Evidence for antenatal vascular insult in testicular regression syndrome: a systematic review and meta-analysis of histopathology in 1,907 patients

Abstract Background Testicular regression syndrome (TRS), also known as vanishing testis syndrome, is a common cause of the non-palpable testis in children. Two major theories are proposed to explain it: a lack of blood supply after late birth or primary agenesis/atrophy in the development. The best way to determine these causes and how to operate is to examine the tissue removed during the surgery. Objective We reviewed the literature to estimate the number of cases of TRS presenting with evidence of previous injury to blood supplies in comparison with those with simple atrophy. Methods According to the PRISMA 2020 guidelines, PubMed, Web of Science, and Google Scholar were searched. Included were observational studies that reported on detailed histology of at least 10 excised TRS remnants that had data on fibrosis, dystrophic calcification, hemosiderin deposition, seminiferous tubules, and viable germ cells. We pooled proportions using 95% confidence intervals (CIs) with a DerSimonian-Laird random-effects model. Results Based on our strict selection criteria, ten retrospective cohorts evaluating 1,907 examined testicular remnants met our inclusion criteria. In 93.8% (95% CI 90.4–96.3%, I2 = 81%) of the cases, remnants displayed clear evidence of a vascular injury (fibrosis, dystrophic calcification, or hemosiderin). Primary atrophy with an absence of these vascular markers was seen in only 6.2% (95% CI 3.7–9.6%; I2 = 74) cases. Residual seminiferous tubules were seen in 8.9% (95% CI 6.1–12.4%), and viable germ cells were seen in 4.7% (95% CI 2.9–7.1%). Consistent secondary observations comprised a predominance of left side occurrences (68–80%) and a closed internal inguinal ring (> 95%). Sensitivity analyses agreed with these findings. Conclusion The burden of histopathologic data suggests that a vascular event (e.g., antenatal torsion) is the primary cause of TRS in more than 93% of cases. Simple atrophy or agenesis is very rare. While the absolute risk of malignancy remains low, the identification of viable germ cells in nearly 5% of cases suggests that surgical excision of easily accessible remnants may be considered to minimize the long-term cancer risk.