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Is routine excision of testicular remnants in testicular regression syndrome indicated?
Journal of Pediatric Urology (2015) 11, 151.e1e151.e5
Is routine excision of testicular remnants in testicular regression syndrome indicated? R.M. Nataraja a, C.M. Asher b, R. Nash c, F.L. Murphy b a
Department of Paediatric Surgery and Urology, Monash Children’s Hospital, Monash Medical Center, 246 Clayton Road, Clayton, Melbourne, Victoria 3168, Australia
b
Department of Paediatric Surgery and Urology, St George’s Healthcare NHS Trust, Blackshaw Rd, London, SW17 0QT, UK
c Department of Histopathology, St George’s Healthcare NHS Trust, Blackshaw Rd, London, SW17 0QT, UK
Correspondence to: R.M. Nataraja, Monash Children’s Hospital, Department of Paediatric Surgery and Urology & Monash University, Monash Medical Center, 246 Clayton Road, Clayton, Melbourne, Victoria, 3168, Australia [email protected] (R.M. Nataraja) [email protected] (C.M. Asher) [email protected] (R. Nash) [email protected] (F.L. Murphy) Keywords Testicular remnants; Testicular regression syndrome; Testicular nubbin; Undescended testicles; Cryptotorchism Received 18 August 2014 Accepted 14 January 2015 Available online 1 April 2015
Summary Background Undescended testicles are a common finding in fullterm male infants. In the majority of these infants, the testicle spontaneously descends in the first year of life. However, in others, it remains impalpable in an abnormal position or there may only be a small abnormal testicular remnant present. For these infants there is still controversy surrounding inguinal exploration and/or excision of these testicular remnants at the time of operative intervention. The controversy centres on their potential future malignant potential. Aim The aim of the study was to ascertain the incidence of the presence of either germ cells (GCs) or seminiferous tubules (SNTS) in the excised testicular remnants. This was performed at a paediatric surgical tertiary centre and contributes to the evidence base for this condition. Method A retrospective data analysis occurring over a 15year period of all excised testicular remnants. The testicular remnants were analysed for age, laterality, histological analysis and clinical diagnosis. Subset analysis included subdivision into both intraabdominal or inguinal positions, and age ranges. Statistical analysis was using Fisher’s exact test and a P-value of <0.05 was considered to be significant. Results A total of 140 paediatric male patients were identified as having had a testicular remnant excised during the study period. Their demographics and also the main results are summarised in the overall summary Table. The mean age at intervention was 3.5 years (range: 3 months to 17 years). A total of 132/140 of the boys underwent excision of an inguinal testicular regression syndrome (TRS) remnant and 8/140 an intra-abdominal remnant.
Comparison of these two groups revealed no significant difference for the presence of GCs (12 (9%) vs 2 (25%), P Z 0.18). However, intra-abdominal TRS remnants were much more likely to contain SNTs (27 (21%) vs 7 (88%), P Z 0.0002). There was no decreased incidence of either GCs or SNTs with increased patient age. Discussion The main reason for the debate over the management of boys with TRS is the variable incidence of viable germ cells reported in different studies: it has been reported between 0 and 16%. The incidence of GCs (10%) and also SNT (24%) in the present series therefore contributes to this evidence base and is in the middle of this range. It is still unclear as to whether these remnants have a future malignancy risk, as there is only one case of intratubular germ cell neoplasia (ITGCN) in a testicular remnant reported in the literature and this was not immunohistochemically supported. The presence of ITGCN, although considered as a precursor to the development of a testicular germ cell tumour in adult patients, has also not been established in paediatric patients. The natural history of the GCs in TRS specimens is also unknown. In the present series, however, there was no decreased incidence demonstrated with increased patient age, although older patient numbers limited this subset analysis. Despite this controversy, as these patients were already under general anaesthetic, an inguinal exploration and excision of any TRS remnant that was present did not significantly increase the operative procedure or time, and removed any potential malignancy risk. Conclusion This evidence supports the exploration and excision of inguinal testicular remnants, as one in ten boys have GCs present and one in four have SNTs, which may have a potential future malignant transformation risk.
http://dx.doi.org/10.1016/j.jpurol.2015.01.018 1477-5131/Crown Copyright ª 2015 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company. All rights reserved.
