Human
germ-cell tumors (GCTs) are a heterogeneous group of
neoplasms. Based on epidemiology, anatomical site of presentation, histology, chromosomal constitution, and pattern of genomic imprinting, GCTs are classified into five entities. Within the testis, three types of GCTs can be diagnosed: type I (
teratomas and
yolk-sac tumors of neonates and infants); type II (
seminomas and nonseminomas); type III (spermatocytic
seminomas). Here the focus is on the type II GCTs, the most frequent type in the adult testis (so-called TGCTs). They can also be diagnosed in dysgenetic gonads (an incomplete or defective formation of the gonad, caused by a disturbed process of migration of the germ cells and/or their correct organization in their fetal gonadal ridge), the anterior mediastinum, and pineal/suprasellar region. In the testis, they originate from the malignant counterpart of primordial germ cells/gonocytes, referred to as
carcinoma in situ (CIS)/intratubular germ-cell
neoplasia unclassified (ITGCNU). CIS/ITGCNU and seminomatous cells are characterized by expression of OCT3/4 and NANOG, while in addition
embryonal carcinoma expresses SOX2, all identified as
transcription factors related to pluripotency in embryonic stem (ES) cells. With the exception of
teratomas, most histological elements of TGCTs are sensitive for (
cisplatin-based)
chemotherapy; CIS/ITGCNU and
seminoma cells are also sensitive to DNA damage induced by irradiation. Similar observations have been made for ES cells and their derivates. Moreover, the genetic constitution of TGCTs (low incidence of mutations and frequent
uniparental disomies) can also be linked to characteristics of ES cells, likely related to their specific inability to repair DNA damage and their high sensitivity to apoptotic cell death. The unusual presence of wild-type P53 in TGCTs is explained by specific expression of a cluster of micro-RNAs (
miRNAs), that is, hsa-miR 371-373, also expressed in ES cells, which prevents P53-driven cellular senescence upon oncogenic stress. Many characteristics of human TGCTs reflect the nonmalignant counterparts from which they originate. Demonstration of these characteristics, in combination with the knowledge of the abnormal niche of these cells, normally occupied by spermatogonia, allows an informative method for (early) diagnosis. The conclusion is that TGCTs are embryonic
cancers found in adults.