Histological Characteristics in XY and 45,X/46,XY Differences of Sex Development and their Role in Clinical Decisions: A 10-year Retrospective Study

A BSTRACT Background/Aims: Differences of sex development (DSD) are complex conditions requiring careful balance between malignancy risk and preservation of fertility and hormonal function. Histological assessment of gonads plays a key role in guiding management, particularly in XY DSD and 45,X/46,XY mixed gonadal dysgenesis (MGD). This study evaluates gonadal and Müllerian histology and correlates findings with clinical decision-making. Methods: A retrospective analysis was performed on histological specimens from patients with XY DSD, MGD, ovotesticular DSD (OTD), and persistent Müllerian duct syndrome (PMDS) managed between 2015 and 2025 at two centres. Patients underwent gonadal biopsy or gonadectomy. Specimens were assessed for gonadal immaturity, dysplasia, and neoplasia. Symptomatic Müllerian remnants were excised. Clinical data, including karyotype, surgical management, and sex of rearing, were analyzed. Results: Twenty-six patients were included (12 XY DSD, 7 MGD, 3 OTD, 4 PMDS). Median age at biopsy was 2 years. In XY DSD, no premalignant changes were identified, 75% showed immature elements; all underwent gonadopexy. In MGD, all streak gonads were excised; 2/7 showed immature/dysplastic elements. OTD cases revealed mature ovarian/testicular tissue on polar biopsy. Müllerian remnants in PMDS contained smooth muscle and uterine elements without dysplasia. Most patients (23/26) were reared male. Over a median 9-year follow-up, no malignancy was observed. Conclusions: High rates of gonadal immaturity in the small cohort of XY DSD in this study support the practice of early gonadopexy. In contrast, dysplasia in MGD supports prophylactic gonadectomy recommended in the literature. Histological evaluation provides objective data to guide DSD management.