstrophy and a 1 cm hyperechoic lesion underwent excision biopsy. Although histological assessment demonstrated a Leydig cell tumor with benign features, the individual asked for secondary orchiectomy because excision biopsy did not guarantee complete tumor
resection (case 2). The third individual with previous grade III epispadias underwent a macroscopically complete tumor resection of a well circumscribed Sertoli cell tumor with tubular differentiation and a low proliferation rate (case 3). All patients had uneventful followup at 10, 28 and 68 months. Followup investigations included testicular ultrasound and initial computerized tomography of the abdomen and chest in the patients with Leydig and Sertoli cell tumors.
DISCUSSION EEC is understood as a spectrum of genitourinary malformations ranging in severity and involving various organ systems. However, the impacts of this congenital anomaly (especially the influence of early developmental factors in utero) and subsequent surgical interventions on long-term outcome, especially the genital system, are not fully understood. Most
Figure 1. Sertoli cell tumor
TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
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Figure 2. Leydig cell tumor
probably EEC results from mechanical alteration of the cloacal membrane during early organogenesis with genetic and environmental factors having an important role. Today as a consequence of sophisticated reconstruction concepts, long-term genital issues have gained significance for adults with EEC. However, data on testicular development in patients with EEC are sparse. Due to the open processus, abnormal scrotal morphology and lack of intra-abdominal pressure with decreased local intramuscular forces, inguinal hernia is a frequent complication of EEC in male newborns.3,4 In current pediatric urology textbooks the testes in bladder exstrophy are reportedly “frequently undescended but without the need for orchiopexy.”5 In the literature the overall incidence of inguinal hernia in males with exstrophy is about 82% and the condition most often is bilateral, either synchronically or metachronically.3 In exstrophy a remarkably wide defect of the internal ring and a lack of obliquity of the inguinal canal have been described as relevant confounding factors. Furthermore, the timing of observation seems relevant, as only 25% of inguinal hernias are found before bladder closure, emphasizing the importance of increased intra-abdominal pressure after abdomen closure to show the underlying pathology.3 In our series all 3 males with EEC and testicular tumors underwent bilateral inguinal hernia repair with prophylactic scrotal orchiopexy around the first year of life. In contrast to mechanical concepts, today testicular descent is recognized as a complex endocrine mediated process, whereas mechanical factors may have a more or less supportive role. Possible anomalies of the gubernaculum or epididymis interfering with normal testis descent have not yet been described for EEC. Contrary to the general assumption of normal testicular development,5 we recently found FSH to be increased in 19% of adults with EEC, predominantly patients with azoosper-
mia, indicating a multifactorial etiology of the wellknown infertility problem, mainly related to postoperative obstruction.8 Of the entire cohort infertility was common with azoospermia in 26.3% and oligoasthenospermia in 57.9%.8 However, no patient with EEC and testicular tumor had increased FSH before tumor treatment, and 1 patient with previous grade III epispadias who had undergone only 1 bladder neck procedure had normospermia on semen analysis. Furthermore, in the present EEC cohort testicular and epididymal pathology was quite frequent, with only 41% of patients with EEC having no pathological findings during scrotal sonography. Compared to a large cohort of patients presenting to a German center for reproductive medicine,9 testicular pathology, especially hydrocele, low testicular volume and nonhomogeneity, seem to be more common in patients with EEC. Testicular microlithiasis was discovered in 9% of patients with EEC, which seems to be greater than the prevalence reported for the general population (1.5% to 5.6%).10 Although TM is not necessarily considered a premalignant condition, all male patients with TM, including those with EEC, should be examined for other criteria of testicular dysgenesis syndrome, such as testicular atrophy, testicular maldescent, or low or zero sperm count, indicating additional evidence for the presence of malignancy and, therefore, the need for testicular biopsy.10,11 Based on this algorithm, the patient with EEC and bilateral testicular volume less than 12 ml underwent biopsy during redo orchiopexy and a testicular intraepithelial neoplasia was found. The other patient with exstrophy, TM, normal testicular volume (18 ml) and normal testis position is monitored with regular self-examination and yearly testicular sonography. In the literature several hereditary disorders and constitutional chromosomal abnormalities are reportedly associated with testis cancer.7 However,
