Complete XY gonadal dysgenesis and aspects of the SRYgenotype and gonadal tumor formation

 XY gonadal dysgenesis can be classified as either complete or incomplete according to gonadal morphology. The disease is a sex-reversal disorder resulting from embryonic testicular regression sequences and is induced by mutations in the sex-determining region Y (SRY) gene. The incidence of SRY mutations is thought to be approximately 20%. As the disease is characterized by a frequent complication of gonadal tumors, patients are usually advised to undergo prophylactic gonadectomy. In this study, we searched for mutations in SRY open reading frames from three patients with the complete form of XY gonadal dysgenesis, and detected missense mutations in two patients. Combined with the results of our previous study, in which SRY abnormalities were also detected in two out of three complete-type patients, the final incidence of SRY abnormalities was 67% (four of six patients), which is much higher than previously thought. The incidence of gonadal tumor formation in patients with SRY abnormalities was 50% (two of four patients), which is similar to the result of a metanalysis of patients with SRY abnormalities that revealed an incidence of 52.5%. Therefore, it is possible that the lower incidences of SRY abnormalities previously reported were caused by the inclusion of patients with the incomplete form or other sex-reversal disorders. Moreover, our results suggest that clinicians should carefully examine patients with SRY abnormalities. Received: December 5, 2001 / Accepted: March 4, 2002     

Participation of OCT3/4 and beta-catenin during dysgenetic gonadal malignant transformation

Gonadoblastoma (GB) is an in situ tumor consisting of a heterogeneous population of mature and immature germ cells, other cells resembling immature Sertoli/granulosa cells, and Leydig/lutein-like cells, may also be present. GB almost exclusively affects a subset of patients with intersex disorders and in 30% of them overgrowth of the germinal component of the tumor is observed and the lesion is term dysgerminoma/seminoma. Several pathways have been proposed to explain the malignant process, and abnormal OCT3/4 expression is the most robust risk factor for malignant transformation. Some authors have suggested that OCT3/4 and beta-catenin might both be involved in the same oncogenic pathway, as both genes are master regulators of cell differentiation and, overexpression of either gene may result in cancer development. The mechanism by which beta-catenin participates in GB transformation is not completely clear and exploration of the E-cadherin pathway did not conclusively show that this pathway participated in the molecular pathogenesis of GB. Here we analyze seven patients with mixed gonadal dysgenesis and GB, in an effort to elucidate the participation of beta-catenin and E-cadherin, as well as OCT3/4, in the oncogenic pathways involved in the transformation of GB into seminoma/dysgerminoma. We conclude that the proliferation of immature germ cells in GB may be due to an interaction between OCT3/4 and accumulated beta-catenin in the nuclei of the immature germ cells.     

Gonadoblastoma: evidence for a stepwise progression to dysgerminoma in a dysgenetic ovary

Gonadoblastomas are neoplasms of dysgenetic gonads which may undergo regression or become overgrown by malignant germ cell tumors (mGCTs). Since little is known about their relationship to normal gonadal development and mGCTs, we studied the phenotype and antigenic profile of gonadoblastomas in comparison with adjacent dysgerminomas and fetal gonads. Three cases of gonadoblastomas and fetal gonads of both sexes were analyzed using oncofetal markers to M2A-antigen (M2A), germ cell alkaline phosphatase (PLAP/GCAP), receptor tyrosine kinase c-kit (c-kit), and somatic angiotensin converting enzyme (sACE) as well as the proliferation marker MIB-1. Morphologically, microfollicular pattern of gonadoblastomas showed a fetal germ cell organization reminiscent of oocytic clusters of fetal ovaries. They contained both cell types, similar to oocytes (M2A-, GCAP-, c-kit+/–, sACE-) and oogonia (M2A+, GCAP+, c-kit+, sACE+). The percentage of germ cells immunoreactive for oncofetal markers and the proliferation index increased from microfollicular over coronary patterns to adjacent dysgerminomas. Supportive cells of gonadoblastomas showed a uniform phenotype (CK18+, vimentin+, sACE+, alpha-inhibin+, M2A-) but in contrast to fetal germ cells lacked a clear equivalence to fetal tissues. Our results show that gonadoblastomas mimic female fetal ovary and exhibit a stepwise progression from follicular pattern to coronary pattern and finally to dysgerminomas.