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Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis
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Journal of Pediatric Urology (2017) xx, 1.e1e1.e6
Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis a
Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
S. Chaudhry a, R. Tadokoro-Cuccaro a, S.E. Hannema b,c, C.L. Acerini a, I.A. Hughes a Summary
b
Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands
c Sophia Children’s Hospital, Erasmus University Medical Centre, Rotterdam, The Netherlands
Correspondence to: R. Tadokoro-Cuccaro, Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ, UK, Tel.: þ44 (0) 1223768615; fax: þ44 (0) 1223 336996 [email protected] (R. Tadokoro-Cuccaro)
Background Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder of sex development (DSD) where affected individuals are phenotypically female, but have an XY karyotype and testes. The risk of gonadal tumour development in CAIS may increase with age; incidence rates have been reported to be 0.8e22% in patients who have retained their gonads into adulthood. Consequently, gonadectomy has been recommended either during childhood or after puberty is complete, although there is no consensus on the optimal timing for this procedure. Objective and hypotheses To establish the frequency of histological abnormalities in CAIS in relation to the age at gonadectomy.
Keywords Androgen insensitivity syndrome; Gonadectomy; Gonadal tumour; Germ cell neoplasia in situ (GCNIS); Carcinoma in situ (CIS)
Method Data were collected from the Cambridge DSD database on patients with CAIS (n Z 225; age range 3e88 years) who had undergone gonadectomy, and their age of gonadectomy, gonadal histology and immunohistochemistry.
Received 5 December 2016 Accepted 13 February 2017 Available online xxx
Results Evaluable data were obtained from 133 patients. Median age at gonadectomy was 14.0 years (range:
Summary table
18 dayse68 years). Pubertal status was: prepuberty, n Z 62; postpuberty, n Z 68. Thirteen cases were aged >20 years at gonadectomy. The pattern of histology is summarised in the Summary table.
Discussion In this large case series of CAIS patients who had undergone gonadectomy, while the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings confirm the low occurrence of gonadal malignancy in CAIS, with a frequency of 1.5%. The two cases of malignancy were postpubertal. Germ cell neoplasia in situ (GCNIS) was observed in six cases, of which one occurred prepuberty and five postpuberty. The study highlighted difficulties in diagnosis of GCNIS and the need for histological analysis in expert centres.
Conclusion The results support the current recommendation that gonads in CAIS can be retained until early adulthood. The small number of individuals with gonadectomy after age 20 years do not allow firm conclusion regarding later adulthood. Therefore, it is recommended that the option of gonadectomy be discussed in adulthood. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal.
Abnormal histology.
Benign tumour n Z 6 Sertoli cell adenoma (SCA) n Z 8 testicular hamartoma (TH) n Z 2 mixed SCA þ TH Germ cell neoplasia in situ (GCNIS) (age at gonadectomy) n Z 6 (2 years 9 months, 16 years, 17 years,*17 years, 20 years,*53 years) *Associated with benign changes Malignant tumour (age at gonadectomy) n Z 1 malignant sex cord stromal tumour (68 years) n Z 1 seminoma (30 years)
http://dx.doi.org/10.1016/j.jpurol.2017.02.013 1477-5131/ª 2017 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
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Introduction Complete androgen insensitivity syndrome (CAIS) is an Xlinked recessive disorder of sex development (DSD) caused by inactivity of the androgen receptor in response to androgens, due to a mutation of the androgen receptor (AR) gene [1]. Affected individuals have an XY karyotype, but an external female phenotype and labial, inguinal or intraabdominal sited gonads, which are testes [2]. Management of CAIS includes a decision on whether and when to remove the gonads because of the risk of developing gonadal malignancy [3]. The risk of gonadal tumour development in CAIS may increase with age; incidence rates of 0.8e22% have been reported in patients who have retained their gonads into adulthood [4,5]. However, the data on adults with CAIS include historical cases where the diagnosis was uncertain. Invasive germ cell tumours of the gonad (including seminoma/non-seminomas, dysgerminoma/non-dysgerminomas) predominate, and are usually preceded by a noninvasive ‘carcinoma in situ’ (CIS) or intratubular germ cell neoplasia unclassified (IGCNU) phase. The term CIS and IGCNU will now be replaced by germ cell neoplasia in situ (GCNIS), as proposed by the World Health Organization Classifications of Tumours of the Male Genital Organs [6]. It has been reported that 50% of GCNIS progresses to invasive germ cell tumour within 5 years [7]. Currently, there are no clinically useful biomarkers available to guide clinicians in predicting tumour risk other than direct gonadal histology and immunohistochemistry. Given the risk of gonadal malignancy in patients with CAIS, recent practice has advocated gonadectomy either in childhood or soon after puberty [8]. However, optimal timing for this procedure has become increasingly controversial, given the purported benefits of natural testosterone production (and its subsequent aromatisation to oestrogen) for patient well-being and quality of life [2]. As a result, many patients and families with CAIS are choosing to defer gonadectomy well into adulthood or to decline this option altogether [5]. The secular trend towards delayed or no gonadectomy has raised concerns that patients may now be at increased risk of developing gonadal malignancy. It is difficult to quantify the risk, given that the prevalence and incidence of early gonadal malignancy changes and tumour development are unclear. Consequently, a retrospective review was undertaken of the gonadal histology reports available from CAIS patients who had their gonads removed, in order to establish the frequency of histological abnormalities in relation to age and timing of gonadectomy.
Patients and methods The resource that was used for this study was the Cambridge DSD database [9]. It contains detailed information on clinical phenotype, results of biochemical and genetic tests and descriptive reports of histological and immunohistochemical analyses of gonadectomy specimens. For the purpose of this study, the diagnosis of CAIS was based on typical clinical and biochemical features, and confirmed by analysis of the AR gene in the majority of cases. Full
S. Chaudhry et al. sequencing of the coding region, including intron/exon boundaries, was performed as previously described [10]. Information regarding patient age at gonadectomy, position of gonads at time of diagnosis, histology report, immunohistochemistry findings and AR mutation was analysed. Histological studies were performed at the local hospital and the reports obtained from the referring clinician. Standard immunohistochemistry, including placental alkaline phosphatase (PLAP), was performed in the majority of cases. For some of the cases where tissue from gonadectomy was available, the pathology was reviewed as previously described [11]. The terms ‘carcinoma in situ’ (CIS) and ‘intratubular germ cell neoplasia unclassified’ (IGCNU), used in the reports, were considered to be equivalent to the new term ‘germ cell neoplasia in situ’ (GCNIS) used in this analysis. Ethics approval for the study was obtained from the local research committee, and institutional approval was obtained from the Research and Development Committee of the Cambridge University Hospitals NHS Foundation Trust.
