Germ Cell Tumors in the Intersex Gonad: Old Paths, New Directions, Moving Frontiers
Martine Cools,
Stenvert L. S. Drop,
Katja P. Wolffenbuttel,
J. Wolter Oosterhuis and
Leendert H. J. Looijenga
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 importantfactor to deal with in the management of patients with disordersof sex development (DSD). However, this risk is often hard topredict. Recently, major progress has been made in identifyinggene-products related to germ cell tumor development (testis-specificprotein-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 gonadaldifferentiation pattern bearing a high risk for the developmentof gonadoblastoma. It is expected that the combination of thesefindings will allow for estimation of the risk for tumor developmentin the individual patient (high risk/intermediate risk/low risk).This article reviews the recent literature regarding the prevalenceof germ cell tumors in patients with DSD. Some major limitationsregarding this topic, including a confusing terminology referringto the different forms of intersex disorders and unclear criteriafor the diagnosis of malignant germ cells at an early age (maturationdelay vs. early steps in malignant transformation) are discussed.Thereafter, an overview of the recent advances that have beenmade in our knowledge of germ cell tumor development and thecorrect diagnosis of early neoplastic lesions in this patientpopulation is provided. A new classification system for patientswith DSD is proposed as a tool to refine our insight in theprevalence of germ cell tumors in specific diagnostic groups.
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