Identification of germ cells at risk for neoplastic transformation in gonadoblastoma: An immunohistochemical study for OCT3/4 and TSPY

Kersemaekers, Anne-Marie F.; Honecker, Friedemann; Stoop, Hans; Cools, Martine; Molier, Michel; Wolffenbuttel, Katja; Bokemeyer, Carsten; Li, Yunmin; Lau, Yun-Fai Chris; Oosterhuis, J. Wolter; Looijenga, Leendert H.J.

doi:10.1016/j.humpath.2005.02.016

« Previous Next »Human Pathology
Volume 36, Issue 5 , Pages 512-521, May 2005

Identification of germ cells at risk for neoplastic transformation in gonadoblastoma:☆

An immunohistochemical study for OCT3/4 and TSPY

Anne-Marie F. Kersemaekers, PhD
- Department of Pathology, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Erasmus MC-University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
- Both authors contributed equally to the work.
Friedemann Honecker, MD
- Department of Pathology, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Erasmus MC-University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
- Department of Hematology/Oncology, University of Tübingen, 72076 Tübingen, Germany
- Both authors contributed equally to the work.
- Current address: Department of Oncology and Hematology, University Hospital Hamburg Eppendorf, Martinstr. 52, 20246 Hamburg, Germany.
Hans Stoop, BSc
- Department of Pathology, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Erasmus MC-University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
Martine Cools, MD
- Department of Pathology, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Erasmus MC-University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
Michel Molier, BSc
- Department of Pathology, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Erasmus MC-University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
- Current address: Department of Oncology and Hematology, University Hospital Hamburg Eppendorf, Martinstr. 52, 20246 Hamburg, Germany.
Katja Wolffenbuttel, MD
- Department of Pediatric Urology, Sophia Children's Hospital, Erasmus MC-University Medical Center Rotterdam, 3015 GJ Rotterdam, The Netherlands
Carsten Bokemeyer, MD
- Department of Hematology/Oncology, University of Tübingen, 72076 Tübingen, Germany
Yunmin Li, PhD
- Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center, University of California, San Francisco, CA 94121, USA
Yun-Fai Chris Lau, PhD
- Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center, University of California, San Francisco, CA 94121, USA
J. Wolter Oosterhuis, MD, PhD
- Department of Pathology, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Erasmus MC-University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
Leendert H.J. Looijenga, PhD
- Department of Pathology, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Erasmus MC-University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
- Corresponding author.

Received 1 February 2005; accepted 15 February 2005.

Summary

Carcinoma in situ (CIS) is the precursor of malignant testicular germ cell tumors (GCTs) of adolescents and young adults, being the neoplastic counterpart of primordial germ cells/gonocytes. Carcinoma in situ cells will develop into invasive seminoma/nonseminoma. Gonadoblastoma (GB) is the precursor of invasive GCTs in dysgenetic gonads, predominantly dysgerminoma (DG). In this process, part of the Y chromosome (GBY region) is involved, for which TSPY is a candidate gene. A detailed immunohistochemical survey was performed for the known diagnostic markers, germ cell/placental alkaline phosphatase (PLAP), c-KIT, and OCT3/4, as well as testis-specific protein on the Y chromosome (TSPY) on a series of GBs, and adjacent invasive DGs. All 5 patients were XY individuals (4 females and 1 male). In contrast to c-KIT, PLAP was positive in all cases. The immature germ cells of GBs were positive for OCT3/4, whereas the mature germ cells were negative for this marker, but positive for TSPY. In every GB, a minor population of germ cells positive for both markers could be identified, similar to most CIS cells and early invasive DG. On progression to an invasive tumor, TSPY can be lost, a process that is also detectable in invasive testicular GCTs compared to CIS. These results indicate that GB is a heterogeneous mix of germ cells, in which the OCT3/4-positive cells have the potential to undergo progression to an invasive tumor. These early invasive stages are initially also positive for TSPY (like CIS), supporting a positive selection mechanism. Therefore, OCT3/4 in combination with TSPY is valuable to identify malignant germ cells in dysgenetic gonads. This could allow better prediction of the risk of progression to a GCT. In addition, the data support the model that GB represents the earliest accessible developmental stage of malignant GCTs.

Abbreviations: GB, Gonadoblastoma, CIS, Carcinoma in situ, CH, Choriocarcinoma, DG, Dysgerminoma, EC, Embryonal carcinoma, (T)GCT, (testicular) germ cell tumor, H&E, Hematoxylin and eosin, OCT3/4, Octamer binding transcription factor involved in regulation of pluripotency, also referred to as POU domain class 5 transcription factor 1 (POU5F1), PLAP, Germ cell/placental alkaline phosphatase, TE, Teratoma, TSPY, Testis-specific protein on the Y chromosome. This gene maps to the gonadoblastoma region on the Y chromosome (GBY), WHO, World Health Organization, YST, Yolk sac tumor

Keywords: Gonadoblastoma, Dysgerminoma, CIS, OCT3/4, TSPY, Progression, Malignant transformation, Clonal selection

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☆ This study was financially supported by the Dutch Cancer Society, grant number 2002 2682 (AMK, HS, JWO, LHJL), and the Deutsche Krebshilfe, Dr Mildred Scheel Stiftung (F.H.), and the European Society for Pediatric Endocrinology, ESPE sponsored by Novo Nordisk A/S (MC).

PII: S0046-8177(05)00085-7

doi:10.1016/j.humpath.2005.02.016

« Previous Next »Human Pathology
Volume 36, Issue 5 , Pages 512-521, May 2005

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