Results A total of 225 patients with CAIS (age range 3e88 years at the time of analysis) were identified in the database, of which 141 had undergone gonadectomy. The following were excluded: no information on gonadal histology available (n Z 6); AR gene screening was not performed (n Z 1); mutation was not identified by single-strand conformation polymorphism (SSCP) and no sequence analysis performed (n Z 1). Six cases that were not screened for an AR mutation, but one had been identified in another affected family member, were included. A total of 133 cases were included in this study. The median age at gonadectomy was 14.0 years (range: 18 dayse63 years). There were two peaks in the age of gonadectomy: during infancy to early childhood, and after puberty (Fig. 1). An equal number of patients had gonadectomy performed before and after puberty (62 and 68 patients, respectively). Timing of gonadectomy in relation to pubertal status was unknown in three cases. In cases that had gonadectomy before the age of 13 years, approximately 60% of gonads were located in the inguinal region. In contrast, in cases that had gonadectomy after age 13 years, 60% of the gonads were intraabdominal or non-palpable (Fig. 2). Histology in relation to age of gonadectomy is shown in Fig. 1. Abnormalities were reported in 27 cases (20.3%). In 18 cases (13.5%) the histology was considered benign. This subset comprised cases of Sertoli cell adenoma (SCA, n Z 6), testicular hamartoma (TH, n Z 8), mixed SCA/TH (n Z 2) and sex cord tumour ‘with annular tubules’ (n Z 2). Immunohistochemistry was negative for PLAP in four cases. The local pathologist reported five cases of premalignant changes (GCNIS). GCNIS was identified in two additional cases on further review; from the original histology reports it was unclear if and what immunohistochemical studies had been performed in these cases (Table 1). Two cases also had concomitant benign changes (SCA þ GCNIS; hamartoma þ GCNIS). In Case 1, premalignancy was reported at an early age, based on areas in the gonad with increased germ cell numbers and cell atypia with some
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
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number of individuals
Gonadal tumour in complete androgen insensitivity syndrome
1.e3
50 45 40 35 30 25 20 15 10 5 0
malignancy GCNIS no malignancy
Age of gonadectomy Figure 1
Malignant and premalignant changes according to age at gonadectomy.
160 140 120
number of gonads
100
unknown non-palpable
80
labia inguinal
60
intra-abdominal 40 20 0 gonadectomy before 13 yrs
aŌer 13 yrs
Figure 2 Location of gonads at time of diagnosis; gonadectomy before and after age 13 years.
multinucleate cells and large nucleoli. GCNIS was further substantiated by staining positive for PLAP. However, on review and with additional immunohistochemical studies, the pattern was probably more consistent with delayed germ cell maturation [11]. An affected relative presented with primary amenorrhoea and had the same AR mutation (Asp733Asn). She had gonadectomy; histology and immunohistochemistry showed no evidence of premalignancy. From the other prepubertal child (Case 2) no histological material was available for review, so it could not be assessed if this child might have had delayed germ cell maturation rather than GCNIS. However, the pathology report, from a UK teaching hospital, described larger cells with clear cytoplasm and sometimes irregular nuclei, with small nucleoli located either in the base of the tubule or more towards the lumen, positive for PLAP, OCT3/4 and
CD117. The cells expressing these markers located at the basement membrane were suggestive for GCNIS. Cases 6 and 7 had histological changes consistent with GCNIS and have been reported previously [11]. Two cases (1.5%) had malignant changes. Case 9 presented with primary amenorrhoea and at laparoscopic gonadectomy a single left-sided gonad was identified. However, she developed a lump in the right groin in adulthood and gonadectomy and histology showed a seminoma. There was no metastasis. Case 8 presented at the age of 68 years with a large abdominal mass arising from a gonadal tumour. Histology was consistent with a malignant sex cord stromal tumour. No metastatic lesion was detected. Histology of the contralateral gonad showed a dysplastic testis without premalignancy. There was no relationship between AR mutation type (for example, nonsenses versus missense mutation) and (pre)malignant changes in this small series. Furthermore, while such changes occurred almost exclusively after puberty, there was no apparent relationship with gonadal site, although the two cases of malignancy occurred in intra-abdominal gonads.
Discussion This study, based on a large cohort of patients with CAIS, was designed to explore an association between age at gonadectomy and gonadal malignancy or premalignancy. This may have implications for management, particularly if gonads are not removed. A low prevalence of 1.5% for malignancy was found in 133 patients with CAIS and was confined to ages >20 years.
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
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Characteristics of CAIS cases with premalignant and malignant changes.
