a Department of Urology and Pediatric Urology, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands b Department of Pathology, Erasmus MC, Josephine Nefkens Institute, Rotterdam, The Netherlands c Department of Urology and Pediatric Urology, Ghent University Hospital, Ghent, Belgium d Department of Pediatrics, Ghent University Hospital, Ghent University, Belgium Correspondence to: K.P. Wolffenbuttel, Department of Urology and Pediatric Urology, Erasmus MC, Sophia Children’s Hospital, Room Sk-1270, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands, Tel.: +31 107061760; fax: +31 107035632 k.wolffenbuttel@eras musmc.nl (K.P. Wolffenbuttel) Keywords Gonadal dysgenesis (GD); Malignant germ cell tumors; Germ cell cancer (GCC); Disorders of sex development (DSD); Surgical management Received 24 May 2016 Accepted 24 August 2016 Available online xxx Review Article Gonadal dysgenesis in disorders of sex development: Diagnosis and surgical management K.P. Wolffenbuttel a , R. Hersmus b , H. Stoop b , K. Biermann b , P. Hoebeke c , M. Cools d , L.H.J. Looijenga b Summary Recent studies on gonadal histology have improved the understanding of germ cell malignancy risk in patients with disorders of sex development (DSD), and evidence-based gonadal management strategies are gradually emerging. Especially in 46,XY DSD and 45,X/46,XY DSD, which are characterized by gonadal dysgenesis, the risk of germ cell malignancy is significantly increased. This paper summarized the progress over the past 10 years in malignancy risk assessment in patients with DSD, and its implications for optimal surgical handling of the involved gonads. Introduction It has long been known that gonadal germ cell cancer (GCC) risk in patients with a disorder of sex development (DSD) is linked to the pres- ence of part of the Y-chromosome e the gonadoblastoma locus (GBY) [1,2]. Subsequent research has identified the testis-specific protein on Y (TSPY) as a putative key factor in tumorigenesis [3,4]. There are great dissimilarities in GCC risk within the various DSD subgroups. For instance, the risk in a patient with 46,XY DSD, which is characterized by a congenital aberrant or incomplete gonadal development that is commonly known as gonadal dysgenesis (GD), is significantly higher than in a case of 46,XY DSD with defective androgen action or biosynthesis (e.g. androgen insensitivity syndrome, AIS) [5]. Meticulous histological research in the last decades on gonadal tissue from patients with DSD has improved insight into GCC risk in various diagnostic groups by identifying distinct histological lesions. These pre- invasive malignancies are carcinoma in situ (CIS), currently known as germ cell neoplasia in situ (GCNIS) [6], and gonadoblastoma (GB), as well as their precursors, including undif- ferentiated gonadal tissue (UGT). The final piece in this evolution was the introduction of histopathological criteria to discriminate pre- malignant germ cells from benign germ cells with delayed maturation [7e9]. Despite these advances, the actual risk assessment of invasive GCC for patients with DSD is currently still incomplete. Another drawback is the requirement of gonadal ma- terial for risk inventory; at present, non- invasive markers for screening are lacking. Conventional serum markers like a-fetoprotein (AFP) and human chorionic gonadotropin (hCG) can only be used for detection of pro- gressed and defined histological types of GCC, and are inappropriate for screening purposes. Non-invasive tools, including (epi)genetic markers associated with increased GCC risk and serum microRNA (miRNA) for early stage malignancy detection, have recently been developed, but have yet to be implemented in clinical practice [8]. These non-invasive tools, although promising, are beyond the scope of this review. This paper summarizes the aforementioned latest insights into GD, either associated with an already known DSD condition, or as an incidental finding during abdominal or inguinal surgery, and focuses on the implications for surgical treatment. Gonadal dysgenesis: embryonic aspects Failure of normal embryonic development in the originally bi-potential gonad may result in a more-or-less aberrant postnatal testis or ovary. Disruption of this genetically controlled, but yet incompletely understood, gonadal differentiation process is believed to underlie the increased risk of GCC in the + MODEL Please cite this article in press as: Wolffenbuttel KP, et al., Gonadal dysgenesis in disorders of sex development: Diagnosis and surgical management, Journal of Pediatric Urology (2016), http://dx.doi.org/10.1016/j.jpurol.2016.08.015 http://dx.doi.org/10.1016/j.jpurol.2016.08.015 1477-5131/ª 2016 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. Journal of Pediatric Urology (2016) xx,1e6