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TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
the coincidence of rare gonadal stromal tumors, such as Sertoli cell and Leydig cell tumors, or testicular germ cell tumors with EEC, has yet not been reported. Hence, Cortes et al provided evidence that mostly patients with bilateral cryptorchidism, not only with intra-abdominal testis location or abnormal karyotype, but also with abnormal congenital genitalia, may have an increased risk of testicular tumors in the range of 5%.6 Interestingly 4 of the 35 patients with cryptorchidism, congenital external genital anomalies and bilateral cryptorchidism reported by Cortes et al presented with epispadias, suggesting that testicular dysgenesis syndrome might be part of the EEC spectrum.6 Due to the rare occurrence of stromal tumors, the literature provides limited experience not only on associated anomalies, but also on treatment and followup recommendations.12–17 The mostly benign Leydig cell tumors may occasionally occur in association with genetic disorders such as Klinefelter syndrome. Malignancy is reported in 10% of cases, with metastasis, as true evidence, possibly being present after a long latency period, with a limited median survival of 2 years.12,13 Testis sparing surgery in adults is still a matter of debate and is usually only recommended for a small group of selected patients, mostly with impalpable tumors or imperative indications of a solitary tumor bearing testis.18 However, for Leydig cell tumors smaller than 2.5 cm testis sparing surgery can be discussed when histological malignant features are excluded, as evidenced by favorable long-term followup results.16,17 This approach was initially applied to patient 2 in our present report, with the patient later wanting orchiectomy. The even more rare Sertoli cell tumor may present with an early onset, as in our patient 3, or late onset, usually unilateral and multifocal in 30% of patients, and associated with endocrine disorders such as gynecomastia and accelerated bone growth in 40%.14,15 Early onset Sertoli cell tumors occur with dysplastic syndromes such as Peutz-Jeghers syndrome, Bourneville syndrome and the Carney complex. Because of the more favorable prognosis, excision of the tumor appears to be the treatment of choice, whereas late onset tumors in older patients require orchiectomy
due to a 23% malignancy risk, most commonly with consecutive retroperitoneal nerve sparing lymphadenectomy.15 Taken together, the occurrence of testicular tumors in EEC is a clinically interesting incidental finding that has not been described before. However, the clinical relevance is still under debate. Selection bias cannot be excluded, because this underlying cohort includes only a small percentage of men with EEC living in Germany. Birth prevalences for epispadias and classic bladder exstrophy in males have been estimated to be 1.2 and 2.2, respectively, per 100,000 live births in a mainly white population.19,20 Taking these figures into account, approximately 350 males with classic bladder exstrophy and 140 with epispadias were born during the relevant birthyears of the overall cohort. Therefore, it would be highly desirable to implement a Germany wide survey to evaluate the true prevalence of testis cancer in the male EEC population. Although our present knowledge does not warrant a population based screening program, we would highly recommend an appropriate preventive health examination at the end of puberty, including testis sonography and FSH measurement, to be aware of the potential risk for testis tumor in patients with EEC.
CONCLUSIONS Due to the occurrence of testicular tumors and the high incidence of abnormal testicular findings, the concept of normal testicular development in EEC needs to be discussed. A preventive health examination after puberty might afford males with EEC the opportunity for further appropriate diagnostics and treatment, if necessary. However, sonographically detected intratesticular lesions require histological clarification with strict attention to oncologic principles. In cases of impalpable tumor or negative tumor markers even in adulthood organ sparing procedures are worth considering, especially when gonadal stromal tumors with mostly benign behavior and, therefore, favorable outcome are discovered. Although the etiology and true incidence of testicular tumors in EEC are still unclear, the current findings highlight the importance of dedicated longterm followup in patients with EEC.