Case Age at diagnosis, presenting symptom
Age at gonadectomy Position of (years, months) gonads
Initial histology
Immunohisto-chemistry Further review [11]
AR mutation
1a
1 month, inguinal hernia
1, 7 mn
Bilateral GCNIS
Unknown (HCG test in Iran)
2, 9 mn
Delayed germ cell maturation N/A
Leu806fs
3
2 years, Lt inguinal hernia
16
Bilateral GCNIS
N/A
His918Arg
4
6 months, Rt inguinal hernia
17
Lt GCNIS
PLAP (þ)
N/A
Met896Thr
5
Age unknown, primary amenorrhoea 20
Bilateral GCNIS
PLAP (þ) CD117 (þ)
N/A
Gln120Stop
6a
16 years, primary amenorrhoea
17
Hamartoma
Unclear if performed
7a
53
Sertoli cell adenoma
Unclear
Bilateral GCNIS Val888fs hamartoma Bilateral GCNIS Ala766Thr Sertoli cell adenoma
8a
53 years, abdominal pain (initially presented primary amenorrhoea at 16 years) 68 years, abdominal mass
Rt inguinal Lt inguinal Rt inguinal Lt inguinal Rt unknown Lt unknown (Both non palpable) Rt intra-abdominal Lt intra-abdominal Rt intra-abdominal Lt intra-abdominal
PLAP (þ) CD117 (þ) PLAP (þ) OCT3/4 (þ) CD117 (þ) PLAP (þ)
Asp733Asn
2
Rt inguinal Lt inguinal Rt intra-abdominal Lt intra-abdominal
9
17 years, primary amenorrhoea
Lt 19 Rt 30
Rt intra-abdominal Lt intra-abdominal Rt inguinal Lt inguinal
Rt malignant sex cord PLAP () stromal tumour Vimentin (þ) Rt seminoma PLAP (þ)
N/A
Arg832Stop
N/A
Arg775Cys
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68
Bilateral GCNIS
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CAIS, complete androgen insensitivity syndrome; PLAP, placental alkaline phosphatase; OCT3/4, octamer-binding transcription factors 3 and 4; CD117, stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit; Rt, right; Lt, left; GCNIS, germ cell neoplasia in situ; HCG, human chorionic gonadotropin. a Reported previously [11,12].
S. Chaudhry et al.
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
Table 1
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Gonadal tumour in complete androgen insensitivity syndrome One patient presented with a testicular seminoma at the age of 30 years; the second patient did not present until aged 68 years and had a sex cord stromal tumour, as previously reported [12]. Seminoma is the most frequent testicular tumour in CAIS [13]. It arises from a precursor stage, GCNIS, and is believed to be due to a failure of normal maturation of foetal germ cells from gonocytes into pre-spermatogonia [14]. The age of presentation for seminoma in CAIS is generally >30 years, although there is a case reported in a teenager [15]. Sex cord stromal tumours are rare, comprising 3e5% of all testicular tumours [16]; they have been reported in adult patients with CAIS [17,18]. The majority are of Leydig cell origin, with malignancy occurring in 10e20%. The results of the present study are consistent with the recommendation that the gonads in CAIS can be retained until early adulthood, due to a low risk of malignancy [8]. Due to the small number of individuals (n Z 13) who had gonadectomy after age 20 years, the risk of gonadal tumours cannot be accurately assessed if gonads are retained beyond early adulthood. In individuals with CAIS, seminiferous tubules contain embryonic germ cells, which rapidly decline after the first year of life [11,19]. One mechanism to explain the lower malignancy risk in CAIS compared to partial AIS (PAIS) may be related to apoptosis of the germ cells in the testis [19]. A certain level of testosterone seems to be needed for GCNIS to develop into an invasive form. This is supported by the observation that patients with hypogonadotropic hypogonadism do not develop germ cell tumours in spite of cryptorchidism [19]. In CAIS, the intra-abdominal location of the gonads may be a factor adding to the risk of malignancy [16]. Analysis of an association between gonadal location and tumour risk in the present study is skewed by the earlier age of presentation in infants with inguinal/ labial gonads and the small number of cases with (pre) malignant changes. The local pathologists reported five cases in this study as having GCNIS and two further cases added following review. While GCNIS is uncommon, it has been reported during childhood and adolescence [20]. In a review of 102 cases of DSD, there were four cases with prepubertal GCNIS. These cases comprised 45,X/46,XY gonadal dysgenesis, multiple congenital anomalies with ambiguous genitalia, and 46,XY DSD associated with a congenital heart defect [21]. The present study identified premalignancy manifest in an infant with CAIS (Case 1, Table 1). This was initially reported as GCNIS, but further review suggested delayed germ cell maturation [11]. On the other hand, two cases with GCNIS were not initially identified by routine histology. This study highlights that the diagnosis of GCNIS can be difficult and the need for expertise in germ cell pathology. What would have been the risk of malignant transformation in Case 1 if gonadectomy had not taken place? Probably low, based on the hypothesis that residual androgen activity is required for progression of premalignant to malignant status [22]. It is perhaps noteworthy that the older affected relative showed no signs of germ cell premalignancy on histology and immunohistochemistry. Both had the same AR mutation. Little is known about the natural history of GCNIS, particularly in CAIS. A study which followed 18 testes from 15 infertile men aged 26e36 years reported a 50% malignant transformation rate within 5 years [7]. This much
1.e5 higher rate compared with that seen in CAIS supports the aforementioned low residual androgen activity hypothesis. The type of AR mutation in CAIS does not appear to predict the risk of malignancy with GCNIS, but the number for analysis was too few in the present study. GCNIS has a characteristic morphological appearance comprising large cells confined to the seminiferous tubules with clear cytoplasm, hyperchromatic nuclei and increased mitotic activity [3,21]. Expression of immunohistochemical markers such as PLAP and octamer-binding transcription factors 3 and 4 (OCT3/4) in adults is characteristic of GCNIS. However, in infants and children, especially those with a DSD, it can be difficult to distinguish between GCNIS and germ cells that show delayed maturation, but are not (yet) malignant. In dysgenetic gonads, germ cells may show prolonged expression of markers such as PLAP and OCT3/4. Age, the distribution pattern of germ cells that express tumour markers and the position of germ cells within the seminiferous tubule are important in making this distinction [23]. This study highlights the difficulty in making a diagnosis of GCNIS when the gonads are removed in infancy. Paediatric surgeons and urologists need to be aware of these findings when performing biopsies to establish the presence of testes in CAIS infants or when undertaking early gonadectomy. Some women with CAIS are now opting to retain their gonads for the long term, to benefit from the effects of endogenous oestrogen produced from aromatisation of androgens and possibly from direct androgenic effects [24]. To address the risk of germ cell malignancy, regular imaging surveillance with either magnetic resonance imaging (MRI) or ultrasonography has been suggested [20]. MRI can detect benign changes such as paratesticular cysts and Sertoli cell adenomas, but premalignant changes such as GCNIS are not visible; to detect these, a gonadal biopsy would be required for histology. One approach adopted is laparoscopic gonadal biopsy and gonadopexy to place the gonads near the abdominal wall [25]. The procedure improved visualisation of the gonads by ultrasonography. Targeted microRNA-based (miRNA) blood tests are currently under investigation for use in detecting early malignant changes in testicular germ cell tumours [6]. These biomarkers measured in serum and cerebrospinal fluid samples from children with gonadal and extra-gonadal germ cell tumours are highly specific and sensitive [26,27]. Although the specific miRNAs are expressed in GCNIS tissue, they are not detectable in serum [28].
