Volume 67, Issue 4, Pages 692-701 (April 2015) Gonadal Maldevelopment as Risk Factor for Germ Cell Cancer: Towards a Clinical Decision Model  Yvonne G. van der Zwan, Katharina Biermann, Katja P. Wolffenbuttel, Martine Cools, Leendert H.J. Looijenga  European Urology  Volume 67, Issue 4, Pages 692-701 (April 2015) DOI: 10.1016/j.eururo.2014.07.011 Copyright © 2014 European Association of Urology Terms and Conditions

Fig. 1 Schematic representation of physiologic development of primary and secondary sex characteristics. The illustration is part of a Web-based tool (animation) (http://www.erasmusmc.nl/47463/51019/4500578/Animation). AMH=anti-Müllerian hormone; DHT=dehydrotestosterone; INSL3=insulin-like 3 (Leydig cell); T=testosterone. European Urology 2015 67, 692-701DOI: (10.1016/j.eururo.2014.07.011) Copyright © 2014 European Association of Urology Terms and Conditions

Fig. 2 Representative examples of (A) gonadoblastoma and (B) carcinoma in situ, showing morphology (haematoxylin and eosin [H&E] staining, left panel), immunohistochemical detection of OCT3/4, TSPY, KITLG (SCF), and FOXL2 (gonadoblastoma), and SOX9 carcinoma in situ, respectively (from left to right). European Urology 2015 67, 692-701DOI: (10.1016/j.eururo.2014.07.011) Copyright © 2014 European Association of Urology Terms and Conditions

Fig. 3 Schematic representation of the integrated model for the role of stress in the formation of the precursor lesion of germ cell cancers, either gonadoblastoma (GB) or carcinoma in situ (CIS). In green (upper panel), physiologic maturation of the gonocyte to either prespermatogonia or oogonia is represented, in which the combination of the genomic constitution and the microenvironment is guiding. This results in the downregulation of OCT3/4 as well as the stem cell factor receptor (c-KIT), and the promoter of AKT remains inactive. In case of exposure to stress during a window of embryonic development, either due to testicular dysgenesis syndrome (TDS), disorders of sex development (DSDs), or microenvironment, p53 is upregulated, leading to increased formation of the KITLG (stem cell factor), either in supportive cells or in the germ cells (represented in the red area). This will result in specific phosphorylation of OCT3/4, release from the AKT promoter, and activation of transcription of this gene. Deciding whether an embryonic germ cell will be sensitive to form either GB or CIS is determined by the bottleneck of stress exposure, of which the susceptibility depends on the genomic constitution (single nucleotide polymorphisms, as for KITLG). European Urology 2015 67, 692-701DOI: (10.1016/j.eururo.2014.07.011) Copyright © 2014 European Association of Urology Terms and Conditions

Fig. 4 Schematic representation of an algorithm for patients with disorders to sex development (DSDs), in which three levels of clinical activities including age of presentation, phenotype (used classifications), and diagnostic tools, as well as cancer risk evaluation including position of the gonad, histology, and diagnostic markers, are represented. GCC=germ cell cancer; SCO=Sertoli cell only; LOC=level of confluence between the urethra and the vagina; EMS=external masculinization score. European Urology 2015 67, 692-701DOI: (10.1016/j.eururo.2014.07.011) Copyright © 2014 European Association of Urology Terms and Conditions

Fig. 5 Schematic representation of a risk stratification model and recommendations for clinical follow-up. Gonadal management in prepubertal boys with 45,X/46,XY or 46,XY disorders of sex development (DSDs) is related to gonadal position. In the case of descended gonads, periodic self-examination from pubertal age onwards is advised. For undescended gonads, we recommend a biopsy during orchidopexy in childhood or orchidectomy in the case of a grossly abnormal gonad or inability to reach a scrotal or inguinal position; follow-up by periodic self-examination from pubertal age; and additional yearly ultrasound performed as indicated, also depending on the result of the biopsy. The same is true for repeat biopsy as indicated and depending on the result of the first biopsy. Gonadectomy in prepubertal girls with 45,X/46,XY or 46,XY DSD (except complete androgen insensitivity syndrome [CAIS] patients) is advised in case of descended gonads as soon as gender identity is clearly female, preferably before puberty. In the case of undescended gonads there is a choice between either gonadectomy at an early age (preferably before puberty) or biopsy with fixation of the gonads in a palpable (inguinal or labial) position, followed by gonadectomy as soon as gender identity is clearly female. The choice for either strategy depends on many factors such as the macroscopic aspect of the gonad, the ability to reach a palpable position, the residual functional potential of the gonad, the preference of the parents, and the predictability of the future gender identity of the particular condition. Individual information on germ cell cancer (GCC) risk by the biopsy will be crucial for timing of further treatment. In 46,XY CAIS, gonadectomy can be postponed until adolescence because the GCC risk is low and gonadal preservation allows spontaneous puberty. Escalation marks indicate points of consideration. CIS=carcinoma in situ; GB=gonadoblastoma; GD=gonadal dysgenesis; MRI=magnetic resonance imaging; PAIS=partial androgen insensitivity syndrome; T-synthesis disorders=testosterone-synthesis disorders; UGT=unclear gender identity. European Urology 2015 67, 692-701DOI: (10.1016/j.eururo.2014.07.011) Copyright © 2014 European Association of Urology Terms and Conditions