Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes.

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.