Testicular germ-cell tumours in a broader perspective

Key Points Germ-cell tumours (GCTs) of all anatomical sites can be classified into five groups, characterized by their chromosomal complement and developmental potential. The most significant recurrent chromosomal aberrations in type I yolk-sac tumours are loss of 1p, 4 and 6q, and gain of 1q, 12(p13) and 20q. In type II seminomas and non-seminomatous GCTs, the most significant recurrent chromosomal aberrations are gain of 7, 8, 12p, 21 and X, and loss of chromosomes 1p, 11, 13 and 18. Aberrations of 12p are the only recurrent structural abnormalities in type II GCTs. In type III spermatocytic seminomas, gain of chromosome 9 is most common. The originating cell is most probably a primitive germ cell of which the developmental potential differs according to its stage of maturation and pattern of genomic imprinting. Animal models are available for the different groups of GCTs, except for the type II seminomas and non-seminomatous GCTs. An activating KIT mutation in codon 816 is an early pathogenetic event in bilateral testicular seminomas and non-seminomatous GCTs. The transcription factor OCT3/4, a characteristic of primordial germ cells and pluripotent stem cells, is a new and robust diagnostic marker for type II seminomas and non-seminomatous GCTs, including their intratubular precursor. Treatment sensitivity and resistance of GCTs probably correlates with retention and loss of embryonic characteristics (in particular, DNA-repair deficiency), respectively. The germ-cell tumours are a fascinating group of neoplasms because of their unusual biology and the spectacular therapeutic results that have been obtained in these tumours. Traditionally, this group of neoplasms is presented in an organ-oriented approach. However, recent clinical and experimental data convincingly demonstrate that these neoplasms are one disease with separate entities that can manifest themselves in different anatomical sites. We propose five entities, in which the developmental potential is determined by the maturation stage and imprinting status of the originating germ cell. Recent progress begins to explain the apparent unpredictable development of germ-cell tumours and offers a basis for understanding their exquisite sensitivity to therapy.