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Morphological and Immunohistochemical Differences between Gonadal Maturation Delay and Early Germ Cell Neoplasia in Patients with Undervirilization Syndromes

Department of Pathology (M.C., K.v.A., A.-M.K., M.B., J.W.O., L.H.J.L.), Erasmus MC, University Medical Center Rotterdam, Daniel den Hoed, Josephine Nefkens Institute, 3000 DR Rotterdam, The Netherlands; Departments of Pediatric Endocrinology (S.L.S.D.) and Pediatric Urology (K.P.W.), Erasmus MC, University Medical Center Rotterdam, 3000 CB Sophia, The Netherlands; and Center for Clinical Decision Sciences (E.W.S.), Department of Public Health, Erasmus MC, University Medical Center, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Leendert 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.

Context: Maturation delay of germ cells and their progression into carcinoma in situ (CIS) frequently occurs in intersex patients. A developmentally delayed germ cell resembles a CIS cell and displays prolonged expression of immunohistochemical markers used for the diagnosis of CIS. This questions their applicability in young children.

Objective: The objective of the study was the elaboration of tools to distinguish germ cells with maturation delay and CIS.

Design: The design was a qualitative and quantitative analysis of the expression of diagnostic markers for CIS in gonads of young patients with undervirilization syndromes.

Setting: The study was conducted in the pathology department of a university center, specializing in germ cell tumor pathogenesis.

Patients: Fifty-eight formalin-fixed, paraffin-embedded testicular tissue samples of 30 undervirilized patients (1 month to 23 yr of age) were analyzed.

Interventions: Interventions included hematoxylin-eosin staining, immunohistochemistry for octamer binding transcription factor (OCT)3/4, gene encoding the stem cell factor receptor that has tyrosine kinase activity c-KIT, placental/germ alkaline phosphatase (PLAP), testis-specific protein Y encoded (TSPY), and VASA, double staining for OCT3/4 and VASA, with ploidy determination by fluorescent in situ hybridization.

Main Outcome Measure: Maturation delay and CIS are characterized by the staining patterns of the immunohistochemical markers.

Results: CIS was diagnosed in three of 30 patients (10%) and four of 58 gonads (6.9%). Patient age, distribution of OCT3/4-positive cells throughout the gonad, and their position within the seminiferous tubule differ between maturation delay and CIS. Abnormal OCT3/4 and testis-specific protein Y encoded expression appear to be of pathogenetic relevance in the development of these lesions.

Conclusion: The dimorphic expression of OCT3/4 allows distinction between maturation delay and CIS. Studies in larger patient series are essential before a biopsy to evaluate the neoplastic risk can eventually be proposed as an alternative for gonadectomy.

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