Conclusion The strength of this study was the large cohort of CAIS patients who had gonadectomy in approximately equal numbers before and after puberty. While the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings showed a frequency for gonadal malignancy as low as 1.5%. Premalignant changes were rare before puberty. The results of this study suggest that it is safe to retain gonads in situ into early adulthood. The small number of individuals with gonadectomy after age 20 years did not allow firm conclusions regarding later adulthood. Therefore, it is the patient’s personal choice to make an
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
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1.e6 informed decision about continued retention of gonads. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal. This study also highlighted the difficulty in making a diagnosis of GCNIS in a gonad removed in infancy. It is recommended that experts in germ cell pathology in DSD review the histology.
Conflict of interest None.
Acknowledgements We are very grateful to all referring clinicians and to their patients for agreeing to provide data and personal information. The Cambridge DSD database is supported by the NIHR Clinical Research Network (CRN-Eastern).
References [1] Jaaskelainen J. Molecular biology of androgen insensitivity. Mol Cell Endocrinol 2012;352:4e12. [2] Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannopoulou K, MacDougall J. Androgen insensitivity syndrome. Lancet 2012;380:1419e28. [3] Pleskacova J, Hersmus R, Oosterhuis JW, Setyawati BA, Faradz SM, Cools M, et al. Tumor risk in disorders of sex development. Sex Dev 2010;4:259e69. [4] Cools M, Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LH. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev 2006;27: 468e84. [5] Deans R, Creighton SM, Liao LM, Conway GS. Timing of gonadectomy in adult women with complete androgen insensitivity syndrome (CAIS): patient preferences and clinical evidence. Clin Endocrinol 2012;76:894e8. [6] Rajpert-De Meyts E, Nielsen JE, Skakkebaek NE, Almstrup K. Diagnostic markers for germ cell neoplasms: from placentallike alkaline phosphatase to micro-RNAs. Folia Histochem Cytobiol 2015;53:177e88. [7] Dieckmann KP, Skakkebaek NE. Carcinoma in situ of the testis: review of biological and clinical features. Int J Cancer 1999; 83:815e22. [8] Hughes IA, Houk C, Ahmed SF, Lee PA, Lawson Wilkins Pediatric Endocrine Society/European Society for Paediatric Endocrinology Consensus G. Consensus statement on management of intersex disorders. J Pediatr Urol 2006;2:148e62. [9] Lek N, Miles H, Bunch T, Pilfold-Wilkie V, Tadokoro-Cuccaro R, Davies J, et al. Low frequency of androgen receptor gene mutations in 46 XY DSD, and fetal growth restriction. Arch Dis Child 2014;99:358e61. [10] Bevan CL, Brown BB, Davies HR, Evans BA, Hughes IA, Patterson MN. Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome. Hum Mol Genet 1996;5:265e73. [11] Hannema SE, Scott IS, Rajpert-De Meyts E, Skakkebaek NE, Coleman N, Hughes IA. Testicular development in the complete androgen insensitivity syndrome. J Pathol 2006;208:518e27.
S. Chaudhry et al. [12] McNeill SA, O’Donnell M, Donat R, Lessells A, Hargreave TB. Estrogen secretion from a malignant sex cord stromal tumor in a patient with complete androgen insensitivity. Am J Obstet Gynecol 1997;177:1541e2. [13] Sakai N, Yamada T, Asao T, Baba M, Yoshida M, Murayama T. Bilateral testicular tumors in androgen insensitivity syndrome. Int J Urol 2000;7:390e2. [14] Looijenga LH, Hersmus R, de Leeuw BH, Stoop H, Cools M, Oosterhuis JW, et al. Gonadal tumours and DSD. Best Pract Res Clin Endocrinol Metab 2010;24:291e310. [15] Hurt WG, Bodurtha JN, McCall JB, Ali MM. Seminoma in pubertal patient with androgen insensitivity syndrome. Am J Obstet Gynecol 1989;161:530e1. [16] Acar C, Gurocak S, Sozen S. Current treatment of testicular sex cord-stromal tumors: critical review. Urology 2009;73: 1165e71. [17] Iwamoto I, Yanazume S, Fujino T, Yoshioka T, Douchi T. Leydig cell tumor in an elderly patient with complete androgen insensitivity syndrome. Gynecol Oncol 2005;96:870e2. [18] Rutgers JL, Scully RE. The androgen insensitivity syndrome (testicular feminization): a clinicopathologic study of 43 cases. Int J Gynecol Pathol 1991;10:126e44. [19] Looijenga LH. Human testicular (non)seminomatous germ cell tumours: the clinical implications of recent pathobiological insights. J Pathol 2009;218:146e62. [20] Nakhal RS, Hall-Craggs M, Freeman A, Kirkham A, Conway GS, Arora R, et al. Evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome. Radiology 2013;268:153e60. [21] Ramani P, Yeung CK, Habeebu SS. Testicular intratubular germ cell neoplasia in children and adolescents with intersex. Am J Surg Pathol 1993;17:1124e33. [22] Kaprova-Pleskacova J, Stoop H, Bruggenwirth H, Cools M, Wolffenbuttel KP, Drop SL, et al. Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology. Mod Pathol 2014;27:721e30. [23] Cools M, van Aerde K, Kersemaekers AM, Boter M, Drop SL, Wolffenbuttel KP, et al. Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes. J Clin Endocrinol Metab 2005;90:5295e303. [24] Mongan NP, Tadokoro-Cuccaro R, Bunch T, Hughes IA. Androgen insensitivity syndrome. Best Pract Res Clin Endocrinol Metab 2015;29:569e80. [25] Wunsch L, Holterhus PM, Wessel L, Hiort O. Patients with disorders of sex development (DSD) at risk of gonadal tumour development: management based on laparoscopic biopsy and molecular diagnosis. BJU Int 2012;110:E958e65. [26] Murray MJ, Bell E, Raby KL, Rijlaarsdam MA, Gillis AJ, Looijenga LH, et al. A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours. Br J Cancer 2016;114:151e62. [27] Dieckmann KP, Radtke A, Spiekermann M, Balks T, Matthies C, Becker P, et al. Serum levels of MicroRNA miR-371a-3p: a sensitive and specific new biomarker for germ Cell tumours. Eur Urol 2017;71:213e20. [28] van Agthoven T, Looijenga LH. Accurate primary germ cell cancer diagnosis using serum based microRNA detection (ampTSmiR test). Oncotarget 2016.