151.e2 Table
R.M. Nataraja et al. Overall summary of the testicular regression syndrome cohort Testicular regression syndrome specimen characteristics
Total patients Mean age (range) Histology Viable germ cells Seminiferous tubules Laterality Right Left Age analysis (10 years vs > 10 years) Viable germ cells Seminiferous tubules
Introduction Undescended testicles affect 3% of full-term male infants, and 0.8% of males at one year of age, with 20% of these found to be clinically impalpable [1]. When the testicle is impalpable it could be present within the peritoneal cavity, the inguinal canal, an ectopic position, or only a small abnormal testicular remnant may be present. In this last subgroup, there is still debate about their optimal management. There are various definitions of testicular regression syndrome (TRS) that exist in the literature, which further adds to this debate [2e8]. The definition for TRS used in this study is a congenital condition in which no normal testicular tissue can be identified following exploration for a clinically impalpable testis [6]. This includes the presence of a testicular remnant, nodule or strand of testicular/paratesticular tissue at the end of the spermatic cord. There are various proposed mechanisms for the aetiology of TRS and these include perinatal torsion as the testicle is more susceptible to torsion during its descent into the scrotum before adherence to the inner scrotum occurs [9]. This theory is supported by the presence of haemosiderin-laden macrophages in the testicular remnant specimens. Other theories include the presence of intrascrotal trauma and genetic abnormalities [10,11]. The concern for these remnants is the presence of either seminiferous tubules (SNTs) or germ cells (GCs), which could indicate a possible future malignant potential if they are not excised. To further develop the evidence base for the management of these testicular remnants, the experience of a single paediatric surgical centre has been reviewed.
Subjects and methods A retrospective review was performed on a prospectively created pathological database for paediatric male patients (18 years) with TRS, who had undergone excision of a testicular remnant over a 15-year period. This period occurred between September 1996 and November 2011. Data was collected from the database, with additional surgical data being extracted from the clinical notes and also the operative records. All patients who had undergone operative intervention for an impalpable undescended
140 3.5 (3 monthse17 years) 14 (10%) 34 (24%) 48 (34%) 92 (66%)
11/125 vs 3/15, P Z 0.18 27/125 vs 7/15, P Z 0.05
testicle and underwent subsequent excision of a testicular remnant in the study time period were included. Ethical approval for patient-level data was prospectively obtained from the local institutional ethics committee. In our institution, all patients with a clinically impalpable testicle undergo an examination under anaesthetic and proceed to a laparoscopy if it is still impalpable. At laparoscopy, if there is no intra-abdominal testis located, the inguinal region is then explored and any testicular remnant is excised. If a macroscopically abnormal intra-abdominal testicular remnant is revealed at laparoscopy, these are also excised. Data analysis included the histological analysis as well as the clinical patient demographics (age, laterality) and operative technique. Histological analysis was primarily for the presence of GCs and SNTs, but also included the presence of epididymis, vas deferens, haemosiderin, calcification, fibrosis and Sertoli or Leydig cells. Haematoxylin eosin and placental alkaline phosphatase immunoperoxidase (PLAP) stains were used to determine the presence of germ cells. Subset analysis included comparison between the histological analysis between intra-abdominal testicular remnants and TRS, as well as the percentage of GCs and SNTs according to the age of the patient. Age was grouped into two-year bands, as well as using the age of 10 years to sub-divide the series. Patients who had undergone excision of an atrophied testicle following a previous orchidopexy were not included in the final analysis. Data analysis included Fisher’s exact test and a P-value of <0.05 was considered to be statistically significant.
Results During the study period, a total of 144 male patients were identified, four of these had undergone a previous orchidopexy and were excluded. Therefore, 140 male patients with excised testicular remnants, with 66% (92/140) being left sided, were included in the final analysis. Of these, 8/ 140 had undergone excision of an intra-abdominal TRS remnant. The mean age at intervention was 3.5 years (range: 3 months to 17 years). Overall, the incidence of germ cells was 10% (14/140), with seminiferous tubules seen in 24% (34/140). For patients with a TRS remnant after inguinal exploration, the
Is routine excision of testicular remnants
151.e3
Table 1 Summary of the histological characteristics for testicular remnant specimens (n Z 140). Histological feature
Total number
%
Viable germ cells Seminiferous tubules Sertoli cells Leydig cells Haemosiderin-laden macrophages Vas deferens Epididymis Calcification Fibrosis
14 34 30 15 49 107 71 45 86
10 24 21 11 35 76 51 32 71
incidence of GCs was 9% (12/132) and SNTs 21% (27/132). Eight patients had an intra-abdominal TRS remnant excised, of which, 25% had GCs present (2/8) and 88% (7/8) had SNTs. A summary of the histological analysis is presented in Table 1. Comparison of these two groups of patients revealed no significant difference with the presence of GCs (12 (9%) vs 2 (25%), P Z 0.18). However, intraabdominal TRS remnants were much more likely to contain SNTs (27 (21%) vs 7 (88%), P < 0.001). A summary of the two groups and an overall analysis is presented in Table 2. None of the specimens contained either germ cell dysplasia or intratubular germ cell neoplasia. The subset analysis of the patients into two-year age bands revealed that there was no significant trend towards either an increase or decrease in the percentage of GCs and SNTs, as seen in Fig. 1. There was also no significant difference between analysis of patients who were 10 years old and >10 years old for either GCs or SNTs: GCs (11/125 vs 3/15, P Z 0.18), SNTs (27/125 vs 7/15, P Z 0.05). Patient numbers limited this subset analysis; the majority were younger than four years old, as expected (73%, 102/140).
