Early manifestations of testicular dysgenesis in children: pathological phenotypes, karyotype correlations and precursor stages of tumour development

Testicular dysgenesis derives from abnormal gonadal development caused by chromosome aberrations/mosaicisms or mutations/deletions in SRY or other genes responsible for testicular differentiation. Dysgenetic male pseudohaermaphroditism has bilateral dysgenetic testes characterized by a cortical network of anastomosing seminiferous cords that penetrate a thin albuginea. In asymmetric gonadal differentiation (or Mixed Gonadal Dysgenesis) a dysgenetic testis associates with a streak gonad with primitive sex cords embedded in an ovarian-like stroma. Uni- or bilateral ovotestes identify true haermaphroditism. Fluorescent in situ hybridisation studies demonstrate that the sex chromosomes of mosaic patients do not distribute homogeneously in asymmetric gonads. 45,X lines predominate over 46,XY in streak gonads, while the relationship between these two is more equivalent in dysgenetic testes, suggesting that testicular or streak differentiation is related to the balance between X0 and XY lines. Testicular dysgenesis is more severe when there is a frank predominance of X0 or YX cells. Higher percentages of XY cells coincide with lesser degrees of dysgenesis. DNA densitometry indicate a higher incidence of neoplastic transformation than previously anticipated. Various specimens showed clear aneuploid histograms but no clear indication of a cytological CIS phenotype. There was a wide cytological variation in aneuploid germ cells, ranging from normally looking big infantile spermatogonia to gonocyte/CIS cells. Aneuploidy probably precedes the full expression of the CIS phenotype. In case of doubt we recommend DNA densitometry to either confirm or discard their neoplastic nature. The earliest recognizable change in germ cell tumorigenesis is probably the polyploidisation of fetal germ cells, followed by the expression of the CIS phenotype in isolated germ cells scattered along infantile seminiferous tubules that later proliferate to give an adult type CIS pattern.