This thesis describes the origin, identification and correct diagnosis of the earliest stages of malignant germ cell tumors, i.e. intra tubular germ cell neoplasia unclassified (ITGNU) and gonadoblastoma, in patients with disorders of sex development. Special attention is given to the possible pathogenetic mechanisms underlying the development of these lesions, in order to identify high-risk patients. Ultimately, this study aims to contribute to the actual process of re-thinking the clinical management of patients with disorders of sex development, in accordance with the intense aspirations of these patients to evolve towards a safe, evidence-based, but more conservative approach regarding gonadectomy and other surgical procedures in the future wherever possible.
Chapter 1 situates the ITGNU and gonadoblastoma lesions within the group of malignant germ cell tumors. It offers an overview of our actual knowledge on normal gonadal and sexual development and describes the recent hypotheses on how this process can be disturbed by environmental influences. The different phenotypes in the various disorders of sex development are described from a developmental point of view, with emphasis on the biology and functioning of the malformed gonad.
In chapter 2, the normal gonadal development is studied in female embryos: the sequential expression of protein markers for germ cells, detectable by immunohistochemisty, in relation to the ultrastructure and cellular organization within the developing ovary is described. Together with a similar study on male gonadal development (Honecker et al, J Pathol 2004, 203 (3): 849-57), this study forms the basis for further research on the process of maturation delay of germ cells, as described in the following chapters.
Chapter 3 examines if and to what extent maturatio