Discussion The main reason for the debate over the management of patients with TRS is the variable incidence of viable germ cells reported in different studies: between 0 and 16% [4e7,12e14]. In the present study, an overall incidence of 10% for GCs and 24% for SNTs was revealed. The concern with the presence of SNTs is that there is the potential for viable germ cells to be present, although they may have not been identified specifically on histological analysis. This variance may be secondary to the different histopathological analysis
Table 2
practices in the various studies. In the present series, an individual histopathologist performed the histological analysis and this therefore decreased any potential bias. There is also variance in the definition of a TRS remnant, and different surgeons define a testicular remnant or nubbin differently. In the present study, a widely accepted definition was used: a congenital condition in which no normal testicular tissue can be identified following exploration for a clinically impalpable testis [6]. This includes the presence of a testicular remnant, nodule or strand of testicular/paratesticular tissue at the end of the spermatic cord. Other definitions include the presence of a hypoplastic vas and vessels entering a closed ring, as revealed on laparoscopy; in the presence of these intra-operative findings, an inguinal exploration is not recommended [8,15]. In the present study, the nature of the vas and vessels was not specifically noted, but all patients without an intra-abdominal testicular remnant underwent inguinal exploration and, hence, the revealed GC and SNT incidence is high enough to support this practice. For the present study, the intra-abdominal remnants were also included in the overall analysis. Although the definition that was used has been applied more widely to inguinal specimens, it was felt that it could also be applied to this patient group. It is established that there is an increased future malignancy risk with congenital undescended testicles, with a standardised incidence ratio of 2.23 (<13 years old at operation) and 5.4 (>13 years old at operation) [16]. Although the exact aetiology of an undescended testicle is unknown, it very likely to be multifactorial, including the complex remodelling of the gubernaculum and its migration to the scrotum, as well as hormonal deficiencies [9]. Although the aetiology of a TRS testicle has not been fully established, it is very likely that this is secondary to a perinatal torsion or vascular obstruction event such as a thrombosis. This has been supported in the present study by there being a higher incidence of TRS on the left (66%), and also by the high presence of fibrosis, calcification and haemosiderin-laden macrophages in the TRS specimens. There is also likely to be a genetic element in certain patients, but none of the present patients were syndromic. This means that the aetiology that leads to TRS is different to a congenital undescended testicle; hence, the future malignancy risk may also be different. Despite this and the lack of a long-term follow-up study specifically monitoring for TRS-associated malignancy, there is an on-going concern. There is, however, only one case of intratubular germ cell neoplasia (ITGCN) in a testicular remnant reported in the literature and this was not immunohistochemically supported [5]. The presence of ITGCN,
Summary of the two groups.
Mean age (range) Patients Viable germ cells Seminiferous tubules
Inguinal testicular regression syndrome n (%)
Intra-abdominal testicular regression syndrome n (%)
P-value
Overall
3.5 (3 monthse17 years) 132 12 (9%) 27 (21%)
7 (3e13 years) 8 2 (25%) 7 (88%)
e e 0.18 <0.001
e 140 14 (10%) 34 (24%)
151.e4
Figure 1
R.M. Nataraja et al.
Comparison of the germ cell and seminiferous tubule percentages to the age of the patients (two-year age bands).
although considered as a precursor to the development of a testicular germ cell tumour in adult patients, has not been established in paediatric patients. This is secondary to the absence of ITGCN in prepubertal testicles with germ cell tumours [17]. No evidence was detected of either germ cell dysplasia or ITGCN in the resected TRS specimens and this is consistent with previous published data [18]. The natural history of TRS is also unknown, although one study indicated that there is significantly less normal testicular tissue identified in specimens resected from older patients [7]. This study was limited by the fact that there were no germ cells identified in any of the specimens. In the present study, there was no significant trend for a decreased incidence of either GCs or SNTs as the patients became older; therefore, these elements persist with advancing age. The indication for intervention is therefore not age-dependent, although smaller patient numbers in the older age groups, as you would clinically expect, limited this subset analysis. There is another subgroup of patients who have not been addressed in this study e those have a palpable scrotal remnant. None of the patients included in the present series had this pathology, although there are some series that would advocate a scrotal incision after a negative laparoscopy for an unilateral impalpable testicle [19]. There are also clinical factors that influence the decision to excise a testicular remnant. It is now accepted practice in paediatric surgical centres to perform laparoscopy for an impalpable testicle so that an intra-abdominal undescended testicle is not missed. Therefore, as these patients are already under general anaesthetic, an inguinal exploration and excision of any TRS remnant that is present does not significantly increase the operative procedure or time, and removes any potential malignancy risk. Although this
malignancy risk remains controversial, it is recommended that these are excised as one in 10 specimens have GCs present and one in four have SNTs.
