title: Identification of germ cells at risk for neoplastic transformation in gonadoblastoma: an immunohistochemical study for OCT3/4 and TSPY.
abstract: 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.
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Daniel de Hoed Cancer Center, Erasmus MC-University Medical Center Rotterdam, The Netherlands.
authors.forename: Anne-Marie F
authors.initials: AM
authors.lastname: Kersemaekers
authors.forename: Friedemann
authors.initials: F
authors.lastname: Honecker
authors.forename: Hans
authors.initials: H
authors.lastname: Stoop
authors.forename: Martine
authors.initials: M
authors.lastname: Cools
authors.forename: Michel
authors.initials: M
authors.lastname: Molier
authors.forename: Katja
authors.initials: K
authors.lastname: Wolffenbuttel
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Yunmin
authors.initials: Y
authors.lastname: Li
authors.forename: Yun-Fai Chris
authors.initials: YF
authors.lastname: Lau
authors.forename: J Wolter
authors.initials: JW
authors.lastname: Oosterhuis
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase; D014408:Biomarkers, Tumor / Q000032:analysis; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004407:Dysgerminoma / Q000378:metabolism / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins; D005854:Germ Cells / Q000473:pathology*; D018238:Gonadoblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D018239:Seminoma / Q000378:metabolism / Q000473:pathology; D051876:Sex-Determining Region Y Protein; D013736:Testicular Neoplasms / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; D007527:Isoenzymes; D009687:Nuclear Proteins; D051876:Sex-Determining Region Y Protein; C497749:TSPY1 protein, human; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental