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Gonadoblastoma Arising in Undifferentiated Gonadal Tissue within Dysgenetic Gonads

Department of Pathology and Daniel den Hoed, Josephine Nefkens Institute, (M.C., H.S., A.-M.F.K., J.W.O., L.H.J.L.), and Departments of Pediatric Endocrinology (S.L.S.D.) and Pediatric Urology (K.P.W.), Erasmus Medical Center, University Medical Center, 3000 DR Rotterdam, The Netherlands; Department of Pediatric Endocrinology (J.-P.B.), University Hospital of Liège, B-4000 Liège, Belgium; Department of Andrology and Reproductive Endocrinology (J.S.-H., K.K.), Medical University of Lodz, 90-419 Lodz, Poland; and Molecular and Cytogenetics Unit (S.M.H.F.), Medical Biotechnology Laboratory, Medical Faculty of Diponegoro University, 50232 Semarang, Indonesia

Address all correspondence and requests for reprints to: Leendert H. J. Looijenga, Department of Pathology, Erasmus Medical Center, University Medical Center Rotterdam, Josephine Nefkens Institute, Room 430b, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.

Purpose: The purpose of the study was to define the histological origin of gonadoblastomas, allowing the identification of high-risk patients.

Experimental Design: Sixty paraffin-embedded gonadectomy or gonadal biopsy samples of 43 patients with gonadal dysgenesis were selected from our archives. We studied the morphology and immunohistochemical properties of the germ cells in 40 samples without neoplastic transformation and compared these findings with the morphological and immunohistochemical characteristics of 20 samples containing gonadoblastoma/dysgerminoma.

Results: The overall incidence of germ cell tumors in our patient series was 35%. In dysgenetic gonads without germ cell neoplasia, besides the presence of areas with testicular and/or ovarian differentiation, areas of undifferentiated gonadal tissue were identified in 13 of 40 samples (32.5%). A subpopulation of germ cells within these undifferentiated areas stained positive for octamer binding transcription factor (OCT)3/4, the stem cell factor receptor, placental-like alkaline phosphatase, and testis-specific protein-Y encoded. Gonadoblastoma germ cells display identical staining results. Moreover, in gonads containing gonadoblastoma, adjacent to this lesion, areas of undifferentiated gonadal tissue with identical immunohistochemical characteristics were identified in 10 of 20 samples (50%). No adjacent tissue was available in five cases, whereas in the five remaining cases, it consisted of streak tissue. In three cases, an accumulation of OCT3/4-positive germ cells in the proximity of the malignant lesions was found, suggesting clonal expansion and final organization into gonadoblastoma nests.

Conclusions: Based on these observations, we hypothesize that gonadoblastomas originate from surviving OCT3/4-positive germ cells in areas of undifferentiated gonadal tissue within the dysgenetic gonad. Supportive evidence was obtained that carcinoma in situ arises in regions with testicular differentiation.

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