Conflict of interest There are no conflicts of interests for any of the authors.
Funding We received no funding for this research.
Ethical approval The local ethical research committee approved the research project.
References [1] Hutson JM, Balic A, Nation T, Southwell B. Cryptorchidism. Semin Pediatr Surg 2010;19:215e24. [2] Bader MI, Peeraully R, Ba’ath M, McPartland J, Baillie C. The testicular regression syndromeedo remnants require routine excision? J Pediatr Surg 2011;46:384e6. [3] Van Savage JG. Avoidance of inguinal incision in laparoscopically confirmed vanishing testis syndrome. J Urol 2001;166: 1421e4. [4] Storm D, Redden T, Aguiar M, Wilkerson M, Jordan G, Sumfest J. Histologic evaluation of the testicular remnant associated with the vanishing testes syndrome: is surgical management necessary? Urology 2007;70:1204e6. [5] Rozanski TA, Wojno KJ, Bloom DA. The remnant orchiectomy. J Urol 1996;155:712e3. discussion 4.
Is routine excision of testicular remnants [6] Law H, Mushtaq I, Wingrove K, Malone M, Sebire NJ. Histopathological features of testicular regression syndrome: relation to patient age and implications for management. Fetal Pediatr Pathol 2006;25:119e29. [7] Hegarty PK, Mushtaq I, Sebire NJ. Natural history of testicular regression syndrome and consequences for clinical management. J Pediatr Urol 2007;3:206e8. [8] Grady RW, Mitchell ME, Carr MC. Laparoscopic and histologic evaluation of the inguinal vanishing testis. Urology 1998;52: 866e9. [9] Hutson JM. Journal of Pediatric Surgery-sponsored Fred McLoed lecture. Undescended testis: the underlying mechanisms and the effects on germ cells that cause infertility and cancer. J Pediatr Surg 2013;48:903e8. [10] Sutcliffe JR, Wilson-Storey D, Smith NM. Ante-natal testicular torsion: only one cause of the testicular regression syndrome? J R Coll Surg Edinb 1996;41:99e101. [11] Imbeaud S, Rey R, Berta P, Chaussain JL, Wit JM, Lustig RH, et al. Testicular degeneration in three patients with the persistent mullerian duct syndrome. Eur J Pediatr 1995;154:187e90. [12] Ueda N, Shiroyanagi Y, Suzuki H, Kim WJ, Yamazaki Y, Tanaka Y. The value of finding a closed internal ring on laparoscopy in unilateral nonpalpable testis. J Pediatr Surg 2013; 48:542e6.
151.e5 [13] Renzulli Ii JF, Shetty R, Mangray S, Anderson KR, Weiss RM, Caldamone AA. Clinical and histological significance of the testicular remnant found on inguinal exploration after diagnostic laparoscopy in the absence of a patent processus vaginalis. J Urol 2005;174:1584e6. [14] Emir H, Ayik B, Elicevik M, Buyukunal C, Danismend N, Dervisoglu S, et al. Histological evaluation of the testicular nubbins in patients with nonpalpable testis: assessment of etiology and surgical approach. Pediatr Surg Int 2007;23:41e4. [15] Godbole PP, Morecroft JA, Mackinnon AE. Laparoscopy for the impalpable testis. Br J Surg 1997;84:1430e2. [16] Pettersson A, Richiardi L, Nordenskjold A, Kaijser M, Akre O. Age at surgery for undescended testis and risk of testicular cancer. N Engl J Med 2007;356:1835e41. [17] Manivel JC, Simonton S, Wold LE, Dehner LP. Absence of intratubular germ cell neoplasia in testicular yolk sac tumors in children. A histochemical and immunohistochemical study. Arch Pathol Lab Med 1988;112:641e5. [18] Pirgon O, Dundar BN. Vanishing testes: a literature review. J Clin Res Pediatr Endocrinol 2012;4:116e20. [19] Snodgrass W, Chen K, Harrison C. Initial scrotal incision for unilateral nonpalpable testis. J Urol 2004;172:1742e5. discussion 5.
