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

Martine Cools, Koen van Aerde, Anne-Marie Kersemaekers, Marjan Boter, Stenvert L S Drop, Katja P Wolffenbuttel, Ewout W Steyerberg, J Wolter Oosterhuis, Leendert H J Looijenga

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)5295-303
Number of pages9
JournalThe Journal of clinical endocrinology and metabolism
Issue number9
Publication statusPublished - Sep 2005
Externally publishedYes


  • Adolescent
  • Adult
  • Carcinoma/metabolism
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Diagnosis, Differential
  • Germinoma/metabolism
  • Gonadal Dysgenesis, 46,XY/genetics
  • Humans
  • Immunohistochemistry/methods
  • Infant
  • Male
  • Ploidies
  • Spermatozoa/pathology
  • Staining and Labeling
  • Testis/pathology


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