Patients with disorders of sex development (DSD) at risk of gonadal tumour development: management based on laparoscopic biopsy and molecular diagnosis

Abstract

Study Type – Therapy (case series)Level of Evidence 4What's known on the subject? and What does the study add?In some individuals with disorders of sex development (DSD), gonadal tumour risk is increased. The individual risk is estimated based on the molecular diagnosis and the age and approaches 30% in the high‐risk group. In the past, early gonadectomy has been advised for all individuals with 46XY DSD. Gonadectomy clearly represents an overtreatment for many individuals with 46XY DSD. Thus, further clinical indicators of individual tumour risk are urgently needed.The present study provides a comprehensive description of gonadal morphology, as seen during laparoscopy. For the first time, laparoscopic features, molecular diagnosis and histopathological findings are presented in a comprehensive context. The present study adds a detailed morphological description of the variability found in different subgroups of 46XY DSD. As three of four detected tumours were microscopic, early diagnosis by inspection appears unfeasible. Biopsy, gonadopexy and precise localisation of the gonad will potentially allow for gonadal preservation in well‐defined clinical situations.OBJECTIVE To investigate the role of laparoscopy for the early detection of gonadal tumours, with emphasis on gonadal preservation, in patients with 46XY disorders of sex development (DSD). In patients with DSD, gonadectomy is frequently recommended and depending on the age and the molecular diagnosis, an increased gonadal tumour risk exists and undesired hormone effects may arise. However, gonadectomy is irreversible and impacts considerably on body image. It represents an overtreatment for some patients and should be considered after a comprehensive diagnostic evaluation. Laparoscopy is an important technique, because it is able to retrieve small gonads and allows guided biopsies. PATIENTS AND METHODS We performed laparoscopic assessment of the gonads in 40 patients with various 46XY DSD. In all, 77 gonads were evaluated, images were analysed and compared with histological findings. Laparoscopic procedures included gonadectomy, biopsy, laparoscopic orchidolysis or the Fowler–Stephens procedure as well as the removal or splitting of uterine remnants. RESULTS In all, 19 patients underwent gonadectomy and tumours were discovered in four. Three patients had only microscopic evidence of tumour, in one the tumour was diagnosed intraoperatively. In 21 patients, biopsies were taken and the gonads preserved. Laparoscopic biopsy and gonadopexy was performed in six patients with complete androgen insensitivity syndrome (CAIS). CONCLUSION Laparoscopy and biopsy detected three microscopic tumours, one tumour was macroscopically evident. In CAIS, gonadopexy improved the visibility of the gonads on postoperative ultrasonography. This procedure facilitated the examination of the gonad at follow‐up. In complete gonadal dysgenesis, a highly variable morphology of the gonads was found. Laparoscopy improved exposure of gonads and Müllerian structures, and facilitated biopsies and organ‐preserving procedures.

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature

“…Precursor lesions of testicular CIS/GCNIS were described in one adolescent with a NR5A1/SF1 mutation (28) and one individual with a StAR mutation (22). In four subjects with CYP11A1 and HSD17B3 mutations, no signs of tumor risk were found (16).…”

“…Case Report M-A Burckhardt and others Histology of HSD3B2 deficiency 173:5 K8 Table 4 (8,9,12,13,14,16,23,24,25,26,27,28,29,30,31,32,33,34,35,36). For spermatogenesis and thus fertility, the few data available suggest that it varies between different androgen biosynthetic defects as well as between individuals carrying defects in the same gene.…”

“…An adrenal rest tumor has been visualized by ultrasound in an 18-year-old 46,XY DSD patient with a HSD3B2 mutation, but no biopsy was performed (5). However, information on tumor risk is needed for clinical decision-making, because several types of 46,XY DSD, especially those characterized by testicular dysgenesis and increased peripubertal virilization, carry an increased risk of germ cell neoplasia (15,16).…”

Characteristic Features of Reproductive Hormone Profiles in Late Adolescent and Adult Females with Complete Androgen Insensitivity Syndrome

“…However, recent observations indicate that the risk of developing germ cell tumors before and during puberty is low in women with CAIS [Lecca et al, 1988;Cools et al, 2006;Hannema et al, 2006;Looijenga et al, 2007;Hersmus et al, 2008;Wünsch et al, 2012]. For those who underwent gonadectomy, hormone replacement therapy (HRT) is mandatory to induce puberty and improve bone health and well-being [Bertelloni et al, 2011].…”

Torsion of an epididymal cyst in a patient of androgen insensitivity: a rare case report

“…In pubertal females a diagnosis between androgen insensitivity and Mullerian agenesis can be made by karyotyping and measuring serum testosterone levels. [4][5][6][7][8] The acute pain and torsion of the epididymal cyst in patient of androgen insensitivity, reported in the present study is the only case of its kind to be reported in the literature.…”