Is routine excision of testicular remnants in testicular regression syndrome indicated? R.M. Nataraja a, C.M. Asher b, R. Nash c, F.L. Murphy b a
Department of Paediatric Surgery and Urology, Monash Children’s Hospital, Monash Medical Center, 246 Clayton Road, Clayton, Melbourne, Victoria 3168, Australia
b
Department of Paediatric Surgery and Urology, St George’s Healthcare NHS Trust, Blackshaw Rd, London, SW17 0QT, UK
c Department of Histopathology, St George’s Healthcare NHS Trust, Blackshaw Rd, London, SW17 0QT, UK
Correspondence to: R.M. Nataraja, Monash Children’s Hospital, Department of Paediatric Surgery and Urology & Monash University, Monash Medical Center, 246 Clayton Road, Clayton, Melbourne, Victoria, 3168, Australia [email protected] (R.M. Nataraja) [email protected] (C.M. Asher) [email protected] (R. Nash) [email protected] (F.L. Murphy) Keywords Testicular remnants; Testicular regression syndrome; Testicular nubbin; Undescended testicles; Cryptotorchism Received 18 August 2014 Accepted 14 January 2015 Available online 1 April 2015
Summary Background Undescended testicles are a common finding in fullterm male infants. In the majority of these infants, the testicle spontaneously descends in the first year of life. However, in others, it remains impalpable in an abnormal position or there may only be a small abnormal testicular remnant present. For these infants there is still controversy surrounding inguinal exploration and/or excision of these testicular remnants at the time of operative intervention. The controversy centres on their potential future malignant potential. Aim The aim of the study was to ascertain the incidence of the presence of either germ cells (GCs) or seminiferous tubules (SNTS) in the excised testicular remnants. This was performed at a paediatric surgical tertiary centre and contributes to the evidence base for this condition. Method A retrospective data analysis occurring over a 15year period of all excised testicular remnants. The testicular remnants were analysed for age, laterality, histological analysis and clinical diagnosis. Subset analysis included subdivision into both intraabdominal or inguinal positions, and age ranges. Statistical analysis was using Fisher’s exact test and a P-value of <0.05 was considered to be significant. Results A total of 140 paediatric male patients were identified as having had a testicular remnant excised during the study period. Their demographics and also the main results are summarised in the overall summary Table. The mean age at intervention was 3.5 years (range: 3 months to 17 years). A total of 132/140 of the boys underwent excision of an inguinal testicular regression syndrome (TRS) remnant and 8/140 an intra-abdominal remnant.
Comparison of these two groups revealed no significant difference for the presence of GCs (12 (9%) vs 2 (25%), P Z 0.18). However, intra-abdominal TRS remnants were much more likely to contain SNTs (27 (21%) vs 7 (88%), P Z 0.0002). There was no decreased incidence of either GCs or SNTs with increased patient age. Discussion The main reason for the debate over the management of boys with TRS is the variable incidence of viable germ cells reported in different studies: it has been reported between 0 and 16%. The incidence of GCs (10%) and also SNT (24%) in the present series therefore contributes to this evidence base and is in the middle of this range. It is still unclear as to whether these remnants have a future malignancy risk, as there is only one case of intratubular germ cell neoplasia (ITGCN) in a testicular remnant reported in the literature and this was not immunohistochemically supported. The presence of ITGCN, although considered as a precursor to the development of a testicular germ cell tumour in adult patients, has also not been established in paediatric patients. The natural history of the GCs in TRS specimens is also unknown. In the present series, however, there was no decreased incidence demonstrated with increased patient age, although older patient numbers limited this subset analysis. Despite this controversy, as these patients were already under general anaesthetic, an inguinal exploration and excision of any TRS remnant that was present did not significantly increase the operative procedure or time, and removed any potential malignancy risk. Conclusion This evidence supports the exploration and excision of inguinal testicular remnants, as one in ten boys have GCs present and one in four have SNTs, which may have a potential future malignant transformation risk.
http://dx.doi.org/10.1016/j.jpurol.2015.01.018 1477-5131/Crown Copyright ª 2015 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company. All rights reserved.