REFERENCES 1. Stang A, Katalinic A, Dieckmann KP et al: A novel approach to estimate the German-wide incidence of testicular cancer. Cancer Epidemiol 2010; 34: 13. 2. Cook MB, Akre O, Forman D et al: A systematic review and meta-analysis of perinatal variables in
relation to the risk of testicular cancer— experiences of the son. Int J Epidemiol 2010; 39: 1605.
4. Quinlan DM, Gearhart JP and Jeffs RD: Abdominal wall defects and cryptorchidism an animal model. J Urol 1988; 140: 1141.
3. Connolly JA, Peppas DS, Jeffs RD et al: Prevalence and repair of inguinal hernias in children with bladder exstrophy. J Urol 1995; 154: 1900.
5. Gearhart JP: The bladder exstrophy-epispadiascloacal exstrophy complex. In: Pediatric Urology. Edited by JP Gearhart, RC Rink and PDE Mori-
TESTICULAR TUMORS IN PATIENTS WITH EXSTROPHY-EPISPADIAS COMPLEX
quand. Philadelphia: WB Saunders Co 2010; chapt 30, pp 386 – 415. 6. Cortes D, Thorup JM and Visfeldt J: Cryptorchidism: aspects of fertility and neoplasms. A study including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism. Horm Res 2001; 55: 21. 7. Lutke Holzik MF, Sijmons RH, Sleijfer DT et al: Syndromic aspects of testicular carcinoma. Cancer 2003; 97: 984. 8. Ebert AK, Bals-Pratsch M, Seifert B et al: Genital and reproductive function in males after functional reconstruction of the exstrophy-epispadias complex—long-term results. Urology 2008; 72: 566. 9. Behre HM, Kliesch S, Schädel F et al: Clinical relevance and transrectal ultrasonography in andrological patients. Int J Androl 1995; 18: 27.
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10. van Casteren NJ, Looijenga LH and Dohle GR: Testicular microlithiasis and carcinoma in situ overview and proposed clinical guideline. Int J Androl 2009; 32: 279.
16. Giannarini G, Mogorovich A, Fabris FM et al: Long-term followup after elective testis sparing surgery for Leydig cell tumors: a single center experience. J Urol 2007; 178: 872.
11. Costabile RA: How worrisome is testicular microlithiasis? Curr Opin Urol 2007; 17: 419.
17. Loeser A, Vergho DC, Katzenberger T et al: Testissparing surgery versus radical orchiectomy in patients with Leydig cell tumors. Urology 2009; 74: 370.
12. Carmignani L, Colombo R, Gadda F et al: Conservative surgical therapy for Leydig cell tumor. J Urol 2007; 178: 507. 13. Kim I, Young RH and Scully RE: Leydig cell tumors of the testis. A clinicopathological analysis of 40 cases and review of the literature. Am J Surg Pathol 1985; 9: 177. 14. Young RH: Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol 2005; 18: 81. 15. Giglio M, Medica M, De Rose AF et al: Testicular Sertoli cell tumors and relative subtypes. Urol Int 2003; 70: 205.
18. Giannarini G, Dieckmann KP, Albers P et al: Organ-sparing surgery for adult testicular tumours: a systematic review of the literature. Eur Urol 2010; 57: 780. 19. Gearhart JP and Jeffs RD: Exstrophy-epispadias complex and bladder anomalies. In: Campbell’s Urology, 7th ed. Edited by PC Walsh, AB Retik, ED Vaughan Jr et al. Philadelphia: WB Saunders Co 1998; pp 1939 –1990. 20. Epidemiology of bladder exstrophy and epispadias: a communication from the International Clearinghouse for Birth Defects Monitoring Systems. Teratology 1987; 36: 221.