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Germ Cell Tumors in the Intersex Gonad: Old Paths, New Directions, Moving Frontiers

Department of Pathology (M.C., J.W.O., L.H.J.L.), Erasmus MC–University Medical Center Rotterdam, Daniel den Hoed Cancer Center, Josephine Nefkens Institute, Rotterdam, The Netherlands; and Departments of Pediatric Endocrinology (M.C., S.L.S.D.) and Pediatric Urology (K.P.W.), Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands

Correspondence: Address all correspondence and requests for reprints to: L. H. J. Looijenga, Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Josephine Nefkens Institute, Room 430b, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: l.looijenga{at}erasmusmc.nl

The risk for the development of germ cell tumors is an important factor to deal with in the management of patients with disorders of sex development (DSD). However, this risk is often hard to predict. Recently, major progress has been made in identifying gene-products related to germ cell tumor development (testis-specific protein-Y encoded and octamer binding transcription factor 3/4) and in recognizing early changes of germ cells (maturation delay, preneoplastic lesions, and in situ neoplasia). The newly recognized "undifferentiated gonadal tissue" has been identified as a gonadal differentiation pattern bearing a high risk for the development of gonadoblastoma. It is expected that the combination of these findings will allow for estimation of the risk for tumor development in the individual patient (high risk/intermediate risk/low risk). This article reviews the recent literature regarding the prevalence of germ cell tumors in patients with DSD. Some major limitations regarding this topic, including a confusing terminology referring to the different forms of intersex disorders and unclear criteria for the diagnosis of malignant germ cells at an early age (maturation delay vs. early steps in malignant transformation) are discussed. Thereafter, an overview of the recent advances that have been made in our knowledge of germ cell tumor development and the correct diagnosis of early neoplastic lesions in this patient population is provided. A new classification system for patients with DSD is proposed as a tool to refine our insight in the prevalence of germ cell tumors in specific diagnostic groups.

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