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
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Journal of Pediatric Urology (2017) xx, 1.e1e1.e6
Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis a
Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
S. Chaudhry a, R. Tadokoro-Cuccaro a, S.E. Hannema b,c, C.L. Acerini a, I.A. Hughes a Summary
b
Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands
c Sophia Children’s Hospital, Erasmus University Medical Centre, Rotterdam, The Netherlands
Correspondence to: R. Tadokoro-Cuccaro, Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ, UK, Tel.: þ44 (0) 1223768615; fax: þ44 (0) 1223 336996 [email protected] (R. Tadokoro-Cuccaro)
Background Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder of sex development (DSD) where affected individuals are phenotypically female, but have an XY karyotype and testes. The risk of gonadal tumour development in CAIS may increase with age; incidence rates have been reported to be 0.8e22% in patients who have retained their gonads into adulthood. Consequently, gonadectomy has been recommended either during childhood or after puberty is complete, although there is no consensus on the optimal timing for this procedure. Objective and hypotheses To establish the frequency of histological abnormalities in CAIS in relation to the age at gonadectomy.
Keywords Androgen insensitivity syndrome; Gonadectomy; Gonadal tumour; Germ cell neoplasia in situ (GCNIS); Carcinoma in situ (CIS)
Method Data were collected from the Cambridge DSD database on patients with CAIS (n Z 225; age range 3e88 years) who had undergone gonadectomy, and their age of gonadectomy, gonadal histology and immunohistochemistry.
Received 5 December 2016 Accepted 13 February 2017 Available online xxx
Results Evaluable data were obtained from 133 patients. Median age at gonadectomy was 14.0 years (range:
Summary table
18 dayse68 years). Pubertal status was: prepuberty, n Z 62; postpuberty, n Z 68. Thirteen cases were aged >20 years at gonadectomy. The pattern of histology is summarised in the Summary table.
Discussion In this large case series of CAIS patients who had undergone gonadectomy, while the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings confirm the low occurrence of gonadal malignancy in CAIS, with a frequency of 1.5%. The two cases of malignancy were postpubertal. Germ cell neoplasia in situ (GCNIS) was observed in six cases, of which one occurred prepuberty and five postpuberty. The study highlighted difficulties in diagnosis of GCNIS and the need for histological analysis in expert centres.
Conclusion The results support the current recommendation that gonads in CAIS can be retained until early adulthood. The small number of individuals with gonadectomy after age 20 years do not allow firm conclusion regarding later adulthood. Therefore, it is recommended that the option of gonadectomy be discussed in adulthood. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal.
Abnormal histology.
Benign tumour n Z 6 Sertoli cell adenoma (SCA) n Z 8 testicular hamartoma (TH) n Z 2 mixed SCA þ TH Germ cell neoplasia in situ (GCNIS) (age at gonadectomy) n Z 6 (2 years 9 months, 16 years, 17 years,*17 years, 20 years,*53 years) *Associated with benign changes Malignant tumour (age at gonadectomy) n Z 1 malignant sex cord stromal tumour (68 years) n Z 1 seminoma (30 years)
http://dx.doi.org/10.1016/j.jpurol.2017.02.013 1477-5131/ª 2017 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
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Introduction Complete androgen insensitivity syndrome (CAIS) is an Xlinked recessive disorder of sex development (DSD) caused by inactivity of the androgen receptor in response to androgens, due to a mutation of the androgen receptor (AR) gene [1]. Affected individuals have an XY karyotype, but an external female phenotype and labial, inguinal or intraabdominal sited gonads, which are testes [2]. Management of CAIS includes a decision on whether and when to remove the gonads because of the risk of developing gonadal malignancy [3]. The risk of gonadal tumour development in CAIS may increase with age; incidence rates of 0.8e22% have been reported in patients who have retained their gonads into adulthood [4,5]. However, the data on adults with CAIS include historical cases where the diagnosis was uncertain. Invasive germ cell tumours of the gonad (including seminoma/non-seminomas, dysgerminoma/non-dysgerminomas) predominate, and are usually preceded by a noninvasive ‘carcinoma in situ’ (CIS) or intratubular germ cell neoplasia unclassified (IGCNU) phase. The term CIS and IGCNU will now be replaced by germ cell neoplasia in situ (GCNIS), as proposed by the World Health Organization Classifications of Tumours of the Male Genital Organs [6]. It has been reported that 50% of GCNIS progresses to invasive germ cell tumour within 5 years [7]. Currently, there are no clinically useful biomarkers available to guide clinicians in predicting tumour risk other than direct gonadal histology and immunohistochemistry. Given the risk of gonadal malignancy in patients with CAIS, recent practice has advocated gonadectomy either in childhood or soon after puberty [8]. However, optimal timing for this procedure has become increasingly controversial, given the purported benefits of natural testosterone production (and its subsequent aromatisation to oestrogen) for patient well-being and quality of life [2]. As a result, many patients and families with CAIS are choosing to defer gonadectomy well into adulthood or to decline this option altogether [5]. The secular trend towards delayed or no gonadectomy has raised concerns that patients may now be at increased risk of developing gonadal malignancy. It is difficult to quantify the risk, given that the prevalence and incidence of early gonadal malignancy changes and tumour development are unclear. Consequently, a retrospective review was undertaken of the gonadal histology reports available from CAIS patients who had their gonads removed, in order to establish the frequency of histological abnormalities in relation to age and timing of gonadectomy.
