Germ cell tumors from a developmental perspective: Cells of origin, pathogenesis, and molecular biology (emerging patterns)

The developmental potential of seven defined types (0-VI) of germ cell tumors (GCT) is determined by the developmental state of the precursor cells from which they originate: the 2C, naïve, or primed state. These basal states are modified by epigenetic changes, particularly genomic imprinting, and by reprogramming, which is mostly due to failure of repression of pluripotency of the precursor cell. Type VI is a new category of neoplasms resembling GCT, resulting from induced pluripotency. In agreement with the plasticity of developmental states, the same precursor cell may generate different types of GCT, and similar GCT may be derived from different precursors. Developmental plasticity also explains intermediate phenotypes between the defined types of GCT. The anatomical distribution of extragonadal GCT favors early germ cells, in particular primordial germ cells (PGC), as their precursors. Most GCT result from dysfunction of the niche of precursor cells; somatic mutation of precursors plays a minor role. Disturbance may be due to internal (and external) systemic factors (genvironment) that will likely affect both gonads, explaining the high incidence of bilaterality of most gonadal GCT, occasionally in combination with extragonadal GCT. Heritable niche-disturbing factors explain familial occurrence of GCT of the same and occasionally different types. The overwhelming preponderance of gonadal and extragonadal type II GCT (seminomatous and non-seminomatous tumors) in males and 46, XY disorders of sex development are likely due to disturbance of the niche allowing co-expression of OCT4 and TSPY in delayed-matured PGC/gonocytes, giving them survival and proliferative advantage. This review of recent and classic data on developmental biology of embryonic stem cells, the germline, and GCT provides a biologically plausible and clinically relevant unifying model for all GCT.