ESPE Yearbook of Paediatric Endocrinology

Brief summary: This review article offers an update on knowledge on prophylactic gonadectomy in differences of sex development (DSDs) and evaluates the latest existing clinical evidence, which is generally limited, on risk of gonadal neoplasia potential in each group of DSDs.

On average 15% of DSD patients with Y chromosome material predispose to gonadal neoplasms especially gonadal germ cell tumors (GGCTs); the overall risk ranges between 0.8% and 40% depending on age and etiological diagnosis [1, 2]. However, the conditions without Y chromosome, and gonads displaying ovarian differentiation confer the lowest risk. The diagnosis of gonadal tumors is based on certain combined histopathological findings, and expression of certain immunohistochemistry markers of pluripotentiality. Prophylactic gonadectomy can only be proposed in DSD patients at risk of GGCTs. This risk, however, varies considerably depending on a multitude of factors that make the decision for prophylactic gonadectomy extremely difficult. In order to make informed recommendations on the convenience of this procedure in cases where there is potential for malignancy, this article evaluates the latest clinical evidence, which is generally low, and updates the existing knowledge in this field.

Two studies from last year provided further insight into gonadal neoplasia potential in various groups of DSDs. Costanzo M, et al. reported histological characteristics and immunoexpression patterns of gonadal parenchyma in 16 patients with SRY-negative 46,XX testicular and ovotesticular DSD at median age of 1.46 yrs (range 0.16–16 years) (3). 12 of these individuals had bilateral ovotestes, with normal ovarian tissue and some dysgenesis in the testicular components. They found significantly increased early prepubertal preinvasive and invasive malignancies in this cohort (five patients had undifferentiated gonadal tissue, five gonadoblastoma, and one dysgerminoma). This may suggest the need for assessment of gonadal histology in 46,XX testicular and ovotesticular DSD.

In a four-center study Peard LM, evaluated the incidence of germ cell neoplasia in situ (GCNIS) and germ cell tumor (GCT) in a large cohort of 83 patients with DSD, who undergone gonadectomy or gonadal biopsy [4]. Eight out of 83 patients (9.6%) had GCNIS or GCT at a median age of 2.95 yrs. Among those, 4 had mixed gonadal dysgenesis, 3 patients had Turner with Y chromosome material, 1 patient had partial gonadal dysgenesis. All of them were cured by surgery alone, none of them had a recurrence or tumor related complications during the mean follow up duration of 6.4 yrs. The results of this study highlight the importance of gonadal surveillance of retained gonads based on risk stratification of DSD etiology for detection of malignant and premalignant gonadal pathologies. Nevertheless long-term oncologic outcomes for these patients are favourable.

References: 1. Slowikowska-Hilczer J, Szarras-Czapnik M, Duranteau L, Rapp M, Walczak-Jedrzejowska R, Marchlewska K, Oszukowska E, Nordenstrom A; dsd-LIFE group. Risk of gonadal neoplasia in patients with disorders/differences of sex development. Cancer Epidemiol. 2020 Dec;69:101800. doi: 10.1016/j.canep.2020.101800. Epub 2020 Sep 6. PMID: 32905884. 2. Lucas-Herald AK, Bryce J, Kyriakou A, Ljubicic ML, Arlt W, Audi L, Balsamo A, Baronio F, Bertelloni S, Bettendorf M, Brooke A, Claahsen van der Grinten HL, Davies JH, Hermann G, de Vries L, Hughes IA, Tadokoro-Cuccaro R, Darendeliler F, Poyrazoglu S, Ellaithi M, Evliyaoglu O, Fica S, Nedelea L, Gawlik A, Globa E, Zelinska N, Guran T, Güven A, Hannema SE, Hiort O, Holterhus PM, Iotova V, Mladenov V, Jain V, Sharma R, Jennane F, Johnston C, Guerra Junior G, Konrad D, Gaisl O, Krone N, Krone R, Lachlan K, Li D, Lichiardopol C, Lisa L, Markosyan R, Mazen I, Mohnike K, Niedziela M, Nordenstrom A, Rey R, Skaeil M, Tack LJW, Tomlinson J, Weintrob N, Cools M, Ahmed SF. Gonadectomy in conditions affecting sex development: a registry-based cohort study. Eur J Endocrinol. 2021 May 4;184(6):791–801. doi: 10.1530/EJE-20-1058. PMID: 33780351. 3. Costanzo M, Touzon MS, Marino R, Guercio G, Ramirez P, Mattone MC, Pérez Garrido N, Bailez MM, Vaiani E, Ciaccio M, Galluzzo Mutti ML, Belgorosky A, Berensztein E. Gonadal tumor development in 46,XX disorders of gonadal development. Eur J Endocrinol. 2022 Jul 29;187(3):451–462. doi: 10.1530/EJE-22-0283. PMID: 35900314. 4. Peard LM, Morin J, Flores V, Graham K, Taylor AS, Pope JC 4th, Halstead V, Cost NG, Roberts EM, Makari JH, Cranford W, Saltzman AF. Gonadal tumors in a contemporary cohort of patients with differences in sex development undergoing surgery – A multi-site study from the Pediatric Urologic Oncology Working Group of the societies for pediatric urology. J Pediatr Urol. 2023 Apr 13:S1477-5131(23)00136-5. doi: 10.1016/j.jpurol.2023.04.008. Epub ahead of print. PMID: 37117082.