Patients and methods The resource that was used for this study was the Cambridge DSD database [9]. It contains detailed information on clinical phenotype, results of biochemical and genetic tests and descriptive reports of histological and immunohistochemical analyses of gonadectomy specimens. For the purpose of this study, the diagnosis of CAIS was based on typical clinical and biochemical features, and confirmed by analysis of the AR gene in the majority of cases. Full
S. Chaudhry et al. sequencing of the coding region, including intron/exon boundaries, was performed as previously described [10]. Information regarding patient age at gonadectomy, position of gonads at time of diagnosis, histology report, immunohistochemistry findings and AR mutation was analysed. Histological studies were performed at the local hospital and the reports obtained from the referring clinician. Standard immunohistochemistry, including placental alkaline phosphatase (PLAP), was performed in the majority of cases. For some of the cases where tissue from gonadectomy was available, the pathology was reviewed as previously described [11]. The terms ‘carcinoma in situ’ (CIS) and ‘intratubular germ cell neoplasia unclassified’ (IGCNU), used in the reports, were considered to be equivalent to the new term ‘germ cell neoplasia in situ’ (GCNIS) used in this analysis. Ethics approval for the study was obtained from the local research committee, and institutional approval was obtained from the Research and Development Committee of the Cambridge University Hospitals NHS Foundation Trust.
Results A total of 225 patients with CAIS (age range 3e88 years at the time of analysis) were identified in the database, of which 141 had undergone gonadectomy. The following were excluded: no information on gonadal histology available (n Z 6); AR gene screening was not performed (n Z 1); mutation was not identified by single-strand conformation polymorphism (SSCP) and no sequence analysis performed (n Z 1). Six cases that were not screened for an AR mutation, but one had been identified in another affected family member, were included. A total of 133 cases were included in this study. The median age at gonadectomy was 14.0 years (range: 18 dayse63 years). There were two peaks in the age of gonadectomy: during infancy to early childhood, and after puberty (Fig. 1). An equal number of patients had gonadectomy performed before and after puberty (62 and 68 patients, respectively). Timing of gonadectomy in relation to pubertal status was unknown in three cases. In cases that had gonadectomy before the age of 13 years, approximately 60% of gonads were located in the inguinal region. In contrast, in cases that had gonadectomy after age 13 years, 60% of the gonads were intraabdominal or non-palpable (Fig. 2). Histology in relation to age of gonadectomy is shown in Fig. 1. Abnormalities were reported in 27 cases (20.3%). In 18 cases (13.5%) the histology was considered benign. This subset comprised cases of Sertoli cell adenoma (SCA, n Z 6), testicular hamartoma (TH, n Z 8), mixed SCA/TH (n Z 2) and sex cord tumour ‘with annular tubules’ (n Z 2). Immunohistochemistry was negative for PLAP in four cases. The local pathologist reported five cases of premalignant changes (GCNIS). GCNIS was identified in two additional cases on further review; from the original histology reports it was unclear if and what immunohistochemical studies had been performed in these cases (Table 1). Two cases also had concomitant benign changes (SCA þ GCNIS; hamartoma þ GCNIS). In Case 1, premalignancy was reported at an early age, based on areas in the gonad with increased germ cell numbers and cell atypia with some
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
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number of individuals
Gonadal tumour in complete androgen insensitivity syndrome
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50 45 40 35 30 25 20 15 10 5 0
malignancy GCNIS no malignancy
Age of gonadectomy Figure 1
Malignant and premalignant changes according to age at gonadectomy.
160 140 120
number of gonads
100
unknown non-palpable
80
labia inguinal
60
intra-abdominal 40 20 0 gonadectomy before 13 yrs
aŌer 13 yrs
Figure 2 Location of gonads at time of diagnosis; gonadectomy before and after age 13 years.
multinucleate cells and large nucleoli. GCNIS was further substantiated by staining positive for PLAP. However, on review and with additional immunohistochemical studies, the pattern was probably more consistent with delayed germ cell maturation [11]. An affected relative presented with primary amenorrhoea and had the same AR mutation (Asp733Asn). She had gonadectomy; histology and immunohistochemistry showed no evidence of premalignancy. From the other prepubertal child (Case 2) no histological material was available for review, so it could not be assessed if this child might have had delayed germ cell maturation rather than GCNIS. However, the pathology report, from a UK teaching hospital, described larger cells with clear cytoplasm and sometimes irregular nuclei, with small nucleoli located either in the base of the tubule or more towards the lumen, positive for PLAP, OCT3/4 and
CD117. The cells expressing these markers located at the basement membrane were suggestive for GCNIS. Cases 6 and 7 had histological changes consistent with GCNIS and have been reported previously [11]. Two cases (1.5%) had malignant changes. Case 9 presented with primary amenorrhoea and at laparoscopic gonadectomy a single left-sided gonad was identified. However, she developed a lump in the right groin in adulthood and gonadectomy and histology showed a seminoma. There was no metastasis. Case 8 presented at the age of 68 years with a large abdominal mass arising from a gonadal tumour. Histology was consistent with a malignant sex cord stromal tumour. No metastatic lesion was detected. Histology of the contralateral gonad showed a dysplastic testis without premalignancy. There was no relationship between AR mutation type (for example, nonsenses versus missense mutation) and (pre)malignant changes in this small series. Furthermore, while such changes occurred almost exclusively after puberty, there was no apparent relationship with gonadal site, although the two cases of malignancy occurred in intra-abdominal gonads.
Discussion This study, based on a large cohort of patients with CAIS, was designed to explore an association between age at gonadectomy and gonadal malignancy or premalignancy. This may have implications for management, particularly if gonads are not removed. A low prevalence of 1.5% for malignancy was found in 133 patients with CAIS and was confined to ages >20 years.
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
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Characteristics of CAIS cases with premalignant and malignant changes.