151.e2 Table
R.M. Nataraja et al. Overall summary of the testicular regression syndrome cohort Testicular regression syndrome specimen characteristics
Total patients Mean age (range) Histology Viable germ cells Seminiferous tubules Laterality Right Left Age analysis (10 years vs > 10 years) Viable germ cells Seminiferous tubules
Introduction Undescended testicles affect 3% of full-term male infants, and 0.8% of males at one year of age, with 20% of these found to be clinically impalpable [1]. When the testicle is impalpable it could be present within the peritoneal cavity, the inguinal canal, an ectopic position, or only a small abnormal testicular remnant may be present. In this last subgroup, there is still debate about their optimal management. There are various definitions of testicular regression syndrome (TRS) that exist in the literature, which further adds to this debate [2e8]. The definition for TRS used in this study is a congenital condition in which no normal testicular tissue can be identified following exploration for a clinically impalpable testis [6]. This includes the presence of a testicular remnant, nodule or strand of testicular/paratesticular tissue at the end of the spermatic cord. There are various proposed mechanisms for the aetiology of TRS and these include perinatal torsion as the testicle is more susceptible to torsion during its descent into the scrotum before adherence to the inner scrotum occurs [9]. This theory is supported by the presence of haemosiderin-laden macrophages in the testicular remnant specimens. Other theories include the presence of intrascrotal trauma and genetic abnormalities [10,11]. The concern for these remnants is the presence of either seminiferous tubules (SNTs) or germ cells (GCs), which could indicate a possible future malignant potential if they are not excised. To further develop the evidence base for the management of these testicular remnants, the experience of a single paediatric surgical centre has been reviewed.
Subjects and methods A retrospective review was performed on a prospectively created pathological database for paediatric male patients (18 years) with TRS, who had undergone excision of a testicular remnant over a 15-year period. This period occurred between September 1996 and November 2011. Data was collected from the database, with additional surgical data being extracted from the clinical notes and also the operative records. All patients who had undergone operative intervention for an impalpable undescended
140 3.5 (3 monthse17 years) 14 (10%) 34 (24%) 48 (34%) 92 (66%)
11/125 vs 3/15, P Z 0.18 27/125 vs 7/15, P Z 0.05
testicle and underwent subsequent excision of a testicular remnant in the study time period were included. Ethical approval for patient-level data was prospectively obtained from the local institutional ethics committee. In our institution, all patients with a clinically impalpable testicle undergo an examination under anaesthetic and proceed to a laparoscopy if it is still impalpable. At laparoscopy, if there is no intra-abdominal testis located, the inguinal region is then explored and any testicular remnant is excised. If a macroscopically abnormal intra-abdominal testicular remnant is revealed at laparoscopy, these are also excised. Data analysis included the histological analysis as well as the clinical patient demographics (age, laterality) and operative technique. Histological analysis was primarily for the presence of GCs and SNTs, but also included the presence of epididymis, vas deferens, haemosiderin, calcification, fibrosis and Sertoli or Leydig cells. Haematoxylin eosin and placental alkaline phosphatase immunoperoxidase (PLAP) stains were used to determine the presence of germ cells. Subset analysis included comparison between the histological analysis between intra-abdominal testicular remnants and TRS, as well as the percentage of GCs and SNTs according to the age of the patient. Age was grouped into two-year bands, as well as using the age of 10 years to sub-divide the series. Patients who had undergone excision of an atrophied testicle following a previous orchidopexy were not included in the final analysis. Data analysis included Fisher’s exact test and a P-value of <0.05 was considered to be statistically significant.
Results During the study period, a total of 144 male patients were identified, four of these had undergone a previous orchidopexy and were excluded. Therefore, 140 male patients with excised testicular remnants, with 66% (92/140) being left sided, were included in the final analysis. Of these, 8/ 140 had undergone excision of an intra-abdominal TRS remnant. The mean age at intervention was 3.5 years (range: 3 months to 17 years). Overall, the incidence of germ cells was 10% (14/140), with seminiferous tubules seen in 24% (34/140). For patients with a TRS remnant after inguinal exploration, the
Is routine excision of testicular remnants
151.e3
Table 1 Summary of the histological characteristics for testicular remnant specimens (n Z 140). Histological feature
Total number
%
Viable germ cells Seminiferous tubules Sertoli cells Leydig cells Haemosiderin-laden macrophages Vas deferens Epididymis Calcification Fibrosis
14 34 30 15 49 107 71 45 86
10 24 21 11 35 76 51 32 71
incidence of GCs was 9% (12/132) and SNTs 21% (27/132). Eight patients had an intra-abdominal TRS remnant excised, of which, 25% had GCs present (2/8) and 88% (7/8) had SNTs. A summary of the histological analysis is presented in Table 1. Comparison of these two groups of patients revealed no significant difference with the presence of GCs (12 (9%) vs 2 (25%), P Z 0.18). However, intraabdominal TRS remnants were much more likely to contain SNTs (27 (21%) vs 7 (88%), P < 0.001). A summary of the two groups and an overall analysis is presented in Table 2. None of the specimens contained either germ cell dysplasia or intratubular germ cell neoplasia. The subset analysis of the patients into two-year age bands revealed that there was no significant trend towards either an increase or decrease in the percentage of GCs and SNTs, as seen in Fig. 1. There was also no significant difference between analysis of patients who were 10 years old and >10 years old for either GCs or SNTs: GCs (11/125 vs 3/15, P Z 0.18), SNTs (27/125 vs 7/15, P Z 0.05). Patient numbers limited this subset analysis; the majority were younger than four years old, as expected (73%, 102/140).
