Pathogenesis of testicular germ cell tumors

Recently, we proposed that human germ cell tumors (GCTs) can be classified into five entities, each characterized by histology, clinical behavior, age of the patient at clinical presentation, and genomic constitution.Within the testis, three of these entities can be found: type I GCTs (teratomas and yolk sac tumors of neonates and infants), type II GCTs (seminomatous and nonseminomatous tumors of adolescents and young adults), and type III GCTs (spermatocytic seminomas). These three types of GCTs each represents a specific stage of normal germ cell development, for which knowledge has revealed the identification of informative markers for (early) diagnosis. Moreover, this difference in origin most likely also explains their characteristic variation in developmental potential of the tumors, i.e. the capacity to form the different lineages of differentiation. This is nicely illustrated by the value of the markers PLAP, c-KIT, and more recently OCT3/4-POU5F1 for the seminomatous and undifferentiated cell type of nonseminomatous tumors (embryonal carcinoma); and XPA, SCP1, and SSX for spermatocytic seminomas. The seminomas and nonseminomas originate from a transformed primordial germ cell/gonocyte-known as carcinoma in situ (CIS)/intratubular germ cell neoplasia, unclassified (ITGCNU) - representing an erased germ cell. The derived tumors are indeed omnipotent, as recently shown by the possible generation of the germ cell lineage within the tumor itself. In contrast, the spermatocytic seminoma represents a spermatocyte (a more mature germ cell of the spermatogenic lineage), which has already undergone partial paternal imprinting. This tumor is highly restricted in its developmental potential. Type I GCTsmost likely originate from a partially erased embryonic germ cell. The three types of germ cell tumors have different pathogeneses, related to different risk factors and genomic changes. The latter are diagnostic on their own, but also facilitate identification of the gene or genes involved in the genesis of the cancer.While type I teratomas do not show genomic imbalances, type I yolk sac tumors show consistent genomic changes, including loss of 1p, 4, and 6q, and gain of 1q and 20q. Type II GCTs (including the teratomas) are always aneuploid with loss of 4, 5, 11, 13, 18, and Y, and gain of 7, 8, 12p, and X as recurrent anomalies. While all invasive type II GCTs show additional copies of the short armof chromosome 12, this is not consistently found in CIS/ITGCNU and is therefore progression-related. The tumor cells of spermatocytic seminomas typically have a diploid, a tetraploid, and a hypertetraploid DNA content. In addition, gain of chromosome 9 is the only consistent anomaly found so far.