Case Age at diagnosis, presenting symptom
Age at gonadectomy Position of (years, months) gonads
Initial histology
Immunohisto-chemistry Further review [11]
AR mutation
1a
1 month, inguinal hernia
1, 7 mn
Bilateral GCNIS
Unknown (HCG test in Iran)
2, 9 mn
Delayed germ cell maturation N/A
Leu806fs
3
2 years, Lt inguinal hernia
16
Bilateral GCNIS
N/A
His918Arg
4
6 months, Rt inguinal hernia
17
Lt GCNIS
PLAP (þ)
N/A
Met896Thr
5
Age unknown, primary amenorrhoea 20
Bilateral GCNIS
PLAP (þ) CD117 (þ)
N/A
Gln120Stop
6a
16 years, primary amenorrhoea
17
Hamartoma
Unclear if performed
7a
53
Sertoli cell adenoma
Unclear
Bilateral GCNIS Val888fs hamartoma Bilateral GCNIS Ala766Thr Sertoli cell adenoma
8a
53 years, abdominal pain (initially presented primary amenorrhoea at 16 years) 68 years, abdominal mass
Rt inguinal Lt inguinal Rt inguinal Lt inguinal Rt unknown Lt unknown (Both non palpable) Rt intra-abdominal Lt intra-abdominal Rt intra-abdominal Lt intra-abdominal
PLAP (þ) CD117 (þ) PLAP (þ) OCT3/4 (þ) CD117 (þ) PLAP (þ)
Asp733Asn
2
Rt inguinal Lt inguinal Rt intra-abdominal Lt intra-abdominal
9
17 years, primary amenorrhoea
Lt 19 Rt 30
Rt intra-abdominal Lt intra-abdominal Rt inguinal Lt inguinal
Rt malignant sex cord PLAP () stromal tumour Vimentin (þ) Rt seminoma PLAP (þ)
N/A
Arg832Stop
N/A
Arg775Cys
MODEL
68
Bilateral GCNIS
+
CAIS, complete androgen insensitivity syndrome; PLAP, placental alkaline phosphatase; OCT3/4, octamer-binding transcription factors 3 and 4; CD117, stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit; Rt, right; Lt, left; GCNIS, germ cell neoplasia in situ; HCG, human chorionic gonadotropin. a Reported previously [11,12].
S. Chaudhry et al.
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
Table 1
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Gonadal tumour in complete androgen insensitivity syndrome One patient presented with a testicular seminoma at the age of 30 years; the second patient did not present until aged 68 years and had a sex cord stromal tumour, as previously reported [12]. Seminoma is the most frequent testicular tumour in CAIS [13]. It arises from a precursor stage, GCNIS, and is believed to be due to a failure of normal maturation of foetal germ cells from gonocytes into pre-spermatogonia [14]. The age of presentation for seminoma in CAIS is generally >30 years, although there is a case reported in a teenager [15]. Sex cord stromal tumours are rare, comprising 3e5% of all testicular tumours [16]; they have been reported in adult patients with CAIS [17,18]. The majority are of Leydig cell origin, with malignancy occurring in 10e20%. The results of the present study are consistent with the recommendation that the gonads in CAIS can be retained until early adulthood, due to a low risk of malignancy [8]. Due to the small number of individuals (n Z 13) who had gonadectomy after age 20 years, the risk of gonadal tumours cannot be accurately assessed if gonads are retained beyond early adulthood. In individuals with CAIS, seminiferous tubules contain embryonic germ cells, which rapidly decline after the first year of life [11,19]. One mechanism to explain the lower malignancy risk in CAIS compared to partial AIS (PAIS) may be related to apoptosis of the germ cells in the testis [19]. A certain level of testosterone seems to be needed for GCNIS to develop into an invasive form. This is supported by the observation that patients with hypogonadotropic hypogonadism do not develop germ cell tumours in spite of cryptorchidism [19]. In CAIS, the intra-abdominal location of the gonads may be a factor adding to the risk of malignancy [16]. Analysis of an association between gonadal location and tumour risk in the present study is skewed by the earlier age of presentation in infants with inguinal/ labial gonads and the small number of cases with (pre) malignant changes. The local pathologists reported five cases in this study as having GCNIS and two further cases added following review. While GCNIS is uncommon, it has been reported during childhood and adolescence [20]. In a review of 102 cases of DSD, there were four cases with prepubertal GCNIS. These cases comprised 45,X/46,XY gonadal dysgenesis, multiple congenital anomalies with ambiguous genitalia, and 46,XY DSD associated with a congenital heart defect [21]. The present study identified premalignancy manifest in an infant with CAIS (Case 1, Table 1). This was initially reported as GCNIS, but further review suggested delayed germ cell maturation [11]. On the other hand, two cases with GCNIS were not initially identified by routine histology. This study highlights that the diagnosis of GCNIS can be difficult and the need for expertise in germ cell pathology. What would have been the risk of malignant transformation in Case 1 if gonadectomy had not taken place? Probably low, based on the hypothesis that residual androgen activity is required for progression of premalignant to malignant status [22]. It is perhaps noteworthy that the older affected relative showed no signs of germ cell premalignancy on histology and immunohistochemistry. Both had the same AR mutation. Little is known about the natural history of GCNIS, particularly in CAIS. A study which followed 18 testes from 15 infertile men aged 26e36 years reported a 50% malignant transformation rate within 5 years [7]. This much
1.e5 higher rate compared with that seen in CAIS supports the aforementioned low residual androgen activity hypothesis. The type of AR mutation in CAIS does not appear to predict the risk of malignancy with GCNIS, but the number for analysis was too few in the present study. GCNIS has a characteristic morphological appearance comprising large cells confined to the seminiferous tubules with clear cytoplasm, hyperchromatic nuclei and increased mitotic activity [3,21]. Expression of immunohistochemical markers such as PLAP and octamer-binding transcription factors 3 and 4 (OCT3/4) in adults is characteristic of GCNIS. However, in infants and children, especially those with a DSD, it can be difficult to distinguish between GCNIS and germ cells that show delayed maturation, but are not (yet) malignant. In dysgenetic gonads, germ cells may show prolonged expression of markers such as PLAP and OCT3/4. Age, the distribution pattern of germ cells that express tumour markers and the position of germ cells within the seminiferous tubule are important in making this distinction [23]. This study highlights the difficulty in making a diagnosis of GCNIS when the gonads are removed in infancy. Paediatric surgeons and urologists need to be aware of these findings when performing biopsies to establish the presence of testes in CAIS infants or when undertaking early gonadectomy. Some women with CAIS are now opting to retain their gonads for the long term, to benefit from the effects of endogenous oestrogen produced from aromatisation of androgens and possibly from direct androgenic effects [24]. To address the risk of germ cell malignancy, regular imaging surveillance with either magnetic resonance imaging (MRI) or ultrasonography has been suggested [20]. MRI can detect benign changes such as paratesticular cysts and Sertoli cell adenomas, but premalignant changes such as GCNIS are not visible; to detect these, a gonadal biopsy would be required for histology. One approach adopted is laparoscopic gonadal biopsy and gonadopexy to place the gonads near the abdominal wall [25]. The procedure improved visualisation of the gonads by ultrasonography. Targeted microRNA-based (miRNA) blood tests are currently under investigation for use in detecting early malignant changes in testicular germ cell tumours [6]. These biomarkers measured in serum and cerebrospinal fluid samples from children with gonadal and extra-gonadal germ cell tumours are highly specific and sensitive [26,27]. Although the specific miRNAs are expressed in GCNIS tissue, they are not detectable in serum [28].
