Germ cell tumors in patients with disorders of sex development: Risk factors, initial developmental stages and targets for early diagnosis

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 maturation delay of germ cells is present in patients with trisomy 21, a condition unrelated to disorders of sex development but also characterized by an increased risk for germ cell tumors in males. Accordingly, a delay in germ cell maturation was mainly found in the male trisomy 21 population. This adds evidence to the “testicular dysgenesis syndrome” hypothesis, suggesting that a disturbed gonadal development is a common underlying mechanism in various, apparently unrelated conditions that are characterized by male subfertility and increased risk for germ cell cancer. The origin and progression of ITGNU lesions in patients with undervirilization syndromes are studied in chapter 4. Aberrant expression of immunohistochemical germ cell markers, a typical finding in young patients with undervirilization has for a long time been interpreted as “a pre-pubertal carcinoma in situ pattern” (i.e. ITGNU), but is now placed in the context of maturation delay of germ cells. This study presents diagnostic tools to discriminate between the benign condition of developmental delay of germ cells and the malignant ITGNU and offers a model for the stepwise progression from the first condition into the second. Chapter 5 focuses on the origin of gonadoblastoma lesions in patients with gonadal dysgenesis. Within these gonads, gonadal differentiation patterns and germ cells which are most prone to malignant transformation are sought, with the aim of identifying high-risk patients. This approach led to the identification of the hitherto undescribed “undifferentiated gonadal tissue” (UGT), a pattern only found in dysgenetic gonads. In this chapter it is hypothesized that gonadoblastomas originate from surviving germ cells residing in UGT. A model for the differential development of the two types of in situ malignant lesions (ITGNU and gonadoblastoma) in patients with disorders of sex development is presented. Chapter 6 describes the progression from the in situ malignant gonadoblastoma cells towards the invasive dysgerminoma. It underscores the heterogeneity of the germ cells regarding their maturation status within a gonadoblastoma lesion, and identifies those germ cells that will escape proliferation-regulating mechanisms and will become invasive. The value and possible pathogenetic relevance of the diagnostic markers OCT3/4 and TSPY in this context becomes apparent from this study. In chapter 7 it is examined to what extent gonadal development and germ cell tumor formation are influenced by the presence of the Y chromosome in patients with gonadal dysgenesis. The results indicate that the peripheral blood and gonadal karyotypes are not a suitable indicator to predict the differentiation patterns present in the dysgenetic gonad, nor do they identify high-risk patients. Chapter 8 offers an extensive and updated review of the literature in order to gain insight in the risk for germ cell cancer in the various types of disorders of sex deelopment. This goal cannot be achieved at present and specific problems in this context are discussed. The results from the studies in the present thesis are interpreted in the light of overcoming these problems in the future. This thesis concludes with the presentation of a new classification system for patients with disorders of sex development, opening perspectives for a better estimation of the risk for germ cell tumor development in the individual patient and thus providing a basis for optimised medical care in accordance with aspirations from patient advocacy groups in the future.

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