Discussion The main reason for the debate over the management of patients with TRS is the variable incidence of viable germ cells reported in different studies: between 0 and 16% [4e7,12e14]. In the present study, an overall incidence of 10% for GCs and 24% for SNTs was revealed. The concern with the presence of SNTs is that there is the potential for viable germ cells to be present, although they may have not been identified specifically on histological analysis. This variance may be secondary to the different histopathological analysis
Table 2
practices in the various studies. In the present series, an individual histopathologist performed the histological analysis and this therefore decreased any potential bias. There is also variance in the definition of a TRS remnant, and different surgeons define a testicular remnant or nubbin differently. In the present study, a widely accepted definition was used: a congenital condition in which no normal testicular tissue can be identified following exploration for a clinically impalpable testis [6]. This includes the presence of a testicular remnant, nodule or strand of testicular/paratesticular tissue at the end of the spermatic cord. Other definitions include the presence of a hypoplastic vas and vessels entering a closed ring, as revealed on laparoscopy; in the presence of these intra-operative findings, an inguinal exploration is not recommended [8,15]. In the present study, the nature of the vas and vessels was not specifically noted, but all patients without an intra-abdominal testicular remnant underwent inguinal exploration and, hence, the revealed GC and SNT incidence is high enough to support this practice. For the present study, the intra-abdominal remnants were also included in the overall analysis. Although the definition that was used has been applied more widely to inguinal specimens, it was felt that it could also be applied to this patient group. It is established that there is an increased future malignancy risk with congenital undescended testicles, with a standardised incidence ratio of 2.23 (<13 years old at operation) and 5.4 (>13 years old at operation) [16]. Although the exact aetiology of an undescended testicle is unknown, it very likely to be multifactorial, including the complex remodelling of the gubernaculum and its migration to the scrotum, as well as hormonal deficiencies [9]. Although the aetiology of a TRS testicle has not been fully established, it is very likely that this is secondary to a perinatal torsion or vascular obstruction event such as a thrombosis. This has been supported in the present study by there being a higher incidence of TRS on the left (66%), and also by the high presence of fibrosis, calcification and haemosiderin-laden macrophages in the TRS specimens. There is also likely to be a genetic element in certain patients, but none of the present patients were syndromic. This means that the aetiology that leads to TRS is different to a congenital undescended testicle; hence, the future malignancy risk may also be different. Despite this and the lack of a long-term follow-up study specifically monitoring for TRS-associated malignancy, there is an on-going concern. There is, however, only one case of intratubular germ cell neoplasia (ITGCN) in a testicular remnant reported in the literature and this was not immunohistochemically supported [5]. The presence of ITGCN,
Summary of the two groups.
Mean age (range) Patients Viable germ cells Seminiferous tubules
Inguinal testicular regression syndrome n (%)
Intra-abdominal testicular regression syndrome n (%)
P-value
Overall
3.5 (3 monthse17 years) 132 12 (9%) 27 (21%)
7 (3e13 years) 8 2 (25%) 7 (88%)
e e 0.18 <0.001
e 140 14 (10%) 34 (24%)
151.e4
Figure 1
R.M. Nataraja et al.
Comparison of the germ cell and seminiferous tubule percentages to the age of the patients (two-year age bands).
although considered as a precursor to the development of a testicular germ cell tumour in adult patients, has not been established in paediatric patients. This is secondary to the absence of ITGCN in prepubertal testicles with germ cell tumours [17]. No evidence was detected of either germ cell dysplasia or ITGCN in the resected TRS specimens and this is consistent with previous published data [18]. The natural history of TRS is also unknown, although one study indicated that there is significantly less normal testicular tissue identified in specimens resected from older patients [7]. This study was limited by the fact that there were no germ cells identified in any of the specimens. In the present study, there was no significant trend for a decreased incidence of either GCs or SNTs as the patients became older; therefore, these elements persist with advancing age. The indication for intervention is therefore not age-dependent, although smaller patient numbers in the older age groups, as you would clinically expect, limited this subset analysis. There is another subgroup of patients who have not been addressed in this study e those have a palpable scrotal remnant. None of the patients included in the present series had this pathology, although there are some series that would advocate a scrotal incision after a negative laparoscopy for an unilateral impalpable testicle [19]. There are also clinical factors that influence the decision to excise a testicular remnant. It is now accepted practice in paediatric surgical centres to perform laparoscopy for an impalpable testicle so that an intra-abdominal undescended testicle is not missed. Therefore, as these patients are already under general anaesthetic, an inguinal exploration and excision of any TRS remnant that is present does not significantly increase the operative procedure or time, and removes any potential malignancy risk. Although this
malignancy risk remains controversial, it is recommended that these are excised as one in 10 specimens have GCs present and one in four have SNTs.