Conclusion The strength of this study was the large cohort of CAIS patients who had gonadectomy in approximately equal numbers before and after puberty. While the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings showed a frequency for gonadal malignancy as low as 1.5%. Premalignant changes were rare before puberty. The results of this study suggest that it is safe to retain gonads in situ into early adulthood. The small number of individuals with gonadectomy after age 20 years did not allow firm conclusions regarding later adulthood. Therefore, it is the patient’s personal choice to make an
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013
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1.e6 informed decision about continued retention of gonads. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal. This study also highlighted the difficulty in making a diagnosis of GCNIS in a gonad removed in infancy. It is recommended that experts in germ cell pathology in DSD review the histology.
Conflict of interest None.
Acknowledgements We are very grateful to all referring clinicians and to their patients for agreeing to provide data and personal information. The Cambridge DSD database is supported by the NIHR Clinical Research Network (CRN-Eastern).
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S. Chaudhry et al. [12] McNeill SA, O’Donnell M, Donat R, Lessells A, Hargreave TB. Estrogen secretion from a malignant sex cord stromal tumor in a patient with complete androgen insensitivity. Am J Obstet Gynecol 1997;177:1541e2. [13] Sakai N, Yamada T, Asao T, Baba M, Yoshida M, Murayama T. Bilateral testicular tumors in androgen insensitivity syndrome. Int J Urol 2000;7:390e2. [14] Looijenga LH, Hersmus R, de Leeuw BH, Stoop H, Cools M, Oosterhuis JW, et al. Gonadal tumours and DSD. Best Pract Res Clin Endocrinol Metab 2010;24:291e310. [15] Hurt WG, Bodurtha JN, McCall JB, Ali MM. Seminoma in pubertal patient with androgen insensitivity syndrome. Am J Obstet Gynecol 1989;161:530e1. [16] Acar C, Gurocak S, Sozen S. Current treatment of testicular sex cord-stromal tumors: critical review. Urology 2009;73: 1165e71. [17] Iwamoto I, Yanazume S, Fujino T, Yoshioka T, Douchi T. Leydig cell tumor in an elderly patient with complete androgen insensitivity syndrome. Gynecol Oncol 2005;96:870e2. [18] Rutgers JL, Scully RE. The androgen insensitivity syndrome (testicular feminization): a clinicopathologic study of 43 cases. Int J Gynecol Pathol 1991;10:126e44. [19] Looijenga LH. Human testicular (non)seminomatous germ cell tumours: the clinical implications of recent pathobiological insights. J Pathol 2009;218:146e62. [20] Nakhal RS, Hall-Craggs M, Freeman A, Kirkham A, Conway GS, Arora R, et al. Evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome. Radiology 2013;268:153e60. [21] Ramani P, Yeung CK, Habeebu SS. Testicular intratubular germ cell neoplasia in children and adolescents with intersex. Am J Surg Pathol 1993;17:1124e33. [22] Kaprova-Pleskacova J, Stoop H, Bruggenwirth H, Cools M, Wolffenbuttel KP, Drop SL, et al. Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology. Mod Pathol 2014;27:721e30. [23] Cools M, van Aerde K, Kersemaekers AM, Boter M, Drop SL, Wolffenbuttel KP, et al. Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes. J Clin Endocrinol Metab 2005;90:5295e303. [24] Mongan NP, Tadokoro-Cuccaro R, Bunch T, Hughes IA. Androgen insensitivity syndrome. Best Pract Res Clin Endocrinol Metab 2015;29:569e80. [25] Wunsch L, Holterhus PM, Wessel L, Hiort O. Patients with disorders of sex development (DSD) at risk of gonadal tumour development: management based on laparoscopic biopsy and molecular diagnosis. BJU Int 2012;110:E958e65. [26] Murray MJ, Bell E, Raby KL, Rijlaarsdam MA, Gillis AJ, Looijenga LH, et al. A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours. Br J Cancer 2016;114:151e62. [27] Dieckmann KP, Radtke A, Spiekermann M, Balks T, Matthies C, Becker P, et al. Serum levels of MicroRNA miR-371a-3p: a sensitive and specific new biomarker for germ Cell tumours. Eur Urol 2017;71:213e20. [28] van Agthoven T, Looijenga LH. Accurate primary germ cell cancer diagnosis using serum based microRNA detection (ampTSmiR test). Oncotarget 2016.
Please cite this article in press as: Chaudhry S, et al., Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis, Journal of Pediatric Urology (2017), http://dx.doi.org/10.1016/j.jpurol.2017.02.013