Conflict of interest There are no conflicts of interests for any of the authors.
Funding We received no funding for this research.
Ethical approval The local ethical research committee approved the research project.
References [1] Hutson JM, Balic A, Nation T, Southwell B. Cryptorchidism. Semin Pediatr Surg 2010;19:215e24. [2] Bader MI, Peeraully R, Ba’ath M, McPartland J, Baillie C. The testicular regression syndromeedo remnants require routine excision? J Pediatr Surg 2011;46:384e6. [3] Van Savage JG. Avoidance of inguinal incision in laparoscopically confirmed vanishing testis syndrome. J Urol 2001;166: 1421e4. [4] Storm D, Redden T, Aguiar M, Wilkerson M, Jordan G, Sumfest J. Histologic evaluation of the testicular remnant associated with the vanishing testes syndrome: is surgical management necessary? Urology 2007;70:1204e6. [5] Rozanski TA, Wojno KJ, Bloom DA. The remnant orchiectomy. J Urol 1996;155:712e3. discussion 4.
Is routine excision of testicular remnants [6] Law H, Mushtaq I, Wingrove K, Malone M, Sebire NJ. Histopathological features of testicular regression syndrome: relation to patient age and implications for management. Fetal Pediatr Pathol 2006;25:119e29. [7] Hegarty PK, Mushtaq I, Sebire NJ. Natural history of testicular regression syndrome and consequences for clinical management. J Pediatr Urol 2007;3:206e8. [8] Grady RW, Mitchell ME, Carr MC. Laparoscopic and histologic evaluation of the inguinal vanishing testis. Urology 1998;52: 866e9. [9] Hutson JM. Journal of Pediatric Surgery-sponsored Fred McLoed lecture. Undescended testis: the underlying mechanisms and the effects on germ cells that cause infertility and cancer. J Pediatr Surg 2013;48:903e8. [10] Sutcliffe JR, Wilson-Storey D, Smith NM. Ante-natal testicular torsion: only one cause of the testicular regression syndrome? J R Coll Surg Edinb 1996;41:99e101. [11] Imbeaud S, Rey R, Berta P, Chaussain JL, Wit JM, Lustig RH, et al. Testicular degeneration in three patients with the persistent mullerian duct syndrome. Eur J Pediatr 1995;154:187e90. [12] Ueda N, Shiroyanagi Y, Suzuki H, Kim WJ, Yamazaki Y, Tanaka Y. The value of finding a closed internal ring on laparoscopy in unilateral nonpalpable testis. J Pediatr Surg 2013; 48:542e6.
151.e5 [13] Renzulli Ii JF, Shetty R, Mangray S, Anderson KR, Weiss RM, Caldamone AA. Clinical and histological significance of the testicular remnant found on inguinal exploration after diagnostic laparoscopy in the absence of a patent processus vaginalis. J Urol 2005;174:1584e6. [14] Emir H, Ayik B, Elicevik M, Buyukunal C, Danismend N, Dervisoglu S, et al. Histological evaluation of the testicular nubbins in patients with nonpalpable testis: assessment of etiology and surgical approach. Pediatr Surg Int 2007;23:41e4. [15] Godbole PP, Morecroft JA, Mackinnon AE. Laparoscopy for the impalpable testis. Br J Surg 1997;84:1430e2. [16] Pettersson A, Richiardi L, Nordenskjold A, Kaijser M, Akre O. Age at surgery for undescended testis and risk of testicular cancer. N Engl J Med 2007;356:1835e41. [17] Manivel JC, Simonton S, Wold LE, Dehner LP. Absence of intratubular germ cell neoplasia in testicular yolk sac tumors in children. A histochemical and immunohistochemical study. Arch Pathol Lab Med 1988;112:641e5. [18] Pirgon O, Dundar BN. Vanishing testes: a literature review. J Clin Res Pediatr Endocrinol 2012;4:116e20. [19] Snodgrass W, Chen K, Harrison C. Initial scrotal incision for unilateral nonpalpable testis. J Urol 2004;172:1742e5. discussion 5.